Gene-environment interactions in human health.

Gene-environment interactions (G × E), the interplay of genetic variation with environmental factors, have a pivotal impact on human complex traits and diseases. Statistically, G × E can be assessed by determining the deviation from expectation of predictive models based solely on the phenotypic effects of genetics or environmental exposures. Despite the unprecedented, widespread and diverse use of G × E analytical frameworks, heterogeneity in their application and reporting hinders their applicability in public health. In this Review, we discuss study design considerations as well as G × E analytical frameworks to assess polygenic liability dependent on the environment, to identify specific genetic variants exhibiting G × E, and to characterize environmental context for these dynamics. We conclude with recommendations to address the most common challenges and pitfalls in the conceptualization, methodology and reporting of G × E studies, as well as future directions.

Newborn Dried Blood Spot Folate in Relation to Maternal Self-reported Folic Acid Intake, Autism Spectrum Disorder, and Developmental Delay.

BACKGROUND: Maternal folic acid intake has been associated with decreased risk for neurodevelopmental disorders including autism spectrum disorder (ASD). Genetic differences in folate metabolism could explain some inconsistencies. To our knowledge, newborn folate concentrations remain unexamined. METHODS: We measured folate in archived newborn dried blood spots of children from the CHARGE (Childhood Autism Risks from Genetics and the Environment) case-control study who were clinically confirmed at 24-60 months to have ASD (n = 380), developmental delay (n = 128), or typical development (n = 247). We quantified monthly folic acid intake from maternally-reported supplements and cereals consumed during pregnancy and 3 months prior. We assessed associations of newborn folate with maternal folic acid intake and with ASD or developmental delay using regression. We stratified estimates across maternal and child MTHFR genotypes. RESULTS: Among typically developing children, maternal folic acid intake in prepregnancy and each pregnancy month and prepregnancy prenatal vitamin intake were positively associated with newborn folate. Among children with ASD, prenatal vitamin intake in pregnancy months 2-9 was positively associated with newborn folate. Among children with developmental delay, maternal folic acid and prenatal vitamins during the first pregnancy month were positively associated with neonatal folate. Associations differed by MTHFR genotype. Overall, neonatal folate was not associated with ASD or developmental delay, though we observed associations with ASD in children with the MTHFR 677 TT genotype (odds ratio: 1.76, 95% CI = 1.19, 2.62; P for interaction = 0.08). CONCLUSION: Maternal prenatal folic acid intake was associated with neonatal folate at different times across neurodevelopmental groups. Neonatal folate was not associated with reduced ASD risk. MTHFR genotypes modulated these relationships.

Epigenetic changes in sperm are associated with paternal and child quantitative autistic traits in an autism-enriched cohort.

There is a need to consider paternal contributions to autism spectrum disorder (ASD) more strongly. Autism etiology is complex, and heritability is not explained by genetics alone. Understanding paternal gametic epigenetic contributions to autism could help fill this knowledge gap. In the present study, we explored whether paternal autistic traits, and the sperm epigenome, were associated with autistic traits in children at 36 months enrolled in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is a pregnancy cohort that recruited and enrolled pregnant women in the first half of pregnancy who already had a child with ASD. After maternal enrollment, EARLI fathers were approached and asked to provide a semen specimen. Participants were included in the present study if they had genotyping, sperm methylation data, and Social Responsiveness Scale (SRS) score data available. Using the CHARM array, we performed genome-scale methylation analyses on DNA from semen samples contributed by EARLI fathers. The SRS-a 65-item questionnaire measuring social communication deficits on a quantitative scale-was used to evaluate autistic traits in EARLI fathers (n = 45) and children (n = 31). We identified 94 significant child SRS-associated differentially methylated regions (DMRs), and 14 significant paternal SRS-associated DMRs (fwer p < 0.05). Many child SRS-associated DMRs were annotated to genes implicated in ASD and neurodevelopment. Six DMRs overlapped across the two outcomes (fwer p < 0.1), and, 16 DMRs overlapped with previous child autistic trait findings at 12 months of age (fwer p < 0.05). Child SRS-associated DMRs contained CpG sites independently found to be differentially methylated in postmortem brains of individuals with and without autism. These findings suggest paternal germline methylation is associated with autistic traits in 3-year-old offspring. These prospective results for autism-associated traits, in a cohort with a family history of ASD, highlight the potential importance of sperm epigenetic mechanisms in autism.

