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To examine associations between adverse childhood experiences (ACEs) and age-specific insufficient sleep duration (ISD) in American youth.Data from the 2016-2017 National Survey of Children's Health, a sample of 46,209 youth ages 6 to 17 were analyzed. The main outcome was sleep duration that did not meet the recent recommendations of the American Academy of Sleep Medicine. Nine types of ACEs, as well as a cumulative count of ACEs, were examined as independent variables in unadjusted and adjusted logistic regression models.Approximately half of U.S. children and adolescents (ages 6-17) experienced at least one ACE and a third did not get sufficient sleep. Among those exposed to any ACE, 40.3% had ISD. Seven of the 9 ACEs examined were significantly associated with a 20% to 60% increase in odds of not getting sufficient sleep (adjusted ORs between 1.2 and 1.6). Children exposed to 2 or more ACEs were nearly twice as likely as those exposed to no ACE to have ISD (adjusted OR = 1.7, 95% CI: 1.5-1.9). Moreover, each individual ACE, except parental death was significantly associated with more than 1 hour less sleep than recommended.This study reports the association of specific and cumulative ACEs with ISD in a nationally representative sample of American youth. The study findings underscore the importance of screening for both ACEs and insufficient sleep during primary care encounters and addressing potential sleep problems in those exposed to ACEs.

The aim of this study was to assess occupational circumstances associated with adverse mental health among health care workers during the COVID-19 pandemic.A cross-sectional study examined responses to an on-line survey conducted among 2076 licensed health care workers during the first pandemic peak. Mental health (depression, anxiety, stress, and anger) was examined as a multivariate outcome for association with COVID-related occupational experiences.Odds of negative mental health were increased among those who worked directly with patients while sick themselves (adjusted odds ratio, 2.29; 95% confidence interval, 1.71-3.08) and were independently associated with working more hours than usual in the past 2 weeks, having family/friends who died due to COVID-19, having COVID-19 symptoms, and facing insufficiencies in personal protective equipment/other shortages.Occupational circumstances were associated with adverse mental health outcomes among health care workers during the COVID-19 pandemic, and some are potentially modifiable.

Epidemiological studies and work in animal models indicate that immune activation may be a risk factor for autism spectrum disorders (ASDs). We measured levels of 60 cytokines and growth factors in 869 maternal mid-gestational (MMG) and 807 child cord blood (CB) plasma samples from 457 ASD (385 boys, 72 girls) and 497 control children (418 boys, 79 girls) from the Norwegian Autism Birth Cohort. We analyzed associations first using sex-stratified unadjusted and adjusted logistic regression models, and then employed machine learning strategies (LASSO + interactions, Random Forests, XGBoost classifiers) with cross-validation and randomly sampled test set evaluation to assess the utility of immune signatures as ASD biomarkers. We found prominent case-control differences in both boys and girls with alterations in a wide range of analytes in MMG and CB plasma including but not limited to IL1RA, TNFα, Serpin E1, VCAM1, VEGFD, EGF, CSF1, and CSF2. MMG findings were most striking, with particularly strong effect sizes in girls. Models did not change appreciably upon adjustment for maternal conditions, medication use, or emotional distress ratings. Findings were corroborated using machine learning approaches, with area under the receiver operating characteristic curve values in the test sets ranging from 0.771 to 0.965. Our results are consistent with gestational immunopathology in ASD, may provide insights into sex-specific differences, and have the potential to lead to biomarkers for early diagnosis.

The purpose of this study was to investigate the association between personal religiosity, mental health, and substance use outcomes among Black and Hispanic adults during the first six months of the COVID-19 outbreak in New York City (NYC). Phone interviews were conducted with 441 adults to obtain information on all variables. Participants self-reported race/ethnicity as Black/African American (n = 108) or Hispanic (n = 333). Logistic regression were used to examine associations between religiosity, mental health, and substance use. There was a significant inverse association of religiosity and substance use. Religious people had a lower prevalence of drinking alcohol (49.0%) compared to non-religious people (67.1%). Religious people also had substantially lower prevalence of cannabis or other drug use (9.1%) in comparison to non-religious people (31%). After adjusting for age, sex, race/ethnicity, and household income, the association of religiosity with alcohol use and with cannabis/other drug use remained statistically significant. Despite restricted access to in-person religious activities and congregational supports, the findings suggest that religiosity itself may be helpful from a public health perspective, independent of serving as a conduit for other social services.

