Methods for mediation analysis with high-dimensional DNA methylation data: Possible choices and comparisons.

Epigenetic researchers often evaluate DNA methylation as a potential mediator of the effect of social/environmental exposures on a health outcome. Modern statistical methods for jointly evaluating many mediators have not been widely adopted. We compare seven methods for high-dimensional mediation analysis with continuous outcomes through both diverse simulations and analysis of DNAm data from a large multi-ethnic cohort in the United States, while providing an R package for their seamless implementation and adoption. Among the considered choices, the best-performing methods for detecting active mediators in simulations are the Bayesian sparse linear mixed model (BSLMM) and high-dimensional mediation analysis (HDMA); while the preferred methods for estimating the global mediation effect are high-dimensional linear mediation analysis (HILMA) and principal component mediation analysis (PCMA). We provide guidelines for epigenetic researchers on choosing the best method in practice and offer suggestions for future methodological development.

Exposure to structural racism-related state laws is associated with worse cardiovascular health among US adults, BRFSS 2011 and 2013.

The objective of this study was to determine whether exposure to structural racism-related state laws is associated with cardiovascular health among a racially and ethnically diverse sample of US adults. Data were from the Database of Structural Racism-Related State Laws and the Behavioral Risk Factor Surveillance System (BRFSS). The sample included 958,019 BRFSS 2011 and 2013 respondents aged 18+ from all 50 US states. The exposure was a summary index of 22 state laws related to the criminal legal system, economics and labor, education, healthcare, housing, immigration, and political participation. The outcome was the American Heart Association's Life's Simple 7 (LS7), a summary index of seven cardiovascular health indicators. Linear regression models included fixed effects for year and state to control for time trends and unmeasured time-invariant state-level contextual factors. In the full sample, a one standard deviation increase in the structural racism state legal index was associated with a 0.06-unit decrease in the LS7 (b=-0.06; 95% CI:-0.09, 0.02; p=0.001), controlling for individual- and state-level covariates. Contrary to expectations, stratified models revealed no statistically significant differences by race and ethnicity in the association between the structural racism state legal index and the LS7.

Could differential under-reporting of loneliness between men and women bias the gender-specific association between loneliness duration and rate of memory decline? A probabilistic bias analysis of effect modification.

Gender is an observed effect modifier of the association between loneliness and memory aging. However, this effect modification may be a result of information bias due to differential loneliness under-reporting by gender. We applied probabilistic bias analyses to examine whether effect modification of the loneliness-memory decline relationship by gender is retained under three simulation scenarios with various magnitudes of differential loneliness under-reporting between men and women. Data were from biennial interviews with adults aged 50+ in the US Health and Retirement Study from 1996-2016 (5,646 women and 3,386 men). Loneliness status (yes vs. no) was measured from 1996-2004 using the CES-D loneliness item and memory was measured from 2004-2016. Simulated sensitivity and specificity of the loneliness measure were informed by a validation study using the UCLA Loneliness Scale as a gold standard. The likelihood of observing effect modification by gender was higher than 90% in all simulations, although the likelihood reduced with an increasing difference in magnitude of the loneliness under-reporting between men and women. The gender difference in loneliness under-reporting did not meaningfully affect the observed effect modification by gender in our simulations. Our simulation approach may be promising to quantify potential information bias in effect modification analyses.

A data harmonization project of three large prospective cardiovascular health-focused cohorts.

Few prospective studies examine multilevel resilience resources and psychosocial factors in relation to cardiovascular health and disease. Recent research indicates that resilience resources are associated with a reduction in the incidence of cardiovascular disease-related events, but few studies have examined this relationship across different racial/ethnic populations or in large cohorts. Harmonization may address these limitations because it allows data from several cohorts to be analyzed together, potentially increasing sample size and in turn power overall and in minority populations. This paper describes the process involved in combining three cardiovascular health-focused cohorts: Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, and Mediators of Atherosclerosis in South Asians Living in America Study. Using a systematic process, we identified appropriate data harmonization techniques to use in harmonizing variables across cohorts. Variables included exposures (e.g., resilience resources), outcomes (e.g., American Heart Association's Life's Simple 7), and covariates (e.g., race and ethnicity). Post harmonization examinations included psychometric analyses of the harmonized variables. A total of 13,284 participants were included in the final harmonized dataset. This project provides opportunities for future research in resilience resources and informs future studies that need to harmonize data. Results based on the harmonized dataset could inform interventions and policies.

