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1.  Association of Race and Sex With Risk of Incident Acute Coronary Heart Disease Events 
CONTEXT
It is unknown whether long-standing disparities in incidence of coronary heart disease (CHD) among US blacks and whites persist.
OBJECTIVE
To examine incident CHD by black and white race and by sex.
DESIGN, SETTING, AND PARTICIPANTS
Prospective cohort study of 24 443 participants without CHD at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, who resided in the continental United States and were enrolled between 2003 and 2007 with follow-up through December 31, 2009.
MAIN OUTCOME MEASURE
Expert-adjudicated total (fatal and nonfatal) CHD, fatal CHD, and nonfatal CHD (definite or probable myocardial infarction [MI]; very small non–ST-elevation MI [NSTEMI] had peak troponin level <0.5 µg/L).
RESULTS
Over a mean (SD) of 4.2 (1.5) years of follow-up, 659 incident CHD events occurred (153 in black men, 138 in black women, 254 in white men, and 114 in white women). Among men, the age-standardized incidence rate per 1000 person-years for total CHD was 9.0 (95% CI, 7.5–10.8) for blacks vs 8.1 (95% CI, 6.9–9.4) for whites; fatal CHD: 4.0 (95% CI, 2.9–5.3) vs 1.9 (95% CI, 1.4–2.6), respectively; and nonfatal CHD: 4.9 (95% CI, 3.8–6.2) vs 6.2 (95% CI, 5.2–7.4). Among women, the age-standardized incidence rate per 1000 person-years for total CHD was 5.0 (95% CI, 4.2–6.1) for blacks vs 3.4 (95% CI, 2.8–4.2) for whites; fatal CHD: 2.0 (95% CI, 1.5–2.7) vs 1.0 (95% CI, 0.7–1.5), respectively; and nonfatal CHD: 2.8 (95% CI, 2.2–3.7) vs 2.2 (95% CI, 1.7–2.9). Age- and region-adjusted hazard ratios for fatal CHD among blacks vs whites was near 2.0 for both men and women and became statistically nonsignificant after multivariable adjustment. The multivariable-adjusted hazard ratio for incident nonfatal CHD for blacks vs whites was 0.68 (95% CI, 0.51–0.91) for men and 0.81 (95% CI, 0.58–1.15) for women. Of the 444 nonfatal CHD events, 139 participants (31.3%) had very small NSTEMIs.
CONCLUSIONS
The higher risk of fatal CHD among blacks compared with whites was associated with cardiovascular disease risk factor burden. These relationships may differ by sex.
doi:10.1001/jama.2012.14306
PMCID: PMC3772637  PMID: 23117777
coronary heart disease; epidemiology; racial disparities; disease incidence; cohort study
2.  Racial Differences in Self-Reported Infertility and Risk Factors for Infertility in a Cohort of Black and White Women: The CARDIA Women’s Study 
Fertility and sterility  2008;90(5):1640-1648.
Objective
To determine racial differences in self-reported infertility and in risk factors for infertility in a cohort of black and white women.
Design
A cross-sectional analyses of data from the longitudinal Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective, epidemiologic investigation of the determinants and evolution of cardiovascular risk factors among black and white young adults and from the ancillary CARDIA Women’s Study (CWS).
Setting
Population-based sample from 4 US communities (Birmingham, AL; Chicago, IL, Minneapolis, MN; and Oakland, CA).
Participants
Women ages 33–44 who had complete data (n=764).
Interventions
none
Main Outcome Measure
Self-report of ever having unprotected sexual intercourse for at least 12 months without becoming pregnant.
Results
Among non-surgically sterile women, blacks had a two-fold increased odds (95% CI = 1.3–3.1) of infertility as compared with whites after adjustment for socioeconomic position (education and ability to pay for basics), correlates of pregnancy intent (marital status and hormonal contraceptive use), and risk factors for infertility (age, smoking, testosterone, fibroid presence, and ovarian volume). The corresponding OR among all women was 1.5 (95% CI 1.0–2.2). Difficulty paying for basics and ovarian volume were associated with infertility among black but not white women.
Conclusions
In this population-based sample, black women were more likely to have experienced infertility. This disparity is not explained by common risk factors for infertility such as smoking and obesity, and among non-surgically sterile women, it is not explained by gynecologic risk factors such as fibroids and ovarian volume.
doi:10.1016/j.fertnstert.2007.09.056
PMCID: PMC2592196  PMID: 18321499
Infertility; race; ethnicity; disparity; fibroids; ovarian volume
3.  Knee Osteoarthritis and Frailty: Findings From the Multicenter Osteoarthritis Study and Osteoarthritis Initiative 
Background.
Knee osteoarthritis (OA) and frailty are two conditions that are associated with functional limitation and disability in elders, yet their relation to one another is not known.
Methods.
We included participants from two large, multicenter studies enriched with community dwelling older adults with knee OA (Multicenter Osteoarthritis Study and Osteoarthritis Initiative). Knee OA was defined radiographically (ROA) and symptomatically (SOA). Frailty was defined using the Study of Osteoporotic Fracture index as the presence of ≥2 of the following: (i) weight loss >5% between two consecutive visits; (ii) inability to arise from chair five times without support; (iii) poor energy. Cross-sectional and longitudinal associations of knee OA with prevalent and incident frailty, respectively, were examined using binomial regression with robust variance estimation, adjusting for potential confounders.
Results.
