Genome-wide DNA methylation association study of recent and cumulative marijuana use in middle aged adults.

Marijuana is a widely used psychoactive substance in the US and medical and recreational legalization has risen over the past decade. Despite the growing number of individuals using marijuana, studies investigating the association between epigenetic factors and recent and cumulative marijuana use remain limited. We therefore investigated the association between recent and cumulative marijuana use and DNA methylation levels. Participants from the Coronary Artery Risk Development in Young Adults Study with whole blood collected at examination years (Y) 15 and Y20 were randomly selected to undergo DNA methylation profiling at both timepoints using the Illumina MethylationEPIC BeadChip. Recent use of marijuana was queried at each examination and used to estimate cumulative marijuana use from Y0 to Y15 and Y20. At Y15 (n = 1023), we observed 22 and 31 methylation markers associated (FDR P ≤ 0.05) with recent and cumulative marijuana use and 132 and 16 methylation markers at Y20 (n = 883), respectively. We replicated 8 previously reported methylation markers associated with marijuana use. We further identified 640 cis-meQTLs and 198 DMRs associated with recent and cumulative use at Y15 and Y20. Differentially methylated genes were statistically overrepresented in pathways relating to cellular proliferation, hormone signaling, and infections as well as schizophrenia, bipolar disorder, and substance-related disorders. We identified numerous methylation markers, pathways, and diseases associated with recent and cumulative marijuana use in middle-aged adults, providing additional insight into the association between marijuana use and the epigenome. These results provide novel insights into the role marijuana has on the epigenome and related health conditions.

Characterizing the spectrum of bladder health and lower urinary tract symptoms among men: Results from the CARDIA study.

OBJECTIVES: To operationalize a new definition for bladder health, we examined the distribution and impact of lower urinary tract symptoms (LUTS), along with risk factors, among men in the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: LUTS were defined by American Urologic Association Symptom Index (AUASI) scores and impact on quality of life (QoL). Separate questions assessed urinary incontinence (UI) and postvoid dribbling. We performed cluster analyses using AUASI scores, with and without urine incontinence and postvoid dribbling, and impact collected in 2010-11. We performed analyses to evaluate sociodemographic and cardiovascular risk factors between clusters. RESULTS: Among CARDIA men (mean age: 50.0, SD = 3.6; range: 42-56 years) with complete LUTS data (n = 929), we identified and compared four clusters: men who reported no or very mild symptoms and no impact on well-being (bladder health, n = 696, 75%), men with moderate symptoms and moderate impact on well-being (moderate symptoms/impact, n = 84, 9%), men with high symptoms and high impact on well-being (severe symptoms/impact, n = 117, 13%), and a separate group that reported moderate symptoms and UI with a high impact on well-being (UI + moderate symptoms/severe impact, n = 32, 3%). Exploration of the groupings showed a large percentage of postvoid dribbling across groups (overall 69%). Sociodemographic and cardiovascular risk factors were not associated with symptom/impact groups. CONCLUSIONS: Bladder health clustered into four categories. A majority of middle-aged men in the community showed no or mild bladder symptoms without impact on QoL. Postvoid dribbling is pervasive but did not cluster with a specific LUTS or impact category.

Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study.

BACKGROUND: Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD. METHODS: In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events. RESULTS: We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A, ABCG1, and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1, SOCS3, and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P=1.22E-05). CONCLUSIONS: Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.

Dynamic relationships between depressive symptoms and insulin resistance over 20 years of adulthood.

