@article {728, title = {Variation in symptoms of sleep-disordered breathing with race and ethnicity: the Sleep Heart Health Study.}, journal = {Sleep}, volume = {26}, year = {2003}, month = {2003 Feb 01}, pages = {74-9}, abstract = {

STUDY OBJECTIVES: To examine the relation of sleep-related symptoms to race and ethnicity in a diverse sample of middle-aged and older men and women.

DESIGN: Cross-sectional questionnaire survey.

SETTING: In the initial phase of the Sleep Heart Health Study, men and women enrolled in participating epidemiologic cohort studies were surveyed.

PARTICIPANTS: 13,194 men and women 40 years of age and older, including 11,517 non-Hispanic white, 648 black, 643 American Indian, 296 Hispanic, and 90 Asian-Pacific Islander.

INTERVENTIONS: Not applicable.

MEASUREMENTS AND RESULTS: After adjustment for BMI and other factors, frequent snoring was more common among Hispanic women (odds ratio (OR) = 2.25, 95\% confidence interval (CI) = 1.48, 3.42) and black women (OR = 1.55, 95\% Ci = 1.13, 2.13) than among non-Hispanic white women. Hispanic men were significantly more likely to report frequent snoring than non-Hispanic white men (OR = 2.30, 95\% CI = 1.43, 3.69). Black, American Indian, and Asian men did not differ significantly from white men in snoring prevalence. American Indian women were significantly more likely to report breathing pauses during sleep than their white, non-Hispanic counterparts (OR = 1.52, 95\% CI 1.03, 2.24), although polysomnography data on a subset of the sample suggested that the association between this symptom reported on questionnaire and objective evidence of sleep-disordered breathing may be weaker among American Indians than among other groups. Mean Epworth Sleepiness Scale scores were slightly higher in black men and women than in their white, non-hispanic counterparts.

CONCLUSIONS: Frequent snoring was more common among black and Hispanic women and Hispanic men than among their white non-Hispanic counterparts, even after adjusting for BMI and other factors. Further research including polysomnography and objective measurements of sleepiness is needed to assess the physiologic and clinical significance of these findings.

}, keywords = {Adult, Cross-Sectional Studies, Electroencephalography, Electrooculography, Ethnic Groups, Female, Heart Rate, Humans, Male, Polysomnography, Severity of Illness Index, Sleep Apnea Syndromes, Snoring, Surveys and Questionnaires}, issn = {0161-8105}, author = {O{\textquoteright}Connor, George T and Lind, Bonnie K and Lee, Elisa T and Nieto, F Javier and Redline, Susan and Samet, Jonathan M and Boland, Lori L and Walsleben, Joyce A and Foster, Gregory L} } @article {860, title = {Vascular events, mortality, and preventive therapy following ischemic stroke in the elderly.}, journal = {Neurology}, volume = {65}, year = {2005}, month = {2005 Sep 27}, pages = {835-42}, abstract = {

BACKGROUND: The authors studied mortality, vascular events, and preventive therapies following ischemic stroke among adults aged > or =65 years.

METHODS: The authors identified 546 subjects with first ischemic stroke during 1989 to 2001 among Cardiovascular Health Study participants. Deaths, recurrent strokes, and coronary heart disease (CHD) events were identified over 3.2 years (median) follow-up.

RESULTS: During the first year of follow-up, rates were 105.4/1,000 for recurrent stroke and 59.3/1,000 for CHD. After the first year, the stroke rate was 52.0/1,000 and the CHD rate was 46.5/1,000. Cardioembolic strokes had the highest mortality (185.4/1,000) and recurrence rates (86.6/1,000). Lacunar strokes had the lowest mortality (119.3/1,000) and recurrence rates (43.0/1,000). Age and male sex predicted death and CHD, but not recurrence. Outcomes did not differ by race. Following stroke, 47.8\% used aspirin and 13.5\% used other antiplatelet agents; 52.6\% of patients with atrial fibrillation used warfarin; 31.3\% of hyperlipidemic subjects, 57.0\% of diabetic patients, and 81.5\% of hypertensive patients were drug-treated; and 40.0\% of hypertensive patients had blood pressure (BP) <140/90 mm Hg. Older subjects were less likely to use lipid-lowering therapy, women were less likely to have BP <140/90 mm Hg, and low-income subjects were less likely to use diabetes medications.

