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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.  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
4.  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
5.  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
6.  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.
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  Relation of Left Ventricular Mass at Age 23 to 35 years to Global Left Ventricular Systolic Function 20 Years Later (From the Coronary Artery Risk Development in Young Adults Study) 
The American journal of cardiology  2013;113(2):377-383.
Left ventricular (LV) mass and LV ejection fraction (EF) are major independent predictors of future cardiovascular disease. The association of LV mass with future LVEF in younger populations has not been studied. We investigated the relation of LV mass index (LVMI) at age 23 to 35 years to LV function after 20 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a longitudinal study that enrolled young adults in 1985–1986. We included participants with echocardiographic examinations at both years-5 and -25. LVMI and LVEF were assessed using M-mode echocardiography at year-5 and using both M-mode and 2-dimensional images at year-25. Statistical analytic models assessed the correlation between LVMI and LV functional parameters both cross-sectionally and longitudinally. A total of 2,339 participants were included. The mean LVEF at year-25 was 62%. Although there was no cross-sectional correlation between LVMI and LVEF at year-5, there was a small, but statistically significant negative correlation between LVMI at year-5 and LVEF 20 years later (r = −0.10, p < 0.0001); this inverse association persisted for LVMI in the multivariable model. High LVMI was an independent predictor of systolic dysfunction (LVEF < 50%) 20 years later (odds ratio 1.46, p = 0.0018). In conclusion, we have shown that LVMI in young adulthood in association with chronic risk exposure impacts systolic function in middle age; the antecedents of heart failure may occur at younger ages than previously thought.
doi:10.1016/j.amjcard.2013.08.052
PMCID: PMC3901209  PMID: 24176073
left ventricular mass; left ventricular ejection fraction; echocardiography; left ventricular remodeling
15.  Estimated GFR and Risk of Hip Fracture in Older Men: Comparison of Associations Using Cystatin C and Creatinine 
Background
Higher serum cystatin C is associated with an increased risk of hip fracture in postmenopausal white women, but there is a paucity of data in men. Whether an estimated GFR (eGFR) based on cystatin C (eGFRcys) is superior in predicting hip fracture risk to an eGFR based on creatinine (eGFRcr) or the combination (eGFRcr-cys) is also uncertain.
Study Design
Nested case-cohort.
Setting & Participants
Participants enrolled in the Osteoporotic Fractures in Men (MrOS) Study (5,994 men aged ≥65 years from six U.S. centers) including a random subcohort of 1602 men and 168 men with incident hip fractures (51 of whom were in the subcohort).
Predictor
eGFRcys, eGFRcr and eGFRcr-cys computed using the CKD-EPI equations and expressed in categories of <60, 60–74, and ≥75 mL/min/l.73 m2 (referent group).
Outcome
Incident hip fracture ascertained by participant contacts every 4 months and confirmed with radiographic reports.
Results
Median eGFRcys was 72.9 (IQR, 60.5–85.7) mL/min/1.73 m2. In unadjusted models, all measures of eGFR were associated with increased hip fracture risk. However, after adjustment for age, race, site and BMI, the association of lower eGFRcys (but not lower eGFRcr or lower eGFRcr-cys) with higher hip fracture risk remained: for <60 vs. ≥75 mL/min/l.73 m2, HRs were 1.96 [95% CI, 1.25–3.09], 0.84 [95% CI, 0.52–1.37], and 1.08 [95% CI, 0.66–1.77] for eGFRcys, eGFRcr, and eGFRcr-cys, respectively. Similarly, after adjustment for age, race, site and BMI, eGFR of <60 ml/min/1.73 m2 defined by eGFRcys but not eGFRcr or eGFRcr-cys, was associated with higher hip fracture risk. The association between eGFRcys and hip fracture was not explained by levels of calcitropic hormones or inflammatory markers, but the relationship was attenuated and no longer reached significance (for <60 vs. ≥75 mL/min/l.73 m2: HR, 1.43; 95% CI, 0.88–2.34) after consideration of additional clinical risk factors and bone mineral density.
Limitations
Findings not generalizable other populations; residual confounding may exist.
Conclusions
Older community-dwelling men with lower eGFRcys have an increased risk of hip fracture that is explained in large part by greater burden of risk factors among men with lower eGFRcys. In contrast, lower eGFRcr or lower eGFRcr-cys were not associated with a higher age-adjusted hip fracture risk.
doi:10.1053/j.ajkd.2013.05.022
PMCID: PMC3833961  PMID: 23890927
kidney function; cystatin C; creatinine; hip fracture; elderly; men
16.  Evaluating the Framingham Hypertension Risk Prediction Model in Young Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Hypertension  2013;62(6):1015-1020.