BACKGROUND: Bidirectional longitudinal relationships between depression and diabetes have been observed, but the dominant direction of their temporal relationships remains controversial. METHODS: The random-intercept cross-lagged panel model decomposes observed variables into a latent intercept representing the traits, and occasion-specific latent 'state' variables. This permits correlations to be assessed between the traits, while longitudinal 'cross-lagged' associations and cross-sectional correlations can be assessed between occasion-specific latent variables. We examined dynamic relationships between depressive symptoms and insulin resistance across five visits over 20 years of adulthood in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Possible differences based on population group (Black v. White participants), sex and years of education were tested. Depressive symptoms and insulin resistance were quantified using the Center for Epidemiologic Studies Depression (CES-D) scale and the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. RESULTS: Among 4044 participants (baseline mean age 34.9 ± 3.7 years, 53% women, 51% Black participants), HOMA-IR and CES-D traits were weakly correlated (r = 0.081, p = 0.002). Some occasion-specific correlations, but no cross-lagged associations were observed overall. Longitudinal dynamics of these relationships differed by population groups such that HOMA-IR at age 50 was associated with CES-D score at age 55 (ß = 0.076, p = 0.038) in White participants only. Longitudinal dynamics were consistent between sexes and based on education. CONCLUSIONS: The relationship between depressive symptoms and insulin resistance was best characterized by weak correlations between occasion-specific states and enduring traits, with weak evidence that insulin resistance might be temporally associated with subsequent depressive symptoms among White participants later in adulthood.

Epigenetic Age Acceleration Reflects Long-Term Cardiovascular Health.

[Figure: see text].

Multivariate longitudinal data for survival analysis of cardiovascular event prediction in young adults: insights from a comparative explainable study.

BACKGROUND: Multivariate longitudinal data are under-utilized for survival analysis compared to cross-sectional data (CS - data collected once across cohort). Particularly in cardiovascular risk prediction, despite available methods of longitudinal data analysis, the value of longitudinal information has not been established in terms of improved predictive accuracy and clinical applicability. METHODS: We investigated the value of longitudinal data over and above the use of cross-sectional data via 6 distinct modeling strategies from statistics, machine learning, and deep learning that incorporate repeated measures for survival analysis of the time-to-cardiovascular event in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. We then examined and compared the use of model-specific interpretability methods (Random Survival Forest Variable Importance) and model-agnostic methods (SHapley Additive exPlanation (SHAP) and Temporal Importance Model Explanation (TIME)) in cardiovascular risk prediction using the top-performing models. RESULTS: In a cohort of 3539 participants, longitudinal information from 35 variables that were repeatedly collected in 6 exam visits over 15 years improved subsequent long-term (17 years after) risk prediction by up to 8.3% in C-index compared to using baseline data (0.78 vs. 0.72), and up to approximately 4% compared to using the last observed CS data (0.75). Time-varying AUC was also higher in models using longitudinal data (0.86-0.87 at 5 years, 0.79-0.81 at 10 years) than using baseline or last observed CS data (0.80-0.86 at 5 years, 0.73-0.77 at 10 years). Comparative model interpretability analysis revealed the impact of longitudinal variables on model prediction on both the individual and global scales among different modeling strategies, as well as identifying the best time windows and best timing within that window for event prediction. The best strategy to incorporate longitudinal data for accuracy was time series massive feature extraction, and the easiest interpretable strategy was trajectory clustering. CONCLUSION: Our analysis demonstrates the added value of longitudinal data in predictive accuracy and epidemiological utility in cardiovascular risk survival analysis in young adults via a unified, scalable framework that compares model performance and explainability. The framework can be extended to a larger number of variables and other longitudinal modeling methods. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00005130, Registration Date: 26/05/2000.

More appendicular lean mass relative to body mass index is associated with lower incident diabetes in middle-aged adults in the CARDIA study.

BACKGROUND AND AIMS: Although lower lean mass is associated with greater diabetes prevalence in cross-sectional studies, prospective data specifically in middle-aged Black and White adults are lacking. Relative appendicular lean mass (ALM), such as ALM adjusted for body mass index (BMI), is important to consider since muscle mass is associated with overall body size. We investigated whether ALM/BMI is associated with incident type 2 diabetes in the Coronary Artery Risk Development in Young Adults study. METHODS AND RESULTS: 1893 middle-aged adults (55% women) were included. ALM was measured by DXA in 2005-06. Incident type 2 diabetes was defined in 2010-11 or 2015-16 as fasting glucose ≥7 mmol/L (126 mg/dL), 2-h glucose on OGTT ≥11.1 mmol/L (200 mg/dL) (2010-11 only), HbA1C ≥48 mmol/mol (6.5%) (2010-11 only), or glucose-lowering medications. Cox regression models with sex stratification were performed. In men and women, ALM/BMI was 1.07 ± 0.14 (mean ± SD) and 0.73 ± 0.12, respectively. Seventy men (8.2%) and 71 women (6.8%) developed type 2 diabetes. Per sex-specific SD higher ALM/BMI, unadjusted diabetes risk was lower by 21% in men [HR 0.79 (0.62-0.99), p = 0.04] and 29% in women [HR 0.71 (0.55-0.91), p = 0.008]. After adjusting for age, race, smoking, education, physical activity, and waist circumference, the association was no longer significant. Adjustment for waist circumference accounted for the attenuation in men. CONCLUSION: Although more appendicular lean mass relative to BMI is associated with lower incident type 2 diabetes in middle-aged men and women over 10 years, its effect may be through other metabolic risk factors such as waist circumference, which is a correlate of abdominal fat mass.

