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1.  Testing Departure from Additivity in Tukey’s Model using Shrinkage: Application to a Longitudinal Setting 
Statistics in medicine  2014;33(29):5177-5191.
While there has been extensive research developing gene-environment interaction (GEI) methods in case-control studies, little attention has been given to sparse and efficient modeling of GEI in longitudinal studies. In a two-way table for GEI with rows and columns as categorical variables, a conventional saturated interaction model involves estimation of a specific parameter for each cell, with constraints ensuring identifiability. The estimates are unbiased but are potentially inefficient because the number of parameters to be estimated can grow quickly with increasing categories of row/column factors. On the other hand, Tukey’s one degree of freedom (df) model for non-additivity treats the interaction term as a scaled product of row and column main effects. Due to the parsimonious form of interaction, the interaction estimate leads to enhanced efficiency and the corresponding test could lead to increased power. Unfortunately, Tukey’s model gives biased estimates and low power if the model is misspecified. When screening multiple GEIs where each genetic and environmental marker may exhibit a distinct interaction pattern, a robust estimator for interaction is important for GEI detection. We propose a shrinkage estimator for interaction effects that combines estimates from both Tukey’s and saturated interaction models and use the corresponding Wald test for testing interaction in a longitudinal setting. The proposed estimator is robust to misspecification of interaction structure. We illustrate the proposed methods using two longitudinal studies — the Normative Aging Study and the Multi-Ethnic Study of Atherosclerosis.
doi:10.1002/sim.6281
PMCID: PMC4227925  PMID: 25112650
adaptive shrinkage estimation; gene-environment interaction; longitudinal data; Tukey’s one df test for non-additivity
2.  Bone mineral density and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis, Abdominal Aortic Calcium Study 
Atherosclerosis  2009;209(1):283-289.
Context
Molecular and cell biology studies have demonstrated an association between bone and arterial wall disease, but the significance of a population-level association is less clear and potentially confounded by inability to account for shared risk factors.
Objective
To test population-level associations between atherosclerosis types and bone integrity.
Main Outcome Measures
Volumetric trabecular lumbar bone mineral density (vBMD), ankle-brachial index (ABI), intima-media thickness of the common carotid (CCA-IMT) and internal carotid (ICA-IMT) arteries, and carotid plaque echogenicity.
Design, Setting and Participants
A random subset of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed between 2002 and 2005.
Results
904 post-menopausal female (62.4 years; 62% non-white; 12% ABI<1; 17% CCA-IMT>1mm; 33% ICA-IMT>1mm) and 929 male (61.4 years; 58% non-white; 6% ABI<1; 25% CCA-IMT>1mm; 40% ICA-IMT>1mm) were included. In serial, sex-specific regression models adjusting for age, ethnicity, body mass index, dyslipidemia, hypertension, smoking, alcohol consumption, diabetes, homocysteine, interleukin-6, sex hormones, and renal function, lower vBMD was associated with lower ABI in men (p for trend <0.01) and greater ICA-IMT in men (p for trend <0.02). CCA-IMT was not associated with vBMD in men or women. Carotid plaque echogenicity was independently associated with lower vBMD in both men (trend p=0.01) and women (trend p<0.04). In all models, adjustment did not materially affect results.
Conclusions
Lower vBMD is independently associated with structural and functional measures of atherosclerosis in men and with more advanced and calcified carotid atherosclerotic plaques in both sexes.
doi:10.1016/j.atherosclerosis.2009.09.011
PMCID: PMC4254856  PMID: 19819456
3.  Null Association between Abdominal Muscle and Calcified Atherosclerosis in Community-Living Persons Without Clinical Cardiovascular Disease: the Multi-Ethnic Study of Atherosclerosis 
Metabolism: clinical and experimental  2013;62(11):10.1016/j.metabol.2013.06.001.
Objective
Detrimental effects of lean muscle loss have been hypothesized to explain J-shaped relationships of body mass index (BMI) with cardiovascular disease (CVD), yet associations of muscle mass with CVD are largely unknown. We hypothesized that low abdominal lean muscle area would be associated with greater calcified atherosclerosis, independent of other CVD risk factors.
Materials/Methods
We investigated 1020 participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinical CVD. Computed tomography (CT) scans at the 4th and 5th lumbar disk space were used to estimate abdominal lean muscle area. Chest and abdominal CT scans were used to assess coronary artery calcification(CAC), thoracic aortic calcification (TAC), and abdominal aortic calcification (AAC).
Results
The mean age was 64±10 years, 48% were female, and mean BMI was 28±5 kg/m2. In models adjusted for demographics, physical activity, caloric intake, and traditional CVD risk factors, there was no inverse association of abdominal muscle mass with CAC(Prevalence Ratio [PR] 1.02 [95% CI 0.95,1.10]), TAC (PR 1.13 [95%CI 0.92, 1.39]) or AAC (PR 0.99 [95%CI 0.94, 1.04]) prevalence. Similarly, there was no significant inverse relationship between abdominal lean muscle area and CAC, TAC, and AAC severity.