Examining the Relationship Between Multilevel Resilience Resources and Cardiovascular Disease Incidence, Overall and by Psychosocial Risks, Among Participants in the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study.

We examined relationships between resilience resources (optimism, social support, and neighborhood social cohesion) and cardiovascular disease (CVD) incidence and assessed potential effect-measure modification by psychosocial risk factors (e.g., stress, depression) among adults without CVD in 3 cohort studies (2000-2018): the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study. We fitted adjusted Cox models accounting for within-neighborhood clustering while censoring at dropout or non-CVD death. We assessed for effect-measure modification by psychosocial risks. In secondary analyses, we estimated standardized risk ratios using inverse-probability-weighted Aalen-Johansen estimators to account for confounding, dropout, and competing risks (non-CVD deaths) and obtained 95% confidence intervals (CIs) using cluster bootstrapping. For high and medium (versus low) optimism (n = 6,243), adjusted hazard ratios (HRs) for incident CVD were 0.94 (95% CI: 0.78, 1.13) and 0.90 (95% CI: 0.75, 1.07), respectively. Corresponding HRs were 0.88 (95% CI: 0.74, 1.04) and 0.92 (95% CI: 0.79, 1.06) for social support (n = 7,729) and 1.10 (95% CI: 0.94, 1.29) and 0.99 (95% CI: 0.85, 1.16) for social cohesion (n = 7,557), respectively. Some psychosocial risks modified CVD HRs. Secondary analyses yielded similar findings. For optimism and social support, an inverse relationship was frequently most compatible with the data, but a positive relationship was also compatible. For neighborhood social cohesion, positive and null relationships were most compatible. Thus, specific resilience resources may be potential intervention targets, especially among certain subgroups.

Gestational diabetes mellitus, epigenetic age and offspring metabolism.

AIMS: No reports examine the relationship between in-utero exposure to gestational diabetes mellitus (GDM), offspring epigenetic age acceleration (EAA), and offspring insulin sensitivity. METHODS: Using data from a cohort study, we examined associations between GDM in-utero exposure and offspring EAA at approximately 10 years of age, using separate regression models adjusting for offspring chronological age and sex. We also examined associations between EAA with updated homeostasis model assessment of insulin sensitivity and secretion (HOMA2-S and HOMA2-ß) measured at approximately 10 and 16 years of age, using mixed linear regression models accounting for repeated measures after adjustment for offspring chronological age and sex. RESULTS: Compared to unexposed offspring (n = 91), offspring exposed to GDM (n = 88) had greater EAA or older extrinsic age compared to chronological age (ß-coefficient 2.00, 95% confidence interval [0.71, 3.28], p = 0.0025), but not greater intrinsic EAA (ß-coefficient -0.07, 95% CI [-0.71, 0.57], p = 0.93). Extrinsic EAA was associated with lower insulin sensitivity (ß-coefficient -0.018, 95% CI [-0.035, -0.002], p = 0.03) and greater insulin secretion (ß-coefficient 0.018, 95% CI [0.006, 0.03], p = 0.003), and these associations persisted after further adjustment for measures of maternal and child adiposity. No associations were observed between intrinsic EAA and insulin sensitivity and secretion, before or after adjustment for measures of maternal and child adiposity. CONCLUSIONS: In this study, children exposed to GDM experience greater extrinsic EAA, which is associated with lower insulin sensitivity and greater insulin secretion. Further studies are needed to determine the directionality of these associations.

Caregiver-reported household food insecurity and child-reported food insecurity in relation to eating disorder risk factors and symptoms among preadolescent children.

OBJECTIVE: To examine the relation of caregiver-reported household food insecurity (FI) and child-reported FI with eating disorder (ED) risk factors and symptoms, including effect modification by gender, in preadolescent children. METHOD: Data were from the Family Food Study, a cross-sectional study of households with incomes ≤200% of the federal poverty line in southeastern Michigan. Children aged 8-10 years (n = 194) and their female primary caregivers reported separately on FI status. Children reported ED risk factors/symptoms via the 24-item Children's Eating Attitudes Test (ChEAT-24), with higher scores indicating more ED risk factors/symptoms. Linear mixed models were used to examine associations between FI measures with the ChEAT-24 total score, plus subscale scores for dieting, food preoccupation, weight preoccupation, vomiting, and social pressure to eat/gain weight. Models were adjusted for child age, child gender, caregiver race/ethnicity, caregiver education, and household income. RESULTS: Among all children, child-reported FI, but not caregiver-reported household FI, was associated with more ED risk factors/symptoms. Child-reported FI (vs. no FI) was associated with higher average ChEAT-24 total score (ß = 2.41, 95% CI: 0.57, 4.25). Child-reported FI was also associated with more food preoccupation, more weight preoccupation, and more social pressure to eat. Caregiver-reported household FI was marginally associated with less dieting in girls, and child-reported FI was associated with more dieting in boys. DISCUSSION: Child-reported FI may be more salient than caregiver-reported household FI as a risk factor for ED-related outcomes in preadolescent children. Gender may modify the association between FI and dieting behavior. PUBLIC SIGNIFICANCE STATEMENT: More child-reported food insecurity, but not parent-reported household food insecurity, was associated with more eating disorder risk factors and symptoms among preadolescent boys and girls. These findings emphasize the need for future studies that investigate the role of food insecurity in the development of eating disorders, especially studies that measure child-reported experience of food insecurity.