In the cross-sectional analyses, frailty was more prevalent among participants with ROA (4.39% vs 2.77%; PR 1.60 [1.07, 2.39]) and SOA (5.88% vs 2.79%; PR 1.92 [1. 35, 2.74]) compared with those without ROA or SOA, respectively. In the longitudinal analyses, risk of developing frailty was greater among those with ROA (4.73% vs 2.50%; RR 1.45 [0.91, 2.30]) and SOA (6.30% vs 2.83%; RR 1.66 [1.11, 2.48]) than those without ROA or SOA, respectively.
Conclusions.
Knee OA is associated with greater prevalence and risk of developing frailty. Understanding the mechanisms linking these two common conditions of older adults would aid in identifying novel targets for treatment or prevention of frailty.
doi:10.1093/gerona/glu102
PMCID: PMC4351392  PMID: 25063080
Osteoarthritis; Knee; Frailty.
4.  Neighborhood socioeconomic status and food environment: a 20-year longitudinal latent class analysis among CARDIA participants 
Health & place  2014;0:145-153.
Cross-sectional studies suggest neighborhood socioeconomic (SES) disadvantage is associated with obesogenic food environments. Yet, it is unknown how exposure to neighborhood SES patterning through adulthood corresponds to food environments that also change over time. We used latent class analysis (LCA) to classify participants in the US-based Coronary Artery Risk Development in Young Adults study [n=5,114 at baseline 1985-1986 to 2005-2006] according to their longitudinal neighborhood SES residency patterns (upward, downward, stable high and stable low). For all classes of residents, the availability of fast food and non-fast food restaurants and supermarkets and convenience stores increased (p<0.001). Yet, socioeconomically disadvantaged neighborhood residents had fewer fast food and non-fast food restaurants, more convenience stores, and the same number of supermarkets in their neighborhoods than the advantaged residents. In addition to targeting the pervasive fast food restaurant and convenient store retail growth, improving neighborhood restaurant options for disadvantaged residents may reduce food environment disparities.
doi:10.1016/j.healthplace.2014.08.011
PMCID: PMC4252601  PMID: 25280107
Geographic Information Systems; Environment; Neighborhood food availability; Neighborhood socioeconomics; Longitudinal study
5.  Association of the Degree of Adiposity and Duration of Obesity with Measures of Cardiac Structure and Function: The CARDIA Study 
Obesity (Silver Spring, Md.)  2014;22(11):2434-2440.
OBJECTIVE
Examine whether there are independent influences of a greater degree of adiposity and longer duration of obesity on cardiac structure and function.
METHODS
Participants of CARDIA were 18-30 years when they underwent a baseline examination in 1985-86. Seven follow-up examinations were conducted every 2-5 years.
RESULTS
Among 2,547 participants who underwent an echocardiogram at the year 25 examination and were not obese at baseline, 34.4% and 35.5% were overall (BMI ≥30 kg/m2) and abdominally obese (waist circumference: men: >102 cm; women: >88 cm) at year 25, respectively. A greater degree of overall and abdominal adiposity at year 25 were each associated with a greater left ventricular (LV) mass (p<0.001), LV volume (p<0.001), LV mass-to-volume ratio (p<0.001), left atrial dimension (p<0.001), and ejection fraction (p<0.05) after adjustment for duration of obesity and other risk factors. In contrast, a longer duration of overall obesity was associated with a greater LV mass (p=0.003) and a trend for a lower ejection fraction (p=0.07).
CONCLUSIONS
A greater degree of adiposity is strongly associated with concentric LV remodeling in midlife, while the cumulative effects of a longer duration of overall obesity during young adulthood contribute to concentric remodeling predominantly by increasing LV mass.
doi:10.1002/oby.20865
PMCID: PMC4224979  PMID: 25124342
cardiovascular risk; obesity; heart; echocardiography
6.  THE TESTOSTERONE TRIALS: THE DESIGN OF SEVEN COORDINATED TRIALS TO DETERMINE IF TESTOSTERONE TREATMENT BENEFITS ELDERLY MEN 
Clinical trials (London, England)  2014;11(3):362-375.
Background
The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results.
Purpose
To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and determine definitively if testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions.
Methods
We present the scientific and clinical rationale for the decisions made in the design of this trial.
Results
We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and also symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, treatment and monitoring and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data safety monitoring board (DSMB), the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in subject selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary end points for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation.
Potential Limitations
Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one subject.
Conclusions
The Testosterone Trials were designed to determine definitively if testosterone treatment of elderly men with low testosterone would have any clinical benefit. Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.
doi:10.1177/1740774514524032
PMCID: PMC4182174  PMID: 24686158
clinical trial; testosterone; hypogonadism; aging; mobility; sexual function; vitality; cognitive function; anemia; CT angiography; volumetric BMD; bone strength
7.  Mediterranean and DASH Diet Scores and Mortality in Women with Heart Failure: The Women’s Health Initiative 
Circulation. Heart failure  2013;6(6):1116-1123.
Background
Current dietary recommendations for heart failure (HF) patients are largely based on data from non-HF populations; evidence regarding associations of dietary patterns with outcomes in HF is limited. We therefore evaluated associations of Mediterranean and DASH diet scores with mortality among postmenopausal women with HF.