Conclusion
In community-living individuals without clinical CVD, greater abdominal lean muscle area is not associated with less calcified atherosclerosis.
doi:10.1016/j.metabol.2013.06.001
PMCID: PMC3740763  PMID: 23916063
Cardiovascular Disease; atherosclerosis; lean muscle
4.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. Urine creatinine is correlated with muscle mass, and low muscle mass is also associated with CVD. Whether low urine creatinine in the denominator of the ACR contributes to the association of ACR with CVD is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
6,770 community-living individuals without CVD.
Predictors
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Outcome
Incident CVD events.
Results
During a mean of 7.1 years’ follow-up, 281 CVD events occurred. Geometric means for spot urine creatinine, urine albumin and ACR were 95 ± 2 (SD) mg/dl, 0.7 ± 3.7 mg/dl and 7.0 ± 3.1 mg/g. Adjusted HRs per 2-fold higher increment in each urinary measures with CVD events were similar (1/UCr: 1.07 [95% CI, 0.94-1.22]; urine albumin: 1.08 [95% CI, 1.01-1.14]; and ACR: 1.11 [95% CI, 1.04-1.18]). Urine creatinine was lower in older, female, and low weight individuals. ACR ≥10 mg/g was more strongly associated with CVD events in individuals with low weight (HR for lowest vs. highest tertile: 4.34 vs. 1.97; p for interaction=0.006). Low weight also modified the association of urine albumin with CVD (p for interaction=0.06), but 1/urine creatinine did not (p for interaction=0.9).
Limitations
We lacked 24-hour urine data.
Conclusions
While ACR is more strongly associated with CVD events among persons with low body weight, this association is not driven by differences in spot urine creatinine. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin and less by urine creatinine.
doi:10.1053/j.ajkd.2013.05.010
PMCID: PMC3783582  PMID: 23830183
5.  The Association Between Physical Activity and Both Incident Coronary Artery Calcification and Ankle Brachial Index Progression: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2013;230(2):278-283.
Objective
Both coronary artery calcification (CAC) and the ankle brachial index (ABI) are measures of subclinical atherosclerotic disease. The influence of physical activity on the longitudinal change in these measures remains unclear. To assess this we examined the association between these measures and self-reported physical activity in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods
At baseline, the MESA participants were free of clinically evident cardiovascular disease. We included all participants with an ABI between 0.90 and 1.40 (n=5656). Predictor variables were based on self-reported measures with physical activity being assessed using the Typical Week Physical Activity Survey from which metabolic equivalent-minutes/week of activity were calculated. We focused on physical activity intensity, intentional exercise, sedentary behavior, and conditioning. Incident peripheral artery disease (PAD) was defined as the progression of ABI to values below 0.90 (given the baseline range of 0.90 to 1.40). Incident CAC was defined as a CAC score >0 Agatston units upon follow up with a baseline score of 0 Agatston units.
Results
Mean age was 61 years, 53% were female, and mean body mass index was 28 kg/m2. After adjusting for traditional cardiovascular risk factors and socioeconomic factors, intentional exercise was protective for incident peripheral artery disease (Relative Risk (RR)= 0.85, 95% Confidence Interval (CI): 0.74 to 0.98). After adjusting for traditional cardiovascular risk factors and socioeconomic factors, there was a significant association between vigorous PA and incident CAC (RR=0.97, 95% CI: 0.94 to 1.00). There was also a significant association between sedentary behavior and increased amount of CAC among participants with CAC at baseline (Δlog(Agatston Units +25)=0.027, 95% CI 0.002, 0.052).
Conclusions
These data suggest that there is an association between physical activity/sedentary behavior and the progression of two different measures of subclinical atherosclerotic disease.
doi:10.1016/j.atherosclerosis.2013.07.045
PMCID: PMC4085097  PMID: 24075757
Ankle Brachial Index; Coronary Artery Calcification; Physical Activity; Epidemiology; Prospective Cohort Study
6.  Association of Obesity and Kidney Function Decline among Non-Diabetic Adults with eGFR > 60 ml/min/1.73m2: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Obesity is associated with higher end-stage renal disease incidence, but associations with earlier forms of kidney disease remain incompletely characterized.
Methods
We studied the association of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with rapid kidney function decline and incident chronic kidney disease in 4573 non-diabetic adults with eGFR ≥ 60 ml/min/1.73m2 at baseline from longitudinal Multi-Ethnic Study of Atherosclerosis cohort. Kidney function was estimated by creatinine and cystatin C. Multivariate analysis was adjusted for age, race, baseline eGFR, and hypertension.
Results
Mean age was 60 years old, BMI 28 kg/m2, baseline eGFRCr 82 and eGFRCys 95 ml/min/1.73m2. Over 5 years of follow up, 25% experienced rapid decline in renal function by eGFRCr and 22% by eGFRCys. Incident chronic kidney disease (CKD) developed in 3.3% by eGFRCys, 11% by eGFRCr, and 2.4% by both makers. Compared to persons with BMI < 25, overweight (BMI 25 – 30) persons had the lowest risk of rapid decline by eGFRCr (0.84, 0.71 – 0.99). In contrast, higher BMI categories were associated with stepwise higher odds of rapid decline by eGFRCys, but remained significant only when BMI ≥ 35 kg/m2 (1.87, 1.41 – 2.48). Associations of BMI with incident CKD were insignificant after adjustment. Large WC and WHR were associated with increased risk of rapid decline only by eGFRCys, and of incident CKD only when defined by both filtration markers.
