@article {1443, title = {Serum fructosamine as a screening test for diabetes in the elderly: a pilot study.}, journal = {J Am Geriatr Soc}, volume = {41}, year = {1993}, month = {1993 Oct}, pages = {1090-4}, abstract = {

OBJECTIVE: To determine the value of serum glycated protein, measured as serum fructosamine, as a screening test for diabetes in the elderly.

DESIGN: Cross-sectional pilot study.

SETTING: Ambulatory research clinic in university setting.

PATIENTS: One hundred fifty-seven consecutive community-dwelling participants in the Cardiovascular Health Study, average age 71.8 + 5 (mean +/- SD, range 65-88 years).

MEASUREMENTS: Serum fructosamine levels (first and second generation assay) were obtained. All subjects who did not have a diagnosis of diabetes were given a 75-g glucose tolerance test (GTT).

RESULTS: Twenty-six subjects (17\%) (10 previously diagnosed, 16 undiagnosed and asymptomatic) had diabetes mellitus, and 38 subjects (24\%) had impaired glucose tolerance by history or by the GTT (WHO criteria). Only the 16 asymptomatic diabetics were included in the analysis for the pilot study. There was a significant difference in the fasting fructosamine level between non-diabetics and asymptomatic diabetics for the first generation (2.06 +/- .21 vs 2.53 +/- .49 mMol/L, P < 0.0015) and second generation assay (221 +/- 27 vs 269 +/- 48 mMol/L, P < 0.0012). Receiver operator curves were constructed to evaluate the test characteristics of serum fructosamine. Using a point of > or = 2.3 mMol/L for the first-generation assay, the sensitivity to detect asymptomatic diabetes was 75\%, specificity 83\%, and positive predictive value 35\%. To detect both diabetes and impaired glucose tolerance using a cutpoint of > or = 2.3 mMol/L, the sensitivity was 24\%, specificity 95\%, and positive predictive value 68\%. Employing a cut point of 250 muMol/L for the second generation assay, the sensitivity to detect diabetes was 81\%, specificity 87\%, and positive predictive value 43\%. However, to detect diabetes and glucose intolerance using the second generation assay, the sensitivity was 39\% and specificity was 86\%.

CONCLUSION: This study demonstrated that a single measurement of either first or second generation fructosamine showed promise as a screening test for diabetes, but not impaired glucose tolerance, in older people.

}, keywords = {Aged, Diabetes Mellitus, Female, Fructosamine, Glucose Tolerance Test, Hexosamines, Humans, Insulin, Male, Pilot Projects, Predictive Value of Tests, Sensitivity and Specificity}, issn = {0002-8614}, author = {Cefalu, W T and Ettinger, W H and Bell-Farrow, A D and Rushing, J T} } @article {1448, title = {Smoking and lung function in elderly men and women. The Cardiovascular Health Study.}, journal = {JAMA}, volume = {269}, year = {1993}, month = {1993 Jun 02}, pages = {2741-8}, abstract = {

OBJECTIVE: To investigate relationships between cigarette smoking and pulmonary function in elderly men and women.

DESIGN: Cross-sectional analysis of baseline data from a prospective, population-based study of risk factors, preclinical, and overt cardiovascular and pulmonary disease.

SETTING: Defined communities in Forsyth County, North Carolina; Pittsburgh, Pa; Sacramento County, California; and Washington County, Maryland.

POPULATION: A total of 5201 noninstitutionalized men and women 65 years of age and older.

MAIN OUTCOME MEASURES: Pulmonary function; means of forced expiratory volume in 1 second (FEV1) and forced vital capacity and prevalence of low FEV1 levels.

RESULTS: Prevalence of cigarette smoking was 10\% to 20\% and higher in women than men and in blacks than whites. Forced vital capacity and FEV1 levels were related positively to height and white race and negatively to age and waist girth. Age- and height-adjusted FEV1 means were 23\% and 18\% lower in male and female current smokers, respectively, than in never smokers but not reduced in never smokers currently living with a smoker. Smokers who quit before age 40 years had FEV1 levels similar to never smokers, but FEV1 levels were lower by 7\% and 14\% in smokers who quit at ages 40 to 60 years and older than 60 years, respectively. Lung function was related inversely to pack-years of cigarette use. Prevalence rates of impaired lung function were highest in current smokers and lowest in never smokers. Regression coefficients for the smoking variables were smaller in persons without cardiovascular or respiratory conditions than in the total cohort.

CONCLUSIONS: Cigarette smoking is associated with reduced pulmonary function in elderly men and women. However, smokers who quit, even after age 60 years, have better pulmonary function than continuing smokers.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Anthropometry, Cardiovascular Diseases, Cross-Sectional Studies, European Continental Ancestry Group, Female, Forced Expiratory Volume, Humans, Lung Diseases, Male, Prevalence, Prospective Studies, Reference Values, Respiratory Function Tests, Risk Factors, Smoking, United States, Vital Capacity}, issn = {0098-7484}, author = {Higgins, M W and Enright, P L and Kronmal, R A and Schenker, M B and Anton-Culver, H and Lyles, M} } @article {1440, title = {Sonographic evaluation of carotid artery atherosclerosis in the elderly: relationship of disease severity to stroke and transient ischemic attack.}, journal = {Radiology}, volume = {188}, year = {1993}, month = {1993 Aug}, pages = {363-70}, abstract = {

Doppler and real-time ultrasound (US) were performed to evaluate the extent of atherosclerotic changes in the carotid artery and to assess their relationship to prevalent cerebrovascular disease. Real-time US scans and Doppler measurements of the carotid arteries were analyzed in 5,201 subjects aged 65 years or older. Severity of atherosclerotic lesions was associated with increased frequencies of hyperechoic, irregular, and heterogeneous textured lesions (P < .0001). The severity of internal carotid artery stenosis was associated with thickening of the intima-media layer of the common carotid artery wall (r = .37, P < .0001). A history of stroke and transient ischemic attack (TIA) was more likely when hyperechoic, heterogeneous, and irregular lesions were seen in the carotid artery. Internal carotid artery stenosis correlated better with prevalent stroke and TIA than did sonographic descriptions of plaque texture. However, the prevalence of hyperechoic, heterogeneous, and irregular lesions increased as the degree of internal carotid stenosis increased. On real-time images alone, the average of the internal carotid artery maximal wall thickness is the sonographic measure of atherosclerosis that enables the best prediction of prevalent stroke and TIA.

}, keywords = {Aged, Arteriosclerosis, Carotid Artery Diseases, Carotid Artery, Internal, Carotid Stenosis, Cerebrovascular Disorders, Female, Humans, Ischemic Attack, Transient, Male, Ultrasonography}, issn = {0033-8419}, doi = {10.1148/radiology.188.2.8327679}, author = {Polak, J F and O{\textquoteright}Leary, D H and Kronmal, R A and Wolfson, S K and Bond, M G and Tracy, R P and Gardin, J M and Kittner, S J and Price, T R and Savage, P J} } @article {1444, title = {Spirometry reference values for women and men 65 to 85 years of age. Cardiovascular health study.}, journal = {Am Rev Respir Dis}, volume = {147}, year = {1993}, month = {1993 Jan}, pages = {125-33}, abstract = {

Pulmonary function was assessed by spirometry in 5,201 ambulatory elderly participants of the Cardiovascular Health Study, sampled from four communities. A stringent quality assurance program exceeded American Thoracic Society (ATS) recommendations for spirometry. Less than 6\% of the participants were unable to perform three acceptable spirometry maneuvers. A "healthy" subgroup of 777 women and men 65 to 85 yr of age was identified by excluding smokers and those with lung disease and other factors determined to independently, significantly, and negatively influence the FEV1. Results from black participants were examined separately. Reference equations and normal ranges for FEV1, FVC, and the FEV1/FVC ratio were determined from the healthy group. The results demonstrate differences in predicted values as great as 20\% (0.5 to 1 L) for elderly patients when compared with the spirometry reference equations that are most commonly used in the United States.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Female, Forced Expiratory Volume, Humans, Male, Reference Values, Smoking, Spirometry, Vital Capacity}, issn = {0003-0805}, doi = {10.1164/ajrccm/147.1.125}, author = {Enright, P L and Kronmal, R A and Higgins, M and Schenker, M and Haponik, E F} } @article {1424, title = {Self-reported causes of physical disability in older people: the Cardiovascular Health Study. CHS Collaborative Research Group.}, journal = {J Am Geriatr Soc}, volume = {42}, year = {1994}, month = {1994 Oct}, pages = {1035-44}, abstract = {

OBJECTIVE: To determine the major conditions and symptoms reported to cause difficulty in 17 physical tasks of daily life and the criterion validity of self-report of diseases given as the causes of the difficulty in functioning, in community-dwelling older people.

DESIGN: Cross sectional analyses of data obtained in an observational cohort study.

SETTING: Research clinics in four US communities: Winston-Salem, NC, Hagerstown, MD, Pittsburgh, PA, and Sacramento, CA.

PARTICIPANTS: 5201 community-dwelling people > or = 65 years old.

RESULTS: Arthritis and other musculoskeletal diseases were given as the primary causes of difficulty in performing physical tasks by 49.0\% of the participants reporting difficulty in any task, followed by heart disease (13.7\%), injury (12.0\%), old age (11.7\%), lung disease (6.0\%), and stroke (2.9\%). The self-reports of diseases that caused disability varied by task. Whereas arthritis was given as a cause of difficulty in most of the 17 different tasks, heart and lung disease were more likely to be reported as causing difficulty with activities requiring high aerobic work capacity such as walking one-half mile or doing heavy housework. Stroke was more likely to be reported as causing difficulty with use of the upper extremities and in performing basic activities of daily living. There was a high degree of consistency (91\%) between the diseases and symptoms reported to cause disabilities. The percentage of people who reported a disease as the cause of their difficulty performing a task and had independent confirmation of the diagnosis was 85\% in men and 71\% in women, and varied according to type of disease and the individual{\textquoteright}s cognitive status and health status.

CONCLUSION: These data suggest that age-related chronic diseases are important causes of disability in older people but that the type of disability is dependent on the underlying disease that causes the disability. Also, self-report of the cause of disability appears to be generally accurate but is influenced by gender, health status, and type of disease.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Arthritis, Cardiovascular Diseases, Chronic Disease, Cohort Studies, Cross-Sectional Studies, Disabled Persons, Female, Health Status, Health Surveys, Heart Diseases, Humans, Lung Diseases, Male, Observer Variation, Reproducibility of Results, Risk Factors, Sex Factors, United States}, issn = {0002-8614}, author = {Ettinger, W H and Fried, L P and Harris, T and Shemanski, L and Schulz, R and Robbins, J} } @article {649, title = {Smoking, Lung Function, and Atherosclerosis in the 5,000 Elderly Participants of the Cardiovascular Health Study.}, journal = {Am J Geriatr Cardiol}, volume = {3}, year = {1994}, month = {1994 Jul}, pages = {35-38}, abstract = {

The Cardiovascular Health Study (CHS) is an observational study of heart disease and stroke designed to evaluate risk factors and noninvasive measures and to describe and predict atherosclerotic events in older adults. Five thousand two hundred one individuals ages 65 or older were recruited from a stratified random sample of Medicare recipients from 4 US communities. This review of cross-sectional data from the CHS baseline examination describes the cigarette smoking habits of elderly persons and the relationships of smoking to lung function (spirometry) and atherosclerosis, as noninvasively measured by the ankle-arm index (AAI) and carotid ultrasonography. Only 10\% of the men and 13\% of the women were current smokers, and about half were former smokers. Forced expiratory flow (FEV1) was about 20\% lower in current smokers when compared with never smokers. Current and former smoking were strongly associated with an increased risk for an abnormal AAI. Common and internal carotid artery walls were thicker and stenosis more common in current smokers and former smokers, when compared with never smokers. Analysis of long-term follow-up morbidity and mortality data from the CHS cohort should provide even stronger evidence of the effects of smoking in the elderly. Vigorous efforts should be made to persuade elderly smokers to quit.

}, issn = {1751-715X}, author = {Enright, Paul L.} } @article {1422, title = {Sex, age, and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly. The Cardiovascular Health Study.}, journal = {Circulation}, volume = {91}, year = {1995}, month = {1995 Mar 15}, pages = {1739-48}, abstract = {

BACKGROUND: Left ventricular (LV) hypertrophy, as measured by M-mode echocardiography, is an independent predictor of mortality and/or morbidity from coronary heart disease (CHD). LV global and segmental systolic dysfunction also have been associated with myocardial ischemia and cardiovascular morbidity and mortality. Echocardiographic data, especially two-dimensional, have not been available previously from multicenter-based studies of the elderly. This report describes the distribution and relation at baseline of echocardiographic LV mass and global and segmental LV wall motion to age, sex, and clinical disease category in the Cardiovascular Health Study (CHS), a cohort of 5201 men and women (4850 white) 65 years of age and older.

METHODS AND RESULTS: M-mode LV mass adjusted for body weight increased modestly with age (P < .0001), increasing less than one gram per year increase in age for both men and women. After adjustment for weight, LV mass was significantly greater in men than in women and in participants with clinical CHD compared with participants with neither clinical heart disease nor hypertension (both P < .001). Across all CHS age subgroups, the difference in weight-adjusted LV mass by sex was greater in magnitude than the difference related to clinical CHD. M-mode measurements of LV mass could not be made in 34\% of CHS participants, and this was highly related to age (29\% in the 65 to 69 year versus 50\% in the 85+ year age group, P < .001) and other risk factors. In participants with clinical CHD and with neither clinical heart disease nor hypertension, LV ejection fraction and segmental wall motion abnormalities were more prevalent in men than women (all P < .001). Of interest, 0.5\% of men and 0.4\% of women with neither clinical heart disease nor hypertension had LV segmental wall motion abnormalities, suggesting silent disease, compared with 26\% of men and 10\% of women in the clinical CHD group (P < .0001). Multivariate analyses revealed male sex and presence of clinical CHD (both P < .001) to be independent predictors of LV akinesis or dyskinesis.

CONCLUSIONS: Significant baseline relations were detected between differences in sex, prevalent disease status, and echocardiographic measurements of LV mass and systolic function in the CHS cohort. Age was weakly associated with LV mass measurements and LV ejection fraction abnormalities. These relations should be considered in evaluating the preclinical and clinical effects of CHD risk factors in the elderly.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Cohort Studies, Coronary Disease, Echocardiography, Female, Humans, Hypertrophy, Left Ventricular, Male, Sex Factors, Systole}, issn = {0009-7322}, author = {Gardin, J M and Siscovick, D and Anton-Culver, H and Lynch, J C and Smith, V E and Klopfenstein, H S and Bommer, W J and Fried, L and O{\textquoteright}Leary, D and Manolio, T A} } @article {1415, title = {Subclinical disease as an independent risk factor for cardiovascular disease.}, journal = {Circulation}, volume = {92}, year = {1995}, month = {1995 Aug 15}, pages = {720-6}, abstract = {

BACKGROUND: The primary aim of the present study was to determine the relation between measures of subclinical cardiovascular disease and the incidence of clinical cardiovascular disease among 5201 adults 65 years of age or older who were participating in the Cardiovascular Health Study.

METHODS AND RESULTS: A new method of classifying subclinical disease at baseline examination in the Cardiovascular Health Study included measures of ankle-brachial blood pressure, carotid artery stenosis and wall thickness, ECG and echocardiographic abnormalities, and positive response to the Rose Angina and Claudication Questionnaire. Participants were followed for an average of 2.39 years (maximum, 3 years). For participants without evidence of clinical cardiovascular disease at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a significant increased risk of incident total coronary heart disease including CHD deaths and nonfatal MI and angina pectoris for both men and women. For individuals with subclinical disease, the increased risk of total coronary heart disease was 2.0 for men and 2.5 for women, and the increased risk of total mortality was 2.9 for men and 1.7 for women. The increased risk changed little after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes.

CONCLUSIONS: The measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.

}, keywords = {Aged, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Female, Humans, Incidence, Longitudinal Studies, Male, Myocardial Infarction, Odds Ratio, Reference Values, Risk Factors}, issn = {0009-7322}, author = {Kuller, L H and Shemanski, L and Psaty, B M and Borhani, N O and Gardin, J and Haan, M N and O{\textquoteright}Leary, D H and Savage, P J and Tell, G S and Tracy, R} } @article {1450, title = {Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {5}, year = {1995}, month = {1995 Jul}, pages = {278-85}, abstract = {

While previous prospective multicenter studies have conducted cardiovascular disease surveillance, few have detailed the techniques relating to the ascertainment of and data collection for events. The Cardiovascular Health Study (CHS) is a population-based study of coronary heart disease and stroke in older adults. This article summarizes the CHS events protocol and describes the methods of surveillance and ascertainment of hospitalized and nonhospitalized events, the use of medical records and other support documents, organizational issues at the field center level, and the classification of events through an adjudication process. We present data on incidence and mortality, the classification of adjudicated events, and the agreement between classification by the Events Subcommittee and the medical records diagnostic codes. The CHS techniques are a successful model for complete ascertainment, investigation, and documentation of events in an older cohort.

}, keywords = {Aged, Cerebrovascular Disorders, Coronary Disease, Epidemiologic Methods, Female, Hospitalization, Humans, Incidence, Longitudinal Studies, Male, Population Surveillance, Quality Control, United States}, issn = {1047-2797}, author = {Ives, D G and Fitzpatrick, A L and Bild, D E and Psaty, B M and Kuller, L H and Crowley, P M and Cruise, R G and Theroux, S} } @article {1463, title = {Short-term predictors of incident stroke in older adults. The Cardiovascular Health Study.}, journal = {Stroke}, volume = {27}, year = {1996}, month = {1996 Sep}, pages = {1479-86}, abstract = {

BACKGROUND AND PURPOSE: Risk factors for incident stroke have been examined in middle-aged persons, but less is known about stroke precursors in the elderly, who suffer the highest rates of stroke. Short-term risk factors for incident stroke were examined in a longitudinal, population-based study including extensive measures of subclinical disease.

METHODS: Prospective study of 5201 women and men aged 65 years and older was undertaken in the multicenter Cardiovascular Health Study.

RESULTS: During an average 3.31-year follow-up, 188 incident strokes occurred. Stroke incidence increased significantly with age and was similar in women and men. Factors associated with increased stroke risk in multivariate analysis included age, aspirin use, diabetes, impaired glucose tolerance, higher systolic blood pressure, increased time needed to walk 15 ft. frequent falls, elevated creatinine level, abnormal left ventricular (LV) wall motion and increased LV mass on echocardiography, ultrasound-defined carotid stenosis, and atrial fibrillation. Increased LV mass and carotid stenosis were associated with twofold and threefold increases in incidences of stroke, respectively (P < .001). Aspirin users had a 52\% higher risk of stroke (relative risk, 1.52; 95\% confidence interval, 1.1 to 2.0; P < .007) after adjustment for other factors. This association was present only among aspirin users without prior coronary disease, atrial fibrillation, claudication, or transient ischemic attack, who had an 84\% higher risk (relative risk, 1.84; 95\% confidence interval, 1.2 to 2.8).

CONCLUSIONS: Short-term risk of stroke has a complex relationship with aspirin use and is strongly related to subclinical disease in this sample of older adults. These relationships should be considered in assessing stroke risk in the elderly, in whom recognized and subclinical cardiovascular disease is highly prevalent.

}, keywords = {Age Factors, Aged, Cardiovascular Physiological Phenomena, Cerebrovascular Disorders, Cohort Studies, Female, Health Status, Humans, Incidence, Longitudinal Studies, Male, Multivariate Analysis, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors, Time Factors}, issn = {0039-2499}, author = {Manolio, T A and Kronmal, R A and Burke, G L and O{\textquoteright}Leary, D H and Price, T R} } @article {1461, title = {Social support as a mediator in the relation between functional status and quality of life in older adults.}, journal = {Psychol Aging}, volume = {11}, year = {1996}, month = {1996 Mar}, pages = {34-44}, abstract = {

The relations among physical functioning, social support, depressive symptoms, and life satisfaction were examined in a national sample of 4,734 adults age 65 and older. Regression analyses were used to examine the relative importance of objective and subjective support measures in understanding the relation between physical impairment and quality of life. Impairment was associated with fewer friendship contacts, fewer family contacts, less perceived belonging support, and less perceived tangible aid, but only measures of perceived support predicted depressive symptomatology. A structural equation modeling approach was then used to explore the mediational role of perceived social support in the relation between impairment and quality of life variables. Results are consistent with the hypothesis that lower reported social support is an important reason for decreases in life satisfaction and increases in depressive symptoms found among older adult populations. Implications for understanding the role of social support in attenuating the effects of physical disability in older adults are discussed.

}, keywords = {Activities of Daily Living, Adaptation, Psychological, Aged, Aged, 80 and over, Aging, Depression, Disabled Persons, Geriatric Assessment, Health Status, Humans, Personal Satisfaction, Quality of Life, Sick Role, Social Support}, issn = {0882-7974}, author = {Newsom, J T and Schulz, R} } @article {1472, title = {Spirometry reference values for healthy elderly blacks. The Cardiovascular Health Study Research Group.}, journal = {Chest}, volume = {110}, year = {1996}, month = {1996 Dec}, pages = {1416-24}, abstract = {

Pulmonary function was assessed by spirometry in 497 black and 2,980 white ambulatory elderly male and female participants of the Cardiovascular Health Study. The quality assurance program prompted technicians to exceed American Thoracic Society recommendations for spirometry. A "healthy" subgroup of 235 black and 1,227 white participants age 65 years and older was identified by excluding current and former smoker, and those with self-reported asthma or emphysema, congestive heart failure, and poor-quality results of spirometry tests, since those factors were associated with a lower FEV1. Reference equations and normal ranges for elderly blacks for measurements of FEV1, FVC, and the FEV1/FVC ratio were then determined from the healthy group. These elderly blacks had an FVC about 6\% lower than elderly whites, even after correcting for standing height, sitting height (trunk length), and age. The popular use of spirometry reference values from studies of middle-aged white subjects by applying a 12\% race correction factor for black patients appears to overestimate predicted values.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, European Continental Ancestry Group, Female, Forced Expiratory Volume, Humans, Male, Reference Values, Spirometry, United States, Vital Capacity}, issn = {0012-3692}, author = {Enright, P L and Arnold, A and Manolio, T A and Kuller, L H} } @article {1474, title = {Spousal similarity in subjective well-being: the Cardiovascular Health Study.}, journal = {Psychol Aging}, volume = {11}, year = {1996}, month = {1996 Dec}, pages = {582-90}, abstract = {

This study examines the extent to which one spouse{\textquoteright}s subjective well-being predicts that of the partner (N = 1,040 spousal pairs, 65 years or older). Prior research is extended in two ways: (a) The similarity of both affective domains (depressive symptoms, feelings about life as a whole, and satisfaction with the meaning and purpose of life) and nonaffective domains (perceived health) are examined, and (b) known predictors of well-being in older adults (sociodemographic variables, self and spouse health status variables, and exposure to common environmental events) are statistically controlled. Results indicate that one spouse{\textquoteright}s assessments of well-being and depression predict the other{\textquoteright}s well-being even after controlling for known predictors of these outcomes. Given the similarity of findings for affective and nonaffective domains, multiple mechanisms, including contagion, mate selection, and common environmental influences, are speculated as likely to contribute to this phenomenon.

}, keywords = {Activities of Daily Living, Adaptation, Psychological, Aged, Cardiovascular Diseases, Depression, Female, Geriatric Assessment, Humans, Male, Personal Satisfaction, Sick Role, Social Environment, Spouses}, issn = {0882-7974}, author = {Bookwala, J and Schulz, R} } @article {1483, title = {Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group.}, journal = {Stroke}, volume = {28}, year = {1997}, month = {1997 Jun}, pages = {1158-64}, abstract = {

BACKGROUND AND PURPOSE: Infarctlike lesions are frequently detected in symptomatic and asymptomatic older persons undergoing cerebral MRI, but their significance in older adults has not been examined. We determined the prevalence of MRI infarcts in a population-based sample of men and women aged > or = 65 years and related these findings to demographic, cognitive, and neurological status.

METHODS: MRI scanning was performed in 3660 Cardiovascular Health Study (CHS) participants after brief neurological examinations and tests of cognitive function. MRIs were read centrally for the presence of an infarct > or = 3 mm in diameter or smaller infarctlike lesions.

RESULTS: MRI infarcts were detected in 1131 of 3647 participants with readable infarct information (31\%) and in 961 of the subgroup of 3397 participants (28\%) without known prior stroke ("silent" MRI infarcts). Smaller infarctlike lesions were found in 196 of 2516 participants who had no MRI infarcts > or = 3 mm. MRI infarcts were more common in participants who were older, had prior stroke, impaired cognition, visual field deficits, slowed repetitive finger tapping (all P < .0001), weakness on toe and heel walking, and history of memory loss, coma, or migraine headaches. Multivariate analysis in those without prior stroke showed strong associations of silent MRI infarcts with older age, history of migraines, lower digit symbol scores, and more abnormalities on neurological examination.

CONCLUSIONS: MRI evidence of brain infarction is common in older men and women without a clinical history of stroke. Their strong associations with impaired cognition and neurological deficits suggest that they are neither silent nor innocuous.

}, keywords = {Aged, Aged, 80 and over, Cerebral Infarction, Cognition, Female, Humans, Magnetic Resonance Imaging, Male, Neurologic Examination}, issn = {0039-2499}, author = {Price, T R and Manolio, T A and Kronmal, R A and Kittner, S J and Yue, N C and Robbins, J and Anton-Culver, H and O{\textquoteright}Leary, D H} } @article {1473, title = {Sleep disturbance, psychosocial correlates, and cardiovascular disease in 5201 older adults: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {45}, year = {1997}, month = {1997 Jan}, pages = {1-7}, abstract = {

OBJECTIVES: To describe the prevalence of self reported sleep disturbances in older men and women and to describe their relationships with health status and cardiovascular disease (CVD).

DESIGN: Cross-sectional study of sleep disturbance, CVD, general health, psychosocial factors, physical function, and use of psychotropic medications.

SETTING: Participants of the Cardiovascular Health Study, 5201 adults aged 65 and older recruited from a random sample of noninstitutionalized Medicare enrollees in four US communities.

MEASURES: Self-reported sleep disturbances and standardized questionnaires for cardiopulmonary symptoms and diseases, depression, social support, activities of daily living, physical activity, cognitive function, and current medications, spirometry, ECG, echocardiography, and carotid ultrasound.

RESULTS: Women were twice as likely as men to report difficulty falling asleep (30\% vs 14\%). Daytime sleepiness, difficulty falling asleep, and frequent awakenings increased in prevalence with age. All symptoms were related strongly to depression. Symptoms of daytime sleepiness were also related strongly to poor health and limitations in activities of daily living in men and women. In multivariate analysis, men taking benzodiazepines were likely to report difficulty falling asleep and daytime sleepiness, whereas women taking benzodiazepines reported difficulty falling asleep and waking up too early. After accounting for these factors, the only cardiovascular disease independently associated with sleep disturbances was angina. Men and women with confirmed angina were 1.6 times more likely to report trouble falling asleep. Independent relationships between sleep disturbances and cardiovascular risk factors such as obesity, hypertension, smoking, and diabetes were relatively weak and inconsistent, though smokers were less likely to report frequent awakenings.

CONCLUSIONS: Sleep disturbances are relatively common in older men and women and are associated with poor health, depression, angina, limitations in activities of daily living, and the use of benzodiazepines.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cross-Sectional Studies, Depression, Female, Geriatric Assessment, Health Surveys, Humans, Male, Prevalence, Psychotropic Drugs, Random Allocation, Risk Factors, Sex Factors, Sleep Wake Disorders, Social Support, Surveys and Questionnaires, United States}, issn = {0002-8614}, author = {Newman, A B and Enright, P L and Manolio, T A and Haponik, E F and Wahl, P W} } @article {1499, title = {The Sleep Heart Health Study: design, rationale, and methods.}, journal = {Sleep}, volume = {20}, year = {1997}, month = {1997 Dec}, pages = {1077-85}, abstract = {

The Sleep Heart Health Study (SHHS) is a prospective cohort study designed to investigate obstructive sleep apnea (OSA) and other sleep-disordered breathing (SDB) as risk factors for the development of cardiovascular disease. The study is designed to enroll 6,600 adult participants aged 40 years and older who will undergo a home polysomnogram to assess the presence of OSA and other SDB. Participants in SHHS have been recruited from cohort studies in progress. Therefore, SHHS adds the assessment of OSA to the protocols of these studies and will use already collected data on the principal risk factors for cardiovascular disease as well as follow-up and outcome information pertaining to cardiovascular disease. Parent cohort studies and recruitment targets for these cohorts are the following: Atherosclerosis Risk in Communities Study (1,750 participants), Cardiovascular Health Study (1,350 participants), Framingham Heart Study (1,000 participants), Strong Heart Study (600 participants), New York Hypertension Cohorts (1,000 participants), and Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study (900 participants). As part of the parent study follow-up procedures, participants will be surveyed at periodic intervals for the incidence and recurrence of cardiovascular disease events. The study provides sufficient statistical power for assessing OSA and other SDB as risk factors for major cardiovascular events, including myocardial infarction and stroke.

}, keywords = {Adult, Aged, Aged, 80 and over, Arteriosclerosis, Cohort Studies, Coronary Disease, Female, Humans, Hypertension, Longitudinal Studies, Male, Middle Aged, Polysomnography, Positive-Pressure Respiration, Prospective Studies, Research Design, Sleep Apnea Syndromes}, issn = {0161-8105}, author = {Quan, S F and Howard, B V and Iber, C and Kiley, J P and Nieto, F J and O{\textquoteright}Connor, G T and Rapoport, D M and Redline, S and Robbins, J and Samet, J M and Wahl, P W} } @article {1469, title = {Sulcal, ventricular, and white matter changes at MR imaging in the aging brain: data from the cardiovascular health study.}, journal = {Radiology}, volume = {202}, year = {1997}, month = {1997 Jan}, pages = {33-9}, abstract = {

PURPOSE: To determine the distribution of changes in sulcal size, ventricular size, and white matter signal intensity depicted on cranial magnetic resonance (MR) images, with stratification according to age, race, and sex.

MATERIALS AND METHODS: Ventricular size, sulcal size, and white matter signal intensity changes were graded on cranial MR images of 3,660 community-living, elderly participants in the Cardiovascular Health Study. A healthier subgroup was also defined. Summary statistics for both groups were generated for age, race, and sex.

RESULTS: Regression models of the entire imaged cohort showed higher grades of all variables with increasing age, and higher ventricular and sulcal grades in men and in nonblack individuals. White matter grade was greater in women and in black individuals. Regression models of the healthier subgroup showed similar associations, except for a lack of association of sulcal and ventricular size with race.

CONCLUSION: Sulcal width, ventricular size, and white matter signal intensity change with age, sex, and race. Knowledge of these changes is important in appropriate interpretation of MR images of the elderly.

}, keywords = {Aged, Aged, 80 and over, Aging, Brain, Cardiovascular Diseases, Cerebral Ventricles, Cohort Studies, Continental Population Groups, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Reproducibility of Results, Sex Factors}, issn = {0033-8419}, doi = {10.1148/radiology.202.1.8988189}, author = {Yue, N C and Arnold, A M and Longstreth, W T and Elster, A D and Jungreis, C A and O{\textquoteright}Leary, D H and Poirier, V C and Bryan, R N} } @article {1495, title = {Sex differences in brain aging: a quantitative magnetic resonance imaging study.}, journal = {Arch Neurol}, volume = {55}, year = {1998}, month = {1998 Feb}, pages = {169-79}, abstract = {

BACKGROUND: Little is known about the effect of sex on age-related changes in brain structure.

METHODS: Quantitative magnetic resonance imaging of the brain was performed in 330 elderly (age range, 66-96 years) volunteers living independently in the community, all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images by means of computer-assisted edge detection and trace methods. High measurement reliabilities were obtained.

RESULTS: Age-specific changes in brain size were significantly greater in men than women for the peripheral (sulcal) cerebrospinal fluid volume, the lateral (sylvian) fissure cerebrospinal fluid volume, and the parieto-occipital region area. Main effects of age were observed for all the remaining brain regions examined (cerebral hemisphere volume, frontal region area, temporoparietal region area, lateral ventricular volume, and third ventricle volume), but these effects were similar in men and women. Asymmetries in brain structures were not affected by aging in either sex.

CONCLUSIONS: Our results are generally consistent with the few published studies on sex differences in brain aging and suggest that, for at least some structures, aging effects may be more apparent in men than women. The neurobiological bases and functional correlates of these sex differences require further investigation.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Aging, Atrophy, Brain, Cerebrospinal Fluid, Diagnosis, Computer-Assisted, Female, Health Status, Humans, Magnetic Resonance Imaging, Male, Regression Analysis, Sex Characteristics, Sex Distribution}, issn = {0003-9942}, author = {Coffey, C E and Lucke, J F and Saxton, J A and Ratcliff, G and Unitas, L J and Billig, B and Bryan, R N} } @article {603, title = {Stability and change in older adults{\textquoteright} social contact and social support: the Cardiovascular Health Study.}, journal = {J Gerontol B Psychol Sci Soc Sci}, volume = {54}, year = {1999}, month = {1999 Sep}, pages = {S302-11}, abstract = {

OBJECTIVES: The aim of this study was to examine the degree of individual change in structural indicators of social support (family network contact and close friend network contact) and functional indicators of social support (belonging, appraisal, and tangible support) during late life.

METHODS: Using a large population-based sample of older adults, hierarchical linear modeling was applied to examine the extent of change in social contact and support as well as sociodemographic characteristics (age, race, gender, and education) that might explain individual variability in contact and support at baseline and over time.

RESULTS: Consistent with predictions, small yet significant increases were observed in belonging support and tangible support. Contrary to predictions, no evidence was found for significant individual change in family network contact, close friend network contact, or appraisal support. Sociodemographic characteristics were more consistent predictors of variability in contact and support at baseline than variability over time.

DISCUSSION: The findings of this study add to a growing literature suggesting that late life is not typically characterized by a decline in important social resources.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Cross-Sectional Studies, Educational Status, Family, Female, Health Status, Humans, Interpersonal Relations, Linear Models, Longitudinal Studies, Male, Predictive Value of Tests, Sex Factors, Social Support, Socioeconomic Factors, Surveys and Questionnaires, Time Factors, United States}, issn = {1079-5014}, doi = {10.1093/geronb/54b.5.s302}, author = {Martire, L M and Schulz, R and Mittelmark, M B and Newsom, J T} } @article {1521, title = {Stroke risk in an elderly population with atrial fibrillation.}, journal = {J Gen Intern Med}, volume = {14}, year = {1999}, month = {1999 Jan}, pages = {56-9}, abstract = {

Patients with nonvalvular atrial fibrillation (AF) have an increased risk of stroke, but the absolute rate of stroke varies widely depending on coexistent vascular disease. We assessed the stroke rate and predictive value of two published schemes for stroke risk stratification in a population-derived cohort of 259 elderly people with nonvalvular AF followed for a median of 5.3 years. The rate of ischemic stroke was 2.8\% per year (95\% confidence interval [CI] 1.9, 3.9). Thirty-one percent were predicted to be at low risk, and their stroke rate was 1.7\% per year (95\% CI 0.6, 3.8). Many people with AF in this population-derived cohort had relatively low rates of stroke. Further studies to reliably stratify stroke risk in patients with AF are needed.

}, keywords = {Aged, Atrial Fibrillation, Cerebrovascular Disorders, Cohort Studies, Humans, Male, Poisson Distribution, Proportional Hazards Models, Risk Factors}, issn = {0884-8734}, author = {Feinberg, W M and Kronmal, R A and Newman, A B and Kraut, M A and Bovill, E G and Cooper, L and Hart, R G} } @article {592, title = {Survival versus years of healthy life: which is more powerful as a study outcome?}, journal = {Control Clin Trials}, volume = {20}, year = {1999}, month = {1999 Jun}, pages = {267-79}, abstract = {

Studies of interventions that are intended to improve patients{\textquoteright} health are often evaluated with survival as the primary outcome, even when a measure adjusted for quality of survival, such as years of healthy life (YHL), would seem more appropriate. The purpose of this article is to determine whether studies based on survival are more or less powerful than studies based on YHL in clinical trials where either measure might be appropriate. We used data from the Cardiovascular Health Study (CHS) to estimate the sample size that would be needed in studies of 156 different health conditions, for the two outcome measures. The median sample size for a 5-year study was 687 if survival was the endpoint and 484 for YHL. YHL usually required lower sample sizes than survival, although survival was more powerful for some health conditions. We also found that lengthy studies, and studies with many follow-up measures per person, did not have appreciably higher power than less intensive studies. We conclude that clinical investigations in which the goal is to improve health may often be performed more efficiently with YHL rather than survival as the primary outcome measure. Such studies can be short in duration, with relatively few measures per person of health status.

}, keywords = {Aged, Angina Pectoris, Female, Follow-Up Studies, Health Status, Humans, Life Expectancy, Male, Quality-Adjusted Life Years, Randomized Controlled Trials as Topic, Research Design, Sample Size, Survival Analysis, Time Factors, Treatment Outcome}, issn = {0197-2456}, doi = {10.1016/s0197-2456(98)00062-2}, author = {Diehr, P and Patrick, D L and Burke, G L and Williamson, J} } @article {663, title = {Silent MRI infarcts and the risk of future stroke: the cardiovascular health study.}, journal = {Neurology}, volume = {57}, year = {2001}, month = {2001 Oct 09}, pages = {1222-9}, abstract = {

BACKGROUND: Silent infarcts are commonly discovered on cranial MRI in the elderly.

OBJECTIVE: To examine the association between risk of stroke and presence of silent infarcts, alone and in combination with other stroke risk factors.

METHODS: Participants (3,324) in the Cardiovascular Health Study (CHS) without a history of stroke underwent cranial MRI scans between 1992 and 1994. Silent infarcts were defined as focal lesions greater than 3 mm that were hyperintense on T2 images and, if subcortical, hypointense on T1 images. Incident strokes were identified and classified over an average follow-up of 4 years. The authors evaluated the risk of subsequent symptomatic stroke and how it was modified by other potential stroke risk factors among those with silent infarcts.

RESULTS: Approximately 28\% of CHS participants had evidence of silent infarcts (n = 923). The incidence of stroke was 18.7 per 1,000 person-years in those with silent infarcts (n = 67) compared with 9.5 per 1,000 person-years in the absence of silent infarcts. The adjusted relative risk of incident stroke increased with multiple (more than one) silent infarcts (hazard ratio 1.9 [1.2 to 2.8]). Higher values of diastolic and systolic blood pressure, common and internal carotid wall thickness, and the presence of atrial fibrillation were associated with an increased risk of strokes in those with silent infarcts (n = 53 strokes).

CONCLUSION: The presence of silent cerebral infarcts on MRI is an independent predictor of the risk of symptomatic stroke over a 4-year follow- up in older individuals without a clinical history of stroke.

}, keywords = {Aged, Cerebral Infarction, Cohort Studies, Female, Follow-Up Studies, Humans, Incidence, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Risk Factors, Stroke}, issn = {0028-3878}, doi = {10.1212/wnl.57.7.1222}, author = {Bernick, C and Kuller, L and Dulberg, C and Longstreth, W T and Manolio, T and Beauchamp, N and Price, T} } @article {636, title = {Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study.}, journal = {Am J Respir Crit Care Med}, volume = {163}, year = {2001}, month = {2001 Jan}, pages = {19-25}, abstract = {

Disordered breathing during sleep is associated with acute, unfavorable effects on cardiovascular physiology, but few studies have examined its postulated association with cardiovascular disease (CVD). We examined the cross-sectional association between sleep- disordered breathing and self-reported CVD in 6,424 free-living individuals who underwent overnight, unattended polysomnography at home. Sleep-disordered breathing was quantified by the apnea-hypopnea index (AHI)-the average number of apneas and hypopneas per hour of sleep. Mild to moderate disordered breathing during sleep was highly prevalent in the sample (median AHI: 4.4; interquartile range: 1.3 to 11.0). A total of 1,023 participants (16\%) reported at least one manifestation of CVD (myocardial infarction, angina, coronary revascularization procedure, heart failure, or stroke). The multivariable-adjusted relative odds (95\% CI) of prevalent CVD for the second, third, and fourth quartiles of the AHI (versus the first) were 0.98 (0.77-1.24), 1.28 (1.02-1.61), and 1.42 (1.13-1.78), respectively. Sleep-disordered breathing was associated more strongly with self-reported heart failure and stroke than with self-reported coronary heart disease: the relative odds (95\% CI) of heart failure, stroke, and coronary heart disease (upper versus lower AHI quartile) were 2.38 (1.22-4.62), 1.58 (1.02- 2.46), and 1.27 (0.99-1.62), respectively. These findings are compatible with modest to moderate effects of sleep-disordered breathing on heterogeneous manifestations of CVD within a range of AHI values that are considered normal or only mildly elevated.

}, keywords = {Aged, Cardiovascular Diseases, Cohort Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Sleep Apnea Syndromes}, issn = {1073-449X}, doi = {10.1164/ajrccm.163.1.2001008}, author = {Shahar, E and Whitney, C W and Redline, S and Lee, E T and Newman, A B and Nieto, F J and O{\textquoteright}Connor, G T and Boland, L L and Schwartz, J E and Samet, J M} } @article {698, title = {Serum potassium level and dietary potassium intake as risk factors for stroke.}, journal = {Neurology}, volume = {59}, year = {2002}, month = {2002 Aug 13}, pages = {314-20}, abstract = {

BACKGROUND: Numerous studies have found that low potassium intake and low serum potassium are associated with increased stroke mortality, but data regarding stroke incidence have been limited. Serum potassium levels, dietary potassium intake, and diuretic use in relation to risk for stroke in a prospectively studied cohort were investigated.

METHODS: The study comprised 5,600 men and women older than 65 years who were free of stroke at enrollment. Baseline data included serum potassium level, dietary potassium intake, and diuretic use. Participants were followed for 4 to 8 years, and the incidence and types of strokes were recorded. Low serum potassium was defined as less than 4.1 mEq/L, and low potassium intake as less than 2.4 g/d.