Introduction Maternal stress during pregnancy has been repeatedly linked to increased risk for schizophrenia; however, no study has examined maternal cortisol during pregnancy and risk for the disorder. Study aims were to determine whether prenatal cortisol was associated with risk for schizophrenia and risk for an intermediate phenotype—decreased fetal growth—previously linked to prenatal cortisol and schizophrenia. Timing of exposure and fetal sex also were examined given previous findings. Methods Participants were 64 cases diagnosed with schizophrenia spectrum disorders (SSD) and 117 controls from a prospective birth cohort study. Maternal cortisol was determined from stored sera from each trimester and psychiatric diagnoses were assessed from offspring using semi-structured interviews and medical records review. Results Maternal cortisol during pregnancy was not associated with risk for offspring schizophrenia. There was a significant interaction between 3rd trimester cortisol and case status on fetal growth. Specifically, cases exposed to higher 3rd trimester maternal cortisol had significantly decreased fetal growth compared to controls. In addition, these findings were restricted to male offspring. Conclusions Our results indicate that higher prenatal cortisol is associated with an intermediate phenotype linked to schizophrenia, fetal growth, but only among male offspring who developed schizophrenia. Findings were consistent with evidence that schizophrenia genes may disrupt placental functioning specifically for male fetuses, as well as findings that males are more vulnerable to maternal cortisol during pregnancy. Finally, results suggest that examining fetal sex and intermediate phenotypes may be important in understanding the mechanisms involved in prenatal contributors to schizophrenia.

Housing subsidies, including public housing and Section 8 vouchers, are key components of the social safety net, intended to promote family and child welfare. Studies evaluating the impact of housing subsidies on child and adolescent mental health, however, are generally inconclusive. This may reflect variation in the influence by type of subsidies to income, improved physical environment, increased access to resources, and improved perception of neighborhood safety. Further, most prior research focused on housing subsidies failed to simultaneously formally assess child psychopathology. In the present study, we examine, among adolescents (ages 9-17) from a low-income, urban minority area, the association of housing with psychiatric symptoms and disorders, as well as with their social functioning. The data were obtained from the Stress & Justice Study (S&J) baseline survey, an investigation designed to examine impact of parental criminal justice system involvement (CJSI) on their children's mental health. Housing type during the past year was categorized from parental report as public housing, section 8, both, or neither. Child mental health was assessed with the Diagnostic Interview Schedule for Children (DISC). Additionally, family resources and physical quality of the housing environment by housing type was assessed, and we tested whether these dimensions mediated associations of housing type with the adolescent's current mental health outcomes. We found that while internalizing and externalizing disorders and impairment were attenuated by individual characteristics (e.g., SES, CJSI), internalizing and externalizing symptom counts were significantly more prevalent among children in subsidized housing, compared to those in non-subsidized housing, after controlling for individual characteristics. These findings have the potential to inform whether, and through which mechanisms, housing subsidies are associated with adolescent mental health.

Modified labeling theory theorizes that when people acquire a label, personally held views about that label gain relevance and exert negative effects. We assessed whether being arrested reduces self-esteem to different extents based on the degree to which individuals hold stigmatizing beliefs about people with arrest records.Adults living in the South Bronx, New York City (N = 532, 56% of whom had ever been arrested) indicated their level of agreement with statements about people with arrest records. We used exploratory factor analysis to identify categories of stigmatizing views, and calculated scores for the two following categories: "stereotype awareness" and "stereotype agreement." Self-esteem was assessed with the Rosenberg self-esteem scale. Using fitted linear regression models, we assessed interaction between arrest history and each stigma score, and calculated mean differences representing the association between arrest history and self-esteem score, for those with stigma scores one standard deviation (SD) below and above the mean.For each type of stigma, participants with stigma scores one SD below the mean had similar self-esteem scores, regardless of arrest history. However, among participants with stigma scores one SD above the mean, those who had experienced an arrest had lower self-esteem scores than those who had not (mean difference = - 2.07, 95% CI - 3.16, - 0.99 for "stereotype awareness"; mean difference = - 2.92, 95% CI - 4.05, - 1.79 for "stereotype agreement").Being arrested affects self-esteem to a greater degree among persons who hold stigmatizing views about people with arrest records. These findings support a modified labeling theory of arrest-related stigma.

Objective Familial recurrence risk is an important population-level measure of the combined genetic and shared familial liability of autism spectrum disorder (ASD). Objectives were to estimate ASD recurrence risk among siblings and cousins by varying degree of relatedness and by sex. Method This is a population-based cohort study of livebirths from 1998 to 2007 in California, Denmark, Finland, Israel, Sweden and Western Australia followed through 2011 to 2015. Subjects were monitored for an ASD diagnosis in their older siblings or cousins (exposure) and for their ASD diagnosis (outcome). The relative recurrence risk was estimated for different sibling and cousin pairs, for each site separately and combined, and by sex. Results During follow-up, 29,998 cases of ASD were observed among the 2,551,918 births used to estimate recurrence in ASD and 33,769 cases of childhood autism (CA) were observed among the 6,110,942 births used to estimate CA recurrence. Compared with the risk in unaffected families, there was an 8.4-fold increase in the risk of ASD following an older sibling with ASD and a 17.4-fold increase in the risk of CA following an older sibling with CA. A 2-fold increase in the risk for cousin recurrence was observed for the 2 disorders. There also was a significant difference in sibling ASD recurrence risk by sex. Conclusion The present estimates of relative recurrence risks for ASD and CA will assist clinicians and families in understanding autism risk in the context of other families in their population. The observed variation by sex underlines the need to deepen the understanding of factors influencing ASD familial risk.