Conclusions
Obesity may be a risk factor for kidney function decline, but associations vary by filtration marker used.
PMCID: PMC4157691  PMID: 25210651
Kidney Function Decline; MESA; Obesity; Waist Circumference; Waist-to-Hip Ratio
7.  Abdominal Aortic Calcium, Coronary Artery Calcium, and Cardiovascular Morbidity and Mortality in the Multi-Ethnic Study of Atherosclerosis 
Objective
To evaluate the predictive value of abdominal aortic calcium (AAC) for incident cardiovascular disease (CVD) independent of coronary artery calcium (CAC).
Approach and Results
We evaluated the association of AAC with CVD in 1974 men and women aged 45 to 84 years randomly selected from the Multi-Ethnic Study of Atherosclerosis participants who had complete AAC and CAC data from computed tomographic scans. AAC and CAC were each divided into following 3 percentile categories: 0 to 50th, 51st to 75th, and 76th to 100th. During a mean of 5.5 years of follow-up, there were 50 hard coronary heart disease events, 83 hard CVD events, 30 fatal CVD events, and 105 total deaths. In multivariable-adjusted Cox models including both AAC and CAC, comparing the fourth quartile with the ≤50th percentile, AAC and CAC were each significantly and independently predictive of hard coronary heart disease and hard CVD, with hazard ratios ranging from 2.4 to 4.4. For CVD mortality, the hazard ratio was highly significant for the fourth quartile of AAC, 5.9 (P=0.01), whereas the association for the fourth quartile of CAC (hazard ratio, 2.1) was not significant. For total mortality, the fourth quartile hazard ratio for AAC was 2.7 (P=0.001), and for CAC, it was 1.9, P=0.04. Area under the receiver operating characteristic curve analyses showed improvement for both AAC and CAC separately, although improvement was greater with CAC for hard coronary heart disease and hard CVD, and greater with AAC for CVD mortality and total mortality. Sensitivity analyses defining AAC and CAC as continuous variables mirrored these results.
Conclusions
AAC and CAC predicted hard coronary heart disease and hard CVD events independent of one another. Only AAC was independently related to CVD mortality, and AAC showed a stronger association than CAC with total mortality.
doi:10.1161/ATVBAHA.114.303268
PMCID: PMC4153597  PMID: 24812323
aortic diseases; calcium; cardiovascular diseases; diagnostic imaging; epidemiology
8.  Association between higher levels of sexual function, activity, and satisfaction and self-rated successful aging in older postmenopausal women 
Objectives
To determine if measures of successful-aging are associated with sexual activity, satisfaction, and function in older post-menopausal women.
Design
Cross-sectional study using self-report surveys; analyses include chi-square and t-tests and multiple linear regression analyses.
Setting
Community-dwelling older post-menopausal women in the greater San Diego Region.
Participants
1,235 community-dwelling women aged 60-89 years participating at the San Diego site of the Women's Health Initiative.
Measurements
Demographics and self-report measures of sexual activity, function, and satisfaction and successful aging.
Results
Sexual activity and functioning (desire, arousal, vaginal tightness, use of lubricants, and ability to climax) were negatively associated with age, as were physical and mental health. In contrast, sexual satisfaction and self-rated successful aging and quality of life remained unchanged across age groups. Successful aging measures were positively associated with sexual measures, especially self-rated quality of life and sexual satisfaction.
Conclusions
Self-rated successful aging, quality of life, and sexual satisfaction appear to be stable in the face of declines in physical health, some cognitive abilities, and sexual activity and function and are positively associated with each other across ages 60-89 years.
doi:10.1111/j.1532-5415.2011.03495.x
PMCID: PMC4151627  PMID: 21797827
Sexual Activity; Sexual Satisfaction; Sexual Function; Post-menopausal Women; Self-Rated Successful aging
9.  Relation of Leptin to Left Ventricular Hypertrophy (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;112(5):726-730.
Increasing adiposity increases the risk for left ventricular hypertrophy. Adipokines are hormone-like substances from adipose tissue that influence several metabolic pathways relevant to LV hypertrophy. Data was from participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent magnetic resonance imaging of the heart and who also had fasting venous blood assayed for 4 distinct adipokines (adiponectin, leptin, tumor necrosis factor – alpha and resistin). 1,464 MESA participants had complete data. The mean age was 61.5 years, the mean body mass index was 27.6 kg/m2 and 49% were female. With adjustment for age, sex, race, height and weight, multivariable linear regression modeling revealed that a 1-SD increment in leptin was significantly associated with smaller LV mass (ß: −4.66 % predicted, p-value: < 0.01), LV volume (−5.87 % predicted, < 0.01), stroke volume (−3.23 ml, p < 0.01) and cardiac output (−120 mL/min, p = 0.01) as well as a lower odds ratio for the presence of LV hypertrophy (OR: 0.65, p < 0.01), but a higher ejection fraction (0.44%, p = 0.05). Additional adjustment for the traditional cardiovascular disease (CVD) risk factors, insulin resistance, physical activity, education, income, inflammatory biomarkers, other selected adipokines and pericardial fat did not materially change the magnitude or significance of the associations. The associations between the other adipokines and LV structure and function were inconsistent and largely non-significant. In conclusion, the results indicate that higher levels of leptin are associated with more favorable values of several measures of LV structure and function.
doi:10.1016/j.amjcard.2013.04.053
PMCID: PMC3745795  PMID: 23711806
leptin; left ventricle; hypertrophy; mass
10.  Changes in Physical Activity and Body Composition in Postmenopausal Women over Time 
Purpose
Higher physical activity (PA) has been associated with greater attenuation of body-fat gain and preservation of lean mass across the lifespan. These analyses aimed to determine relationships of change in PA to changes in fat and lean body mass in a longitudinal prospective study of postmenopausal women.