RESULTS: Among diuretic users, there was an increased risk for stroke associated with lower serum potassium (relative risk [RR]: 2.5, p < 0.0001). Among individuals not taking diuretics, there was an increased risk for stroke associated with low dietary potassium intake (RR: 1.5, p < 0.005). The small number of diuretic users with lower serum potassium and atrial fibrillation had a 10-fold greater risk for stroke compared with those with higher serum potassium and normal sinus rhythm.

CONCLUSIONS: A lower serum potassium level in diuretic users, and low potassium intake in those not taking diuretics were associated with increased stroke incidence among older individuals. Lower serum potassium was associated with a particularly high risk for stroke in the small number of diuretic users with atrial fibrillation. Further study is required to determine if modification of these factors would prevent strokes.

}, keywords = {Aged, Cohort Studies, Confidence Intervals, Diuretics, Humans, Linear Models, Male, Potassium, Potassium, Dietary, Proportional Hazards Models, Prospective Studies, Risk Factors, Stroke}, issn = {0028-3878}, doi = {10.1212/wnl.59.3.314}, author = {Green, D M and Ropper, A H and Kronmal, R A and Psaty, B M and Burke, G L} } @article {714, title = {Short-term variability of respiration and sleep during unattended nonlaboratory polysomnography--the Sleep Heart Health Study. [corrected].}, journal = {Sleep}, volume = {25}, year = {2002}, month = {2002 Dec}, pages = {843-9}, abstract = {

STUDY OBJECTIVES: To determine the short-term variability of indices of disturbed respiration and sleep during 2 nights of unattended nonlaboratory polysomnography conducted several months apart.

DESIGN: Participants were randomly selected using a block design with stratification on preliminary estimates of 2 criteria: respiratory disturbance index [RDI3\% (apnea or hypopnea events associated with > or = 3\% O2 desaturation): < 15/hour total sleep time, > or = 15/hour total sleep time] and sleep efficiency (SEff: < 85\% and > or = 85\%). The RDI and sleep data from initial and repeated polysomnography were compared.

SETTING: NA.

PARTICIPANTS: A subset of 99 participants in the Sleep Heart Health Study who agreed to have a repeat polysomnogram within 4 months of their original study.

INTERVENTIONS: NA.

MEASUREMENTS AND RESULTS: Acceptable repeat polysomnograms were obtained in 91 subjects (mean study interval: 77 +/- 18 [sd] days; range: 31-112 days). There was no significant bias in RDI between study nights using several different RDI definitions including RDI3\% and RDI4\% (apnea or hypopnea events associated with > or = 4\% O2 desaturation). Variability between studies estimated using intraclass correlations (ICC) ranged from 0.77 to 0.81. For subjects with a RDI3\% < 15, variability increased as a function of increasing RDI, but for those with a RDI3\% > or = 15, variability was constant. Body mass index, SEff, gender, or age did not directly predict RDI variability. Using RDI4\% cutpoints of < or = 5, < or = 10 and < or = 15 events per hour of sleep demonstrated that 79.1\%, 85.7\%, and 87.9\% of subjects, respectively, had the same classification of SDB status on both nights of study. There also was no significant bias in sleep staging, sleep efficiency, or arousal index between studies. However, variability was greater with ICC values ranging from 0.37 (\% time in REM) to 0.76 (arousal index).

CONCLUSION: In the Sleep Heart Health Study, accurate estimates of the severity of sleep-disordered breathing and the quality of sleep were obtained from a single night of unattended nonlaboratory polysomnography. These findings may be applicable to other large epidemiologic studies provided that similar recording techniques and quality-assurance procedures are followed.

}, keywords = {Adult, Aged, Aged, 80 and over, Apnea, Arousal, Body Mass Index, Circadian Rhythm, Electrocardiography, Electromyography, Electrooculography, Female, Humans, Male, Middle Aged, Oxygen Consumption, Polysomnography, Respiration, Sleep Apnea Syndromes, Sleep Stages, Time Factors}, issn = {0161-8105}, author = {Quan, Stuart F and Griswold, Michael E and Iber, Conrad and Nieto, F Javier and Rapoport, David M and Redline, Susan and Sanders, Mark and Young, Terry} } @article {676, title = {A stroke prediction score in the elderly: validation and Web-based application.}, journal = {J Clin Epidemiol}, volume = {55}, year = {2002}, month = {2002 Feb}, pages = {129-36}, abstract = {

The objective of this study was to construct a prediction model for predicting stroke in an elderly U.S. population, and to assess the accuracy in this population of other previously published prediction models. The subjects were participants in the Cardiovascular Health Study: 2,495 men and 3,393 women age 65 years and older at baseline, and followed for 6.3 years. Among 5,711 participants free of baseline stroke, 399 strokes occurred. Sex-specific prediction equations were constructed using study variables that were most importantly related to incident stroke: age, systolic blood pressure, diabetes, ECG diagnosis of atrial fibrillation or left ventricular hypertrophy, confirmed history of cardiovascular disease, diabetes, time to walk 15 ft, and serum creatinine. The prediction rule was implemented as a risk score and in a Web-based interactive Java applet. Overall, the model predicted 5-year stroke risks ranging from less than 1 to 59\%. The 20\% of subjects in the highest predicted risk group had a 5-year actual stroke incidence rate of 15\%, while the 20\% lowest risk group had a 1\% incidence. Risk scores from two other studies performed well in these study participants. Effective discrimination between low and high stroke risk in the elderly was possible in this cohort with data that are easy to obtain. Evaluation of the generalizability and clinical usefulness of this prediction model requires further research.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Female, Follow-Up Studies, Humans, Incidence, Male, Models, Cardiovascular, Predictive Value of Tests, Risk Factors, ROC Curve, Stroke, United States}, issn = {0895-4356}, doi = {10.1016/s0895-4356(01)00434-6}, author = {Lumley, Thomas and Kronmal, Richard A and Cushman, Mary and Manolio, Teri A and Goldstein, Steven} } @article {726, title = {Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE).}, journal = {Am J Hematol}, volume = {72}, year = {2003}, month = {2003 Mar}, pages = {192-200}, abstract = {

We sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95\% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95\% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95\% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.

}, keywords = {Aged, Aging, Animals, Case-Control Studies, Cohort Studies, Factor V, Female, Genotype, Homocysteine, Humans, Longitudinal Studies, Male, Methylenetetrahydrofolate Reductase (NADPH2), Middle Aged, Odds Ratio, Oxidoreductases Acting on CH-NH Group Donors, Polymorphism, Genetic, Prospective Studies, Risk Factors, Venous Thrombosis}, issn = {0361-8609}, doi = {10.1002/ajh.10287}, author = {Tsai, Albert W and Cushman, Mary and Tsai, Michael Y and Heckbert, Susan R and Rosamond, Wayne D and Aleksic, Nena and Yanez, N David and Psaty, Bruce M and Folsom, Aaron R} } @article {715, title = {Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease.}, journal = {Am J Respir Crit Care Med}, volume = {167}, year = {2003}, month = {2003 Jan 01}, pages = {7-14}, abstract = {

Neither the association between obstructive airways disease (OAD) and sleep apnea-hypopnea (SAH) nor the sleep consequences of each disorder alone and together have been characterized in an adult community setting. Our primary aims were (1) to determine if there is an association between OAD and SAH and (2) identify predictors of oxyhemoglobin desaturation during sleep in persons having OAD with and without SAH. Polysomnography and spirometry results from 5,954 participants in the Sleep Heart Health Study were analyzed. OAD was defined by a FEV1/FVC value less than 70\%. Assessment of SAH prevalence in OAD was performed using thresholds of respiratory disturbance index (RDI) greater than 10 and greater than 15. A total of 1,132 participants had OAD that was predominantly mild (FEV1/FVC 63.81 +/- 6.56\%, mean +/- SD). SAH was not more prevalent in participants with OAD than in those without OAD (22.32 versus 28.86\%, with and without OAD, respectively, at RDI threshold values greater than 10; and 13.97 versus 18.63\%, with and without OAD, respectively, at RDI threshold value greater than 15). In the absence of SAH, the adjusted odds ratio for sleep desaturation (> 5\% total sleep time with saturation < 90\%) was greater than 1.9 when FEV1/FVC was less than 65\%. Participants with both OAD and SAH had greater sleep perturbation and desaturation than those with one disorder. Generally mild OAD alone was associated with minimally altered sleep quality. We conclude that (1) there is no association between generally mild OAD and SAH; (2) exclusive of SAH and after adjusting for demographic factors and awake oxyhemoglobin saturation, an FEV1/FVC value less than 65\% is associated with increased risk of sleep desaturation; (3) desaturation is greater in persons with both OAD and SAH compared with each of these alone; and (4) individuals with generally mild OAD and without SAH in the community have minimally perturbed sleep.

}, keywords = {Aged, Cohort Studies, Female, Forced Expiratory Volume, Humans, Male, Middle Aged, Oxyhemoglobins, Polysomnography, Prospective Studies, Pulmonary Disease, Chronic Obstructive, Sleep, Sleep Apnea, Obstructive, Spirometry, Vital Capacity}, issn = {1073-449X}, doi = {10.1164/rccm.2203046}, author = {Sanders, Mark H and Newman, Anne B and Haggerty, Catherine L and Redline, Susan and Lebowitz, Michael and Samet, Jonathan and O{\textquoteright}Connor, George T and Punjabi, Naresh M and Shahar, Eyal} } @article {757, title = {"Successful aging": effect of subclinical cardiovascular disease.}, journal = {Arch Intern Med}, volume = {163}, year = {2003}, month = {2003 Oct 27}, pages = {2315-22}, abstract = {

BACKGROUND: Cardiovascular diseases are the primary cause of death in older adults. Among those without clinical disease, high levels of subclinical disease are associated with poor survival. The effect of the extent of subclinical cardiovascular disease on the quality of the remaining years has not been defined.

METHODS: In a longitudinal cohort study, 2932 men and women aged 65 years and older were followed up for 8 years to determine the likelihood of maintaining intact health and functioning. Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and with intact physical and cognitive functioning.

RESULTS: Younger age at study entry and a lower extent of subclinical cardiovascular disease were independently associated with the likelihood of maintaining successful aging. In age-stratified summaries, those with subclinical disease had a trajectory of decline similar to subjects 5 years older without subclinical vascular disease. Regression analyses showed that the decline associated with subclinical disease was equivalent to 6.5 (95\% confidence interval, 6.4-6.6) years of aging for women and 5.6 (95\% confidence interval, 5.4-5.8) years of aging for men. Individual measures of the extent of cardiovascular disease, diabetes mellitus, smoking, and higher C-reactive protein level were also independently predictive of fewer years of successful aging, but none of these factors substantially attenuated the effect of age itself.

CONCLUSIONS: There is a graded relationship between the extent of vascular disease measured noninvasively and the likelihood of maintaining intact health and function. Prevention of subclinical vascular disease may increase the quality and the quantity of years in late life.

}, keywords = {Aged, Aged, 80 and over, Aging, C-Reactive Protein, Cardiovascular Diseases, Female, Health Status, Humans, Longitudinal Studies, Male, Quality of Life, Regression Analysis, Risk Factors}, issn = {0003-9926}, doi = {10.1001/archinte.163.19.2315}, author = {Newman, Anne B and Arnold, Alice M and Naydeck, Barbara L and Fried, Linda P and Burke, Gregory L and Enright, Paul and Gottdiener, John and Hirsch, Calvin and O{\textquoteright}Leary, Daniel and Tracy, Russell} } @article {792, title = {Self-reported alcohol consumption and falls in older adults: cross-sectional and longitudinal analyses of the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {52}, year = {2004}, month = {2004 Jul}, pages = {1174-9}, abstract = {

OBJECTIVES: To assess the cross-sectional and longitudinal associations between alcohol consumption and risk of falls in older adults.

DESIGN: Cross-sectional and longitudinal analyses.

SETTING: Four U.S. communities.

PARTICIPANTS: A total of 5,841 older adults enrolled in the Cardiovascular Health Study, an ongoing, population-based, prospective cohort study, participated.

MEASUREMENTS: Self-reported alcohol consumption at baseline, self-reported frequent falls at baseline, and the 4-year risk of falls of participants who denied frequent falls at baseline.

RESULTS: Cross-sectional analysis indicated an apparent inverse association between alcohol consumption and risk of frequent falls (adjusted odds ratio in consumers of 14 or more drinks per week=0.41; 95\% confidence interval (CI)=0.14-1.17; P for trend=.06), but longitudinal analysis indicated a similar 4-year risk of falls in abstainers and light to moderate drinkers but a 25\% higher risk in consumers of 14 or more drinks per week (95\% CI=3-52\%; P for trend=.07). Similar results were found in analyses stratified by age, sex, race, and physical activity.

CONCLUSION: Consumption of 14 or more drinks per week is associated with an increased risk of subsequent falls in older adults. Cross-sectional studies may fail to identify this risk of heavier drinking, perhaps because older adults at risk for falls decrease their alcohol use over time or because heavier drinkers at risk for falls tend not to enroll in cohort studies. However, because this study relied upon annual reporting of falls, further prospective studies should be conducted to confirm these findings.

}, keywords = {Accidental Falls, Aged, Alcohol Drinking, Chi-Square Distribution, Cross-Sectional Studies, Female, Humans, Longitudinal Studies, Male, Regression Analysis, Risk Factors, Self Disclosure, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2004.52318.x}, author = {Mukamal, Kenneth J and Mittleman, Murray A and Longstreth, W T and Newman, Anne B and Fried, Linda P and Siscovick, David S} } @article {776, title = {Sleep and reported daytime sleepiness in normal subjects: the Sleep Heart Health Study.}, journal = {Sleep}, volume = {27}, year = {2004}, month = {2004 Mar 15}, pages = {293-8}, abstract = {

STUDY OBJECTIVES: To describe the distribution of nocturnal sleep characteristics and reports of daytime sleepiness in a large well-defined group of healthy adults.

DESIGN: The Sleep Heart Health Study is a multicenter study examining sleep and cardiopulmonary parameters through nocturnal polysomnography in adults enrolled in geographically distinct cardiovascular cohorts.

SETTING: Community setting.

PARTICIPANTS: 470 subjects enrolled in the Sleep Heart Health Study (n = 6440) were selected as a {\textquoteright}normative{\textquoteright} group based on screening of health conditions and daily habits that could interfere with sleep.

MEASUREMENTS AND RESULTS: Home-based nocturnal polysomnography was obtained on all participants and centrally scored for sleep and respiratory parameters. Demographic and health-related data were obtained and updated at the time of the home visit. Sleep efficiency decreased by 1.6\% for each 10 years of increased age. Sleep time decreased by 0.1 hours (6.0 minutes) for each 10-year age increase and was longer in women. The arousal index increased by 0.8 for each 10-year increase in age and was lower by 1.4 in women. Women had a lower mean percentage of stage 1 and stage 2 sleep. Mean percentage of slow-wave sleep was higher in women (by 6.7\%). Percentage of slow-wave sleep decreased with increased age for men only (by 1.9\% for each 10-year age change).

CONCLUSIONS: Data suggest a clear lessening in the quantity and quality of sleep with age that appears to be more rapid in males compared to females.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Circadian Rhythm, Cohort Studies, Disorders of Excessive Somnolence, Female, Health Status, Humans, Male, Middle Aged, Polysomnography, Sleep, Sleep Stages, Surveys and Questionnaires}, issn = {0161-8105}, doi = {10.1093/sleep/27.2.293}, author = {Walsleben, Joyce A and Kapur, Vishesh K and Newman, Anne B and Shahar, Eyal and Bootzin, Richard R and Rosenberg, Carl E and O{\textquoteright}Connor, George and Nieto, F Javier} } @article {752, title = {Sleep apnea and markers of vascular endothelial function in a large community sample of older adults.}, journal = {Am J Respir Crit Care Med}, volume = {169}, year = {2004}, month = {2004 Feb 01}, pages = {354-60}, abstract = {

Clinical studies have suggested that sleep apnea is associated with impaired brachial artery flow-mediated dilation, a surrogate of endothelial dysfunction. We examined this question among older participants in the baseline examination of the Sleep Heart Health/Cardiovascular Health Study cohort (n = 1,037, age 68 years or older, 56\% female). Indices of sleep apnea, derived from 12-channel home polysomnography, were the apnea-hypopnea index (average number of apneas/hypopneas per hour) and the hypoxemia index (percentage of time below 90\% O2 saturation). Baseline arterial diameter and percentage of flow-mediated dilation were measured by ultrasound. Sleep apnea measures were associated with baseline diameter and the percentage of flow-mediated dilation, although these associations were weakened after adjustment for other cardiovascular risk factors, particularly body mass index. However, a statistically significant linear association between the hypoxemia index and baseline diameter was observed even after adjustment for body mass index and other confounders (p < 0.01). The associations were stronger among participants who were younger than 80 years and among those who with hypertension. This study adds to the growing body of evidence linking sleep apnea with vascular dysfunction in older subjects. Whether these relationships are entirely independent of obesity is unclear. This association might be one of the mechanisms explaining the relationship between sleep apnea, hypertension, and cardiovascular disease.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Body Mass Index, Brachial Artery, Cardiovascular Diseases, Cohort Studies, Comorbidity, Endothelium, Vascular, Female, Humans, Hypertension, Linear Models, Male, Polysomnography, Prevalence, Probability, Residence Characteristics, Risk Assessment, Sampling Studies, Severity of Illness Index, Sleep Apnea Syndromes, Ultrasonography, Doppler}, issn = {1073-449X}, doi = {10.1164/rccm.200306-756OC}, author = {Nieto, F Javier and Herrington, David M and Redline, Susan and Benjamin, Emelia J and Robbins, John A} } @article {783, title = {Sleep-disordered breathing and white matter disease in the brainstem in older adults.}, journal = {Sleep}, volume = {27}, year = {2004}, month = {2004 May 01}, pages = {474-9}, abstract = {

STUDY OBJECTIVES: To examine whether sleep-disordered breathing is associated with white matter disease in the brainstem.

DESIGN: A population-based longitudinal study.

SETTING: Allegheny County, PA; Sacramento County, CA; and Washington County, MD.

PATIENTS OR PARTICIPANTS: A total of 789 individuals, aged 68 years or older, drawn from the Sleep Heart Health Study.

INTERVENTIONS: N/A.

MEASUREMENTS AND RESULTS: The participants underwent home polysomnography in 1995-1998 and cerebral magnetic resonance imaging in both 1992-1993 and 1997-1998. The apnea-hypopnea index was not associated with white matter disease in the brainstem, with or without adjusting for age, sex, race, community, body mass index, smoking status, alcohol use, systolic blood pressure, and the use of antihypertensive medication. In contrast, the arousal index (number of arousals per hour of sleep) was inversely associated with brainstem white matter disease (odds ratio = 0.75 for a SD increase in the arousal index, 95\% confidence interval: 0.62, 0.92).

CONCLUSIONS: The frequency of apneas and hypopneas was not associated with brainstem white matter disease in these older adults. A unique relationship with arousal frequency suggests that ischemic changes in the brainstem may be associated with arousals during sleep.

}, keywords = {Aged, Arousal, Brain, Brain Stem, Cerebrovascular Disorders, Electrooculography, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Polysomnography, Population Surveillance, Severity of Illness Index, Sleep Apnea Syndromes, Sleep Stages}, issn = {0161-8105}, doi = {10.1093/sleep/27.3.474}, author = {Ding, Jingzhong and Nieto, F Javier and Beauchamp, Norman J and Harris, Tamara B and Robbins, John A and Hetmanski, Jacqueline B and Fried, Linda P and Redline, Susan} } @article {800, title = {Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study.}, journal = {Am J Epidemiol}, volume = {160}, year = {2004}, month = {2004 Sep 15}, pages = {521-30}, abstract = {

Clinic-based studies suggest that sleep-disordered breathing (SDB) is associated with glucose intolerance and insulin resistance. However, in the available studies, researchers have not rigorously controlled for confounding variables to assess the independent relation between SDB and impaired glucose metabolism. The objective of this study was to determine whether SDB was associated with glucose intolerance and insulin resistance among community-dwelling subjects (n=2,656) participating in the Sleep Heart Health Study (1994-1999). SDB was characterized with the respiratory disturbance index and measurements of oxygen saturation during sleep. Fasting and 2-hour glucose levels measured during an oral glucose tolerance test were used to assess glycemic status. Relative to subjects with a respiratory disturbance index of less than 5.0 events/hour (the reference category), subjects with mild SDB (5.0-14.9 events/hour) and moderate to severe SDB (> or =15 events/hour) had adjusted odds ratios of 1.27 (95\% confidence interval: 0.98, 1.64) and 1.46 (95\% confidence interval: 1.09, 1.97), respectively, for fasting glucose intolerance (p for trend < 0.01). Sleep-related hypoxemia was also associated with glucose intolerance independently of age, gender, body mass index, and waist circumference. The results of this study suggest that SDB is independently associated with glucose intolerance and insulin resistance and may lead to type 2 diabetes mellitus.

}, keywords = {Aged, Blood Gas Analysis, Body Constitution, Body Mass Index, Cohort Studies, Confounding Factors, Epidemiologic, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Fasting, Female, Glucose Intolerance, Glucose Tolerance Test, Humans, Insulin Resistance, Linear Models, Male, Middle Aged, Multivariate Analysis, Oxyhemoglobins, Polysomnography, Research Design, Risk Factors, Severity of Illness Index, Sleep Apnea Syndromes}, issn = {0002-9262}, doi = {10.1093/aje/kwh261}, author = {Punjabi, Naresh M and Shahar, Eyal and Redline, Susan and Gottlieb, Daniel J and Givelber, Rachel and Resnick, Helaine E} } @article {782, title = {Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the Sleep Heart Health Study.}, journal = {Sleep}, volume = {27}, year = {2004}, month = {2004 May 01}, pages = {467-73}, abstract = {

STUDY OBJECTIVE: Sleep apnea and milder forms of sleep-disordered breathing (SDB) have been associated with overt clinical cardiovascular disease, but it is unknown whether SDB is associated with arterial microvascular pathology. We examined the relation between SDB and retinal microvascular abnormalities.

DESIGN: Cross-sectional study.

PARTICIPANTS: Subjects were 2,927 men and women, aged 51 to 97 years, who participated in the Sleep Heart Health Study and had retinal photographs taken within approximately 3 years of overnight, unattended, at-home polysomnography.

MEASUREMENTS AND RESULTS: A respiratory disturbance index (RDI), calculated as the average number of apneas and hypopneas per hour of sleep, was used as an indicator of SDB in analysis. The overall prevalence of retinopathy was slightly higher in people with higher RDI values (5.4\%, 4.9\%, 8.6\%, and 7.6\%, respectively, in increasing quartiles of RDI), but after adjustment for age, body-mass index, hypertension, diabetes, and other factors, the presence of retinopathy was not associated with SDB. With the possible exceptions of microaneurysms and generalized arteriolar narrowing, as measured by lower arteriole-to-venule ratio, specific retinal abnormalities were not associated consistently with the RDI. Relative to the first quartile of RDI, the adjusted odds ratios (95\% confidence interval) for the presence of microaneurysm in the second, third, and fourth quartiles of RDI were 1.05 (0.44-2.55), 1.97 (0.89-4.37), and 1.79 (0.78-4.10), respectively. An increase of RDI from 0 to 10 was associated with a predicted decrease in arteriole-to-venule ratio of 0.01. Results were similar when analyses were conducted in normotensive and nondiabetic persons separately.

CONCLUSIONS: These data do not demonstrate a notable relation between SDB and retinal abnormalities. However, since this is the first investigation of a link between retinopathy and SDB, similar studies should be conducted in other population samples to demonstrate either consistency or inconsistency of our findings across studies.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Coronary Disease, Cross-Sectional Studies, Female, Humans, Hypoxia, Middle Aged, Polysomnography, Positive-Pressure Respiration, Retina, Retinal Vessels, Sleep Apnea Syndromes}, issn = {0161-8105}, doi = {10.1093/sleep/27.3.467}, author = {Boland, Lori L and Shahar, Eyal and Wong, Tien Y and Klein, Ronald and Punjabi, Naresh and Robbins, John A and Newman, Anne B} } @article {801, title = {Stroke risk factors and loss of high cognitive function.}, journal = {Neurology}, volume = {63}, year = {2004}, month = {2004 Sep 14}, pages = {793-9}, abstract = {

BACKGROUND: Modifiable stroke risk factors may contribute to age-associated declines in cognitive function. Individuals with high levels of cognitive function after midlife may have less exposure to these stroke risk factors or may be less susceptible to their effects on cognition.

METHODS: The Cardiovascular Health Study (CHS)* is a population-based, longitudinal cohort study of 5,888 people age 65 years and older. Participants (n = 4,129) who were free of dementia, stroke, or TIA at the time of baseline cranial MRI were selected for analysis. High cognitive function at baseline was defined by performance at or above midlife norms on the Modified Mini-Mental State Examination (3MS).

RESULTS: The odds of having high cognitive function at baseline decreased by quartile of stroke risk (highest vs lowest risk quartile, adjusted odds ratio [OR] 0.68; 95\% CI 0.52 to 0.88; p for trend = 0.005). Stroke risk was a predictor of decline on the 3MS in those with typical levels of cognitive function at baseline, even in the absence of incident stroke or TIA (highest vs lowest risk quartile for 3MS decline, adjusted OR 2.11; 95\% CI 1.42 to 3.13; p for trend < 0.001). In contrast, stroke risk was not associated with decline on the 3MS in those with high cognitive function at baseline (p = 0.03 for interaction).

CONCLUSIONS: In a cohort of older adults without stroke, TIA, or dementia, cognitive function and incident cognitive decline were associated with risk for stroke. Additional studies are needed to determine whether modification of stroke risk factors can reduce the cognitive decline that is often attributed to normal aging.

}, keywords = {Aged, Aged, 80 and over, Aging, Cognition Disorders, Cohort Studies, Comorbidity, Female, Follow-Up Studies, Higher Nervous Activity, Humans, Incidence, Male, Risk Assessment, Risk Factors, Sampling Studies, Sensitivity and Specificity, Severity of Illness Index, Stroke, United States}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000137014.36689.7f}, author = {Elkins, J S and O{\textquoteright}Meara, E S and Longstreth, W T and Carlson, M C and Manolio, T A and Johnston, S C} } @article {778, title = {Subclinical cardiovascular disease in older adults: insights from the Cardiovascular Health Study.}, journal = {Am J Geriatr Cardiol}, volume = {13}, year = {2004}, month = {2004 May-Jun}, pages = {137-51}, abstract = {

Knowledge about the epidemiology of subclinical cardiovascular disease (SCVD) in older adults may hold the key for improved opportunities for primary prevention of cardiovascular disease (CVD), a top clinical and public health priority. This review reports findings on the prevalence of SCVD and the ability of SCVD measures to predict incident and adverse outcomes from one of the largest (N=5888) and most comprehensive prospective observational studies on SCVD in older adults, the Cardiovascular Health Study. According to a composite index that combined SCVD measures from different vascular beds, the overall prevalence of SCVD was 37\%, making it as common as clinically overt CVD in older adults. SCVD measures strongly predicted incident CVD, stroke, mortality, frailty, and physical and cognitive decline, even after adjustment for traditional CVD risk factors. Ongoing research will address the potential use of SCVD for clinical decision making in older adults.

}, keywords = {Aged, Cardiovascular Diseases, Coronary Artery Disease, Heart Failure, Humans, Longitudinal Studies, Prevalence, Risk Assessment, Risk Factors}, issn = {1076-7460}, doi = {10.1111/j.1076-7460.2004.02120.x}, author = {Chaves, Paulo H M and Kuller, Lewis H and O{\textquoteright}Leary, Daniel H and Manolio, Teri A and Newman, Anne B} } @article {802, title = {Survival associated with two sets of diagnostic criteria for congestive heart failure.}, journal = {Am J Epidemiol}, volume = {160}, year = {2004}, month = {2004 Oct 01}, pages = {628-35}, abstract = {

Congestive heart failure (CHF) definitions vary across epidemiologic studies. The Framingham Heart Study criteria include CHF signs and symptoms assessed by a physician panel. In the Cardiovascular Health Study, a committee of physicians adjudicated CHF diagnoses, confirmed by signs, symptoms, clinical tests, and/or medical therapy. The authors used data from the Cardiovascular Health Study, a population-based cohort study of 5,888 elderly US adults, to compare CHF incidence and survival patterns following onset of CHF as defined by Framingham and/or Cardiovascular Health Study criteria. They constructed an inception cohort of nonfatal, hospitalized CHF patients. Of 875 participants who had qualifying CHF hospitalizations between 1989 and 2000, 54\% experienced a first CHF event that fulfilled both sets of diagnostic criteria (concordant), 31\% fulfilled only the Framingham criteria (Framingham only), and 15\% fulfilled only the Cardiovascular Health Study criteria (Cardiovascular Health Study only). No significant survival difference was found between the Framingham-only group (hazard ratio = 0.87, 95\% confidence interval: 0.71, 1.07) or the Cardiovascular Health Study-only group (hazard ratio = 0.89, 95\% confidence interval: 0.68, 1.15) and the concordant group (referent). Compared with Cardiovascular Health Study central adjudication, Framingham criteria for CHF identified a larger group of participants with incident CHF, but all-cause mortality rates were similar across these diagnostic classifications.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Diagnosis, Differential, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Prognosis, Severity of Illness Index, Survival Analysis}, issn = {0002-9262}, doi = {10.1093/aje/kwh268}, author = {Schellenbaum, Gina D and Rea, Thomas D and Heckbert, Susan R and Smith, Nicholas L and Lumley, Thomas and Roger, Veronique L and Kitzman, Dalane W and Taylor, Herman A and Levy, Daniel and Psaty, Bruce M} } @article {858, title = {Sleepiness in patients with moderate to severe sleep-disordered breathing.}, journal = {Sleep}, volume = {28}, year = {2005}, month = {2005 Apr}, pages = {472-7}, abstract = {

BACKGROUND: Population-based studies suggest that complaints of sleepiness are absent in many individuals with sleep-disordered breathing. We investigated the prevalence of sleepiness as well as factors associated with sleepiness in individuals with moderate to severe sleep-disordered breathing (apnea-hypopnea index > or = 15).

DESIGN: Cross-sectional study.

SETTING: The Sleep Heart Health Study.

PARTICIPANTS: Sleep Heart Health Study participants (N = 6440).

MEASUREMENTS AND RESULTS: Sleepiness was defined as an Epworth Sleepiness Scale score >10 or a report of at least frequently feeling unrested or sleepy. Forty-six percent of participants with moderate to severe sleep-disordered breathing (n = 1149) reported sleepiness. Characteristics associated with sleepiness after adjustment for confounders included presence of respiratory disease, shorter self-reported weekday and weekend sleep, sleep durations, complaints of insufficient sleep, complaints of sleep maintenance insomnia, early morning awakening, habitual snoring, and complaints of awakening with leg cramps or leg jerks. Some respiratory polysomnography measures were associated with sleepiness, but sleep-stage percentages and measures of sleep disruption were not.

CONCLUSIONS: In this community-based cohort, subjective sleepiness is absent in many individuals with significant sleep-disordered breathing. Comorbid conditions, including respiratory disease, sleep restriction, insomnia, and nocturnal leg complaints, are important risk factors for sleepiness in individuals with moderate to severe sleep-disordered breathing.

}, keywords = {Aged, Body Mass Index, Cohort Studies, Cross-Sectional Studies, Disorders of Excessive Somnolence, Female, Humans, Male, Middle Aged, Oxygen, Polysomnography, Prevalence, Risk Factors, Severity of Illness Index, Sleep Apnea Syndromes, Sleep Arousal Disorders, Sleep Stages, Surveys and Questionnaires}, issn = {0161-8105}, doi = {10.1093/sleep/28.4.472}, author = {Kapur, Vishesh K and Baldwin, Carol M and Resnick, Helaine E and Gottlieb, Daniel J and Nieto, F Javier} } @article {859, title = {Sometimes higher heart rate variability is not better heart rate variability: results of graphical and nonlinear analyses.}, journal = {J Cardiovasc Electrophysiol}, volume = {16}, year = {2005}, month = {2005 Sep}, pages = {954-9}, abstract = {

OBJECTIVE: To determine the prevalence and effect on traditional heart rate variability (HRV) indices of abnormal HRV patterns in the elderly.

METHODS: Hourly Poincar{\'e} plots and plots of spectral HRV from normal-to-normal interbeat intervals and hourly nonlinear HRV values were examined in a subset of 290 consecutive participants in the Cardiovascular Health Study. Only subjects in normal sinus rhythm with > or = 18 hours of usable data were included. Eligible subjects were 71 +/- 5 years. During 7 years of follow-up, 21.7\% had died. Hours were scored as normal (0), borderline (0.5), or abnormal (1) from a combination of plot appearance and HRV. Summed scores were normalized to 100\% to create an abnormality score (ABN). Short-term HRV versus each 5th percentile of ABN was plotted and a cutpoint for markedly increased HRV identified. The t-tests compared HRV for subjects above and below this cutpoint. Cox regression evaluated the association of ABN and mortality.

RESULTS: Of 5,815 eligible hourly plots, 64.4\% were normal, 14.5\% borderline, and 21.1\% abnormal. HR, SDNN, SDNNIDX, ln VLF and LF power, and power law slope did not differ by the cutpoint for increased short-term HRV, while SDANN and ln ULF power were significantly lower for those above the cutpoint. However, many HRV indices including LF/HF ratio and normalized LF and HF power were significantly different between groups (P < 0.001). Increased ABN was significantly associated with mortality (P = 0.019). Despite similar values for many HRV indices, being in the group above the cutpoint was significantly associated with mortality (P = 0.04).

CONCLUSIONS: Abnormal HR patterns that elevate many HRV indices are prevalent among the elderly and associated with higher risk of mortality. Consideration of abnormal HRV may improve HRV-based risk stratification.

}, keywords = {Aged, Aged, 80 and over, Algorithms, Arrhythmia, Sinus, Cohort Studies, Diagnosis, Computer-Assisted, Electrocardiography, Female, Heart Rate, Humans, Male, Models, Cardiovascular, Nonlinear Dynamics, Numerical Analysis, Computer-Assisted, Prevalence, Proportional Hazards Models, Reproducibility of Results, Risk Assessment, Risk Factors, Sensitivity and Specificity, United States}, issn = {1045-3873}, doi = {10.1111/j.1540-8167.2005.40788.x}, author = {Stein, Phyllis K and Domitrovich, Peter P and Hui, Nelson and Rautaharju, Pentti and Gottdiener, John} } @article {846, title = {Statin use and the risk of incident dementia: the Cardiovascular Health Study.}, journal = {Arch Neurol}, volume = {62}, year = {2005}, month = {2005 Jul}, pages = {1047-51}, abstract = {

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk through mechanisms that might affect the development of dementia.

OBJECTIVE: To evaluate whether statin use is associated with a lower risk of dementia compared with never use of lipid-lowering agents (LLAs).

DESIGN: Cohort study of community-dwelling adults 65 years and older. The analysis included 2798 participants free of dementia at baseline.

MAIN OUTCOME MEASURES: Using Cox proportional hazards regression analysis, we estimated the risk of incident all-cause and type-specific dementia associated with time-dependent statin therapy compared with never use of LLAs. The primary analyses incorporated a 1-year lag between exposure and outcome. Secondary analyses included the final year of exposure and modeled statin use as current use vs nonuse to simulate a case-control approach.

RESULTS: Compared with never use of LLAs, ever use of statins was not associated with the risk of all-cause dementia (multivariable-adjusted hazard ratio [HR], 1.08; 95\% confidence interval [CI], 0.77-1.52), Alzheimer disease alone (HR, 1.21; 95\% CI, 0.76-1.91), mixed Alzheimer disease and vascular dementia (HR, 0.87; 95\% CI, 0.44-1.72), or vascular dementia alone (HR, 1.36; 95\% CI, 0.61-3.06). In contrast, in secondary analyses, current use of statins compared with nonuse of LLAs was associated with HRs of 0.69 (95\% CI, 0.46-1.02) for all-cause dementia and 0.56 (95\% CI, 0.35-0.92) for any Alzheimer disease.

CONCLUSIONS: In this cohort study, statin therapy was not associated with a decreased risk of dementia. Methodological differences may explain why results of this cohort investigation differ from those of prior case-control studies. Additional investigation is needed to determine whether and for whom statin use may affect dementia risk.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, Dementia, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Male}, issn = {0003-9942}, doi = {10.1001/archneur.62.7.1047}, author = {Rea, Thomas D and Breitner, John C and Psaty, Bruce M and Fitzpatrick, Annette L and Lopez, Oscar L and Newman, Anne B and Hazzard, William R and Zandi, Peter P and Burke, Gregory L and Lyketsos, Constantine G and Bernick, Charles and Kuller, Lewis H} } @article {869, title = {Statins and cognitive function in the elderly: the Cardiovascular Health Study.}, journal = {Neurology}, volume = {65}, year = {2005}, month = {2005 Nov 08}, pages = {1388-94}, abstract = {

OBJECTIVE: To examine the association of statin drug use on cognitive and MRI change in older adults.

METHODS: Participants in the Cardiovascular Health Study, a longitudinal study of people age 65 or older, were classified into three groups determined by whether they were taking statin drugs on a continuous basis, intermittently, or not at all. The untreated group was further divided into categories based on National Cholesterol Education Program recommendations for lipid-lowering treatment. Participants with prevalent or incident clinical TIA or stroke or with baseline Modified Mini-Mental State Examination (3MS) scores at or below 80 were excluded. Outcomes examined included rate of change on the 3MS over an average observational period of 7 years, along with changes in MRI white matter grade and measures of atrophy.

RESULTS: Three thousand three hundred thirty-four participants had adequate data for analysis. At baseline, the untreated group in which lipid-lowering drug treatment was recommended were slightly older, less likely to be on estrogen replacement, and had higher serum cholesterol and lower 3MS scores than the statin-treated group. The rate of decline on the 3MS was 0.48 point/year less in those taking statins compared with the untreated group for which treatment was recommended (p = 0.069) and 0.49 point/year less in statin users compared with the group in which lipid-lowering treatment was not recommended (p = 0.009). This effect remained after controlling for serum cholesterol levels. One thousand seven hundred thirty participants with baseline 3MS scores of > 80 underwent cranial MRI scans on two occasions separated by 5 years. There was no significant difference in white matter grade change or atrophy measures between groups.

CONCLUSION: Statin drug use was associated with a slight reduction in cognitive decline in an elderly population. This relationship could not be completely explained by the effect of statins on lowering of serum cholesterol.

}, keywords = {Aged, Aged, 80 and over, Aging, Anticholesteremic Agents, Atrophy, Brain, Cholesterol, Cognition Disorders, Cohort Studies, Dementia, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Longitudinal Studies, Male, Memory Disorders, Nootropic Agents, Treatment Outcome}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000182897.18229.ec}, author = {Bernick, C and Katz, R and Smith, N L and Rapp, S and Bhadelia, R and Carlson, M and Kuller, L} } @article {830, title = {Subclinical brain magnetic resonance imaging abnormalities predict physical functional decline in high-functioning older adults.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Apr}, pages = {649-54}, abstract = {

OBJECTIVES: To determine whether severity of subclinical brain magnetic resonance imaging (MRI) abnormalities predicts incident self-reported physical impairment or rate of decline in motor performance.

DESIGN: Longitudinal analysis, average follow-up time: 4.0 years.

SETTING: Cardiovascular Health Study (CHS).

PARTICIPANTS: CHS participants with modified Mini-Mental State Examination (3MS) score of 80 or greater, no self-reported disability, no history of stroke, and at least one assessment of mobility (n=2,450, mean age=74.4).

MEASUREMENTS: Brain MRI abnormalities (ventricular enlargement, white matter hyperintensities, subcortical and basal ganglia small brain infarcts), self-reported physical impairment (difficulty walking half a mile or with one or more activities of daily living), and motor performance (gait speed, timed chair stand).

RESULTS: After adjusting for demographics, cardiovascular risk factors, and diseases, risk of incident self-reported physical impairment was 35\% greater for those with severe ventricular enlargement than for those with minimal ventricular enlargement, 22\% greater for those with moderate white matter hyperintensities than for those with minimal white matter hyperintensities, and 26\% greater for participants with at least one brain infarct than for those with no infarcts. Those with moderate to severe brain abnormalities experienced faster gait speed decline (0.02 m/s per year) than those with no MRI abnormalities (0.01 m/s per year). Further adjustment for incident stroke, incident dementia, and 3MS score did not substantially attenuate hazard ratios for incident self-reported physical impairment or coefficients for decline in gait speed.