CONCLUSIONS: Recurrent strokes were nearly twice as frequent as coronary heart disease (CHD) events during the first year after initial stroke, but stroke and CHD rates were similar after the first year. Preventive drug therapies were underused, which may reflect clinical uncertainty due to the lack of clinical trials among the elderly. Utilization was lower among the oldest patients, women, and low-income individuals.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Anticoagulants, Antihypertensive Agents, Brain Ischemia, Cohort Studies, Comorbidity, Coronary Artery Disease, Drug Utilization, Female, Humans, Hyperlipidemias, Hypertension, Hypolipidemic Agents, Male, Mortality, Prospective Studies, Recurrence, Sex Factors, Stroke, Treatment Outcome}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000176058.09848.bb}, author = {Kaplan, R C and Tirschwell, D L and Longstreth, W T and Manolio, T A and Heckbert, S R and Lefkowitz, D and El-Saed, A and Psaty, B M} } @article {946, title = {Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction: the Cardiovascular Health Study.}, journal = {J Am Coll Cardiol}, volume = {49}, year = {2007}, month = {2007 Mar 06}, pages = {972-81}, abstract = {

OBJECTIVES: The purpose of this study was to evaluate left ventricular (LV) size and structure in elderly subjects with hypertension (HTN) and heart failure who have a normal ejection fraction (HFNEF) in a large population-based sample.

BACKGROUND: The pathophysiology of HFNEF is incompletely understood but is generally attributed to LV diastolic dysfunction with normal or reduced LV diastolic chamber size despite greater than normal filling pressures.

METHODS: In the Cardiovascular Health Study (n = 5,888), demographic and clinical characteristics and ventricular structure and function were compared in healthy normal subjects (healthy; n = 499), subjects with HTN but not heart failure (HTN; n = 2,184), and subjects with HTN and HFNEF (HFNEF; n = 167).

RESULTS: Subjects with HFNEF were older, more obese, and more often African American than healthy and HTN subjects and had a higher prevalence of diabetes, coronary heart disease, and anemia than HTN subjects. Serum creatinine and cystatin-C were increased in HFNEF subjects. Average LV diastolic dimension was significantly increased in HFNEF subjects (5.2 +/- 0.8 cm) compared with healthy (4.8 +/- 0.6 cm) and HTN (4.9 +/- 0.6 cm) subjects. As a result, average calculated stroke volume (89 +/- 25 ml vs. 78 +/- 20 ml and 80 +/- 20 ml) and cardiac output (6.0 +/- 2.0 l/min vs. 4.8 +/- 1.3 l/min and 5.1 +/- 1.4 l/min) were increased in HFNEF compared with healthy and HTN subjects, respectively.

CONCLUSIONS: As a group, HFNEF subjects have increased LV diastolic diameter and increased calculated stroke volume. They also have increased prevalence of multiple comorbidities, including anemia, renal dysfunction, and obesity, that can cause volume overload. These data suggest that extracardiac factors, via volume overload, may contribute to the pathophysiology of HFNEF in the elderly.

}, keywords = {Age Distribution, Aged, Body Size, Case-Control Studies, Cohort Studies, Comorbidity, Continental Population Groups, Echocardiography, Female, Heart Failure, Heart Ventricles, Humans, Hypertension, Longitudinal Studies, Male, Multivariate Analysis, Prevalence, Regression Analysis, Risk Factors, Sex Distribution, Stroke Volume, United States}, issn = {1558-3597}, doi = {10.1016/j.jacc.2006.10.061}, author = {Maurer, Mathew S and Burkhoff, Daniel and Fried, Linda P and Gottdiener, John and King, Donald L and Kitzman, Dalane W} } @article {889, title = {Ventricular volume and dementia progression in the Cardiovascular Health Study.}, journal = {Neurobiol Aging}, volume = {28}, year = {2007}, month = {2007 Mar}, pages = {389-97}, abstract = {

Elevated cerebral ventricular volume may be associated with dementia risk and progression. A fully-automated technique that agreed highly with radiological readings was used to estimate lateral ventricle volume on MR scans done at baseline in 1997-99 of 377 subjects in the Cardiovascular Health Study (CHS) from the Pittsburgh Center. 327 subjects were normal or diagnosed with mild cognitive impairment (MCI) at baseline and were evaluated 4 years later. Baseline ventricular volume was analyzed in multivariate models with age, gender, education level, presence and incidence of cerebral infarcts, and dementia category (normal, MCI, or dementia) at baseline and follow-up as fixed effects. Ventricular volume at baseline was significantly higher among subjects normal at baseline and demented 4 years later. Age, gender, education level, and dementia progression were significant factors affecting ventricular volume. Ventricular volume was higher in dementia compared to MCI, higher in MCI compared to controls, and higher in Possible-Alzheimer{\textquoteright}s-disease (AD) dementia compared to Probable-AD. Larger ventricles in healthy subjects may indicate susceptibility to, or progression of, dementia-related pathology.