Methods and Results
Women’s Health Initiative participants were followed from the date of HF hospitalization through the date of death or last participant contact prior to August 2009. Mediterranean and DASH diet scores were calculated from food-frequency questionnaires. Cox proportional hazards models adjusted for demographics, health behaviors, and health status were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Over a median of 4.6 years of follow-up, 1,385 of 3,215 (43.1%) participants who experienced a HF hospitalization died. Multivariable-adjusted HRs were 1 (reference), 1.05 (95% CI 0.89–1.24), 0.97 (95% CI 0.81–1.17), and 0.85 (95% CI 0.70–1.02) across quartiles of the Mediterranean diet score (p-trend = 0.08) and 1 (reference), 1.04 (95% CI 0.89–1.21), 0.83 (95% CI 0.70–0.98), and 0.84 (95% CI 0.70–1.00) across quartiles of the DASH diet score (p-trend = 0.01). Diet score components vegetables, must, and whole grain intake were inversely associated with mortality.
Conclusions
Higher DASH diet scores were associated with modestly lower mortality in women with HF, and there was a non-significant trend towards an inverse association with Mediterranean diet scores. These data provide support for the concept that dietary recommendations developed for other cardiovascular conditions or general populations may also be appropriate in HF patients.
doi:10.1161/CIRCHEARTFAILURE.113.000495
PMCID: PMC4564006  PMID: 24107587
diet; heart failure; mortality; nutrition
8.  No association between daily walking and structural changes in people at risk of or with mild knee osteoarthritis. Prospective data from the Multicenter Osteoarthritis Study 
The Journal of rheumatology  2015;42(9):1685-1693.
Objective
We investigated the association between objectively measured daily walking and knee structural change, defined either as radiographic worsening or as cartilage loss, in people at risk of or with knee osteoarthritis (OA).
Methods
Participants from the Multicenter Osteoarthritis (MOST) study with Kellgren and Lawrence (KL) grades 0–2 and daily walking (measured with the StepWatch) at the 60-month visit, were included. Participants had fixed flexion weight bearing radiographs and knee magnetic resonance images (MRIs) at 60 and 84 months. Radiographic worsening was read in both knees using the OARSI grading, and MRIs were read for one knee using WORMS semiquantitative scoring. Odds ratios (OR) and 95% confidence intervals (CI) were calculated comparing those in the middle tertile against the lowest and highest tertiles of daily walking using logistic regression models and generalized estimating equations. Data on walking with moderate to vigorous intensity (minutes with >100 steps/min/day) was associated to structural change using multivariate and logistic regression models.
Results
The 1179 study participants (59% females) were 67.0 (±7.6) years, with a mean (±SD) body mass index of 29.8 (±5.3) kg/m2 who walked 6981 (±2630) steps/day. After adjusting for confounders, we found no significant associations between daily walking and radiographic worsening or cartilage loss. More time spent walking at a moderate to vigorous intensity was not associated with either radiographic worsening or cartilage loss.
Conclusion
Results from the MOST study indicated no association between daily walking and structural changes over two years in people at risk of or with mild knee OA.
doi:10.3899/jrheum.150071
PMCID: PMC4558377  PMID: 26077404
physical activity; osteoarthritis; structural changes; MRI
9.  Relationship between Perceived Discrimination and Sedentary Behavior in Adults 
Objective
To identify psychosocial factors associated with sedentary behavior, we tested whether perceived discrimination is associated with sedentary behavior.
Methods
Black and white men and women (N = 3270) from the Coronary Artery Risk Development in Young Adults (CARDIA) Study reported experiences of discrimination and time engaged in total and screen time sedentary behaviors in 2010–11.
Results
There were no associations of discriminatory experiences with total sedentary behavior time. However, discriminatory experiences were positively associated with screen time for black men (OR 1.81, 95% CI: 1.14, 2.86) and white women (OR 1.51, 95% CI: 1.14, 2.00) after adjusting for demographic and traditional cardiovascular disease risk factors.
Conclusion
Among black men and white women, discriminatory experiences were correlated with more screen time sedentary behavior.
doi:10.5993/AJHB.38.5.1
PMCID: PMC4229242  PMID: 24933133
sedentary behaviors; discrimination; stress
10.  Impact of an Intensive Lifestyle Intervention on Use and Cost of Medical Services Among Overweight and Obese Adults With Type 2 Diabetes: The Action for Health in Diabetes 
Diabetes Care  2014;37(9):2548-2556.
OBJECTIVE
To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial.
RESEARCH DESIGN AND METHODS
A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years.
RESULTS
ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385–7,175); however, these were not evident among individuals with a history of cardiovascular disease.
CONCLUSIONS
Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs.
doi:10.2337/dc14-0093
PMCID: PMC4140155  PMID: 25147253
11.  Objective sleep, a novel risk factor for alterations in kidney function: the CARDIA Study 
Sleep medicine  2014;15(9):1140-1146.
Objective
To determine the association between objectively measured sleep and 10-year changes in estimated glomerular filtration rate (eGFR).
Methods
From 2003 to 2005, an ancillary sleep study was conducted at the Chicago site of the Coronary Artery Disease in Young Adults (CARDIA) study. Community-based black and white adults (aged 32–51 years) wore a wrist actigraph up to six nights to record sleep duration and fragmentation. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Participants without history of cardiovascular or chronic kidney diseases, proteinuria, or hypertension at the 2000–2001 CARDIA examination were followed over 10 years (n = 463). eGFR was estimated from serum creatinine (eGFRCr) at the 2000–2001, 2005–2006, and 2010–2011 CARDIA examinations, whereas cystatin-C-estimated eGFR (eGFRCys) was measured at the 2000–2001 and 2005–2006 examinations. Generalized estimating equation regression and linear models estimated the associations of each sleep parameter with changes in eGFRCr and eGFRCys, controlling for cardiovascular and renal risk.