CONCLUSION: Subclinical structural brain abnormalities in high-functioning older adults can increase the risk of developing physical disabilities and declining in motor performance.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Brain, Female, Follow-Up Studies, Gait, Humans, Incidence, Magnetic Resonance Imaging, Male, Proportional Hazards Models, Psychomotor Disorders, Risk Factors, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53214.x}, author = {Rosano, Caterina and Kuller, Lewis H and Chung, Hyoju and Arnold, Alice M and Longstreth, William T and Newman, Anne B} } @article {823, title = {Survival following dementia onset: Alzheimer{\textquoteright}s disease and vascular dementia.}, journal = {J Neurol Sci}, volume = {229-230}, year = {2005}, month = {2005 Mar 15}, pages = {43-9}, abstract = {

Survival following the onset of dementia has been reported to vary from 3 to over 9 years. We examined mortality in 3602 participants of the Cardiovascular Health (CHS) Cognition Study in four US communities evaluated for dementia incidence between 1992 and 1999 and followed for 6.5 years. By June 2000, 33 of 62 (53.2\%) participants who developed vascular dementia (VaD) had died compared to 79 of 245 (32.2\%) with Alzheimer{\textquoteright}s disease (AD), 66 of 151 (43.7\%) with both AD and VaD, and 429 of 2318 (18.5\%) with normal cognition. Using Cox proportional hazards regression with a time-dependent covariate for dementia status adjusted for age, gender and race, individuals with VaD were more than four times as likely to die during follow-up than those with normal cognition (HR: 4.4, 95\% CI: 3.1-6.3). The hazard ratios were 2.1 (95\% CI: 1.6-2.7) for AD and 2.5 (95\% CI: 1.9-3.3) for both types. Adjusted accelerated life models estimated median survival from dementia onset to death as 3.9 years for those with VaD, 7.1 years for AD, 5.4 years for mixed dementia, and 11.0 years for matched controls with normal cognition. While persons with VaD died primarily from cerebrovascular disease, those with AD/mixed dementia died more frequently from dementia/failure to thrive.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Brain, Capillaries, Cerebral Amyloid Angiopathy, Cerebrovascular Circulation, Cerebrovascular Disorders, Female, Frontal Lobe, Humans, Male, Middle Aged, Prospective Studies}, issn = {0022-510X}, doi = {10.1016/j.jns.2004.11.022}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Lopez, Oscar L and Kawas, Claudia H and Jagust, William} } @article {849, title = {The sensitivity and specificity of markers for event times.}, journal = {Biostatistics}, volume = {7}, year = {2006}, month = {2006 Apr}, pages = {182-97}, abstract = {

The statistical literature on assessing the accuracy of risk factors or disease markers as diagnostic tests deals almost exclusively with settings where the test, Y, is measured concurrently with disease status D. In practice, however, disease status may vary over time and there is often a time lag between when the marker is measured and the occurrence of disease. One example concerns the Framingham risk score (FR-score) as a marker for the future risk of cardiovascular events, events that occur after the score is ascertained. To evaluate such a marker, one needs to take the time lag into account since the predictive accuracy may be higher when the marker is measured closer to the time of disease occurrence. We therefore consider inference for sensitivity and specificity functions that are defined as functions of time. Semiparametric regression models are proposed. Data from a cohort study are used to estimate model parameters. One issue that arises in practice is that event times may be censored. In this research, we extend in several respects the work by Leisenring et al. (1997) that dealt only with parametric models for binary tests and uncensored data. We propose semiparametric models that accommodate continuous tests and censoring. Asymptotic distribution theory for parameter estimates is developed and procedures for making statistical inference are evaluated with simulation studies. We illustrate our methods with data from the Cardiovascular Health Study, relating the FR-score measured at enrollment to subsequent risk of cardiovascular events.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Biometry, Cardiovascular Diseases, Female, Humans, Male, Models, Statistical, Risk Factors, ROC Curve, Sensitivity and Specificity, Time Factors}, issn = {1465-4644}, doi = {10.1093/biostatistics/kxi047}, author = {Cai, Tianxi and Pepe, Margaret Sullivan and Zheng, Yingye and Lumley, Thomas and Jenny, Nancy Swords} } @article {926, title = {Sleep apnea in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the Sleep Heart Health Study.}, journal = {J Am Soc Nephrol}, volume = {17}, year = {2006}, month = {2006 Dec}, pages = {3503-9}, abstract = {

Sleep-disordered breathing (SDB) has been noted commonly in hemodialysis (HD) patients, but it is not known whether this is related directly to the treatment of kidney failure with HD or to the higher prevalence of obesity and older age. Forty-six HD patients were compared with 137 participants from the Sleep Heart Health Study (SHHS) who were matched for age, gender, body mass index (BMI), and race. Home unattended polysomnography was performed and scored using similar protocols. The study sample was 62.7 +/- 10.1 yr, was predominantly male (72\%) and white (63\%), and had an average BMI of 28 +/- 5.3 kg/m(2). The HD sample had a higher systolic BP (137 versus 121 mmHg; P < 0.01) and a higher prevalence of diabetes (33 versus 9\%; P < 0.01) and cardiovascular disease (33 versus 13\%; P < 0.01) compared with the SHHS sample. The HD group had significantly less sleep time (320 versus 379 min; P < 0.0001) but similar sleep efficiency. HD patients had a higher frequency of arousals per hour (25.1 versus 17.1; P < 0.0001) and apnea-hypopneas per hour (27.2 versus 15.2; P < 0.0001) and greater percentage of the total sleep time below an oxygen saturation of 90\% (7.2 versus 1.8; P < 0.0001). HD patients were more likely to have severe SDB (>30 respiratory events per hour) compared with the SHHS sample (odds ratio 4.07; 95\% confidence interval 1.83 to 9.07). There was a strong association of HD with severe SDB and nocturnal hypoxemia independent of age, BMI, and the higher prevalence of chronic disease. The potential mechanisms for the higher likelihood of SDB in the HD population must be identified to provide specific prevention and therapy.

}, keywords = {Blood Pressure, Body Mass Index, Cardiovascular Diseases, Case-Control Studies, Cross-Sectional Studies, Diabetes Mellitus, Female, Humans, Kidney Failure, Chronic, Male, Middle Aged, Prevalence, Renal Dialysis, Severity of Illness Index, Sleep Apnea Syndromes}, issn = {1046-6673}, doi = {10.1681/ASN.2006060659}, author = {Unruh, Mark L and Sanders, Mark H and Redline, Susan and Piraino, Beth M and Umans, Jason G and Hammond, Terese C and Sharief, Imran and Punjabi, Naresh M and Newman, Anne B} } @article {880, title = {Soluble intracellular adhesion molecule-1 is associated with cardiovascular disease risk and mortality in older adults.}, journal = {J Thromb Haemost}, volume = {4}, year = {2006}, month = {2006 Jan}, pages = {107-13}, abstract = {

BACKGROUND: Intracellular adhesion molecule-1 (ICAM-1) regulates leukocyte-endothelial attachment, a process crucial to atherosclerosis. Circulating soluble ICAM-1 (sICAM-1) may serve as a marker of cardiovascular disease (CVD) progression.

OBJECTIVES: We examined the association of sICAM-1 with measures of subclinical CVD and risk of incident CVD events and death in older men and women (age > or = 65 years) from the Cardiovascular Health Study.

METHODS: Selected participants were free of clinical CVD at baseline. Non-exclusive incident case groups were angina (n = 534), myocardial infarction (n = 304), stroke (n = 327), and death (n = 842; CVD death = 310). A total 643 subjects were free of events during follow-up.

RESULTS: sICAM-1 was positively associated with C-reactive protein, interleukin-6 and fibrinogen and measures of subclinical CVD in these older men and women. In Cox regression models adjusted for age, gender, and race, increasing levels of sICAM-1 were associated with increased risk of all cause mortality in men and women. Hazard ratios (95\% confidence intervals) for a one standard deviation increase in sICAM-1 (89.7 ng mL(-1)) were 1.3 (1.1-1.4) in men and 1.2 (1.1-1.3) in women. sICAM-1 was associated with increased risk of CVD death in women (1.2; 1.0-1.5), but not men (1.1; 0.9-1.3). There were no associations of sICAM-1 with non-fatal CVD events.

CONCLUSIONS: While sICAM-1 was associated with death in older men and women, there was a more marked association between sICAM-1 and CVD death in women.

}, keywords = {Aged, Aged, 80 and over, Angina Pectoris, Biomarkers, Cardiovascular Diseases, Female, Humans, Incidence, Intercellular Adhesion Molecule-1, Male, Mortality, Myocardial Infarction, Regression Analysis, Risk Factors, Sex Factors, Solubility, Stroke}, issn = {1538-7933}, doi = {10.1111/j.1538-7836.2005.01678.x}, author = {Jenny, N S and Arnold, A M and Kuller, L H and Sharrett, A R and Fried, L P and Psaty, B M and Tracy, R P} } @article {916, title = {Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {4}, year = {2006}, month = {2006 Sep}, pages = {1903-8}, abstract = {

BACKGROUND: Recent reports have suggested an association of atherosclerosis with risk of venous thrombosis.

OBJECTIVE: To confirm whether subclinical atherosclerosis is a risk factor for venous thrombosis (VT) among men and women age 65 and older.

METHODS: Participants of the Cardiovascular Health Study (n = 4,108) without baseline clinical cardiovascular disease, anticoagulant use or previous VT were followed for a median of 11.7 years after non-invasive assessment of subclinical atherosclerosis using carotid ultrasound (intima-media thickness and presence of plaques), ankle-brachial blood pressure index and electrocardiogram. Each event was classified as idiopathic or secondary. We used Cox proportional hazards regression to estimate the relative risk of overall and idiopathic VT for individuals with and without baseline subclinical atherosclerosis.

RESULTS: There were 133 first time VT events. No subclinical atherosclerosis measures were associated with increased risk of overall or idiopathic VT. The adjusted relative risks of overall and idiopathic VT for presence of any type of subclinical disease were 0.60 (95\% confidence interval 0.39-0.91) and 0.32 (0.18-0.59), respectively. Most of this association was explained by an inverse association of high-risk carotid plaques (prevalent in 54\% of those at risk) with VT.

CONCLUSION: Non-invasively measured subclinical atherosclerosis was not associated with increased risk of overall or idiopathic VT in this observational study. Carotid plaques and arterial events during follow up were inversely associated, a finding that requires further study.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Carotid Artery Thrombosis, Cohort Studies, Female, Humans, Male, Proportional Hazards Models, Risk Factors, Ultrasonography, Venous Thrombosis}, issn = {1538-7933}, doi = {10.1111/j.1538-7836.2006.02096.x}, author = {van der Hagen, P B and Folsom, A R and Jenny, N S and Heckbert, S R and O{\textquoteright}Meara, E S and Reich, L M and Rosendaal, F R and Cushman, M} } @article {930, title = {Serum amyloid P and cardiovascular disease in older men and women: results from the Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {27}, year = {2007}, month = {2007 Feb}, pages = {352-8}, abstract = {

OBJECTIVE: Serum amyloid P (SAP), a pentraxin like C-reactive protein (CRP), functions in innate immunity. However, associations of SAP with cardiovascular disease (CVD) are unknown.

METHODS AND RESULTS: We examined these associations in the Cardiovascular Health Study using a case-cohort design. Nonexclusive case groups were incident angina (n=523), myocardial infarction (MI; n=308), stroke (n=323), and CVD death (n=288). 786 participants had no events. SAP was correlated with CRP, CVD risk factors (obesity, blood pressure, lipids), common and internal carotid wall thickness, and ankle-brachial index (all P<0.02). In Cox regression models adjusted for age, sex, and ethnicity, a standard deviation increase in SAP (9.8 mg/L) was associated with angina (hazard ratio; 95\% confidence interval 1.3; 1.2 to 1.5) and MI (1.3; 1.1 to 1.5), but not stroke (1.1; 0.9 to 1.3) or CVD death (1.1; 0.9 to 1.3). Adding CRP to the models had no significant effect on associations. Adjusting for CVD risk factors slightly attenuated SAP associations with CVD events; however, associations with angina and MI remained significant.

CONCLUSIONS: Although both are pentraxins, SAP and CRP may represent different facets of inflammation. The association of SAP with CVD in these older adults further supports the role of innate immunity in atherosclerosis.

}, keywords = {Aged, Aged, 80 and over, Aging, Angina, Unstable, Atherosclerosis, C-Reactive Protein, Cardiovascular Diseases, Case-Control Studies, Female, Humans, Hypertension, Immunity, Innate, Male, Myocardial Infarction, Obesity, Prevalence, Proportional Hazards Models, Risk Factors, Serum Amyloid P-Component}, issn = {1524-4636}, doi = {10.1161/01.ATV.0000254150.97741.fe}, author = {Jenny, Nancy Swords and Arnold, Alice M and Kuller, Lewis H and Tracy, Russell P and Psaty, Bruce M} } @article {963, title = {Socioeconomic position and incident mobility impairment in the Cardiovascular Health Study.}, journal = {BMC Geriatr}, volume = {7}, year = {2007}, month = {2007 May 10}, pages = {11}, abstract = {

BACKGROUND: We investigated if personal socioeconomic position (SEP) factors and neighborhood characteristics were associated with incident mobility impairment in the elderly.

METHODS: We used data from the Cardiovascular Health Study, a longitudinal, population-based examination of coronary heart disease and stroke among persons aged 65 and older in the United States.

RESULTS: Among 3,684 persons without baseline mobility impairment, lower baseline SEP was associated with increased risk of incident mobility disability during the 10-year follow-up period, although the strengths of these associations varied by socioeconomic indicator and race/sex group.

CONCLUSION: Among independent-living elderly, SEP affected development of mobility impairment into later life. Particular effort should be made to prevent or delay its onset among the elderly with low income, education, and/or who live in economically disadvantaged neighborhoods.

}, keywords = {Aged, Aged, 80 and over, Coronary Disease, Disabled Persons, Education, Female, Follow-Up Studies, Humans, Incidence, Longitudinal Studies, Male, Mobility Limitation, Residence Characteristics, Social Class, Stroke, United States}, issn = {1471-2318}, doi = {10.1186/1471-2318-7-11}, author = {Nordstrom, Cheryl K and Diez Roux, Ana V and Schulz, Richard and Haan, Mary N and Jackson, Sharon A and Balfour, Jennifer L} } @article {1051, title = {Sleep disordered breathing and hypertension: does self-reported sleepiness modify the association?}, journal = {Sleep}, volume = {31}, year = {2008}, month = {2008 Aug}, pages = {1127-32}, abstract = {

STUDY OBJECTIVES: Epidemiologic studies that demonstrate increased risk of hypertension in persons with sleep disordered breathing indicate that only a minority of these persons report significant subjective sleepiness. Studies also suggest that presence of self-reported sleepiness may identify a subset of persons with sleep disordered breathing who are at greatest risk of cardiovascular sequelae, including hypertension. We explore whether self-reported sleepiness modifies the relationship between sleep disordered breathing and prevalent hypertension.

DESIGN: Cross-sectional.

SETTING: Multicenter study.

PARTICIPANTS: 6046 subjects from the Sleep Heart Health Study.

MEASUREMENTS: Polysomnography, systolic and diastolic blood pressure, antihypertensive medication use, questionnaire determined excessive sleepiness and Epworth Sleepiness Scale, and covariates.

RESULTS: The odds of hypertension at higher apnea hypopnea index categories were larger in participants identified as sleepy based on responses to a frequency of sleepiness question or the Epworth score. For example, for those with AHI > or =30 compared to AHI <1.5, the adjusted odds ratio for hypertension was 2.83 (1.33-6.04) among those reporting sleepiness > or =5 days per month, but only 1.22 (0.89-1.68) among those reporting less frequent daytime sleepiness. In adjusted logistic regression models, there was statistical evidence for effect modification by frequency of sleepiness (P = 0.033) of the association between apnea hypopnea index and hypertension. In adjusted models that included the Epworth score as a continuous variable, the interaction term fell slightly short of statistical significance (beta = 0.010, P = 0.07).

CONCLUSION: This study finds that the association of sleep disordered breathing with hypertension is stronger in individuals who report daytime sleepiness than in those who do not.

}, keywords = {Aged, Antihypertensive Agents, Comorbidity, Cross-Sectional Studies, Disorders of Excessive Somnolence, Female, Health Surveys, Humans, Hypertension, Male, Middle Aged, Odds Ratio, Oxygen, Polysomnography, Sleep Apnea, Obstructive, United States}, issn = {0161-8105}, author = {Kapur, Vishesh K and Resnick, Helaine E and Gottlieb, Daniel J} } @article {1018, title = {Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas.}, journal = {Am J Respir Crit Care Med}, volume = {177}, year = {2008}, month = {2008 May 15}, pages = {1150-5}, abstract = {

RATIONALE: Epidemiologic studies on the consequences of sleep-disordered breathing invariably use the apnea-hypopnea index as the primary measure of disease severity. Although hypopneas constitute a majority of disordered breathing events, significant controversy remains about the best criteria used to define these events.

OBJECTIVES: The current investigation sought to assess the most appropriate definition for hypopneas that would be best correlated with cardiovascular disease.

METHODS: A community sample of middle-aged and older adults was recruited as part of the Sleep Heart Health Study. Full-montage polysomnography was conducted and hypopneas were defined using different thresholds of oxyhemoglobin desaturation with and without arousals. Prevalent cardiovascular disease was assessed based on self-report. Logistic regression analysis was used to characterize the independent association between the hypopnea index and prevalent cardiovascular disease.

MEASUREMENTS AND MAIN RESULTS: Using a sample of 6,106 adults with complete data on cardiovascular disease status and polysomnography, the current study found that hypopneas associated with an oxyhemoglobin desaturation of 4\% or more were associated with prevalent cardiovascular disease independent of confounding covariates. The adjusted prevalent odds ratios for quartiles of the hypopnea index using a 4\% desaturation criterion were as follows: 1.00 (<1.10 events/h), 1.10 (1.01-3.20 events/h), 1.33 (3.21-7.69 events/h), and 1.41 (>7.69 events/h). Hypopnea measures based on less than 4\% oxyhemoglobin desaturation or presence of arousals showed no association with cardiovascular disease.

CONCLUSIONS: Hypopneas comprise a significant component of sleep-disordered breathing in the general community. By varying the criteria for defining hypopneas, this study demonstrates that hypopneas with a desaturation of at least 4\% are independently associated with cardiovascular disease. In contrast, no association was observed between cardiovascular disease and hypopneas associated with milder desaturations or arousals.

}, keywords = {Aged, Apnea, Cardiovascular Diseases, Cohort Studies, Female, Humans, Male, Middle Aged, Odds Ratio, Oxyhemoglobins, Polysomnography, Sleep Apnea Syndromes, Terminology as Topic}, issn = {1535-4970}, doi = {10.1164/rccm.200712-1884OC}, author = {Punjabi, Naresh M and Newman, Anne B and Young, Terry B and Resnick, Helaine E and Sanders, Mark H} } @article {1016, title = {Sleep-disordered breathing and impaired glucose metabolism in normal-weight and overweight/obese individuals: the Sleep Heart Health Study.}, journal = {Diabetes Care}, volume = {31}, year = {2008}, month = {2008 May}, pages = {1001-6}, abstract = {

OBJECTIVE: To characterize the association between sleep-disordered breathing (SDB) and impaired fasting glucose (IFG), impaired glucose tolerance (IGT), combined IFG and IGT, and occult diabetes in individuals of different body habitus.

RESEARCH DESIGN AND METHODS: Cross-sectional analysis of 2,588 participants (aged 52-96 years; 46\% men) without known diabetes. SDB was defined as respiratory disturbance index >or=10 events/h. IFG, IGT, occult diabetes, and body weight were classified according to recent accepted guidelines. Participants with and without SDB were compared on prevalence and odds ratios for measures of impaired glucose metabolism (IGM), adjusting for age, sex, race, BMI, and waist circumference.

RESULTS: SDB was observed in 209 nonoverweight and 1,036 overweight/obese participants. SDB groups had significantly higher adjusted prevalence and adjusted odds of IFG, IFG plus IGT, and occult diabetes. The adjusted odds ratio for all subjects was 1.3 (95\% CI 1.1-1.6) for IFG, 1.2 (1.0-1.4) for IGT, 1.4 (1.1-2.7) for IFG plus IGT, and 1.7 (1.1-2.7) for occult diabetes.

CONCLUSIONS: SDB was associated with occult diabetes, IFG, and IFG plus IGT, after adjusting for age, sex, race, BMI, and waist circumference. The magnitude of these associations was similar in nonoverweight and overweight participants. The consistency of associations across all measures of IGM and body habitus groups and the significant association between SDB and IFG plus IGT, a risk factor for rapid progression to diabetes, cardiovascular disease, and mortality, suggests the importance of SDB as a risk factor for clinically important levels of metabolic dysfunction.

}, keywords = {Aged, Aged, 80 and over, Body Weight, Cardiovascular Diseases, Cross-Sectional Studies, Female, Glucose Intolerance, Glucose Tolerance Test, Humans, Male, Middle Aged, Obesity, Overweight, Polysomnography, Reference Values, Sleep Wake Disorders}, issn = {1935-5548}, doi = {10.2337/dc07-2003}, author = {Seicean, Sinziana and Kirchner, H Lester and Gottlieb, Daniel J and Punjabi, Naresh M and Resnick, Helaine and Sanders, Mark and Budhiraja, Rohit and Singer, Mendel and Redline, Susan} } @article {970, title = {Stance time and step width variability have unique contributing impairments in older persons.}, journal = {Gait Posture}, volume = {27}, year = {2008}, month = {2008 Apr}, pages = {431-9}, abstract = {

Gait variability may have multiple causes. We hypothesized that central nervous system (CNS) impairments would affect motor control and be manifested as increased stance time and step length variability, while sensory impairments would affect balance and be manifested as increased step width variability. Older adults (mean+/-standard deviation (S.D.) age=79.4+/-4.1, n=558) from the Pittsburgh site of the Cardiovascular Health Study participated. The S.D. across steps was the indicator of gait variability, determined for three gait measures, step length, stance time and step width, using a computerized walkway. Impairment measures included CNS function (modified mini-mental state examination, Trails A and B, Digit Symbol Substitution, finger tapping), sensory function (lower extremity (LE) vibration, vision), strength (grip strength, repeated chair stands), mood, and LE pain. Linear regression models were fit for the three gait variability characteristics using impairment measures as independent variables, adjusted for age, race, gender, and height. Analyses were repeated stratified by gait speed. All measures of CNS impairment were directly related to stance time variability (p<0.01), with increased CNS impairment associated with increased stance time variability. CNS impairments were not related to step length or width variability. Both sensory impairments were inversely related to step width (p<0.01) but not step length or stance time variability. CNS impairments affected stance time variability especially in slow walkers while sensory impairments affected step width variability in fast walkers. Specific patterns of gait variability may imply different underlying causes. Types of gait variability should be specified. Interventions may be targeted at specific types of gait variability.

}, keywords = {Aged, Aged, 80 and over, Biomechanical Phenomena, Female, Gait Disorders, Neurologic, Humans, Linear Models, Longitudinal Studies, Male, Neuropsychological Tests, Postural Balance, Range of Motion, Articular, Risk Factors, Signal Processing, Computer-Assisted}, issn = {0966-6362}, doi = {10.1016/j.gaitpost.2007.05.016}, author = {Brach, Jennifer S and Studenski, Stephanie and Perera, Subashan and VanSwearingen, Jessie M and Newman, Anne B} } @article {1053, title = {Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.}, journal = {J Am Coll Cardiol}, volume = {52}, year = {2008}, month = {2008 Sep 30}, pages = {1152-9}, abstract = {

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities.

BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited.

METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism.

RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95\% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF.

CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Echocardiography, Female, Heart, Heart Failure, Heart Function Tests, Humans, Hyperthyroidism, Hypertrophy, Left Ventricular, Hypothyroidism, Male, Risk Factors, Time Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2008.07.009}, author = {Rodondi, Nicolas and Bauer, Douglas C and Cappola, Anne R and Cornuz, Jacques and Robbins, John and Fried, Linda P and Ladenson, Paul W and Vittinghoff, Eric and Gottdiener, John S and Newman, Anne B} } @article {1041, title = {Subjective and objective sleep quality in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the sleep heart health study.}, journal = {Am J Kidney Dis}, volume = {52}, year = {2008}, month = {2008 Aug}, pages = {305-13}, abstract = {

BACKGROUND: Studies examining sleep in the hemodialysis (HD) population have largely lacked an adequate comparison group. It therefore is uncertain whether poor sleep quality in the HD population reflects age, chronic health conditions, or effects of conventional HD therapy.

STUDY DESIGN: Cross-sectional matched-group study.

SETTING \& PARTICIPANTS: Forty-six in-center HD patients were compared with 137 community participants participating in the Sleep Heart Health Study matched for age, sex, body mass index, and race.

PREDICTOR: HD patients compared with community-dwelling non-HD participants.

OUTCOMES \& MEASUREMENTS: Home unattended polysomnography was performed and scored by using similar protocols. Sleep habits and sleepiness were assessed by using the Sleep Habits Questionnaire and Epworth Sleepiness Scale.

RESULTS: Average age of study samples was 63 years, 72\% were white, and average body mass index was 28 +/- 5 kg/m(2). HD patients were significantly more likely than community participants to have short sleep (odds ratio, 3.27; 95\% confidence interval, 1.16 to 9.25) and decreased sleep efficiency (odds ratio, 5.5; 95\% confidence interval, 1.5 to 19.6). HD patients reported more difficulty getting back to sleep (odds ratio, 2.25; 95\% confidence interval, 1.11 to 4.60) and waking up too early (odds ratio, 2.39; 95\% confidence interval, 1.01 to 5.66). There was no association between polysomnography sleep time and self-reported sleep time (r = 0.09; P = 0.6) or between the Epworth Sleepiness Scale and severity of sleep apnea (r = 0.10; P = 0.5) in the HD population.

LIMITATIONS: The study was limited to participants older than 45 years.

CONCLUSIONS: Kidney failure treated with thrice-weekly HD is significantly associated with poor subjective and objective sleep quality.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cross-Sectional Studies, Disease Progression, Female, Follow-Up Studies, Heart Rate, Humans, Incidence, Kidney Failure, Chronic, Male, Middle Aged, Odds Ratio, Pennsylvania, Polysomnography, Prognosis, Renal Dialysis, Retrospective Studies, Risk Factors, Severity of Illness Index, Sleep, Sleep Apnea Syndromes, Surveys and Questionnaires}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2008.04.019}, author = {Unruh, Mark L and Sanders, Mark H and Redline, Susan and Piraino, Beth M and Umans, Jason G and Chami, Hassan and Budhiraja, Rohit and Punjabi, Naresh M and Buysse, Daniel and Newman, Anne B} } @article {1146, title = {Sibling history of myocardial infarction or stroke and risk of cardiovascular disease in the elderly: the Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {19}, year = {2009}, month = {2009 Dec}, pages = {858-66}, abstract = {

PURPOSE: To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults.

METHODS: Prospective cohort study of 5,888 older adults participating in the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle-brachial index), CVD risk factors differed between groups.

RESULTS: More than 91\% (n = 5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile.

CONCLUSIONS: Sibling history of MI and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention.

}, keywords = {Aged, Atherosclerosis, Female, Genetic Predisposition to Disease, Humans, Incidence, Male, Myocardial Infarction, Odds Ratio, Prevalence, Prospective Studies, Risk Factors, Siblings, Stroke, United States}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2009.07.095}, author = {Yanez, N David and Burke, Gregory L and Manolio, Teri and Gardin, Julius M and Polak, Joseph} } @article {1103, title = {Sleep-disordered breathing and frailty in the Cardiovascular Health Study Cohort.}, journal = {Am J Epidemiol}, volume = {170}, year = {2009}, month = {2009 Jul 15}, pages = {193-202}, abstract = {

Sleep-disordered breathing (SDB) is associated with pathophysiology that may influence the development and progression of frailty. Using data collected in 1995-1996, the authors explored the relation between SDB and components of frailty among 1,042 participants of the Cardiovascular Health Study. Diagnosis of SDB was based on the results of overnight polysomnography, and severe SDB was defined as an apnea-hypopnea index of >30 per hour of sleep. Slow walking speed, low grip strength, exhaustion, low physical activity, and unexplained weight loss were referred to as frailty indicator variables. There were 584 (56\%) female and 458 (44\%) male participants, and the mean age was 77 (standard deviation, 4) years. There was independent association between severe SDB and 1 or more frailty indicator variables (adjusted odds ratio = 4.85, 95\% confidence interval: 1.40, 16.78), slow walking speed (adjusted odds ratio = 2.67, 95\% confidence interval: 1.04, 6.84), and low grip strength (adjusted odds ratio = 3.29, 95\% confidence interval: 1.36, 7.96) among female study participants. The finding of an independent association between SDB and frailty indicator variables among older women could have important implications in interventions aimed at preventing or delaying the progression of frailty.

}, keywords = {Activities of Daily Living, Aged, Cardiovascular Diseases, Cardiovascular System, Cohort Studies, Confidence Intervals, Exercise Tolerance, Female, Frail Elderly, Hand Strength, Humans, Logistic Models, Male, Mobility Limitation, Models, Statistical, Motor Activity, Muscle Strength, Odds Ratio, Polysomnography, Psychometrics, Risk Factors, Sleep Apnea, Obstructive, Weight Loss}, issn = {1476-6256}, doi = {10.1093/aje/kwp108}, author = {Endeshaw, Yohannes W and Unruh, Mark L and Kutner, Michael and Newman, Anne B and Bliwise, Donald L} } @article {1122, title = {Sleep-disordered breathing and mortality: a prospective cohort study.}, journal = {PLoS Med}, volume = {6}, year = {2009}, month = {2009 Aug}, pages = {e1000132}, abstract = {

BACKGROUND: Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

METHODS AND FINDINGS: We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea-hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0-14.9 events/h), moderate (AHI: 15.0-29.9 events/h), and severe (AHI: >or=30.0 events/h) sleep-disordered breathing were 0.93 (95\% CI: 0.80-1.08), 1.17 (95\% CI: 0.97-1.42), and 1.46 (95\% CI: 1.14-1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40-70 y (hazard ratio: 2.09; 95\% CI: 1.31-3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease-related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

CONCLUSIONS: Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40-70 y with severe sleep-disordered breathing. Please see later in the article for the Editors{\textquoteright} Summary.

}, keywords = {Aged, Coronary Artery Disease, Female, Humans, Hypoxia, Male, Middle Aged, Odds Ratio, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors, Sleep Apnea Syndromes, Survival Analysis}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1000132}, author = {Punjabi, Naresh M and Caffo, Brian S and Goodwin, James L and Gottlieb, Daniel J and Newman, Anne B and O{\textquoteright}Connor, George T and Rapoport, David M and Redline, Susan and Resnick, Helaine E and Robbins, John A and Shahar, Eyal and Unruh, Mark L and Samet, Jonathan M} } @article {1102, title = {Spousal suffering and partner{\textquoteright}s depression and cardiovascular disease: the Cardiovascular Health Study.}, journal = {Am J Geriatr Psychiatry}, volume = {17}, year = {2009}, month = {2009 Mar}, pages = {246-54}, abstract = {

OBJECTIVES: To assess the effects of suffering in a spouse on prevalent and incident psychiatric (depression) and physical morbidity (cardiovascular disease [CVD]) in their partner, controlling for known risk factors for depression and CVD.

DESIGN: Descriptive longitudinal study.

PARTICIPANTS: A total of 1,330 older married couples enrolled in the Cardiovascular Health Study, a large epidemiologic study of the elderly.

MEASUREMENTS: Predictor variables were physical, psychological, and existential/spiritual indicators of suffering. Primary outcomes were prevalent and incident depression and CVD.

RESULTS: Controlling for known risk factors for depression, the authors found a dose-response relationship between suffering in a spouse and concurrent depression in their partner as well as a relationship between suffering and the partner{\textquoteright}s future risk for depression. With respect to CVD, and controlling for subclinical CVD at baseline, husbands whose wives reported high levels of suffering also had higher rates of prevalent CVD, but there were no significant associations between wives suffering and husbands incident CVD. There were no associations between husbands{\textquoteright} suffering and wives{\textquoteright} prevalent or incident CVD.

CONCLUSION: Exposure to spousal suffering is an independent and unique source of distress in married couples that contributes to psychiatric and physical morbidity. More attention should be paid to the interpersonal effects of suffering in married couples and to its role in contributing to morbidity.

}, keywords = {Activities of Daily Living, Aged, Cardiovascular Diseases, Caregivers, Depression, Female, Follow-Up Studies, Humans, Incidence, Logistic Models, Longitudinal Studies, Male, Prevalence, Risk Factors, Socioeconomic Factors, Spouses, Stress, Psychological, Surveys and Questionnaires}, issn = {1545-7214}, doi = {10.1097/JGP.0b013e318198775b}, author = {Schulz, Richard and Beach, Scott R and Hebert, Randy S and Martire, Lynn M and Monin, Joan K and Tompkins, Connie A and Albert, Steven M} } @article {1079, title = {Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.}, journal = {Stat Med}, volume = {28}, year = {2009}, month = {2009 Apr 15}, pages = {1218-37}, abstract = {

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

}, keywords = {Cohort Studies, Computer Simulation, Coronary Disease, Data Interpretation, Statistical, Female, Fibrinogen, Humans, Male, Meta-Analysis as Topic, Models, Statistical}, issn = {0277-6715}, doi = {10.1002/sim.3540}, author = {Jackson, Dan and White, Ian and Kostis, J B and Wilson, A C and Folsom, A R and Wu, K and Chambless, L and Benderly, M and Goldbourt, U and Willeit, J and Kiechl, S and Yarnell, J W G and Sweetnam, P M and Elwood, P C and Cushman, M and Psaty, B M and Tracy, R P and Tybjaerg-Hansen, A and Haverkate, F and de Maat, M P M and Thompson, S G and Fowkes, F G R and Lee, A J and Smith, F B and Salomaa, V and Harald, K and Rasi, V and Vahtera, E and Jousilahti, P and D{\textquoteright}Agostino, R and Kannel, W B and Wilson, P W F and Tofler, G and Levy, D and Marchioli, R and Valagussa, F and Rosengren, A and Wilhelmsen, L and Lappas, G and Eriksson, H and Cremer, P and Nagel, D and Curb, J D and Rodriguez, B and Yano, K and Salonen, J T and Nyyss{\"o}nen, K and Tuomainen, T-P and Hedblad, B and Engstrom, G and Berglund, G and Loewel, H and Koenig, W and Hense, H W and Meade, T W and Cooper, J A and De Stavola, B and Knottenbelt, C and Miller, G J and Cooper, J A and Bauer, K A and Rosenberg, R D and Sato, S and Kitamura, A and Naito, Y and Iso, H and Salomaa, V and Harald, K and Rasi, V and Vahtera, E and Jousilahti, P and Palosuo, T and Ducimetiere, P and Amouyel, P and Arveiler, D and Evans, A E and Ferrieres, J and Juhan-Vague, I and Bingham, A and Schulte, H and Assmann, G and Cantin, B and Lamarche, B and Despr{\'e}s, J-P and Dagenais, G R and Tunstall-Pedoe, H and Lowe, G D O and Woodward, M and Ben-Shlomo, Y and Davey Smith, G and Palmieri, V and Yeh, J L and Meade, T W and Rudnicka, A and Brennan, P and Knottenbelt, C and Cooper, J A and Ridker, P and Rodeghiero, F and Tosetto, A and Shepherd, J and Lowe, G D O and Ford, I and Robertson, M and Brunner, E and Shipley, M and Feskens, E J M and Di Angelantonio, E and Kaptoge, S and Lewington, S and Lowe, G D O and Sarwar, N and Thompson, S G and Walker, M and Watson, S and White, I R and Wood, A M and Danesh, J} } @article {1157, title = {Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study.}, journal = {Am J Epidemiol}, volume = {171}, year = {2010}, month = {2010 Feb 01}, pages = {292-302}, abstract = {

Recent studies have found that smoking is associated with an increased risk of dementia, but the effects of secondhand smoke (SHS) on dementia risk are not known to have previously been studied. The authors used Cox proportional hazards marginal structural models to examine the association between self-reported lifetime household SHS exposure and risk of incident dementia over 6 years among 970 US participants in the Cardiovascular Health Cognition Study (performed from 1991 to 1999) who were never smokers and were free of clinical cardiovascular disease (CVD), dementia, and mild cognitive impairment at baseline. In addition, because prior studies have found that SHS is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, the authors tested for interactions between SHS and measures of clinical and subclinical CVD on dementia risk. Moderate (16-25 years) and high (>25 years) SHS exposure levels were not independently associated with dementia risk; however, subjects with >25 years of SHS exposure and >25\% carotid artery stenosis had a 3-fold increase (hazard ratio = 3.00, 95\% confidence interval: 1.03, 9.72) in dementia risk compared with subjects with no/low (0-15 years) SHS exposure and < or =25\% carotid artery stenosis. High lifetime SHS exposure may increase the risk of dementia in elderly with undiagnosed CVD.

}, keywords = {Aged, Dementia, Female, Humans, Incidence, Male, Risk Factors, Tobacco Smoke Pollution, Vascular Diseases}, issn = {1476-6256}, doi = {10.1093/aje/kwp376}, author = {Barnes, Deborah E and Haight, Thaddeus J and Mehta, Kala M and Carlson, Michelle C and Kuller, Lewis H and Tager, Ira B} } @article {1184, title = {Serum albumin and risk of venous thromboembolism.}, journal = {Thromb Haemost}, volume = {104}, year = {2010}, month = {2010 Jul}, pages = {100-4}, abstract = {

The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n = 462 in ARIC and n = 174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated glomerular filtration rate, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95\% confidence interval [CI] = 1.08, 1.31) in ARIC and 1.10 (95\% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (vs. above) the fifth percentile was 1.28 (95\% CI = 0.90, 1.84) in ARIC and 1.80 (95\% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.

}, keywords = {Aged, Biomarkers, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Risk Factors, Serum Albumin, United States, Venous Thromboembolism}, issn = {2567-689X}, doi = {10.1160/TH09-12-0856}, author = {Folsom, Aaron R and Lutsey, Pamela L and Heckbert, Susan R and Cushman, Mary} } @article {1196, title = {Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies.}, journal = {Am Heart J}, volume = {159}, year = {2010}, month = {2010 May}, pages = {864-70}, abstract = {

BACKGROUND: Many African Americans carry an amyloidogenic transthyretin mutation (TTR V122I), with a high risk for cardiac TTR amyloid deposition after the age of 65 years. We wished to determine the allele frequency and its clinical penetrance in community-dwelling African Americans.

METHODS: Five thousand consenting African Americans, aged 41 to 93 years, in 2 community studies of cardiovascular risk (CHS and ARIC) were included in the study. The following were performed: genotyping of banked DNA for TTR V122I allele status and review of cardiovascular and demographic parameters in CHS and ARIC databases, with statistical comparisons of the frequency of congestive heart failure, survival, and occurrence of features of cardiac amyloidosis in carriers of the amyloidogenic allele and controls.

RESULTS: One hundred nineteen (3.23\%) of 3,712 ARIC and 17 (2.12\%) of 805 CHS African Americans carried TTR V122I. After the age of 65 years (CHS), the frequencies of congestive heart failure (38\% vs 15\%, relative risk 2.62, P = .04) and mortality (76\% vs 53\%, relative risk 1.46, P = .08) were higher in V122I allele carriers than in age-, gender- and ethnically matched controls. In ARIC (all subjects <65 years old), there were no differences between carriers and noncarriers in mortality, frequency of congestive heart failure, or findings consistent with cardiac amyloidosis.

CONCLUSIONS: Heterozygosity for the amyloidogenic TTR V122I mutation is relatively common in community-dwelling African Americans. Before the age of 65 years, the allele has no discernible impact on cardiac function or mortality. After the age of 70 years, carriers show a higher frequency of congestive failure and greater mortality with more echocardiographic evidence suggestive of cardiac amyloidosis, findings consistent with age-dependent clinical penetrance of this autosomal dominant gene.

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Amyloidosis, Female, Gene Frequency, Heart Diseases, Humans, Isoleucine, Kaplan-Meier Estimate, Male, Middle Aged, Mutation, Prealbumin, Ultrasonography, Valine}, issn = {1097-6744}, doi = {10.1016/j.ahj.2010.02.006}, author = {Buxbaum, Joel and Alexander, Alice and Koziol, James and Tagoe, Clement and Fox, Ervin and Kitzman, Dalane} } @article {1189, title = {Sleep disturbances, quality of life, and ethnicity: the Sleep Heart Health Study.}, journal = {J Clin Sleep Med}, volume = {6}, year = {2010}, month = {2010 Apr 15}, pages = {176-83}, abstract = {

STUDY OBJECTIVES: To compare health-related quality of life (HR-QOL) across subgroups defined by sleep disturbances and ethnicity.

METHODS: Men (47\%) and women (53\%) Sleep Heart Health Study participants age 40 and older (N = 5237) underwent overnight polysomnography and completed self-report questionnaires on symptoms of sleep disturbances. The physical and mental composite scales (PCS and MCS) of the Medical Outcomes Study 36-item short form survey assessed HR-QOL and were compared to sleep data.

RESULTS: Participants self-identified as Caucasian/White (n = 4482, 86\%), African American/Black (n = 490, 9\%), or Hispanic/Mexican American (n = 265, 5\%). The prevalence of obstructive sleep apnea (OSA) was 17\%, frequent snoring was 34\%, difficulty initiating or maintaining sleep (DIMS; insomnia symptoms) was 30\%, and excessive daytime sleepiness (EDS) was 25\%. African American participants with frequent snoring, insomnia symptoms, or EDS had significantly poorer physical health compared to Caucasians (p < 0.001). Hispanics with frequent snoring, insomnia symptoms, or EDS had significantly poorer mental health than Caucasian participants (p <0.001). Neither PCS nor MCS scores differed significantly across ethnic subgroups for participants with moderate to severe OSA (respiratory disturbance index > 15, 4\% desaturation).

CONCLUSIONS: Across ethnic/racial subgroups, sleep disturbances are associated with worse physical and better mental HR-QOL than the U.S. norm, but this relationship may be moderated by comorbid health conditions. This study replicates and extends prior research indicating differences among minority and non-minority participants and highlights the need for future studies of sleep disturbances with larger samples of minorities that control for comorbid health conditions.

}, keywords = {African Americans, Cohort Studies, Ethnic Groups, European Continental Ancestry Group, Female, Health Status, Heart Diseases, Hispanic Americans, Humans, Longitudinal Studies, Male, Mental Health, Middle Aged, Polysomnography, Prevalence, Quality of Life, Sleep Apnea, Obstructive, Sleep Initiation and Maintenance Disorders, Sleep Wake Disorders, Snoring, Surveys and Questionnaires, United States}, issn = {1550-9389}, author = {Baldwin, Carol M and Ervin, Ann-Margret and Mays, Mary Z and Robbins, John and Shafazand, Shirin and Walsleben, Joyce and Weaver, Terri} } @article {1161, title = {Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing.}, journal = {Am J Respir Crit Care Med}, volume = {181}, year = {2010}, month = {2010 May 01}, pages = {997-1002}, abstract = {

RATIONALE: The impact of REM-predominant sleep-disordered breathing (SDB) on sleepiness, quality of life (QOL), and sleep maintenance is uncertain.

OBJECTIVE: To evaluate the association of SDB during REM sleep with daytime sleepiness, health-related QOL, and difficulty maintaining sleep, in comparison to their association with SDB during non-REM sleep in a community-based cohort.

METHODS: Cross-sectional analysis of 5,649 Sleep Heart Health Study participants (mean age 62.5 [SD = 10.9], 52.6\% women, 22.6\% ethnic minorities). SDB during REM and non-REM sleep was quantified using polysomnographically derived apnea-hypopnea index in REM (AHI(REM)) and non-REM (AHI(NREM)) sleep. Sleepiness, sleep maintenance, and QOL were respectively quantified using the Epworth Sleepiness Scale (ESS), the Sleep Heart Health Study Sleep Habit Questionnaire, and the physical and mental composites scales of the Medical Outcomes Study Short Form (SF)-36.

