The objective of this study was to establish a large, densely sampled, U.S. population‐based cohort of people with autism spectrum disorder (ASD). The Rhode Island Consortium for Autism Research and Treatment (RI‐CART) represents a unique public‐private‐academic collaboration involving all major points of service for families in Rhode Island affected by ASD. Diagnosis was based on direct behavioral observation via the Autism Diagnostic Observation Schedule, Second Edition. For the first 1,000 participants, ages ranged from 21 months to 64 years. Using Geographic Information System and published prevalence rates, the overall cohort is estimated to represent between 20% and 49% of pediatric age persons in Rhode Island with ASD, with demographics representative of U.S. Census. We observed a high rate of co‐occurring medical and psychiatric conditions in affected individuals. Among the most prominent findings of immediate clinical importance, we found that females received a first diagnosis of ASD at a later age than males, potentially due to more advanced language abilities in females with ASD. In summary, this is the first analysis of a large, population‐based U.S. cohort with ASD. Given the depth of sampling, the RI‐CART study reflects an important new resource for studying ASD in a representative U.S. population. Psychiatric and medical comorbidities in ASD constitute a substantial burden and warrant adequate attention as part of overall treatment. Our study also suggests that new strategies for earlier diagnosis of ASD in females may be warranted. Autism Res 2020, 13: 474–488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary The Rhode Island Consortium for Autism Research and Treatment (RI‐CART) represents a unique public‐private‐academic collaboration involving all major points of service for families in Rhode Island affected by autism spectrum disorder (ASD). In this article, we provide results from the first 1,000 participants, estimated to represent >20% of affected families in the state. Importantly, we find a later age at first diagnosis of ASD in females, which potentially calls attention to the need for improved early diagnosis in girls. Also, we report a high rate of co‐occurring medical and psychiatric conditions in affected individuals.

The purpose of this study was to examine family psychiatric history in individuals with autism spectrum disorder (ASD) and its association with clinical presentation. Participants were 798 individuals with a clinical diagnosis of ASD, confirmed by the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), enrolled in Rhode Island Consortium for Autism Research and Treatment, a statewide research registry. Prior research suggests a specific behavioral phenotype in individuals with ASD who have family members with psychiatric diagnoses, including higher IQ and less severe language impairment. However, studies have not specifically investigated autism severity. We hypothesized that increased psychiatric family history would be associated with increased autism severity symptoms. Results show a strong association of increased burden of firstdegree family psychiatric history with higher autism symptom severity as measured by Social Responsiveness Scale, Second Edition (SRS-2), but not with ADOS-2 severity scores, IQ, or adaptive functioning. These findings support the importance of investigating the contribution of psychiatric family history toward clinical ASD presentation. Lay SummaryThis study explored how family psychiatric history is related to clinical presentation of Autism Spectrum Disorder (ASD). Higher amounts of first-degree family psychiatric history was associated with higher autism symptom severity as measured by the Social Responsiveness Scale, Second Edition (SRS-2). The contribution of psychiatric family history requires ongoing investigation.

Early life stress can result in persistent alterations of an individual's stress regulation through epigenetic modifications. Epigenetic alteration of the NR3C1 gene is associated with changes in the stress response system during infancy as measured by cortisol reactivity. Although autonomic nervous system (ANS) reactivity is a key component of the stress response, we have a limited understanding of the effects of NR3C1 DNA methylation on ANS reactivity. To examine this relation, ANS stress responses of term, 4-5-month-old healthy infants were elicited using the face-to-face still-face paradigm, which involved five, 2-min episodes. Two of these episodes were the "still-face" in which the mother was non-responsive to her infant. EKG was acquired continuously and analyzed in 30 s-intervals. Cheek swabs were collected, and DNA was extracted from buccal cells. Respiratory sinus arrhythmia (RSA) was measured as heart rate variability (HRV). Mean HRV was calculated for each 30-s "face to face" episode. DNA methylation of NR3C1 was calculated using bisulfite pyrosequencing. Percent DNA methylation was computed for each of the 13 NR3C1 CpG sites. The relations between mean HRV for each "face to face" episode and percent DNA methylation was examined averaged over CpG sites 1-6 and 7-13 and at each individual CpG site. Higher HRV at baseline, first reunion, and second still-face was related to greater methylation of NR3C1 CpG sites 1-6. Higher HRV at the second reunion was related to greater methylation of NR3C1 CpG sites 12 and 13. These data provide evidence that increased methylation of NR3C1 at CpG sites 12 and 13 are associated with increased activation of parasympathetic pathways as represented by increased HRV.

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