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1.  Adiposity and Cognitive Decline in the Cardiovascular Health Study 
Neuroepidemiology  2013;40(4):274-281.
Background
Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis (BIA), body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.
Methods
Cognitive performance was assessed with the modified Mini Mental State Examination (3MS), the Digit Symbol Substitution Test (DSST), and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.
Results
The final sample was comprised of 2,681 women (57.9%) and 1,949 men (42.1%) aged 73 ± 5.2 and 73.9 ± 5.6 years. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.
Conclusions
Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by pre-existing conditions.
doi:10.1159/000345136
PMCID: PMC4044822  PMID: 23445925
adiposity; fat mass; bioelectrical impedance; body mass index; waist circumference; cognition
2.  Insulin Resistance and Risk of Incident Heart Failure: Cardiovascular Health Study 
Circulation. Heart failure  2013;6(3):364-370.
Background
Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance (IR) as compared with matched controls. IR leads to structural abnormalities in the heart, such as increased left atrial (LA) size, left ventricular (LV) mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether IR precedes the development of HF or whether the relationship between IR and HF is present among adults with HF due to non-ischemic heart disease.
Methods and Results
We examined 4425 participants (60% female) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry.
There were 1216 cases of incident HF (1103 without antecedent MI) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (HR = 1.10, 95% CI 1.05, 1.15, per SD change) when adjusted for age, gender, race, field center, physical activity, smoking, alcohol intake, HDL cholesterol, total cholesterol, and systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent MI (HR= 1.10, 95% CI 1.05, 1.15). Measures of LA size, LV mass, and peak A velocity at baseline were associated both with fasting insulin levels and with heart failure ; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (HR= 1.08, 95% CI 1.03, 1.14 per1-SD increase in fasting insulin).
Conclusion
Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in CHS participants, including those without an antecedent MI.
doi:10.1161/CIRCHEARTFAILURE.112.000022
PMCID: PMC3888807  PMID: 23575256
heart failure; insulin; epidemiology
3.  Plasma Fatty Acid Binding Protein 4 and Risk of Sudden Cardiac Death in Older Adults 
Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95–1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07–1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62–1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.
doi:10.1155/2013/181054
PMCID: PMC3888692  PMID: 24455402
4.  Omega-3 Fatty Acids and incident Type 2 Diabetes: A Systematic Review and Meta-Analysis 
The British journal of nutrition  2012;107(0 2):S214-S227.
The relationship between omega-3 polyunsaturated fatty acids (n-3 PUFA) from seafood (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) or plant (alpha-linolenic acid, ALA) sources and risk of type 2 diabetes mellitus (DM) remains unclear. We systematically searched multiple literature databases through June 2011 to identify prospective studies examining relations of dietary n-3 PUFA, dietary fish and/or seafood, and circulating n-3 PUFA biomarkers with incidence of DM. Data were independently extracted in duplicate by 2 investigators, including multivariate-adjusted relative risk (RR) estimates and corresponding 95% CIs. Generalized least-squares trend estimation was used to assess dose-response relationships, with pooled summary estimates calculated by both fixed-effect and random-effect models. From 288 identified abstracts, 16 studies met inclusion criteria, including 18 separate cohorts comprising 540,184 individuals and 25,670 cases of incident DM. Consumption of fish and/or seafood was not significantly associated with DM (n=13 studies; RR per 100g/d=1.12, 95% CI=0.94, 1.34); nor were consumption of EPA+DHA (n=16 cohorts; RR per 250mg/d=1.04, 95% CI=0.97, 1.10) or circulating levels of EPA+DHA biomarkers (n=5 cohorts; RR per 3% of total fatty acids=0.94, 95% CI=0.75, 1.17). Both dietary ALA (n=7 studies; RR per 0.5g/d=0.93, 95% CI=0.83, 1.04) and circulating ALA biomarker levels (n=6 studies; RR per 0.1% of total fatty acid=0.90, 95% CI=0.80, 1.00, P=0.06) were associated with non-significant trend towards lower risk of DM. Substantial heterogeneity (I2~80%) was observed among studies of fish/seafood or EPA+DHA and DM; moderate heterogeneity (<55%) was seen for dietary and biomarker ALA and DM. In unadjusted meta-regressions, study location (Asia vs. North America/Europe), mean BMI, and duration of follow-up each modified the association between fish/seafood and EPA+DHA consumption and DM risk (P-Interaction ≤ 0.02 each). We had limited statistical power to determine the independent effect of these sources of heterogeneity due to their high collinearity. The overall pooled findings do not support either major harms or benefits of fish/seafood or EPA+DHA on development of DM, and suggest that ALA may be associated with modestly lower risk. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation.
doi:10.1017/S0007114512001602
PMCID: PMC3744862  PMID: 22591895
5.  Plasma Fatty Acid–Binding Protein 4, Nonesterified Fatty Acids, and Incident Diabetes in Older Adults 
Diabetes Care  2012;35(8):1701-1707.
