[Show abstract][Hide abstract] 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.
Personalized Medicine 11/2015; 2015(5):440-451. DOI:10.3390/jpm5040440 · 1.34 Impact Factor
[Show abstract][Hide abstract] 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 (HF) were defined in three ways: 1) the CHS adjudicated event (CHS[adj]); 2) selected ICD9 diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare and Medicaid Services (CMS[1(st)]); and 3) the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values (PPVs) but low sensitivities. For instance, the PPV of an ICD9 code of 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 were low. For MI, the incidence was 14.9 events per 1000 person years for CHS[adj] MI, 8.6 for CMS[1(st)] and 12.2 for CMS[any]. In general, CVD risk factor associations were similar across the three methods of defining events. Indeed, traditional CVD risk factors were also associated with all first hospitalizations not due to an MI.
-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 endpoint that includes the outcome of interest and selected (misclassified) non-event hospitalizations.
[Show abstract][Hide abstract] ABSTRACT: Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Context: The appropriateness of current reference ranges for thyroid function testing in older adults has been questioned. Objective: To determine the relationship between thyroid function tests within the euthyroid range and adverse outcomes in older adults not taking thyroid medication. Design, Setting, and Participants: 2843 US community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with TSH, free T4 (FT4), and total T3 concentrations in the euthyroid range Main Outcome Measures: Incidence of atrial fibrillation, coronary heart disease, heart failure, hip fracture, dementia, and all-cause death Results: No departures from linearity were detected. Higher TSH was negatively associated (p=0.03) and higher FT4 was positively associated (p=0.007) with mortality. Higher FT4 was associated with atrial fibrillation (p<0.001) and heart failure (p=0.004). Compared with the first quartile, individuals with TSH in the fourth quartile had a 9.6 per 1000 person-year lower incidence of dementia (p<0.05) and those with FT4 in the fourth quartile had higher incidences of atrial fibrillation, coronary heart disease, heart failure and mortality (11.0, 8.0, 7.8, and 14.3 per 1000 person-years, respectively, all p <0.05). Total T3 was not associated with any outcome. Conclusions: Higher TSH and lower FT4 concentrations within the euthyroid range are associated with lower risk of multiple adverse events in older people, including mortality. This suggests tolerance for lower thyroid hormone levels in this age group. Clinical trials are needed to evaluate the risk-benefit profile of new thresholds for initiating treatment and optimal target concentrations for thyroid hormone replacement in older people.
[Show abstract][Hide abstract] ABSTRACT: Background:
Slowed gait is an important health indicator in older adults but a single identifiable cause is often lacking. We assessed whether a summary index measuring impairments across multiple physiologic systems was associated with slowed gait in older individuals.
Data from the Cardiovascular Health Study (n = 3,010) were used to assess associations between baseline physiologic index (measuring vasculature, brain, kidneys, lungs, and glucose metabolism; range 0-10 with 0-2 points/system and lower score indicating higher function) and annual gait speed (m/s) over 6 years. Participants with complete data on the physiologic index and at least two gait speed measures were included. Mean gait speed and 95% confidence intervals (CI) by category of index were calculated using mixed effects models.
Those with scores of three or higher on the index had significantly slower gait speed at baseline compared to those with scores of 0-2 (7-10: mean speed = 0.83 m/s, 95% CI: 0.80, 0.84; 0-2: mean speed = 1.01 m/s, 95% CI: 0.99, 1.03). Those with higher indices also had faster decline in gait speed compared to those with lower scores after adjustment for demographic and health characteristics (7-10: change in speed = -0.020 m/s/year, 95% CI: -0.024, -0.016; 0-2: change in speed= -0.010 m/s/year, 95% CI: -0.014, -0.006).
Greater impairment across five organ systems was associated with slower gait speed and greater declines in gait speed over 6 years. Impairments accumulated over multiple physiologic systems may make older adults more vulnerable to slow gait speed.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 11/2014; 70(3). DOI:10.1093/gerona/glu176 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
[Show abstract][Hide abstract] 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.DesignCohort study.SettingCardiovascular Health Study.ParticipantsIndividuals born between June 30, 1918, and June 30, 1921 (N = 2,082; aged 70–75 at baseline (1992–93)).MeasurementsA 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.ResultsA 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.ConclusionA 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.
Journal of the American Geriatrics Society 09/2014; 62(9). DOI:10.1111/jgs.13018 · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress – such as diabetes, chronic kidney disease and aging – where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined.
To test the hypothesis that circulating levels of Nɛ-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older.
During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase = 1.11, 95% confidence interval [CI] = 1.03–1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke.
