Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% [95% confidence interval (CI), 62.9 to 100], correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified [specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3)]. These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD.
Racial differences in parent report of concerns about their child’s development to healthcare providers may contribute to delayed autism spectrum disorder diagnoses in Black children. We tested the hypotheses that compared to White parents, Black parents of children with autism spectrum disorder would report fewer concerns about autism symptoms and would be more likely to report concerns about disruptive behaviors. A sample of 18- to 40-month-old toddlers ( N = 174) with autism spectrum disorder and their parent participated. After screening positive for autism spectrum disorder risk, but prior to a diagnostic evaluation, parents completed free-response questions soliciting concerns about their child’s development. Parent responses were coded for the presence or the absence of 10 possible concerns, which were grouped into autism concerns (e.g. social and restricted and repetitive behavior concerns) or non-autism concerns (e.g. general developmental and disruptive behavior concerns). Compared to White parents, Black parents reported significantly fewer autism concerns and fewer social and restricted and repetitive behavior concerns. However, Black parents did not report significantly fewer non-autism concerns. Race did not influence parent report of disruptive behavior concerns. Lower reporting of autism concerns by Black parents may impact providers’ abilities to identify children who need further screening or evaluation.
Autism spectrum disorder (ASD) is a complex and heterogeneous disorder, diagnosed on the basis of behavioral symptoms during the second year of life or later. Finding scalable biomarkers for early detection is challenging because of the variability in presentation of the disorder and the need for simple measurements that could be implemented routinely during well-baby checkups. EEG is a relatively easy-to-use, low cost brain measurement tool that is being increasingly explored as a potential clinical tool for monitoring atypical brain development. EEG measurements were collected from 99 infants with an older sibling diagnosed with ASD, and 89 low risk controls, beginning at 3 months of age and continuing until 36 months of age. Nonlinear features were computed from EEG signals and used as input to statistical learning methods. Prediction of the clinical diagnostic outcome of ASD or not ASD was highly accurate when using EEG measurements from as early as 3 months of age. Specificity, sensitivity and PPV were high, exceeding 95% at some ages. Prediction of ADOS calibrated severity scores for all infants in the study using only EEG data taken as early as 3 months of age was strongly correlated with the actual measured scores. This suggests that useful digital biomarkers might be extracted from EEG measurements.
Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.
The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.
OBJECTIVES: To investigate if children after receiving an ASD diagnosis obtain their remaining scheduled vaccines according to the Advisory Committee on Immunization Practices (ACIP) recommendations and to compare the vaccination patterns of younger siblings of children with ASD with the vaccination patterns of younger siblings of children without ASD.
DESIGN, SETTING, AND PARTICIPANTS: This investigation was a retrospective matched cohort study. The setting was 6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink. Participants were children born between January 1, 1995, and September 30, 2010, and their younger siblings born between January 1, 1997, and September 30, 2014. The end of follow-up was September 30, 2015.
EXPOSURES: Recommended childhood vaccines between ages 1 month and 12 years.
MAIN OUTCOME AND MEASURE: The proportion of children who received all of their vaccine doses according to ACIP recommendations.
RESULTS: The study included 3729 children with ASD (676 [18.1%] female), 592 907 children without ASD, and their respective younger siblings. Among children without ASD, 250 193 (42.2%) were female. For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD (adjusted rate ratio, 0.87; 95% CI, 0.85-0.88). Within each age category, vaccination rates were significantly lower among younger siblings of children with ASD compared with younger siblings of children without ASD. The adjusted rate ratios varied from 0.86 for siblings younger than 1 year to 0.96 for those 11 to 12 years old. Parents who had a child with ASD were more likely to refuse at least 1 recommended vaccine for that child’s younger sibling and to limit the number of vaccines administered during the younger sibling’s first year of life.
CONCLUSIONS AND RELEVANCE: Children with ASD and their younger siblings were undervaccinated compared with the general population. The results of this study suggest that children with ASD and their younger siblings are at increased risk of vaccine-preventable diseases.
IMPORTANCE: In recent years, rates of vaccination have been declining. Whether this phenomenon disproportionately affects children with autism spectrum disorder (ASD) or their younger siblings is unknown.
OBJECTIVES: To investigate if children after receiving an ASD diagnosis obtain their remaining scheduled vaccines according to the Advisory Committee on Immunization Practices (ACIP) recommendations and to compare the vaccination patterns of younger siblings of children with ASD with the vaccination patterns of younger siblings of children without ASD.
DESIGN, SETTING, AND PARTICIPANTS: This investigation was a retrospective matched cohort study. The setting was 6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink. Participants were children born between January 1, 1995, and September 30, 2010, and their younger siblings born between January 1, 1997, and September 30, 2014. The end of follow-up was September 30, 2015.
EXPOSURES: Recommended childhood vaccines between ages 1 month and 12 years.
MAIN OUTCOME AND MEASURE: The proportion of children who received all of their vaccine doses according to ACIP recommendations.
RESULTS: The study included 3729 children with ASD (676 [18.1%] female), 592 907 children without ASD, and their respective younger siblings. Among children without ASD, 250 193 (42.2%) were female. For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD (adjusted rate ratio, 0.87; 95% CI, 0.85-0.88). Within each age category, vaccination rates were significantly lower among younger siblings of children with ASD compared with younger siblings of children without ASD. The adjusted rate ratios varied from 0.86 for siblings younger than 1 year to 0.96 for those 11 to 12 years old. Parents who had a child with ASD were more likely to refuse at least 1 recommended vaccine for that child’s younger sibling and to limit the number of vaccines administered during the younger sibling’s first year of life.
CONCLUSIONS AND RELEVANCE: Children with ASD and their younger siblings were undervaccinated compared with the general population. The results of this study suggest that children with ASD and their younger siblings are at increased risk of vaccine-preventable diseases.
Preschoolers with severe autism and minimal speech were assigned either a discrete trial or a naturalistic language treatment, and parents of all participants also received parent responsiveness training. After 12 weeks, both groups showed comparable improvement in number of spoken words produced, on average. Approximately half the children in each group achieved benchmarks for the first stage of functional spoken language development, as defined by Tager-Flusberg et al. (J Speech Lang Hear Res, 52: 643-652, 2009). Analyses of moderators of treatment suggest that joint attention moderates response to both treatments, and children with better receptive language pre-treatment do better with the naturalistic method, while those with lower receptive language show better response to the discrete trial treatment. The implications of these findings are discussed.