OBJECTIVE
To examine the relation of fatty acid–binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.
RESEARCH DESIGN AND METHODS
We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992–2007) based on the use of hypoglycemic medications, fasting glucose ≥126 mg/dL, or nonfasting glucose ≥200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993.
RESULTS
Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10–1.65) for women and 1.45 (1.13–1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m2 (HR per SD: 1.78 [95% CI 1.13–2.81]). There was a modest and nonsignificant association of NEFA with diabetes (Ptrend = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12–2.53), and 1.63 (1.07–2.50) across consecutive tertiles of NEFA (Ptrend = 0.03).
CONCLUSIONS
Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.
doi:10.2337/dc11-1690
PMCID: PMC3402261  PMID: 22584136
6.  Association of Fetuin-A with Incident Diabetes in Community-Living Older Adults: The Cardiovascular Health Study 
Circulation  2012;125(19):2316-2322.
Background
The liver secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes in older persons, and to determine if the association differs by age, sex, and race, and among persons with CVD.
Methods and Results
Among 3,710 community-living individuals aged ≥ 65 years without diabetes at baseline, serum fetuin-A was measured in serum collected in 1992–93. Participants were followed for 10.6 years (median) for incident diabetes. Cox regression models evaluated the association of fetuin-A with incident diabetes. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75years, 60% were female, 15% were black, and 16% had CVD. Mean fetuin-A concentrations were 0.47 ± 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10g/L (SD) greater fetuin-A was associated with 19% higher risk of diabetes (HR 1.19; 95%CI 1.06–1.33) after adjusting for demographics, life-style factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and CRP) moderately attenuated the association (HR 1.13; 95% CI 1.00–1.28). Results were similar by sex, race, and CVD status, but were stronger in persons <75 years old (P-interaction 0.01).
Conclusions
Higher fetuin-A is associated with incident diabetes in older persons, irrespective of sex, race, or prevalent CVD status. The association may be attenuated in those aged ≥ 75 years.
doi:10.1161/CIRCULATIONAHA.111.072751
PMCID: PMC3390925  PMID: 22511752
cardiovascular disease; cardiovascular diseases; diabetes mellitus; fetuin-A; risk factors
7.  Serum 25-Hydroxyvitamin D Concentration and Risk for Major Clinical Disease Events in a Community-Based Population of Older Adults 
Annals of internal medicine  2012;156(9):627-634.
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.
doi:10.1059/0003-4819-156-9-201205010-00004
PMCID: PMC3632351  PMID: 22547472
8.  Non-esterified Fatty Acids and Risk of Sudden Cardiac Death in Older Adults 
Background
While non-esterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.
Methods and Results
Using a prospective design, we studied 4,657 older men and women (mean age 75 y) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95% CI) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first five years of follow up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.
Conclusions
Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.
doi:10.1161/CIRCEP.111.967661
PMCID: PMC3329563  PMID: 22281952
epidemiology; sudden death; fatty acid binding protein 4; risk factors
9.  Insulin Resistance and Incident Peripheral Artery Disease in the Cardiovascular Health Study 
Type 2 diabetes is a risk factor for PAD, and insulin resistance is a key feature of diabetes and pre-diabetes. No longitudinal epidemiological study has examined the relation between insulin resistance and PAD. Our study analyzed the association of quartiles of the homeostatic model of insulin resistance (HOMA-IR) and the development of PAD defined by 2 methods. PAD was first defined as the development of an abnormal ankle brachial index (ABI) (dichotomous outcome) after six years of follow-up. PAD was alternatively defined as the development of clinical PAD (time to event analysis). The study samples included adults over the age of 65 who were enrolled in the Cardiovascular Health Study, had fasting measurements of insulin and glucose, had ABI measurements, and were not receiving treatment for diabetes. Multivariable models were adjusted for potential confounders, including age, sex, field center and cohort, BMI, smoking status, alcohol use, and exercise intensity. Additional models adjusted for potential mediators, including blood pressure, lipids, kidney function, and prevalent vascular disease. In the ABI analysis (n=2108), multivariable adjusted models demonstrated a positive relation between HOMA-IR and incident PAD (Odds Ratio=1.80 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval 1.20-2.71). In the clinical PAD analysis (n=4208), we found a similar relation (Hazard ratio=2.30 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval 1.15-4.58). As expected, further adjustment for potential mediators led to some attenuation of effect estimates. In conclusion, insulin resistance is associated with a higher risk of PAD in older adults.