Results
Sleep parameters were not related to 5-year change in eGFRCys. However, each 1 h decrease in sleep duration was significantly associated with a 1.5 mL/min/1.73 m2 higher eGFRCr [95% confidence interval (CI), 0.2–2.7], and each one-point increase in PSQI was significantly associated with a 0.5 mL/min/1.73 m2 higher eGFRCr (95% CI, 0.04–0.9) over 10 years.
Conclusion
In this community-based sample, shorter sleep and poorer sleep quality were related to higher kidney filtration rates over 10 years.
doi:10.1016/j.sleep.2014.05.021
PMCID: PMC4145022  PMID: 25037841
Objective sleep; Kidney function; Sleep quality; Sex; Race
12.  Daily walking and the risk of incident functional limitation in knee OA: An observational study 
Arthritis care & research  2014;66(9):1328-1336.
Background
Physical activity is recommended to mitigate functional limitations associated with knee osteoarthritis (OA). However, it is unclear whether walking on its own protects against the development of functional limitation.
Methods
Walking over 7 days was objectively measured as steps/day within a cohort of people with or at risk of knee OA from the Multicenter Osteoarthritis Study. Incident functional limitation over two years was defined by performance-based (gait speed ≤ 1.0 m/s) and self-report (WOMAC physical function ≥ 28/68) measures. We evaluated the association of steps/day at baseline with developing functional limitation two years later by calculating risk ratios adjusted for potential confounders. The number of steps/day that best distinguished risk for developing functional limitation was estimated from the maximum distance from chance on Receiver Operator Characteristic curves.
Results
Among 1788 participants (mean age 67, mean BMI 31 kg/m2, female 60%), each additional 1000 steps/day was associated with a 16% and 18% reduction in incident functional limitation by performance-based and self-report measures, respectively. Walking < 6000 and < 5900 steps/day were the best thresholds to distinguish incident functional limitation by performance-based (67.3%/71.8% [sensitivity/specificity]) and self-report (58.7%/68.9%) measures, respectively.
Conclusions
More walking was associated with less risk of functional limitation over two years. Walking ≥ 6000 steps/day provides a preliminary estimate of the level of walking activity to protect against developing functional limitation in people with or at risk of knee OA.
doi:10.1002/acr.22362
PMCID: PMC4146701  PMID: 24923633
Physical Activity; Arthritis; Physical Function
13.  Left atrial dimension and traditional cardiovascular risk factors predict 20-year clinical cardiovascular events in young healthy adults: the CARDIA study 
Aims
We investigated whether the addition of left atrial (LA) size determined by echocardiography improves cardiovascular risk prediction in young adults over and above the clinically established Framingham 10-year global CV risk score (FRS).
Methods and results
We included white and black CARDIA participants who had echocardiograms in Year-5 examination (1990–91). The combined endpoint after 20 years was incident fatal or non-fatal cardiovascular disease: myocardial infarction, heart failure, cerebrovascular disease, peripheral artery disease, and atrial fibrillation/flutter. Echocardiography-derived M-mode LA diameter (LAD; n = 4082; 149 events) and 2D four-chamber LA area (LAA; n = 2412; 77 events) were then indexed by height or body surface area (BSA). We used Cox regression, areas under the receiver operating characteristic curves (AUC), and net reclassification improvement (NRI) to assess the prediction power of LA size when added to calculated FRS or FRS covariates. The LAD and LAA cohorts had similar characteristics; mean LAD/height was 2.1 ± 0.3 mm/m and LAA/height 9.3 ± 2.0 mm2/m. After indexing by height and adjusting for FRS covariates, hazard ratios were 1.31 (95% CI 1.12, 1.60) and 1.43 (95% CI 1.13, 1.80) for LAD and LAA, respectively; AUC was 0.77 for LAD and 0.78 for LAA. When LAD and LAA were indexed to BSA, the results were similar but slightly inferior. Both LAD and LAA showed modest reclassification ability, with non-significant NRIs.
Conclusion
LA size measurements independently predict clinical outcomes. However, it only improves discrimination over clinical parameters modestly without altering risk classification. Indexing LA size by height is at least as robust as by BSA. Further research is needed to assess subgroups of young adults who may benefit from LA size information in risk stratification.
doi:10.1093/ehjci/jeu018
PMCID: PMC4215562  PMID: 24534011
Left atrial size; Cardiovascular events; Echocardiography; Young adults
14.  Validity of Diabetes Self-Reports in the Women's Health Initiative 
Menopause (New York, N.Y.)  2014;21(8):861-868.
Objective
To determine positive and negative predictive values of self-reported diabetes during the Women's Health Initiative (WHI) clinical trials.
Methods
All WHI trial participants from four field centers who self-reported diabetes at baseline or during follow up, as well as a random sample who did not self-report diabetes, were identified. Women were surveyed regarding diagnosis and treatment. Medical records were obtained and reviewed for documented treatment with anti-diabetic medications or physician diagnosis of diabetes supported by laboratory measurements of glucose.