Methods
Among 11,491 women enrolled at three Women’s Health Initiative (WHI) clinical centers were selected to undergo dual-energy x-ray absorptiometry (DXA), 8,352 had baseline body composition measurements, with at least one repeated measure at yr 1, 3, and 6. PA data were obtained by self-report at baseline, 3 and 6 yr of follow-up. Time-varying PA impact on change in lean and fat mass during the six-yr study period for age groups (50–59y, 60–69y, 70–79y) was estimated using mixed effects linear regression.
Results
Baseline PA and body composition differed significantly among the three age groups. The association of change in fat mass from baseline and time-varying PA differed across the three age groups (p=0.0006). In women aged 50–59, gain in fat mass from baseline was attenuated with higher levels of physical activity. Women aged 70–79 lost fat mass at all PA levels. In contrast, change in lean mass from baseline and time-varying PA did not differ by age group (p=0.1935).
Conclusions
The association between PA and change in fat mass varies by age group, with younger, but not older, women benefitting from higher levels of aerobic PA. Higher levels of aerobic activity are not associated with changes in lean mass, which tends to decrease in older women regardless of activity level. Greater attention to resistance training exercises may be needed to prevent lean mass loss as women age.
doi:10.1249/MSS.0b013e31828af8bd
PMCID: PMC3715578  PMID: 23439422
lean mass changes; exercise; aging; women; sarcopenia
11.  Associations Between Nocturnal Blood Pressure Dipping and the Metabolic Syndrome in High- Vs. Low-Acculturated Mexican American Women 
American Journal of Hypertension  2013;26(8):1030-1036.
BACKGROUND
Less nocturnal blood pressure (BP) dipping has been associated with greater odds for the metabolic syndrome (MetS), a constellation of risk factors associated with cardiovascular disease (CVD). Little work has examined this association in Hispanics, who have elevated rates of MetS, or investigated differences in this relationship by level of acculturation. The purpose of this study was to examine the association between BP dipping and MetS in Hispanic women and to determine if this association is moderated by acculturation status.
METHODS
Two hundred eighty-six Mexican American women underwent assessment of MetS components (BP, waist circumference, fasting glucose, high-density lipoprotein cholesterol, and triglycerides) and completed a 36-hour ambulatory BP monitoring protocol, during which systolic BP (SBP) and diastolic BP readings were obtained. Nocturnal BP dipping was calculated as the percentage difference between average daytime and nighttime BP. Acculturation was defined by the language (Spanish, English) in which participants preferred to complete study instruments.
RESULTS
Although no significant main effects for BP dipping or acculturation emerged for MetS, the SBP dipping by acculturation interaction was significantly related to MetS (P < 0.01). Simple slope analyses revealed that less SBP dipping related to greater odds of MetS in high-acculturated women, but SBP dipping and MetS were unrelated in low-acculturated women.
CONCLUSIONS
The strength of the association between BP dipping and CVD risk (as measured by MetS) appears to vary by acculturation in Hispanic women. Future studies should explore mechanisms behind the BP dipping and CVD risk association and relevant modifying factors.
doi:10.1093/ajh/hpt061
PMCID: PMC3706207  PMID: 23645325
acculturation; blood pressure; blood pressure dipping; Hispanic; hypertension; metabolic syndrome.
12.  Electrocardiographic Repolarization‐Related Variables as Predictors of Coronary Heart Disease Death in the Women's Health Initiative Study 
Background
We evaluated 25 repolarization‐related ECG variables for the risk of coronary heart disease (CHD) death in 52 994 postmenopausal women from the Women's Health Initiative study.
Methods and Results
Hazard ratios from Cox regression were computed for subgroups of women with and without cardiovascular disease (CVD). During the average follow‐up of 16.9 years, 941 CHD deaths occurred. Based on electrophysiological considerations, 2 sets of ECG variables with low correlations were considered as candidates for independent predictors of CHD death: Set 1, Ѳ(Tp|Tref), the spatial angle between T peak (Tp) and normal T reference (Tref) vectors; Ѳ(Tinit|Tterm), the angle between the initial and terminal T vectors; STJ depression in V6 and rate‐adjusted QTp interval (QTpa); and Set 2, TaVR and TV1 amplitudes, heart rate, and QRS duration. Strong independent predictors with over 2‐fold increased risk for CHD death in women with and without CVD were Ѳ(Tp|Tref) >42° from Set 1 and TaVR amplitude >−100 μV from Set 2. The risk for these CHD death predictors remained significant after multivariable adjustment for demographic/clinical factors. Other significant predictors for CHD death in fully adjusted risk models were Ѳ(Tinit|Tterm) >30°, TV1 >175 μV, and QRS duration >100 ms.