}, keywords = {Aged, Aged, 80 and over, Aging, Cognition Disorders, Cross-Sectional Studies, Dementia, Disease Progression, Female, Follow-Up Studies, Humans, Lateral Ventricles, Linear Models, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Prospective Studies, Retrospective Studies, Time Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2006.01.006}, author = {Carmichael, Owen T and Kuller, Lewis H and Lopez, Oscar L and Thompson, Paul M and Dutton, Rebecca A and Lu, Allen and Lee, Sharon E and Lee, Jessica Y and Aizenstein, Howard J and Meltzer, Carolyn Cidis and Liu, Yanxi and Toga, Arthur W and Becker, James T} } @article {1114, title = {Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Aug}, pages = {879-81}, abstract = {

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

}, keywords = {Atrial Fibrillation, Chromosomes, Human, Pair 16, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins, Humans, Meta-Analysis as Topic, Mutation, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.416}, author = {Benjamin, Emelia J and Rice, Kenneth M and Arking, Dan E and Pfeufer, Arne and van Noord, Charlotte and Smith, Albert V and Schnabel, Renate B and Bis, Joshua C and Boerwinkle, Eric and Sinner, Moritz F and Dehghan, Abbas and Lubitz, Steven A and D{\textquoteright}Agostino, Ralph B and Lumley, Thomas and Ehret, Georg B and Heeringa, Jan and Aspelund, Thor and Newton-Cheh, Christopher and Larson, Martin G and Marciante, Kristin D and Soliman, Elsayed Z and Rivadeneira, Fernando and Wang, Thomas J and Eiriksdottir, Gudny and Levy, Daniel and Psaty, Bruce M and Li, Man and Chamberlain, Alanna M and Hofman, Albert and Vasan, Ramachandran S and Harris, Tamara B and Rotter, Jerome I and Kao, W H Linda and Agarwal, Sunil K and Stricker, Bruno H Ch and Wang, Ke and Launer, Lenore J and Smith, Nicholas L and Chakravarti, Aravinda and Uitterlinden, Andr{\'e} G and Wolf, Philip A and Sotoodehnia, Nona and K{\"o}ttgen, Anna and van Duijn, Cornelia M and Meitinger, Thomas and Mueller, Martina and Perz, Siegfried and Steinbeck, Gerhard and Wichmann, H-Erich and Lunetta, Kathryn L and Heckbert, Susan R and Gudnason, Vilmundur and Alonso, Alvaro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T and Witteman, Jacqueline C M} } @article {1247, title = {Validation of an atrial fibrillation risk algorithm in whites and African Americans.}, journal = {Arch Intern Med}, volume = {170}, year = {2010}, month = {2010 Nov 22}, pages = {1909-17}, abstract = {

BACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.

METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2\%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.

RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95\% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95\% CI, 0.66-0.70); and CHS African Americans, 0.66 (95\% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0\% (AGES) and 63.6\% (FHS) of the population-attributable risk.

CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64\% of risk.

}, keywords = {African Continental Ancestry Group, Age Factors, Aged, Aged, 80 and over, Algorithms, Atrial Fibrillation, Blood Pressure, Body Mass Index, Cohort Studies, Electrocardiography, Europe, European Continental Ancestry Group, Female, Follow-Up Studies, Heart Failure, Humans, Hypertension, Incidence, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Sex Factors, Systole, United States}, issn = {1538-3679}, doi = {10.1001/archinternmed.2010.434}, author = {Schnabel, Renate B and Aspelund, Thor and Li, Guo and Sullivan, Lisa M and Suchy-Dicey, Astrid and Harris, Tamara B and Pencina, Michael J and D{\textquoteright}Agostino, Ralph B and Levy, Daniel and Kannel, William B and Wang, Thomas J and Kronmal, Richard A and Wolf, Philip A and Burke, Gregory L and Launer, Lenore J and Vasan, Ramachandran S and Psaty, Bruce M and Benjamin, Emelia J and Gudnason, Vilmundur and Heckbert, Susan R} } @article {1194, title = {Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {3}, year = {2010}, month = {2010 Jul}, pages = {495-502}, abstract = {

BACKGROUND: The recently developed and internally validated Health ABC HF model uses 9 routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model.

METHODS AND RESULTS: Observed 5-year incidence of heart failure, defined as first hospitalization for new-onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5\%) participants developed heart failure over 5 years versus 364 (6.8\%) predicted by the Health ABC HF model (predicted-to-observed ratio, 0.90). Observed versus predicted 5-year heart failure probabilities were 3.2\% versus 2.8\%, 9.0\% versus 7.0\%, 15.9\% versus 13.7\%, and 24.6\% versus 30.8\% for the <5\%, 5\% to 10\%, 10\% to 20\%, and >20\% 5-year risk categories, respectively. The Hosmer-Lemeshow chi(2) was 14.72 (degrees of freedom, 10; P=0.14), and the C index was 0.74 (95\% CI, 0.72 to 0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however, risk was underestimated in white men, especially in the 5\% to 10\% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results.

CONCLUSIONS: The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to whom to target heart failure prevention efforts.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Cause of Death, Cohort Studies, Confidence Intervals, Disease Progression, Echocardiography, Doppler, Female, Heart Failure, Humans, Incidence, Male, Models, Statistical, Predictive Value of Tests, Prognosis, Severity of Illness Index, Sex Distribution, Survival Analysis, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.109.904300}, author = {Kalogeropoulos, Andreas and Psaty, Bruce M and Vasan, Ramachandran S and Georgiopoulou, Vasiliki and Smith, Andrew L and Smith, Nicholas L and Kritchevsky, Stephen B and Wilson, Peter W F and Newman, Anne B and Harris, Tamara B and Butler, Javed} } @article {1329, title = {Vitamin D, parathyroid hormone, and cardiovascular events among older adults.}, journal = {J Am Coll Cardiol}, volume = {58}, year = {2011}, month = {2011 Sep 27}, pages = {1433-41}, abstract = {

OBJECTIVES: The aim of this study was to evaluate associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentrations separately and in combination with incident cardiovascular events and mortality during 14 years of follow-up in the CHS (Cardiovascular Health Study).

