Background: Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health. Results: The discovery study population was derived from three Women’s Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm β value, the risk of incident CHD increased by 9% in one site and decreased by 6–10% in two sites over 25 years. Conclusions: Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.

Introduction: Periapical images are routinely made in endodontics to support diagnosis and treatment decisions, but conventional imaging may not readily demonstrate inflammatory changes. This study aims to quantify disagreement in the radiologic interpretation of apical periodontitis/rarefying osteitis between 2 expert examiners and to determine if differences exist based on anatomic location. Methods: We used 1717 pretreatment periapical images made before orthograde endodontic treatment as part of the Predicting Outcomes of Root Canal Treatment (PREDICT) study conducted within the National Dental Practice-Based Research Network. Periapical changes were assessed independently by 2 board-certified specialists, an oral and maxillofacial radiologist and an endodontist, blinded to other clinical information. If the examiners disagreed about whether a diagnosis of apical periodontitis/rarefying osteitis was justified, an adjudication was made by a third examiner. Results: The overall prevalence of this radiologic diagnosis in the periapical images was 55%, and interexaminer agreement measured with the Cohen kappa statistic was calculated to be 0.56 (95% confidence interval, 0.52–0.60). Diagnostic disagreements between the 2 examiners occurred for 377 teeth (22%), with disagreements more frequent for jaw location (P = .038) and tooth type (P = .021). Differences between root number (P = .058) and jaw location and tooth groups (P = .069) were found not to be statistically significant. Conclusions: The variability of diagnostic disagreements across anatomic location and tooth type may reflect the inability of periapical images to reveal bone changes masked by the complexity and density of overlying anatomic structures, a limitation that could potentially be overcome with the use of 3-dimensional imaging.

Objectives Electronic health records (EHR) are a convenient data source for clinical trial recruitment and allow for inexpensive participant screening. However, EHR may lack pertinent screening variables. One strategy is to identify surrogate EHR variables which can predict the screening variable of interest. In this article, we use BMI to develop a prediction rule for arm circumference using data from the Atherosclerosis Risk in Communities (ARIC) Study. This work applies to EHR patient screening for clinical trials of hypertension. Methods We included 11 585 participants aged 52–75 years with BMI and arm circumference measured at ARIC follow-up visit 4 (1996–1998). We selected the following arm circumference cutpoints based on the American Heart Association recommendations for blood pressure (BP) cuffs: small adult (≤26 cm), adult (≤34 cm) and large adult (≤44 cm). We calculated the sensitivity and specificity of BMI values for predicting arm circumference using receiver operating characteristic curves. We report the BMI threshold that maximized Youden’s Index for each arm circumference upper limit of a BP cuff. Results Participants’ mean BMI and arm circumference were 28.8 ± 5.6 kg/m2 and 33.4 ± 4.3 cm, respectively. The BMI-arm circumference Pearson’s correlation coefficient was 0.86. The BMI threshold for arm circumference≤26 cm was 23.0 kg/m2, arm circumference≤34 cm was 29.2 kg/m2 and arm circumference≤44 cm was 37.4 kg/m2. Only the BMI threshold for arm circumference≤34 cm varied significantly by sex. Conclusions BMI predicts arm circumference with high sensitivity and specificity and can be an accurate surrogate variable for arm circumference. These findings are useful for participant screening for hypertension trials. Providers can use this information to counsel patients on appropriate cuff size for BP self-monitoring.

This study investigated whether changes in neighborhood context induced by neighborhood relocation mediated the impact of the Moving to Opportunity (MTO) housing voucher experiment on adolescent mental health. Mediators included participant-reported neighborhood safety, social control, disorder, and externally-collected neighborhood collective efficacy. For treatment group members, improvement in neighborhood disorder and drug activity partially explained MTO's beneficial effects on girls' distress. Improvement in neighborhood disorder, violent victimization, and informal social control helped counteract MTO's adverse effects on boys' behavioral problems, but not distress. Housing mobility policy targeting neighborhood improvements may improve mental health for adolescent girls, and mitigate harmful effects for boys.