Conclusions
Ѳ(Tp|Tref) angle and TaVR amplitude are associated with CHD mortality in postmenopausal women. The use of these measures to identify high‐risk women for further diagnostic evaluation or more intense preventive intervention warrants further study.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.
doi:10.1161/JAHA.114.001005
PMCID: PMC4310391  PMID: 25074699
coronary heart disease; electrocardiography; mortality; repolarization; risk factors
13.  Thoracic Aortic Calcification and Coronary Heart Disease Events: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;215(1):196-202.
Background
The presence and extent of coronary artery calcium (CAC) is an independent predictor of coronary heart disease (CHD) morbidity and mortality. Few studies have evaluated interactions or independent incremental risk for coronary and thoracic aortic calcification (TAC). The independent predictive value of TAC for CHD events is not well-established.
Methods
This study used risk factor and computed tomography scan data from 6,807 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Using the same images for each participant, TAC and CAC were each computed using the Agatston method. The study subjects were free of incident CHD at entry into the study.
Results
The mean age of the study population (n=6807) was 62±10 years (47% males). At baseline, the prevalence of TAC and CAC was 28 % (1,904/6,809) and 50% (3393/6809), respectively. Over 4.5±0.9 years, a total of 232 participants (3.41%) had CHD events, of which 132 (1.94%) had a hard event (myocardial infarction, resuscitated cardiac arrest, or CHD death). There was a significant interaction between gender and TAC for CHD events (p<0.05). Specifically, in women, the risk of all CHD event was nearly 3-fold greater among those with any TAC (hazard ratio: 3.04, 95% CI; 1.60–5.76). After further adjustment for increasing CAC score, this risk was attenuated but remained robust (HR: 2.15, 95% CI: 1.10–4.17). Conversely, there was no significant association between TAC and incident CHD in men. In women, the likelihood ratio chi square statistics indicate that the addition of TAC contributed significantly to predicting incident CHD event above that provided by traditional risk factors alone (chi square= 12.44, p=0.0004) as well as risk factors + CAC scores (chi square= 5.33, p=0.02) . On the other hand, addition of TAC only contributed in the prediction of hard CHD events to traditional risk factors (chi-square=4.33, p=0.04) in women, without contributing to the model containing both risk factors and CAC scores (chi square=1.55, p=0.21).
Conclusion
Our study indicates that TAC is a significant predictor of future coronary events only in women, independent of CAC. On studies obtained for either cardiac or lung applications, determination of TAC may provide modest supplementary prognostic information in women with no extra cost or radiation.
doi:10.1016/j.atherosclerosis.2010.11.017
PMCID: PMC4110678  PMID: 21227418
atherosclerosis; cardiac CT; coronary calcium; multi-detector CT; prognosis; thoracic atherosclerosis
14.  Prevalence of and Risk Factors for Subclinical Cardiovascular Disease in Selected US Hispanic Ethnic Groups 
American journal of epidemiology  2008;167(8):962-969.
In this study, the authors determined the prevalence and extent of cardiovascular disease (CVD) risk factors and subclinical CVD in four US Hispanic subgroups, as well as associations between the CVD risk factors and subclinical CVD in these groups. Participants were 1,437 Hispanic men and women enrolled in the Multi-Ethnic Study of Atherosclerosis in 2000–2002. Fifty-six percent were Mexican-American, 12% were Dominican-American, 14% were Puerto Rican-American, and 18% were Other Hispanic-American. All participants underwent clinical examinations for coronary artery calcium, thoracic aortic calcium, carotid intimal-medial thickness, ankle-brachial index, left ventricular mass, and left ventricular size. Mexican Americans had the highest levels of coronary artery calcium, thoracic aortic calcium, and carotid intimal-medial thickness, while Puerto Rican Americans had the highest prevalence of an ankle-brachial index less than 1.0 and levels of left ventricular mass. The magnitudes of the associations between coronary artery calcium and age, sex, and body mass index were similar across all Hispanic subgroups. However, there were differences in the magnitude and significance of the associations between coronary artery calcium and hypertension, hypercholesterolemia, and cigarette smoking among the different Hispanic subgroups. This finding was also present for the other subclinical CVD measures. These results suggest a differential relationship between risk factors and either prevalence or extent of subclinical disease by Hispanic subgroup.
doi:10.1093/aje/kwm402
PMCID: PMC4107279  PMID: 18283034
atherosclerosis; cardiovascular diseases; ethnic groups; Hispanic Americans; risk factors
15.  The Association of Bone Density and Calcified Atherosclerosis is Stronger in Women Without Dyslipidemia: The Multi-Ethnic Study of Atherosclerosis 
We tested whether the association between bone mineral density (BMD) and coronary artery calcification (CAC) varies according to dyslipidemia in community-living individuals. Between 2002 and 2005, 305 women and 631 men (mean age of 64 years) and naïve to lipid-modifying medications and estrogen use were assessed for spine BMD, CAC, and total (TC), HDL- and LDL-cholesterol and triglycerides.
Participants
Random sample of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) without clinical cardiovascular disease.
Predictor variable
Spine BMD at the L3 vertebrate by computer tomography (CT).
Main outcome
CAC prevalence by CT.
Effect Modifier
Total cholesterol to HDL ratio (TC:HDL) ≥ 5.0.