Maternal fever during pregnancy is associated with several adverse child outcomes. We investigated associations between maternal fever and ADHD among offspring, as well as the sub-dimensions of ADHD - inattention and hyperactivity/impulsivity. Data came from the Norwegian Mother and Child Cohort Study, including more than 114,000 children. Information about children’s ADHD diagnoses was obtained from the Norwegian Patient Register. Mothers reported on inattention and hyperactivity/impulsivity symptoms in questionnaires at 8 years. Logistic regression analysis showed that children exposed to maternal fever in the first trimester received an ADHD diagnosis more often than unexposed children (Odds Ratio (OR) = 1.31, 95% confidence interval (CI) = 1.06–1.61). For children exposed twice or more in the first trimester, the OR was 2.64 (CI = 1.36–5.14). Linear regression analysis showed elevated inattention symptoms among children exposed to fever in the first (Cohen’s d = 0.09, CI = 0.03–0.15) and second (Cohen’s d = 0.05, CI = 0.01–0.09) trimester. Results were similar whether the mother had taken acetaminophen for their fever or not. Hyperactivity/impulsivity symptoms were not related to maternal fever. The results indicate that maternal fever in early pregnancy may be a risk factor for ADHD, and particularly for inattention problems. This risk is neither mitigated nor inflated by use of acetaminophen.

Studies of the relationship between neighborhood characteristics and childhood/adolescent psychopathology in large samples examined one outcome only, and/or general (e.g., ‘psychological distress’) or aggregate (e.g., ‘any anxiety disorder’) measures of psychopathology. Thus, in the only representative sample of New York City public school 4th-12th graders (N = 8202) surveyed after the attacks of 9/11/2001, this study examined whether (1) indices of neighborhood Socioeconomic Status, Quality, and Safety and (2) neighborhood disadvantage (defined as multidimensional combinations of SES, Quality and Safety indicators) are associated with eight psychiatric disorders: posttraumatic stress disorder, separation anxiety disorder (SAD), agoraphobia, generalized anxiety disorder (GAD), panic disorder, major depression, conduct disorder, and alcohol use disorder (AUD). (1) The odds ratios (OR) of psychiatric disorders were between 0.55 (AUD) and 1.55 (agoraphobia), in low and intermediate-low SES neighborhoods, respectively, between 0.50 (AUD) and 2.54 (agoraphobia) in low Quality neighborhoods, and between 0.52 (agoraphobia) and 0.65 (SAD) in low Safety neighborhoods. (2) In neighborhoods characterized by high disadvantage, the OR were between 0.42 (AUD) and 1.36 (SAD). This study suggests that neighborhood factors are important social determinants of childhood/adolescent psychopathology, even in the aftermath of mass trauma. At the community level, interventions on modifiable neighborhood characteristics and targeted resources allocation to high-risk contexts could have a cost-effective broad impact on children's mental health. At the individual-level, increased knowledge of the living environment during psychiatric assessment and treatment could improve mental health outcomes; for example, specific questions about neighborhood factors could be incorporated in DSM-5's Cultural Formulation Interview.

Background: Maternal acetaminophen use during pregnancy is associated with increased risk of ADHD in the child. This could reflect causal influence of acetaminophen on fetal neurodevelopment or could be due to confounding factors. The aim of the current study was to examine unmeasured familial confounding factors of this association. Methods: We used data from 26,613 children from 12,902 families participating in the prospective Norwegian Mother, Father, and Child Cohort Study (MoBa). The MoBa was linked to the Norwegian Medical Birth Register and the Norwegian Patient Registry. Siblings discordant for prenatal acetaminophen exposure were compared regarding risk of having an ADHD diagnosis. Results: Children exposed to acetaminophen up to 28 days during pregnancy did not have increased risk of receiving an ADHD diagnosis compared to unexposed children. The adjusted Hazard ratio (aHR) was 0.87 (95% C.I. = 0.70-1.08) for exposure 1 to 7 days, and 1.13 (95% C.I. = 0.82–1.49) for 8–28 days. Long-term exposure (29 days or more) was associated with a two-fold increase in risk of ADHD diagnosis (aHR = 2.02, 95% C.I = 1.17–3.25). In the sibling control model, the association between long-term acetaminophen use and ADHD in the child was aHR = 2.77 (95% C.I. = 1.48–5.05) at the between-family level, and aHR = 1.06 (95% C.I. = 0.51–2.05) at the within-family level. Conclusions: Both the exposed and the unexposed children of mothers with long-term use of acetaminophen in one of the pregnancies had increased risk of receiving an ADHD diagnosis. This indicates that the observed association between long-term acetaminophen use during pregnancy and ADHD in the child may at least partly be confounded by unobserved family factors. publishedVersion