doi:10.1177/1358863X11436195
PMCID: PMC3563259  PMID: 22402937
Peripheral artery disease; Diabetes; Insulin Resistance; Epidemiology
10.  Markers of Inflammation in Prevalent and Incident Parkinson’s Disease in the Cardiovascular Health Study 
Parkinsonism & related disorders  2011;18(3):274-278.
Background
Studies demonstrate existence of inflammation in prevalent Parkinson’s disease (PD). We assessed associations of baseline levels of inflammatory markers with prevalent PD at baseline (1989) and incident PD identified over 13 years of follow-up of the Cardiovascular Health Study.
Methods
Blood samples at baseline were measured for fibrinogen, interleukin-6, tumor necrosis factor–α, C-reactive protein, albumin, and white blood cells. The analysis included 60 prevalent and 154 incident PD cases.
Results
Risk of prevalent PD was significantly higher per doubling of IL-6 among women (odds ratio [OR] = 1.5, 95% confidence interval [CI]: 1.0, 2.4) and WBC among men (OR: 2.4, 95% CI: 1.2, 4.9) in multivariate models. Risk of incident PD was not associated with higher levels of any biomarker after adjusting for age, smoking, African American race, and history of diabetes. Inverse associations with incident PD were observed per doubling of C-reactive protein (OR=0.9; 95% CI: 0.8, 1.0) and of fibrinogen among women (OR=0.4; 95% CI: 0.2, 0.8).
Conclusions
Although inflammation exists in PD, it may not represent an etiologic factor. Our findings suggest the need for larger studies that measure inflammatory markers before PD onset.
doi:10.1016/j.parkreldis.2011.11.003
PMCID: PMC3288759  PMID: 22119505
albumins; C-reactive protein; inflammation; interleukin-6; odds ratio; Parkinson’s disease; tumor necrosis factor-α
11.  Gender Differences in Tea, Coffee, and Cognitive Decline in the Elderly: The Cardiovascular Health Study 
Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually by an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.
doi:10.3233/JAD-2011-110431
PMCID: PMC3577072  PMID: 21841254
Caffeine; coffee; cognition; tea
12.  Association of Weight Status with Mortality in Adults with Incident Diabetes 
Context
Type 2 diabetes in normal weight (body mass index [BMI] <25kg/m2) adults is an intriguing representation of the metabolically obese normal weight phenotype with unknown mortality consequences.
Objective
To minimize the influence of diabetes duration and voluntary weight loss on mortality, we tested the association of weight status with mortality in adults with new onset diabetes.
Design
Pooled analysis of five longitudinal cohort studies: Atherosclerosis Risk in Communities Study, 1990–2006; Cardiovascular Health Study, 1992–2008; Coronary Artery Risk Development in Young Adults, 1987–2011; Framingham Offspring Study, 1979–2007; Multi-Ethnic Study of Atherosclerosis, 2002–2011. Participants contributed 27,125 person-years of follow-up.
Setting
2,625 participants with incident diabetes
Participants
Men and women (age>40 years) who developed incident diabetes based on fasting glucose ≥ 126 mg/dL or newly-initiated diabetes medication and who had concurrent measurements of body mass index (BMI). Participants were classified as normal weight if their BMI was 18.5 to 24.99kg/m2 or overweight/obese if BMI≥25 kg/m2.