Results
The association of BMD with CAC differed in women with TC:HDL < 5.0 vs. higher (p-interaction =0.01). In age and race adjusted models, among women with TC:HDL < 5.0, each SD (43.4 mg/cc) greater BMD was associated with a 25% lower prevalence of CAC (Prevalence Ratio [PR] 0.75, 95% confidence interval [CI] 0.63–0.89), whereas among women with higher TC:HDL, higher BMD was not significantly associated with CAC (PR 1.22, 95% CI 0.82–1.82). Results were similar using other definitions of hyperlipidemia. In contrast, no consistent association was observed between BMD and CAC in men irrespective of the TC:HDL ratio (p interaction 0.54).
Conclusion
The inverse association of BMD with CAC is stronger in women without dyslipidemia. These data argue against the hypothesis that dyslipidemia is the key factor responsible for the inverse association of BMD with atherosclerosis.
doi:10.1002/jbmr.469
PMCID: PMC4100475  PMID: 21834088
16.  Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events 
Importance
Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD.
Objective
To determine the independent associations of CAC volume and CAC density with incident CVD events.
Design, Setting, and Participants
Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010.
Main Outcomes and Measures
Incident coronary heart disease (CHD) and all CVD events
Results
During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 5.5 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 8.2 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02.
Conclusions and Relevance
CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.
doi:10.1001/jama.2013.282535
PMCID: PMC4091626  PMID: 24247483
17.  Intraindividual variability of C-reactive protein: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2012;224(1):274-279.
Background
The intraindividual variability of C-reactive protein (CRP) remains uncertain. Although guidelines suggest stability of serial CRP values comparable to that of cholesterol measures, several studies indicate greater fluctuations of CRP. We sought to compare the intraindividual variability of CRP with that of cholesterol measures using the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods
CRP measurements were available in 760 MESA participants after exclusion of those with comorbidities or medications known to affect CRP or CRP≥10 mg/L. Serial values were available for 255 participants. The intraclass correlation coefficient (ICC) was quantified for CRP, total cholesterol (TC), and non-HDL-cholesterol (non-HDL-C) as the ratio of between-subject variance to the sum of between-subject and within-subject variance. Fluctuation between baseline and follow-up categories was calculated by cross-classifying participants according to baseline tertiles.
Results
The multivariable-adjusted ICC of CRP was 0.62 (95% CI, 0.55–0.68), significantly lower than that of TC (0.75; 95% CI, 0.70–0.81; p=0.001 vs CRP) and non-HDL-C (0.76; 95% CI, 0.71–0.81; p=0.001 vs CRP). 51% of participants in the highest baseline CRP tertile had discordant values on follow-up, while 54% and 27% were discordant in the middle and lowest baseline CRP tertiles. Among participants with baseline CRP levels exceeding 3 mg/L, a clinical threshold for higher risk, 69% had subsequent measurements falling within a lower risk category.
Conclusions
In the MESA cohort, intraindividual variation of CRP was significantly greater than that for cholesterol measures. Our results suggest that further evaluation of CRP variability is needed in large prospective studies using shorter intervals between measurements.
doi:10.1016/j.atherosclerosis.2012.07.017
PMCID: PMC4085141  PMID: 22846611
18.  ADIPOKINES ARE ASSOCIATED WITH LOWER EXTREMITY VENOUS DISEASE: THE SAN DIEGO POPULATION STUDY 
Background
Obesity is a risk factor for venous disease. We tested the associations between adipokines and the presence and severity of venous disease.
Methods
Participants for this analysis were drawn from a cohort of 2,408 employees and retirees of a university in San Diego who were examined for venous disease using duplex ultrasonography. From this cohort, a case-control study sample of all 352 subjects with venous disease and 352 age-, sex- and race-matched subjects without venous disease were included in this analysis. All subjects completed health history questionnaires, had a physical examination with anthropometric measurements and venous blood analyzed for adipokines.
Results
After adjustment for age, sex and race, those with venous disease had significantly higher levels of body mass index (BMI), leptin and interleukin-6. Levels of resistin and tumor necrosis factor-alpha were also higher but of borderline significance (0.05 < p < 0.10). Compared to the lowest tertile and with adjustment for age, sex, race and BMI, the 2nd and 3rd tertiles of resistin (Odds Ratios: 1.9 & 1.7 respectively), leptin (1.7 & 1.7) and tumor necrosis factor-alpha (1.4 & 1.7) were associated with increasing severity of venous disease. Conversely, a 5 kg/m2 increment in BMI was associated with an increased odds (1.5) for venous disease, which was independent of the adipokines included in this study.