Results
We identified 1,275 eligible participants; 732 consented and provided survey data. Medical records were obtained for 715 (207 prevalent diabetes, 325 incident diabetes, and 183 no diabetes). Records confirmed 91.8% (95% CI 87.0%-95.0%) of self-reported prevalent diabetes and 82.2% (95% CI 77.5%-86.1%) incident diabetes. Of those who never self-reported diabetes, there was no medical record or laboratory evidence for diabetes in 94.5% (95% CI 89.9%-97.2%). Women with higher BMI were more likely to accurately self-report incident diabetes. In a subgroup of participants enrolled in fee-for-service Medicare, a claims algorithm correctly classified nearly all diabetes cases and non-cases.
Conclusions
Among WHI clinical trial participants, there was a high positive predictive value of self-reported prevalent (91.8%) and incident diabetes (82.2%) and a high negative predictive value (94.5%) when diabetes was not reported. For participants enrolled in fee-for-service Medicare, a claims algorithm also had a high positive and negative predictive value.
doi:10.1097/GME.0000000000000189
PMCID: PMC4278641  PMID: 24496083
Diabetes mellitus; type 2; medical record; self report; validation studies; questionnaires; reproducibility of results
15.  Associations between Nonalcoholic Fatty Liver Disease and Subclinical Atherosclerosis in Middle-Aged Adults: The Coronary Artery Risk Development in Young Adults Study 
Atherosclerosis  2014;235(2):599-605.
Objective
Non-alcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular mortality. Yet, whether or not NAFLD is independently related to atherosclerosis is unclear. In a population-based cross-sectional sample of middle-aged adults free from liver or heart disease, we tested the hypothesis that NAFLD is associated with subclinical atherosclerosis (coronary artery (CAC) and abdominal aortic calcification (AAC)) independent of obesity.
Methods
Participants from the Coronary Artery Risk Development in Young Adults study with CT quantification of liver fat, CAC and AAC were included (n=2,424). NAFLD was defined as liver attenuation ≤ 40 Hounsfield Units after exclusion of other causes of liver fat. CAC and AAC presence was defined as Agatston score > 0.
Results
Mean participant age was 50.1±3.6 years, (42.7% men, 50.0% black) and BMI was 30.6±7.2 kg/m2. The prevalence of NAFLD, CAC, and AAC was 9.6%, 27.1%, and 51.4%. NAFLD participants had increased prevalence of CAC (37.9% vs. 26.0%, p<0.001) and AAC (65.1% vs. 49.9%, p<0.001). NAFLD remained associated with CAC (OR, 1.33; 95% CI, 1.001–1.82) and AAC (OR, 1.74; 95% CI, 1.29–2.35) after adjustment for demographics and health behaviors. However, these associations were attenuated after additional adjustment for visceral adipose tissue (CAC OR, 1.05; 95% CI, 0.74–1.48, AAC OR=1.20; 95% CI, 0.86–1.67). There was no interaction by race or sex.
Conclusion
In contrast to prior research, these findings suggest that obesity attenuates the relationship between NAFLD and subclinical atherosclerosis. Further studies evaluating the role of NAFLD duration on atherosclerotic progression and cardiovascular events are needed.
doi:10.1016/j.atherosclerosis.2014.05.962
PMCID: PMC4124046  PMID: 24956534
calcium; cardiovascular diseases; epidemiology; imaging; liver; obesity; risk factors
16.  Macronutrients, Diet Quality, and Frailty in Older Men 
Background.
Frailty, a phenotype of multisystem impairment and expanding vulnerability, is associated with higher risk of adverse health outcomes not entirely explained by advancing age. We investigated associations of macronutrients, dietary fiber, and overall diet quality with frailty status in older community-dwelling men.
Methods.
Participants were 5,925 men aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study at six U.S. centers. Diet was assessed at baseline with a food frequency questionnaire. We assessed frailty status (robust, intermediate, or frail) at baseline and at a second clinic visit (a mean of 4.6 years later) using a slightly modified Cardiovascular Health Study frailty index. We used multinomial logistic regression to assess associations between macronutrient intake, dietary fiber, and the Diet Quality Index Revised with frailty status at baseline and at the second clinic visit.
Results.
At baseline, 2,748 (46.4%) participants were robust, 2,681 (45.2%) were intermediate, and 496 (8.4%) were frail. Carbohydrate, fat, protein, and dietary fiber showed no consistent associations with frailty status. Overall diet quality exhibited fairly consistent associations with frailty status. The Diet Quality Index Revised was inversely associated with frail status relative to robust status at the baseline visit (odds ratio for Q5 vs Q1 = 0.44, 95% confidence interval: 0.30, 0.63; p for trend < .0001) and at the second clinic visit (odds ratio for Q5 vs Q1 = 0.18, 95% confidence interval: 0.03, 0.97; p for trend = .0180).
Conclusions.
Overall diet quality was inversely associated with prevalent and future frailty status in this cohort of older men.
doi:10.1093/gerona/glt196
PMCID: PMC4022097  PMID: 24304504
Frailty; Nutrition; Epidemiology.
17.  Effect of a Long-Term Behavioral Weight Loss Intervention on Nephropathy in Overweight or Obese Adults with Type 2 Diabetes: the Look AHEAD Randomized Clinical Trial 
Background
Long-term effects of behavioral weight loss interventions on diabetes complications are unknown. We assessed whether an intensive lifestyle intervention (ILI) affects the development of nephropathy in Look AHEAD, a multicenter randomized clinical trial in type 2 diabetes.