Associations of prenatal exposure to a mixture of persistent organic pollutants with social traits and cognitive and adaptive function in early childhood: Findings from the EARLI study.

BACKGROUND: Literature suggests that maternal exposure to persistent organic pollutants (POPs) may influence child neurodevelopment. Evidence linking prenatal POPs and autism spectrum disorder has been inconclusive and few studies have examined the mixture effect of the POPs on autism-related traits. OBJECTIVE: To evaluate the associations between prenatal exposure to a mixture of POPs and autism-related traits in children from the Early Autism Risk Longitudinal Investigation study. METHODS: Maternal serum concentrations of 17 POPs (11 polychlorinated biphenyls [PCBs], 4 polybrominated diphenyls [PBDEs], and 2 persistent pesticides) in 154 samples collected during pregnancy were included in this analysis. We examined the independent associations of the natural log-transformed POPs with social, cognitive, and behavioral traits at 36 months of age, including Social Responsiveness Scale (SRS), Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC), and Vineland Adaptive Behavior Scales (VABS) scores, using linear regression models. We applied Bayesian kernel machine regression and quantile g-computation to examine the joint effect and interactions of the POPs. RESULTS: Higher ln-PBDE47 was associated with greater deficits in social reciprocity (higher SRS score) (ß = 6.39, 95% CI: 1.12, 11.65) whereas higher ln-p,p'-DDE was associated with lower social deficits (ß = -8.34, 95% CI: -15.32, -1.37). Positive associations were observed between PCB180 and PCB187 and cognitive (MSEL-ELC) scores (ß = 5.68, 95% CI: 0.18, 11.17; ß = 4.65, 95% CI: 0.14, 9.17, respectively). Adaptive functioning (VABS) scores were positively associated with PCB170, PCB180, PCB187, PCB196/203, and p,p'-DDE. In the mixture analyses, we did not observe an overall mixture effect of POPs on the quantitative traits. Potential interactions between PBDE99 and other PBDEs were identified in association with MSEL-ELC scores. CONCLUSIONS: We observed independent effects of PCB180, PCB187, PBDE47, and p,p' DDE with ASD-related quantitative traits and potential interactions between PBDEs. Our findings highlight the importance of assessing the effect of POPs as a mixture.

Cardiometabolic Pregnancy Complications in Association With Autism-Related Traits as Measured by the Social Responsiveness Scale in ECHO.

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998-2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (ß = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (ß = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population.

The association of unconventional natural gas development with diagnosis and treatment of internalizing disorders among adolescents in Pennsylvania using electronic health records.

BACKGROUND: Unconventional natural gas development (UNGD) introduces physical and psychosocial hazards into communities, which could contribute to psychosocial stress in adolescents and an increased risk of internalizing disorders, common and impactful health outcomes. OBJECTIVES: To evaluate associations between a 180-day composite UNGD activity metric and new onset of internalizing disorders, overall and separately for anxiety and depressive disorders, and effect modification by sex. METHODS: We used a nested case-control design from 2008 to 2016 in 38 Pennsylvania counties using electronic health records from adolescent Geisinger subjects. Cases were defined by at least two diagnoses or medication orders indicating new onset of an internalizing disorder, and controls frequency-matched 4:1 on age, sex, and year. To evaluate associations, we used generalized estimating equations, with logit link, robust standard errors, and an exchangeable correlation structure within community. RESULTS: We identified 7,974 adolescents (65.9% female, mean age 15.0 years) with new onset internalizing disorders. There were no associations when we used data from the entire study period. When restricted to years with higher UNGD activity (2010-2016), comparing the highest to lowest quartile, UNGD activity was associated (odds ratio [95% confidence level]) with new onset internalizing disorders (1.15 [1.06, 1.25]). Associations were slightly stronger for depressive disorders. Associations were only present in females (p = 0.009). DISCUSSION: This is the first epidemiologic study of UNGD in relation to adolescent mental health, an important health outcome in a potentially susceptible group to the environmental and community impacts of UNGD. UNGD activity was associated with new onset internalizing disorders in females in this large sample in an area of active UNGD.

Placental morphology in association with autism-related traits in the EARLI study.