Conclusions
Both obesity and adipokines are significantly associated with venous disease. These associations appear to be independent of each other suggesting potentially different pathways to venous disease.
doi:10.1111/j.1538-7836.2010.03941.x
PMCID: PMC4078899  PMID: 20546124
19.  Sleep, Type 2 Diabetes, Dyslipidemia, and Hypertension in Elderly Alzheimer’s Caregivers 
Research indicates that very short or long durations of sleep and inefficient sleep, are associated with higher total cholesterol and risk of type 2 diabetes and hypertension. This study tested the hypothesis that inefficient sleep or short/long sleep durations are associated with an elevated prevalence of type 2 diabetes, dyslipidemia, and hypertension in a community-dwelling sample of elderly Alzheimer’s caregivers. Participants were 126 caregivers for spouses with Alzheimer’s disease who underwent in-home sleep assessment by wrist actigraphy for 72 consecutive hours. Sleep data were averaged across the 3 days/nights; nighttime sleep and daytime napping were computed. Morning fasting blood samples were collected to determine measures of blood lipids and glucose. The average of three resting blood pressure measurements was used to estimate mean resting blood pressure. Logistic regression models including covariates related to sleep and metabolic regulation indicated that nighttime sleep duration, percent sleep at night, and daytime naps were not significantly associated with odds of having diabetes (OR, 0.92; 95%CI, 0.56–1.53; OR, 0.93; 95%CI, 0.83–1.03; OR, 1.75; 95%CI, 0.74–4.11, respectively), dyslipidemia (OR, 0.83; 95%CI, 0.57–1.20; OR, 0.99; 95%CI, 0.92–1.07; OR, 0.64; 95%CI: 0.33–1.24, respectively), or hypertension (OR, 0.97; 95%CI, 0.62–1.52; OR, 1.02; 95%CI, 0.93–1.11; OR, 1.10; 95%CI, 0.44–2.74, respectively). When categorical and combined sleep parameters were examined, there were no significant associations with any of the metabolic conditions (all p>0.05). The current study suggests that in an elderly sample of Alzheimer’s caregivers, nighttime sleep duration, nighttime sleep efficiency and daytime naps are not significantly associated with prevalent type 2 diabetes, dyslipidemia, or hypertension. As several of the associations demonstrated clinically relevant magnitudes of the associations, larger studies to more fully test these hypotheses are warranted.
doi:10.1016/j.archger.2013.02.008
PMCID: PMC3696346  PMID: 23522093
Sleep; type 2 diabetes; hypertension; dyslipidemia; caregivers
20.  Prevalence and Risk Factors for Hypertension in Hemophilia 
Hypertension  2013;62(1):10.1161/HYPERTENSIONAHA.113.01174.
Hypertension is a major risk factor for intracranial hemorrhage. We therefore investigated the prevalence, treatment and control of hypertension in adult patients with hemophilia (PWH). PWH ≥18 years (n=458) from 3 geographically different cohorts in the United States were evaluated retrospectively for hypertension and risk factors. Results were compared to the nationally representative sample provided by the contemporary National Health and Nutrition Examination Survey (NHANES). PWH had a significantly higher prevalence of hypertension compared to NHANES. Overall, the prevalence of hypertension was 49.1% in PWH compared to 31.7 % in NHANES. At ages 18–44, 45–64, 65–74, and ≥ 75 the prevalence of hypertension for PWH was 31.8%, 72.6%, 89.7%, and 100.0% compared to 12.5%, 41.2%, 64.1%, and 71.7% in NHANES, respectively. Of treated hypertensive PWH, only 27.1% were controlled, compared to 47.7% in NHANES (all p-values <0.05). Age, body mass index, diabetes and renal function were independently associated with hypertension. Among patients with moderate or severe hemophilia there was a trend (~ 1.5-fold) for higher odds of having hypertension compared to patients with mild hemophilia. Based on these results, new care models for adult PWH and further studies for the etiology of hypertension in hemophilia are recommended.
doi:10.1161/HYPERTENSIONAHA.113.01174
PMCID: PMC3850775  PMID: 23630949
Hypertension; Blood Pressure; Hemophilia; cardiovascular disease risk factors; prevalence; NHANES
21.  Genetic ancestry and lower extremity peripheral artery disease in the Multi-Ethnic Study of Atherosclerosis 
Using self-report of race/ethnicity, African Americans consistently have a higher prevalence of peripheral artery disease (PAD) compared to other ethnic groups. We aimed to determine the associations between estimated genetic admixture and PAD among African and Hispanic Americans. We studied the association between genetic ancestry and PAD among 1417 African and Hispanic American participants in the Multi-Ethnic Study of Atherosclerosis who were genotyped for ancestry informative markers (AIMs). PAD was defined as an ankle–brachial index (ABI) < 0.90. The overall prevalence of PAD among the 712 self-identified African American subjects was 15.2% and 4.6% among the 705 self-identified Hispanic Americans. A one standard deviation increment in European ancestry was associated with non-significant reductions in the odds for PAD among African (OR: 0.96 [95% CI: 0.78–1.18]) and Hispanic Americans (0.84 [0.58–1.23]), while the same increment in Native American ancestry was significantly associated with a lower odds of PAD in Hispanic Americans (0.56 [0.36–0.96]). Adjustment for demographic variables, field center, cardiovascular disease (CVD) risk factors and inflammatory markers strengthened the odds for European ancestry among African (0.85 [0.66–1.10]) and Hispanic Americans (0.68 [0.41–1.11]). The magnitude of the association for Native American ancestry among Hispanic Americans did not materially change (0.56 [0.29–1.09]). In conclusion, a higher percent Native American ancestry in Hispanics is associated with a lower odds of PAD while in both Hispanics and African Americans, greater European ancestry does not appear to be associated with lower odds for PAD.
doi:10.1177/1358863X10375586
PMCID: PMC4077267  PMID: 20926494
epidemiology; genetics; peripheral artery disease
22.  The Relationship of Sedentary Behavior and Physical Activity to Incident Cardiovascular Disease: Results from the Women’s Health Initiative 
Objectives
The aim was to examine the independent and joint associations of sitting time and physical activity with risk of incident cardiovascular disease (CVD).