Examining relationships between perceived neighborhood social cohesion and ideal cardiovascular health and whether psychosocial stressors modify observed relationships among JHS, MESA, and MASALA participants.

BACKGROUND: Psychosocial stressors increase the risks for cardiovascular disease across diverse populations. However, neighborhood level resilience resources may protect against poor cardiovascular health (CVH). This study used data from three CVH cohorts to examine longitudinally the associations of a resilience resource, perceived neighborhood social cohesion (hereafter referred to as neighborhood social cohesion), with the American Heart Association's Life's Simple 7 (LS7), and whether psychosocial stressors modify observed relationships. METHODS: We examined neighborhood social cohesion (measured in tertiles) and LS7 in the Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, and Mediators of Atherosclerosis in South Asians Living in America study. We used repeated-measures, modified Poisson regression models to estimate the relationship between neighborhood social cohesion and LS7 (primary analysis, n = 6,086) and four biological metrics (body mass index, blood pressure, cholesterol, blood glucose; secondary analysis, n = 7,291). We assessed effect measure modification by each psychosocial stressor (e.g., low educational attainment, discrimination). RESULTS: In primary analyses, adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) for ideal/intermediate versus poor CVH among high or medium (versus low) neighborhood social cohesion were 1.01 (0.97-1.05) and 1.02 (0.98-1.06), respectively. The psychosocial stressors, low education and discrimination, functioned as effect modifiers. Secondary analyses showed similar findings. Also, in the secondary analyses, there was evidence for effect modification by income. CONCLUSION: We did not find much support for an association between neighborhood social cohesion and LS7, but did find evidence of effect modification. Some of the effect modification results operated in unexpected directions. Future studies should examine neighborhood social cohesion more comprehensively and assess for effect modification by psychosocial stressors.

Heavy metal blood concentrations in association with sociocultural characteristics, anthropometry and anemia among Kenyan adolescents.

OBJECTIVES: To measure heavy metal concentrations among Kenyan youth and quantify associations with sociocultural, demographic, and health factors as well as anthropometry. METHODS: Using data from a study of semi-nomadic pastoralists in Samburu County, Kenya, we measured blood concentrations of lead (Pb), mercury (Hg), and cadmium (Cd) in 161 adolescents. We identified sociocultural, demographic and health characteristics associated with each metal and quantified the association between metals and adolescent anthropometry. RESULTS: Median blood concentrations of Pb, Cd, and Hg were 1.82 µg/dL, 0.24 µg/L and 0.16 µg/L, respectively. Place of residence (highlands vs lowlands) was a determinant of metal concentrations. Hg was inversely related to anemia, and metals were not associated with anthropometry. CONCLUSIONS: In this population of Samburu adolescents, median Pb and Cd blood concentrations were higher than other North American or European biomonitoring studies. These findings motivate further investigation into the environmental sources of metals in this community.

A mixed-methods study on the dietary practices of early postpartum women during the summer rainy season in Belgaum, Karnataka, India.

The current mixed-method study uses Food Frequency Questionnaires and 24-hour dietary recalls (n = 41) to assess the food/nutrient intake; and qualitative interviews to identify local perceptions of food among 41 early postpartum women in Belgaum, India. The results show that total energy, protein, and most micronutrient intake were significantly lower than the Recommended Dietary Allowance of India (p < .05 individually); ninety percent of mothers restricted the consumption of some specific fruits, vegetables, and other foods during postpartum due to their perceptions of foods, folk medicines, and health beliefs. Culturally sensitive programs relevant to postpartum diet practices for women should be implemented.