Factors associated with self-report of polycystic ovary syndrome in the Coronary Artery Risk Development in Young Adults study (CARDIA).

BACKGROUND: Polycystic ovary syndrome (PCOS) is underdiagnosed, but factors associated with women's report of diagnosis are not well-understood, particularly social determinants of health. Therefore, in a population-based cohort, we compared the characteristics of women with self-reported PCOS vs. women who have unrecognized PCOS vs. women without PCOS. METHODS: We performed a secondary data analysis of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a population-based, prospective cohort of Black and White women. Participants were women (n = 2028) who responded to the question, "Did a doctor or nurse ever tell you that you had polycystic ovarian syndrome or polycystic ovarian disease?" at the year 15 examination. Women who answered "yes" were defined as having self-reported PCOS. Women who answered "no or not sure" were defined as having unrecognized PCOS if they also had irregular menses and hyperandrogenemia between 20 and 30 years of age. Exposures of interest included social determinants of health, symptoms including irregular menses and hirsutism, and comorbid conditions. RESULTS: Forty-three (2.1%) of women had self-reported PCOS, 135 (6.7%) had unrecognized PCOS, and 1850 (91%) women were without PCOS. In logistic regression models adjusting for age, race, and center, women with self-reported PCOS were more likely to have obesity (OR 1.83, 95% CI 1.22, 2.75) and diabetes (OR 2.37, 95% CI 1.05, 5.33) compared to women without PCOS. Women with unrecognized PCOS were more likely to have hypertension (OR 1.68, 95% CI 1.03, 2.74) and food insecurity (OR 1.94, 95% CI 1.25, 3.01) compared to women without PCOS. CONCLUSIONS: Unrecognized PCOS is common. Self-report of PCOS is not associated with access to healthcare. Women who report PCOS are more often obese and comorbidities may contribute to recognition of PCOS.

Depressive Symptom Subgroups and Their Association with Prevalent and Incident Cardiovascular Risk Factors in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

BACKGROUND: We sought to identify depressive symptom subgroups in a community sample of young adults, investigate their stability over time, and determine their association with prevalent and incident cardiovascular disease (CVD) risk factors. METHOD: Participants were 3377 adults from the Coronary Artery Risk Development in Young Adults study. Using latent class and latent transition analysis, we derived subgroups based on items of the 20-item version of the Center for Epidemiologic Studies Depression Scale in 1990, and examined patterns of change over a 10-year period (1990-2000). Cox regression models were used to examine associations between subgroup membership and prevalent (2000) and incident (2000 to 2016) obesity, hypertension, and diabetes. RESULTS: Three baseline subgroups were identified and labeled: "No Symptoms" (63.5%), "Lack of Positive Affect" (PA, 25.6%), and "Depressed Mood" (10.9%). At 10-year follow-up, individuals in "No Symptoms" subgroup had the highest probability (0.84) of being classified within the same subgroup. Participants classified as "Lack of PA" were likely (0.46) to remain in the same subgroup or be classified as "No Symptoms." Participants in the "Depressed Mood" were most likely to transition to the "Lack of PA" subgroup (0.38). Overall, 30.5% of participants transitioned between subgroups, with 11.4% classified as "Worsening" and 19.1% as "Improving." Relative to the "No Symptoms Stable," other subgroups ("Depressed Stable," "Worsening," and "Improving") were associated with prevalent obesity and hypertension. CONCLUSION: We identified distinct depressive symptom subgroups that are variably stable over time, and their change patterns were differentially associated with CVD risk factor prevalence.