MEASUREMENTS AND MAIN RESULTS: AHI(REM) was not associated with the ESS scores or the physical and mental components scales scores of the SF-36 after adjusting for demographics, body mass index, and AHI(NREM) x AHI(REM) was not associated with frequent difficulty maintaining sleep or early awakening from sleep. AHI(NREM) was associated with the ESS score (beta = 0.25; 95\% confidence interval [CI], 0.16 to 0.34) and the physical (beta = -0.12; 95\% CI, -0.42 to -0.01) and mental (beta = -0.20; 95\% CI, -0.20 to -0.01) components scores of the SF-36 adjusting for demographics, body mass index, and AHI(REM).

CONCLUSIONS: In a community-based sample of middle-aged and older adults, REM-predominant SDB is not independently associated with daytime sleepiness, impaired health-related QOL, or self-reported sleep disruption.

}, keywords = {Aged, Disorders of Excessive Somnolence, Female, Humans, Male, Middle Aged, Polysomnography, Quality of Life, Sleep, Sleep Apnea Syndromes, Sleep, REM}, issn = {1535-4970}, doi = {10.1164/rccm.200908-1304OC}, author = {Chami, Hassan A and Baldwin, Carol M and Silverman, Angela and Zhang, Ying and Rapoport, David and Punjabi, Naresh M and Gottlieb, Daniel J} } @article {1260, title = {Study of the relationship between the interleukin-6 gene and obstructive sleep apnea.}, journal = {Clin Transl Sci}, volume = {3}, year = {2010}, month = {2010 Dec}, pages = {337-9}, keywords = {Adult, African Americans, Alleles, Female, Humans, Interleukin-6, Male, Middle Aged, Polymorphism, Single Nucleotide, Sleep Apnea, Obstructive}, issn = {1752-8062}, author = {Larkin, Emma K and Patel, Sanjay R and Zhu, Xiaofeng and Tracy, Russell P and Jenny, Nancy S and Reiner, Alex P and Walston, Jeremy and Redline, Susan} } @article {1231, title = {Subclinical hypothyroidism and the risk of coronary heart disease and mortality.}, journal = {JAMA}, volume = {304}, year = {2010}, month = {2010 Sep 22}, pages = {1365-74}, abstract = {

CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants{\textquoteright} age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.

OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.

DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.

DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.

RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2\%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95\% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95\% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95\% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95\% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95\% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95\% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.

CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Coronary Disease, Female, Humans, Hypothyroidism, Male, Middle Aged, Mortality, Prospective Studies, Risk, Thyrotropin, Young Adult}, issn = {1538-3598}, doi = {10.1001/jama.2010.1361}, author = {Rodondi, Nicolas and den Elzen, Wendy P J and Bauer, Douglas C and Cappola, Anne R and Razvi, Salman and Walsh, John P and Asvold, Bj{\o}rn O and Iervasi, Giorgio and Imaizumi, Misa and Collet, Tinh-Hai and Bremner, Alexandra and Maisonneuve, Patrick and Sgarbi, Jos{\'e} A and Khaw, Kay-Tee and Vanderpump, Mark P J and Newman, Anne B and Cornuz, Jacques and Franklyn, Jayne A and Westendorp, Rudi G J and Vittinghoff, Eric and Gussekloo, Jacobijn} } @article {1246, title = {Subclinical thyroid dysfunction and incident hip fracture in older adults.}, journal = {Arch Intern Med}, volume = {170}, year = {2010}, month = {2010 Nov 22}, pages = {1876-83}, abstract = {

BACKGROUND: Subclinical thyroid dysfunction is common in older adults and affects bone metabolism, but its effects on fracture risk have not been reported. We sought to determine prospectively whether older men and women with subclinical hyperthyroidism or hypothyroidism have an increased risk of hip fracture.

METHODS: Prospective cohort of 3567 US community-dwelling adults, 65 years or older, with biochemically defined subclinical thyroid dysfunction or euthyroidism was enrolled from June 10, 1989, through May 30, 1990, and followed up through 2004. Main outcome measures included incidence and hazard ratios (HRs), with 95\% confidence intervals (CIs), of confirmed incident hip fractures for groups with subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroidism as defined at baseline.

RESULTS: During 39 952 person-years (median follow-up, 13 years), hip fracture incidence (per 1000 men-years) was 13.65 in men with subclinical hyperthyroidism (n = 29) and 10.27 in men with subclinical hypothyroidism (n = 184), both greater than 5.0 in men with euthyroidism (n = 1159). Men with subclinical hypothyroidism had a multivariable-adjusted HR of 2.31 (95\% CI, 1.25-4.27); those with subclinical hyperthyroidism, 3.27 (0.99-11.30). After excluding those with baseline use of thyroid-altering medications, men with endogenous subclinical hyperthyroidism had a higher HR of 4.91 (95\% CI, 1.13-21.27), as did men with endogenous subclinical hypothyroidism (2.45, 1.27-4.73). Hip fracture incidence (per 1000 women-years) was 8.93 in women with subclinical hypothyroidism (n = 359) and 10.90 in women with subclinical hyperthyroidism (n = 142) compared with 10.18 in women with euthyroidism (n = 1694). No clear association between subclinical dysfunction and fracture was observed in women.

CONCLUSIONS: Older men with subclinical hyperthyroidism or hypothyroidism are at increased risk for hip fracture. Whether treatment of the subclinical syndrome reduces this risk is unknown.

}, keywords = {Aged, Female, Follow-Up Studies, Hip Fractures, Humans, Hyperthyroidism, Hypothyroidism, Incidence, Male, Multivariate Analysis, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Distribution, Thyrotropin, United States}, issn = {1538-3679}, doi = {10.1001/archinternmed.2010.424}, author = {Lee, Jennifer S and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Vu, Joseph and Carbone, Laura and Chen, Zhao and Cauley, Jane and Bauer, Doug C and Cappola, Anne R and Robbins, John} } @article {1353, title = {Seasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study.}, journal = {Am J Epidemiol}, volume = {174}, year = {2011}, month = {2011 Dec 15}, pages = {1363-72}, abstract = {

Low circulating concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with adverse health outcomes in diverse populations. However, 25(OH)D concentrations vary seasonally with varying exposure to sunlight, so single measurements may poorly reflect long-term 25(OH)D exposure. The authors investigated cyclical trends in average serum 25(OH)D concentrations among 2,298 individuals enrolled in the Cardiovascular Health Study of community-based older adults (1992-1993). A sinusoidal model closely approximated observed 25(OH)D concentrations and fit the data significantly better than did a mean model (P < 0.0001). The mean annual 25(OH)D concentration was 25.1 ng/mL (95\% confidence interval: 24.7, 25.5), and the mean peak-trough difference was 9.6 ng/mL (95\% confidence interval: 8.5, 10.7). Male sex, higher latitude of study site, and greater physical activity levels were associated with larger peak-trough difference in 25(OH)D concentration (each P < 0.05). Serum concentrations of intact parathyroid hormone and bone-specific alkaline phosphatase also varied in a sinusoidal fashion (P < 0.0001), inversely to 25(OH)D. In conclusion, serum 25(OH)D varies in a sinusoidal manner, with large seasonal differences relative to mean concentration and laboratory evidence of biologic sequelae. Single 25(OH)D measurements might not capture overall vitamin D status, and the extent of misclassification could vary by demographic and behavioral factors. Accounting for collection time may reduce bias in research studies and improve decision-making in clinical care.

}, keywords = {Aged, Biomarkers, Continental Population Groups, Exercise, Female, Humans, Male, Residence Characteristics, Seasons, Sex Factors, Vitamin D}, issn = {1476-6256}, doi = {10.1093/aje/kwr258}, author = {Shoben, Abigail B and Kestenbaum, Bryan and Levin, Gregory and Hoofnagle, Andrew N and Psaty, Bruce M and Siscovick, David S and de Boer, Ian H} } @article {1563, title = {Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies.}, journal = {Lancet}, volume = {377}, year = {2011}, month = {2011 Mar 26}, pages = {1085-95}, abstract = {

BACKGROUND: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.

METHODS: We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) higher BMI, 12.6 cm higher waist circumference, and 0.083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.

RESULTS: Individual records were available for 221,934 people in 17 countries (14,297 incident cardiovascular disease outcomes; 1.87 million person-years at risk). Serial adiposity assessments were made in up to 63,821 people (mean interval 5.7 years [SD 3.9]). In people with BMI of 20 kg/m(2) or higher, HRs for cardiovascular disease were 1.23 (95\% CI 1.17-1.29) with BMI, 1.27 (1.20-1.33) with waist circumference, and 1.25 (1.19-1.31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1.07 (1.03-1.11) with BMI, 1.10 (1.05-1.14) with waist circumference, and 1.12 (1.08-1.15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of -0.0001, -0.0001, and 0.0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement -0.19\%, -0.05\%, and -0.05\%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0.95, 95\% CI 0.93-0.97) than for waist circumference (0.86, 0.83-0.89) or waist-to-hip ratio (0.63, 0.57-0.70).

INTERPRETATION: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.

FUNDING: British Heart Foundation and UK Medical Research Council.

}, keywords = {Age Factors, Blood Pressure, Body Mass Index, Cardiovascular Diseases, Cholesterol, Cholesterol, HDL, Diabetes Mellitus, Female, Humans, Male, Middle Aged, Obesity, Abdominal, Proportional Hazards Models, Prospective Studies, Risk Assessment, Sex Factors, Smoking, Systole, Waist Circumference, Waist-Hip Ratio}, issn = {1474-547X}, doi = {10.1016/S0140-6736(11)60105-0}, author = {Wormser, David and Kaptoge, Stephen and Di Angelantonio, Emanuele and Wood, Angela M and Pennells, Lisa and Thompson, Alex and Sarwar, Nadeem and Kizer, Jorge R and Lawlor, Debbie A and Nordestgaard, B{\o}rge G and Ridker, Paul and Salomaa, Veikko and Stevens, June and Woodward, Mark and Sattar, Naveed and Collins, Rory and Thompson, Simon G and Whitlock, Gary and Danesh, John} } @article {1312, title = {Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate.}, journal = {Clin J Am Soc Nephrol}, volume = {6}, year = {2011}, month = {2011 Sep}, pages = {2141-9}, abstract = {

BACKGROUND AND OBJECTIVES: Mounting evidence suggests that 1,25-dihydroxyvitamin D prevents the progression of chronic kidney disease (CKD). It is not clear whether "nutritional" forms of vitamin D affect GFR.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: We tested whether serum 25-hydroxyvitamin D concentration (25(OH)D), a measure of total vitamin D intake from cutaneous synthesis and dietary consumption, is associated with loss of estimated GFR among 1705 older adults with predominantly normal baseline kidney function participating in the Cardiovascular Health Study. Baseline 25(OH)D was measured by HPLC-tandem mass spectrometry. GFR was estimated at baseline and 4 years later using the CKD-EPI formula, with rapid GFR loss defined as 12 ml/min per 1.73 m(2) or more over 4 years.

RESULTS: Rapid GFR loss was observed for 207 participants (12\%). Each 10 ng/ml lower 25(OH)D was associated with a 25\% greater risk of rapid GFR loss (95\% confidence interval [CI] 5\%, 49\%, P = 0.01), adjusting for potential confounding characteristics. Compared with 25(OH)D >=30 ng/ml, 25(OH)D concentrations 15 to 29 ng/ml and <15 ng/ml were associated with 29\% (95\% CI -13\%, 91\%) and 68\% (95\% CI 1\%, 177\%) greater adjusted risks of rapid GFR loss, respectively. Magnitudes of association were largest among participants with diabetes.

RESULTS: were similar evaluating a composite outcome of rapid GFR loss, end stage renal disease, and death. Conclusions Insufficient 25(OH)D may be a modifiable risk factor for early GFR loss. We recommend clinical trials to determine whether vitamin D supplementation prevents the development and progression of CKD.

}, keywords = {Aged, Female, Glomerular Filtration Rate, Humans, Kidney Diseases, Male, Prospective Studies, Vitamin D}, issn = {1555-905X}, doi = {10.2215/CJN.02640311}, author = {de Boer, Ian H and Katz, Ronit and Chonchol, Michel and Ix, Joachim H and Sarnak, Mark J and Shlipak, Michael G and Siscovick, David S and Kestenbaum, Bryan} } @article {1352, title = {Serum 25-hydroxyvitamin D and physical function in older adults: the Cardiovascular Health Study All Stars.}, journal = {J Am Geriatr Soc}, volume = {59}, year = {2011}, month = {2011 Oct}, pages = {1793-801}, abstract = {

OBJECTIVES: To examine the association between 25-hydroxyvitamin D (25(OH)D) and physical function in adults of advanced age.

DESIGN: Cross-sectional and longitudinal analysis of physical function over 3~years of follow-up in the Cardiovascular Health Study All Stars.

SETTING: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania.

PARTICIPANTS: Community-dwelling adults aged 77 to 100 (N~=~988).

MEASUREMENTS: Serum 25-hydroxyvitamin D 25(OH)D), Short Physical Performance Battery (SPPB), and grip and knee extensor strength assessed at baseline. Mobility disability (difficulty walking half a mile or up 10 steps) and activities of daily living (ADLs) disability were assessed at baseline and every 6~months over 3~years of follow-up.

RESULTS: Almost one-third (30.8\%) of participants were deficient in 25(OH)D (<20~ng/mL). SPPB scores were lower in those with deficient 25(OH)D (mean (standard error) 6.53~(0.24)) than in those with sufficient 25(OH)D (>=30~ng/mL) (7.15~(0.25)) after adjusting for sociodemographic characteristics, season, health behaviors, and chronic conditions (P~=~.006). Grip strength adjusted for body size was also lower in those with deficient 25(OH)D than in those with sufficient 25(OH)D (24.7~(0.6)~kg vs 26.0~(0.6)~kg, P~=~.02). Participants with deficient 25(OH)D were more likely to have prevalent mobility (OR~=~1.44, 95\% confidence interval (CI))~=~0.96-2.14) and ADL disability (OR~=~1.51, 95\% CI~=~1.01-2.25) at baseline than those with sufficient 25(OH)D. Furthermore, participants with deficient 25(OH)D were at greater risk of incident mobility disability over 3~years of follow-up (hazard ratio~=~1.56, 95\% CI~=~1.06-2.30).

CONCLUSION: Vitamin D deficiency was common and was associated with poorer physical performance, lower muscle strength, and prevalent mobility and ADL disability in community-dwelling older adults. Moreover, vitamin D deficiency predicted incident mobility disability.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Female, Follow-Up Studies, Geriatric Assessment, Health Surveys, Humans, Male, Mobility Limitation, Muscle Strength, Physical Fitness, Proportional Hazards Models, Reference Values, United States, Vitamin D, Vitamin D Deficiency}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2011.03601.x}, author = {Houston, Denise K and Tooze, Janet A and Davis, Cralen C and Chaves, Paulo H M and Hirsch, Calvin H and Robbins, John A and Arnold, Alice M and Newman, Anne B and Kritchevsky, Stephen B} } @article {1300, title = {Subclinical vascular disease burden and risk for death and cardiovascular events in older community dwellers.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Sep}, pages = {986-93}, abstract = {

BACKGROUND: Individual measures and previous composite measures of subclinical vascular disease defined high risk for cardiovascular events, but did not detect low and modest risk. A different approach might better describe the spectrum from low to high risk. Methods and Results. In the Cardiovascular Health Study, 3,252 participants without history of clinical cardiovascular disease (M {\textpm} SD 74.3 years {\textpm} 5.1, 63\% women, 17\% African Americans) had noninvasive vascular assessments in 1992-1993. We assigned a score of 0, 1, or 2 (no, mild, or severe abnormalities) to ankle-arm index, electrocardiogram, and common carotid intima-media thickness, based on clinical cutoffs. A summary index (range 0-6, absent to severe disease) summed individual scores. Abdominal aortic ultrasound and brain magnetic resonance imaging were collected in a subsample. Mortality and incident cardiovascular events were identified through June 2008. Event and death rates increased across index grades. Comparing grades 1 to 5+ with absent disease, and adjusting for demographics, hazard ratios for cardiovascular events within 8 years ranged from 1.1 (95\% confidence interval 0.8-1.6) to 4.7 (3.4-6.9) and, for mortality, from 1.5 (1.0-2.3) to 5.0 (3.3-7.7) (p for trend across grades <.001 for both outcomes). Adjustment for cardiovascular risk factors did not substantially change the associations. The index improved mortality risk classification over demographics and risk factors in participants who did not die during the follow-up. Including in the index the aortic ultrasound and the brain magnetic resonance imaging further improved risk classification.

CONCLUSIONS: Older adults with minimal subclinical vascular disease had low cardiovascular events risk and mortality. This approach might more fully account for vascular burden.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cost of Illness, Female, Humans, Male, Risk, Vascular Diseases}, issn = {1758-535X}, doi = {10.1093/gerona/glr069}, author = {Inzitari, Marco and Arnold, Alice M and Patel, Kushang V and Mercer, Laina D and Karlamangla, Arun and Ding, Jingzhong and Psaty, Bruce M and Williamson, Jeff D and Kuller, Lewis H and Newman, Anne B} } @article {1338, title = {Surrogate screening models for the low physical activity criterion of frailty.}, journal = {Aging Clin Exp Res}, volume = {23}, year = {2011}, month = {2011 Jun}, pages = {209-16}, abstract = {

BACKGROUND AND AIMS: Low physical activity, one of five criteria in a validated clinical phenotype of frailty, is assessed by a standardized, semiquantitative questionnaire on up to 20 leisure time activities. Because of the time demanded to collect the interview data, it has been challenging to translate to studies other than the Cardiovascular Health Study (CHS), for which it was developed. Considering subsets of activities, we identified and evaluated streamlined surrogate assessment methods and compared them to one implemented in the Women{\textquoteright}s Health and Aging Study (WHAS).

METHODS: Using data on men and women ages 65 and older from the CHS, we applied logistic regression models to rank activities by "relative influence" in predicting low physical activity.We considered subsets of the most influential activities as inputs to potential surrogate models (logistic regressions). We evaluated predictive accuracy and predictive validity using the area under receiver operating characteristic curves and assessed criterion validity using proportional hazards models relating frailty status (defined using the surrogate) to mortality.

RESULTS: Walking for exercise and moderately strenuous household chores were highly influential for both genders. Women required fewer activities than men for accurate classification. The WHAS model (8 CHS activities) was an effective surrogate, but a surrogate using 6 activities (walking, chores, gardening, general exercise, mowing and golfing) was also highly predictive.

CONCLUSIONS: We recommend a 6 activity questionnaire to assess physical activity for men and women. If efficiency is essential and the study involves only women, fewer activities can be included.

}, keywords = {Activities of Daily Living, Aged, Cohort Studies, Exercise, Female, Follow-Up Studies, Frail Elderly, Geriatric Assessment, Humans, Leisure Activities, Logistic Models, Male, Motor Activity, Prospective Studies, Surveys and Questionnaires, Women{\textquoteright}s Health}, issn = {1594-0667}, author = {Eckel, Sandrah P and Bandeen-Roche, Karen and Chaves, Paulo H M and Fried, Linda P and Louis, Thomas A} } @article {1294, title = {Systolic blood pressure and incident heart failure in the elderly. The Cardiovascular Health Study and the Health, Ageing and Body Composition Study.}, journal = {Heart}, volume = {97}, year = {2011}, month = {2011 Aug}, pages = {1304-11}, abstract = {

BACKGROUND: The exact form of the association between systolic blood pressure (SBP) and heart failure (HF) risk in the elderly remains incompletely defined, especially in individuals not receiving antihypertensive drugs.

OBJECTIVE: To examine the association between SBP and HF risk in the elderly.

DESIGN: Competing-risks proportional hazards modelling of incident HF risk, using 10-year follow-up data from two NIH-sponsored cohort studies: the Cardiovascular Health Study (inception: 1989-90 and 1992-3) and the Health ABC Study (inception: 1997-8).

SETTING: Community-based cohorts.

PARTICIPANTS: 4408 participants (age, 72.8 (4.9) years; 53.1\% women, 81.7\% white; 18.3\% black) without prevalent HF and not receiving antihypertensive drugs at baseline.

MAIN OUTCOME MEASURES: Incident HF, defined as first adjudicated hospitalisation for HF.

RESULTS: Over 10 years, 493 (11.2\%) participants developed HF. Prehypertension (120-139 mm Hg), stage 1 (140-159 mm Hg), and stage 2 (>=160 mm Hg) hypertension were associated with escalating HF risk; HRs versus optimal SBP (<120 mm Hg) in competing-risks models controlling for clinical characteristics were 1.63 (95\% CI 1.23 to 2.16; p=0.001), 2.21 (95\% CI 1.65 to 2.96; p<0.001) and 2.60 (95\% CI 1.85 to 3.64; p<0.001), respectively. Overall 255/493 (51.7\%) HF events occurred in participants with SBP <140 mm Hg at baseline. Increasing SBP was associated with higher HF risk in women than in men; no race-SBP interaction was seen. In analyses with continuous SBP, HF risk had a continuous positive association with SBP to levels as low as 113 mm Hg in men and 112 mm Hg in women.

CONCLUSIONS: There is a continuous positive association between SBP and HF risk in the elderly for levels of SBP as low as <115 mm Hg; over half of incident HF events occur in individuals with SBP <140 mm Hg.

}, keywords = {Aged, Aged, 80 and over, Aging, Blood Pressure, Body Composition, Epidemiologic Methods, Female, Heart Failure, Humans, Hypertension, Male, Myocardial Infarction, Sex Factors, Stroke, Stroke Volume}, issn = {1468-201X}, doi = {10.1136/hrt.2011.225482}, author = {Butler, Javed and Kalogeropoulos, Andreas P and Georgiopoulou, Vasiliki V and Bibbins-Domingo, Kirsten and Najjar, Samer S and Sutton-Tyrrell, Kim C and Harris, Tamara B and Kritchevsky, Stephen B and Lloyd-Jones, Donald M and Newman, Anne B and Psaty, Bruce M} } @article {1549, title = {A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.}, journal = {Clin Pharmacol Ther}, volume = {91}, year = {2012}, month = {2012 May}, pages = {896-904}, abstract = {

An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95\% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17\%) than in those receiving atorvastatin (0\%, OR infinity; 95\% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8.

}, keywords = {Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Aryl Hydrocarbon Hydroxylases, Case-Control Studies, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Drug Interactions, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Platelet Aggregation Inhibitors, Pyridines, Rhabdomyolysis, Ticlopidine}, issn = {1532-6535}, doi = {10.1038/clpt.2011.295}, author = {Floyd, J S and Kaspera, R and Marciante, K D and Weiss, N S and Heckbert, S R and Lumley, T and Wiggins, K L and Tamraz, B and Kwok, P-Y and Totah, R A and Psaty, B M} } @article {1384, title = {Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study.}, journal = {Ann Intern Med}, volume = {156}, year = {2012}, month = {2012 May 01}, pages = {627-34}, abstract = {

BACKGROUND: Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration.

OBJECTIVE: To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D.

DESIGN: Cohort study.

SETTING: The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis.

PARTICIPANTS: 1621 white older adults.

MEASUREMENTS: Serum 25-(OH)D concentration (using a high-performance liquid chromatography-tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death.

RESULTS: Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63\%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of -0.54 best discriminated risk for the composite outcome and was associated with a 24\% higher risk in adjusted analyses (95\% CI, 9\% to 42\%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively.

LIMITATION: The observational study was restricted to white participants.

CONCLUSION: Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk.

PRIMARY FUNDING SOURCE: National Institutes of Health.

}, keywords = {Aged, Cause of Death, Female, Follow-Up Studies, Hip Fractures, Humans, Male, Myocardial Infarction, Neoplasms, Proportional Hazards Models, Risk Assessment, Risk Factors, Seasons, United States, Vitamin D, Vitamin D Deficiency}, issn = {1539-3704}, doi = {10.7326/0003-4819-156-9-201205010-00004}, author = {de Boer, Ian H and Levin, Gregory and Robinson-Cohen, Cassianne and Biggs, Mary L and Hoofnagle, Andy N and Siscovick, David S and Kestenbaum, Bryan} } @article {1540, title = {Sleep-disordered breathing and caffeine consumption: results of a community-based study.}, journal = {Chest}, volume = {142}, year = {2012}, month = {2012 Sep}, pages = {631-638}, abstract = {

BACKGROUND: Sleepiness is one of the most burdensome symptoms of sleep-disordered breathing (SDB). While caffeine is frequently used to avert sleepiness, the association between SDB and caffeine use has not been thoroughly explored. The current study examined whether SDB is associated with caffeine consumption and if factors such as sex, age, and daytime sleepiness explain or modify the association.

METHODS: Data from the Sleep Heart Health Study, a community-based study on the consequences of SDB, were used to characterize the association between SDB and caffeine intake. SDB was assessed with full-montage polysomnography. Caffeine use was quantified as the number of cans of soda or the cups of coffee or tea consumed daily. The Epworth Sleepiness Scale was used to assess daytime sleepiness. Multivariable negative binomial regression models were used to characterize the independent association between SDB and caffeine use.

RESULTS: Caffeinated soda, but not tea or coffee, intake was independently associated with SDB severity. Compared with participants without SDB, the relative ratios for caffeinated soda consumption in women with mild, moderate, and severe SDB were 1.20 (CI, 1.03-1.41), 1.46 (CI, 1.14-1.87), and 1.73 (CI, 1.23-2.42), respectively. For men, an association was only noted with severe SDB and caffeinated soda use. Age did not modify the SDB-caffeine association, and sleepiness could not explain the observed associations.

CONCLUSIONS: SDB is independently associated with caffeinated soda use in the general community. Identifying excessive caffeine used in SDB has potential significance given the cardiovascular effects of caffeine and untreated SDB.

}, keywords = {Age Factors, Aged, Caffeine, Carbonated Beverages, Coffee, Data Collection, Drinking Behavior, Female, Humans, Male, Middle Aged, Polysomnography, Prevalence, Retrospective Studies, Sex Factors, Sleep Apnea Syndromes, Tea}, issn = {1931-3543}, doi = {10.1378/chest.11-2894}, author = {Aurora, R Nisha and Crainiceanu, Ciprian and Caffo, Brian and Punjabi, Naresh M} } @article {1334, title = {Slower gait, slower information processing and smaller prefrontal area in older adults.}, journal = {Age Ageing}, volume = {41}, year = {2012}, month = {2012 Jan}, pages = {58-64}, abstract = {

BACKGROUND: Slower gait in older adults is related to smaller volume of the prefrontal area (PFAv). The pathways underlying this association have not yet been explored. Understanding slowing gait could help improve function in older age. We examine whether the association between smaller PFAv and slower gait is explained by lower performance on numerous neuropsychological tests.

HYPOTHESIS: We hypothesise that slower information processing explains this association, while tests of language or memory will not.

METHODS: Data on brain imaging, neuropsychological tests (information processing speed, visuospatial attention, memory, language, mood) and time to walk 15 feet were obtained in 214 adults (73.3 years, 62\% women) free from stroke and dementia. Covariates included central (white matter hyperintensities, vision) and peripheral contributors of gait (vibration sense, muscle strength, arthritis, body mass index), demographics (age, race, gender, education), as well as markers of prevalent vascular diseases (cardiovascular disease, diabetes and ankle arm index).

RESULTS: In linear regression models, smaller PFAv was associated with slower time to walk independent of covariates. This association was no longer significant after adding information processing speed to the model. None of the other neuropsychological tests significantly attenuated this association.

CONCLUSIONS: We conclude that smaller PFAv may contribute to slower gait through slower information processing. Future longitudinal studies are warranted to examine the casual relationship between focal brain atrophy with slowing in information processing and gait.

}, keywords = {Affect, Aged, Aged, 80 and over, Aging, Attention, Body Mass Index, Cross-Sectional Studies, Female, Gait Disorders, Neurologic, Geriatric Assessment, Humans, Male, Memory, Mental Disorders, Mental Processes, Muscle Strength, Neuroimaging, Neuropsychological Tests, Prefrontal Cortex, Prevalence, Walking}, issn = {1468-2834}, doi = {10.1093/ageing/afr113}, author = {Rosano, Caterina and Studenski, Stephanie A and Aizenstein, Howard J and Boudreau, Robert M and Longstreth, William T and Newman, Anne B} } @article {1545, title = {Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.}, journal = {Arch Intern Med}, volume = {172}, year = {2012}, month = {2012 May 28}, pages = {799-809}, abstract = {

BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.

METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.

RESULTS: Of 52 674 participants, 2188 (4.2\%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95\% CI, 1.06-1.46), CHD mortality (HR,1.29; 95\% CI, 1.02-1.62), CHD events (HR, 1.21; 95\%CI, 0.99-1.46), and AF (HR, 1.68; 95\% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5\% for total mortality to 41.5\% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03).

CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

}, keywords = {Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Atrial Fibrillation, Cause of Death, Cohort Studies, Coronary Artery Disease, Female, Humans, Hyperthyroidism, Male, Middle Aged, Prognosis, Prospective Studies, Risk Assessment, Severity of Illness Index, Sex Distribution, Survival Analysis, Switzerland, Thyroid Function Tests, Thyrotropin, Young Adult}, issn = {1538-3679}, doi = {10.1001/archinternmed.2012.402}, author = {Collet, Tinh-Hai and Gussekloo, Jacobijn and Bauer, Douglas C and den Elzen, Wendy P J and Cappola, Anne R and Balmer, Philippe and Iervasi, Giorgio and Asvold, Bj{\o}rn O and Sgarbi, Jos{\'e} A and V{\"o}lzke, Henry and Gencer, Bari{\c s} and Maciel, Rui M B and Molinaro, Sabrina and Bremner, Alexandra and Luben, Robert N and Maisonneuve, Patrick and Cornuz, Jacques and Newman, Anne B and Khaw, Kay-Tee and Westendorp, Rudi G J and Franklyn, Jayne A and Vittinghoff, Eric and Walsh, John P and Rodondi, Nicolas} } @article {6087, title = {Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.}, journal = {Circulation}, volume = {126}, year = {2012}, month = {2012 Aug 28}, pages = {1040-9}, abstract = {

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events.

METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1\%) had subclinical hypothyroidism and 648 (2.6\%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95\% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95\% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95\% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95\% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95\% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors.

CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH >=10 and <0.10 mIU/L.

}, keywords = {Adult, Aged, Aged, 80 and over, Comorbidity, Female, Follow-Up Studies, Heart Failure, Humans, Hypothyroidism, Male, Middle Aged, Prospective Studies, Risk, Risk Factors, Sensitivity and Specificity, Thyrotropin, Thyroxine}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.112.096024}, author = {Gencer, Bari{\c s} and Collet, Tinh-Hai and Virgini, Vanessa and Bauer, Douglas C and Gussekloo, Jacobijn and Cappola, Anne R and Nanchen, David and den Elzen, Wendy P J and Balmer, Philippe and Luben, Robert N and Iacoviello, Massimo and Triggiani, Vincenzo and Cornuz, Jacques and Newman, Anne B and Khaw, Kay-Tee and Jukema, J Wouter and Westendorp, Rudi G J and Vittinghoff, Eric and Aujesky, Drahomir and Rodondi, Nicolas} } @article {6028, title = {Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013 Jun}, pages = {e1003500}, abstract = {

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5\%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5{\texttimes}10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

}, keywords = {Anthropometry, Body Height, Body Mass Index, Body Weight, Body Weights and Measures, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Sex Characteristics, Waist Circumference, Waist-Hip Ratio}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003500}, author = {Randall, Joshua C and Winkler, Thomas W and Kutalik, Zolt{\'a}n and Berndt, Sonja I and Jackson, Anne U and Monda, Keri L and Kilpel{\"a}inen, Tuomas O and Esko, T{\~o}nu and M{\"a}gi, Reedik and Li, Shengxu and Workalemahu, Tsegaselassie and Feitosa, Mary F and Croteau-Chonka, Damien C and Day, Felix R and Fall, Tove and Ferreira, Teresa and Gustafsson, Stefan and Locke, Adam E and Mathieson, Iain and Scherag, Andre and Vedantam, Sailaja and Wood, Andrew R and Liang, Liming and Steinthorsdottir, Valgerdur and Thorleifsson, Gudmar and Dermitzakis, Emmanouil T and Dimas, Antigone S and Karpe, Fredrik and Min, Josine L and Nicholson, George and Clegg, Deborah J and Person, Thomas and Krohn, Jon P and Bauer, Sabrina and Buechler, Christa and Eisinger, Kristina and Bonnefond, Am{\'e}lie and Froguel, Philippe and Hottenga, Jouke-Jan and Prokopenko, Inga and Waite, Lindsay L and Harris, Tamara B and Smith, Albert Vernon and Shuldiner, Alan R and McArdle, Wendy L and Caulfield, Mark J and Munroe, Patricia B and Gr{\"o}nberg, Henrik and Chen, Yii-Der Ida and Li, Guo and Beckmann, Jacques S and Johnson, Toby and Thorsteinsdottir, Unnur and Teder-Laving, Maris and Khaw, Kay-Tee and Wareham, Nicholas J and Zhao, Jing Hua and Amin, Najaf and Oostra, Ben A and Kraja, Aldi T and Province, Michael A and Cupples, L Adrienne and Heard-Costa, Nancy L and Kaprio, Jaakko and Ripatti, Samuli and Surakka, Ida and Collins, Francis S and Saramies, Jouko and Tuomilehto, Jaakko and Jula, Antti and Salomaa, Veikko and Erdmann, Jeanette and Hengstenberg, Christian and Loley, Christina and Schunkert, Heribert and Lamina, Claudia and Wichmann, H Erich and Albrecht, Eva and Gieger, Christian and Hicks, Andrew A and Johansson, Asa and Pramstaller, Peter P and Kathiresan, Sekar and Speliotes, Elizabeth K and Penninx, Brenda and Hartikainen, Anna-Liisa and Jarvelin, Marjo-Riitta and Gyllensten, Ulf and Boomsma, Dorret I and Campbell, Harry and Wilson, James F and Chanock, Stephen J and Farrall, Martin and Goel, Anuj and Medina-G{\'o}mez, Carolina and Rivadeneira, Fernando and Estrada, Karol and Uitterlinden, Andr{\'e} G and Hofman, Albert and Zillikens, M Carola and den Heijer, Martin and Kiemeney, Lambertus A and Maschio, Andrea and Hall, Per and Tyrer, Jonathan and Teumer, Alexander and V{\"o}lzke, Henry and Kovacs, Peter and T{\"o}njes, Anke and Mangino, Massimo and Spector, Tim D and Hayward, Caroline and Rudan, Igor and Hall, Alistair S and Samani, Nilesh J and Attwood, Antony Paul and Sambrook, Jennifer G and Hung, Joseph and Palmer, Lyle J and Lokki, Marja-Liisa and Sinisalo, Juha and Boucher, Gabrielle and Huikuri, Heikki and Lorentzon, Mattias and Ohlsson, Claes and Eklund, Niina and Eriksson, Johan G and Barlassina, Cristina and Rivolta, Carlo and Nolte, Ilja M and Snieder, Harold and van der Klauw, Melanie M and van Vliet-Ostaptchouk, Jana V and Gejman, Pablo V and Shi, Jianxin and Jacobs, Kevin B and Wang, Zhaoming and Bakker, Stephan J L and Mateo Leach, Irene and Navis, Gerjan and van der Harst, Pim and Martin, Nicholas G and Medland, Sarah E and Montgomery, Grant W and Yang, Jian and Chasman, Daniel I and Ridker, Paul M and Rose, Lynda M and Lehtim{\"a}ki, Terho and Raitakari, Olli and Absher, Devin and Iribarren, Carlos and Basart, Hanneke and Hovingh, Kees G and Hypp{\"o}nen, Elina and Power, Chris and Anderson, Denise and Beilby, John P and Hui, Jennie and Jolley, Jennifer and Sager, Hendrik and Bornstein, Stefan R and Schwarz, Peter E H and Kristiansson, Kati and Perola, Markus and Lindstr{\"o}m, Jaana and Swift, Amy J and Uusitupa, Matti and Atalay, Mustafa and Lakka, Timo A and Rauramaa, Rainer and Bolton, Jennifer L and Fowkes, Gerry and Fraser, Ross M and Price, Jackie F and Fischer, Krista and Krjut{\r a} Kov, Kaarel and Metspalu, Andres and Mihailov, Evelin and Langenberg, Claudia and Luan, Jian{\textquoteright}an and Ong, Ken K and Chines, Peter S and Keinanen-Kiukaanniemi, Sirkka M and Saaristo, Timo E and Edkins, Sarah and Franks, Paul W and Hallmans, G{\"o}ran and Shungin, Dmitry and Morris, Andrew David and Palmer, Colin N A and Erbel, Raimund and Moebus, Susanne and N{\"o}then, Markus M and Pechlivanis, Sonali and Hveem, Kristian and Narisu, Narisu and Hamsten, Anders and Humphries, Steve E and Strawbridge, Rona J and Tremoli, Elena and Grallert, Harald and Thorand, Barbara and Illig, Thomas and Koenig, Wolfgang and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Boehm, Bernhard O and Kleber, Marcus E and M{\"a}rz, Winfried and Winkelmann, Bernhard R and Kuusisto, Johanna and Laakso, Markku and Arveiler, Dominique and Cesana, Giancarlo and Kuulasmaa, Kari and Virtamo, Jarmo and Yarnell, John W G and Kuh, Diana and Wong, Andrew and Lind, Lars and de Faire, Ulf and Gigante, Bruna and Magnusson, Patrik K E and Pedersen, Nancy L and Dedoussis, George and Dimitriou, Maria and Kolovou, Genovefa and Kanoni, Stavroula and Stirrups, Kathleen and Bonnycastle, Lori L and Nj{\o}lstad, Inger and Wilsgaard, Tom and Ganna, Andrea and Rehnberg, Emil and Hingorani, Aroon and Kivimaki, Mika and Kumari, Meena and Assimes, Themistocles L and Barroso, In{\^e}s and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Frayling, Timothy and Groop, Leif C and Haritunians, Talin and Hunter, David and Ingelsson, Erik and Kaplan, Robert and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Schlessinger, David and Strachan, David P and Stefansson, Kari and van Duijn, Cornelia M and Abecasis, Goncalo R and McCarthy, Mark I and Hirschhorn, Joel N and Qi, Lu and Loos, Ruth J F and Lindgren, Cecilia M and North, Kari E and Heid, Iris M} } @article {5878, title = {Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium.}, journal = {J Am Heart Assoc}, volume = {2}, year = {2013}, month = {2013 Mar 18}, pages = {e000102}, abstract = {

BACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.

METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19\% African Americans, 81\% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95\% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95\% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95\% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95\% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95\% CI, 0.664 to 0.747) and calibration was adequate.

CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Atrial Fibrillation, Cohort Studies, Diabetes Mellitus, European Continental Ancestry Group, Female, Heart Failure, Humans, Hypertension, Iceland, Incidence, Male, Middle Aged, Myocardial Infarction, Netherlands, Proportional Hazards Models, Risk Assessment, Smoking, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.112.000102}, author = {Alonso, Alvaro and Krijthe, Bouwe P and Aspelund, Thor and Stepas, Katherine A and Pencina, Michael J and Moser, Carlee B and Sinner, Moritz F and Sotoodehnia, Nona and Fontes, Jo{\~a}o D and Janssens, A Cecile J W and Kronmal, Richard A and Magnani, Jared W and Witteman, Jacqueline C and Chamberlain, Alanna M and Lubitz, Steven A and Schnabel, Renate B and Agarwal, Sunil K and McManus, David D and Ellinor, Patrick T and Larson, Martin G and Burke, Gregory L and Launer, Lenore J and Hofman, Albert and Levy, Daniel and Gottdiener, John S and K{\"a}{\"a}b, Stefan and Couper, David and Harris, Tamara B and Soliman, Elsayed Z and Stricker, Bruno H C and Gudnason, Vilmundur and Heckbert, Susan R and Benjamin, Emelia J} } @article {6189, title = {Sleep and insulin-like growth factors in the Cardiovascular Health Study.}, journal = {J Clin Sleep Med}, volume = {9}, year = {2013}, month = {2013 Dec 15}, pages = {1245-51}, abstract = {

STUDY OBJECTIVES: Sleep and sleep disordered breathing (obstructive sleep apnea [OSA]) are known to affect the growth hormone/insulin-like growth factor (GH/IGF) axis. There are few relevant population studies in this area, particularly in the elderly. We conducted this study to investigate the relationship between sleep (architecture and OSA) and circulating IGF-I (insulin-like growth factor-1), IGFBP-1 (insulin-like growth factor binding protein-1), and IGFBP-3 (insulin-like growth factor binding protein-3) levels in an elderly population.

DESIGN SETTING: Cross-sectional analysis of participants from the year 9 visit of the Cardiovascular Health Study (CHS) who were enrolled in the Sleep Heart Health Study (SHHS).

PATIENTS OR PARTICIPANTS: 1,233 elderly participants from the CHS and SHHS.

MEASUREMENTS AND RESULTS: The mean age of males (n = 526) and females (n = 697) was 77 years. The mean value of IGF-I (ng/mL) in males was 112.4 vs. 97.1 in females (p < 0.01). Mean IGFBP-1 and IGFBP-3 levels were higher in females than males (p < 0.01). As expected, slow wave sleep was better preserved in females compared to males (22\% total sleep time vs. 9\% total sleep time, p < 0.01). Furthermore, as expected, OSA (apneahypopnea index [AHI] >= 5/h) was more prevalent in males compared to females (60\% vs. 46\%, p < 0.01). Multivariable linear regression was used to determine the relationship between objective sleep parameters and circulating IGF-I, IGFBP-1, and IGFBP-3 levels, with adjustment for age, sex, race, BMI, diabetes, estrogen use, progestin use, and physical activity. We did not detect a significant association between slow wave sleep (SWS) (per 5 min) and IGF-I, IGFBP-1, and IGFBP-3 levels (ng/mL). We found no significant linear association between OSA (AHI >= 5/h) and IGF-I, IGFBP-1, and IGFBP-3 levels. Gender-stratification of the entire cohort did not alter these findings. Sensitivity analyses excluding diabetics revealed that moderate OSA (AHI >= 5 and < 15) is inversely associated with IGFBP-3 levels in women. Conclusions The relationship between SWS and GH/IGF system is not significant in the elderly. Furthermore, OSA does not appear to adversely influence the GH/IGF axis, as reported in younger individuals. Whether our study findings are due to diminished GH/IGF-I axis activity in elderly needs further investigation by replication in other large population based elderly cohorts.