BACKGROUND: In prior work we observed differences in morphology features in placentas from an autism-enriched cohort as compared to those from a general population sample. Here we sought to examine whether these differences associate with ASD-related outcomes in the child. METHODS: Participants (n = 101) were drawn from the Early Autism Risk Longitudinal Investigation (EARLI), a cohort following younger siblings of children with autism spectrum disorder (ASD). ASD-related outcomes, including the Social Responsiveness Scale (SRS), Mullen Scales of Early Learning (MSEL) Early Learning Composite, and ASD diagnosis, were assessed at age 3. Crude and adjusted linear regression was used to examine associations between placental morphological features (parametrized continuously and in quartiles) and SRS and MSEL scores; comparisons by ASD case status were explored as secondary analyses due to the small number of cases (n = 20). RESULTS: In adjusted analyses, we observed a modest positive association between umbilical cord eccentricity, defined as the ratio of the maximum:minimum radius from the cord insertion point, and SRS scores (Beta = 1.68, 95%CI = 0.45, 2.9). Positive associations were also suggested between placental maximum thickness and cord centrality and SRS scores, though these were estimated with little precision. Associations between other placental morphological features and outcomes were not observed. CONCLUSIONS: Our analyses suggested a potential association between umbilical cord features and ASD-related traits, of interest as non-central cord insertion may reflect reduced placenta efficiency. Future studies with larger sample sizes are needed to further examine these and other placental features in association with ASD-related outcomes.

Prenatal air pollution exposure and neurodevelopment: A review and blueprint for a harmonized approach within ECHO.

BACKGROUND: Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants. OBJECTIVES: We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO. METHODS: We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO. DISCUSSION: While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research. CONCLUSIONS: In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children's health.

A framework for assessing the impact of chemical exposures on neurodevelopment in ECHO: Opportunities and challenges.

The Environmental influences on Child Health Outcomes (ECHO) Program is a research initiative funded by the National Institutes of Health that capitalizes on existing cohort studies to investigate the impact of early life environmental factors on child health and development from infancy through adolescence. In the initial stage of the program, extant data from 70 existing cohort studies are being uploaded to a database that will be publicly available to researchers. This new database will represent an unprecedented opportunity for researchers to combine data across existing cohorts to address associations between prenatal chemical exposures and child neurodevelopment. Data elements collected by ECHO cohorts were determined via a series of surveys administered by the ECHO Data Analysis Center. The most common chemical classes quantified in multiple cohorts include organophosphate pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, environmental phenols (including bisphenol A), phthalates, and metals. For each of these chemicals, at least four ECHO cohorts also collected behavioral data during infancy/early childhood using the Child Behavior Checklist. For these chemicals and this neurodevelopmental assessment (as an example), existing data from multiple ECHO cohorts could be pooled to address research questions requiring larger sample sizes than previously available. In addition to summarizing the data that will be available, the article also describes some of the challenges inherent in combining existing data across cohorts, as well as the gaps that could be filled by the additional data collection in the ECHO Program going forward.

Prenatal Exposure to Endocrine-disrupting Chemicals in Relation to Autism Spectrum Disorder and Intellectual Disability.

BACKGROUND: Exposure to endocrine disruptors is unavoidable. Many such compounds are suspected to impact neurologic development of children, but most studies conducted have considered effects of individual chemicals in isolation. Because exposures co-occur, it is important to consider their health impacts in a single regression framework. METHODS: We applied Bayesian statistical tools (including shared mean and mixture priors for 25 unique chemicals) to study independent associations of endocrine disruptor biomarkers with autism spectrum disorder (ASD) (n = 491) and intellectual disability (n = 155), compared with 373 general population controls, in the Early Markers for Autism study. We measured biomarkers in maternal serum collected and stored from midpregnancy and considered them individually or as a class (i.e., summed polychlorinated biphenyls). We adjusted all models for original matching factors (child sex and month and year of birth), maternal age, maternal race/ethnicity, parity, and maternal education at the time samples were collected. We estimated the change in the odds of ASD or intellectual disability per 1 SD increase in the z-score of measured biomarker concentration for each chemical. RESULTS: Odds of ASD and intellectual disability did not change with increasing concentration for any specific endocrine disruptor. The effect estimates for each chemical were centered on or near an odds ratio of 1.00 in both models where we applied a shared mean or a mixture prior. CONCLUSION: Our mixtures analyses do not suggest an independent relationship with ASD or intellectual disability with any of the 25 chemicals examined together in this mixtures analysis.

Gene-Environment Interactions in Psychiatry: Recent Evidence and Clinical Implications.