Methods
5145 overweight or obese persons aged 45–76 years with type 2 diabetes were randomized to ILI designed to achieve and maintain weight loss through reduced caloric consumption and increased physical activity or to a diabetes support and education (DSE) group. Randomization to ILI or DSE, in a 1:1 ratio, was implemented in a central web-based data management system, stratified by clinical center, and blocked with random block sizes. Outcomes assessors and laboratory staff were masked to treatment. The interventions ended early because of lack of effect on the primary outcome of cardiovascular disease events. Albuminuria and estimated glomerular filtration rate were prespecified “other” outcomes and were assessed from baseline through 9.6 years (median) of follow-up until the interventions ended. They were combined post-hoc to define the main outcome for this report: very-high-risk chronic kidney disease (CKD) based on the 2013 Kidney Disease Improving Global Outcomes classification. Data were analyzed by intention to treat. The trial is registered as Clinicaltrials.gov NCT00017953.
Findings
The incidence rate of very-high-risk CKD was 31% lower in ILI than DSE with hazard rates of 0.90 cases/100 person-years in DSE and 0.63 in ILI (difference=0.27 cases/100 person-years, hazard ratio and 95% confidence interval: HR=0.69, 0.55 to 0.87). This effect was partly attributable to reductions in weight, HbA1c, and blood pressure.
Interpretation
Weight loss should be considered as an adjunct to medical therapies to prevent or delay progression of CKD in overweight or obese persons with type 2 diabetes.
Primary Funding
National Institute of Diabetes and Digestive and Kidney Diseases.
doi:10.1016/S2213-8587(14)70156-1
PMCID: PMC4443484  PMID: 25127483
18.  Serum Urate Association with Hypertension in Young Adults: Analysis from the Coronary Artery Risk Development in Young Adults Cohort 
Annals of the rheumatic diseases  2012;72(8):1321-1327.
Objective
To determine if serum urate concentration is associated with development of hypertension in young adults.
Methods
Retrospective cohort analysis from 4752 participants with available serum urate and without hypertension at baseline from the Coronary Artery Risk Development in Young Adults (CARDIA) Study; a mixed race (African-American and White) cohort established in 1985 with 20 years of follow-up data for this analysis. Associations between baseline serum urate concentration and incident hypertension (defined as a blood pressure greater or equal to 140/90 or being on antihypertensive drugs) were investigated in sex-stratified bivariate and multivariable Cox-proportional analyses.
Results
Mean age (standard deviation) at baseline was 24.8 (3.6) years for men and 24.9 (3.7) years for women. Compared with the referent category, we found a greater hazard of developing hypertension starting at 345 μmol/L (5.8 mg/ dL) of serum urate for men and 214 μmol/L (3.6 mg/dL) for women. There was a 25% increase in the hazard of developing hypertension in men (HR1.25 [95% CI 1.15-1.36]) per each mg/dL increase in serum urate but no significant increase in women (HR 1.06 [95%CI 0.97-1.16]).
Conclusions
We found a significant independent association between higher serum urate concentrations and the subsequent hazard of incident hypertension, even at concentrations below the conventional hyperuricemia threshold of 404 μmol/L (6.8 mg/dL).
doi:10.1136/annrheumdis-2012-201916
PMCID: PMC4428756  PMID: 22984170
health services research; hypertension; epidemiology
19.  Body Mass Index and Early Kidney Function Decline in Young Adults: A Longitudinal Analysis of the CARDIA (Coronary Artery Risk Development in Young Adults) Study 
Background
Identifying potentially modifiable risk factors is critically important for reducing the burden of chronic kidney disease. We sought to examine the association of body mass index (BMI) with kidney function decline in a cohort of young adults with preserved glomerular filtration at baseline.
Study Design
Longitudinal cohort.
Setting & Participants
2,891 black and white young adults with cystatin C-based estimated glomerular filtration rate (eGFRcys) >90 ml/min/1.73 m2 taking part in the year-10 examination (in 1995–1996) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Predictor
BMI, categorized as 18.5–24.9 (reference), 25.0–29.9. 30.0–39.9, and ≥40.0 kg/m2.
Outcomes
Trajectory of kidney function decline, rapid decline (>3% per year), and incident eGFRcys <60 ml/min/1.73 m2 over 10 years of follow-up.
Measurements
GFRcys estimated from the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation for calibrated cystatin C at CARDIA years 10, 15, and 20.
Results
At year 10, participants had a mean age of 35.1 years, median eGFRcys of 114 ml/min/1.73 m2, and 24.5% had BMI ≥30.0 kg/m2. After age 30 years, average eGFRcys was progressively lower with each increment of BMI after adjustment for baseline age, race, sex, hyperlipidemia, smoking status, and physical activity. Higher BMI category was associated with successively higher odds of rapid decline (for 25.0–29.9, 30.0–39.9, and ≥40.0 kg/m2, the adjusted ORs were 1.50 [95% CI, 1.21–1.87], 2.01 [95% CI, 1.57–2.87], and 2.57 [95% CI, 1.67–3.94], respectively). Eighteen participants (0.6%) had incident eGFRcys <60 ml/min/1.73 m2. In unadjusted analysis, higher BMI category was associated with incident eGFRcys <60 ml/min/1.73 m2 (for 25.0–29.9, 30.0–39.9, and ≥40.0 kg/m2, the ORs were 5.17 [95% CI, 1.10–25.38], 7.44 [95% CI, 1.54–35.95], and 5.55 [95% CI, 0.50–61.81], respectively); adjusted associations were no longer significant.