}, keywords = {Aged, Cardiovascular Diseases, Cohort Studies, Cross-Sectional Studies, Female, Geriatric Assessment, Health Surveys, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Sex Distribution, Sleep, Sleep Apnea, Obstructive, Somatomedins, United States}, issn = {1550-9397}, doi = {10.5664/jcsm.3260}, author = {Shah, Neomi and Rice, Tom and Tracy, Daniel and Rohan, Thomas and B{\r u}zkov{\'a}, Petra and Newman, Anne and Kaplan, Robert C} } @article {1564, title = {Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {33}, year = {2013}, month = {2013 Jan}, pages = {158-64}, abstract = {

OBJECTIVE: CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.

METHODS AND RESULTS: We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the CD14 locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of PIGC, which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults.

CONCLUSIONS: CD14 independently predicts risk mortality in older adults.

}, keywords = {African Americans, Age Factors, Aged, Biomarkers, Cardiovascular Diseases, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Hexosyltransferases, Humans, Incidence, Inflammation Mediators, Linear Models, Lipopolysaccharide Receptors, Logistic Models, Male, Membrane Proteins, Multivariate Analysis, Phenotype, Polymorphism, Single Nucleotide, Principal Component Analysis, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.112.300421}, author = {Reiner, Alex P and Lange, Ethan M and Jenny, Nancy S and Chaves, Paulo H M and Ellis, Jaclyn and Li, Jin and Walston, Jeremy and Lange, Leslie A and Cushman, Mary and Tracy, Russell P} } @article {6218, title = {Strategy to control type I error increases power to identify genetic variation using the full biological trajectory.}, journal = {Genet Epidemiol}, volume = {37}, year = {2013}, month = {2013 Jul}, pages = {419-30}, abstract = {

Genome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.

}, keywords = {Cohort Studies, Computer Simulation, Genetic Variation, Genome-Wide Association Study, Humans, Linear Models, Models, Genetic, Polymorphism, Single Nucleotide}, issn = {1098-2272}, doi = {10.1002/gepi.21733}, author = {Benke, K S and Wu, Y and Fallin, D M and Maher, B and Palmer, L J} } @article {6628, title = {A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003171}, abstract = {

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 {\texttimes} 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, African Americans, Aged, Aged, 80 and over, Alleles, Body Mass Index, Chromosome Mapping, Continental Population Groups, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Metagenomics, Middle Aged, Obesity, Proteins}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003171}, author = {Peters, Ulrike and North, Kari E and Sethupathy, Praveen and Buyske, Steve and Haessler, Jeff and Jiao, Shuo and Fesinmeyer, Megan D and Jackson, Rebecca D and Kuller, Lew H and Rajkovic, Aleksandar and Lim, Unhee and Cheng, Iona and Schumacher, Fred and Wilkens, Lynne and Li, Rongling and Monda, Keri and Ehret, Georg and Nguyen, Khanh-Dung H and Cooper, Richard and Lewis, Cora E and Leppert, Mark and Irvin, Marguerite R and Gu, C Charles and Houston, Denise and B{\r u}zkov{\'a}, Petra and Ritchie, Marylyn and Matise, Tara C and Le Marchand, Lo{\"\i}c and Hindorff, Lucia A and Crawford, Dana C and Haiman, Christopher A and Kooperberg, Charles} } @article {9409, title = {A self-report risk index to predict occurrence of dementia in three independent cohorts of older adults: the ANU-ADRI.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e86141}, abstract = {

BACKGROUND AND AIMS: The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer{\textquoteright}s disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.

METHODS: This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age >=53 years), the Kungsholmen Project (KP) (n = 905, age >=75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age >=65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.

RESULTS: For the ANU-ADRI using available data, the MAP study c-statistic was 0{\textperiodcentered}637 (95\% CI 0{\textperiodcentered}596-0{\textperiodcentered}678), for the KP study it was 0{\textperiodcentered}740 (0{\textperiodcentered}712-0{\textperiodcentered}768) and for the CVHS it was 0{\textperiodcentered}733 (0{\textperiodcentered}691-0{\textperiodcentered}776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95\% CI 0.650-0.727), 0.666 (0.628-0.704) and 0.734 (0.707-0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427-0.554) to 0.595 (0.565-0.625).

CONCLUSION: A composite risk score derived from the ANU-ADRI weights including 8-10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.

}, keywords = {Adult, Aged, Aged, 80 and over, Alzheimer Disease, Dementia, Female, Humans, Incidence, Male, Middle Aged, Risk, ROC Curve, Self Report}, issn = {1932-6203}, doi = {10.1371/journal.pone.0086141}, author = {Anstey, Kaarin J and Cherbuin, Nicolas and Herath, Pushpani M and Qiu, Chengxuan and Kuller, Lewis H and Lopez, Oscar L and Wilson, Robert S and Fratiglioni, Laura} } @article {6338, title = {Separate prediction of intracerebral hemorrhage and ischemic stroke.}, journal = {Neurology}, volume = {82}, year = {2014}, month = {2014 May 20}, pages = {1804-12}, abstract = {

OBJECTIVES: To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).

METHODS: We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45\% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38\% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41\% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions{\textquoteright} performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.

RESULTS: High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross-validation. Models were well calibrated in all cohorts. Correlations between 10-year ICH and IS risks were moderate in each cohort.

CONCLUSIONS: We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual{\textquoteright}s stroke risk.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Body Mass Index, Brain Ischemia, Cholesterol, Female, Humans, Incidence, Intracranial Hemorrhages, Male, Middle Aged, Models, Statistical, Predictive Value of Tests, Risk Assessment, Risk Factors, Stroke}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000000427}, author = {Ferket, Bart S and van Kempen, Bob J H and Wieberdink, Renske G and Steyerberg, Ewout W and Koudstaal, Peter J and Hofman, Albert and Shahar, Eyal and Gottesman, Rebecca F and Rosamond, Wayne and Kizer, Jorge R and Kronmal, Richard A and Psaty, Bruce M and Longstreth, W T and Mosley, Thomas and Folsom, Aaron R and Hunink, M G Myriam and Ikram, M Arfan} } @article {6618, title = {Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e109155}, abstract = {

BACKGROUND: Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).

METHODS AND RESULTS: Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (>=50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF<=1\%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r{\texttwosuperior} = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r{\texttwosuperior} = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.

CONCLUSION: Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.

}, keywords = {Aging, Blood Pressure, Cohort Studies, Heart, Humans, Sequence Analysis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0109155}, author = {Morrison, Alanna C and Bis, Joshua C and Hwang, Shih-Jen and Ehret, Georg B and Lumley, Thomas and Rice, Kenneth and Muzny, Donna and Gibbs, Richard A and Boerwinkle, Eric and Psaty, Bruce M and Chakravarti, Aravinda and Levy, Daniel} } @article {6579, title = {Sequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {344-9}, abstract = {

BACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.

METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1\%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29\%; P=3.46{\texttimes}10(-4)) using a Bonferroni threshold of P<4.6{\texttimes}10(-4). Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11{\texttimes}10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3{\textquoteright} genome-wide association study region.

CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.

}, keywords = {Adult, Aged, Aging, Body Mass Index, Cohort Studies, Female, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.13.000067}, author = {Liu, Ching-Ti and Young, Kristin L and Brody, Jennifer A and Olden, Matthias and Wojczynski, Mary K and Heard-Costa, Nancy and Li, Guo and Morrison, Alanna C and Muzny, Donna and Gibbs, Richard A and Reid, Jeffrey G and Shao, Yaming and Zhou, Yanhua and Boerwinkle, Eric and Heiss, Gerardo and Wagenknecht, Lynne and McKnight, Barbara and Borecki, Ingrid B and Fox, Caroline S and North, Kari E and Cupples, L Adrienne} } @article {6547, title = {Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {359-64}, abstract = {

BACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).

METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency >=1\%), which were independently meta-analyzed. A 3{\textquoteright} untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1\%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).

CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.

}, keywords = {Aged, Aged, 80 and over, Aging, Atherosclerosis, Class Ib Phosphatidylinositol 3-Kinase, Cohort Studies, European Continental Ancestry Group, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Sodium-Phosphate Cotransporter Proteins, Type I}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000116}, author = {Bis, Joshua C and White, Charles C and Franceschini, Nora and Brody, Jennifer and Zhang, Xiaoling and Muzny, Donna and Santibanez, Jireh and Gibbs, Richard and Liu, Xiaoming and Lin, Honghuang and Boerwinkle, Eric and Psaty, Bruce M and North, Kari E and Cupples, L Adrienne and O{\textquoteright}Donnell, Christopher J} } @article {6583, title = {Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {365-73}, abstract = {

BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.

METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1\%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute{\textquoteright}s Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3{\texttimes}10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25{\texttimes}10(-4) and P=5.2{\texttimes}10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82{\texttimes}10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35{\texttimes}10(-7) and P=2.69{\texttimes}10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67{\texttimes}10(-5)).

CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Conduction System, Heart Diseases, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000098}, author = {Magnani, Jared W and Brody, Jennifer A and Prins, Bram P and Arking, Dan E and Lin, Honghuang and Yin, Xiaoyan and Liu, Ching-Ti and Morrison, Alanna C and Zhang, Feng and Spector, Tim D and Alonso, Alvaro and Bis, Joshua C and Heckbert, Susan R and Lumley, Thomas and Sitlani, Colleen M and Cupples, L Adrienne and Lubitz, Steven A and Soliman, Elsayed Z and Pulit, Sara L and Newton-Cheh, Christopher and O{\textquoteright}Donnell, Christopher J and Ellinor, Patrick T and Benjamin, Emelia J and Muzny, Donna M and Gibbs, Richard A and Santibanez, Jireh and Taylor, Herman A and Rotter, Jerome I and Lange, Leslie A and Psaty, Bruce M and Jackson, Rebecca and Rich, Stephen S and Boerwinkle, Eric and Jamshidi, Yalda and Sotoodehnia, Nona} } @article {6243, title = {Serum carboxymethyl-lysine, disability, and frailty in older persons: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Jun}, pages = {710-6}, abstract = {

BACKGROUND: Advanced glycation endproducts are biologically active compounds that accumulate in disordered metabolism and normal aging. Carboxymethyl-lysine (CML), a ubiquitous human advanced glycation endproduct, has been associated with age-related conditions and mortality. Our objective was to ascertain the relationship between CML and geriatric outcomes (disability and frailty) in a large cohort of older men and women.

METHODS: In 1996-1997, serum CML was measured in 3,373 Cardiovascular Health Study participants (mean age 78.1 {\textpm} 4.8 years). Disability, defined as difficulty in any of six activities of daily living, was assessed every 6-12 months for 14 years. Frailty was defined according to five standard criteria at the 1996-1997 visit. Cox proportional hazard models estimated the relationship between CML and incident disability (N = 2,643). Logistic regression models estimated the relationship between CML and prevalent frailty.

RESULTS: Adjusting for multiple potential confounders, higher CML was associated with incident disability (hazard ratio per standard deviation [225 ng/mL] increase: 1.05, 95\% CI 1.01-1.11). In men, odds of frailty increased with higher CML values (odds ratio = 1.30 per standard deviation, 95\% CI 1.14-1.48), but the relationship was attenuated by adjustment for cognitive status, kidney function, and arthritis. CML was not associated with frailty in women.

CONCLUSIONS: Higher serum CML levels in late life are associated with incident disability and prevalent frailty. Further work is needed to understand CML{\textquoteright}s value as a risk stratifier, biomarker, or target for interventions that promote healthy aging.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Aging, Biomarkers, Cardiac Rehabilitation, Cardiovascular Diseases, Disabled Persons, Female, Follow-Up Studies, Frail Elderly, Health Status, Humans, Incidence, Lysine, Male, Prevalence, Prognosis, Retrospective Studies, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glt155}, author = {Whitson, Heather E and Arnold, Alice M and Yee, Laura M and Mukamal, Kenneth J and Kizer, Jorge R and Djouss{\'e}, Luc and Ix, Joachim H and Siscovick, David and Tracy, Russell P and Thielke, Stephen M and Hirsch, Calvin and Newman, Anne B and Zieman, Susan} } @article {6370, title = {Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Jan}, pages = {24-36}, abstract = {

BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.

METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.

RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5{\texttimes}10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62{\texttimes}10(-7)) and ABO (PIS=2.6{\texttimes}10(-4)), as well as at HDAC9 (PLAS=2.32{\texttimes}10(-12)), 9p21 (PLAS=3.70{\texttimes}10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69{\texttimes}10(-5)), EDNRA (PLAS=7.29{\texttimes}10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9{\texttimes}10(-4)).

CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

}, keywords = {Brain Ischemia, Coronary Artery Disease, Data Interpretation, Statistical, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.113.002707}, author = {Dichgans, Martin and Malik, Rainer and K{\"o}nig, Inke R and Rosand, Jonathan and Clarke, Robert and Gretarsdottir, Solveig and Thorleifsson, Gudmar and Mitchell, Braxton D and Assimes, Themistocles L and Levi, Christopher and O{\textquoteright}Donnell, Christopher J and Fornage, Myriam and Thorsteinsdottir, Unnur and Psaty, Bruce M and Hengstenberg, Christian and Seshadri, Sudha and Erdmann, Jeanette and Bis, Joshua C and Peters, Annette and Boncoraglio, Giorgio B and M{\"a}rz, Winfried and Meschia, James F and Kathiresan, Sekar and Ikram, M Arfan and McPherson, Ruth and Stefansson, Kari and Sudlow, Cathie and Reilly, Muredach P and Thompson, John R and Sharma, Pankaj and Hopewell, Jemma C and Chambers, John C and Watkins, Hugh and Rothwell, Peter M and Roberts, Robert and Markus, Hugh S and Samani, Nilesh J and Farrall, Martin and Schunkert, Heribert} } @article {6608, title = {Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Feb}, pages = {165-73}, abstract = {

BACKGROUND: Individual measurements of inflammation have been utilized to assess adverse outcomes risk in older adults with varying degrees of success. This study was designed to identify biologically informed, aggregate measures of inflammation for optimal risk assessment and to inform further biological study of inflammatory pathways.

METHODS: In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI.

RESULTS: The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index (hazards ratio = 1.62; 95\% CI: 1.54, 1.70) compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study (hazards ratio 1.33; 95\% CI: 1.17-1.52). Stratification by sex and CVD status further strengthened the association of inflammation index score with mortality.

CONCLUSION: A simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, C-Reactive Protein, Cohort Studies, Female, Humans, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-18, Interleukin-6, Longevity, Male, Receptors, Tumor Necrosis Factor, Type I, Risk Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glt023}, author = {Varadhan, Ravi and Yao, Wenliang and Matteini, Amy and Beamer, Brock A and Xue, Qian-Li and Yang, Huanle and Manwani, Bhavish and Reiner, Alexander and Jenny, Nancy and Parekh, Neel and Fallin, M Daniele and Newman, Anne and Bandeen-Roche, Karen and Tracy, Russell and Ferrucci, Luigi and Walston, Jeremy} } @article {6270, title = {Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes.}, journal = {Diabetologia}, volume = {57}, year = {2014}, month = {2014 Feb}, pages = {339-46}, abstract = {

AIMS/HYPOTHESIS: Short and long sleep duration are associated with increased risk of type 2 diabetes. We aimed to investigate whether genetic variants for fasting glucose or type 2 diabetes associate with short or long sleep duration and whether sleep duration modifies the association of genetic variants with these traits.

METHODS: We examined the cross-sectional relationship between self-reported habitual sleep duration and prevalence of type 2 diabetes in individuals of European descent participating in five studies included in the Candidate Gene Association Resource (CARe), totalling 1,474 cases and 8,323 controls. We tested for association of 16 fasting glucose-associated variants, 27 type 2 diabetes-associated variants and aggregate genetic risk scores with continuous and dichotomised (<=5~h or >=9~h) sleep duration using regression models adjusted for age, sex and BMI. Finally, we tested whether a gene {\texttimes} behaviour interaction of variants with sleep duration had an impact on fasting glucose or type 2 diabetes risk.

RESULTS: Short sleep duration was significantly associated with type 2 diabetes in CARe (OR 1.32; 95\% CI 1.08, 1.61; p = 0.008). Variants previously associated with fasting glucose or type 2 diabetes and genetic risk scores were not associated with sleep duration. Furthermore, no study-wide significant interaction was observed between sleep duration and these variants on glycaemic traits. Nominal interactions were observed for sleep duration and PPARG rs1801282, CRY2 rs7943320 and HNF1B rs4430796 in influencing risk of type 2 diabetes (p < 0.05).

CONCLUSIONS/INTERPRETATION: Our findings suggest that differences in habitual sleep duration do not mediate or modify the relationship between common variants underlying glycaemic traits (including in circadian rhythm genes) and diabetes.

}, keywords = {Blood Glucose, Body Composition, Body Mass Index, Cross-Sectional Studies, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Fasting, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Glucose Intolerance, Glycated Hemoglobin A, Humans, Insulin Resistance, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Sleep, Surveys and Questionnaires, Time Factors, United States}, issn = {1432-0428}, doi = {10.1007/s00125-013-3110-y}, author = {Tare, Archana and Lane, Jacqueline M and Cade, Brian E and Grant, Struan F A and Chen, Ting-Hsu and Punjabi, Naresh M and Lauderdale, Diane S and Zee, Phyllis C and Gharib, Sina A and Gottlieb, Daniel J and Scheer, Frank A J L and Redline, Susan and Saxena, Richa} } @article {6578, title = {Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {335-43}, abstract = {

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with >=1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency >=1\%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Research Design, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000350}, author = {Lin, Honghuang and Wang, Min and Brody, Jennifer A and Bis, Joshua C and Dupuis, Jos{\'e}e and Lumley, Thomas and McKnight, Barbara and Rice, Kenneth M and Sitlani, Colleen M and Reid, Jeffrey G and Bressler, Jan and Liu, Xiaoming and Davis, Brian C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Kovar, Christie L and Dinh, Huyen and Wu, Yuanqing and Newsham, Irene and Chen, Han and Broka, Andi and DeStefano, Anita L and Gupta, Mayetri and Lunetta, Kathryn L and Liu, Ching-Ti and White, Charles C and Xing, Chuanhua and Zhou, Yanhua and Benjamin, Emelia J and Schnabel, Renate B and Heckbert, Susan R and Psaty, Bruce M and Muzny, Donna M and Cupples, L Adrienne and Morrison, Alanna C and Boerwinkle, Eric} } @article {6213, title = {Subclinical hypothyroidism, weight change, and body composition in the elderly: the Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Apr}, pages = {1220-6}, abstract = {

BACKGROUND: Subclinical hypothyroidism is common in the elderly, yet its relationship with weight and body composition is unclear.

OBJECTIVE: We examined the relationship between subclinical hypothyroidism and weight change and body composition in older adults.

METHODS: A total of 427 subclinically hypothyroid and 2864 euthyroid U.S. individuals >=65 years old enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of 6-year weight change were performed, compared by thyroid status. A cross-sectional analysis of thyroid status and body composition was performed in a subset of 1276 participants who had dual-energy x-ray absorptiometry scans. Models were risk factor-adjusted and stratified by sex.

RESULTS: Overall, participants lost weight during follow-up (-0.38 kg/y in men, -0.37 kg/y in women). Subclinical hypothyroidism, when assessed at a single time point or persisting over 2 years, was not associated with a difference in weight change compared with euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared with euthyroidism. A TSH level 1 mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51-kg higher baseline weight in women only (P < .001) but not with weight change in either sex. A 1 ng/dL higher free T4 level was associated with lower baseline weight and 0.32 kg/y greater weight loss in women only (P = .003). Baseline weight and weight change did not differ by T3 levels.

CONCLUSIONS: Our data do not support a clinically significant impact of subclinical hypothyroidism on weight status in the elderly.

}, keywords = {Aged, Aged, 80 and over, Asymptomatic Diseases, Body Composition, Body Mass Index, Cohort Studies, Female, Humans, Hypothyroidism, Male, Thyroid Gland, Weight Loss}, issn = {1945-7197}, doi = {10.1210/jc.2013-3591}, author = {Garin, Margaret C and Arnold, Alice M and Lee, Jennifer S and Tracy, Russell P and Cappola, Anne R} } @article {6401, title = {Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Aug}, pages = {2657-64}, abstract = {

BACKGROUND: Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear.

OBJECTIVE: We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults.

METHODS: A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex.

RESULTS: No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95\% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95\% CI 0.52-1.21 for two time points] or men (HR 1.27, 95\% CI 0.82-1.95 for a single and HR 1.09, 95\% CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95\% CI 0.55-2.25 in women and HR 1.78, 95\% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites.

CONCLUSIONS: Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidism and hip fracture risk or BMD in older men and women. Additional data are needed to improve the precision of estimates for subclinical hyperthyroidism and in men.

}, keywords = {Absorptiometry, Photon, Aged, Aged, 80 and over, Asymptomatic Diseases, Bone Density, Cardiovascular System, Cohort Studies, Cross-Sectional Studies, Female, Hip Fractures, Humans, Male, Osteoporotic Fractures, Risk Factors, Sex Factors, Thyroid Diseases}, issn = {1945-7197}, doi = {10.1210/jc.2014-1051}, author = {Garin, Margaret C and Arnold, Alice M and Lee, Jennifer S and Robbins, John and Cappola, Anne R} } @article {6589, title = {Subclinical vascular disease burden and longer survival.}, journal = {J Am Geriatr Soc}, volume = {62}, year = {2014}, month = {2014 Sep}, pages = {1692-8}, abstract = {

OBJECTIVES: To determine the contribution of gradations of subclinical vascular disease (SVD) to the likelihood of longer survival and to determine what allows some individuals with SVD to live longer.

DESIGN: Cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals born between June 30, 1918, and June 30, 1921 (N~=~2,082; aged 70-75 at baseline (1992-93)).

MEASUREMENTS: A SVD index was scored as 0 for no abnormalities, 1 for mild abnormalities, and 2 for severe abnormalities on ankle-arm index, electrocardiogram, and common carotid intima-media thickness measured at baseline. Survival groups were categorized as 80 and younger, 81 to 84, 85 to 89, and 90 and older.

RESULTS: A 1-point lower SVD score was associated with 1.22 greater odds (95\% confidence interval~=~1.14-1.31) of longer survival, independent of potential confounders. This association was unchanged after adjustment for intermediate incident cardiovascular events. There was suggestion of an interaction between kidney function, smoking, and C-reactive protein and SVD; the association between SVD and longer survival appeared to be modestly greater in persons with poor kidney function, inflammation, or a history of smoking.

CONCLUSION: A lower burden of SVD is associated with longer survival, independent of intermediate cardiovascular events. Abstinence from smoking, better kidney function, and lower inflammation may attenuate the effects of higher SVD and promote longer survival.

}, keywords = {Aged, Aged, 80 and over, C-Reactive Protein, Carotid Intima-Media Thickness, Cohort Studies, Cystatin C, Depression, Diabetes Mellitus, Electrocardiography, Female, Humans, Inflammation, Kidney Diseases, Male, Smoking, Survival Analysis, United States, Vascular Diseases}, issn = {1532-5415}, doi = {10.1111/jgs.13018}, author = {Odden, Michelle C and Yee, Laura M and Arnold, Alice M and Sanders, Jason L and Hirsch, Calvin and DeFilippi, Christopher and Kizer, Jorge R and Inzitari, Marco and Newman, Anne B} } @article {6398, title = {Systolic and diastolic blood pressure, incident cardiovascular events, and death in elderly persons: the role of functional limitation in the Cardiovascular Health Study.}, journal = {Hypertension}, volume = {64}, year = {2014}, month = {2014 Sep}, pages = {472-80}, abstract = {

Whether limitation in the ability to perform activities of daily living (ADL) or gait speed can identify elders in whom the association of systolic and diastolic blood pressure (DBP) with cardiovascular events (CVDs) and death differs is unclear. We evaluated whether limitation in ADL or gait speed modifies the association of systolic blood pressure or DBP with incident CVD (n=2358) and death (n=3547) in the Cardiovascular Health Study. Mean age was 78{\textpm}5 and 21\% reported limitation in >=1 ADL. There were 778 CVD and 1289 deaths over 9 years. Among persons without and those with ADL limitation, systolic blood pressure was associated with incident CVD: hazard ratio [HR] (per 10-mm Hg increase) 1.08 (95\% confidence interval, 1.03, 1.13) and 1.06 (0.97, 1.17), respectively. ADL modified the association of DBP with incident CVD. Among those without ADL limitation, DBP was weakly associated with incident CVD, HR 1.04 (0.79, 1.37) for DBP >80, compared with <65 mm Hg. Among those with ADL limitation, DBP was inversely associated with CVD: HR 0.65 (0.44, 0.96) for DBP 66 to 80 mm Hg and HR 0.49 (0.25, 0.94) for DBP >80, compared with DBP <=65. Among people with ADL limitation, a DBP of 66 to 80 had the lowest risk of death, HR 0.72 (0.57, 0.91), compared with a DBP of <=65. Associations did not vary by 15-feet walking speed. ADL can identify elders in whom diastolic hypotension is associated with higher cardiovascular risk and death. Functional status, rather than chronologic age alone, should inform design of hypertension trials in elders.

}, keywords = {Activities of Daily Living, African Continental Ancestry Group, Aged, Aged, 80 and over, Blood Pressure, Cardiovascular Diseases, Diastole, European Continental Ancestry Group, Female, Follow-Up Studies, Gait, Heart Rate, Humans, Incidence, Longitudinal Studies, Male, Risk Factors, Survival Rate, Systole}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.114.03831}, author = {Peralta, Carmen A and Katz, Ronit and Newman, Anne B and Psaty, Bruce M and Odden, Michelle C} } @article {6702, title = {Serial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults.}, journal = {Heart Rhythm}, volume = {12}, year = {2015}, month = {2015 May}, pages = {879-85}, abstract = {

BACKGROUND: Various mechanisms in cardiac remodeling related to atrial fibrillation (AF) lead to elevated circulating cardiac troponin levels, but little is known about such elevations upstream to AF onset.

OBJECTIVE: The purpose of this study was to study the association between circulating troponin levels as assessed by a highly sensitive cardiac troponin T (hs-cTnT) assay and incident atrial fibrillation (AF).

METHODS: In a large prospective cohort of ambulatory older adults [the Cardiovascular Health Study (CHS)], hs-cTnT levels were measured in sera that were collected at enrollment from 4262 participants without AF (2871 with follow-up measurements). Incident AF was identified by electrocardiograms during CHS visits, hospital discharge diagnoses, and Medicare files, including outpatient and physician claims diagnoses.

RESULTS: Over median follow-up of 11.2 years (interquartile range 6.1-16.5), 1363 participants (32.0\%) developed AF. Higher baseline levels of hs-cTnT were associated with incident AF in covariate-adjusted analyses accounting for demographics, traditional risk factors, and incident heart failure in time-dependent analyzes (hazard ratio for 3rd tertile vs undetectable 1.75, 95\% confidence interval 1.48-2.08). This association was statistically significant in analyses that additionally adjusted for biomarkers of inflammation and hemodynamic strain (hazard ratio for 3rd tertile vs undetectable 1.38, 95\% confidence interval 1.16-1.65). Significant associations were also found when hs-cTnT levels were treated as a continuous variable and when examining change from baseline of hs-cTnT levels and incident AF.

CONCLUSION: The findings show a significant association of circulating troponin levels in ambulatory older adults with incident AF beyond that of traditional risk factors, incident heart failure, and biomarkers of inflammation and hemodynamic strain.

}, keywords = {Aged, Atrial Fibrillation, Biomarkers, Electrocardiography, Female, Heart Failure, Humans, Incidence, Longitudinal Studies, Male, Outpatients, Risk Assessment, Risk Factors, Statistics as Topic, Troponin T, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2015.01.020}, author = {Hussein, Ayman A and Bartz, Traci M and Gottdiener, John S and Sotoodehnia, Nona and Heckbert, Susan R and Lloyd-Jones, Donald and Kizer, Jorge R and Christenson, Robert and Wazni, Oussama and DeFilippi, Christopher} } @article {6624, title = {Serum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study.}, journal = {Metabolism}, volume = {64}, year = {2015}, month = {2015 Mar}, pages = {438-46}, abstract = {

PURPOSE: Uric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults.

METHODS: 1963 men and 2729 women >=65 years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex a priori.

RESULTS: There was a U-shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and >=6.88 mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95\% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women.

CONCLUSION: In this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cohort Studies, Estrogen Replacement Therapy, Female, Health Surveys, Hip Fractures, Humans, Kaplan-Meier Estimate, Male, Prospective Studies, Risk, Sex Factors, United States, Uric Acid}, issn = {1532-8600}, doi = {10.1016/j.metabol.2014.11.006}, author = {Mehta, Tapan and B{\r u}zkov{\'a}, Petra and Sarnak, Mark J and Chonchol, Michel and Cauley, Jane A and Wallace, Erin and Fink, Howard A and Robbins, John and Jalal, Diana} } @article {6934, title = {Sex, Race, and Age Differences in Observed Years of Life, Healthy Life, and Able Life among Older Adults in The Cardiovascular Health Study.}, journal = {J Pers Med}, volume = {5}, year = {2015}, month = {2015}, pages = {440-51}, abstract = {

OBJECTIVE: Longevity fails to account for health and functional status during aging. We sought to quantify differences in years of total life, years of healthy life, and years of able life among groups defined by age, sex, and race.

DESIGN: Primary analysis of a cohort study.

SETTING: 18 years of annual evaluations in four U.S. communities.

PARTICIPANTS: 5888 men and women aged 65 and older.

MEASUREMENTS: Years of life were calculated as the time from enrollment to death or 18 years. Years of total, healthy, and able life were determined from self-report during annual or semi-annual contacts. Cumulative years were summed across each of the age and sex groups.

RESULTS: White women had the best outcomes for all three measures, followed by white men, non-white women, and non-white men. For example, at the mean age of 73, a white female participant could expect 12.9 years of life, 8.9 of healthy life and 9.5 of able life, while a non-white female could expect 12.6, 7.0, and 8.0 years, respectively. A white male could expect 11.2, 8.1, and 8.9 years of life, healthy life, and able life, and a non-white male 10.3, 6.2, and 7.9 years. Regardless of starting age, individuals of the same race and sex groups spent similar amounts (not proportions) of time in an unhealthy or unable state.

CONCLUSION: Gender had a greater effect on longevity than did race, but race had a greater effect on years spent healthy or able. The mean number of years spent in an unable or sick state was surprisingly independent of the lifespan.

}, issn = {2075-4426}, doi = {10.3390/jpm5040440}, author = {Thielke, Stephen M and Diehr, Paula H and Yee, Laura M and Arnold, Alice M and Qui{\~n}ones, Ana R and Whitson, Heather E and Jacob, Mini E and Newman, Anne B} } @article {6813, title = {Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.}, journal = {Neurology}, volume = {84}, year = {2015}, month = {2015 May 26}, pages = {2132-45}, abstract = {

OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.

METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.

RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 {\texttimes} 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 {\texttimes} 10(-20) for the CE score in MO).

CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

}, keywords = {Brain Ischemia, Genome-Wide Association Study, Humans, Migraine with Aura, Migraine without Aura, Stroke}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000001606}, author = {Malik, Rainer and Freilinger, Tobias and Winsvold, Bendik S and Anttila, Verneri and Vander Heiden, Jason and Traylor, Matthew and de Vries, Boukje and Holliday, Elizabeth G and Terwindt, Gisela M and Sturm, Jonathan and Bis, Joshua C and Hopewell, Jemma C and Ferrari, Michel D and Rannikmae, Kristiina and Wessman, Maija and Kallela, Mikko and Kubisch, Christian and Fornage, Myriam and Meschia, James F and Lehtim{\"a}ki, Terho and Sudlow, Cathie and Clarke, Robert and Chasman, Daniel I and Mitchell, Braxton D and Maguire, Jane and Kaprio, Jaakko and Farrall, Martin and Raitakari, Olli T and Kurth, Tobias and Ikram, M Arfan and Reiner, Alex P and Longstreth, W T and Rothwell, Peter M and Strachan, David P and Sharma, Pankaj and Seshadri, Sudha and Quaye, Lydia and Cherkas, Lynn and Sch{\"u}rks, Markus and Rosand, Jonathan and Ligthart, Lannie and Boncoraglio, Giorgio B and Davey Smith, George and van Duijn, Cornelia M and Stefansson, Kari and Worrall, Bradford B and Nyholt, Dale R and Markus, Hugh S and van den Maagdenberg, Arn M J M and Cotsapas, Chris and Zwart, John A and Palotie, Aarno and Dichgans, Martin} } @article {6854, title = {Sleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {38}, year = {2015}, month = {2015 Nov}, pages = {2050-8}, abstract = {

OBJECTIVE: We examined the associations of symptoms of sleep-disordered breathing (SDB), which was defined as loud snoring, stopping breathing for a while during sleep, and daytime sleepiness, and insomnia with glucose metabolism and incident type 2 diabetes in older adults.

RESEARCH DESIGN AND METHODS: Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 participants >=65 years of age from four U.S. communities. Participants reported SDB and insomnia symptoms yearly through 1989-1994. In 1989-1990, participants underwent an oral glucose tolerance test, from which insulin secretion and insulin sensitivity were estimated. Fasting glucose levels were measured in 1989-1990 and again in 1992-1993, 1994-1995, 1996-1997, and 1998-1999, and medication use was ascertained yearly. We determined the cross-sectional associations of sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, and insulin secretion using generalized estimated equations and linear regression models. We determined the associations of updated and averaged sleep symptoms with incident diabetes in Cox proportional hazards models. We adjusted for sociodemographics, lifestyle factors, and medical history.

RESULTS: Observed apnea, snoring, and daytime sleepiness were associated with higher fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and higher insulin secretion. The risk of the development of type 2 diabetes was positively associated with observed apnea (hazard ratio [HR] 1.84 [95\% CI 1.19-2.86]), snoring (HR 1.27 [95\% CI 0.95-1.71]), and daytime sleepiness (HR 1.54 [95\% CI 1.13-2.12]). In contrast, we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes.

CONCLUSIONS: Easily collected symptoms of SDB are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults. Monitoring glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy. Further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults.

}, keywords = {Adult, Aged, Blood Glucose, Cardiovascular System, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Fasting, Female, Glucose Tolerance Test, Humans, Incidence, Insulin, Insulin Resistance, Male, Middle Aged, Sleep Apnea Syndromes, Sleep Initiation and Maintenance Disorders, Snoring, United States}, issn = {1935-5548}, doi = {10.2337/dc15-0137}, author = {Strand, Linn Beate and Carnethon, Mercedes and Biggs, Mary Lou and Djouss{\'e}, Luc and Kaplan, Robert C and Siscovick, David S and Robbins, John A and Redline, Susan and Patel, Sanjay R and Janszky, Imre and Mukamal, Kenneth J} } @article {6928, title = {Social Network Size and Cranial Magnetic Resonance Imaging Findings in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {63}, year = {2015}, month = {2015 Nov}, pages = {2430-2}, keywords = {Aged, Brain, Cardiovascular Diseases, Cross-Sectional Studies, Female, Geriatric Assessment, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Social Participation, Social Support}, issn = {1532-5415}, doi = {10.1111/jgs.13805}, author = {Flatt, Jason D and Rosso, Andrea L and Aizenstein, Howard J and Schulz, Richard and Longstreth, W T and Newman, Anne B and Fowler, Nicole R and Rosano, Caterina} } @article {6800, title = {Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 Jun}, pages = {2181-91}, abstract = {

OBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism.

DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels.

DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95\% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95\% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95\% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95\% CI, 1.08-16.55) and 2.86 (95\% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95\% CI, 0.86-1.18) or >= 80 years old (HR, 1.31; 95\% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations.

CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

}, keywords = {Adult, Asymptomatic Diseases, Female, Humans, Hypothyroidism, Incidence, Male, Risk Factors, Stroke, Thyrotropin}, issn = {1945-7197}, doi = {10.1210/jc.2015-1438}, author = {Chaker, Layal and Baumgartner, Christine and den Elzen, Wendy P J and Ikram, M Arfan and Blum, Manuel R and Collet, Tinh-Hai and Bakker, Stephan J L and Dehghan, Abbas and Drechsler, Christiane and Luben, Robert N and Hofman, Albert and Portegies, Marileen L P and Medici, Marco and Iervasi, Giorgio and Stott, David J and Ford, Ian and Bremner, Alexandra and Wanner, Christoph and Ferrucci, Luigi and Newman, Anne B and Dullaart, Robin P and Sgarbi, Jos{\'e} A and Ceresini, Graziano and Maciel, Rui M B and Westendorp, Rudi G and Jukema, J Wouter and Imaizumi, Misa and Franklyn, Jayne A and Bauer, Douglas C and Walsh, John P and Razvi, Salman and Khaw, Kay-Tee and Cappola, Anne R and V{\"o}lzke, Henry and Franco, Oscar H and Gussekloo, Jacobijn and Rodondi, Nicolas and Peeters, Robin P} } @article {6795, title = {Subclinical thyroid dysfunction and fracture risk: a meta-analysis.}, journal = {JAMA}, volume = {313}, year = {2015}, month = {2015 May 26}, pages = {2055-65}, abstract = {

IMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking.

OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures.

DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures.

DATA EXTRACTION: Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH >=4.50-19.99 mIU/L) with normal thyroxine concentrations.

MAIN OUTCOME AND MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes.

RESULTS: Among 70,298 participants, 4092 (5.8\%) had subclinical hypothyroidism and 2219 (3.2\%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6\%; 12 studies), any fracture in 2528 participants (9.0\%; 8 studies), nonspine fracture in 2018 participants (8.4\%; 8 studies), and spine fracture in 296 participants (1.3\%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95\% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95\% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95\% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95\% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95\% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95\% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95\% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95\% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95\% CI, 1.19-1.93) for hip fracture, 1.42 (95\% CI, 1.16-1.74) for any fracture, and 1.74 (95\% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk.

CONCLUSIONS AND RELEVANCE: Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Female, Fractures, Bone, Hip Fractures, Humans, Hyperthyroidism, Hypothyroidism, Male, Middle Aged, Risk Factors, Spinal Fractures, Thyrotropin, Young Adult}, issn = {1538-3598}, doi = {10.1001/jama.2015.5161}, author = {Blum, Manuel R and Bauer, Douglas C and Collet, Tinh-Hai and Fink, Howard A and Cappola, Anne R and da Costa, Bruno R and Wirth, Christina D and Peeters, Robin P and Asvold, Bj{\o}rn O and den Elzen, Wendy P J and Luben, Robert N and Imaizumi, Misa and Bremner, Alexandra P and Gogakos, Apostolos and Eastell, Richard and Kearney, Patricia M and Strotmeyer, Elsa S and Wallace, Erin R and Hoff, Mari and Ceresini, Graziano and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Stott, David J and Westendorp, Rudi G J and Khaw, Kay-Tee and Langhammer, Arnuf and Ferrucci, Luigi and Gussekloo, Jacobijn and Williams, Graham R and Walsh, John P and J{\"u}ni, Peter and Aujesky, Drahomir and Rodondi, Nicolas} } @article {6926, title = {Soluble CD14 and fracture risk.}, journal = {Osteoporos Int}, volume = {27}, year = {2016}, month = {2016 May}, pages = {1755-63}, abstract = {

UNLABELLED: Soluble CD14 (sCD14) is an inflammatory marker associated with osteoclasts. Using Cox proportional hazards models, we found a positive association between plasma levels of sCD14 and risk of incident fracture among participants in the Cardiovascular Health Study. sCD14 may be useful in identifying those at risk for fracture.

INTRODUCTION: Soluble CD14, a proinflammatory cytokine, is primarily derived from macrophages/monocytes that can differentiate into osteoclasts. The purpose of this study was to examine the relationship between sCD14 levels and osteoporotic fractures.

METHODS: In the Cardiovascular Health Study, 5462 men and women had sCD14 levels measured at baseline. Incident hip fractures (median follow-up time 12.5~years) and incident composite fractures (defined as the first hip, pelvis, humerus, or distal radius fracture, median follow-up 8.6~years) were identified from hospital discharge summaries and/or Medicare claims data. Cox proportional hazards models were used to model the association between sCD14 levels and time to incident hip or composite fracture, overall and as a function of race and gender.

RESULTS: In unadjusted models, there was a positive association between sCD14 levels (per 1 standard deviation increase, i.e., 361.6~ng/mL) and incident hip (HR, 1.26; 95~\% CI, 1.17, 1.36) and composite (HR, 1.20; 95~\% CI, 1.12, 1.28) fractures. When models were fully adjusted for demographics, lifestyle factors, and medication use, these associations were no longer significant. However, in whites, the association of sCD14 levels with hip fractures remained significant in fully adjusted models (HR, 1.11; 95~\% CI, 1.01-1.23). Associations of sCD14 levels with hip and composite fracture did not differ between men and women.

CONCLUSIONS: In this large cohort of community-dwelling older adults, higher sCD14 levels were associated with an increased risk of incident hip fractures in whites.

}, issn = {1433-2965}, doi = {10.1007/s00198-015-3439-9}, author = {Bethel, M and B{\r u}{\v z}kov{\'a}, P and Fink, H A and Robbins, J A and Cauley, J A and Lee, J and Barzilay, J I and Jalal, D I and Carbone, L D} } @article {7130, title = {Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community-Dwelling Population.}, journal = {J Am Heart Assoc}, volume = {5}, year = {2016}, month = {2016 Aug}, abstract = {

BACKGROUND: Soluble ST2 (sST2), a marker of myocyte stretch and fibrosis, has prognostic value in many cardiovascular diseases. We hypothesized that sST2 levels are associated with incident heart failure (HF), including subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fraction, and cardiovascular death.