PURPOSE OF REVIEW: We identify the recent evidence for gene-by-environment interaction studies in relation to psychiatric disorders. We focus on the key genotypic data as well as environmental exposures and how they interact to predict psychiatric disorders and psychiatric symptomatology. We direct our focus on the psychiatric outcomes that were focused on by the Psychiatric Genetics Consortium. RECENT FINDINGS: Many of the studies focus on candidate gene approaches, with most of the studies drawing upon previous literature to decide the genes of interest. Other studies used a genome-wide approach. While some studies demonstrated positive replication of previous findings, replication is still an issue within gene-by-environment interaction studies. Gene-by-environment interaction research in psychiatry globally suggests some susceptibility to environmental exposures based on genotype; however, greater clarity is needed around the idea that genetic risk may not be disorder specific.

Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring.

BACKGROUND: To examine the prospective association between multivitamin supplementation during pregnancy and biomarker measures of maternal plasma folate and vitamin B12 levels at birth and child's Autism Spectrum Disorder (ASD) risk. METHODS: This report included 1257 mother-child pairs, who were recruited at birth and prospectively followed through childhood at the Boston Medical Center. ASD was defined from diagnostic codes in electronic medical records. Maternal multivitamin supplementation was assessed via questionnaire interview; maternal plasma folate and B12 were measured from samples taken 2-3 days after birth. RESULTS: Moderate (3-5 times/week) self-reported supplementation during pregnancy was associated with decreased risk of ASD, consistent with previous findings. Using this as the reference group, low (≤2 times/week) and high (>5 times/week) supplementation was associated with increased risk of ASD. Very high levels of maternal plasma folate at birth (≥60.3 nmol/L) had 2.5 times increased risk of ASD [95% confidence interval (CI) 1.3, 4.6] compared to folate levels in the middle 80th percentile, after adjusting for covariates including MTHFR genotype. Similarly, very high B12 (≥536.8 pmol/L) showed 2.5 times increased risk (95% CI 1.4, 4.5). CONCLUSION: There was a 'U shaped' relationship between maternal multivitamin supplementation frequency and ASD risk. Extremely high maternal plasma folate and B12 levels at birth were associated with ASD risk. This hypothesis-generating study does not question the importance of consuming adequate folic acid and vitamin B12 during pregnancy; rather, raises new questions about the impact of extremely elevated levels of plasma folate and B12 exposure in-utero on early brain development.

The Changing Epidemiology of Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.

Measuring Anhedonia in Adolescents: A Psychometric Analysis.

Anhedonia-the reduced capacity to experience pleasure-is a trait implicated in mental and physical health. Yet, psychometric data on anhedonia measures in adolescents are absent. We conducted an in-depth psychometric analysis of the Snaith-Hamilton Pleasure Scale (SHAPS; Snaith et al., 1995 )-a self-report measure of anticipated pleasure response to 14 pleasant experiences-in adolescents. Adolescents (N = 585, M age = 14.5) completed the SHAPS and other paper-and-pencil surveys. Item response theory models were used to evaluate the psychometric performance of each SHAPS item. Correlations of the SHAPS with other personality and psychopathology measures were calculated to evaluate construct validity. Results showed that (a) certain items (e.g., reported pleasure from basic experiences like "seeing smiling faces" or "smelling flowers") provided more information about latent anhedonia than others; and (b) SHAPS scales exhibited construct-consistent convergent and discriminant validity (i.e., stronger correlations with low positive affect constructs, weaker correlations with negative affect). Reporting diminished pleasure from basic pleasant experiences accurately indicates adolescent anhedonia, which is important for future scale development and understanding the phenomenology of anhedonia in teens. These data support using the SHAPS for assessing anhedonia in epidemiological research and school-based universal prevention programming in general adolescent populations.

Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene.

BACKGROUND: Independent studies report association of autism spectrum disorder with air pollution exposure and a functional promoter variant (rs1858830) in the MET receptor tyrosine kinase (MET) gene. Toxicological data find altered brain Met expression in mice after prenatal exposure to a model air pollutant. Our objective was to investigate whether air pollution exposure and MET rs1858830 genotype interact to alter the risk of autism spectrum disorder. METHODS: We studied 252 cases of autism spectrum disorder and 156 typically developing controls from the Childhood Autism Risk from Genetics and the Environment Study. Air pollution exposure was assigned for local traffic-related sources and regional sources (particulate matter, nitrogen dioxide, and ozone). MET genotype was determined by direct resequencing. RESULTS: Subjects with both MET rs1858830 CC genotype and high air pollutant exposures were at increased risk of autism spectrum disorder compared with subjects who had both the CG/GG genotypes and lower air pollutant exposures. There was evidence of multiplicative interaction between NO2 and MET CC genotype (P= 0.03). CONCLUSIONS: MET rs1858830 CC genotype and air pollutant exposure may interact to increase the risk of autism spectrum disorder.