BACKGROUND: Vitamin D deficiency and PTH excess are common in older adults and may adversely affect cardiovascular health.

METHODS: A total of 2,312 participants who were free of cardiovascular disease at baseline were studied. Vitamin D and intact PTH were measured from previously frozen serum using mass spectrometry and a 2-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all-cause mortality.

RESULTS: There were 384 participants (17\%) with serum 25-OHD concentrations <15 ng/ml and 570 (25\%) with serum PTH concentrations >= 65 pg/ml. After adjustment, each 10 ng/ml lower 25-OHD concentration was associated with a 9\% greater (95\% confidence interval [CI]: 2\% to 17\% greater) relative hazard of mortality and a 25\% greater (95\% CI: 8\% to 44\% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml were associated with a 29\% greater (95\% CI: 5\% to 55\% greater) risk for mortality. Serum PTH concentrations >= 65 pg/ml were associated with a 30\% greater risk for heart failure (95\% CI: 6\% to 61\% greater) but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events.

CONCLUSIONS: Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cohort Studies, Female, Follow-Up Studies, Humans, Male, Parathyroid Hormone, Prospective Studies, Vitamin D}, issn = {1558-3597}, doi = {10.1016/j.jacc.2011.03.069}, author = {Kestenbaum, Bryan and Katz, Ronit and de Boer, Ian and Hoofnagle, Andy and Sarnak, Mark J and Shlipak, Michael G and Jenny, Nancy S and Siscovick, David S} } @article {1350, title = {Vitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study.}, journal = {Hypertension}, volume = {58}, year = {2011}, month = {2011 Dec}, pages = {1021-8}, abstract = {

Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-OHD >=20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 events per 1000 for PTH <65 pg/mL and 4 events per 1000 for PTH >=65 pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7\% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95\% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.

}, keywords = {Aged, Cardiovascular Diseases, Comorbidity, Death, Sudden, Cardiac, Diabetes Mellitus, Female, Follow-Up Studies, Humans, Hypertension, Incidence, Kidney, Male, Middle Aged, Minerals, Parathyroid Hormone, Proportional Hazards Models, Risk Factors, Socioeconomic Factors, United States, Vitamin D}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.111.179135}, author = {Deo, Rajat and Katz, Ronit and Shlipak, Michael G and Sotoodehnia, Nona and Psaty, Bruce M and Sarnak, Mark J and Fried, Linda F and Chonchol, Michel and de Boer, Ian H and Enquobahrie, Daniel and Siscovick, David and Kestenbaum, Bryan} } @article {1543, title = {Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.}, journal = {Invest Ophthalmol Vis Sci}, volume = {53}, year = {2012}, month = {2012 Jun 28}, pages = {4152-7}, abstract = {

PURPOSE: Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.

METHODS: Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.

RESULTS: Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3{\texttimes}10(-3) and 7{\texttimes}10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7{\texttimes}10(-3) and 7.7{\texttimes}10(-4), respectively. Meta P values of 4.0{\texttimes}10(-5) and 4.0{\texttimes}10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.

CONCLUSIONS: Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.