METHODS AND RESULTS: Baseline serum sST2 was measured in 3915 older, community-dwelling subjects from the Cardiovascular Health Study without prevalent HF. sST2 levels were associated with older age, male sex, black race, traditional cardiovascular risk factors, other biomarkers of inflammation, cardiac stretch, myocardial injury, and fibrosis, and abnormal echocardiographic parameters. In longitudinal analysis, greater sST2 was associated with a higher risk of incident HF and cardiovascular death; however, in multivariate models adjusting for other cardiac risk factors and the cardiac-specific biomarker, N-terminal pro-type B natriuretic peptide, these associations were attenuated. In these models, an sST2 level above the US Food and Drug Administration-approved cut-off value (>35~ng/mL) was significantly associated with incident HF (hazard ratio [HR], 1.20; 95\% CI, 1.02-1.43) and cardiovascular death (HR, 1.21; 95\% CI, 1.02-1.44), and greater sST2 was continuously associated with cardiovascular death (per 1-ln increment: HR, 1.24; 95\% CI, 1.02-1.50). sST2 was not associated with the HF subtypes of HFpEF and HFrEF in adjusted analysis. Addition of sST2 to existing risk models of HF and cardiovascular death modestly improved discrimination and reclassification into a higher risk.

CONCLUSIONS: The predictive value of sST2 for HF of all subtypes and cardiovascular death is modest in an elderly population despite strong cross-sectional associations with risk factors and underlying cardiac pathology.

}, issn = {2047-9980}, doi = {10.1161/JAHA.115.003188}, author = {Parikh, Ravi H and Seliger, Stephen L and Christenson, Robert and Gottdiener, John S and Psaty, Bruce M and deFilippi, Christopher R} } @article {7255, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, year = {2016}, month = {2016 Dec 05}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7{\texttimes}10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4{\texttimes}10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {7127, title = {Spousal Associations Between Frailty and Depressive Symptoms: Longitudinal Findings from the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Apr}, pages = {824-30}, abstract = {

OBJECTIVES: To determine whether older adult spouses{\textquoteright} frailty states and depressive symptoms are interrelated over time.

DESIGN: Longitudinal, dyadic path analysis using the Actor-Partner Interdependence Model.

SETTING: Data were from baseline (1989-90), Wave 3 (1992-93), and Wave 7 (1996-97), all waves in which frailty and depressive symptoms were measured, of the Cardiovascular Health Study (CHS), a multisite, longitudinal, observational study of risk factors for cardiovascular disease in adults aged 65 and older.

PARTICIPANTS: Spouses in 1,260 community-dwelling married couples.

MEASUREMENTS: Frailty was measured using the CHS criteria, categorized as nonfrail, prefrail, or frail. Depressive symptoms were measured using the 10-item Center for Epidemiologic Studies Depression Scale.

RESULTS: Within individuals (actor effects), greater frailty predicted greater subsequent depressive symptoms, and greater depressive symptoms predicted greater subsequent frailty. Between spouses (partner effects), an individual{\textquoteright}s greater frailty predicted the spouse{\textquoteright}s greater frailty, and an individual{\textquoteright}s greater depressive symptoms predicted the spouse{\textquoteright}s greater depressive symptoms.

CONCLUSION: Frailty and depressive symptoms are interrelated in older adult spouses. For older couples, interventions to prevent or treat frailty and depression that focus on couples may be more effective than those that focus on individuals.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Depression, Female, Frail Elderly, Humans, Longitudinal Studies, Male, Risk Factors, Spouses, United States}, issn = {1532-5415}, doi = {10.1111/jgs.14023}, author = {Monin, Joan and Doyle, Margaret and Levy, Becca and Schulz, Richard and Fried, Terri and Kershaw, Trace} } @article {6932, title = {Study of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.}, journal = {Circulation}, volume = {133}, year = {2016}, month = {2016 Jan 12}, pages = {156-64}, abstract = {

BACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.

METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare \& Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6\%, but this code identified only 53.8\% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.

CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.

}, keywords = {Blood Glucose, Cardiovascular Diseases, Female, Follow-Up Studies, Health Surveys, Hospitalization, Hospitals, Veterans, Humans, Insurance Claim Review, International Classification of Diseases, Lipids, Male, Managed Care Programs, Medicare, Risk Factors, Sampling Studies, Treatment Outcome, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.115.018610}, author = {Psaty, Bruce M and Delaney, Joseph A and Arnold, Alice M and Curtis, Lesley H and Fitzpatrick, Annette L and Heckbert, Susan R and McKnight, Barbara and Ives, Diane and Gottdiener, John S and Kuller, Lewis H and Longstreth, W T} } @article {6998, title = {Subclinical Cardiovascular Disease and Death, Dementia, and Coronary Heart Disease in Patients 80+ Years.}, journal = {J Am Coll Cardiol}, volume = {67}, year = {2016}, month = {2016 Mar 8}, pages = {1013-22}, abstract = {

BACKGROUND: The successful prevention and treatment of coronary heart disease (CHD) and stroke has resulted in a substantial increase in longevity, with subsequent growth in the population of older people at risk for dementia.

OBJECTIVES: The authors evaluated the relationship of coronary and other peripheral atherosclerosis to risk of death, dementia, and CHD in the very elderly. Because the extent of vascular disease differs substantially between men and women, sex- and race-specific analyses were included, with a specific focus on women with low coronary artery calcium (CAC) Agatston scores.

METHODS: We evaluated the relationship between measures of subclinical cardiovascular disease (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) and risk of dementia, CHD, and total mortality in 532 participants of the Cardiovascular Health Study-Cognition Study from 1998/1999 (mean age, 80 years) to 2012/2013 (mean age, 93 years).

RESULTS: Thirty-six percent of participants had CAC scores >400. Women and African-Americans had lower CAC scores. Few men had low CAC scores. CAC score and number of coronary calcifications were directly related to age-adjusted total mortality and CHD. The age-specific incidence of dementia was higher than for CHD. Only about 25\% of deaths were caused by CHD and 16\% by dementia. Approximately 64\% of those who died had a prior diagnosis of dementia. White women with low CAC scores had a significantly decreased incidence of dementia.

CONCLUSIONS: In subjects 80+ years of age, there is a greater incidence of dementia than of CHD. CAC, as a marker of atherosclerosis, is a determinant of mortality, and risk of CHD and myocardial infarction. White women with low CAC scores had a significantly decreased risk of dementia. A very important unanswered question, especially in the very elderly, is whether prevention of atherosclerosis and its complications is associated with less Alzheimer disease pathology and dementia. (Cardiovascular Health Study [CHS]; NCT00005133).

}, keywords = {Age Factors, Aged, 80 and over, Cause of Death, Coronary Artery Disease, Dementia, Female, Humans, Incidence, Male, Pennsylvania, Retrospective Studies, Risk Factors, Survival Rate}, issn = {1558-3597}, doi = {10.1016/j.jacc.2015.12.034}, author = {Kuller, Lewis H and Lopez, Oscar L and Mackey, Rachel H and Rosano, Caterina and Edmundowicz, Daniel and Becker, James T and Newman, Anne B} } @article {7119, title = {Systemic markers of microvascular disease and bone mineral density in older adults : The cardiovascular health study.}, journal = {Osteoporos Int}, volume = {27}, year = {2016}, month = {2016 Nov}, pages = {3217-3225}, abstract = {

Here we report that abnormal brain white matter and, to a lesser extent, albuminuria are associated with reduced bone mineral density in the hip, spine, and total body in men and women. These findings may explain the increased hip fracture risk reported in some studies in association with microvascular disorders.

INTRODUCTION: Markers of microvascular disease have been individually associated with increased risk of osteoporotic fractures in some studies. Here, we examine whether these markers are associated with reduced bone mineral density (BMD) individually and together.

METHODS: BMD testing using dual x-ray absorptiometry of the hip, lumbar spine, and total body was performed in 1473 participants from the Cardiovascular Health Study (mean age~~~78~years): 1215 were assessed for urinary albumin-creatinine ratio, 944 for abnormal white matter disease (AWMD) by brain MRI, and 541 for retinal vascular disease with fundus photographs. Linear regression models were used to evaluate the cross-sectional association of each marker with BMD accounting for potentially confounding factors.

RESULTS: AWMD was associated with lower hip, spine, and total body BMD in women (β -3.08 to -4.53; p~<~0.01 for all) and lower hip and total body BMD in men (β -2.90 to -4.24; p~=~0.01-0.03). Albuminuria was associated with lower hip (β -3.37; p~=~.05) and total body (β -3.21; p~=~.02) BMD in men, but not in women. The associations of AWMD and albuminuria with BMD persisted with mutual adjustment and appeared to be additive to each other. Retinal vascular disease was not associated with BMD in men or women.

CONCLUSION: AWMD and, to a lesser extent, albuminuria were independently associated with lower BMD, suggesting that microvascular disease may play a role in the pathogenesis of reduced BMD. These findings need to be confirmed by longitudinal studies.

}, issn = {1433-2965}, doi = {10.1007/s00198-016-3649-9}, author = {Barzilay, J I and B{\r u}{\v z}kov{\'a}, P and Fink, H A and Cauley, J A and Robbins, J A and Garimella, P S and Jalal, D I and Mukamal, K J} } @article {7564, title = {Short telomere length is associated with impaired cognitive performance in European ancestry cohorts.}, journal = {Transl Psychiatry}, volume = {7}, year = {2017}, month = {2017 04 18}, pages = {e1100}, abstract = {

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2{\textpm}8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95\% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95\% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=-0.053; 95\% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95\% CI: 0.045, 0.117; P=1.0 {\texttimes} 10-5), whereas carriers performed better in STROOP (β=-0.074; 95\% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (β=-0.598 per s.d.-increase of TL; 95\% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (β=-0.699; 95\% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

}, keywords = {Adult, Aged, Apolipoprotein E4, Cognitive Dysfunction, Cohort Studies, European Continental Ancestry Group, Female, Genetic Carrier Screening, Genotype, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neuropsychological Tests, Psychometrics, Statistics as Topic, Telomere}, issn = {2158-3188}, doi = {10.1038/tp.2017.73}, author = {H{\"a}gg, S and Zhan, Y and Karlsson, R and Gerritsen, L and Ploner, A and van der Lee, S J and Broer, L and Deelen, J and Marioni, R E and Wong, A and Lundquist, A and Zhu, G and Hansell, N K and Sillanp{\"a}{\"a}, E and Fedko, I O and Amin, N A and Beekman, M and de Craen, A J M and Degerman, S and Harris, S E and Kan, K-J and Martin-Ruiz, C M and Montgomery, G W and Adolfsson, A N and Reynolds, C A and Samani, N J and Suchiman, H E D and Viljanen, A and von Zglinicki, T and Wright, M J and Hottenga, J-J and Boomsma, D I and Rantanen, T and Kaprio, J A and Nyholt, D R and Martin, N G and Nyberg, L and Adolfsson, R and Kuh, D and Starr, J M and Deary, I J and Slagboom, P E and van Duijn, C M and Codd, V and Pedersen, N L} } @article {7572, title = {Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 May}, pages = {e1006728}, abstract = {

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25{\texttimes}10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

}, keywords = {African Americans, Animals, Basic Helix-Loop-Helix Transcription Factors, Blood Pressure, Cadherins, Case-Control Studies, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Membrane Proteins, Mice, Multifactorial Inheritance, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006728}, author = {Liang, Jingjing and Le, Thu H and Edwards, Digna R Velez and Tayo, Bamidele O and Gaulton, Kyle J and Smith, Jennifer A and Lu, Yingchang and Jensen, Richard A and Chen, Guanjie and Yanek, Lisa R and Schwander, Karen and Tajuddin, Salman M and Sofer, Tamar and Kim, Wonji and Kayima, James and McKenzie, Colin A and Fox, Ervin and Nalls, Michael A and Young, J Hunter and Sun, Yan V and Lane, Jacqueline M and Cechova, Sylvia and Zhou, Jie and Tang, Hua and Fornage, Myriam and Musani, Solomon K and Wang, Heming and Lee, Juyoung and Adeyemo, Adebowale and Dreisbach, Albert W and Forrester, Terrence and Chu, Pei-Lun and Cappola, Anne and Evans, Michele K and Morrison, Alanna C and Martin, Lisa W and Wiggins, Kerri L and Hui, Qin and Zhao, Wei and Jackson, Rebecca D and Ware, Erin B and Faul, Jessica D and Reiner, Alex P and Bray, Michael and Denny, Joshua C and Mosley, Thomas H and Palmas, Walter and Guo, Xiuqing and Papanicolaou, George J and Penman, Alan D and Polak, Joseph F and Rice, Kenneth and Taylor, Ken D and Boerwinkle, Eric and Bottinger, Erwin P and Liu, Kiang and Risch, Neil and Hunt, Steven C and Kooperberg, Charles and Zonderman, Alan B and Laurie, Cathy C and Becker, Diane M and Cai, Jianwen and Loos, Ruth J F and Psaty, Bruce M and Weir, David R and Kardia, Sharon L R and Arnett, Donna K and Won, Sungho and Edwards, Todd L and Redline, Susan and Cooper, Richard S and Rao, D C and Rotter, Jerome I and Rotimi, Charles and Levy, Daniel and Chakravarti, Aravinda and Zhu, Xiaofeng and Franceschini, Nora} } @article {7336, title = {Sleep-disordered breathing is associated with higher carboxymethyllysine level in elderly women but not elderly men in the cardiovascular health study.}, journal = {Biomarkers}, volume = {22}, year = {2017}, month = {2017 May - Jun}, pages = {361-366}, abstract = {

CONTEXT: Carboxymethyl-lysine (CML) results from oxidative stress and has been linked to cardiovascular disease.

OBJECTIVE: The objective of this study is to investigate the association between sleep-disordered breathing (SDB) - a source of oxidative stress - and CML.

MATERIALS AND METHODS: About 1002 participants in the Cardiovascular Health Study (CHS) were studied.

RESULTS: Women with SDB had significantly higher CML concentration compared with those without SDB (OR = 1.63, 95\%CI = 1.03-2.58, p = 0.04). The association was not significant among men.

DISCUSSION: SDB was associated with CML concentration among elderly women but not men in the Cardiovascular Health Study.

CONCLUSION: Accumulation of CML may be an adverse health consequence of SDB.

}, issn = {1366-5804}, doi = {10.1080/1354750X.2016.1276966}, author = {Ahiawodzi, Peter D and Kerber, Richard A and Taylor, Kira C and Groves, Frank D and O{\textquoteright}Brien, Elizabeth and Ix, Joachim H and Kizer, Jorge R and Djouss{\'e}, Luc and Tracy, Russell P and Newman, Anne B and Siscovick, David S and Robbins, John and Mukamal, Kenneth} } @article {7592, title = {Soluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study.}, journal = {J Bone Miner Res}, year = {2017}, month = {2017 Oct 04}, abstract = {

Several in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up. We assessed the association of four inflammatory markers with the risk of incident hip fractures among 5265 participants of the Cardiovascular Health Study (CHS) and a composite endpoint of incident fractures of the hip, pelvis, humerus, or proximal forearm in 4477 participants. Among CHS participants followed between 1992 and 2009, we observed 480 incident hip fractures during a median follow-up of 11 years. In the composite fracture analysis cohort of 4477 participants, we observed 711 fractures during a median follow-up of 7 years. Adjusted hazard ratios (HRs) and 95\% confidence intervals (CIs) for hip fracture associated with doubling of IL-6 were HR 1.15 (95\% CI, 1.02 to 1.30) overall and HR 1.17 (95\% CI, 1.01 to 1.35) in women. We also observed a positive association between each unit increase in white blood cell (WBC) count and risk of hip fracture: HR 1.04 (95\% CI, 1.01 to 1.06) overall and HR 1.06 (95\% CI, 0.95 to 1.20) in women. We observed no significant associations between any of the four inflammatory markers and a composite fracture endpoint. Our findings suggest that chronic inflammatory and immune processes may be related to higher rates of incident hip fractures. {\textcopyright} 2017 American Society for Bone and Mineral Research.

}, issn = {1523-4681}, doi = {10.1002/jbmr.3301}, author = {Stojanovi{\'c}, Danijela and B{\r u}zkov{\'a}, Petra and Mukamal, Kenneth J and Heckbert, Susan R and Psaty, Bruce M and Fink, Howard A and Cauley, Jane A and Wallace, Erin and Curtis, Lesley H and Hirsch, Calvin and Budoff, Matthew and Li, Dong and Young, Rebekah and Jalal, Diana and Delaney, Joseph Ac} } @article {7570, title = {Subclinical Atherosclerosis, Cardiac and Kidney Function, Heart Failure, and Dementia in the Very Elderly.}, journal = {J Am Heart Assoc}, volume = {6}, year = {2017}, month = {2017 Jul 22}, abstract = {

BACKGROUND: Heart failure (HF) and dementia are major causes of disability and death among older individuals. Risk factors and biomarkers of HF may be determinants of dementia in the elderly. We evaluated the relationship between biomarkers of cardiovascular disease and HF and risk of dementia and death. Three hypotheses were tested: (1) higher levels of high-sensitivity cardiac troponin T, N-terminal of prohormone brain natriuretic peptide, and cystatin C predict risk of death, cardiovascular disease, HF, and dementia; (2) higher levels of cardiovascular disease biomarkers are associated with increased risk of HF and then secondary increased risk of dementia; and (3) risk of dementia is lower among participants with a combination of lower coronary artery calcium, atherosclerosis, and lower high-sensitivity cardiac troponin T (myocardial injury).

METHODS AND RESULTS: The Cardiovascular Health Study Cognition Study was a continuation of the Cardiovascular Health Study limited to the Pittsburgh, PA, center from 1998-1999 to 2014. In 1992-1994, 924 participants underwent magnetic resonance imaging of the brain. There were 199 deaths and 116 developed dementia before 1998-1999. Of the 609 participants eligible for the Pittsburgh Cardiovascular Health Study Cognition Study, 87.5\% (n=532) were included in the study. There were 120 incident HF cases and 72\% had dementia. In 80 of 87, dementia preceded HF. A combination of low coronary artery calcium score and low high-sensitivity cardiac troponin T was significantly associated with reduced risk of dementia and HF.

CONCLUSIONS: Most participants with HF had dementia but with onset before HF. Lower high-sensitivity cardiac troponin T and coronary artery calcium was associated with low risk of dementia based on a small number of events.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, issn = {2047-9980}, doi = {10.1161/JAHA.116.005353}, author = {Kuller, Lewis H and Lopez, Oscar L and Gottdiener, John S and Kitzman, Dalane W and Becker, James T and Chang, Yuefang and Newman, Anne B} } @article {8558, title = {Systems biology approach to late-onset Alzheimer{\textquoteright}s disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.}, journal = {Alzheimers Dement}, volume = {13}, year = {2017}, month = {2017 Oct}, pages = {1133-1142}, abstract = {

INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer{\textquoteright}s disease (LOAD) loci.

METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.

DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

}, keywords = {Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Animals, Genetically Modified, Antigens, Neoplasm, Caenorhabditis elegans, Disease Models, Animal, Early Growth Response Protein 1, Female, Gene Expression Regulation, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Humans, Male, Membrane Transport Proteins, Mitochondrial ADP, ATP Translocases, NADH Dehydrogenase, Polymorphism, Single Nucleotide, Protein Interaction Maps, RNA Interference, Systems Biology, Temporal Lobe}, issn = {1552-5279}, doi = {10.1016/j.jalz.2017.01.016}, author = {Mukherjee, Shubhabrata and Russell, Joshua C and Carr, Daniel T and Burgess, Jeremy D and Allen, Mariet and Serie, Daniel J and Boehme, Kevin L and Kauwe, John S K and Naj, Adam C and Fardo, David W and Dickson, Dennis W and Montine, Thomas J and Ertekin-Taner, Nilufer and Kaeberlein, Matt R and Crane, Paul K} } @article {7918, title = {Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the Cardiovascular Health Study: prospective cohort study.}, journal = {BMJ}, volume = {363}, year = {2018}, month = {2018 Oct 17}, pages = {k4067}, abstract = {

OBJECTIVE: To determine the longitudinal association between serial biomarker measures of circulating omega 3 polyunsaturated fatty acid (n3-PUFA) levels and healthy ageing.

DESIGN: Prospective cohort study.

SETTING: Four communities in the United States (Cardiovascular Health Study) from 1992 to 2015.

PARTICIPANTS: 2622 adults with a mean (SD) age of 74.4 (4.8) and with successful healthy ageing at baseline in 1992-93.

EXPOSURE: Cumulative levels of plasma phospholipid n3-PUFAs were measured using gas chromatography in 1992-93, 1998-99, and 2005-06, expressed as percentage of total fatty acids, including α-linolenic acid from plants and eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid from seafoood.

MAIN OUTCOME MEASURE: Healthy ageing defined as survival without chronic diseases (ie, cardiovascular disease, cancer, lung disease, and severe chronic kidney disease), the absence of cognitive and physical dysfunction, or death from other causes not part of the healthy ageing outcome after age 65. Events were centrally adjudicated or determined from medical records and diagnostic tests.

RESULTS: Higher levels of long chain n3-PUFAs were associated with an 18\% lower risk (95\% confidence interval 7\% to 28\%) of unhealthy ageing per interquintile range after multivariable adjustments with time-varying exposure and covariates. Individually, higher eicosapentaenoic acid and docosapentaenoic acid (but not docosahexaenoic acid) levels were associated with a lower risk: 15\% (6\% to 23\%) and 16\% (6\% to 25\%), respectively. α-linolenic acid from plants was not noticeably associated with unhealthy ageing (hazard ratio 0.92, 95\% confidence interval 0.83 to 1.02).

CONCLUSIONS: In older adults, a higher cumulative level of serially measured circulating n3-PUFAs from seafood (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid), eicosapentaenoic acid, and docosapentaenoic acid (but not docosahexaenoic acid from seafood or α-linolenic acid from plants) was associated with a higher likelihood of healthy ageing. These findings support guidelines for increased dietary consumption of n3-PUFAs in older adults.

}, issn = {1756-1833}, doi = {10.1136/bmj.k4067}, author = {Lai, Heidi Tm and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and McKnight, Barbara and Song, Xiaoling and King, Irena B and Chaves, Paulo Hm and Odden, Michelle C and Newman, Anne B and Siscovick, David S and Mozaffarian, Dariush} } @article {7790, title = {Serial measures of circulating biomarkers of dairy fat and total and cause-specific mortality in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, year = {2018}, month = {2018 Jul 11}, abstract = {

Background: Controversy has emerged about the benefits compared with harms of dairy fat, including concerns over long-term effects. Previous observational studies have assessed self-reported estimates of consumption or a single biomarker measure at baseline, which may lead to suboptimal estimation of true risk.

Objective: The aim of this study was to investigate prospective associations of serial measures of plasma phospholipid fatty acids pentadecanoic (15:0), heptadecanoic (17:0), and trans-palmitoleic (trans-16:1n-7) acids with total mortality, cause-specific mortality, and cardiovascular disease (CVD) risk among older adults.

Design: Among 2907 US adults aged >=65 y and free of CVD at baseline, circulating fatty acid concentrations were measured serially at baseline, 6 y, and 13 y. Deaths and CVD events were assessed and adjudicated centrally. Prospective associations were assessed by multivariate-adjusted Cox models incorporating time-dependent exposures and covariates.

Results: During 22 y of follow-up, 2428 deaths occurred, including 833 from CVD, 1595 from non-CVD causes, and 1301 incident CVD events. In multivariable models, circulating pentadecanoic, heptadecanoic, and trans-palmitoleic acids were not significantly associated with total mortality, with extreme-quintile HRs of 1.05 for pentadecanoic (95\% CI: 0.91, 1.22), 1.07 for heptadecanoic (95\% CI: 0.93, 1.23), and 1.05 for trans-palmitoleic (95\% CI: 0.91, 1.20) acids. Circulating heptadecanoic acid was associated with lower CVD mortality (extreme-quintile HR: 0.77; 95\% CI: 0.61, 0.98), especially stroke mortality, with a 42\% lower risk when comparing extreme quintiles of heptadecanoic acid concentrations (HR: 0.58; 95\% CI: 0.35, 0.97). In contrast, heptadecanoic acid was associated with a higher risk of non-CVD mortality (HR: 1.27; 95\% CI: 1.07, 1.52), which was not clearly related to any single subtype of non-CVD death. No significant associations of pentadecanoic, heptadecanoic, or trans-palmitoleic acids were seen for total incident CVD, coronary heart disease, or stroke.

Conclusions: Long-term exposure to circulating phospholipid pentadecanoic, heptadecanoic, or trans-palmitoleic acids was not significantly associated with total mortality or incident CVD among older adults. High circulating heptadecanoic acid was inversely associated with CVD and stroke mortality and potentially associated with higher risk of non-CVD death.

}, issn = {1938-3207}, doi = {10.1093/ajcn/nqy117}, author = {de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Song, Xiaoling and King, Irena B and Siscovick, David S and Mozaffarian, Dariush} } @article {7670, title = {Serum Androgens and Risk of Atrial Fibrillation in Older Men: The Cardiovascular Health Study.}, journal = {Clin Cardiol}, year = {2018}, month = {2018 Apr 19}, abstract = {

BACKGROUND: Decline in serum androgens is common among older men and has been associated with cardiovascular disease, although its role in risk of atrial fibrillation (AF) has not been well defined.

HYPOTHESIS: Low serum androgens are associated with an increased risk of AF.

METHODS: We examined the prospective associations between testosterone, its more active metabolite dihydrotestosterone (DHT), and sex-hormone binding globulin (SHBG) with risk of AF among 1019 otherwise healthy men of average age 76.3{\textpm}4.9 years in the Cardiovascular Health Study.

RESULTS: After median follow-up of 9.5 years, 304 (30\%) men developed AF. We detected a nonlinear association with risk of incident AF in both free and total DHT, in which subjects with the lowest levels had a higher risk of incident AF. After adjustment for demographics, clinical risk factors, left atrial diameter, and serum NT-proBNP levels, men with free DHT less than 0.16 ng/dL were at increased risk compared with men with higher levels (HR 1.48, CI 1.01-2.17, p<0.05). Sensitivity analyses confirmed that the increased risk was not cutpoint-specific, with a significant association noted up to cutpoints less than ~0.2 ng/dL. We also detected a complex nonlinear association between SHBG and incident AF, in which subjects in the middle quintile (52.9 - 65.3 nmol/L) had increased risk.

CONCLUSION: Among older men, low free DHT is associated with an increased risk of incident atrial fibrillation. Further studies are needed to explore mechanisms for this association.

}, issn = {1932-8737}, doi = {10.1002/clc.22965}, author = {Rosenberg, Michael A and Shores, Molly M and Matsumoto, Alvin M and B{\r u}zkov{\'a}, Petra and Lange, Leslie A and Kronmal, Richard A and Heckbert, Susan R and Mukamal, Kenneth J} } @article {7685, title = {Sex and Race Differences in Lifetime Risk of Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction.}, journal = {Circulation}, volume = {137}, year = {2018}, month = {2018 Apr 24}, pages = {1814-1823}, abstract = {

BACKGROUND: Lifetime risk of heart failure has been estimated to range from 20\% to 46\% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.

METHODS: Participant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF >=45\%) and HFrEF (EF <45\%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.

RESULTS: We included 12 417 participants >45 years of age (22.2\% blacks, 44.8\% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4\% versus 23.8\%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6\% versus 5.8\%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9\% versus 22.4\%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2\% versus 7.7\%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.

CONCLUSIONS: Lifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.117.031622}, author = {Pandey, Ambarish and Omar, Wally and Ayers, Colby and LaMonte, Michael and Klein, Liviu and Allen, Norrina B and Kuller, Lewis H and Greenland, Philip and Eaton, Charles B and Gottdiener, John S and Lloyd-Jones, Donald M and Berry, Jarett D} } @article {7787, title = {Sleep characteristics that predict atrial fibrillation.}, journal = {Heart Rhythm}, volume = {15}, year = {2018}, month = {2018 Sep}, pages = {1289-1295}, abstract = {

BACKGROUND: The relationship between sleep disruption, independent of obstructive sleep apnea (OSA), and atrial fibrillation (AF) is unknown.

OBJECTIVE: The purpose of this study was to determine whether poor sleep itself is a risk factor for AF.

METHODS: We first performed an analysis of participants in the Health eHeart Study and validated those findings in the longitudinal Cardiovascular Health Study, including a subset of patients undergoing polysomnography. To determine whether the observed relationships readily translated to medical practice, we examined 2005-2009 data from the California Healthcare Cost and Utilization Project.

RESULTS: Among 4553 Health eHeart participants, the 526 with AF exhibited more frequent nighttime awakening (odd ratio [OR] 1.47; 95\% confidence interval [CI] 1.14-1.89; P = .003). In 5703 Cardiovascular Health Study participants followed for a median 11.6 years, frequent nighttime awakening predicted a 33\% greater risk of AF (hazard ratio [HR] 1.33; 95\% CI 1.17-1.51; P <.001). In patients with polysomnography (N = 1127), every standard deviation percentage decrease in rapid eye movement (REM) sleep was associated with a 18\% higher risk of developing AF (HR 1.18; 95\% CI 1.00-1.38; P = .047). Among 14,330,651 California residents followed for a median 3.9 years, an insomnia diagnosis predicted a 36\% increased risk of new AF (HR 1.36; 95\% CI 1.30-1.42; P <.001).

CONCLUSION: Sleep disruption consistently predicted AF before and after adjustment for OSA and other potential confounders across several different populations. Sleep quality itself may be important in the pathogenesis of AF, potentially representing a novel target for prevention.

}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2018.05.008}, author = {Christensen, Matthew A and Dixit, Shalini and Dewland, Thomas A and Whitman, Isaac R and Nah, Gregory and Vittinghoff, Eric and Mukamal, Kenneth J and Redline, Susan and Robbins, John A and Newman, Anne B and Patel, Sanjay R and Magnani, Jared W and Psaty, Bruce M and Olgin, Jeffrey E and Pletcher, Mark J and Heckbert, Susan R and Marcus, Gregory M} } @article {7656, title = {Social Network Trajectories in Myocardial Infarction Versus Ischemic Stroke.}, journal = {J Am Heart Assoc}, volume = {7}, year = {2018}, month = {2018 Apr 13}, abstract = {

BACKGROUND: Changes in social networks are rarely examined before and after various diseases because of insufficient data. CHS (The Cardiovascular Health Study) offers an opportunity to compare social network trajectories surrounding well-adjudicated myocardial infarction (MI) or stroke events. We tested the hypothesis that social networks will be stable after MI and decrease after stroke.

METHODS AND RESULTS: We examined trajectories of the Lubben Social Network Scale score (LSNS, range 0-50) before and after vascular events over 11~years. The LSNS assesses engagement in family networks, friends{\textquoteright} networks, and social supports. We used a linear mixed model with repeated measures and fixed effects to compare the change in social network score before and after events in 395 people with MI and 382 with ischemic stroke. Over a mean of 12.4~years of follow-up for MI and 11.1~years for stroke, we examined an average of 4 social network scores for each participant. We controlled for sociodemographics, baseline cognitive function, and comorbidities. The participants{\textquoteright} mean age was 73.5, 51\% were women, and 88\% were non-Hispanic white. After MI, the social network trajectory remained stable compared with the baseline trajectory (-0.06 points per year, adjusted =0.2356). After stroke, the social network trajectory declined compared with the baseline trajectory (-0.14 points per year, adjusted =0.0364).

CONCLUSIONS: Social networks remained stable after MI and declined after stroke. This small and persistent decline after adjustment for potential confounders is notable because it deviates from stable network trajectories found in CHS participants and is specific to stroke.

}, issn = {2047-9980}, doi = {10.1161/JAHA.117.008029}, author = {Dhand, Amar and Longstreth, W T and Chaves, Paulo H M and Dhamoon, Mandip S} } @article {7673, title = {Spirometric impairments, cardiovascular outcomes, and noncardiovascular death in older persons.}, journal = {Respir Med}, volume = {137}, year = {2018}, month = {2018 Apr}, pages = {40-47}, abstract = {

BACKGROUND: In prior work involving older persons, the reported associations of spirometric impairments with cardiovascular outcomes may have been confounded by age-related changes in lung function. Hence, using more age-appropriate spirometric criteria from the Global Lung Function Initiative (GLI), we have evaluated the associations of spirometric impairments, specifically restrictive-pattern and airflow-obstruction, with cardiovascular death (CV-death) and hospitalization (CV-hospitalization). In these analyses, we also evaluated the competing outcome of noncardiovascular death (nonCV-death) and calculated measures of relative and absolute risk.

METHODS: Our study sample was drawn from the Cardiovascular Health Study (CHS), including 4232 community-dwelling white persons aged >=65 years. Multivariable regression models included the following baseline predictors: GLI-defined restrictive-pattern and airflow-obstruction, age, male gender, obesity, waist circumference, current smoker status, >=10 pack-years of smoking, hypertension, dyslipidemia, diabetes, and cardiovascular and cerebrovascular disease. Outcomes included adjudicated CV-death, CV-hospitalization, and nonCV-death, ascertained over 10 years of follow-up. Measures of association included hazard ratios (HRs), rate ratios (RRs), and average attributable fraction (AAF), each with 95\% confidence intervals.

RESULTS: Restrictive-pattern and airflow-obstruction were associated with CV-death (adjusted HRs: 1.57 [1.18, 2.09] and 1.29 [1.04, 1.60]) and with nonCV-death (adjusted HRs: 2.10 [1.63, 2.69] and 1.79 [1.51, 2.12]), respectively. Airflow-obstruction, but not restrictive-pattern, was also associated with CV-hospitalization (adjusted RRs: 1.18 [1.02, 1.36] and 1.20 [0.96, 1.50], respectively). The adjusted AAFs of restrictive-pattern and airflow-obstruction were 1.68\% (0.46, 3.06) and 2.35\% (0.22, 4.72) for CV-death, and 3.44\% (1.97, 5.08) and 7.77\% (5.15, 10.60) for nonCV-death, respectively.

CONCLUSION: Assessment of GLI-defined spirometric impairments contributes to broad geriatric risk stratifications for both cardiovascular and non-cardiovascular outcomes.

}, issn = {1532-3064}, doi = {10.1016/j.rmed.2018.02.018}, author = {Vaz Fragoso, Carlos A and Van Ness, Peter H and Murphy, Terrence E and McAvay, Gail J} } @article {8257, title = {Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.}, journal = {Aging (Albany NY)}, volume = {10}, year = {2018}, month = {2018 03 29}, pages = {492-514}, abstract = {

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1\%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7\%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9\%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

}, keywords = {Aging, Computational Biology, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide}, issn = {1945-4589}, doi = {10.18632/aging.101407}, author = {Kulminski, Alexander M and Huang, Jian and Loika, Yury and Arbeev, Konstantin G and Bagley, Olivia and Yashkin, Arseniy and Duan, Matt and Culminskaya, Irina} } @article {7788, title = {Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 May 29}, pages = {2098}, abstract = {

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 {\texttimes} 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3\% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04362-x}, author = {Davies, Gail and Lam, Max and Harris, Sarah E and Trampush, Joey W and Luciano, Michelle and Hill, W David and Hagenaars, Saskia P and Ritchie, Stuart J and Marioni, Riccardo E and Fawns-Ritchie, Chloe and Liewald, David C M and Okely, Judith A and Ahola-Olli, Ari V and Barnes, Catriona L K and Bertram, Lars and Bis, Joshua C and Burdick, Katherine E and Christoforou, Andrea and DeRosse, Pamela and Djurovic, Srdjan and Espeseth, Thomas and Giakoumaki, Stella and Giddaluru, Sudheer and Gustavson, Daniel E and Hayward, Caroline and Hofer, Edith and Ikram, M Arfan and Karlsson, Robert and Knowles, Emma and Lahti, Jari and Leber, Markus and Li, Shuo and Mather, Karen A and Melle, Ingrid and Morris, Derek and Oldmeadow, Christopher and Palviainen, Teemu and Payton, Antony and Pazoki, Raha and Petrovic, Katja and Reynolds, Chandra A and Sargurupremraj, Muralidharan and Scholz, Markus and Smith, Jennifer A and Smith, Albert V and Terzikhan, Natalie and Thalamuthu, Anbupalam and Trompet, Stella and van der Lee, Sven J and Ware, Erin B and Windham, B Gwen and Wright, Margaret J and Yang, Jingyun and Yu, Jin and Ames, David and Amin, Najaf and Amouyel, Philippe and Andreassen, Ole A and Armstrong, Nicola J and Assareh, Amelia A and Attia, John R and Attix, Deborah and Avramopoulos, Dimitrios and Bennett, David A and B{\"o}hmer, Anne C and Boyle, Patricia A and Brodaty, Henry and Campbell, Harry and Cannon, Tyrone D and Cirulli, Elizabeth T and Congdon, Eliza and Conley, Emily Drabant and Corley, Janie and Cox, Simon R and Dale, Anders M and Dehghan, Abbas and Dick, Danielle and Dickinson, Dwight and Eriksson, Johan G and Evangelou, Evangelos and Faul, Jessica D and Ford, Ian and Freimer, Nelson A and Gao, He and Giegling, Ina and Gillespie, Nathan A and Gordon, Scott D and Gottesman, Rebecca F and Griswold, Michael E and Gudnason, Vilmundur and Harris, Tamara B and Hartmann, Annette M and Hatzimanolis, Alex and Heiss, Gerardo and Holliday, Elizabeth G and Joshi, Peter K and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and Karlsson, Ida and Kleineidam, Luca and Knopman, David S and Kochan, Nicole A and Konte, Bettina and Kwok, John B and Le Hellard, Stephanie and Lee, Teresa and Lehtim{\"a}ki, Terho and Li, Shu-Chen and Liu, Tian and Koini, Marisa and London, Edythe and Longstreth, Will T and Lopez, Oscar L and Loukola, Anu and Luck, Tobias and Lundervold, Astri J and Lundquist, Anders and Lyytik{\"a}inen, Leo-Pekka and Martin, Nicholas G and Montgomery, Grant W and Murray, Alison D and Need, Anna C and Noordam, Raymond and Nyberg, Lars and Ollier, William and Papenberg, Goran and Pattie, Alison and Polasek, Ozren and Poldrack, Russell A and Psaty, Bruce M and Reppermund, Simone and Riedel-Heller, Steffi G and Rose, Richard J and Rotter, Jerome I and Roussos, Panos and Rovio, Suvi P and Saba, Yasaman and Sabb, Fred W and Sachdev, Perminder S and Satizabal, Claudia L and Schmid, Matthias and Scott, Rodney J and Scult, Matthew A and Simino, Jeannette and Slagboom, P Eline and Smyrnis, Nikolaos and Soumar{\'e}, A{\"\i}cha and Stefanis, Nikos C and Stott, David J and Straub, Richard E and Sundet, Kjetil and Taylor, Adele M and Taylor, Kent D and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andre and Vitart, Veronique and Voineskos, Aristotle N and Kaprio, Jaakko and Wagner, Michael and Wagner, Holger and Weinhold, Leonie and Wen, K Hoyan and Widen, Elisabeth and Yang, Qiong and Zhao, Wei and Adams, Hieab H H and Arking, Dan E and Bilder, Robert M and Bitsios, Panos and Boerwinkle, Eric and Chiba-Falek, Ornit and Corvin, Aiden and De Jager, Philip L and Debette, Stephanie and Donohoe, Gary and Elliott, Paul and Fitzpatrick, Annette L and Gill, Michael and Glahn, David C and H{\"a}gg, Sara and Hansell, Narelle K and Hariri, Ahmad R and Ikram, M Kamran and Jukema, J Wouter and Vuoksimaa, Eero and Keller, Matthew C and Kremen, William S and Launer, Lenore and Lindenberger, Ulman and Palotie, Aarno and Pedersen, Nancy L and Pendleton, Neil and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Raitakari, Olli T and Ramirez, Alfredo and Reinvang, Ivar and Rudan, Igor and Schmidt, Reinhold and Schmidt, Helena and Schofield, Peter W and Schofield, Peter R and Starr, John M and Steen, Vidar M and Trollor, Julian N and Turner, Steven T and van Duijn, Cornelia M and Villringer, Arno and Weinberger, Daniel R and Weir, David R and Wilson, James F and Malhotra, Anil and McIntosh, Andrew M and Gale, Catharine R and Seshadri, Sudha and Mosley, Thomas H and Bressler, Jan and Lencz, Todd and Deary, Ian J} } @article {7576, title = {Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis.}, journal = {Diabetologia}, volume = {61}, year = {2018}, month = {2018 Feb}, pages = {317-330}, abstract = {

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits.

METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway.

RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β~{\textpm}~SE 0.014~{\textpm}~0.004 [mmol/l], p~=~1.5~{\texttimes}~10-3) and higher fasting insulin (0.030~{\textpm}~0.005 [log e pmol/l], p~=~2.0~{\texttimes}~10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030~{\textpm}~0.011 log e pmol/l, uncorrected p~=~0.006), results in the replication cohorts and combined meta-analyses were non-significant.

CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.

TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses{\textquoteright} Health Study).