Prenatal air pollution and children's autism traits score: Examination of joint associations with maternal intake of vitamin D, methyl donors, and polyunsaturated fatty acids using mixture methods.

Background: Maternal nutrient intake may moderate associations between environmental exposures and children's neurodevelopmental outcomes, but few studies have assessed joint effects. We aimed to evaluate whether prenatal nutrient intake influences the association between air pollutants and autism-related trait scores. Methods: We included 126 participants from the EARLI (Early Autism Risk Longitudinal Investigation, 2009-2012) cohort, which followed US pregnant mothers who previously had a child with autism. Bayesian kernel machine regression and traditional regression models were used to examine joint associations of prenatal nutrient intake (vitamins D, B12, and B6; folate, choline, and betaine; and total omega 3 and 6 polyunsaturated fatty acids, reported via food frequency questionnaire), air pollutant exposure (particulate matter <2.5 µm [PM2.5], nitrogen dioxide [NO2], and ozone [O3], estimated at the address level), and children's autism-related traits (measured by the Social Responsiveness Scale [SRS] at 36 months). Results: Most participants had nutrient intakes and air pollutant exposures that met US standards. Bayesian kernel machine regression mixture models and traditional regression models provided little evidence of individual or joint associations of nutrients and air pollutants with SRS scores or of an association between the overall mixture and SRS scores. Conclusion: In this cohort with a high familial likelihood of autism, we did not observe evidence of joint associations between air pollution exposures and nutrient intake with autism-related traits. Future work should examine the use of these methods in larger, more diverse samples, as our results may have been influenced by familial liability and/or relatively high nutrient intakes and low air pollutant exposures.

The association between prenatal oxidative stress levels measured by isoprostanes and offspring neurodevelopmental outcomes at 36 months.

Oxidative stress during pregnancy has been a mechanistic pathway implicated in autism development, yet few studies have examined this association directly. Here, we examined the association of prenatal levels of 8-iso-PGF2α, a widely used measure of oxidative stress, and several neurodevelopmental outcomes related to autism in children. Participants included 169 mother-child pairs from the Early Autism Risk Longitudinal Investigation (EARLI), which enrolled mothers who had an autistic child from a previous pregnancy and followed them through a subsequent pregnancy and until that child reached age 3 years. Maternal urine samples were collected during the second trimester of pregnancy and were later measured for levels of isoprostanes. Child neurodevelopmental assessments included the Mullen Scales of Early Learning (MSEL), the Social Responsiveness Scale (SRS), and the Vineland Adaptive Behavior Scale (VABS), and were conducted around 36 months of age. Primary analyses examined associations between interquartile range (IQR) increases in 8-iso-PGF2α levels, and total composite scores from each assessment using quantile regression. In adjusted analyses, we did not observe statistically significant associations, though estimates suggested modestly lower cognitive scores (ß for MSEL = -3.68, 95% CI: -10.09, 2.70), and minor increases in autism-related trait scores (ß for SRS T score = 1.68, 95% CI: -0.24, 3.60) with increasing 8-iso-PGF2α. These suggestive associations between decreased cognitive scores and increased autism-related traits with increasing prenatal oxidative stress point to the need for continued investigation in larger samples of the role of oxidative stress as a mechanistic pathway in autism and related neurodevelopmental outcomes.

Pre-Pandemic Factors Associated with Pandemic Impact and Psychosocial Distress Among Mothers of Young Children.