PDAY risk score predicts cardiovascular events in young adults: the CARDIA study.

AIMS: Atherosclerotic cardiovascular disease (ASCVD) risk prediction equations apply to older adults. For this study, the Pathobiologic Determinants of Atherosclerosis in Youth (PDAY) risk score, based on post-mortem measurements of atherosclerosis in 15-34-year olds dying accidentally, was used to predict ASCVD events, specifically myocardial infarction and revascularization, in middle age, from risk measured at ≤40 years of age. METHODS AND RESULTS: The Coronary Artery Risk Development in Young Adults Study (CARDIA) collected longitudinal cardiovascular risk data, coronary artery calcium (CAC) scores, and ASCVD data beginning at age 18 and 30 years with 30-year follow-up. Predictive accuracy for ASCVD of the PDAY risk score, calculated at baseline (mean age 24) and at all six CARDIA examinations up until year 15, was examined. We also examined whether the presence of CAC improved model discrimination. The cohort for this study comprised 5004 Black and White men and women, at baseline and 3558 with data at year 15. Each standard deviation increase in PDAY score, at each examination, was significantly associated with future ASCVD. Hazard ratios (per standard deviation) increased from 1.74 to 2.04 from year 0 to year 15. C-statistics ranged from 0.771 to 0.794. Coronary artery calcium measurement at age 33-45 years improved risk prediction only if the score was 0. Cumulative risk exposure over the first 15 years of the CARDIA study also had high-predictive value (c-statistic 0.798, 95% confidence interval 0.762-0.835). CONCLUSION: The PDAY risk score may be used in young adults, prior to age 40 years to predict ASCVD events.

Alcohol Use and Blood Pressure Among Adults with Hypertension: the Mediating Roles of Health Behaviors.

BACKGROUND: Alcohol use is associated with increased blood pressure among adults with hypertension, but it is unknown whether some of the observed relationship is explained by mediating behaviors related to alcohol use. OBJECTIVE: We assess the potential indirect role of smoking, physical inactivity, unhealthy diet, and poor medication adherence on the association between alcohol use and blood pressure among Black and White men and women with hypertension. DESIGN: Adjusted repeated-measures analyses using generalized estimating equations and mediation analyses using inverse odds ratio weighting. PARTICIPANTS: 1835 participants with hypertension based on ACC/AHA 2017 guidelines in three most recent follow-up exams of the longitudinal Coronary Artery Risk Development in Young Adults cohort study (2005-2016). MAIN MEASURES: Alcohol use was assessed using both self-reported average ethanol intake (drinks/day) and engagement in heavy episodic drinking (HED) in the past 30 days. Systolic and diastolic blood pressure (SBP, DBP) were measured by trained technicians (mmHg). Smoking, physical inactivity, and diet were self-reported and categorized according to American Heart Association criteria, and medication adherence was assessed using self-reported typical adherence to antihypertensive medications. KEY RESULTS: At baseline (2005-2006), 57.9% of participants were Black and 51.4% were women. Mean age (standard deviation) was 45.5 (3.6) years, mean SBP was 128.7 (15.5) mmHg, and mean DBP was 83.2 (10.1) mmHg. Each additional drink per day was significantly associated with higher SBP (ß = 0.713 mmHg, 95% confidence interval (CI): 0.398, 1.028) and DBP (ß = 0.398 mmHg, 95% CI: 0.160, 0.555), but there was no evidence of mediation by any of the behaviors. HED was not associated with blood pressure independent of average consumption. CONCLUSIONS: These findings support the direct nature of the association of alcohol use with blood pressure and the utility of advising patients with hypertension to limit consumption in addition to other behavioral and pharmacological interventions.

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Racial differences in the association of accelerated aging with future cardiovascular events and all-cause mortality: the coronary artery risk development in young adults study, 2007-2018.