BackgroundDelayed walking is common in intellectual disability (ID) but may be less common when ID occurs with autism spectrum disorder (ASD). Previous studies examining this were limited by reliance on clinical samples and exclusion of children with severe motor deficits.ObjectiveTo examine in a population-based sample if age of walking is differentially related to intellectual ability in children with ASD versus other neurodevelopmental disorders (NDD).MethodsParticipants were from the nested Autism Birth Cohort Study of the Norwegian Mother, Father and Child Cohort Study (MoBa). Cox proportional hazards regression assessed if diagnosis (ASD n=212 vs. NDD n=354), continuous nonverbal IQ, and their interaction, were associated with continuous age of walking.ResultsThe relationship between nonverbal IQ and age of walking was stronger for NDD than for ASD (Group×nonverbal IQ interaction, χ2 =13.93, p=.0002). This interaction was characterized by a 21% decrease in the likelihood of walking onset at any given time during the observation period per 10-point decrease in nonverbal IQ (hazard ratio=0.79, 95% CI: 0.78-0.85) in the NDD group compared to 8% (hazard ratio=0.92, 95% CI: 0.86-0.98) in the ASD group.ConclusionsThe finding that age of walking is less strongly related to low intellectual ability in children with ASD than in children without other NDDs supports the hypothesis that ID in ASD may result from heterogeneous developmental pathways. Late walking may be a useful stratification variable in etiological research focused on ASD and other NDDs.

While both direct and indirect exposure to mass trauma are increasing in the United States, relatively little is known about the potential link between mass trauma and risk of panic disorder early in life. It is also unclear whether history of prior individual trauma increases risk of panic disorder even further among those with exposure to mass trauma. The current study investigated the association between exposure to a mass trauma event (the World Trade Center (WTC) attack) and risk of panic disorder among children, how panic disorder varies by exposure severity and sociodemographic characteristics, and whether there is an interaction between individual and mass trauma exposure in the risk of panic disorder. Data were from an epidemiologic study of probable mental disorders among New York City schoolchildren exposed to the WTC terrorist attack. Severe (adjusted odds ratio [AOR] = 2.0 (1.1, 3.7)) exposure to the WTC disaster was associated with increased odds of probable panic disorder, relative to mild exposure. The prevalence of panic disorder increased with higher level of WTC exposure among all sociodemographic strata. Prior individual trauma exposure was associated with increased odds of panic disorder (AOR = 2.4 (1.6, 3.5)), but there was no evidence of interaction between prior individual trauma exposure and exposure to the WTC disaster. Preventive measures to address the widespread nature of mass disaster exposure at increasingly earlier ages and via media could mitigate the potential impact on mental health.

Objective To examine the association between parental occupational exposure to traumatic events and their children's mental health in families of First Responders (FRs), a neglected area of research. Methods In 208 families of Israeli FRs, children's symptoms and comorbidity patterns of seven psychiatric disorders were regressed on parental work-related variables, controlling for relevant covariates. Results Having a father working as a FR and higher paternal exposure were associated with a greater number of separation anxiety and posttraumatic stress symptoms, respectively. Maternal exposure was associated with a greater number of symptoms of generalized anxiety, panic disorder, depression, and oppositional defiant disorder, and with increased odds of comorbid internalizing symptomatology. Conclusions Additional research on children of FRs is encouraged. An adaption to this understudied population of family-centered interventions available for military families could inform targeted prevention efforts.

Early identification of autism spectrum disorder (ASD) is regarded as crucial for swift access to early intervention and, subsequently, better outcomes later in life. However, current instruments miss large proportions of children who later go on to be diagnosed with ASD, raising a question of what these instruments measure. The present study utilized data from the Norwegian Mother, Father, and Child Cohort Study and the Autism Birth Cohort study to explore the subsequent developmental and diagnostic characteristics of children raising developmental concern on the six-critical discriminative item criterion of the M-CHAT (DFA6) at 18 months of age (N = 834). The DFA6 identified 28.8% of children diagnosed with ASD (N = 163), but 4.4% with language disorder (N = 188) and 81.3% with intellectual disability (N = 32) without ASD. Scoring in the «at-risk» range was associated with lower IQ, impaired functional language, and greater severity of autism symptoms whether children had ASD or not.