Background: DNA methylation patterns associated with habitual diet have not been well studied. Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. Results: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P<1.6×10-3). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (P=5.7×10-15). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (P<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR P<4.5×10-4). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR, P=1.5×10-14).and hypermethylation of cg02079413 (SNORA54; NAP1L4) was associated with body mass index (corrected MR, P=1×10-6). Conclusions: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

Background/Objectives:There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time.Subjects/Methods:Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-Analysis.Results:Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10 â '7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10 â '7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study.Conclusions:Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

We used the Moving to Opportunity (MTO) housing experiment to inform how housing choice vouchers and housing mobility policies can assist families living in high-poverty areas to make opportunity moves to higher quality neighborhoods, across a wide range of neighborhood attributes. We compared the neighborhood attainment of the three randomly-assigned MTO treatment groups (Low Poverty voucher, Section 8 voucher, Control group) at 1997 and 2002 locations (4-7 years after baseline), by using survey reports, and by linking residential histories to numerous different administrative and population-based datasets. Compared to controls, families in Low-Poverty and Section 8 groups experienced substantial improvements in neighborhood conditions across diverse measures, including economic conditions, social systems (e.g., collective efficacy), physical features of the environment (e.g., tree cover) and health outcomes. The Low-poverty voucher group moreover achieved better neighborhood attainment compared to Section 8. Treatment effects were largest for New York and Los Angeles. We discuss the implications of our findings for expanding affordable housing policy.

OBJECTIVES To assess the mental health effects on adolescents of low-income families residing in high-poverty public housing who received housing vouchers to assist relocation. METHODS We defined treatment effects to compare 2829 adolescents aged 12 to 19 years in families offered housing vouchers versus those living in public housing in the Moving to Opportunity experiment (1994-1997; Boston, MA; Baltimore, MD; Chicago, IL; Los Angeles, CA; New York, NY). We employed model-based recursive partitioning to identify subgroups with heterogeneous treatment effects on psychological distress and behavior problems measured in 2002. We tested 35 potential baseline treatment modifiers. RESULTS For psychological distress, Chicago participants experienced null treatment effects. Outside Chicago, boys experienced detrimental effects, whereas girls experienced beneficial effects. Behavior problems effects were null for adolescents who were aged 10 years or younger at baseline. For adolescents who were older than 10 years at baseline, violent crime victimization, unmarried parents, and unsafe neighborhoods increased adverse treatment effects. Adolescents who were older than 10 years at baseline without learning problems or violent crime victimization, and whose parents moved for better schools, experienced beneficial effects. CONCLUSIONS Health effects of housing vouchers varied across subgroups. Supplemental services may be necessary for vulnerable subgroups for whom housing vouchers alone may not be beneficial.

BACKGROUND Childhood maltreatment has been linked to adulthood cardiovascular disease (CVD). Little is known about the relationship between intimate partner violence (IPV) in late adolescence and young adulthood and CVD risk later in adulthood. PURPOSE To examine whether IPV perpetration and victimization experienced in late adolescence and young adulthood are associated with CVD risk among adults in the United States and whether this relationship differs by sex. METHODS Data include 9976 participants (50% female) in the National Longitudinal Study of Adolescent to Adult Health. Physical and sexual IPV were measured at wave 3 (2001/02) with items from the revised Conflict Tactics Scales. Participants'30-year risk of CVD was calculated at wave 4 (2008/09) using a Framingham prediction model. Linear regression models adjusted for confounders and IPV by sex interaction terms were tested to examine the relationship. RESULTS The mean CVD risk score was 13.18% (95% CI: 12.71, 13.64). Aone-standard deviation increase in the victimization score was associated with a 0.28% (95% CI: 0.03, 0.54) increase in CVD risk. Perpetration was similarly positively associated with CVD risk (beta: 0.33, 95% CI: 0.03, 0.62). When measured as a composite, all violence types were associated with increased CVD risk but only prior exposure to both victimization and perpetration reached statistical significance (0.62%, 95% CI: 0.01, 1.22). No differences by sex were detected. CONCLUSIONS Effect sizes are not large, but early detection of increased CVD risk in this relatively young population is notable and worthy of further study to inform the clinical response.