A prediction model was developed in the Framingham Heart Study (FHS) to evaluate short-term risk of hypertension. Our goal was to determine the predictive ability of the FHS hypertension model in a cohort of young adults advancing into middle age and compare it with the predictive ability of prehypertension, and individual components of the FHS model. We studied 4,388 participants, age 18-30 years without hypertension at baseline, enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study who participated in 2 consecutive exams occurring 5 years apart between the baseline (1985-1986) and Year 25 examination (2010-2011). Weibull regression was used to assess the association of the FHS model overall, individual components of the FHS model, and prehypertension with incident hypertension. Over the 25 year follow-up period, 1179 participants developed incident hypertension. The FHS hypertension model (c-index=0.84, 95% CI=0.83, 0.85) performed well in discriminating those who did and did not develop hypertension and was better than prehypertension alone (c-index=0.71, 95% CI=0.70, 0.73). The predicted risk from the FHS hypertension model was systematically lower than the observed hypertension incidence initially (χ2= 249.4; p<0.001), but demonstrated a good fit after recalibration (χ2= 14.6; p=0.067). In summary, the FHS model performed better than prehypertension and may be a useful tool for identifying young adults with a high risk for developing hypertension.
doi:10.1161/HYPERTENSIONAHA.113.01539
PMCID: PMC4019674  PMID: 24041951
hypertension; prehypertension; epidemiology; risk
17.  Association Between Duration of Overall and Abdominal Obesity Beginning in Young Adulthood and Coronary Artery Calcification in Middle Age 
JAMA  2013;310(3):280-288.
IMPORTANCE
Younger individuals are experiencing a greater cumulative exposure to excess adiposity over their lifetime. However, few studies have determined the consequences of long-term obesity.
OBJECTIVE
To examine whether the duration of overall and abdominal obesity was associated with the presence and 10-year progression of coronary artery calcification (CAC), a subclinical predictor of coronary heart disease.
DESIGN, SETTING, AND PARTICIPANTS
Prospective study of 3275 white and black adults aged 18 to 30 years at baseline in 1985–1986 who did not initially have overall obesity (body mass index [BMI] ≥30) or abdominal obesity (men: waist circumference [WC] >102 cm; women: >88 cm) in the multicenter, community-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants completed computed tomography scanning for the presence of CAC during the 15-, 20-, or 25-year follow-up examinations. Duration of overall and abdominal obesity was calculated using repeat measurements of BMI and WC, respectively, performed 2, 5, 7, 10, 15, 20, and 25 years after baseline.
MAIN OUTCOMES AND MEASURES
Presence of CAC was measured by computed tomography at the year 15 (2000–2001), year 20 (2005–2006), or year 25 (2010–2011) follow-up examinations. Ten-year progression of CAC (2000–2001 to 2010–2011) was defined as incident CAC in 2010–2011 or an increase in CAC score of 20 Agatston units or greater.
RESULTS
During follow-up, 40.4% and 41.0% developed overall and abdominal obesity, respectively. Rates of CAC per 1000 person-years were higher for those who experienced more than 20 years vs 0 years of overall obesity (16.0 vs 11.0, respectively) and abdominal obesity (16.7 vs 11.0). Approximately 25.2% and 27.7% of those with more than 20 years of overall and abdominal obesity, respectively, experienced progression of CAC vs 20.2% and 19.5% of those with 0 years. After adjustment for BMI or WC and potential confounders, the hazard ratios for CAC for each additional year of overall or abdominal obesity were 1.02 (95% CI, 1.01–1.03) and 1.03 (95% CI, 1.02–1.05), respectively. The adjusted odds ratios for CAC progression were 1.04 (95% CI, 1.01–1.06) and 1.04 (95% CI, 1.01–1.07), respectively. Associations were attenuated but largely persisted following additional adjustment for potential intermediate metabolic factors during follow-up.
CONCLUSIONS AND RELEVANCE
Longer duration of overall and abdominal obesity was associated with subclinical coronary heart disease and its progression through midlife independent of the degree of adiposity. Preventing or at least delaying the onset of obesity in young adulthood may lower the risk of developing atherosclerosis through middle age.
doi:10.1001/jama.2013.7833
PMCID: PMC4226407  PMID: 23860986
19.  The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases 
IMPORTANCE
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
OBJECTIVE
To provide a comprehensive, integrated overview of findings from the two Women’s Health Initiative (WHI) hormone therapy (HT) trials with extended post-intervention follow up.
DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS
27,347 postmenopausal women, age 50–79 years, were enrolled at 40 US centers. Interventions were conjugated equine estrogens (CEE, 0.625 mg/day) with medroxyprogesterone acetate (MPA, 2.5 mg/day) for women with an intact uterus (N = 16,608) and CEE alone for women with hysterectomy (N= 10,739), or their placebos. Intervention continued for 5.6 and 7.2 years (median), respectively, with cumulative follow-up of 13 years through September 30, 2010.
MAIN OUTCOMES AND MEASURES
The primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and deaths. Secondary and quality-of-life outcomes were also assessed.
RESULTS
During the intervention phase for CEE+MPA, the hazard ratio (HR) for CHD was 1.18 (95% confidence interval [CI] 0.95–1.45) and overall risks outweighed benefits, with increases in invasive breast cancer, stroke, pulmonary embolism, and the global index. Other risks included increased dementia (in women >65 years), gallbladder disease, and urinary incontinence, while benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Post-intervention, most risks and benefits dissipated, although some elevation in breast cancer risk persisted (cumulative hazard ratio [HR] =1.28; 95% confidence interval, 1.11–1.48). During intervention for CEE alone, risks and benefits were more balanced, with a HR for CHD of 0.94 (0.78–1.14), increased stroke and venous thrombosis, decreased hip fractures and diabetes, and over cumulative follow-up, decreased breast cancer (HR=0.79 [0.65–0.97]). Neither regimen affected all-cause mortality. With CEE, younger women (50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P values for trend by age <0.05), but not for stroke and venous thrombosis. Absolute risks of adverse events (measured by the global index) per 10,000 women per year on CEE+MPA ranged from 12 excess cases for age 50–59 to 38 for age 70–79 and, for CEE, from 19 fewer cases for age 50–59 to 51 excess cases for age 70–79. Results for quality of life outcomes in both trials were mixed.
CONCLUSIONS AND RELEVANCE
Menopausal hormone therapy has a complex pattern of risks and benefits. While appropriate for symptom management in some women, its use for chronic disease prevention is not supported by the WHI randomized trials.
TRIAL REGISTRATION
clinical trials.gov Identifier: NCT00000611
doi:10.1001/jama.2013.278040
PMCID: PMC3963523  PMID: 24084921
20.  Impact of Weight Loss on Ankle-Brachial Index and Inter-Artery Blood Pressures in Overweight and Obese Adults with Diabetes 
Obesity (Silver Spring, Md.)  2014;22(4):1032-1041.
Objective
To assess whether weight loss improves markers of peripheral artery disease and vascular stenosis.
Design and Methods
The Action for Health in Diabetes randomized clinical trial compared intensive lifestyle intervention (ILI) for weight loss to a control condition of diabetes support and education (DSE) in overweight or obese adults with type 2 diabetes. Annual ankle and brachial blood pressures over four years were used compute ankle-brachial indices (ABIs) and to assess inter-artery blood pressure differences in 5018 participants.
Results
ILI, compared to DSE, produced 7.8% (Year 1) to 3.6% (Year 4) greater weight losses. These did not affect prevalence of low (<0.90) ABI (3.60% in DSE versus 3.14% in ILI; p=0.20) or elevated (>1.40) ABI (7.52% in DSE versus 7.59% in ILI: p=0.90), but produced smaller mean (SE) maximum inter-artery systolic blood pressure differences among ankle sites [19.7 (0.2) mmHg for ILI versus 20.6 (0.2) mmHg for DSE (p<0.001)] and between arms [5.8 (0.1) mmHg for ILI versus 6.1 (0.1) mmHg for DSE (p=0.01)].
Conclusions
Four years of intensive behavioral weight loss intervention did not significantly alter prevalence of abnormal ABI, however it did reduce differences in systolic blood pressures among arterial sites.
doi:10.1002/oby.20658
PMCID: PMC3968218  PMID: 24174392
Peripheral artery disease; Weight loss; Diabetes
21.  Effect of Intensive Lifestyle Intervention on Sexual Dysfunction in Women With Type 2 Diabetes 
Diabetes Care  2013;36(10):2937-2944.
OBJECTIVE
Sexual dysfunction is a prevalent problem in obese women with type 2 diabetes. This study examined the effects of intensive lifestyle intervention (ILI) in these women.
