Although many disciplines saw increases in manuscript submissions coinciding with lockdown measures, numerous studies have documented widening gender gaps in academic productivity. Chi-squared anal...

There is a growing demand for methods to determine the effects that chemical mixtures have on human health. One statistical challenge is identifying true “bad actors” from a mixture of highly correlated predictors, a setting in which standard approaches such as linear regression become highly variable. Weighted Quantile Sum regression has been proposed to address this problem, through a two-step process where mixture component weights are estimated using bootstrap aggregation in a training dataset and inference on the overall mixture effect occurs in a held-out test set. Weighted Quantile Sum regression is popular in applied papers, but the reliance on data splitting is suboptimal, and analysts who use the same data for both steps risk inflating the Type I error rate. We therefore propose a modification of Weighted Quantile Sum regression that uses a permutation test for inference, which allows for weight estimation using the entire dataset and preserves Type I error. To minimize computational burden, we propose replacing the bootstrap with L1 or L2 penalization and describe how to choose the appropriate penalty given expert knowledge about a mixture of interest. We apply our method to a national pregnancy cohort study of prenatal phthalate exposure and child health outcomes.

Lower extremity lymphedema (LEL) can result in detriments to quality of life (QOL) and impose a significant economic burden on patients and payers. A common component of treatment is pneumatic compression, which requires patients to remain immobile. We investigated a novel non-pneumatic compression device (NPCD) that allows patients to remain active during compression treatment, to see if it reduces swelling and improves QOL. We conducted a non-randomized, open-label, 12-week pilot study of adult patients with primary or secondary unilateral LEL, and measured changes in limb edema and QOL using the Lymphedema Quality of Life Questionnaire (LYMQOL). Twenty-four subjects were enrolled; the majority were female (17) with secondary lymphedema (21). Eighteen completed the study. Statistically significant improvements were observed in overall QOL, aggregated LYMQOL total score, and three of four LYMQOL subscales (Function, Appearance, Mood). The fourth (Symptoms) trended toward significant improvement (p = 0.06). The average reduction in affected limb edema was 39.4%. The novel NPCD produced statistically significant improvements in QOL, functioning, and edema volume of patients with LEL. Innovations in devices to manage LEL can be effective while allowing patients to maintain mobility and physical activity during treatment.

Accumulating evidence suggests that maternal exposure to objectively stressful events and subjective distress during pregnancy may have intergenerational impacts on children’s mental health, yet evidence is limited. In a multisite longitudinal cohort (N = 454), we used multi-variable linear regression models to evaluate the predictive value of exposure to stressful events and perceived distress in pregnancy for children’s internalizing problems, externalizing problems, and adaptive skills at age 4. We also explored two- and three-way interactions between stressful events, distress, and child sex. Both objective and subjective maternal stress independently predicted children’s behavior, with more stressful events and higher distress predicting more internalizing and externalizing problems and worse adaptability; stress types did not significantly interact. There was some evidence that more stressful events predicted higher externalizing behaviors only for girls. Three-way interactions were not significant. The current findings highlight the importance of considering the type of stress measurement being used (e.g., counts of objective event exposure or subjective perceptions), suggest prenatal stress effects may be transdiagnostic, and meet calls for rigor and reproducibility by confirming these independent main effects in a relatively large group of families across multiple U.S. regions. Results point to adversity prevention having a two-generation impact and that pre- and postnatal family-focused intervention targets may help curb the rising rates of children’s mental health problems.

We examined the knowledge and attitudes of reproductive-age women toward environmental chemicals and determined how these affect consumer behaviors. At the 2018 Minnesota State Fair, a large community sample of reproductive-age women was recruited to complete a survey on environmental health attitudes and behaviors. Descriptive statistics, chi-square tests, and logistic regression models were used to characterize current attitudes about chemicals. Multivariable logistic regression models examined how sociodemographic characteristics predict knowledge, attitudes, and consumer behaviors. A total of 871 women completed the survey; 74% strongly agreed that chemicals in the environment are dangerous, and 44% of women reported having heard of phthalates, while only 29% reported always practicing at least one environmentally healthy behavior (such as consuming food and beverages from safe plastics). Older age (35–39 versus 18–24: aOR 2.3, 95% CI 1.3, 4.3; 40–44 versus 18–24; aOR 2.0, 95% CI 1.2, 3.2) and working in a healthcare profession (aOR: 1.7, 95% CI: 1.2, 2.5) were associated with strong agreement that chemicals in the environmental are dangerous. Women who strongly agreed chemicals are dangerous were more likely to practice consumer behaviors to reduce their exposure. Interventions targeting knowledge and attitudes towards environmental chemicals could be an effective strategy for reducing harmful exposures.

Women’s social experiences can have long-term implications for their offspring’s health, but little is known about the potential independent contributions of multiple periods of stress exposures over time. This study examined associations of maternal exposure to adversity in childhood and pregnancy with children’s anxiety and depression symptoms in a large, sociodemographically diverse sample. Participants were 1389 mother-child dyads (child age M = 8.83 years; SD = 0.66; 42% Black, 42% White; 6% Hispanic) in the ECHO-PATHWAYS Consortium’s three U.S. pregnancy cohorts. Women reported their exposure to childhood traumatic events (CTE) and pregnancy stressful life events (PSLE). Children self-reported on their symptoms of anxiety and depression at age 8–9 years. Regression analyses estimated associations between maternal stressors and children’s internalizing problems, adjusting for confounders, and examined child sex as a modifier. Exploratory interaction analyses examined whether geospatially-linked postnatal neighborhood quality buffered effects. In adjusted models, PSLE counts positively predicted levels of children’s anxiety and depression symptoms ([ßAnxiety=0.08, 95%CI [0.02, 0.13]; ßDepression=0.09, 95%CI [0.03, 0.14]); no significant associations were observed with CTE. Each additional PSLE increased odds of clinically significant anxiety symptoms by 9% (95%CI [0.02, 0.17]). Neither sex nor neighborhood quality moderated relations. Maternal stressors during pregnancy appear to have associations with middle childhood anxiety and depression across diverse sociodemographic contexts, whereas maternal history of childhood adversity may not. Effects appear comparable for boys and girls. Policies and programs addressing prevention of childhood internalizing symptoms may benefit from considering prenatal origins and the potential two-generation impact of pregnancy stress prevention and intervention.

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.

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.

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/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.