Background
Sedentary behavior is recognized as a distinct construct beyond lack of leisure-time physical activity, but limited data exists on the interrelationship between these two components of energy balance.
Methods
Participants in the prospective Women’s Health Initiative Observational Study (N = 71,018), aged 50–79 and free of CVD at baseline (1993–1998), provided information on sedentary behavior, defined as hours of sitting per day, and usual physical activity at baseline and during follow-up through September 2010. First CVD (coronary heart disease or stroke) events were centrally adjudicated.
Results
Sitting ≥ 10 hours/day compared to ≤ 5 hours/day was associated with increased CVD risk (HR=1.18, 95% CI 1.09, 1.29) in multivariable models including physical activity. Low physical activity was also associated with higher CVD risk (P, trend <0.001). When women were cross-classified by sitting time and physical activity (P, interaction = 0.94), CVD risk was highest in inactive women (≤1.7 MET-hrs/week) who also reported ≥10 hrs/day of sitting. Results were similar for CHD and stroke when examined separately. Associations between prolonged sitting and risk of CVD were stronger in overweight versus normal weight women and women aged 70 years and older compared to younger women.
Conclusions
Prolonged sitting time was associated with increased CVD risk, independent of leisure-time physical activity, in postmenopausal women without a history of CVD. A combination of low physical activity and prolonged sitting augments CVD risk.
doi:10.1016/j.jacc.2013.03.031
PMCID: PMC3676694  PMID: 23583242
cardiovascular disease; women; physical activity; sedentary behavior
24.  Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density 
The Journal of Clinical Investigation  2014;124(6):2736-2749.
Patient bone mineral density (BMD) predicts the likelihood of osteoporotic fracture. While substantial progress has been made toward elucidating the genetic determinants of BMD, our understanding of the factors involved remains incomplete. Here, using a systems genetics approach in the mouse, we predicted that bicaudal C homolog 1 (Bicc1), which encodes an RNA-binding protein, is responsible for a BMD quantitative trait locus (QTL) located on murine chromosome 10. Consistent with this prediction, mice heterozygous for a null allele of Bicc1 had low BMD. We used a coexpression network–based approach to determine how Bicc1 influences BMD. Based on this analysis, we inferred that Bicc1 was involved in osteoblast differentiation and that polycystic kidney disease 2 (Pkd2) was a downstream target of Bicc1. Knock down of Bicc1 and Pkd2 impaired osteoblastogenesis, and Bicc1 deficiency–dependent osteoblast defects were rescued by Pkd2 overexpression. Last, in 2 human BMD genome-wide association (GWAS) meta-analyses, we identified SNPs in BICC1 and PKD2 that were associated with BMD. These results, in both mice and humans, identify Bicc1 as a genetic determinant of osteoblastogenesis and BMD and suggest that it does so by regulating Pkd2 transcript levels.
doi:10.1172/JCI73072
PMCID: PMC4038574  PMID: 24789909
25.  Improvement in Stroke Risk Prediction: Role of c-reactive protein (CRP) and Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) in the Women’s Health Initiative 
Background and Purpose
Classification of risk of ischemic stroke is important for medical care and public health reasons. Whether addition of biomarkers adds to predictive power of the Framingham Stroke Risk or other traditional risk factors has not been studied in older women.
Methods
The Hormones and Biomarkers Predicting Stroke (HaBPS) Study is a case-control study of blood biomarkers assayed in 972 ischemic stroke cases and 972 controls, nested in the Women’s Health Initiative Observational Study of 93,676 postmenopausal women followed for an average of 8 years. We evaluated additive predictive value of two commercially available biomarkers: c-reactive protein (CRP) and Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) to determine if they added to risk prediction by the Framingham Stroke Risk Score (FSRS) or by traditional risk factors (TRF) which included lipids and other variables not included in the FSRS. As measures of additive predictive value, we used the c-statistic, Net Reclassification Improvement (NRI), category-less NRI, and Integrated Discrimination Improvement Index (IDI).
Results
Addition of CRP to Framingham risk models or additional traditional risk factors overall modestly improved prediction of ischemic stroke and resulted in overall NRI of 6.3%, (case NRI=3.9%, control NRI=2.4%) .In particular, hs-CRP was useful in prediction of cardioembolic strokes (NRI=12.0%; 95%CI: 4.3-19.6%) and in strokes occurring in less than 3 years (NRI=7.9%, 95%CI: 0.8-14.9%). Lp-PLA2 was useful in risk prediction of large artery strokes (NRI=19.8%, 95%CI: 7.4 -32.1%) and in early strokes (NRI=5.8%, 95%CI: 0.4-11.2%).
Conclusions
CRP and Lp-PLA2 can improve prediction of certain subtypes of ischemic stroke in older women, over the Framingham stroke risk model and traditional risk factors, and may help to guide surveillance and treatment of women at risk.
doi:10.1111/j.1747-4949.2012.00860.x
PMCID: PMC3556354  PMID: 23088183

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