OBJECTIVE: To describe COVID-19 pandemic impact among mothers of young children (0-8 yrs.) and assess pre-pandemic factors associated with greater pandemic impact and psychosocial distress. METHODS: Mothers from three US birth cohorts (n=301, mean child age 2.4 years) reported on demographics and psychosocial distress (anxiety, perceived stress, financial stress) before the pandemic (2/2015-2/2020). During the pandemic (7/2020-6/2021), they completed a supplemental survey about the impact of the pandemic on their families (Coronavirus Impact Scale) and psychosocial distress. Multivariable linear and ordinal logistic regression were used to evaluate pre-pandemic factors associated with pandemic impact overall and by domain. RESULTS: Compared to pre-pandemic reports, maternal anxiety symptoms increased by 9.4%, perceived stress increased by 13.3%, and financial stress increased by 41.7%, of which all were statistically significant changes. Participants reported the most severe pandemic impact in family routines (72.4%), experiences of stress (40.2%), and social support (38.6%). Mothers with some college or a 4-year degree experienced higher overall pandemic impact compared to mothers with the least and highest education. Pre-pandemic distress was not associated with pandemic impact however, mid-pandemic, all three distress measures were significantly positively associated with overall CIS, with the largest effect size noted for perceived stress (B=1.36, 95% CI: 0.90,1.82). CONCLUSIONS: While, on average, mothers of young children experienced worsening psychosocial stress during the COVID-19 pandemic, pre-pandemic psychosocial stress alone was not prospectively associated with greater pandemic impact, suggesting that the COVID-19 pandemic may have both elaborated existing systemic social inequalities and created new burdens. WHAT'S NEW: While mothers of young children experienced worsening psychosocial distress during the pandemic, pre-pandemic psychosocial distress alone was not associated with greater family pandemic impact. The pandemic may have both exacerbated existing systemic social inequalities and created new burdens.

Association of Time in Bed, Social Jetlag, and Sleep Disturbances With Cognitive Performance in Children With ADHD.

OBJECTIVES: Children with ADHD commonly exhibit sleep disturbances, but there is limited knowledge about how sleep and sleep timing are associated with cognitive dysfunction in children with ADHD. METHODS: Participants were 350 children aged 5 to 12 years diagnosed with ADHD. Three sleep-related constructs-time in bed, social jetlag (i.e., discrepancy in sleep timing pattern between school nights and weekend nights), and sleep disturbances were measured using a caregiver-report questionnaire. Linear regression models assessed the associations between sleep-related constructs and cognitive performance. RESULTS: After adjustment for sociodemographic variables, there were few associations between time in bed or sleep disturbances and cognitive performance, however, greater social jetlag was negatively associated with processing speed (ß = -.20, 95% CI [-0.35, -0.06]), visually-based reasoning (ß = -.13, 95% CI [-0.27, 0.00]), and language-based reasoning (ß = -.22, 95% CI [-0.36, -0.08]); all p < .05). CONCLUSION: Social jetlag, but not time in bed or disturbances, was associated with lower cognitive performance among children with ADHD.

Mixture of air pollution, brominated flame retardants, polychlorinated biphenyls, per- and polyfluoroalkyl substances, and organochlorine pesticides in relation to vitamin D concentrations in pregnancy.

Over two-thirds of pregnant women in the U.S. have insufficient 25(OH)D (Vitamin D) concentrations, which can adversely impact fetal health. Several pollutants have been associated with 25(OH)D, but have not been considered in the context of chemical co-exposures. We aimed to determine associations between a broad mixture of prenatal environmental chemical exposures and 25(OH)D concentrations in mid-pregnancy. Stored mid-pregnancy serum samples were assayed from 421 women delivering live births in Southern California in 2000-2003. 25(OH)D, six BFRs, eleven polychlorinated biphenyls (PCBs), six per- and polyfluoroalkyl substances, and two organochlorine pesticides were detected in ≥60% of specimens. Gestational exposures to airborne particulate matter ≤ 10 µm (PM10) and ≤ 2.5 µm (PM2.5), nitrogen monoxide (NO), nitrogen dioxide (NO2), and ozone concentrations were derived from monitoring station data. Bayesian Hierarchical Modeling (BHM) and Bayesian Kernel Machine Regression (BKMR) analyses estimated overall mixture and individual chemical associations accounting for co-exposures and covariates with mean 25(OH)D levels, and BHM was used to estimate associations with insufficient (<75 nMol/L) 25(OH)D levels. Non-mixture associations for each chemical were estimated with linear and logistic models. PM10 [BHM estimate: -0.133 nmol/l 95% Credible Interval (-0.240, -0.026)] was associated with lower 25(OH)D in BHM and BKMR. Higher quantiles of combined exposures were associated with lower 25(OH)D, though with wide credible intervals. In non-mixture models, PM10, PM2.5, NO, and NO2 were associated with lower concentrations, while O3 and PBDE153 were associated with higher 25(OH)D and/or lower insufficiency. While some chemicals were associated with increased and others with decreased 25(OH)D concentrations, the overall mixture was associated with lower concentrations. Mixture analyses differed from non-mixture regressions, highlighting the importance of mixtures approaches for estimating real-world associations.