Main Outcome Measures
Total, cardiovascular, and non-cardiovascular mortality
Results
The proportion of adults who were normal weight at the time of incident diabetes ranged from 9–21% (overall=12%). Over follow-up, 449 participants died, 178 from cardiovascular causes and 253 from non-cardiovascular causes (18 were not classified). The rate of total, cardiovascular and non-cardiovascular mortality was higher in normal weight participants (248.8, 99.8, and 198.1 per 10,000 person-years, respectively) than overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). Following adjustment for demographic characteristics and blood pressure, lipids, waist circumference and smoking status, hazard ratios comparing normal weight participants to overweight/obese participants for total, cardiovascular, and non-cardiovascular mortality were 2.08 (95% confidence interval [CI]: 1.52, 2.85), 1.52 (95% CI: 0.89, 2.58) and 2.32 (95% CI: 1.55, 3.48), respectively.
Conclusions
Adults who are normal weight at the time of incident diabetes have higher mortality than adults who are overweight or obese.
doi:10.1001/jama.2012.9282
PMCID: PMC3467944  PMID: 22871870
type 2 diabetes; obesity; cardiovascular disease; longitudinal studies
13.  Association of Increased Upper Trunk and Decreased Leg Fat With 2-h Glucose in Control and HIV-Infected Persons 
Diabetes Care  2011;34(11):2448-2453.
OBJECTIVE
Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.
RESEARCH DESIGN AND METHODS
A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.
RESULTS
The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.
CONCLUSIONS
In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
doi:10.2337/dc11-0616
PMCID: PMC3198295  PMID: 21926283
14.  Association of Body Mass Index With Peripheral Arterial Disease in Older Adults 
American Journal of Epidemiology  2011;174(9):1036-1043.
The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)2) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged ≥65 years at baseline (1989–1990 or 1992–1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age.
doi:10.1093/aje/kwr228
PMCID: PMC3243937  PMID: 21920948
ankle brachial index; body mass index; cardiovascular diseases; peripheral arterial disease
15.  Demographic, medical, and behavioral characteristics associated with over the counter non-steroidal anti-inflammatory drug use in a population based cohort: results from the Multi-Ethnic Study of Atherosclerosis 
Background
Three types of non-steroidal anti-inflammatory drugs (NSAIDs) can be obtained both over the counter (OTC) and by prescription in the United States. OTC NSAID use is not recorded in prescription claims databases; this might lead to differential misclassification of NSAID exposure status in studies that use computerized pharmacy databases to study NSAID use.
Objective
To evaluate characteristics of OTC versus prescription NSAID users
Methods
This analysis is set within the Multi-Ethnic Study of Atherosclerosis (MESA) study; a prospective cohort study of 6,814 adults from 4 ethnic groups (European descent, Asian, African-American and Hispanic) with a mean age of 62 years. The cohort was restricted to those who initiated NSAID use (aspirin, ibuprofen or naproxen) during follow-up. We compared information about age, sex, ethnicity, body mass index, smoking, diabetes, medication use, education, income, health insurance status and exercisebetween groups.
Results
OTC NSAID use was prevalent at baseline (25% Aspirin, 9% Ibuprofen, 2% Naproxen). Compared to prescribed NSAID use, OTC NSAID use was lower for users of non-European descent for all classes: aspirin (p<0.0001), ibuprofen (p<0.0001) and naproxen (p=0.0094). For aspirin, differences were seen for male gender (Relative Risk (RR):0.92; 95%(Confidence interval) CI:0.86–0.98), use of lipid lowering drugs (RR:0.88; 95% CI: 0.80–0.96), low income (RR:0.89; 95%CI:0.81–0.97), and participants one standard deviation above average in intentional exercise (RR:1.03; 95%CI:1.01–1.05).
Conclusions
OTC NSAID use is prevalent in an older multi-ethnic population and OTC users differ from prescription NSAID users. Caution should be exercised when using prescribed NSAIDs as a proxy for NSAID use.
doi:10.1002/pds.2065
PMCID: PMC3014611  PMID: 21182156
Aspirin; over the counter drug use; ethnicity; Multi-Ethnic Study of Atherosclerosis
16.  Measures of Adiposity and Future Risk of Ischemic Stroke and Coronary Heart Disease in Older Men and Women 
American Journal of Epidemiology  2010;173(1):10-25.
The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989–2007) in 3,754 community-dwelling US adults aged 65–100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥30 kg/m2) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25–29.9 kg/m2) was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.
doi:10.1093/aje/kwq311
PMCID: PMC3025638  PMID: 21123850
aging; body composition; body size; coronary disease; stroke
17.  Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima–media thickness 
AIDS (London, England)  2010;24(14):2201-2209.