Limitations
Inability to describe kidney function before differences by BMI category were already evident. Absence of data on measured GFR or GFR estimated from serum creatinine.
Conclusions
Higher BMI categories are associated with greater declines in kidney function among a cohort of young adults with preserved GFR at baseline. Clinicians should vigilantly monitor overweight and obese patients for evidence of early kidney function decline.
doi:10.1053/j.ajkd.2013.10.055
PMCID: PMC3969447  PMID: 24295611
20.  Accumulation of Metabolic Cardiovascular Risk Factors in Black and White Young Adults Over 20 Years 
Background
Cross‐sectional clustering of metabolic risk factors for cardiovascular disease in middle‐aged adults is well described, but less is known regarding the order in which risk factors develop through young adulthood and their relation to subclinical atherosclerosis.
Method and Results
A total of 3178 black and white women and men in the Coronary Artery Risk Development in Young Adults study were assessed to identify the order in which cardiovascular disease risk factors including diabetes, hypertension, dyslipidemia (low high‐density lipoprotein cholesterol or high triglyceride levels), hypercholesterolemia (high total or low‐density lipoprotein cholesterol), and obesity develop. Observed patterns of risk factor development were compared with those expected if risk factors accumulated randomly, given their overall distribution in the population. Over the 20 years of follow‐up, 80% of participants developed at least 1 risk factor. The first factor to occur was dyslipidemia in 39% of participants, obesity in 20%, hypercholesterolemia in 11%, hypertension in 7%, and diabetes in 1%. Dyslipidemia was the only risk factor both to occur first and to be followed by additional risk factors more often than expected (P<0.001 for both). Order of risk factor accrual did not affect subclinical atherosclerosis at year 20. Results were similar by sex, race, and smoking status.
Conclusions
Multiple patterns of cardiovascular risk factor development were observed from young adulthood to middle age. Dyslipidemia, a potentially modifiable condition, often preceded the development of other risk factors and may be a useful target for intervention and monitoring.
doi:10.1161/JAHA.114.001548
PMCID: PMC4579950  PMID: 25911605
atherosclerosis; epidemiology; lipids; obesity; primary prevention; risk factors; type 2 diabetes
21.  Vascular Factors and Multiple Measures of Early Brain Health: CARDIA Brain MRI Study 
PLoS ONE  2015;10(3):e0122138.
Objective
To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF).
Design
Cross-sectional brain Magnetic Resonance I (MRI) study.
Setting
Community based cohort in three U.S. sites.
Participants
A Caucasian and African-American sub-sample (n= 680; mean age 50.3 yrs) attending the 25 year follow-up exam of the Coronary Artery Risk Development in Young Adults Study.
Primary and Secondary Outcomes
3T brain MR images processed for quantitative estimates of: total brain (TBV) and abnormal white matter (AWM) volume; white matter fractional anisotropy (WM-FA); and gray matter cerebral blood flow (GM-CBF). Total intracranial volume is TBV plus cerebral spinal fluid (TICV). A Global Cognitive Function (GCF) score was derived from tests of speed, memory and executive function.
Results
Adjusting for TICV and demographic factors, current smoking was significantly associated with lower GM-CBF and TBV, and more AWM (all <0.05); SA with lower GM-CBF, WM-FA and TBV (p=0.01); increasing BMI with decreasing GM-CBF (p<0003); hypertension with lower GM-CBF, WM-FA, and TBV and higher AWM (all <0.05); and diabetes with lower TBV (p=0.007). The GCS was lower as TBV decreased, AWM increased, and WM-FA (all p<0.01).
Conclusion
In middle age adults, CVRF are associated with brain health, reflected in MRI measures of structure and perfusion, and cognitive functioning. These findings suggest markers of mid-life cardiovascular and brain health should be considered as indication for early intervention and future risk of late-life cerebrovascular disease and dementia.
doi:10.1371/journal.pone.0122138
PMCID: PMC4374951  PMID: 25812012
22.  Lipoprotein particles and size, total and high molecular weight adiponectin, and leptin in relation to incident coronary heart disease among severely obese postmenopausal women: The Women's Health Initiative Observational Study☆☆☆★ 
BBA Clinical  2015;3:243-250.
Background
We hypothesized that higher concentrations of LDL particles (LDL-P) and leptin, and lower concentrations of HDL particles (HDL-P), and total and high molecular weight (HMW) adiponectin, would predict incident coronary heart disease (CHD) among severely obese postmenopausal women.
Methods
In a case–cohort study nested in the Women's Health Initiative Observational Study, we sampled 677 of the 1852 white or black women with body mass index (BMI) ≥ 40 kg/m2 and no prevalent cardiovascular disease (CVD), including all 124 cases of incident CHD over mean 5.0 year follow-up. Biomarkers were assayed on stored blood samples.
Results
In multivariable-adjusted weighted Cox models, higher baseline levels of total and small LDL-P, and lower levels of total and medium HDL-P, and smaller mean HDL-P size were significantly associated with incident CHD. In contrast, large HDL-P levels were inversely associated with CHD only for women without diabetes, and higher total and HMW adiponectin levels and lower leptin levels were associated with CHD only for women with diabetes. Higher total LDL-P and lower HDL-P were associated with CHD risk independently of confounders including CV risk factors and other lipoprotein measures, with adjusted HR (95% CIs) of 1.55 (1.28, 1.88) and 0.70 (0.57, 0.85), respectively, and similar results for medium HDL-P.