RESEARCH DESIGN AND METHODS
Look AHEAD is a 16-center, randomized, controlled trial evaluating the health effects of ILI compared with a control group (diabetes support and education [DSE]). The Look AHEAD Sexual Function Ancillary study included 375 female participants at five Look AHEAD sites. Participants completed the Female Sexual Function Inventory (FSFI) and Beck Depression Inventory (BDI), and assessments of weight and cardiovascular risk factors at baseline and 1 year were made.
RESULTS
At baseline, 50% of the 229 participants who reported being sexually active met criteria for female sexual dysfunction (FSD); only BDI score was related to FSD. One-year weight losses were greater in the ILI group than in the DSE group (7.6 vs. 0.45 kg; P < 0.001). Among women with FSD at baseline, those in the ILI group (N = 60) compared with those in the DSE group (N = 53) were significantly more likely to remain sexually active (83 vs. 64%; P < 0.008), reported greater improvement in total FSFI scores and in most FSFI domains (P < 0.05), and were more likely to experience remission of FSD (28 vs. 11%; P < 0.04) at 1 year. No significant differences between ILI and DSE were seen in women who did not have FSD at baseline.
CONCLUSIONS
Participation in ILI appeared to have beneficial effects on sexual functioning among obese women with diabetes, particularly in those who had FSD at baseline.
doi:10.2337/dc13-0315
PMCID: PMC3781524  PMID: 23757437
22.  The Diagnostic Performance of Anterior Knee Pain and Activity-related Pain in Identifying Knees with Structural Damage in the Patellofemoral Joint: The Multicenter Osteoarthritis Study 
The Journal of rheumatology  2014;41(8):1695-1702.
Objective
To determine the diagnostic test performance of location of pain and activity-related pain in identifying knees with patellofemoral joint (PFJ) structural damage.
Methods
The Multicenter Osteoarthritis Study is a US National Institutes of Health-funded cohort study of older adults with or at risk of knee osteoarthritis. Subjects identified painful areas around the knee on a knee pain map and the Western Ontario and McMaster Universities Osteoarthritis Index was used to assess pain with stairs and walking on level ground. Cartilage damage and bone marrow lesions were assessed from knee magnetic resonance imaging. We determined the sensitivity, specificity, positive and negative predictive values for presence of anterior knee pain (AKP), pain with stairs, absence of pain while walking on level ground, and combinations of tests in discriminating knees with isolated PFJ structural damage from those with isolated tibiofemoral joint (TFJ) or no structural damage. Knees with mixed PFJ/TFJ damage were removed from our analyses because of the inability to determine which compartment was causing pain.
Results
There were 407 knees that met our inclusion criteria. “Any” AKP had a sensitivity of 60% and specificity of 53%; and if AKP was the only area of pain, the sensitivity dropped to 27% but specificity rose to 81%. Absence of moderate pain with walking on level ground had the greatest sensitivity (93%) but poor specificity (13%). The combination of “isolated” AKP and moderate pain with stairs had poor sensitivity (9%) but the greatest specificity (97%) of strategies tested.
Conclusion
Commonly used questions purported to identify knees with PFJ structural damage do not identify this condition with great accuracy.
doi:10.3899/jrheum.131555
PMCID: PMC4182011  PMID: 24931959
OSTEOARTHRITIS; PAIN; MAGNETIC RESONANCE IMAGING
23.  Blood Pressure Trajectories in Early Adulthood and Subclinical Atherosclerosis in Middle Age 
Importance
Single measures of blood pressure (BP) levels are associated with the development of atherosclerosis; however, long-term patterns in BP and their impact on CVD risk are poorly characterized.
Objective
To identify common BP trajectories throughout early adulthood and to determine their association with presence of coronary artery calcification (CAC) during middle age.
Design
We used data from the CARDIA study from baseline in 1985-1986 through 25 years of follow-up (2010-2011).
Setting
Prospective cohort study
Participants
CARDIA participants were Black and White men and women aged 18-30 years at baseline.
Exposures
We examined systolic BP, diastolic BP, and mid-BP [calculated as (SBP+DBP)/2 and an important marker of CHD risk among younger populations] at baseline and years 2, 5, 7, 10, 15, 20, and 25. Latent mixture modeling was used to identify trajectories in SBP, DBP and mid-BP over time.
Main Outcome Measure
Coronary artery calcification greater than or equal to Agatston score of 100 Agatston units at year 25.