The parental report-based Autism Diagnostic Interview-Revised (ADI-R) and the clinician observation-based Autism Diagnostic Observation Schedule (ADOS) have been validated primarily in U.S. clinics specialized in autism spectrum disorder (ASD), in which most children are referred by their parents because of ASD concern. This study assessed diagnostic agreement of the ADOS-2 and ADI-R toddler algorithms in a more broadly based sample of 679 toddlers (age 35–47 months) from the Norwegian Mother and Child Cohort. We also examined whether parental concern about ASD influenced instrument performance, comparing toddlers identified based on parental ASD concern (n = 48) and parent-reported signs of developmental problems (screening) without a specific concern about ASD (n = 400). The ADOS cutoffs showed consistently well-balanced sensitivity and specificity. The ADI-R cutoffs demonstrated good specificity, but reduced sensitivity, missing 43% of toddlers whose parents were not specifically concerned about ASD. The ADI-R and ADOS dimensional scores agreed well with clinical diagnoses (area under the curve ≥ 0.85), contributing additively to their prediction. On the ADI-R, different cutoffs were needed according to presence or absence of parental ASD concern, in order to achieve comparable balance of sensitivity and specificity. These results highlight the importance of taking parental concern about ASD into account when interpreting scores from parental report-based instruments such as the ADI-R. While the ADOS cutoffs performed consistently well, the additive contributions of ADI-R and ADOS scores to the prediction of ASD diagnosis underscore the value of combining instruments based on parent accounts and clinician observation in evaluation of ASD. Autism Res 2017, 10: 1672–1686. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Background and objectives Cumulative exposure to work-related traumatic events (CE) is a foreseeable risk for psychiatric disorders in first responders (FRs). Our objective was to examine the impact of work-related CE that could serve as predictor of posttraumatic stress disorder (PTSD) and/or depression in FRs. Design Cross-sectional examination of previous CE and past-month PTSD outcomes and depression in 209 FRs. Methods Logistic (probable PTSD; probable depression) and Poisson regressions (PTSD score) of the outcomes on work-related CE indexes, adjusting for demographic variables. Differences across occupational groups were also examined. Receiver operating characteristic analysis determined the sensitivity and specificity of CE indexes. Results All indexes were significantly and differently associated with PTSD; associations with depression were non-significant. The index capturing the sheer number of different incidents experienced regardless of frequency (‘Variety’) showed conceptual, practical and statistical advantages compared to other indexes. In general, the indexes showed poor to fair discrimination accuracy. Conclusions Work-related CE is specifically associated with PTSD. Focusing on the variety of exposures may be a simple and effective strategy to predict PTSD in FRs. Further research on sensitivity and specificity of exposure indexes, preferably examined prospectively, is needed and could lead to early identification of individuals at risk.

Background Early identification and diagnosis is beneficial for children with autism spectrum disorder (ASD). Universal early screening is recommended by many experts, but disputed because evidence is limited, and sensitivity and specificity in general populations are largely unknown. Aims To estimate the sensitivity and specificity of early population-based screening for ASDs. Method The study was based on the Norwegian Mother and Child Cohort Study. The 36-month cohort questionnaire included the Social Communication Questionnaire (SCQ), a 40-item screening instrument for ASD. Results A total of 58 520 mothers (58%) responded to the questionnaire. By the end of follow-up on 31 December 2015, 385 (0.7%) individuals with ASD had been identified among the responders' children. The distributions of SCQ scores in those with ASD and other children had large degrees of overlap. With the cut-off of 15 recommended in the SCQ manual, screening sensitivity was 20% (95% CI 16–24) for ASD overall. For children with ASD who had not developed phrase speech at 36 months, sensitivity was 46% (95% CI 35–57%), whereas it was 13% (95% CI 9–17) for children with ASD with phrase speech. Screening specificity was 99% (95% CI 99–99). With the currently recommended cut-off of 11, sensitivity increased to 42% for ASD overall (95% CI 37–47), 69% (95% CI 58–79) for ASD without phrase speech and 34% (95% CI 29–40) for ASD with phrase speech. Specificity was then reduced to 89% (95% CI 89–90). Conclusions Early ASD screening with a parent checklist had low sensitivity. It identified mainly individuals with ASD with significant developmental delay and captured very few children with ASD with cognitive skills in the normal range. Increasing sensitivity was not possible without severely compromising specificity. Declaration of interest C.L. receives royalty for the Social Communication Questionnaire, which she has co-authored.