OBJECTIVE: Variability of Cardiovascular disease (CVD) risk, including racial difference, is not fully accounted for by the variability of traditional CVD risk factors. We used a multiple biomarker model as a framework to explore known racial differences in CVD burden. DESIGN: We measured associations between accelerated aging (AccA) measured by a combination of biomarkers, and cardiovascular morbidity and all-cause mortality using data from the Coronary Artery Risk Development in Young Adults study (CARDIA). AccA was defined as the difference between biological age, calculated using biomarkers with the Klemera and Doubal method, and chronological age. Using logistic regression, we assessed overall and race-specific associations between AccA, CVD, and all-cause mortality. RESULTS: Among our cohort of 2959 Black or White middle-aged adults, after adjustment, a one-year increase in AccA was associated with increased odds of CVD (Odds Ratio (OR) = 1.04; 95% CI: 1.02, 1.06), stroke (OR = 1.12; 95% CI: 1.07, 1.17), and all-cause mortality (OR = 1.05; 95% CI: 1.02, 1.08). We did not find significant overall racial differences, but we did find race by sex differences where Black men differed markedly from White men in the strength of association with CVD (OR = 1.06, 95% CI: 1.01, 1.12). CONCLUSIONS: We provide evidence that AccA is associated with future CVD.

A Plant-Centered Diet and Markers of Early Chronic Kidney Disease during Young to Middle Adulthood: Findings from the Coronary Artery Risk Development in Young Adults (CARDIA) Cohort.

BACKGROUND: Few studies have evaluated whether plant-centered diets prevent progression of early stage chronic kidney disease (CKD). OBJECTIVES: We examined the association between plant-centered diet quality and early CKD markers. METHODS: We prospectively examined 2869 black and white men and women in the Coronary Artery Risk Development in Young Adults Study free of diagnosed kidney failure in 2005-2006 [examination year 20 (Y20); mean age: 45.3 ± 3.6  y]. CKD marker changes from Y20 to 2015-2016 (Y30) were considered, including estimated glomerular filtration rate (eGFR; serum creatinine), urinary albumin-to-creatinine ratio (ACR), and both. Diet was assessed through interviewer-administered diet histories at Y0, Y7, and Y20, and plant-centered diet quality was quantified with the A Priori Diet Quality Score (APDQS). Linear regression models were used to examine the association of APDQS and subsequent 10-y changes in CKD markers. RESULTS: After adjustment for sociodemographic, behavioral, and diet factors, we found that higher APDQS was related to less adverse changes in CKD markers in the subsequent 10-y period. Compared with the lowest APDQS quintile, the highest quintile was associated with an attenuated increase in lnACR (-0.25 mg/g; 95% CI: -0.37, -0.13 mg/g; P-trend < 0.001), whereas the highest quintile was associated with an attenuated decrease in eGFR (4.45 mL·min-1·1.73 m-2; 95% CI: 2.46, 6.43 mL·min-1·1.73 m-2). There was a 0.50 lower increase in combined CKD markers [ln(ACR) z score - eGFR z score] when comparing the extreme quintiles. Associations remained similar after further adjustment for hypertension, diabetes, and obesity as potential mediating factors. The attenuated worsening CKD marker changes associated with higher APDQS strengthened across increasing initial CKD category; those with the best diet and microalbuminuria in Y10-Y20 returned to high normal albuminuria (all P-interaction < 0.001). CONCLUSIONS: Individuals who consumed plant-centered, high-quality diets were less likely to experience deterioration of kidney function through midlife, especially among participants with initial stage characterized as mild CKD.

Cardiovascular risk and functional burden at midlife: Prospective associations of isotemporal reallocations of accelerometer-measured physical activity and sedentary time in the CARDIA study.