}, keywords = {Case-Control Studies, Cornea, Corneal Topography, DNA, Family, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Keratoconus, Polymorphism, Genetic, Protein-Lysine 6-Oxidase}, issn = {1552-5783}, doi = {10.1167/iovs.11-9268}, author = {Bykhovskaya, Yelena and Li, Xiaohui and Epifantseva, Irina and Haritunians, Talin and Siscovick, David and Aldave, Anthony and Szczotka-Flynn, Loretta and Iyengar, Sudha K and Taylor, Kent D and Rotter, Jerome I and Rabinowitz, Yaron S} } @article {6692, title = {A variant of sparse partial least squares for variable selection and data exploration.}, journal = {Front Neuroinform}, volume = {8}, year = {2014}, month = {2014}, pages = {18}, abstract = {When data are sparse and/or predictors multicollinear, current implementation of sparse partial least squares (SPLS) does not give estimates for non-selected predictors nor provide a measure of inference. In response, an approach termed "all-possible" SPLS is proposed, which fits a SPLS model for all tuning parameter values across a set grid. Noted is the percentage of time a given predictor is chosen, as well as the average non-zero parameter estimate. Using a "large" number of multicollinear predictors, simulation confirmed variables not associated with the outcome were least likely to be chosen as sparsity increased across the grid of tuning parameters, while the opposite was true for those strongly associated. Lastly, variables with a weak association were chosen more often than those with no association, but less often than those with a strong relationship to the outcome. Similarly, predictors most strongly related to the outcome had the largest average parameter estimate magnitude, followed by those with a weak relationship, followed by those with no relationship. Across two independent studies regarding the relationship between volumetric MRI measures and a cognitive test score, this method confirmed a priori hypotheses about which brain regions would be selected most often and have the largest average parameter estimates. In conclusion, the percentage of time a predictor is chosen is a useful measure for ordering the strength of the relationship between the independent and dependent variables, serving as a form of inference. The average parameter estimates give further insight regarding the direction and strength of association. As a result, all-possible SPLS gives more information than the dichotomous output of traditional SPLS, making it useful when undertaking data exploration and hypothesis generation for a large number of potential predictors.}, issn = {1662-5196}, doi = {10.3389/fninf.2014.00018}, author = {Olson Hunt, Megan J and Weissfeld, Lisa and Boudreau, Robert M and Aizenstein, Howard and Newman, Anne B and Simonsick, Eleanor M and Van Domelen, Dane R and Thomas, Fridtjof and Yaffe, Kristine and Rosano, Caterina} } @article {7017, title = {Vitamin D and the risk of dementia and Alzheimer disease.}, journal = {Neurology}, volume = {83}, year = {2014}, month = {2014 Sep 2}, pages = {920-8}, abstract = {

OBJECTIVE: To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.

METHODS: One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer{\textquoteright}s Disease and Related Disorders Association criteria.

RESULTS: During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95\% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (>=25 to <50 nmol/L) were 2.25 (95\% CI: 1.23-4.13) and 1.53 (95\% CI: 1.06-2.21) compared to participants with sufficient concentrations (>=50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95\% CI: 1.02-4.83) and 1.69 (95\% CI: 1.06-2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.

CONCLUSION: Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.

}, keywords = {Aged, Alzheimer Disease, Dementia, Female, Follow-Up Studies, Humans, Incidence, Male, Proportional Hazards Models, Risk Factors, United States, Vitamin D, Vitamin D Deficiency}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000000755}, author = {Littlejohns, Thomas J and Henley, William E and Lang, Iain A and Annweiler, Cedric and Beauchet, Olivier and Chaves, Paulo H M and Fried, Linda and Kestenbaum, Bryan R and Kuller, Lewis H and Langa, Kenneth M and Lopez, Oscar L and Kos, Katarina and Soni, Maya and Llewellyn, David J} } @article {6561, title = {Variation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults.}, journal = {Heart}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {132-8}, abstract = {

OBJECTIVE: Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults.

METHODS: 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively.

RESULTS: 262 subjects had an incident MI event (13\%) and 1326 died (67\%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95\% CI 1.05 to 1.20) and variation (HR 1.08; 95\% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex.

CONCLUSIONS: Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Electrocardiography, Female, Follow-Up Studies, Heart Rate, Humans, Incidence, Linear Models, Male, Myocardial Infarction, Outcome Assessment (Health Care), Prognosis, Proportional Hazards Models, Prospective Studies, Rest, Risk Factors, Time, Washington}, issn = {1468-201X}, doi = {10.1136/heartjnl-2014-306046}, author = {Floyd, James S and Sitlani, Colleen M and Wiggins, Kerri L and Wallace, Erin and Suchy-Dicey, Astrid and Abbasi, Siddique A and Carnethon, Mercedes R and Siscovick, David S and Sotoodehnia, Nona and Heckbert, Susan R and McKnight, Barbara and Rice, Kenneth M and Psaty, Bruce M} } @article {6767, title = {Ventricular Ectopy as a Predictor of Heart Failure and Death.}, journal = {J Am Coll Cardiol}, volume = {66}, year = {2015}, month = {2015 Jul 14}, pages = {101-9}, abstract = {

BACKGROUND: Studies of patients presenting for catheter ablation suggest that premature ventricular contractions (PVCs) are a modifiable risk factor for congestive heart failure (CHF). The relationship among PVC frequency, incident CHF, and mortality in the general population remains unknown.

OBJECTIVES: The goal of this study was to determine whether PVC frequency ascertained using a 24-h Holter monitor is a predictor of a decrease in the left ventricular ejection fraction (LVEF), incident CHF, and death in a population-based cohort.

METHODS: We studied 1,139 Cardiovascular Health Study (CHS) participants who were randomly assigned to 24-h ambulatory electrocardiography (Holter) monitoring and who had a normal LVEF and no history of CHF. PVC frequency was quantified using Holter studies, and LVEF was measured from baseline and 5-year echocardiograms. Participants were followed for incident CHF and death.