}, issn = {1432-0428}, doi = {10.1007/s00125-017-4475-0}, author = {McKeown, Nicola M and Dashti, Hassan S and Ma, Jiantao and Haslam, Danielle E and Kiefte-de Jong, Jessica C and Smith, Caren E and Tanaka, Toshiko and Graff, Mariaelisa and Lemaitre, Rozenn N and Rybin, Denis and Sonestedt, Emily and Frazier-Wood, Alexis C and Mook-Kanamori, Dennis O and Li, Yanping and Wang, Carol A and Leermakers, Elisabeth T M and Mikkil{\"a}, Vera and Young, Kristin L and Mukamal, Kenneth J and Cupples, L Adrienne and Schulz, Christina-Alexandra and Chen, Tzu-An and Li-Gao, Ruifang and Huang, Tao and Oddy, Wendy H and Raitakari, Olli and Rice, Kenneth and Meigs, James B and Ericson, Ulrika and Steffen, Lyn M and Rosendaal, Frits R and Hofman, Albert and K{\"a}h{\"o}nen, Mika and Psaty, Bruce M and Brunkwall, Louise and Uitterlinden, Andr{\'e} G and Viikari, Jorma and Siscovick, David S and Sepp{\"a}l{\"a}, Ilkka and North, Kari E and Mozaffarian, Dariush and Dupuis, Jos{\'e}e and Orho-Melander, Marju and Rich, Stephen S and de Mutsert, Ren{\'e}e and Qi, Lu and Pennell, Craig E and Franco, Oscar H and Lehtim{\"a}ki, Terho and Herman, Mark A} } @article {7676, title = {Systemic inflammation as a predictor of brain aging: Contributions of physical activity, metabolic risk, and genetic risk.}, journal = {Neuroimage}, volume = {172}, year = {2018}, month = {2018 May 15}, pages = {118-129}, abstract = {

Inflammatory processes may contribute to risk for Alzheimer{\textquoteright}s disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline. We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77.3 {\textpm} 3.4 years) who remained non-demented for the duration of the 9-year longitudinal study. We used structural equation modeling (SEM) in a subset of 226 adults to evaluate whether measures of baseline peripheral inflammation (serum C-reactive protein levels; CRP), mediated the baseline contributions of genetic and metabolic risk, and physical activity, to regional cortical thickness in AD-relevant brain regions at study year 9. We found that both baseline metabolic risk and AD risk variant apolipoprotein E ε4 (APOE4), modulated baseline serum CRP. Higher baseline CRP levels, in turn, predicted thinner regional cortex at year 9, and mediated an effect between higher metabolic risk and thinner cortex in those regions. A higher polygenic risk score composed of variants in immune-associated AD risk genes (other than APOE) was associated with thinner regional cortex. However, CRP levels did not mediate this effect, suggesting that other mechanisms may be responsible for the elevated AD risk. We found interactions between genetic and environmental factors and structural brain health. Our findings support the role of metabolic risk and peripheral inflammation in age-related brain decline.

}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2017.12.027}, author = {Corlier, Fabian and Hafzalla, George and Faskowitz, Joshua and Kuller, Lewis H and Becker, James T and Lopez, Oscar L and Thompson, Paul M and Braskie, Meredith N} } @article {8199, title = {Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Nov 07}, pages = {1057-1068}, abstract = {

Average arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9~{\texttimes} 10). A risk score for these variants, built on an independent dataset, explains 0.97\% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.10.002}, author = {Liang, Jingjing and Cade, Brian E and He, Karen Y and Wang, Heming and Lee, Jiwon and Sofer, Tamar and Williams, Stephanie and Li, Ruitong and Chen, Han and Gottlieb, Daniel J and Evans, Daniel S and Guo, Xiuqing and Gharib, Sina A and Hale, Lauren and Hillman, David R and Lutsey, Pamela L and Mukherjee, Sutapa and Ochs-Balcom, Heather M and Palmer, Lyle J and Rhodes, Jessica and Purcell, Shaun and Patel, Sanjay R and Saxena, Richa and Stone, Katie L and Tang, Weihong and Tranah, Gregory J and Boerwinkle, Eric and Lin, Xihong and Liu, Yongmei and Psaty, Bruce M and Vasan, Ramachandran S and Cho, Michael H and Manichaikul, Ani and Silverman, Edwin K and Barr, R Graham and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Redline, Susan and Zhu, Xiaofeng} } @article {8275, title = {Serial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {8}, year = {2019}, month = {2019 Nov 19}, pages = {e012881}, abstract = {

Background Synthesized fatty acids (FAs) from de novo lipogenesis may affect cardiometabolic health, but longitudinal associations between serially measured de novo lipogenesis-related fatty acid biomarkers and mortality or cardiovascular disease (CVD) are not well established. Methods and Results We investigated longitudinal associations between de novo lipogenesis-related fatty acids with all-cause mortality, cause-specific mortality, and incident CVD among 3869 older US adults, mean (SD) age 75 (5) years and free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), oleic acid (18:1n-9), and other risk factors were serially measured at baseline, 6~years, and 13~years. All-cause mortality, cause-specific mortality, and incident fatal and nonfatal CVD were centrally adjudicated. Risk was assessed in multivariable-adjusted Cox models with time-varying FAs and covariates. During 13~years, median follow-up (maximum 22.4~years), participants experienced 3227 deaths (1131 CVD, 2096 non-CVD) and 1753 incident CVD events. After multivariable adjustment, higher cumulative levels of 16:0, 16:1n-7, and 18:1n-9 were associated with higher all-cause mortality, with extreme-quintile hazard ratios (95\% CIs) of 1.35 (1.17-1.56), 1.40 (1.21-1.62), and 1.56 (1.35-1.80), respectively, whereas higher levels of 18:0 were associated with lower mortality (hazard ratio=0.76; 95\% CI=0.66-0.88). Associations were generally similar for CVD mortality versus non-CVD mortality, as well as total incident CVD. Changes in levels of 16:0 were positively, and 18:0 inversely, associated with all-cause mortality (hazard ratio=1.23, 95\% CI=1.08-1.41; and hazard ratio=0.78, 95\% CI=0.68-0.90). Conclusions Higher long-term levels of 16:0, 16:1n-7, and 18:1n-9 and changes in 16:0 were positively, whereas long-term levels and changes in 18:0 were inversely, associated with all-cause mortality in older adults.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.012881}, author = {Lai, Heidi T M and de Oliveira Otto, Marcia C and Lee, Yujin and Wu, Jason H Y and Song, Xiaoling and King, Irena B and Psaty, Bruce M and Lemaitre, Rozenn N and McKnight, Barbara and Siscovick, David S and Mozaffarian, Dariush} } @article {7978, title = {Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study.}, journal = {Neurology}, volume = {92}, year = {2019}, month = {2019 Feb 26}, pages = {e944-e950}, abstract = {

OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.

METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).

RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95\% confidence interval [CI] 0.69-0.89; = 1.3 {\texttimes} 10) for all ischemic stroke, 0.63 (95\% CI 0.50-0.80; = 1.6 {\texttimes} 10) for cardioembolic stroke, and 0.60 (95\% CI 0.44-0.82; = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95\% CI 0.67-1.20; = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95\% CI 0.88-1.21) or with any subtype.

CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000007001}, author = {Larsson, Susanna C and Traylor, Matthew and Burgess, Stephen and Boncoraglio, Giorgio B and Jern, Christina and Micha{\"e}lsson, Karl and Markus, Hugh S} } @article {8277, title = {{Sex Differences in the Association Between Pentraxin 3 and Cognitive Decline: The Cardiovascular Health Study}, journal = {J. Gerontol. A Biol. Sci. Med. Sci.}, year = {2019}, month = {Dec}, abstract = {The importance of systemic inflammation, measured by C-reactive protein, in cognitive decline has been demonstrated; however, the role of vascular inflammation is less understood. Pentraxin 3 (PTX3) is a novel marker of vascular inflammation.\ We followed adults 65 and older, free of cardiovascular disease (CVD) for up to 9 years (n = 1,547) in the Cardiovascular Health Study. We evaluated the relationship between PTX3 and change in cognitive function, measured using the Modified Mini-Mental State Examination (3MSE), and incident cognitive impairment (3MSE < 80). Mediation by CVD events, and effect modification by sex and apolipoprotein E {\'E}{\guilsinglright}4 allele (APOE4) were also examined.\ The average decline in 3MSE was 0.77 points per year. The association between PTX3 and change in 3MSE differed between women and men (p = .02). In the adjusted model, each standard deviation higher in PTX3 was associated with a 0.20 greater decline in 3MSE score per year in women over follow-up (95\% CI: -0. 37, -0.03; p = .02), compared to no change in men ({\^I}{\texttwosuperior} = 0.07; 95\% CI: -0.08, 0.22). CVD events had a minor effect on the associations. No effect modification by APOE4 was found, although we observed the association of PTX3 and cognitive impairment in women was attenuated and nonsignificant after adjustment for APOE4. There was a paradoxical protective association between PTX3 and reduced cognitive impairment in men, even after adjustment for APOE4.\ We found that vascular inflammation was significantly associated with cognitive decline in older women, but not men.}, author = {Miller, L. M. and Jenny, N. S. and Rawlings, A. M. and Arnold, A. M. and Fitzpatrick, A. L. and Lopez, O. L. and Odden, M. C.} } @article {8528, title = {{Soluble CD14 and CD14 Variants, Other Inflammatory Markers, and Glucose Dysregulation in Older Adults: The Cardiovascular Health Study}, journal = {Diabetes Care}, volume = {42}, year = {2019}, month = {11}, pages = {2075{\textendash}2082}, abstract = {Experimental studies have implicated soluble (s)CD14, an effector of lipopolysaccharide-induced inflammation, in insulin resistance, but its role in human metabolic endotoxemia has not been studied. We evaluated sCD14 in relation to dysglycemia in older adults and how this compares to other markers of inflammation.\ We investigated associations of sCD14, interleukin-6 (IL-6), CRP, and white blood cell (WBC) count with insulin resistance (quantitative insulin-sensitivity check index and HOMA 2 of insulin resistance) and incident type 2 diabetes in a population-based cohort of older adults. We also assessed the causal role of sCD14 in insulin resistance using an instrumental variable approach by Mendelian randomization.\ After adjustment for conventional risk factors, each of the four biomarkers showed positive cross-sectional associations with both insulin resistance measures. These associations persisted after mutual adjustment for all markers except sCD14. Over a median follow-up of 11.6 years, 466 cases of diabetes occurred. All biomarkers except sCD14 were positively associated with diabetes, although only WBC count remained associated (hazard ratio 1.43 per doubling [95\% CI 1.07, 1.90]) after mutual adjustment. Instrumental variable analysis did not support a causal role for sCD14 in insulin resistance.\ Among older adults, sCD14 was associated with insulin resistance, but this disappeared after adjustment for other biomarkers, showed no evidence of a causal basis, and was not accompanied by a similar association with diabetes. IL-6, CRP, and WBC count were each associated with insulin resistance and diabetes, WBC count most robustly. These findings do not support a central role for sCD14, but they highlight the preeminence of WBC count as an inflammatory measure of diabetes risk in this population.}, author = {Shitole, S. G. and Biggs, M. L. and Reiner, A. P. and Mukamal, K. J. and Djouss?, L. and Ix, J. H. and Barzilay, J. I. and Tracy, R. P. and Siscovick, D. and Kizer, J. R.} } @article {8292, title = {Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study.}, journal = {Pharmacogenomics J}, year = {2019}, month = {2019 Dec 05}, abstract = {

It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, n = 40,914) and DIAGRAM (n = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (r = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95\% CI: 0.97, 1.03) per 10\% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20\% increase in response (95\% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.

}, issn = {1473-1150}, doi = {10.1038/s41397-019-0125-x}, author = {Smit, Roelof A J and Trompet, Stella and Leong, Aaron and Goodarzi, Mark O and Postmus, Iris and Warren, Helen and Theusch, Elizabeth and Barnes, Michael R and Arsenault, Benoit J and Li, Xiaohui and Feng, QiPing and Chasman, Daniel I and Cupples, L Adrienne and Hitman, Graham A and Krauss, Ronald M and Psaty, Bruce M and Rotter, Jerome I and Cessie, Saskia le and Stein, C Michael and Jukema, J Wouter} } @article {8100, title = {Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight.}, journal = {Genome Biol}, volume = {20}, year = {2019}, month = {2019 05 20}, pages = {97}, abstract = {

BACKGROUND: The human genome contains "dark" gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions.

RESULTS: Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7\% are completely dark and 35.2\% are >= 5\% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5\%, 35.6\%, and 9.6\%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer{\textquoteright}s Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer{\textquoteright}s disease gene, found in disease cases but not in controls.

CONCLUSIONS: While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer{\textquoteright}s disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.

}, keywords = {Genetic Predisposition to Disease, Genome, Human, Humans, Mutation}, issn = {1474-760X}, doi = {10.1186/s13059-019-1707-2}, author = {Ebbert, Mark T W and Jensen, Tanner D and Jansen-West, Karen and Sens, Jonathon P and Reddy, Joseph S and Ridge, Perry G and Kauwe, John S K and Belzil, Veronique and Pregent, Luc and Carrasquillo, Minerva M and Keene, Dirk and Larson, Eric and Crane, Paul and Asmann, Yan W and Ertekin-Taner, Nilufer and Younkin, Steven G and Ross, Owen A and Rademakers, Rosa and Petrucelli, Leonard and Fryer, John D} } @article {8241, title = {Serial Biomarkers of De Novo Lipogenesis Fatty Acids and Incident Heart Failure in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {9}, year = {2020}, month = {2020 Feb 18}, pages = {e014119}, abstract = {

Background De novo lipogenesis (DNL) is an endogenous pathway that converts excess dietary starch, sugar, protein, and alcohol into specific fatty acids (FAs). Although elevated DNL is linked to several metabolic abnormalities, little is known about how long-term habitual levels and changes in levels of FAs in the DNL pathway relate to incident heart failure (HF). Methods and Results We investigated whether habitual levels and changes in serial measures of FAs in the DNL pathway were associated with incident HF among 4249 participants free of HF at baseline. Plasma phospholipid FAs were measured at baseline, 6~years, and 13~years using gas chromatography, and risk factors for HF were measured using standardized methods. Incident HF was centrally adjudicated using medical records. We prospectively evaluated associations with HF risk of (1) habitual FA levels, using cumulative updating to assess long-term exposure, and (2) changes in FA levels over time. During 22.1~years of follow-up, 1304 HF cases occurred. After multivariable adjustment, habitual levels and changes in levels of palmitic acid (16:0) were positively associated with incident HF (interquintile hazard ratio [95\% CI]=1.17 [1.00-1.36] and 1.26 [1.03-1.55], respectively). Changes in levels of 7-hexadecenoic acid (16:1n-9) and vaccenic acid (18:1n-7) were each positively associated with risk of HF (1.36 [1.13-1.62], and 1.43 [1.18-1.72], respectively). Habitual levels and changes in levels of myristic acid (14:0), palmitoleic acid (16:1n-7), stearic acid (18:0), and oleic acid (18:1n-9) were not associated with incident HF. Conclusions Both habitual levels and changes in levels of 16:0 were positively associated with incident HF in older adults. Changes in 16:1n-9 and 18:1n-7 were also positively associated with incident HF. These findings support a potential role of DNL or these DNL-related FAs in the development of HF.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.014119}, author = {Lee, Yujin and Lai, Heidi T M and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and McKnight, Barbara and King, Irena B and Song, Xiaoling and Huggins, Gordon S and Vest, Amanda R and Siscovick, David S and Mozaffarian, Dariush} } @article {8399, title = {Sex Differences in the Association Between Pentraxin 3 and Cognitive Decline: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {75}, year = {2020}, month = {2020 Jul 13}, pages = {1523-1529}, abstract = {

BACKGROUND: The importance of systemic inflammation, measured by C-reactive protein, in cognitive decline has been demonstrated; however, the role of vascular inflammation is less understood. Pentraxin 3 (PTX3) is a novel marker of vascular inflammation.

METHODS: We followed adults 65 and older, free of cardiovascular disease (CVD) for up to 9 years (n = 1,547) in the Cardiovascular Health Study. We evaluated the relationship between PTX3 and change in cognitive function, measured using the Modified Mini-Mental State Examination (3MSE), and incident cognitive impairment (3MSE < 80). Mediation by CVD events, and effect modification by sex and apolipoprotein E ɛ4 allele (APOE4) were also examined.

RESULTS: The average decline in 3MSE was 0.77 points per year. The association between PTX3 and change in 3MSE differed between women and men (p = .02). In the adjusted model, each standard deviation higher in PTX3 was associated with a 0.20 greater decline in 3MSE score per year in women over follow-up (95\% CI: -0. 37, -0.03; p = .02), compared to no change in men (β = 0.07; 95\% CI: -0.08, 0.22). CVD events had a minor effect on the associations. No effect modification by APOE4 was found, although we observed the association of PTX3 and cognitive impairment in women was attenuated and nonsignificant after adjustment for APOE4. There was a paradoxical protective association between PTX3 and reduced cognitive impairment in men, even after adjustment for APOE4.

CONCLUSIONS: We found that vascular inflammation was significantly associated with cognitive decline in older women, but not men.

}, issn = {1758-535X}, doi = {10.1093/gerona/glz217}, author = {Miller, Lindsay M and Jenny, Nancy S and Rawlings, Andreea M and Arnold, Alice M and Fitzpatrick, Annette L and Lopez, Oscar L and Odden, Michelle C} } @article {8488, title = {Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart~Failure.}, journal = {J Am Coll Cardiol}, volume = {76}, year = {2020}, month = {2020 Sep 22}, pages = {1455-1465}, abstract = {

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.

OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF.

METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.

RESULTS: Among 22,756 participants (mean age 60 {\textpm} 13 years, 53\% women), HF occurred in 2,095 participants (47\% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p~<~0.001), and the combined clinical model had good discrimination in men (C-statistic~=~0.80) and in women (C-statistic~=~0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic~=~0.006; likelihood ratio chi-square~=~146; p~<~0.001), and after adding cardiac troponins in women (ΔC-statistic~=~0.003; likelihood ratio chi-square~=~73; p~<~0.001).

CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in~a~clinical HF risk prediction model is limited in both sexes.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.07.044}, author = {Suthahar, Navin and Lau, Emily S and Blaha, Michael J and Paniagua, Samantha M and Larson, Martin G and Psaty, Bruce M and Benjamin, Emelia J and Allison, Matthew A and Bartz, Traci M and Januzzi, James L and Levy, Daniel and Meems, Laura M G and Bakker, Stephan J L and Lima, Jo{\~a}o A C and Cushman, Mary and Lee, Douglas S and Wang, Thomas J and deFilippi, Christopher R and Herrington, David M and Nayor, Matthew and Vasan, Ramachandran S and Gardin, Julius M and Kizer, Jorge R and Bertoni, Alain G and Allen, Norrina B and Gansevoort, Ron T and Shah, Sanjiv J and Gottdiener, John S and Ho, Jennifer E and de Boer, Rudolf A} } @article {8376, title = {Soluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults.}, journal = {J Card Fail}, volume = {26}, year = {2020}, month = {2020 May}, pages = {410-419}, abstract = {

BACKGROUND: CD14 is a membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation. Soluble CD14 (sCD14) levels carry a poor prognosis in chronic heart failure (HF), but whether elevations in sCD14 precede HF is unknown. We tested the hypothesis that sCD14 is associated with HF incidence and its subtypes independent of major inflammatory biomarkers among older adults.

METHODS AND RESULTS: We included participants in the Cardiovascular Health Study without preexisting HF and available baseline sCD14. We evaluated the associations of sCD14, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and white blood cell count (WBC) with incident HF and subtypes using Cox regression. Among 5217 participants, 1878 had incident HF over 13.6 years (609 classifiable as HF with preserved ejection fraction [HFpEF] and 419 as HF with reduced ejection fraction [HFrEF]). After adjusting for clinical and laboratory covariates, sCD14 was significantly associated with incident HF (hazard ratio [HR]: 1.56 per doubling, 95\% confidence interval [CI]: 1.29-1.89), an association that was numerically stronger than for hsCRP (HR per doubling: 1.10, 95\% CI: 1.06-1.15), IL-6 (HR: 1.18, 95\% CI: 1.10-1.25), and WBC (HR: 1.24, 95\% CI: 1.09-1.42), and that remained significant after adjustment for the other markers of inflammation. This association for sCD14 was observed with HFpEF (HR: 1.50, 95\% CI: 1.07-2.10) but not HFrEF (HR: 0.99, 95\% CI: 0.67-1.49).

CONCLUSIONS: Plasma sCD14 was associated with incident HF independently and numerically more strongly than other major inflammatory markers. This association was only observed with HFpEF in the subset with classifiable HF subtypes. Pending replication, these findings have potentially important therapeutic implications.

}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2020.03.003}, author = {Al-Kindi, Sadeer G and B{\r u}zkov{\'a}, Petra and Shitole, Sanyog G and Reiner, Alex P and Garg, Parveen K and Gottdiener, John S and Psaty, Bruce M and Kizer, Jorge R} } @article {8628, title = {A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber and reduced kidney function.}, journal = {Kidney Int}, year = {2020}, month = {2020 Aug 15}, abstract = {

Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 μm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2 \% of 33,222 and 11.3 \% of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95\% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95- 1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2020.06.033}, author = {Lye, Weng Kit and Paterson, Euan and Patterson, Christopher C and Maxwell, Alexander P and Binte Mohammed Abdul, Riswana Banu and Tai, E Shyong and Cheng, Ching Yu and Kayama, Takamasa and Yamashita, Hidetoshi and Sarnak, Mark and Shlipak, Michael and Matsushita, Kunihiro and Mutlu, Unal and Ikram, Mohammad A and Klaver, Caroline and Kifley, Annette and Mitchell, Paul and Myers, Chelsea and Klein, Barbara E and Klein, Ronald and Wong, Tien Y and Sabanayagam, Charumathi and McKay, Gareth J} } @article {8666, title = {Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.}, journal = {Nature}, volume = {590}, year = {2021}, month = {2021 02}, pages = {290-299}, abstract = {

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400~million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400~million detected variants, 97\% have frequencies of less than 1\% and 46\% are singletons that are present in only one individual (53\% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01\%.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03205-y}, author = {Taliun, Daniel and Harris, Daniel N and Kessler, Michael D and Carlson, Jedidiah and Szpiech, Zachary A and Torres, Raul and Taliun, Sarah A Gagliano and Corvelo, Andr{\'e} and Gogarten, Stephanie M and Kang, Hyun Min and Pitsillides, Achilleas N and LeFaive, Jonathon and Lee, Seung-Been and Tian, Xiaowen and Browning, Brian L and Das, Sayantan and Emde, Anne-Katrin and Clarke, Wayne E and Loesch, Douglas P and Shetty, Amol C and Blackwell, Thomas W and Smith, Albert V and Wong, Quenna and Liu, Xiaoming and Conomos, Matthew P and Bobo, Dean M and Aguet, Francois and Albert, Christine and Alonso, Alvaro and Ardlie, Kristin G and Arking, Dan E and Aslibekyan, Stella and Auer, Paul L and Barnard, John and Barr, R Graham and Barwick, Lucas and Becker, Lewis C and Beer, Rebecca L and Benjamin, Emelia J and Bielak, Lawrence F and Blangero, John and Boehnke, Michael and Bowden, Donald W and Brody, Jennifer A and Burchard, Esteban G and Cade, Brian E and Casella, James F and Chalazan, Brandon and Chasman, Daniel I and Chen, Yii-Der Ida and Cho, Michael H and Choi, Seung Hoan and Chung, Mina K and Clish, Clary B and Correa, Adolfo and Curran, Joanne E and Custer, Brian and Darbar, Dawood and Daya, Michelle and de Andrade, Mariza and DeMeo, Dawn L and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Eng, Celeste and Fatkin, Diane and Fingerlin, Tasha and Forer, Lukas and Fornage, Myriam and Franceschini, Nora and Fuchsberger, Christian and Fullerton, Stephanie M and Germer, Soren and Gladwin, Mark T and Gottlieb, Daniel J and Guo, Xiuqing and Hall, Michael E and He, Jiang and Heard-Costa, Nancy L and Heckbert, Susan R and Irvin, Marguerite R and Johnsen, Jill M and Johnson, Andrew D and Kaplan, Robert and Kardia, Sharon L R and Kelly, Tanika and Kelly, Shannon and Kenny, Eimear E and Kiel, Douglas P and Klemmer, Robert and Konkle, Barbara A and Kooperberg, Charles and K{\"o}ttgen, Anna and Lange, Leslie A and Lasky-Su, Jessica and Levy, Daniel and Lin, Xihong and Lin, Keng-Han and Liu, Chunyu and Loos, Ruth J F and Garman, Lori and Gerszten, Robert and Lubitz, Steven A and Lunetta, Kathryn L and Mak, Angel C Y and Manichaikul, Ani and Manning, Alisa K and Mathias, Rasika A and McManus, David D and McGarvey, Stephen T and Meigs, James B and Meyers, Deborah A and Mikulla, Julie L and Minear, Mollie A and Mitchell, Braxton D and Mohanty, Sanghamitra and Montasser, May E and Montgomery, Courtney and Morrison, Alanna C and Murabito, Joanne M and Natale, Andrea and Natarajan, Pradeep and Nelson, Sarah C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pankratz, Nathan and Peloso, Gina M and Peyser, Patricia A and Pleiness, Jacob and Post, Wendy S and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Roden, Dan and Rotter, Jerome I and Ruczinski, Ingo and Sarnowski, Chloe and Schoenherr, Sebastian and Schwartz, David A and Seo, Jeong-Sun and Seshadri, Sudha and Sheehan, Vivien A and Sheu, Wayne H and Shoemaker, M Benjamin and Smith, Nicholas L and Smith, Jennifer A and Sotoodehnia, Nona and Stilp, Adrienne M and Tang, Weihong and Taylor, Kent D and Telen, Marilyn and Thornton, Timothy A and Tracy, Russell P and Van Den Berg, David J and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Vrieze, Scott and Weeks, Daniel E and Weir, Bruce S and Weiss, Scott T and Weng, Lu-Chen and Willer, Cristen J and Zhang, Yingze and Zhao, Xutong and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Boerwinkle, Eric and Gabriel, Stacey and Gibbs, Richard and Rice, Kenneth M and Rich, Stephen S and Silverman, Edwin K and Qasba, Pankaj and Gan, Weiniu and Papanicolaou, George J and Nickerson, Deborah A and Browning, Sharon R and Zody, Michael C and Z{\"o}llner, Sebastian and Wilson, James G and Cupples, L Adrienne and Laurie, Cathy C and Jaquish, Cashell E and Hernandez, Ryan D and O{\textquoteright}Connor, Timothy D and Abecasis, Goncalo R} } @article {8704, title = {Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults.}, journal = {Cardiology}, year = {2021}, month = {2021 Feb 25}, pages = {1-8}, abstract = {

BACKGROUND: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined.

OBJECTIVE: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults.

METHODS: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee.

RESULTS: The mean age was 77.7 {\textpm} 4.4 years, and 38.8\% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95\% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF.

CONCLUSION: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.

}, issn = {1421-9751}, doi = {10.1159/000513917}, author = {Djouss{\'e}, Luc and Biggs, Mary L and Matthan, Nirupa R and Ix, Joachim H and Fitzpatrick, Annette L and King, Irena and Lemaitre, Rozenn N and McKnight, Barbara and Kizer, Jorge R and Lichtenstein, Alice H and Mukamal, Kenneth J and Siscovick, David S} } @article {8702, title = {Serum non-esterified fatty acid levels and hip fracture risk: The Cardiovascular Health Study.}, journal = {Osteoporos Int}, year = {2021}, month = {2021 Mar 02}, abstract = {

Among elderly participants from the Cardiovascular Health Study, we found that non-esterified trans fatty acid levels had a significant prospective association with hip fracture risk. Other non-esterified fatty acid classes were not associated with hip fracture risk.

INTRODUCTION: Serum non-esterified fatty acids (NEFAs) are bioactive metabolic intermediates that can be taken up by bone tissue. Their associations with hip fracture risk have not been previously examined.

METHODS: Thirty-five individual NEFAs in five classes (saturated [SFA], mono-un-saturated [MUFA], poly-unsaturated n-6 and n-3 [PUFA], and trans-FA) were measured in Cardiovascular Health Study participants (n = 2139, mean age 77.8 years) without known diabetes. The multivariable associations of NEFA levels with hip fracture risk were evaluated in Cox hazards models.

RESULTS: We documented 303 incident hip fractures during 11.1 years of follow-up. Among the five NEFA classes, total trans FA levels were positively associated with higher hip fracture risk (HR 1.17 [95\% CI, 1.04, 1.31; p = 0.01] per one standard deviation higher level). The SFA lignoceric acid (24:0) was positively associated with higher risk (HR 1.09 [1.04, 1.1]; p < 0.001), while behenic (22:0) and docosatetraenoic (22:4 n6) acids were associated with lower risk (HR 0.76 [0.61, 0.94]; p = 0.01; 0.84 [0.70, 1.00]; p = 0.05, respectively).

CONCLUSION: Total plasma trans NEFA levels are related to hip fracture risk, suggesting an unrecognized benefit of their systematic removal from food. Novel associations of individual NEFAs with hip fracture risk require confirmation in other cohort studies.

}, issn = {1433-2965}, doi = {10.1007/s00198-021-05897-4}, author = {Barzilay, J I and B{\r u}{\v z}kov{\'a}, P and Djouss{\'e}, L and Ix, J and Kizer, J and Cauley, J and Matthan, N and Lichtenstein, A H and Mukamal, K J} } @article {8993, title = {Serum Nonesterified Fatty Acids and Incident Stroke: The CHS.}, journal = {J Am Heart Assoc}, volume = {10}, year = {2021}, month = {2021 11 16}, pages = {e022725}, abstract = {

Background Significant associations between total nonesterified fatty acid (NEFA) concentrations and incident stroke have been reported in some prospective cohort studies. We evaluated the associations between incident stroke and serum concentrations of nonesterified saturated, monounsaturated, polyunsaturated, and fatty acids. Methods and Results CHS (Cardiovascular Health Study) participants (N=2028) who were free of stroke at baseline (1996-1997) and had an archived fasting serum sample were included in this study. A total of 35 NEFAs were quantified using gas chromatography. Cox proportional hazards regression models were used to evaluate associations of 5 subclasses (nonesterified saturated, monounsaturated, omega (n)-6 polyunsaturated, n-3 polyunsaturated, and fatty acids) of NEFAs and individual NEFAs with incident stroke. Sensitivity analysis was conducted by excluding cases with hemorrhagic stroke (n=45). A total of 338 cases of incident stroke occurred during the median 10.5-year follow-up period. Total n-3 (hazard ratio [HR], 0.77 [95\% CI, 0.61-0.97]) and n-6 (HR, 1.32 [95\% CI, 1.01-1.73]) subclasses of NEFA were negatively and positively associated with incident stroke, respectively. Among individual NEFAs, dihomo-γ-linolenic acid (20:3n-6) was associated with higher risk (HR, 1.29 [95\% CI, 1.02-1.63]), whereas -7-hexadecenoic acid (16:1n-9) and arachidonic acid (20:4n-6) were associated with a lower risk (HR, 0.67 [95\% CI, 0.47-0.97]; HR, 0.81 [95\% CI. 0.65-1.00], respectively) of incident stroke per standard deviation increment. After the exclusion of cases with hemorrhagic stroke, these associations did not remain significant. Conclusions A total of 2 NEFA subclasses and 3 individual NEFAs were associated with incident stroke. Of these, the NEFA n-3 subclass and dihomo-γ-linolenic acid are diet derived and may be potential biomarkers for total stroke risk.

}, keywords = {8,11,14-Eicosatrienoic Acid, Fatty Acids, Nonesterified, Fatty Acids, Omega-3, Hemorrhagic Stroke, Humans, Prospective Studies, Risk Factors, Stroke, Trans Fatty Acids}, issn = {2047-9980}, doi = {10.1161/JAHA.121.022725}, author = {Huang, Neil K and Biggs, Mary L and Matthan, Nirupa R and Djouss{\'e}, Luc and Longstreth, W T and Mukamal, Kenneth J and Siscovick, David S and Lichtenstein, Alice H} } @article {8911, title = {Serum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS).}, journal = {Nutrients}, volume = {13}, year = {2021}, month = {2021 Aug 31}, abstract = {

Elevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with ( = 255 for carotid IMT, 301 for FMD) or without ( = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. In multivariable adjusted linear regression models per SD increment, the non-esterified fatty acid conjugated linoleic acid (-18:2 CLA) was positively associated with carotid IMT [β (95\% CI): 44.8 (19.2, 70.4), = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), = 1.000]. Non-esterified -palmitoleic acid (16:1n-7) was positively associated with FMD [19.7 (8.34, 31.0), = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Biomarkers, Brachial Artery, Carotid Artery, Common, Carotid Intima-Media Thickness, Dilatation, Fatty Acids, Monounsaturated, Fatty Acids, Nonesterified, Female, Humans, Linoleic Acid, Male, Regional Blood Flow, Risk Factors, Ultrasonography}, issn = {2072-6643}, doi = {10.3390/nu13093052}, author = {Huang, Neil K and B{\r u}zkov{\'a}, Petra and Matthan, Nirupa R and Djouss{\'e}, Luc and Kizer, Jorge R and Mukamal, Kenneth J and Polak, Joseph F and Lichtenstein, Alice H} } @article {8709, title = {Sex Differences in Cognitive Decline Among US Adults.}, journal = {JAMA Netw Open}, volume = {4}, year = {2021}, month = {2021 02 01}, pages = {e210169}, abstract = {

Importance: Sex differences in dementia risk are unclear, but some studies have found greater risk for women.

Objective: To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk.

Design, Setting, and Participants: This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020.

Exposure: Sex.

Main Outcomes and Measures: The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.

Results: Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7\%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9\%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4\%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95\% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95\% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95\% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95\% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95\% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95\% CI, -0.023 to 0.014; P = .61).

Conclusions and Relevance: The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.

}, keywords = {Aged, Cognitive Dysfunction, Cognitive Reserve, Cohort Studies, Executive Function, Humans, Memory, Middle Aged, Risk, Sex Factors, Time Factors, United States}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2021.0169}, author = {Levine, Deborah A and Gross, Alden L and Brice{\~n}o, Emily M and Tilton, Nicholas and Giordani, Bruno J and Sussman, Jeremy B and Hayward, Rodney A and Burke, James F and Hingtgen, Stephanie and Elkind, Mitchell S V and Manly, Jennifer J and Gottesman, Rebecca F and Gaskin, Darrell J and Sidney, Stephen and Sacco, Ralph L and Tom, Sarah E and Wright, Clinton B and Yaffe, Kristine and Galecki, Andrzej T} } @article {8618, title = {{Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {01}, pages = {24}, abstract = {Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.}, author = {Lagou, V. and M?gi, R. and Hottenga, J. J. and Grallert, H. and Perry, J. R. B. and Bouatia-Naji, N. and Marullo, L. and Rybin, D. and Jansen, R. and Min, J. L. and Dimas, A. S. and Ulrich, A. and Zudina, L. and G?din, J. R. and Jiang, L. and Faggian, A. and Bonnefond, A. and Fadista, J. and Stathopoulou, M. G. and Isaacs, A. and Willems, S. M. and Navarro, P. and Tanaka, T. and Jackson, A. U. and Montasser, M. E. and O{\textquoteright}Connell, J. R. and Bielak, L. F. and Webster, R. J. and Saxena, R. and Stafford, J. M. and Pourcain, B. S. and Timpson, N. J. and Salo, P. and Shin, S. Y. and Amin, N. and Smith, A. V. and Li, G. and Verweij, N. and Goel, A. and Ford, I. and Johnson, P. C. D. and Johnson, T. and Kapur, K. and Thorleifsson, G. and Strawbridge, R. J. and Rasmussen-Torvik, L. J. and Esko, T. and Mihailov, E. and Fall, T. and Fraser, R. M. and Mahajan, A. and Kanoni, S. and Giedraitis, V. and Kleber, M. E. and Silbernagel, G. and Meyer, J. and M?ller-Nurasyid, M. and Ganna, A. and Sarin, A. P. and Yengo, L. and Shungin, D. and Luan, J. and Horikoshi, M. and An, P. and Sanna, S. and Boettcher, Y. and Rayner, N. W. and Nolte, I. M. and Zemunik, T. and Iperen, E. V. and Kovacs, P. and Hastie, N. D. and Wild, S. H. and McLachlan, S. and Campbell, S. and Polasek, O. and Carlson, O. and Egan, J. and Kiess, W. and Willemsen, G. and Kuusisto, J. and Laakso, M. and Dimitriou, M. and Hicks, A. A. and Rauramaa, R. and Bandinelli, S. and Thorand, B. and Liu, Y. and Miljkovic, I. and Lind, L. and Doney, A. and Perola, M. and Hingorani, A. and Kivimaki, M. and Kumari, M. and Bennett, A. J. and Groves, C. J. and Herder, C. and Koistinen, H. A. and Kinnunen, L. and Faire, U. and Bakker, S. J. L. and Uusitupa, M. and Palmer, C. N. A. and Jukema, J. W. and Sattar, N. and Pouta, A. and Snieder, H. and Boerwinkle, E. and Pankow, J. S. and Magnusson, P. K. and Krus, U. and Scapoli, C. and de Geus, E. J. C. N. and Bl?her, M. and Wolffenbuttel, B. H. R. and Province, M. A. and Abecasis, G. R. and Meigs, J. B. and Hovingh, G. K. and Lindstr?m, J. and Wilson, J. F. and Wright, A. F. and Dedoussis, G. V. and Bornstein, S. R. and Schwarz, P. E. H. and T?njes, A. and Winkelmann, B. R. and Boehm, B. O. and M?rz, W. and Metspalu, A. and Price, J. F. and Deloukas, P. and K?rner, A. and Lakka, T. A. and Keinanen-Kiukaanniemi, S. M. and Saaristo, T. E. and Bergman, R. N. and Tuomilehto, J. and Wareham, N. J. and Langenberg, C. and M?nnist?, S. and Franks, P. W. and Hayward, C. and Vitart, V. and Kaprio, J. and Visvikis-Siest, S. and Balkau, B. and Altshuler, D. and Rudan, I. and Stumvoll, M. and Campbell, H. and van Duijn, C. M. and Gieger, C. and Illig, T. and Ferrucci, L. and Pedersen, N. L. and Pramstaller, P. P. and Boehnke, M. and Frayling, T. M. and Shuldiner, A. R. and Peyser, P. A. and Kardia, S. L. R. and Palmer, L. J. and Penninx, B. W. and Meneton, P. and Harris, T. B. and Navis, G. and Harst, P. V. and Smith, G. D. and Forouhi, N. G. and Loos, R. J. F. and Salomaa, V. and Soranzo, N. and Boomsma, D. I. and Groop, L. and Tuomi, T. and Hofman, A. and Munroe, P. B. and Gudnason, V. and Siscovick, D. S. and Watkins, H. and Lecoeur, C. and Vollenweider, P. and Franco-Cereceda, A. and Eriksson, P. and Jarvelin, M. R. and Stefansson, K. and Hamsten, A. and Nicholson, G. and Karpe, F. and Dermitzakis, E. T. and Lindgren, C. M. and McCarthy, M. I. and Froguel, P. and Kaakinen, M. A. and Lyssenko, V. and Watanabe, R. M. and Ingelsson, E. and Florez, J. C. and Dupuis, J. and Barroso, I. and Morris, A. P. and Prokopenko, I.} } @article {8663, title = {{Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {01}, pages = {24}, abstract = {Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.}, author = {Lagou, V. and M{\"a}gi, R. and Hottenga, J. J. and Grallert, H. and Perry, J. R. B. and Bouatia-Naji, N. and Marullo, L. and Rybin, D. and Jansen, R. and Min, J. L. and Dimas, A. S. and Ulrich, A. and Zudina, L. and G{\r a}din, J. R. and Jiang, L. and Faggian, A. and Bonnefond, A. and Fadista, J. and Stathopoulou, M. G. and Isaacs, A. and Willems, S. M. and Navarro, P. and Tanaka, T. and Jackson, A. U. and Montasser, M. E. and O{\textquoteright}Connell, J. R. and Bielak, L. F. and Webster, R. J. and Saxena, R. and Stafford, J. M. and Pourcain, B. S. and Timpson, N. J. and Salo, P. and Shin, S. Y. and Amin, N. and Smith, A. V. and Li, G. and Verweij, N. and Goel, A. and Ford, I. and Johnson, P. C. D. and Johnson, T. and Kapur, K. and Thorleifsson, G. and Strawbridge, R. J. and Rasmussen-Torvik, L. J. and Esko, T. and Mihailov, E. and Fall, T. and Fraser, R. M. and Mahajan, A. and Kanoni, S. and Giedraitis, V. and Kleber, M. E. and Silbernagel, G. and Meyer, J. and M{\"u}ller-Nurasyid, M. and Ganna, A. and Sarin, A. P. and Yengo, L. and Shungin, D. and Luan, J. and Horikoshi, M. and An, P. and Sanna, S. and Boettcher, Y. and Rayner, N. W. and Nolte, I. M. and Zemunik, T. and Iperen, E. V. and Kovacs, P. and Hastie, N. D. and Wild, S. H. and McLachlan, S. and Campbell, S. and Polasek, O. and Carlson, O. and Egan, J. and Kiess, W. and Willemsen, G. and Kuusisto, J. and Laakso, M. and Dimitriou, M. and Hicks, A. A. and Rauramaa, R. and Bandinelli, S. and Thorand, B. and Liu, Y. and Miljkovic, I. and Lind, L. and Doney, A. and Perola, M. and Hingorani, A. and Kivimaki, M. and Kumari, M. and Bennett, A. J. and Groves, C. J. and Herder, C. and Koistinen, H. A. and Kinnunen, L. and Faire, U. and Bakker, S. J. L. and Uusitupa, M. and Palmer, C. N. A. and Jukema, J. W. and Sattar, N. and Pouta, A. and Snieder, H. and Boerwinkle, E. and Pankow, J. S. and Magnusson, P. K. and Krus, U. and Scapoli, C. and de Geus, E. J. C. N. and Bl{\"u}her, M. and Wolffenbuttel, B. H. R. and Province, M. A. and Abecasis, G. R. and Meigs, J. B. and Hovingh, G. K. and Lindstr{\"o}m, J. and Wilson, J. F. and Wright, A. F. and Dedoussis, G. V. and Bornstein, S. R. and Schwarz, P. E. H. and Tonjes, A. and Winkelmann, B. R. and Boehm, B. O. and M{\"a}rz, W. and Metspalu, A. and Price, J. F. and Deloukas, P. and K{\"o}rner, A. and Lakka, T. A. and Keinanen-Kiukaanniemi, S. M. and Saaristo, T. E. and Bergman, R. N. and Tuomilehto, J. and Wareham, N. J. and Langenberg, C. and M{\"a}nnist{\"o}, S. and Franks, P. W. and Hayward, C. and Vitart, V. and Kaprio, J. and Visvikis-Siest, S. and Balkau, B. and Altshuler, D. and Rudan, I. and Stumvoll, M. and Campbell, H. and van Duijn, C. M. and Gieger, C. and Illig, T. and Ferrucci, L. and Pedersen, N. L. and Pramstaller, P. P. and Boehnke, M. and Frayling, T. M. and Shuldiner, A. R. and Peyser, P. A. and Kardia, S. L. R. and Palmer, L. J. and Penninx, B. W. and Meneton, P. and Harris, T. B. and Navis, G. and Harst, P. V. and Smith, G. D. and Forouhi, N. G. and Loos, R. J. F. and Salomaa, V. and Soranzo, N. and Boomsma, D. I. and Groop, L. and Tuomi, T. and Hofman, A. and Munroe, P. B. and Gudnason, V. and Siscovick, D. S. and Watkins, H. and Lecoeur, C. and Vollenweider, P. and Franco-Cereceda, A. and Eriksson, P. and Jarvelin, M. R. and Stefansson, K. and Hamsten, A. and Nicholson, G. and Karpe, F. and Dermitzakis, E. T. and Lindgren, C. M. and McCarthy, M. I. and Froguel, P. and Kaakinen, M. A. and Lyssenko, V. and Watanabe, R. M. and Ingelsson, E. and Florez, J. C. and Dupuis, J. and Barroso, I. and Morris, A. P. and Prokopenko, I.} } @article {8785, title = {Silent Myocardial Infarction and Subsequent Ischemic Stroke in the Cardiovascular Health Study.}, journal = {Neurology}, year = {2021}, month = {2021 May 24}, abstract = {

OBJECTIVE: To test the hypothesis that silent MI is a risk factor for ischemic stroke, we evaluated the association between silent MI and subsequent ischemic stroke in the Cardiovascular Health Study.