BACKGROUND: Maternal stress during pregnancy has been repeatedly linked to increased risk for schizophrenia; however, no study has examined whether maternal cortisol during pregnancy is associated with risk for the disorder. This study aimed to determine whether higher maternal cortisol during pregnancy was associated with increased risk for schizophrenia and risk for an intermediate phenotype-decreased fetal growth-previously linked to higher prenatal cortisol and schizophrenia. Timing of exposure and fetal sex also were examined given previous findings indicating that these variables are important in fetal responses to cortisol. METHODS: Participants were 64 cases diagnosed with schizophrenia spectrum disorders (SSD) and 117 controls from a prospective birth cohort study. Maternal cortisol during pregnancy was determined from stored sera from each trimester and psychiatric diagnoses were assessed from offspring using semi-structured interviews and medical records review. RESULTS: Maternal cortisol during pregnancy was not associated with risk for offspring schizophrenia. There was a significant interaction between 3rd trimester cortisol and case status on birth weight, controlling for gestational age. Specifically, cases exposed to higher 3rd trimester cortisol had significantly decreased fetal growth compared to controls. In addition, these findings were restricted to male offspring. DISCUSSION: Our results indicate that higher prenatal cortisol is associated with an intermediate phenotype linked to schizophrenia, fetal growth, but only among male offspring who developed schizophrenia. These results are consistent with evidence suggesting that schizophrenia genes may disrupt placental functioning specifically for male fetuses, as well as findings indicating that males are more vulnerable to maternal cortisol during pregnancy. Finally, our results suggest that examining fetal sex and intermediate phenotypes may be important in understanding the mechanisms involved in prenatal contributors to schizophrenia.

There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10 −7 . Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR . Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.

Background Subclinical psychotic experiences (PLEs) are among the frequently reported mental health problems in children/adolescents. PLEs identified in cross sectional studies of children/adolescents are associated with current and future mental health problems. These associations are stronger for PLEs that persist over time. Hence, it could be useful to examine which children/adolescents with PLEs at a first assessment (baseline) are more likely to have PLEs at subsequent assessments. Methods We conducted a scoping review of studies that examined whether characteristics of children/adolescents (≤18 years) with PLEs at baseline predict whether PLEs are likely to be persistent or remittent at subsequent assessments. We included studies published between January 2002 and December 2017, conducted on general child/adolescent populations of ≥300 individuals, that provided data on PLEs for at least 2 time points, had available follow-up data for ≥50% of those assessed for PLEs at baseline and targeted for follow-up examination, and reported the differences between individuals with PLEs that persisted or remitted during the study period. Results Six studies met our criteria. Each of them investigated a wide range of baseline characteristics but no predictor of persistence was replicated. Conclusions Our knowledge about which children/adolescents with PLEs at an initial assessment are likely to have persistent PLEs at subsequent assessments is sparse. A handful of predictors of persistent PLEs have been investigated so far, and none replicated. A better understanding of these predictors would be an important complement to investigations examining the evolution of PLEs and of mental health problems in children/adolescents.

Pakistan has been in a continuous state of low- and sometimes medium-intensity war on terrorism for nearly two decades. During this time, school children have increasingly become the target of terrorist attacks. The 2012 assassination attempt on Nobel Laureate Malala Yousafzai, a young human rights activist, brought these activities into high relief, arousing national and international sympathies and outrage. The largest, most brutal attack occurred on Dec 16, 2014, in Peshawar, when 150 children were killed while in school. The Army Public School massacre was unique. The catastrophic devastation affected not only victims and their close relatives but the whole country. The immediate challenge was to address the mental health needs and psychosocial rehabilitation of those living in the affected community. Government social intervention efforts were necessarily complemented by community mobilization. Horizon, a local NGO with expertise in psychosocial rehabilitation following disasters, volunteered to perform a quantitative needs assessment and diagnostic evaluation study with 50 affected families in the nearby community. At the end of 6 months, more than 36% of children studied met the criteria for PTSD. Special training workshops for teachers, doctors, and media were arranged. These workshops prepared the affected families and community to increase their resilience. Given the limited capacity to respond to these crises, the concluding recommendation is that the government become more involved in helping make available an improved system of mental health care, both to prevent problems and respond to them.

Low Apgar score has been associated with higher risk for several neurological and psychiatric disorders, including cerebral palsy and intellectual disability. Studies of the association between Apgar score and autism spectrum disorder (ASD) have been inconsistent. We aimed to investigate (1) the association between low Apgar score at 5 min and risk for ASD, and (2) the modifying effects of gestational age and sex on this association in the largest multinational database of ASD. We included prospective data from 5.5 million individuals and over 33,000 cases of ASD from Norway, Sweden, Denmark and Western Australia who were born between 1984 and 2007. We calculated crude and adjusted risk ratios (RR) with 95% confidence intervals (95% CIs) for the associations between low Apgar score and ASD. All analyses for ASD were repeated for autistic disorder (AD). We used interaction terms and stratified analysis to investigate the effects of sex, gestational age, and birth weight on the association. In fully adjusted models, low Apgar scores (1-3) (RR, 1.42; 95% CI, 1.16-1.74), and intermediate Apgar scores (4-6) (RR, 1.50; 95% CI, 1.36-1.65) were associated with a higher RR of ASD than optimal Apgar score (7-10). The point estimates for low (RR, 1.88; 95% CI, 1.41-2.51) and intermediate Apgar score (RR, 1.54; 95% CI, 1.32-1.81) were larger for AD than for ASD. This study suggests that low Apgar score is associated with higher risk of ASD, and in particular AD. We did not observe any major modifying effects of gestational age and sex, although there seems to be substantial confounding by gestational age and birth weight on the observed association.