Cardiovascular risk and functional burden, or the accumulation of cardiovascular risk factors coupled with functional decline, may be an important risk state analogy to multimorbidity. We investigated prospective associations of sedentary time (ST), light intensity physical activity (LPA), and moderate to vigorous intensity physical activity (MVPA) with cardiovascular risk and functional burden at midlife. Participants were 1648 adults (mean ± SD age = 45 ± 4 years, 61% female, 39% Black) from Coronary Artery Risk Development in Young Adults (CARDIA) who wore accelerometers in 2005-2006 and 2015-2016. Cardiovascular risk and functional burden was defined as ≥2 cardiovascular risk factors (untreated/uncontrolled hypertension and hypercholesterolemia, type 2 diabetes, reduced kidney function) and/or functional decline conditions (reduced physical functioning and depressive symptoms). Prospective logistic regression models tested single activity, partition, and isotemporal substitution associations of accelerometer-measured ST, LPA, and MVPA with cardiovascular risk and functional burden 10 years later. In isotemporal models of baseline activity, reallocating 24 min of ST to MVPA was associated with 15% lower odds of cardiovascular risk and functional burden (OR: 0.85; CI: 0.75, 0.96). Reallocating 24 min of LPA to MVPA was associated with a 14% lower odds of cardiovascular risk and functional burden (OR: 0.86; CI: 0.75, 0.99). In longitudinal isotemporal models, similar beneficial associations were observed when 10-year increases in MVPA replaced time in ST or LPA. Findings suggest that maintaining an MVPA dose reflecting daily physical activity recommendations in early midlife is associated with lower odds of cardiovascular risk and functional burden later in midlife.

Multiple predictively equivalent risk models for handling missing data at time of prediction: With an application in severe hypoglycemia risk prediction for type 2 diabetes.

The presence of missing data at the time of prediction limits the application of risk models in clinical and research settings. Common ways of handling missing data at the time of prediction include measuring the missing value and employing statistical methods. Measuring missing value incurs additional cost, whereas previously reported statistical methods results in reduced performance compared to when all variables are measured. To tackle these challenges, we introduce a new strategy, the MMTOP algorithm (Multiple models for Missing values at Time Of Prediction), which does not require measuring additional data elements or data imputation. Specifically, at model construction time, the MMTOP constructs multiple predictively equivalent risk models utilizing different risk factor sets. The collection of models are stored and to be queried at prediction time. To predict an individual's risk in the presence of incomplete data, the MMTOP selects the risk model based on measurement availability for that individual from the collection of predictively equivalent models and makes the risk prediction with the selected model. We illustrate the MMTOP with severe hypoglycemia (SH) risk prediction based on data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. We identified 77 predictively equivalent models for SH with cross-validated c-index of 0.77 ± 0.03. These models are based on 77 distinct risk factor sets containing 12-17 risk factors. In terms of handling missing data at the time of prediction, the MMTOP outperforms all four tested competitor methods and maintains consistent performance as the number of missing variables increase.

African genetic ancestry interacts with body mass index to modify risk for uterine fibroids.

Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10-5) around ADTRP (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes COL5A2, and TFPI, an immediate downstream target of ADTRP. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.

Fasting glucose variability in young adulthood and incident diabetes, cardiovascular disease and all-cause mortality.

AIMS/HYPOTHESIS: The aim of this study was to determine whether long-term intra-individual variability in fasting glucose (FG) during young adulthood is associated with incident diabetes, cardiovascular disease (CVD) and mortality. METHODS: We included participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 18-30 years at baseline (1985-1986) and followed with eight examinations for up to 30 years. Long-term glucose variability was assessed using the CV (CV-FG) and the absolute difference between successive FG measurements (average real variability; ARV-FG). For participants who developed any event (diabetes, CVD or mortality), FG variability measurement was censored at the examination prior to event ascertainment. We estimated HRs for incident diabetes, CVD and mortality with adjustment for demographics, baseline FG, change in FG (censor - baseline) and time-varying education, smoking, alcohol consumption, BMI, physical activity, systolic BP, BP medications, LDL-cholesterol and cholesterol medications (and incident diabetes and diabetes medications for CVD and mortality outcomes). RESULTS: Among 3769 black and white participants, there were 317 incident diabetes cases (102,677 person-years), 159 incident CVD events (110,314 person-years) and 174 deaths (111,390 person-years). After adjustment, HRs per 1 SD higher ARV-FG were 1.64 (95% CI 1.52, 1.78) for diabetes, 1.15 (95% CI 1.01, 1.31) for CVD and 1.25 (95% CI 1.11, 1.40) for mortality. The HRs per 1 SD higher CV-FG were 1.39 (95% CI 1.21, 1.58) for diabetes, 1.32 (95% CI 1.13, 1.54) for CVD and 1.08 (95% CI 0.92, 1.27) for mortality, after adjustment. The cause-specific HRs per 1 SD higher ARV-FG were 1.29 (95% CI 1.14, 1.47) for non-CVD death and 1.05 (95% CI 0.76, 1.45) for CVD death. We did not observe evidence for effect modification of any association by sex or race. CONCLUSIONS/INTERPRETATION: Our results suggest that higher intra-individual FG variability during young adulthood before the onset of diabetes is associated with incident diabetes, CVD and mortality.