Conclusions
Higher CHD risk among severely obese postmenopausal women is strongly associated with modifiable concentrations of LDL-P and HDL-P, independent of diabetes, smoking, hypertension, physical activity, BMI and waist circumference.
General significance
Severely obese postmenopausal women should be considered high risk candidates for lipid lowering therapy.
Highlights
•CHD risk is ~ 2-fold higher for severely obese postmenopausal women (BMI ≥ 40 kg/m2).•Baseline risk factors were measured among 677 severely obese postmenopausal women.•5-year CHD risk related to higher LDL particles, lower total, medium HDL particles.•Paradoxical or no relations of adiponectin (total, HMW) and leptin with CHD risk•Clinical implications: Statins reduce LDL particles and increase HDL particles.
doi:10.1016/j.bbacli.2015.03.005
PMCID: PMC4375554  PMID: 25825692
Extreme obesity; Severe obesity; Coronary heart disease; Lipoproteins; Adiponectin; Postmenopausal women
23.  Framingham Score and LV Mass predict Events in Young Adults: CARDIA Study 
International journal of cardiology  2014;172(2):350-355.
Background
Framingham risk score (FRS) underestimates risk in young adults. LV mass (LVM) relates to cardiovascular disease (CVD), with unclear value in youth. In a young biracial cohort, we investigate how FRS predicts CVD over 20 years and the incremental value of LVM. We also explore the predictive ability of different cut-points for hypertrophy.
Methods
We assessed FRS and echocardiography-derived LVM (indexed by BSA or height2.7) from 3980 African-American and white CARDIA participants (1990-1991); and followed over 20 years for a combined endpoint: cardiovascular death; nonfatal myocardial infarction, heart failure, cerebrovascular disease, and peripheral artery disease. We assessed the predictive ability of FRS for CVD and also calibration, discrimination, and net reclassification improvement for adding LVM to FRS.
Results
Mean age was 30±4 years, 46% males, and 52% white. Event incidence (n = 118) across FRS groups was, respectively, 1.3%, 5.4%, and 23.1% (p<0.001); and was 1.4%, 1.3%, 3.7%, and 5.4% (p<0.001) across quartiles of LVM (cut-points 117g, 144g, and 176g). LVM predicted CVD independently of FRS, with the best performance in normal weight participants. Adding LVM to FRS modestly increased discrimination and had a statistically significant reclassification. The 85th percentile (≥116 g/m2 for men; ≥96 g/m2 for women) showed event prediction more robust than currently recommended cut-points for hypertrophy.
Conclusion
In a biracial cohort of young adults, FRS and LVM are helpful independent predictors of CVD. LVM can modestly improve discrimination and reclassify participants beyond FRS. Currently recommended cut-points for hypertrophy may be too high for young adults.
doi:10.1016/j.ijcard.2014.01.003
PMCID: PMC4068332  PMID: 24507735
young adults; cardiovascular risk; left ventricular hypertrophy; echocardiography
24.  Social Relationships and Longitudinal Changes in Body Mass Index and Waist Circumference: The Coronary Artery Risk Development in Young Adults Study 
American Journal of Epidemiology  2014;179(5):567-575.
Few studies have examined longitudinal associations between close social relationships and weight change. Using data from 3,074 participants in the Coronary Artery Risk Development in Young Adults Study who were examined in 2000, 2005, and 2010 (at ages 33–45 years in 2000), we estimated separate logistic regression random-effects models to assess whether patterns of exposure to supportive and negative relationships were associated with 10% or greater increases in body mass index (BMI) (weight (kg)/height (m)2) and waist circumference. Linear regression random-effects modeling was used to examine associations of social relationships with mean changes in BMI and waist circumference. Participants with persistently high supportive relationships were significantly less likely to increase their BMI values and waist circumference by 10% or greater compared with those with persistently low supportive relationships after adjustment for sociodemographic characteristics, baseline BMI/waist circumference, depressive symptoms, and health behaviors. Persistently high negative relationships were associated with higher likelihood of 10% or greater increases in waist circumference (odds ratio = 1.62, 95% confidence interval: 1.15, 2.29) and marginally higher BMI increases (odds ratio = 1.50, 95% confidence interval: 1.00, 2.24) compared with participants with persistently low negative relationships. Increasingly negative relationships were associated with increases in waist circumference only. These findings suggest that supportive relationships may minimize weight gain, and that adverse relationships may contribute to weight gain, particularly via central fat accumulation.
doi:10.1093/aje/kwt311
PMCID: PMC3927980  PMID: 24389018
body mass index; longitudinal study; social relationships; waist circumference
25.  Race–Ethnic and Sex Differences in Left Ventricular Structure and Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Background
We investigated race–ethnic and sex‐specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age.
Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985–1986 (Year‐0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year‐25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle‐tracking echocardiography. In the multivariable models, we used, in addition to race–ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year‐0 and ‐25 examinations as independent predictors of echocardiographic outcomes at the Year‐25 examination (LV end‐diastolic volume [LVEDV]/height, LV end‐systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race–ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment.
Conclusions
African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial‐ethnic differences are partially but not completely explained by established cardiovascular risk factors.
doi:10.1161/JAHA.114.001264
PMCID: PMC4392424  PMID: 25770024
echocardiography; left ventricular function; left ventricular mass; speckle‐tracking echocardiography

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