In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML’s value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Context. Low testosterone (T) is associated with prevalent cardiovascular disease (CVD) and mortality. Dihydrotestosterone (DHT), a more potent androgen, may also be associated with CVD and mortality, but few studies have examined this. Objective. The study objective was to examine if T and DHT are risk factors for incident CVD and mortality. Design. In a longitudinal cohort study, we evaluated whether total T, calculated free T (cFT), DHT, and calculated free DHT were associated with incident CVD and mortality in men in the Cardiovascular Health Study (mean age 76, range 66-97) who were free of CVD at the time of blood collection. Main outcome. The main outcomes were incident CVD and all-cause mortality. Results. Among 1032 men followed for a median of 9 years, 436 incident CVD events and 777 deaths occurred. In models adjusted for cardiovascular risk factors, total T and cFT were not associated with incident CVD or all-cause mortality, while DHT and calculated free DHT had curvilinear associations with incident CVD (p<0.002 and p=0.04, respectively) and all-cause mortality (p<0.001 for both). Conclusions. In a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortality. Further studies are needed to confirm these results and to clarify the underlying physiologic mechanisms.
The Journal of Clinical Endocrinology and Metabolism 03/2014; 99(6):jc20133576. DOI:10.1210/jc.2013-3576 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Ischemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine if testosterone (T) or dihydrotestosterone (DHT) were associated with incident ischemic stroke in elderly men.DesignCohort study.ParticipantsElderly men in the Cardiovascular Health Study who had no history of stroke, heart disease, or prostate cancer as of 1994 and were followed until December 2010.MeasurementsAdjudicated ischemic stroke.ResultsAmong 1032 men (mean age 76, range 66-97), followed for a median of 10 years, 114 had an incident ischemic stroke. Total T and free T were not significantly associated with stroke risk while DHT had a nonlinear association with incident stroke (p= .006) in analyses adjusted for stroke risk factors. The lowest risk for stroke was at DHT levels of 50-75 ng/dL, with greater risk for stroke at DHT levels above 75 ng/dl or below 50ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischemic stroke with HR 0.77 (95% CI, 0.61, 0.98) per standard deviation in analyses adjusted for stroke risk factors.ConclusionsDHT had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify if there is an optimal androgen range associated with the least risk for adverse outcomes in elderly men.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Age at menopause marks the end of a woman¡¦s reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified twenty-seven loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from eleven studies across the United States. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (p-value <0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of fourteen loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in United States.
Human Molecular Genetics 02/2014; 23(12). DOI:10.1093/hmg/ddu041 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
[Show abstract][Hide abstract] 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: 427 subclinically hypothyroid and 2864 euthyroid US individuals ≥ 65 yr 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 DXA scans. Models were risk factor adjusted and stratified by sex. Results: Overall, participants lost weight during follow-up (-0.38 kg/yr in men, -0.37 kg/yr in women). Subclinical hypothyroidism, when assessed at a single timepoint or persisting over two years, was not associated with a difference in weight change compared to euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared to euthyroidism. A TSH level one mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51 kg higher baseline weight in women only (p<0.001), though not with weight change in either sex. A one ng/dL higher free thyroxine level was associated with lower baseline weight and 0.32 kg/yr greater weight loss in women only (p=0.003). 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.
The Journal of Clinical Endocrinology and Metabolism 01/2014; 99(4):jc20133591. DOI:10.1210/jc.2013-3591 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe infections, often requiring ICU admission, have been associated with persistent cognitive dysfunction. Less severe infections are more common and whether they are associated with an increased risk of dementia is unclear. We determined the association of pneumonia hospitalization with risk of dementia in well-functioning older adults.
Secondary analysis of a randomized multicenter trial to determine the effect of Gingko biloba on incident dementia.
Five academic medical centers in the United States.
Healthy community volunteers (n = 3,069) with a median follow-up of 6.1 years.
We identified pneumonia hospitalizations using International Classification of Diseases, 9th Edition-Coding Manual codes and validated them in a subset. Less than 3% of pneumonia cases necessitated ICU admission, mechanical ventilation, or vasopressor support. Dementia was adjudicated based on neuropsychological evaluation, neurological examination, and MRI. Two hundred twenty-one participants (7.2%) incurred at least one hospitalization with pneumonia (mean time to pneumonia = 3.5 yr). Of these, dementia was developed in 38 (17%) after pneumonia, with half of these cases occurring 2 years after the pneumonia hospitalization. Hospitalization with pneumonia was associated with increased risk of time to dementia diagnosis (unadjusted hazard ratio = 2.3; CI, 1.6-3.2; p < 0.0001). The association remained significant when adjusted for age, sex, race, study site, education, and baseline mini-mental status examination (hazard ratio = 1.9; CI, 1.4-2.8; p < 0.0001). Results were unchanged when additionally adjusted for smoking, hypertension, diabetes, heart disease, and preinfection functional status. Results were similar using propensity analysis where participants with pneumonia were matched to those without pneumonia based on age, probability of developing pneumonia, and similar trajectories of cognitive and physical function prior to pneumonia (adjusted prevalence rates, 91.7 vs 65 cases per 1,000 person-years; adjusted prevalence rate ratio = 1.6; CI, 1.06-2.7; p = 0.03). Sensitivity analyses showed that the higher risk also occurred among those hospitalized with other infections.
Hospitalization with pneumonia is associated with increased risk of dementia.
Critical care medicine 12/2013; 42(5). DOI:10.1097/CCM.0000000000000123 · 6.31 Impact Factor