Results
Among 4,681 participants, we identified 5 distinct mid-BP trajectories: Low-Stable (22% [95% CI 19.9-23.7], n=987), Moderate-Stable (42% [40.3-44.3], n=2,085), Moderate-Increasing (12% [10.4-14.0], n=489), Elevated-Stable (19% [17.1-20.0], n=903) and Elevated-Increasing (5% [4.0-5.5], n=217). As compared to the Low-Stable group, trajectories with elevated BP levels had greater odds of having CAC >100. Adjusted odds ratios (95% CI) were 1.44 (0.83-2.49) for Moderate-Stable, 1.86 (0.91-3.82) for Moderate-Increasing, 2.28 (1.24-3.70) for Elevated-Stable, and 3.70 (1.66-8.20) for Elevated-Increasing groups. The adjusted prevalence of CAC ≥ 100 was 5.8% in the Low-Stable group. These ORs represent an absolute increase of 2.7%, 5%, 6.3% and 12.9% for the prevalence of CAC ≥100 for the Moderate-Stable, Moderate-Increasing, Elevated Stable and Elevated Increasing groups respectively as compared to the Low-Stable Group. Associations were not altered after adjustment for baseline and year 25 BP. Findings were similar for trajectories of isolated systolic BP trajectories, but were attenuated for diastolic BP trajectories.
Conclusions and Relevance
BP trajectories throughout young adulthood vary and higher BP trajectories were associated with an increased risk of CAC in middle age. Long-term trajectories in BP may assist in more accurate identification of individuals with subclinical atherosclerosis.
doi:10.1001/jama.2013.285122
PMCID: PMC4122296  PMID: 24496536
blood pressure; calcium; epidemiology; risk factors
24.  The Multicenter Osteoarthritis Study (MOST): Opportunities for Rehabilitation Research 
PM & R : the journal of injury, function, and rehabilitation  2013;5(8):10.1016/j.pmrj.2013.04.014.
The Multicenter Osteoarthritis Study (MOST) is a longitudinal observational study of the effects of biomechanical, bone and joint structural, and nutritional factors on the incidence and progression of knee symptoms and radiographic and symptomatic knee osteoarthritis (OA). It is the first large-scale epidemiologic study to focus on symptomatic knee OA in a community-based sample of adultswith or at high risk for knee OA, based on thepresence of knee symptoms, history of knee injury or surgery or being overweight. Beginning in 2003, 3026 individuals (60.1% women) age 50-79 years were enrolled. Examinations at baseline, and 15, 30, 60, 72 and 84 months later included assessment of risk factors, disease characteristics, body functions and structure, and measures of physical activity and participation. The wealth of data from this longitudinal cohort of community-dwelling older adults affords valuable opportunities for rehabilitation researchers.
doi:10.1016/j.pmrj.2013.04.014
PMCID: PMC3867287  PMID: 23953013
25.  Antral Follicle Count Predicts Natural Menopause in a Population-Based Sample: The CARDIA Women’s Study 
Menopause (New York, N.Y.)  2013;20(8):825-830.
Objective
The timing of menopause is associated with multiple chronic diseases. Tools to predict this milestone have relevance for clinical and research purposes. Among infertile women, a positive relationship exists between antral follicle count (AFC) and response to controlled ovarian hyperstimulation, a marker of ovarian reserve. However, a relationship between AFC and menopause that is age-independent has not been demonstrated. Thus, our objective was to evaluate the relationship between AFC measured in women at ages 34–49 and incident natural menopause over 7-years of follow-up.
Methods
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a longitudinal community-based study (Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California) begun in 1985–1986. In 2002–03, the CARDIA Women’s Study measured FSH levels and performed a transvaginal ultrasound protocol that included AFC (2mm–10mm follicles on both ovaries). Incident natural menopause was assessed by survey in 2005–06 and 2009–10.
Results
In our sample (n=456), median AFC and FSH were 5 (IQR 2–9) and 7.8 mIU/mL (IQR 5.6–11.0), respectively, at a mean age of 42 (range 34–49) in 2002–03. 101 women reported natural menopause by 2009–10. In Cox models, current smoking, stable menses, FSH>13, and AFC ≤4 were independently associated with incident natural menopause. Compared to AFC >4, those with AFC ≤4 were nearly twice as likely to have undergone menopause over 7-years of follow-up (HR 1.89, 95% CI 1.19–3.02) after adjustment for covariates.
Conclusion
AFC is independently associated with natural menopause over 7-years of follow-up after controlling for other markers of ovarian aging.
doi:10.1097/GME.0b013e31827f06c2
PMCID: PMC3675173  PMID: 23422869
Antral Follicle Count; Menopause; Ovarian Aging; Ovarian Reserve; FSH

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