RESULTS: Those in the upper quartile versus the lowest quartile of PVC frequency had a multivariable-adjusted, 3-fold greater odds of a 5-year decrease in LVEF (odds ratio [OR]: 3.10; 95\% confidence interval [CI]: 1.42 to 6.77; p = 0.005), a 48\% increased risk of incident CHF (HR: 1.48; 95\% CI: 1.08 to 2.04; p = 0.02), and a 31\% increased risk of death (HR: 1.31; 95\% CI: 1.06 to 1.63; p = 0.01) during a median follow-up of >13 years. Similar statistically significant results were observed for PVCs analyzed as a continuous variable. The specificity for the 15-year risk of CHF exceeded 90\% when PVCs included at least 0.7\% of ventricular beats. The population-level risk for incident CHF attributed to PVCs was 8.1\% (95\% CI: 1.2\% to 14.9\%).

CONCLUSIONS: In a population-based sample, a higher frequency of PVCs was associated with a decrease in LVEF, an increase in incident CHF, and increased mortality. Because of the capacity to prevent PVCs through medical or ablation therapy, PVCs may represent a modifiable risk factor for CHF and death.

}, keywords = {Aged, Catheter Ablation, Echocardiography, Electrocardiography, Ambulatory, Female, Forecasting, Heart Failure, Humans, Male, Risk Factors, Stroke Volume, Ventricular Premature Complexes}, issn = {1558-3597}, doi = {10.1016/j.jacc.2015.04.062}, author = {Dukes, Jonathan W and Dewland, Thomas A and Vittinghoff, Eric and Mandyam, Mala C and Heckbert, Susan R and Siscovick, David S and Stein, Phyllis K and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Marcus, Gregory M} } @article {6773, title = {Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer{\textquoteright}s Disease.}, journal = {J Alzheimers Dis}, volume = {46}, year = {2015}, month = {2015}, pages = {167-78}, abstract = {

The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer{\textquoteright}s disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study-Cognition Study (mean age = 79.2 {\textpm} 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p <  0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5{\texttimes}10 -8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person{\textquoteright}s increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Chi-Square Distribution, Disease Progression, Female, Gray Matter, Humans, Incidence, Magnetic Resonance Imaging, Male, Mild Cognitive Impairment, Neuropsychological Tests, Psychiatric Status Rating Scales, Survival Analysis}, issn = {1875-8908}, doi = {10.3233/JAD-150047}, author = {Zeifman, Lubov E and Eddy, William F and Lopez, Oscar L and Kuller, Lewis H and Raji, Cyrus and Thompson, Paul M and Becker, James T} } @article {6999, title = {Vitamin D and Memory Decline: Two Population-Based Prospective Studies.}, journal = {J Alzheimers Dis}, volume = {50}, year = {2016}, month = {2016}, pages = {1099-108}, abstract = {

BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown.

OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline.

METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey{\textquoteright}s Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively.

RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95\% CI: -0.06 to 0.01) and -0.10 SD (95\% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95\% CI: -0.01 to 0.02) and -0.01 SD (95\% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34).

CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

}, issn = {1875-8908}, doi = {10.3233/JAD-150811}, author = {Ku{\'z}ma, El{\.z}bieta and Soni, Maya and Littlejohns, Thomas J and Ranson, Janice M and van Schoor, Natasja M and Deeg, Dorly J H and Comijs, Hannie and Chaves, Paulo H M and Kestenbaum, Bryan R and Kuller, Lewis H and Lopez, Oscar L and Becker, James T and Langa, Kenneth M and Henley, William E and Lang, Iain A and Ukoumunne, Obioha C and Llewellyn, David J} } @article {7126, title = {Vitamin D and Risk of Neuroimaging Abnormalities.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0154896}, abstract = {

Vitamin D deficiency has been linked with an increased risk of incident all-cause dementia and Alzheimer{\textquoteright}s disease. The aim of the current study was to explore the potential mechanisms underlying these associations by determining whether low vitamin D concentrations are associated with the development of incident cerebrovascular and neurodegenerative neuroimaging abnormalities. The population consisted of 1,658 participants aged >=65 years from the US-based Cardiovascular Health Study who were free from prevalent cardiovascular disease, stroke and dementia at baseline in 1992-93. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected at baseline. The first MRI scan was conducted between 1991-1994 and the second MRI scan was conducted between 1997-1999. Change in white matter grade, ventricular grade and presence of infarcts between MRI scan one and two were used to define neuroimaging abnormalities. During a mean follow-up of 5.0 years, serum 25(OH)D status was not significantly associated with the development of any neuroimaging abnormalities. Using logistic regression models, the multivariate adjusted odds ratios (95\% confidence interval) for worsening white matter grade in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (>=25-50 nmol/L) were 0.76 (0.35-1.66) and 1.09 (0.76-1.55) compared to participants with sufficient concentrations (>=50 nmol/L). The multivariate adjusted odds ratios for ventricular grade in participants who were severely 25(OH)D deficient and deficient were 0.49 (0.20-1.19) and 1.12 (0.79-1.59) compared to those sufficient. The multivariate adjusted odds ratios for incident infarcts in participants who were severely 25(OH)D deficient and deficient were 1.95 (0.84-4.54) and 0.73 (0.47-1.95) compared to those sufficient. Overall, serum vitamin D concentrations could not be shown to be associated with the development of cerebrovascular or neurodegenerative neuroimaging abnormalities in Cardiovascular Health Study participants.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0154896}, author = {Littlejohns, Thomas J and Kos, Katarina and Henley, William E and Lang, Iain A and Annweiler, Cedric and Beauchet, Olivier and Chaves, Paulo H M and Kestenbaum, Bryan R and Kuller, Lewis H and Langa, Kenneth M and Lopez, Oscar L and Llewellyn, David J} } @article {8572, title = {Visit-to-Visit Blood Pressure Variability and Mortality and Cardiovascular Outcomes Among Older Adults: The Health, Aging, and Body Composition Study.}, journal = {Am J Hypertens}, volume = {30}, year = {2017}, month = {2017 Feb}, pages = {151-158}, abstract = {