Background
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
Objective
To identify HIV-related risk factors for increased cIMT.
Methods
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
Results
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
Conclusion
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
doi:10.1097/QAD.0b013e32833d2132
PMCID: PMC3224487  PMID: 20671544
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
18.  Diabetes and Coronary Heart Disease as Risk Factors for Mortality in Older Adults 
The American journal of medicine  2010;123(6):556.e1-556.e9.
Background
Type 2 diabetes has been described a coronary heart disease (CHD) “risk equivalent”. We tested whether cardiovascular and all-cause mortality rates were similar between participants with prevalent CHD versus diabetes in an older adult population in whom both glucose disorders and pre-existing atherosclerosis are common.
Methods
The Cardiovascular Health Study is a longitudinal study of men and women (n= 5784) aged ≥65 years at baseline who were followed from baseline (1989/92-93) through 2005 for mortality. Diabetes was defined by fasting plasma glucose ≥7.0 mmol/L or use of diabetes control medications. Prevalent CHD was determined by confirmed history of myocardial infarction (MI), angina, or coronary revascularization.
Results
Following multivariable adjustment for other cardiovascular disease risk factors and subclinical atherosclerosis, CHD mortality risk was similar between participants with CHD alone vs. diabetes alone (hazard ratio [HR]=1.04, 95% CI, 0.83-1.30). The proportion of mortality attributable to prevalent diabetes (Population Attributable Risk Percent =8.4%) and prevalent CHD (6.7%) was similar in women, but the proportion of mortality attributable to CHD (16.5%) as compared with diabetes (6.4%) was markedly higher in men. Patterns were similar for cardiovascular disease mortality. By contrast, the adjusted relative hazard of total mortality was lower among participants with CHD alone (HR =0.85, 95% CI, 0.75-0.96) as compared with those who had diabetes alone.
Conclusions
Among older adults, diabetes alone confers a similar risk for cardiovascular mortality as established clinical CHD. The public health burden of both diabetes and CHD is substantial, particularly among women.
doi:10.1016/j.amjmed.2009.11.023
PMCID: PMC3145803  PMID: 20569763
type 2 diabetes; cardiovascular disease; longitudinal studies; older adults
19.  Ginkgo biloba and risk of cancer: Secondary Analysis of the Ginkgo Evaluation of Memory (GEM) Study 
Purpose
Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date.
Methods
A total of 3,069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo.
Results
During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.87–1.36; p=0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95% CI, 0.97–4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92–2.87; p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43–1.17; p=0.18).
Conclusions
Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer.
doi:10.1002/pds.1979
PMCID: PMC2917376  PMID: 20582906
Ginkgo biloba; randomized controlled trial; breast cancer; prostate cancer; complimentary and alternative medicine
20.  Association Between Adiposity in Midlife and Older Age and Risk of Diabetes in Older Adults 
Context
Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults.
Objective
To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older.
Design, Setting, and Participants
Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later.
Main Outcome Measure
Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater.
Results
Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (±2 kg), those who gained the most weight from 50 years of age to baseline (≥9 kg), and from baseline to the third follow-up visit (≥6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less.
Conclusion
Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.
doi:10.1001/jama.2010.843
PMCID: PMC3047456  PMID: 20571017
21.  Differential White Blood Cell Count and Type 2 Diabetes: Systematic Review and Meta-Analysis of Cross-Sectional and Prospective Studies 
PLoS ONE  2010;5(10):e13405.
Objective
Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.
Research Design and Methods
Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.
Results
The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10−18). Substantial heterogeneity was present (I2 = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10−4), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10−13), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10−5). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.
Conclusions
A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.
doi:10.1371/journal.pone.0013405
PMCID: PMC2956635  PMID: 20976133
22.  C-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older 
Cancer causes & control : CCC  2009;20(7):1193-1203.
