Background

Sibling sex ratios have been applied as an indirect test of a hypothesized association between prenatal testosterone levels and risk for autism, a developmental disorder disproportionately affecting males. Differences in sibling sex ratios between those with and without autism would provide evidence of a shared risk factor for autism and offspring sex. Conclusions related to prenatal testosterone, however, require additional assumptions. Here, we used directed acyclic graphs (DAGs) to clarify the elements required for a valid test of the hypothesis that sibling sex ratios differ between children with and without autism. We then conducted such a test using a large, population-based sample of children.

Methods

Over 1.1 million subjects, born in California from 1992-2007, and identified through birth records, were included. The association between autism diagnosis, determined using the administrative database of the California Department of Developmental Services, and the sex of the subsequent sibling was examined using generalized estimating equations. Sources of potential bias identified using DAGs were addressed.

Results

Among male children with autism, 52.2% of next-born siblings were brothers, versus 51.0% for unaffected males. For females with autism, 50.2% of following siblings were brothers versus 51.2% among control females. The relative risk of a subsequent male sibling associated with autism diagnosis was 1.02 (95% confidence interval: 0.99, 1.04).

Conclusions

In a large, population-based sample we failed to find evidence suggesting an excess of brothers among children with autism while controlling for several threats to validity. This test cannot rule out a role of any given exposure, including prenatal testosterone, in either risk of autism or offspring sex ratio, but suggests against a common cause of both.

Background

Sibling sex ratios have been applied as an indirect test of a hypothesized association between prenatal testosterone levels and risk for autism, a developmental disorder disproportionately affecting males. Differences in sibling sex ratios between those with and without autism would provide evidence of a shared risk factor for autism and offspring sex. Conclusions related to prenatal testosterone, however, require additional assumptions. Here, we used directed acyclic graphs (DAGs) to clarify the elements required for a valid test of the hypothesis that sibling sex ratios differ between children with and without autism. We then conducted such a test using a large, population-based sample of children.

Methods

Over 1.1 million subjects, born in California from 1992-2007, and identified through birth records, were included. The association between autism diagnosis, determined using the administrative database of the California Department of Developmental Services, and the sex of the subsequent sibling was examined using generalized estimating equations. Sources of potential bias identified using DAGs were addressed.

Results

Among male children with autism, 52.2% of next-born siblings were brothers, versus 51.0% for unaffected males. For females with autism, 50.2% of following siblings were brothers versus 51.2% among control females. The relative risk of a subsequent male sibling associated with autism diagnosis was 1.02 (95% confidence interval: 0.99, 1.04).

Conclusions

In a large, population-based sample we failed to find evidence suggesting an excess of brothers among children with autism while controlling for several threats to validity. This test cannot rule out a role of any given exposure, including prenatal testosterone, in either risk of autism or offspring sex ratio, but suggests against a common cause of both.

In this article we consider the importance of assessing endocrine disruption in a large new cohort that has been proposed, the National Children's Study (NCS). We briefly review evidence that endocrine disruption is a potentially important hypothesis for human studies and weigh the need to assess endocrine disruption in the NCS. We note the salient features of earlier, similar cohort studies that serve as reference points for the design of the NCS. Finally, we discuss features of the NCS that would allow or enhance assessment of endocrine disruption, even if endocrine disruption were not a primary hypothesis motivating the study. At this time, the evidence supporting endocrine disruption in humans with background-level exposures is not strong. Thus, a compelling rationale for the NCS will probably need to be based on core hypotheses that focus on other issues. Nonetheless, if properly designed, the NCS could serve as an excellent resource for investigating future hypotheses regarding endocrine disruption.

For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Early theories about psychic conflict and toxic parenting have been replaced by more recent formulations of complex interactions of genes and environment. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. The mechanisms for these effects remain almost as much a mystery today as they were a century ago. Recent studies suggest that maternal diet can program offspring growth and metabolic pathways, altering lifelong susceptibility to diabetes and obesity. If maternal psychosocial experience has similar programming effects on the developing offspring, one might expect a comparable contribution to neurodevelopmental disorders, including affective disorders, schizophrenia, autism, and eating disorders. Due to their early onset, prevalence, and chronicity, some of these disorders, such as depression and schizophrenia, are among the highest causes of disability worldwide according to the World Health Organization 2002 report. Consideration of the early life programming and transcriptional regulation in adult exposures supports a critical need to understand epigenetic mechanisms as a critical determinant in disease predisposition. Incorporating the latest insight gained from clinical and epidemiological studies with potential epigenetic mechanisms from basic research, the following review summarizes findings from a workshop on Early Life Programming and Neurodevelopmental Disorders held at the University of Pennsylvania in 2009.

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.

Extensive evidence leads us to expect that health disparities by race and socioeconomic status found in one generation might be reproduced in the next. To the extent that this occurs it is important to assess life course processes responsible for the reproduction. Prospective evidence concerning such life course processes is hard to come by as it requires long-term follow-up of individuals from childhood through adult life. We present data from the Child Health and Development Disparities study that provides evidence relevant to this issue with respect to self-rated health. Mothers and offspring recruited in California's Bay Area between 1959 and 1967 were assessed during pregnancy with follow-up exams of offspring along with in-person interviews with mothers (at offspring ages 5, 9-11, 15-17) and offspring (at ages 15-17, ∼50). Available data allow us to assess the importance of three potential life course pathways in the reproduction of inequalities in self-rated health - socioeconomic pathways, cognitive pathways and pathways involving emerging health itself. As expected we found that race and SES disparities in SRH are reproduced across generations. They are evident in mothers, not strong or significant in offspring at 15-17, but present once again in offspring at age ∼50. Concerning potential pathways, we found that indicators of child health were related to adult SRH and played some role in accounting for race but not SES disparities in adult SRH. Cognitive abilities were unrelated to adult SRH with childhood SES controlled. Childhood SES was associated with adult SRH independent of other childhood factors and is reduced to non-significance only when offspring college attainment is controlled. Race and SES disparities in self-reported health in one generation are re-expressed in the next with strongest support for SES pathways in this transmission.

Background

Delayed 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.

Objective

To 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).

Methods

Participants 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.

Results

The 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.

Conclusions

The 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.

Extensive evidence leads us to expect that health disparities by race and socioeconomic status found in one generation might be reproduced in the next. To the extent that this occurs it is important to assess life course processes responsible for the reproduction. Prospective evidence concerning such life course processes is hard to come by as it requires long-term follow-up of individuals from childhood through adult life. We present data from the Child Health and Development Disparities study that provides evidence relevant to this issue with respect to self-rated health. Mothers and offspring recruited in California's Bay Area between 1959 and 1967 were assessed during pregnancy with follow-up exams of offspring along with in-person interviews with mothers (at offspring ages 5, 9-11, 15-17) and offspring (at ages 15-17, ∼50). Available data allow us to assess the importance of three potential life course pathways in the reproduction of inequalities in self-rated health - socioeconomic pathways, cognitive pathways and pathways involving emerging health itself. As expected we found that race and SES disparities in SRH are reproduced across generations. They are evident in mothers, not strong or significant in offspring at 15-17, but present once again in offspring at age ∼50. Concerning potential pathways, we found that indicators of child health were related to adult SRH and played some role in accounting for race but not SES disparities in adult SRH. Cognitive abilities were unrelated to adult SRH with childhood SES controlled. Childhood SES was associated with adult SRH independent of other childhood factors and is reduced to non-significance only when offspring college attainment is controlled. Race and SES disparities in self-reported health in one generation are re-expressed in the next with strongest support for SES pathways in this transmission.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.