BACKGROUND: Level of blood pressure (BP) is strongly associated with cardiovascular (CV) events and mortality. However, it is questionable whether mean BP can fully capture BP-related vascular risk. Increasing attention has been given to the value of visit-to-visit BP variability.

METHODS: We examined the association of visit-to-visit BP variability with mortality, incident myocardial infarction (MI), and incident stroke among 1,877 well-functioning elders in the Health, Aging, and Body Composition Study. We defined visit-to-visit diastolic BP (DBP) and systolic BP (SBP) variability as the root-mean-square error of person-specific linear regression of BP as a function of time. Alternatively, we counted the number of considerable BP increases and decreases (separately; 10mm Hg for DBP and 20mm Hg for SBP) between consecutive visits for each individual.

RESULTS: Over an average follow-up of 8.5 years, 623 deaths (207 from CV disease), 153 MIs, and 156 strokes occurred. The median visit-to-visit DBP and SBP variability was 4.96 mmHg and 8.53 mmHg, respectively. After multivariable adjustment, visit-to-visit DBP variability was related to higher all-cause (hazard ratio (HR) = 1.18 per 1 SD, 95\% confidence interval (CI) = 1.01-1.37) and CV mortality (HR = 1.35, 95\% CI = 1.05-1.73). Additionally, individuals having more considerable decreases of DBP (>=10mm Hg between 2 consecutive visits) had higher risk of all-cause (HR = 1.13, 95\% CI = 0.99-1.28) and CV mortality (HR = 1.30, 95\% CI = 1.05-1.61); considerable increases of SBP (>=20mm Hg) were associated with higher risk of all-cause (HR = 1.18, 95\% CI = 1.03-1.36) and CV mortality (HR = 1.37, 95\% CI = 1.08-1.74).

CONCLUSIONS: Visit-to-visit DBP variability and considerable changes in DBP and SBP were risk factors for mortality in the elderly.

}, keywords = {Aged, Aging, Blood Pressure, Blood Pressure Determination, Body Composition, California, Cohort Studies, Female, Health Status, Humans, Hypertension, Incidence, Longitudinal Studies, Male, Myocardial Infarction, Office Visits, Prognosis, Retrospective Studies, Risk Factors, Stroke, Survival Rate}, issn = {1941-7225}, doi = {10.1093/ajh/hpw106}, author = {Wu, Chenkai and Shlipak, Michael G and Stawski, Robert S and Peralta, Carmen A and Psaty, Bruce M and Harris, Tamara B and Satterfield, Suzanne and Shiroma, Eric J and Newman, Anne B and Odden, Michelle C} } @article {7931, title = {Validation of the REGARDS Severe Sepsis Risk Score.}, journal = {J Clin Med}, volume = {7}, year = {2018}, month = {2018 Dec 11}, abstract = {

There are no validated systems for characterizing long-term risk of severe sepsis in community-dwelling adults. We tested the ability of the REasons for Geographic and Racial Differences in Stroke-Severe Sepsis Risk Score (REGARDS-SSRS) to predict 10-year severe sepsis risk in separate cohorts of community-dwelling adults. We internally tested the REGARDS-SSRS on the REGARDS-Medicare subcohort. We then externally validated the REGARDS-SSRS using (1) the Cardiovascular Health Study (CHS) and (2) the Atherosclerosis Risk in Communities (ARIC) cohorts. Participants included community-dwelling adults: REGARDS-Medicare, age >=65 years, = 9522; CHS, age >=65 years, = 5888; ARIC, age 45$^{-}$64 years, = 11,584. The primary exposure was 10-year severe sepsis risk, predicted by the REGARDS-SSRS from participant sociodemographics, health behaviors, chronic medical conditions and select biomarkers. The primary outcome was first severe sepsis hospitalizations, defined as the concurrent presence of ICD-9 discharge diagnoses for a serious infection and organ dysfunction. Median SSRS in the cohorts were: REGARDS-Medicare 11 points (IQR 7$^{-}$16), CHS 10 (IQR 6$^{-}$15), ARIC 7 (IQR 5$^{-}$10). Severe sepsis incidence rates were: REGARDS-Medicare 30.7 per 1000 person-years (95\% CI: 29.2$^{-}$32.2); CHS 11.9 (10.9$^{-}$12.9); ARIC 6.8 (6.3$^{-}$7.3). SSRS discrimination for first severe sepsis events were: REGARDS-Medicare C-statistic 0.704 (95\% CI: 0.691$^{-}$0.718), CHS 0.696 (0.675$^{-}$0.716), ARIC 0.697 (0.677$^{-}$0.716). The REGARDS-SRSS may potentially play a role in identifying community-dwelling adults at high severe sepsis risk.