Inflammation is believed to play a role in prostate cancer (PCa) etiology, but it is unclear whether inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) associate with PCa risk in older men. Using Cox regression, we assessed the relationship between baseline concentrations of CRP and IL-6 and subsequent PCa risk in the Cardiovascular Health Study, a population-based cohort study of mostly European American men ages >64 years (n=2234; mean follow-up = 8.7 years; 215 incident PCa cases). We also tested associations between CRP and IL-6 tagSNPs and PCa risk, focusing on SNPs known to associate with circulating CRP and/or IL-6. Results: Neither CRP nor IL-6 blood concentrations were associated with PCa risk. The C allele of IL-6 SNP rs1800795 (-174), a known functional variant, was associated with increased risk in a dominant model (HR=1.44; 95% CI=1.03-2.01; p=0.03) but was not statistically significant after accounting for multiple tests (permutation p=0.21). Our results suggest that circulating CRP and IL-6 do not influence PCa risk. SNPs at the CRP locus are not associated with PCa risk in this cohort, while the association between rs1800795 and PCa risk warrants further investigation.
doi:10.1007/s10552-009-9320-4
PMCID: PMC2846958  PMID: 19267250
Prostate cancer; inflammation; C-reactive protein (CRP); interleukin-6 (IL-6); IL-6 rs1800795 (-174)
23.  PHYSICAL ACTIVITY IN ADOLESCENCE AND TESTICULAR GERM CELL CANCER RISK 
Cancer causes & control : CCC  2009;20(8):1281-1290.
Objective
Several, but not all, studies have observed increased risks of testicular germ cell cancer (TGCC) associated with bicycling and other recreational activities. To further examine whether physical activity (PA) in adolescence is associated with TGCC risk, the authors conducted a case-control study in western Washington State.
Methods
Cases (n=391) were men diagnosed with TGCC who were identified through a population-based cancer registry. Controls (n=1023) were men identified from the general population in western Washington State by using random digit telephone dialing. Participants were queried about various specific PA in grades 7–12 including bicycling, horseback riding, competitive sports, physical education class, as well as moderate, vigorous, and sedentary activities in general.
Results
In multivariate analyses, bicycling, vigorous-intensity activities, and sedentary activities were not associated with TGCC risk, while horseback riding and wrestling were associated with decreased risks, and moderate-intensity activities, soccer, basketball and intermediate duration of competitive activities were associated with increased risks.
Conclusions
The lack of internal consistency of the findings within the current study and of findings among prior studies, suggests that PA contributes little, if any, to the risk of TGCC.
doi:10.1007/s10552-009-9347-6
PMCID: PMC2890221  PMID: 19399630
testicular cancer; physical activity; case-control study; adolescent
24.  Polymorphisms in the Mitochondrial DNA Control Region and Frailty in Older Adults 
PLoS ONE  2010;5(6):e11069.
Background
Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults.
Methodology/Principal Findings
To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989–1990, 1992–1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07–3.60, p = 0.020) and lower grip strength (adjusted coefficient = −2.04, 95% CI = −3.33– −0.74, p = 0.002).
Conclusions
This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.
doi:10.1371/journal.pone.0011069
PMCID: PMC2883558  PMID: 20548781
25.  Association of Marijuana Use and the Incidence of Testicular Germ Cell Tumors 
Cancer  2009;115(6):1215-1223.
Background
The incidence of testicular germ cell tumors (TGCT) has been increasing the past 4–6 decades, but exposures accounting for this rise have not been identified. Marijuana use has also grown over this time period, and chronic marijuana use produces adverse effects on the human endocrine and reproductive systems. We tested the hypothesis that marijuana use is a risk factor for TGCT.
Methods
A population-based case-control study of 369 men age 18–44 years diagnosed with a TGCT from January 1999– January 2006 was conducted in King, Pierce and Snohomish Counties in Washington State. Their responses to questions on lifetime marijuana use were compared to those of 979 age-matched controls residing in the same three counties during the case diagnosis period.
Results
Men with a TGCT were more likely to be current marijuana smokers at reference date compared to controls, OR (odds ratio) =1.7, 95% CI (Confidence Interval) =1.1–2.5. When we conducted analyses according to histologic type, most of the association between current marijuana use and TGCT was in nonseminomas-mixed histology tumors, OR current use=2.3, 95% CI=1.3–4.0. Age at first use among current users appeared to modify risk (age<18 OR=2.8 vs. age≥18 OR=1.3) as did frequency of use (daily or weekly OR=3.0 vs.
Conclusions
We observed an association between marijuana use and occurrence of nonseminoma germ cell tumors of the testis. Additional studies of TGCTs are needed to test this hypothesis, including molecular analyses of cannabinoid receptors and endocannabinoid signaling that may provide clues to biologic mechanisms.
doi:10.1002/cncr.24159
PMCID: PMC2759698  PMID: 19204904
Marijuana Use; testicular tumors

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