BACKGROUND We describe bias resulting from individualized treatment selection, which occurs when treatment has heterogeneous effects and individuals selectively choose treatments of greatest benefit to themselves. This pernicious bias may confound estimates from observational studies and lead to important misinterpretation of intent-to-treat analyses of randomized trials. Despite the potentially serious threat to inferences, individualized treatment selection has rarely been formally described or assessed. METHODS The Moving To Opportunity trial randomly assigned subsidized rental vouchers to low-income families in high-poverty public housing. We assessed the Kessler-6 psychological distress and Behavior Problems Index outcomes for 2,829 adolescents 4-7 years after randomization. Among families randomly assigned to receive vouchers, we estimated probability of moving (treatment), predicted by prerandomization characteristics (c statistic = 0.63). We categorized families into tertiles of this estimated probability of moving, and compared instrumental variable effect estimates for moving on behavior problems index and Kessler-6 across tertiles. RESULTS Instrumental variable estimated effects of moving on behavioral problems index were most adverse for boys least likely to move (b = 0.93; 95% confidence interval: 0.33, 1.53) compared with boys most likely to move (b = 0.14; 95% confidence interval: -0.15, 0.44; P = 0.02 for treatment × tertile interaction). Effects on Kessler-6 were more beneficial for girls least likely to move compared with girls most likely to move (-0.62 vs. 0.02; interaction; P = 0.03). CONCLUSIONS Evidence of individualized treatment selection differed by child gender and outcome and should be evaluated in randomized trial reports, especially when heterogeneous treatment effects are likely and nonadherence is common.

Despite the recent flourishing of mediation analysis techniques, many modern approaches are difficult to implement or applicable to only a restricted range of regression models. This report provides practical guidance for implementing a new technique utilizing inverse odds ratio weighting (IORW) to estimate natural direct and indirect effects for mediation analyses. IORW takes advantage of the odds ratio's invariance property and condenses information on the odds ratio for the relationship between the exposure (treatment) and multiple mediators, conditional on covariates, by regressing exposure on mediators and covariates. The inverse of the covariate-adjusted exposure-mediator odds ratio association is used to weight the primary analytical regression of the outcome on treatment. The treatment coefficient in such a weighted regression estimates the natural direct effect of treatment on the outcome, and indirect effects are identified by subtracting direct effects from total effects. Weighting renders treatment and mediators independent, thereby deactivating indirect pathways of the mediators. This new mediation technique accommodates multiple discrete or continuous mediators. IORW is easily implemented and is appropriate for any standard regression model, including quantile regression and survival analysis. An empirical example is given using data from the Moving to Opportunity (1994-2002) experiment, testing whether neighborhood context mediated the effects of a housing voucher program on obesity. Relevant Stata code (StataCorp LP, College Station, Texas) is provided.

BACKGROUND: The relationship between the alcohol policy environment (ie, the combined effectiveness and implementation of multiple existing alcohol policies) and youth drinking in the United States has not been assessed. We hypothesized that stronger alcohol policy environments are inversely associated with youth drinking, and this relationship is partly explained by adult drinking. METHODS: Alcohol Policy Scale (APS) scores that characterized the strength of the state-level alcohol policy environments were assessed with repeated cross-sectional Youth Risk Behavior Survey data of representative samples of high school students in grades 9 to 12, from biennial years between 1999 and 2011. RESULTS: In fully adjusted models, a 10 percentage point increase in APS scores (representing stronger policy environments) was associated with an 8% reduction in the odds of youth drinking and a 7% reduction in the odds of youth binge drinking. After we accounted for youth-oriented alcohol policies, the subgroup of population-oriented policies was independently associated with lower odds of youth drinking (adjusted odds ratio 0.94; 95% confidence interval 0.92-0.97) and youth binge drinking (adjusted odds ratio 0.96; 95% confidence interval 0.94-0.99). State-level per capita consumption mediated the relationship between population-oriented alcohol policies and binge drinking among youth. CONCLUSIONS: Stronger alcohol policies, including those that do not target youth specifically, are related to a reduced likelihood of youth alcohol consumption. These findings suggest that efforts to reduce youth drinking should incorporate population-based policies to reduce excessive drinking among adults as part of a comprehensive approach to preventing alcohol-related harms. Future research should examine influence of alcohol policy subgroups and discrete policies.