Background Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. Methods We quantified neonatal methylomic variation in 1263 infants—of whom ~ 50% went on to subsequently develop ASD—using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. Results We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of − 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. Conclusions This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants. Electronic supplementary material The online version of this article (10.1186/s13073-018-0527-4) contains supplementary material, which is available to authorized users.

Supplementary Tables S1–S7 and S9–S10. (PDF 339 kb)

Supplementary Figures S1–S23. (PDF 8163 kb)

BACKGROUND: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations.METHODS: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates 'virtual pooling' where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage.RESULTS: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory.CONCLUSIONS: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/].

The causes of most cases of autism spectrum disorders (ASD) are unknown. Some epidemiological studies suggest that maternal gestational influenza virus infection may increase the risk of ASD in offspring. Here, we describe an analysis of a large birth cohort with results based on questionnaires that prospectively addressed subjective reports of influenza-like illness and serological assays for objective determination of influenza virus infection. Although serologic evidence of gestational influenza virus infection alone was not associated with risk, positive serology and symptoms of influenza-like illness cannot yet be definitely ruled out as a risk factor., The literature concerning gestational maternal influenza virus infection and risk of autism spectrum disorders (ASD) is inconclusive. To address this uncertainty, we obtained information from questionnaires and samples from the Autism Birth Cohort, a prospective birth cohort comprising mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaires, referrals, and linkages to the Norwegian National Patient Registry, we identified 338 mothers of children with ASD and 348 frequency-matched controls for whom plasma samples that had been collected midpregnancy and after delivery were available for influenza virus serology via luciferase immunoprecipitation and hemagglutinin inhibition assays for influenza virus strains circulating during the study period. Assay data were combined to define serological status and integrated with self-reports of influenza-like illness to estimate ASD risk. Neither influenza A nor influenza B virus infection was associated with increased ASD risk. Integration of reports of symptoms of influenza-like illness with serology revealed an increase in risk for seropositive women with symptoms, but this increase did not achieve statistical significance (a level of P < 0.05) in the comparison with seronegative women without symptoms (adjusted odds ratio, 1.93; 95% confidence interval, 0.95 to 3.89; P = 0.068). Although chance may explain our findings, the magnitude of the potential association may be of biological importance, and dismissing our findings could result in failure to detect a bona fide association (type II error). If the association is true, we posit that the risk is due to activation of the maternal immune system following infection rather than direct fetal infection. Data on levels of cytokines or other mediators of inflammation would allow us to test the validity of this hypothesis. IMPORTANCE The causes of most cases of autism spectrum disorders (ASD) are unknown. Some epidemiological studies suggest that maternal gestational influenza virus infection may increase the risk of ASD in offspring. Here, we describe an analysis of a large birth cohort with results based on questionnaires that prospectively addressed subjective reports of influenza-like illness and serological assays for objective determination of influenza virus infection. Although serologic evidence of gestational influenza virus infection alone was not associated with risk, positive serology and symptoms of influenza-like illness cannot yet be definitely ruled out as a risk factor.

The extensive comorbidity of psychiatric disorders in children and adolescents leads to clinical heterogeneity, and is an often-overlooked issue in etiopathogenic and treatment studies in developmental psychopathology. In a representative sample (N=8236) of New York City public school students assessed six months after 9/11, latent class analysis was applied to 48 symptoms across seven disorders: posttraumatic stress, agoraphobia, separation anxiety, panic disorder, generalized anxiety (GAD), major depression (MDD) and conduct disorder (CD). Our objective was to identify classes defined by homogenous symptom profiles, and to examine the association between class membership and gender, age, race, different types of exposure to 9/11, and impairment. Eight homogenous comorbidity patterns were identified, including four severe disturbance classes: a multimorbid internalizing class (INT), a class with a high probability of CD, MDD, and GAD symptoms (Distress/EXT), a non-comorbid externalizing class, and a non-comorbid MDD class. Demographic and 9/11-related exposures showed some degree of specificity in their association with severe symptom profiles. Impairment was particularly high in the INT and Distress/EXT classes. A better characterization of phenomic data, that takes comorbidity into account, is essential to understand etiopathogenic processes, and to move psychiatric research forward towards personalized medicine. The high probability of endorsing symptoms of multiple disorders in the INT and Distress/EXT classes supports the use of treatments focusing on multimorbidity. Clinical trials should evaluate the effectiveness of disorder-specific versus transdiagnostic interventions. The association between class membership and demographic and exposure variables suggests that interventions may be improved by considering specific predictors of class membership.

Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to

The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy., Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and HSV-2 in plasma collected at midpregnancy and after delivery were measured by multiplexed immunoassays. High levels of HSV-2 IgG antibodies in maternal midpregnancy plasma were associated with increased risk of ASD in male offspring (an increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was associated with an odds ratio of 2.07; 95% confidence interval, 1.06 to 4.06; P = 0.03) when adjusted for parity and child’s birth year. No association was found between ASD and the presence of IgG antibodies to Toxoplasma gondii, rubella virus, CMV, or HSV-1. Additional studies are needed to test for replicability of risk and specificity of the sex effect and to examine risk associated with other infections. IMPORTANCE The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy.

Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born greater than or equal to 32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09–1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks' gestation (aOR, 3.12; 1.28–7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks' gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD. publishedVersion

Background Previous research on clinical and high-risk samples suggests that signs of autism spectrum disorder (ASD) can be detected between 1 and 2 years of age. We investigated signs of ASD at 18 months in a population-based sample and the association with later ASD diagnosis. Methods The study sample includes 52 026 children born 2003 through 2008 and is a subset of children that participated in the Norwegian Mother and Child Cohort (MoBa), a population-based longitudinal study, and the Autism Birth Cohort (ABC), a sub-study on ASD. Parents completed all 23 items from the Modified Checklist for Autism in Toddlers (M-CHAT) at 18 months. Results The M-CHAT 6-critical-item criterion and the 23-item criterion had a specificity of 97.9% and 92.7% and a sensitivity of 20.8% and 34.1%, respectively. In the 173 children diagnosed with ASD to date, 60 children (34.7%) scored above the cut-off on either of the screening criteria. The items with the highest likelihood ratios were ‘interest in other children’, ‘show objects to others’ and ‘response to name’. Conclusion Even though one-third of the children who later received an ASD diagnosis were identified through M-CHAT items, the majority scored below cut-off on the screening criteria at 18 months. The results imply that it might not be possible to detect all children with ASD at this age.

BACKGROUND A recent California study reported increased risk of autistic disorder in children conceived within a year after the birth of a sibling. METHODS We assessed the association between interpregnancy interval and risk of autistic disorder using nationwide registry data on pairs of singleton full siblings born in Norway. We defined interpregnancy interval as the time from birth of the first-born child to conception of the second-born child in a sibship. The outcome of interest was autistic disorder in the second-born child. Analyses were restricted to sibships in which the second-born child was born in 1990-2004. Odds ratios (ORs) were estimated by fitting ordinary logistic models and logistic generalized additive models. RESULTS The study sample included 223,476 singleton full-sibling pairs. In sibships with interpregnancy intervals

Background This study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders.

The reported prevalence of autism spectrum disorders (ASDs) has increased by 5- to 10-fold over the past 20 years. Whether ASDs are truly more frequent is controversial; nonetheless, the burden is profound in human and economic terms. Although autism is among the most heritable of mental disorders, its pathogenesis remains obscure. Environmental factors are proposed; however, none is implicated. Furthermore, there are no biomarkers to screen for ASD or risk of ASD. The Autism Birth Cohort (ABC) was initiated to analyze gene x environment x timing interactions and enable early diagnosis. It uses a large, unselected birth cohort in which cases are prospectively ascertained through population screening. Samples collected serially through pregnancy and childhood include parental blood, maternal urine, cord blood, milk teeth and rectal swabs. More than 107,000 children are continuously screened through questionnaires, referral, and a national registry. Cases are compared with a control group from the same cohort in a 'nested case-control' design. Early screening and diagnostic assessments and re-assessments are designed to provide a rich view of longitudinal trajectory. Genetic, proteomic, immunologic, metagenomic and microbiological tools will be used to exploit unique biological samples. The ABC is a paradigm for analyzing the role of genetic and environmental factors in complex disorders.

To study autism outside of a narrow range of settings previously studied, and in a particularly distinctive setting in the Caribbean. The aim of the Aruba Autism Project was to determine the prevalence of autism spectrum disorders (ASDs) in birth years 1990–1999 in Aruba. A record review study was conducted; cases were ascertained from children treated at the Child & Adolescent Psychiatry Clinic of Aruba, the first and only child psychiatry service on the island. In these 10 birth years we found a prevalence for autistic disorder (AD) of 1.9 per 1,000 (95% CI 1.2–2.8) and for autism spectrum disorders of 5.3 per 1,000 (95% CI 4.1–6.7). Comparison analysis with a cumulative incidence report from the UK, showed a similar cumulative incidence to age five in Aruba. Prevalence of ASDs in birth years 1990–1999 and cumulative incidence to age five in Aruba are similar to recent reports from the United Kingdom and the United States.