METHODS: The Cardiovascular Health Study prospectively enrolled community-dwelling individuals >=65 years of age. We included participants without prevalent stroke or baseline evidence of MI. Our exposures were silent and clinically apparent, overt MI. Silent MI was defined as new evidence of Q-wave MI, without clinical symptoms of MI, on ECGs performed during annual study visits from 1989-1999. The primary outcome was incident ischemic stroke. Secondary outcomes were ischemic stroke subtypes: non-lacunar, lacunar, and other/unknown. Cox proportional hazards analysis was used to model the association between time-varying MI status (silent, overt, or no MI) and stroke after adjustment for baseline demographics and vascular risk factors.

RESULTS: Among 4,224 participants, 362 (8.6\%) had an incident silent MI, 421 (10.0\%) an incident overt MI, and 377 (8.9\%) an incident ischemic stroke during a median follow-up of 9.8 years. After adjustment for demographics and comorbidities, silent MI was independently associated with subsequent ischemic stroke (HR, 1.51; 95\% CI, 1.03-2.21). Overt MI was associated with ischemic stroke both in the short term (HR, 80; 95\% CI, 53-119) and long term (HR, 1.60; 95\% CI, 1.04-2.44). In secondary analyses, the association between silent MI and stroke was limited to non-lacunar ischemic stroke (HR 2.40; 95\% CI, 1.36-4.22).

CONCLUSION: In a community-based sample, we found an association between silent MI and ischemic stroke.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000012249}, author = {Merkler, Alexander E and Bartz, Traci M and Kamel, Hooman and Soliman, Elsayed Z and Howard, Virginia and Psaty, Bruce M and Okin, Peter M and Safford, Monika M and Elkind, Mitchell S V and Longstreth, W T} } @article {8840, title = {Statins and cognitive decline in the Cardiovascular Health Study: A comparison of different analytical approaches.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2021}, month = {2021 Jul 31}, abstract = {

BACKGROUND: Despite their well-established benefits for the prevention of cardiovascular disease, robust evidence on the effects of statins on cognition is largely inconclusive. We apply various study designs and analytical approaches to mimic randomized controlled trial (RCT) effects from observational data.

METHODS: We used observational data from 5,580 participants enrolled in the Cardiovascular Health Study from 1989/90 to 1999/2000. We conceptualized the cohort as an overlapping sequence of non-randomized trials. We compared multiple selection (eligible population, prevalent users, new-users) and analytic approaches (multivariable adjustment, inverse probability treatment weights, propensity score matching) to evaluate the association between statin use and 5-year change in global cognitive function, assessed using the Modified Mini-Mental State (3MS) examination.

RESULTS: When comparing prevalent users to non-users (N=2,772), statin use was associated with slower cognitive decline over 5 years (adjusted annual change in 3MSE = 0.34 points/year; 95\% CI:0.05;0.63). Compared to prevalent user design, estimates from new user designs (e.g. comparing eligible statin initiators to non-initiators) were attenuated showing either null or negative association, though not significant. For example, in a propensity score-matched sample of statin-eligible individuals (N=454), annual 3MS change comparing statin initiators to non-initiators was -0.21 points/year (95\% CI:-0.81;0.39).

CONCLUSIONS: The association of statin use and cognitive decline is attenuated towards the null when using rigorous analytical approaches that more closely mimic RCTs. Point estimates, even within the same study, may vary depending on the analytical methods used. Further studies that leverage natural or quasi experiments around statin use are needed to replicate our findings.

}, issn = {1758-535X}, doi = {10.1093/gerona/glab220}, author = {Zeki Al Hazzouri, Adina and Jawadekar, Neal and Grasset, Leslie and Kaiser, Paulina and Kezios, Katrina and Calonico, Sebastian and Glymour, M Maria and Hirsch, Calvin and Arnold, Alice M and Varadhan, Ravi and Opoodden, Michelle C} } @article {8830, title = {Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 Aug}, pages = {e003288}, abstract = {

BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia.

METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.

RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95\% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95\% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).

CONCLUSIONS: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.120.003288}, author = {Haslam, Danielle E and Peloso, Gina M and Guirette, Melanie and Imamura, Fumiaki and Bartz, Traci M and Pitsillides, Achilleas N and Wang, Carol A and Li-Gao, Ruifang and Westra, Jason M and Pitk{\"a}nen, Niina and Young, Kristin L and Graff, Mariaelisa and Wood, Alexis C and Braun, Kim V E and Luan, Jian{\textquoteright}an and K{\"a}h{\"o}nen, Mika and Kiefte-de Jong, Jessica C and Ghanbari, Mohsen and Tintle, Nathan and Lemaitre, Rozenn N and Mook-Kanamori, Dennis O and North, Kari and Helminen, Mika and Mossavar-Rahmani, Yasmin and Snetselaar, Linda and Martin, Lisa W and Viikari, Jorma S and Oddy, Wendy H and Pennell, Craig E and Rosendall, Frits R and Ikram, M Arfan and Uitterlinden, Andr{\'e} G and Psaty, Bruce M and Mozaffarian, Dariush and Rotter, Jerome I and Taylor, Kent D and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Livingston, Kara A and Voortman, Trudy and Forouhi, Nita G and Wareham, Nick J and de Mutsert, Ren{\'e}e and Rich, Steven S and Manson, JoAnn E and Mora, Samia and Ridker, Paul M and Merino, Jordi and Meigs, James B and Dashti, Hassan S and Chasman, Daniel I and Lichtenstein, Alice H and Smith, Caren E and Dupuis, Jos{\'e}e and Herman, Mark A and McKeown, Nicola M} } @article {8839, title = {Supplemental Association of Clonal Hematopoiesis With Incident Heart~Failure.}, journal = {J Am Coll Cardiol}, volume = {78}, year = {2021}, month = {2021 07 06}, pages = {42-52}, abstract = {

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF.

METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10\%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

RESULTS: Of 56,597 individuals (59\% women, mean age 58 years at baseline), 3,406 (6\%) had CHIP, and 4,694 developed HF (8.3\%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25\% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95\% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95\% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

}, keywords = {Aged, Clonal Hematopoiesis, Correlation of Data, Demography, DNA-Binding Proteins, Female, Heart Failure, Humans, Janus Kinase 2, Male, Middle Aged, Mutation, Proportional Hazards Models, Proto-Oncogene Proteins, Repressor Proteins, Risk Factors, Stroke Volume, Ventricular Dysfunction, Left, Whole Exome Sequencing}, issn = {1558-3597}, doi = {10.1016/j.jacc.2021.04.085}, author = {Yu, Bing and Roberts, Mary B and Raffield, Laura M and Zekavat, Seyedeh Maryam and Nguyen, Ngoc Quynh H and Biggs, Mary L and Brown, Michael R and Griffin, Gabriel and Desai, Pinkal and Correa, Adolfo and Morrison, Alanna C and Shah, Amil M and Niroula, Abhishek and Uddin, Md Mesbah and Honigberg, Michael C and Ebert, Benjamin L and Psaty, Bruce M and Whitsel, Eric A and Manson, JoAnn E and Kooperberg, Charles and Bick, Alexander G and Ballantyne, Christie M and Reiner, Alex P and Natarajan, Pradeep and Eaton, Charles B} } @article {8713, title = {A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.}, journal = {Am J Epidemiol}, year = {2021}, month = {2021 Apr 16}, abstract = {

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute{\textquoteright}s Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

}, issn = {1476-6256}, doi = {10.1093/aje/kwab115}, author = {Stilp, Adrienne M and Emery, Leslie S and Broome, Jai G and Buth, Erin J and Khan, Alyna T and Laurie, Cecelia A and Wang, Fei Fei and Wong, Quenna and Chen, Dongquan and D{\textquoteright}Augustine, Catherine M and Heard-Costa, Nancy L and Hohensee, Chancellor R and Johnson, William Craig and Juarez, Lucia D and Liu, Jingmin and Mutalik, Karen M and Raffield, Laura M and Wiggins, Kerri L and de Vries, Paul S and Kelly, Tanika N and Kooperberg, Charles and Natarajan, Pradeep and Peloso, Gina M and Peyser, Patricia A and Reiner, Alex P and Arnett, Donna K and Aslibekyan, Stella and Barnes, Kathleen C and Bielak, Lawrence F and Bis, Joshua C and Cade, Brian E and Chen, Ming-Huei and Correa, Adolfo and Cupples, L Adrienne and de Andrade, Mariza and Ellinor, Patrick T and Fornage, Myriam and Franceschini, Nora and Gan, Weiniu and Ganesh, Santhi K and Graffelman, Jan and Grove, Megan L and Guo, Xiuqing and Hawley, Nicola L and Hsu, Wan-Ling and Jackson, Rebecca D and Jaquish, Cashell E and Johnson, Andrew D and Kardia, Sharon L R and Kelly, Shannon and Lee, Jiwon and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and North, Kari E and Nouraie, Seyed Mehdi and Oelsner, Elizabeth C and Pankratz, Nathan and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Taylor, Kent D and Vasan, Ramachandran S and Weeks, Daniel E and Weiss, Scott T and Wilson, Carla G and Yanek, Lisa R and Psaty, Bruce M and Heckbert, Susan R and Laurie, Cathy C} } @article {9263, title = {{A saturated map of common genetic variants associated with human height}, journal = {Nature}, volume = {610}, year = {2022}, month = {Oct}, pages = {704{\textendash}712}, abstract = {) account for 40\% (45\%) of phenotypic variance in populations of European ancestry but only around 10-20\% (14-24\%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.}, author = {Yengo, L. and Vedantam, S. and Marouli, E. and Sidorenko, J. and Bartell, E. and Sakaue, S. and Graff, M. and Eliasen, A. U. and Jiang, Y. and Raghavan, S. and Miao, J. and Arias, J. D. and Graham, S. E. and Mukamel, R. E. and Spracklen, C. N. and Yin, X. and Chen, S. H. and Ferreira, T. and Highland, H. H. and Ji, Y. and Karaderi, T. and Lin, K. and ll, K. and Malden, D. E. and Medina-Gomez, C. and Machado, M. and Moore, A. and eger, S. and Sim, X. and Vrieze, S. and Ahluwalia, T. S. and Akiyama, M. and Allison, M. A. and Alvarez, M. and Andersen, M. K. and Ani, A. and Appadurai, V. and Arbeeva, L. and Bhaskar, S. and Bielak, L. F. and Bollepalli, S. and Bonnycastle, L. L. and Bork-Jensen, J. and Bradfield, J. P. and Bradford, Y. and Braund, P. S. and Brody, J. A. and Burgdorf, K. S. and Cade, B. E. and Cai, H. and Cai, Q. and Campbell, A. and adas-Garre, M. and Catamo, E. and Chai, J. F. and Chai, X. and Chang, L. C. and Chang, Y. C. and Chen, C. H. and Chesi, A. and Choi, S. H. and Chung, R. H. and Cocca, M. and Concas, M. P. and Couture, C. and Cuellar-Partida, G. and Danning, R. and Daw, E. W. and Degenhard, F. and Delgado, G. E. and Delitala, A. and Demirkan, A. and Deng, X. and Devineni, P. and Dietl, A. and Dimitriou, M. and Dimitrov, L. and Dorajoo, R. and Ekici, A. B. and Engmann, J. E. and Fairhurst-Hunter, Z. and Farmaki, A. E. and Faul, J. D. and Fernandez-Lopez, J. C. and Forer, L. and Francescatto, M. and Freitag-Wolf, S. and Fuchsberger, C. and Galesloot, T. E. and Gao, Y. and Gao, Z. and Geller, F. and Giannakopoulou, O. and Giulianini, F. and Gjesing, A. P. and Goel, A. and Gordon, S. D. and Gorski, M. and Grove, J. and Guo, X. and Gustafsson, S. and Haessler, J. and Hansen, T. F. and Havulinna, A. S. and Haworth, S. J. and He, J. and Heard-Costa, N. and Hebbar, P. and Hindy, G. and Ho, Y. A. and Hofer, E. and Holliday, E. and Horn, K. and Hornsby, W. E. and Hottenga, J. J. and Huang, H. and Huang, J. and Huerta-Chagoya, A. and Huffman, J. E. and Hung, Y. J. and Huo, S. and Hwang, M. Y. and Iha, H. and Ikeda, D. D. and Isono, M. and Jackson, A. U. and ger, S. and Jansen, I. E. and Johansson, I. and Jonas, J. B. and Jonsson, A. and rgensen, T. and Kalafati, I. P. and Kanai, M. and Kanoni, S. and rhus, L. L. and Kasturiratne, A. and Katsuya, T. and Kawaguchi, T. and Kember, R. L. and Kentistou, K. A. and Kim, H. N. and Kim, Y. J. and Kleber, M. E. and Knol, M. J. and Kurbasic, A. and Lauzon, M. and Le, P. and Lea, R. and Lee, J. Y. and Leonard, H. L. and Li, S. A. and Li, X. and Li, X. and Liang, J. and Lin, H. and Lin, S. Y. and Liu, J. and Liu, X. and Lo, K. S. and Long, J. and Lor{\'e}s-Motta, L. and Luan, J. and Lyssenko, V. and inen, L. P. and Mahajan, A. and Mamakou, V. and Mangino, M. and Manichaikul, A. and Marten, J. and Mattheisen, M. and Mavarani, L. and McDaid, A. F. and Meidtner, K. and Melendez, T. L. and Mercader, J. M. and Milaneschi, Y. and Miller, J. E. and Millwood, I. Y. and Mishra, P. P. and Mitchell, R. E. and llehave, L. T. and Morgan, A. and Mucha, S. and Munz, M. and Nakatochi, M. and Nelson, C. P. and Nethander, M. and Nho, C. W. and Nielsen, A. A. and Nolte, I. M. and Nongmaithem, S. S. and Noordam, R. and Ntalla, I. and Nutile, T. and Pandit, A. and Christofidou, P. and rna, K. and Pauper, M. and Petersen, E. R. B. and Petersen, L. V. and nen, N. and ek, O. and Poveda, A. and Preuss, M. H. and Pyarajan, S. and Raffield, L. M. and Rakugi, H. and Ramirez, J. and Rasheed, A. and Raven, D. and Rayner, N. W. and Riveros, C. and Rohde, R. and Ruggiero, D. and Ruotsalainen, S. E. and Ryan, K. A. and Sabater-Lleal, M. and Saxena, R. and Scholz, M. and Sendamarai, A. and Shen, B. and Shi, J. and Shin, J. H. and Sidore, C. and Sitlani, C. M. and Slieker, R. C. and Smit, R. A. J. and Smith, A. V. and Smith, J. A. and Smyth, L. J. and Southam, L. and Steinthorsdottir, V. and Sun, L. and Takeuchi, F. and Tallapragada, D. S. P. and Taylor, K. D. and Tayo, B. O. and Tcheandjieu, C. and Terzikhan, N. and Tesolin, P. and Teumer, A. and Theusch, E. and Thompson, D. J. and Thorleifsson, G. and Timmers, P. R. H. J. and Trompet, S. and Turman, C. and Vaccargiu, S. and van der Laan, S. W. and van der Most, P. J. and van Klinken, J. B. and van Setten, J. and Verma, S. S. and Verweij, N. and Veturi, Y. and Wang, C. A. and Wang, C. and Wang, L. and Wang, Z. and Warren, H. R. and Bin Wei, W. and Wickremasinghe, A. R. and Wielscher, M. and Wiggins, K. L. and Winsvold, B. S. and Wong, A. and Wu, Y. and Wuttke, M. and Xia, R. and Xie, T. and Yamamoto, K. and Yang, J. and Yao, J. and Young, H. and Yousri, N. A. and Yu, L. and Zeng, L. and Zhang, W. and Zhang, X. and Zhao, J. H. and Zhao, W. and Zhou, W. and Zimmermann, M. E. and Zoledziewska, M. and Adair, L. S. and Adams, H. H. H. and Aguilar-Salinas, C. A. and Al-Mulla, F. and Arnett, D. K. and Asselbergs, F. W. and svold, B. O. and Attia, J. and Banas, B. and Bandinelli, S. and Bennett, D. A. and Bergler, T. and Bharadwaj, D. and Biino, G. and Bisgaard, H. and Boerwinkle, E. and ger, C. A. and nnelykke, K. and Boomsma, D. I. and rglum, A. D. and Borja, J. B. and Bouchard, C. and Bowden, D. W. and Brandslund, I. and Brumpton, B. and Buring, J. E. and Caulfield, M. J. and Chambers, J. C. and Chandak, G. R. and Chanock, S. J. and Chaturvedi, N. and Chen, Y. I. and Chen, Z. and Cheng, C. Y. and Christophersen, I. E. and Ciullo, M. and Cole, J. W. and Collins, F. S. and Cooper, R. S. and Cruz, M. and Cucca, F. and Cupples, L. A. and Cutler, M. J. and Damrauer, S. M. and Dantoft, T. M. and de Borst, G. J. and de Groot, L. C. P. G. M. and De Jager, P. L. and de Kleijn, D. P. V. and Janaka de Silva, H. and Dedoussis, G. V. and den Hollander, A. I. and Du, S. and Easton, D. F. and Elders, P. J. M. and Eliassen, A. H. and Ellinor, P. T. and hl, S. and Erdmann, J. and Evans, M. K. and Fatkin, D. and Feenstra, B. and Feitosa, M. F. and Ferrucci, L. and Ford, I. and Fornage, M. and Franke, A. and Franks, P. W. and Freedman, B. I. and Gasparini, P. and Gieger, C. and Girotto, G. and Goddard, M. E. and Golightly, Y. M. and Gonzalez-Villalpando, C. and Gordon-Larsen, P. and Grallert, H. and Grant, S. F. A. and Grarup, N. and Griffiths, L. and Gudnason, V. and Haiman, C. and Hakonarson, H. and Hansen, T. and Hartman, C. A. and Hattersley, A. T. and Hayward, C. and Heckbert, S. R. and Heng, C. K. and Hengstenberg, C. and Hewitt, A. W. and Hishigaki, H. and Hoyng, C. B. and Huang, P. L. and Huang, W. and Hunt, S. C. and Hveem, K. and nen, E. and Iacono, W. G. and Ichihara, S. and Ikram, M. A. and Isasi, C. R. and Jackson, R. D. and Jarvelin, M. R. and Jin, Z. B. and ckel, K. H. and Joshi, P. K. and Jousilahti, P. and Jukema, J. W. and nen, M. and Kamatani, Y. and Kang, K. D. and Kaprio, J. and Kardia, S. L. R. and Karpe, F. and Kato, N. and Kee, F. and Kessler, T. and Khera, A. V. and Khor, C. C. and Kiemeney, L. A. L. M. and Kim, B. J. and Kim, E. K. and Kim, H. L. and Kirchhof, P. and Kivimaki, M. and Koh, W. P. and Koistinen, H. A. and Kolovou, G. D. and Kooner, J. S. and Kooperberg, C. and ttgen, A. and Kovacs, P. and Kraaijeveld, A. and Kraft, P. and Krauss, R. M. and Kumari, M. and Kutalik, Z. and Laakso, M. and Lange, L. A. and Langenberg, C. and Launer, L. J. and Le Marchand, L. and Lee, H. and Lee, N. R. and ki, T. and Li, H. and Li, L. and Lieb, W. and Lin, X. and Lind, L. and Linneberg, A. and Liu, C. T. and Liu, J. and Loeffler, M. and London, B. and Lubitz, S. A. and Lye, S. J. and Mackey, D. A. and gi, R. and Magnusson, P. K. E. and Marcus, G. M. and Vidal, P. M. and Martin, N. G. and rz, W. and Matsuda, F. and McGarrah, R. W. and McGue, M. and McKnight, A. J. and Medland, S. E. and m, D. and Metspalu, A. and Mitchell, B. D. and Mitchell, P. and Mook-Kanamori, D. O. and Morris, A. D. and Mucci, L. A. and Munroe, P. B. and Nalls, M. A. and Nazarian, S. and Nelson, A. E. and Neville, M. J. and Newton-Cheh, C. and Nielsen, C. S. and then, M. M. and Ohlsson, C. and Oldehinkel, A. J. and Orozco, L. and Pahkala, K. and Pajukanta, P. and Palmer, C. N. A. and Parra, E. J. and Pattaro, C. and Pedersen, O. and Pennell, C. E. and Penninx, B. W. J. H. and P{\'e}russe, L. and Peters, A. and Peyser, P. A. and Porteous, D. J. and Posthuma, D. and Power, C. and Pramstaller, P. P. and Province, M. A. and Qi, Q. and Qu, J. and Rader, D. J. and Raitakari, O. T. and Ralhan, S. and Rallidis, L. S. and Rao, D. C. and Redline, S. and Reilly, D. F. and Reiner, A. P. and Rhee, S. Y. and Ridker, P. M. and Rienstra, M. and Ripatti, S. and Ritchie, M. D. and Roden, D. M. and Rosendaal, F. R. and Rotter, J. I. and Rudan, I. and Rutters, F. and Sabanayagam, C. and Saleheen, D. and Salomaa, V. and Samani, N. J. and Sanghera, D. K. and Sattar, N. and Schmidt, B. and Schmidt, H. and Schmidt, R. and Schulze, M. B. and Schunkert, H. and Scott, L. J. and Scott, R. J. and Sever, P. and Shiroma, E. J. and Shoemaker, M. B. and Shu, X. O. and Simonsick, E. M. and Sims, M. and Singh, J. R. and Singleton, A. B. and Sinner, M. F. and Smith, J. G. and Snieder, H. and Spector, T. D. and Stampfer, M. J. and Stark, K. J. and Strachan, D. P. and {\textquoteright}t Hart, L. M. and Tabara, Y. and Tang, H. and Tardif, J. C. and Thanaraj, T. A. and Timpson, N. J. and njes, A. and Tremblay, A. and Tuomi, T. and Tuomilehto, J. and -Luna, M. T. and Uitterlinden, A. G. and van Dam, R. M. and van der Harst, P. and Van der Velde, N. and van Duijn, C. M. and van Schoor, N. M. and Vitart, V. and lker, U. and Vollenweider, P. and lzke, H. and Wacher-Rodarte, N. H. and Walker, M. and Wang, Y. X. and Wareham, N. J. and Watanabe, R. M. and Watkins, H. and Weir, D. R. and Werge, T. M. and Wid{\'e}n, E. and Wilkens, L. R. and Willemsen, G. and Willett, W. C. and Wilson, J. F. and Wong, T. Y. and Woo, J. T. and Wright, A. F. and Wu, J. Y. and Xu, H. and Yajnik, C. S. and Yokota, M. and Yuan, J. M. and Zeggini, E. and Zemel, B. S. and Zheng, W. and Zhu, X. and Zmuda, J. M. and Zonderman, A. B. and Zwart, J. A. and Chasman, D. I. and Cho, Y. S. and Heid, I. M. and McCarthy, M. I. and Ng, M. C. Y. and O{\textquoteright}Donnell, C. J. and Rivadeneira, F. and Thorsteinsdottir, U. and Sun, Y. V. and Tai, E. S. and Boehnke, M. and Deloukas, P. and Justice, A. E. and Lindgren, C. M. and Loos, R. J. F. and Mohlke, K. L. and North, K. E. and Stefansson, K. and Walters, R. G. and Winkler, T. W. and Young, K. L. and Loh, P. R. and Yang, J. and Esko, T. and Assimes, T. L. and Auton, A. and Abecasis, G. R. and Willer, C. J. and Locke, A. E. and Berndt, S. I. and Lettre, G. and Frayling, T. M. and Okada, Y. and Wood, A. R. and Visscher, P. M. and Hirschhorn, J. N. and Partida, G. C. and Sun, Y. and Croteau-Chonka, D. and Vonk, J. M. and Chanock, S. and Le Marchand, L.} } @article {9248, title = {Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults.}, journal = {J Am Geriatr Soc}, year = {2022}, month = {2022 Nov 05}, abstract = {

BACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent.

METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n~=~2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n~=~1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC.

RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR~=~1.41 per 0.1-g/cm decrement [95\% CI~=~1.23-1.62]), and showed the same to be true for White men (HR~=~1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men.

CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

}, issn = {1532-5415}, doi = {10.1111/jgs.18121}, author = {Gao, Hans and Patel, Sheena and Fohtung, Raymond B and Cawthon, Peggy M and Newman, Anne B and Cauley, Jane A and Carbone, Laura and Chaves, Paulo H M and Stein, Phyllis K and Civitelli, Roberto and Kizer, Jorge R} } @article {9003, title = {Sleep problems and risk of cancer incidence and mortality in an older cohort: The Cardiovascular Health Study (CHS).}, journal = {Cancer Epidemiol}, volume = {76}, year = {2022}, month = {2022 Feb}, pages = {102057}, abstract = {

BACKGROUND: Sleep problems (SP) can indicate underlying sleep disorders, such as obstructive sleep apnea, which may adversely impact cancer risk and mortality.

METHODS: We assessed the association of baseline and longitudinal sleep apnea and insomnia symptoms with incident cancer (N~=~3930) and cancer mortality (N~=~4580) in the Cardiovascular Health Study. We used Cox proportional hazards regression to calculate adjusted hazard ratios (HR) and 95\% confidence intervals (CI) to evaluate the associations.

RESULTS: Overall, 885 incident cancers and 804 cancer deaths were identified over a median follow-up of 12 and 14 years, respectively. Compared to participants who reported no sleep apnea symptoms, the risk of incident cancer was inversely associated [(HR (95\%CI)] with snoring [0.84 (0.71, 0.99)]. We noted an elevated prostate cancer incidence for apnea [2.34 (1.32, 4.15)] and snoring [1.69 (1.11, 2.57)]. We also noted an elevated HR for lymphatic or hematopoietic cancers [daytime sleepiness: 1.81 (1.06, 3.08)]. We found an inverse relationship for cancer mortality with respect to snoring [0.73 (0.62, 0.8)] and apnea [(0.69 (0.51, 0.94))]. We noted a significant inverse relationship between difficulty falling asleep and colorectal cancer death [0.32 (0.15, 0.69)] and snoring with lung cancer death [0.56 (0.35, 0.89)].

CONCLUSIONS: The relationship between SP and cancer risk and mortality was heterogeneous. Larger prospective studies addressing more cancer sites, molecular type-specific associations, and better longitudinal SP assessments are needed for improved delineation of SP-cancer risk dyad.

}, issn = {1877-783X}, doi = {10.1016/j.canep.2021.102057}, author = {Sillah, Arthur and Watson, Nathaniel F and Peters, Ulrike and Biggs, Mary L and Nieto, F Javier and Li, Christopher I and Gozal, David and Thornton, Timothy and Barrie, Sonnah and Phipps, Amanda I} } @article {9172, title = {Stroke genetics informs drug discovery and risk prediction across ancestries.}, journal = {Nature}, year = {2022}, month = {2022 Sep 30}, abstract = {

Previous genome-wide association studies (GWASs) of stroke~-~the second leading cause of death worldwide~-~were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33\% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30\% non-European) and 1,013,843 control individuals, 87\% of the primary stroke risk loci and 60\% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

}, issn = {1476-4687}, doi = {10.1038/s41586-022-05165-3}, author = {Mishra, Aniket and Malik, Rainer and Hachiya, Tsuyoshi and J{\"u}rgenson, Tuuli and Namba, Shinichi and Posner, Daniel C and Kamanu, Frederick K and Koido, Masaru and Le Grand, Quentin and Shi, Mingyang and He, Yunye and Georgakis, Marios K and Caro, Ilana and Krebs, Kristi and Liaw, Yi-Ching and Vaura, Felix C and Lin, Kuang and Winsvold, Bendik Slagsvold and Srinivasasainagendra, Vinodh and Parodi, Livia and Bae, Hee-Joon and Chauhan, Ganesh and Chong, Michael R and Tomppo, Liisa and Akinyemi, Rufus and Roshchupkin, Gennady V and Habib, Naomi and Jee, Yon Ho and Thomassen, Jesper Qvist and Abedi, Vida and C{\'a}rcel-M{\'a}rquez, Jara and Nygaard, Marianne and Leonard, Hampton L and Yang, Chaojie and Yonova-Doing, Ekaterina and Knol, Maria J and Lewis, Adam J and Judy, Renae L and Ago, Tetsuro and Amouyel, Philippe and Armstrong, Nicole D and Bakker, Mark K and Bartz, Traci M and Bennett, David A and Bis, Joshua C and Bordes, Constance and B{\o}rte, Sigrid and Cain, Anael and Ridker, Paul M and Cho, Kelly and Chen, Zhengming and Cruchaga, Carlos and Cole, John W and De Jager, Phil L and de Cid, Rafael and Endres, Matthias and Ferreira, Leslie E and Geerlings, Mirjam I and Gasca, Natalie C and Gudnason, Vilmundur and Hata, Jun and He, Jing and Heath, Alicia K and Ho, Yuk-Lam and Havulinna, Aki S and Hopewell, Jemma C and Hyacinth, Hyacinth I and Inouye, Michael and Jacob, Mina A and Jeon, Christina E and Jern, Christina and Kamouchi, Masahiro and Keene, Keith L and Kitazono, Takanari and Kittner, Steven J and Konuma, Takahiro and Kumar, Amit and Lacaze, Paul and Launer, Lenore J and Lee, Keon-Joo and Lepik, Kaido and Li, Jiang and Li, Liming and Manichaikul, Ani and Markus, Hugh S and Marston, Nicholas A and Meitinger, Thomas and Mitchell, Braxton D and Montellano, Felipe A and Morisaki, Takayuki and Mosley, Thomas H and Nalls, Mike A and Nordestgaard, B{\o}rge G and O{\textquoteright}Donnell, Martin J and Okada, Yukinori and Onland-Moret, N Charlotte and Ovbiagele, Bruce and Peters, Annette and Psaty, Bruce M and Rich, Stephen S and Rosand, Jonathan and Sabatine, Marc S and Sacco, Ralph L and Saleheen, Danish and Sandset, Else Charlotte and Salomaa, Veikko and Sargurupremraj, Muralidharan and Sasaki, Makoto and Satizabal, Claudia L and Schmidt, Carsten O and Shimizu, Atsushi and Smith, Nicholas L and Sloane, Kelly L and Sutoh, Yoichi and Sun, Yan V and Tanno, Kozo and Tiedt, Steffen and Tatlisumak, Turgut and Torres-Aguila, Nuria P and Tiwari, Hemant K and Tr{\'e}gou{\"e}t, David-Alexandre and Trompet, Stella and Tuladhar, Anil Man and Tybj{\ae}rg-Hansen, Anne and van Vugt, Marion and Vibo, Riina and Verma, Shefali S and Wiggins, Kerri L and Wennberg, Patrik and Woo, Daniel and Wilson, Peter W F and Xu, Huichun and Yang, Qiong and Yoon, Kyungheon and Millwood, Iona Y and Gieger, Christian and Ninomiya, Toshiharu and Grabe, Hans J and Jukema, J Wouter and Rissanen, Ina L and Strbian, Daniel and Kim, Young Jin and Chen, Pei-Hsin and Mayerhofer, Ernst and Howson, Joanna M M and Irvin, Marguerite R and Adams, Hieab and Wassertheil-Smoller, Sylvia and Christensen, Kaare and Ikram, Mohammad A and Rundek, Tatjana and Worrall, Bradford B and Lathrop, G Mark and Riaz, Moeen and Simonsick, Eleanor M and K{\~o}rv, Janika and Fran{\c c}a, Paulo H C and Zand, Ramin and Prasad, Kameshwar and Frikke-Schmidt, Ruth and de Leeuw, Frank-Erik and Liman, Thomas and Haeusler, Karl Georg and Ruigrok, Ynte M and Heuschmann, Peter Ulrich and Longstreth, W T and Jung, Keum Ji and Bastarache, Lisa and Par{\'e}, Guillaume and Damrauer, Scott M and Chasman, Daniel I and Rotter, Jerome I and Anderson, Christopher D and Zwart, John-Anker and Niiranen, Teemu J and Fornage, Myriam and Liaw, Yung-Po and Seshadri, Sudha and Fernandez-Cadenas, Israel and Walters, Robin G and Ruff, Christian T and Owolabi, Mayowa O and Huffman, Jennifer E and Milani, Lili and Kamatani, Yoichiro and Dichgans, Martin and Debette, Stephanie} } @article {9415, title = {{Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study}, journal = {Alzheimers Dement}, year = {2023}, month = {Jul}, abstract = {Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated.\ We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline.\ 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline.\ Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.}, author = {{\'e}, H. T. and Liu, X. and Odden, M. C. and Moseholm, K. F. and Seshadri, S. and Satizabal, C. L. and Lopez, O. L. and Bis, J. C. and {\'e}, L. and Fohner, A. E. and Psaty, B. M. and Tracy, R. P. and Longstreth, W. T. and Jensen, M. K. and Mukamal, K. J.} } @article {9417, title = {Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Jul 03}, pages = {e2325152}, abstract = {

IMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.

OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.

DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.

EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG.

MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.

RESULTS: Across cohorts, 5946 adults (1875 females [31.5\%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9\% to 28.9\%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1\% increase, 0.08; 95\% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95\% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] >=5) was associated with poorer global cognition (pooled β, -0.06; 95\% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95\% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.

CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.25152}, author = {Pase, Matthew P and Harrison, Stephanie and Misialek, Jeffrey R and Kline, Christopher E and Cavuoto, Marina and Baril, Andree-Ann and Yiallourou, Stephanie and Bisson, Alycia and Himali, Dibya and Leng, Yue and Yang, Qiong and Seshadri, Sudha and Beiser, Alexa and Gottesman, Rebecca F and Redline, Susan and Lopez, Oscar and Lutsey, Pamela L and Yaffe, Kristine and Stone, Katie L and Purcell, Shaun M and Himali, Jayandra J} } @article {9317, title = {Social networks, social support, and life expectancy in older adults: the Cardiovascular Health Study.}, journal = {Arch Gerontol Geriatr}, volume = {111}, year = {2023}, month = {2023 Mar 03}, pages = {104981}, abstract = {

BACKGROUND: Social support and social networks have long been postulated to impact health outcomes but their impact on life expectancy and disability in older adults remains poorly quantified.

METHODS: As part of the Cardiovascular Health Study, we followed 5,749 adults aged 65 years and older from 4 US field centers for 25 years. We assessed the Lubben social network score [range 0-50] and a social support score [range 0-24] derived from the Interpersonal Support Evaluation List (ISEL-12) in two consecutive years starting at study recruitment. We used remaining years of life (YOL) from study enrollment to death to approximate life expectancy. We defined years of active life (YAL) as the number of study years in which participants lived without any difficulties in activities of daily living. We used compression of disability to reflect the proportion of life lived able (YAL/YOL). We used linear regression to adjust for socio-demographics and comorbidity.

RESULTS: The mean (standard deviation [SD]) scores were 32.3~{\textpm}~6.8 points for social network score and 8.3~{\textpm}~2.4 points for social support score. For every 1-SD increase in social network score, adjusted participant life expectancy was 0.40 years higher (95\% CI 0.22-0.58; p<0.0001) and disability-free life expectancy 0.35 years higher (95\% CI 0.18-0.53; p<0.0001). The association with life expectancy was modified by participant age (p<0.001), but it remained significant even among participants aged >=75 years (3 months per SD; 95\% CI 0.1-6 months, p~=~0.04). Further adjustment for frailty did not attenuate the estimates. The social support scale was not significantly associated with YOL or YAL after adjustment for social network score, and neither measure was associated with compression of disability.

DISCUSSION: In older adults, higher social network scores are significantly associated with longer life expectancy and disability-free life expectancy.

}, issn = {1872-6976}, doi = {10.1016/j.archger.2023.104981}, author = {Bhatia, Roma and Hirsch, Calvin and Arnold, Alice M and Newman, Anne B and Mukamal, Kenneth J} } @article {9543, title = {A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {bioRxiv}, year = {2023}, month = {2023 Nov 02}, abstract = {

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

}, doi = {10.1101/2023.10.30.564764}, author = {Li, Xihao and Chen, Han and Selvaraj, Margaret Sunitha and Van Buren, Eric and Zhou, Hufeng and Wang, Yuxuan and Sun, Ryan and McCaw, Zachary R and Yu, Zhi and Arnett, Donna K and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Carson, April P and Carlson, Jenna C and Chami, Nathalie and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Gu, Charles and Heard-Costa, Nancy L and He, Jiang and Hou, Lifang and Hung, Yi-Jen and Irvin, Marguerite R and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Tanika and Konigsberg, Iain and Kooperberg, Charles and Kral, Brian G and Li, Changwei and Loos, Ruth J F and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Minster, Ryan L and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Tiwari, Hemant and Vasan, Ramachandran S and Wang, Zhe and Yanek, Lisa R and Yu, Bing and Rice, Kenneth M and Rotter, Jerome I and Peloso, Gina M and Natarajan, Pradeep and Li, Zilin and Liu, Zhonghua and Lin, Xihong} } @article {9508, title = {{Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer{\textquoteright}s Diseases Sequencing Project Subjects}, journal = {medRxiv}, year = {2023}, month = {Sep}, abstract = {. We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.\ Alzheimer{\textquoteright}s disease, Structural variation, Copy number variation.}, author = {Wang, H. and Dombroski, B. A. and Cheng, P. L. and Tucci, A. and Si, Y. Q. and Farrell, J. J. and Tzeng, J. Y. and Leung, Y. Y. and Malamon, J. S. and Wang, L. S. and Vardarajan, B. N. and Farrer, L. A. and Schellenberg, G. D. and Lee, W. P.} } @article {9542, title = {{Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer{\textquoteright}s Diseases Sequencing Project Subjects}, journal = {Res Sq}, year = {2023}, month = {Oct}, abstract = {. We also identified 16 SVs associated with AD and 13 SVs linked to AD-related pathological/cognitive endophenotypes. This study highlights the pivotal role of SVs in shaping our understanding of AD genetics.}, author = {Lee, W. P. and Wang, H. and Dombroski, B. and Cheng, P. L. and Tucci, A. and Si, Y. Q. and Farrell, J. and Tzeng, J. Y. and Leung, Y. Y. and Malamon, J. and Wang, L. S. and Vardarajan, B. and Farrer, L. and Schellenberg, G.} } @article {9445, title = {Substitution of self-reported measures for objectively assessed grip strength and slow walk in the Physical Frailty Phenotype: ramifications for validity.}, journal = {BMC Geriatr}, volume = {23}, year = {2023}, month = {2023 Jul 22}, pages = {451}, abstract = {

BACKGROUND: Frailty assessment promises to identify older adults at risk for adverse consequences following stressors and target interventions to improve health outcomes. The Physical Frailty Phenotype (PFP) is a widely-studied, well validated assessment but incorporates performance-based slow walk and grip strength criteria that challenge its use in some clinical settings. Variants replacing performance-based elements with self-reported proxies have been proposed. Our study evaluated whether commonly available disability self-reports could be substituted for the performance-based criteria in the PFP while still identifying as "frail" the same subpopulations of individuals.

METHODS: Parallel analyses were conducted in 3393 female and 2495 male Cardiovascular Health Study, Round 2 participants assessed in 1989-90. Candidate self-reported proxies for the phenotype{\textquoteright}s "slowness" and "weakness" criteria were evaluated for comparable prevalence and agreement by mode of measurement. For best-performing candidates: Frailty status (3 + positive criteria out of 5) was compared for prevalence and agreement between the PFP and mostly self-reported versions. Personal characteristics were compared between those adjudicated as frail by (a) only a self-reported version; (b) only the PFP; (c) both, using bivariable analyses and multinomial logistic regression.

RESULTS: Self-reported difficulty walking {\textonehalf} mile was selected as a proxy for the phenotype{\textquoteright}s slowness criterion. Two self-reported weakness proxies were examined: difficulty transferring from a bed or chair or gripping with hands, and difficulty as just defined or in lifting a 10-pound bag. Prevalences matched to within 4\% between self-reported and performance-based criteria in the whole sample, but in all cases the self-reported prevalence for women exceeded that for men by 11\% or more. Cross-modal agreement was moderate, with by-criterion and frailty-wide Kappa statistics of 0.55-0.60 in all cases. Frail subgroups (a), (b), (c) were independently discriminated (p < 0.05) by race, BMI, and depression in women; by age in men; and by self-reported health for both.

CONCLUSIONS: Commonly used self-reported disability items cannot be assumed to stand in for performance-based criteria in the PFP. We found subpopulations identified as frail by resultant phenotypes versus the original phenotype to systematically differ. Work to develop self-reported proxies that more closely replicate their objective phenotypic counterparts than standard disability self-reports is needed.

}, keywords = {Advance Directives, Female, Frailty, Hand Strength, Humans, Male, Phenotype, Self Report}, issn = {1471-2318}, doi = {10.1186/s12877-023-04105-8}, author = {Bandeen-Roche, Karen and Tian, Jing and Buta, Brian and Walston, Jeremy and Xue, Qian-Li} }