}, issn = {2077-0383}, doi = {10.3390/jcm7120536}, author = {Wang, Henry E and Donnelly, John P and Yende, Sachin and Levitan, Emily B and Shapiro, Nathan I and Dai, Yuling and Zhao, Hong and Heiss, Gerardo and Odden, Michelle and Newman, Anne and Safford, Monika} } @article {8529, title = {{Variants Associated with the Ankle Brachial Index Differ by Hispanic/Latino Ethnic Group: a genome-wide association study in the Hispanic Community Health Study/Study of Latinos}, journal = {Sci Rep}, volume = {9}, year = {2019}, month = {08}, pages = {11410}, abstract = {Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 {\~A}{\textemdash} 10-5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10-7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 {\~A}{\textemdash} 10-4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.}, author = {Sofer, T. and Emery, L. and Jain, D. and Ellis, A. M. and Laurie, C. C. and Allison, M. A. and Lee, J. and Kurniansyah, N. and Kerr, K. F. and Gonz?lez, H. M. and Tarraf, W. and Criqui, M. H. and Lange, L. A. and Palmas, W. R. and Franceschini, N. and Wassel, C. L.} } @article {9109, title = {The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.}, journal = {Front Endocrinol (Lausanne)}, volume = {13}, year = {2022}, month = {2022}, pages = {863893}, abstract = {

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) >=1\%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI >= 30 kg/m), and extreme obesity (BMI >= 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1\% of variation in BMI, and 18.3\% and 22.5\% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49\%, and 2.97\% and 3.68\%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24\% for obesity and 0.51\% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.

}, keywords = {Gene Frequency, Genetic Variation, Genome-Wide Association Study, Humans, Obesity, Whole Genome Sequencing}, issn = {1664-2392}, doi = {10.3389/fendo.2022.863893}, author = {Wang, Zhe and Choi, Shing Wan and Chami, Nathalie and Boerwinkle, Eric and Fornage, Myriam and Redline, Susan and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Kim, Wonji and McDonald, Merry-Lynn N and Regan, Elizabeth A and Silverman, Edwin K and Liu, Ching-Ti and Vasan, Ramachandran S and Kalyani, Rita R and Mathias, Rasika A and Yanek, Lisa R and Arnett, Donna K and Justice, Anne E and North, Kari E and Kaplan, Robert and Heckbert, Susan R and de Andrade, Mariza and Guo, Xiuqing and Lange, Leslie A and Rich, Stephen S and Rotter, Jerome I and Ellinor, Patrick T and Lubitz, Steven A and Blangero, John and Shoemaker, M Benjamin and Darbar, Dawood and Gladwin, Mark T and Albert, Christine M and Chasman, Daniel I and Jackson, Rebecca D and Kooperberg, Charles and Reiner, Alexander P and O{\textquoteright}Reilly, Paul F and Loos, Ruth J F} } @article {9509, title = {Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer{\textquoteright}s Disease.}, journal = {J Alzheimers Dis}, year = {2023}, month = {2023 Oct 03}, abstract = {

Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer{\textquoteright}s disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65-75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers. We conclude that pneumococcal polysaccharide vaccine is a promising candidate for genotype-tailored AD prevention.

}, issn = {1875-8908}, doi = {10.3233/JAD-230088}, author = {Ukraintseva, Svetlana and Duan, Matt and Simanek, Amanda M and Holmes, Rachel and Bagley, Olivia and Rajendrakumar, Aravind L and Yashkin, Arseniy P and Akushevich, Igor and Tropsha, Alexander and Whitson, Heather and Yashin, Anatoliy and Arbeev, Konstantin} } @article {9408, title = {Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations.}, journal = {J Prev Alzheimers Dis}, volume = {10}, year = {2023}, month = {2023}, pages = {478-487}, abstract = {

BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research.

OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer{\textquoteright}s disease (AD) using cohort studies.

DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model.

RESULTS: The performance of the tool varied between studies. The overall AUC and 95\% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project.

CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.

}, keywords = {Aging, Alzheimer Disease, Cohort Studies, Dementia, Humans, Independent Living}, issn = {2426-0266}, doi = {10.14283/jpad.2023.38}, author = {Kootar, S and Huque, M H and Eramudugolla, R and Rizzuto, D and Carlson, M C and Odden, M C and Lopez, O L and Qiu, C and Fratiglioni, L and Han, S D and Bennett, D A and Peters, R and Anstey, K J} }