Longitudinal Associations of Smoke-Free Policies and Incident Cardiovascular Disease: CARDIA Study.

BACKGROUND: Smoke-free legislation has been associated with lower rates of cardiovascular disease hospital admissions in ecological studies. However, prior studies lacked detailed information on individual-level factors (eg, sociodemographic and clinical characteristics) that could potentially confound associations. Our objective was to estimate associations of smoke-free policies with incident cardiovascular disease in a longitudinal cohort after controlling for sociodemographics, cardiovascular disease risk factors, and policy covariates. METHODS: Longitudinal data from 3783 black and white adults in the CARDIA study (Coronary Artery Risk Development in Young Adults; 1995-2015) were linked to state, county, and local 100% smoke-free policies in bars, restaurants, and nonhospitality workplaces by Census tract. Extended Cox regression estimated hazard ratios (HRs) of incident cardiovascular disease associated with time-dependent smoke-free policy exposures. Models were adjusted for sociodemographic characteristics, cardiovascular disease risk factors, state cigarette tax, participant-reported presence of a smoking ban at their workplace, field center, and metropolitan statistical area poverty. RESULTS: During a median follow-up of 20 years (68 332 total person-years), 172 participants had an incident cardiovascular disease event (2.5 per 1000 person-years). Over the follow-up period, 80% of participants lived in areas with smoke-free policies in restaurants, 67% in bars, and 65% in nonhospitality workplaces. In fully adjusted models, participants living in an area with a restaurant, bar, or workplace smoke-free policy had a lower risk of incident cardiovascular disease compared with those in areas without smoke-free policies (HR, 0.75, 95% confidence interval, 0.49-1.15; HR, 0.76, 95% confidence interval, 0.47-1.24; HR, 0.54, 95% confidence interval, 0.34-0.86, respectively; HR, 0.58, 95% confidence interval, 0.33-1.00 for living in an area with all 3 types of policies compared with none). The estimated preventive fraction was 25% for restaurant policies, 24% for bar policies, and 46% for workplace policies. CONCLUSIONS: Consistent with prior ecological studies, these individual-based data add to the evidence that 100% smoke-free policies are associated with lower risk of cardiovascular disease among middle-aged adults.

Depressive Symptomatology, Racial Discrimination Experience, and Brain Tissue Volumes Observed on Magnetic Resonance Imaging.

Not much is known about brain structural change in younger populations and minorities. The cross-sectional relationship between depressive symptomatology and racial discrimination with structural measures of brain tissue volume was investigated using magnetic resonance images of 710 participants in the Coronary Artery Risk Development in Young Adults CARDIA Study in 2010. Those reporting depressive symptoms and racial discrimination had lower total brain matter volume compared with those who reported neither (-8.8 mL, 95% confidence interval (CI): -16.4, -1.2), those who reported depressive symptoms only (-10.9 mL, 95% CI: -20.4, -1.4), and those who reported racial discrimination only (-8.6 mL, 95% CI: -16.5, -0.8). Results were similar for total normal white matter. There were 103% higher odds (odds ratio = 2.03, 95% CI: 1.32, 3.14) of being in the highest quartile of white matter hyperintensities in those with depressive symptoms only compared to those without. Although tests for interaction by race were not statistically significant, sensitivity analyses stratified by race revealed inverse associations with total brain matter and total white matter volumes only among black participants with combined depressive symptomatology and experience of racial discrimination, and positive associations only among white participants with depressive symptoms with presence of white matter hyperintensities, suggesting future studies may focus on race.