Objective To examine differences in behavioral symptoms and cognitive functioning between males and females with autism spectrum disorder (ASD). Method We analyzed data from 2,418 probands with autism (304 females, 2,114 males) included in the Simons Simplex Collection. Sex differences were evaluated across measures of autism symptoms, cognitive and motor functioning, adaptive behavior, and associated behavior problems. Measurement bias was examined using latent variable models of symptoms. Unadjusted and propensity-adjusted analyses were computed to ensure sex differences were not due to unbalanced sampling. Moderator and mediator analyses evaluated whether sex differences were modified by clinical characteristics or driven by cognitive ability. Results Females with ASD had greater social communication impairment, lower levels of restricted interests, lower cognitive ability, weaker adaptive skills, and greater externalizing problems relative to males. Symptom differences could not be accounted for by measurement differences, indicating that diagnostic instruments captured autism similarly in males and females. IQ reductions mediated greater social impairment and reduced adaptive behavior in females with ASD, but did not mediate reductions in restricted interests or increases in irritability. Conclusions A specific female ASD phenotype is emerging that cannot be accounted for by differential symptom measurement. The present data suggest that the relatively low proportion of high functioning females may reflect the effect of protective biological factors or may be due to under-identification. Additional carefully-accrued samples are needed to confirm the present pattern and to evaluate whether observed sex ratios in high functioning cases are reduced if female-specific indicators of restricted interests are included.

Objective The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for Autism Spectrum Disorder (ASD). Method We analyzed symptoms from 14,744 siblings (8,911 ASD; 5,863 non-ASD) included in a national registry, the Interactive Autism Network. Youth aged 2–18 were included if at least one child in the family was diagnosed with ASD. Caregivers reported symptoms using the Social Responsiveness Scale and the Social Communication Questionnaire. The structure of autism symptoms was examined using latent variable models that included categories, dimensions, or hybrid models specifying categories and sub-dimensions. Diagnostic efficiency statistics evaluated the proposed DSM-5 algorithm in identifying ASD. Results A hybrid model that included both a category (ASD vs. non-ASD) and two symptom dimensions (social communication/interaction and restricted/repetitive behaviors) was more parsimonious than all other models and replicated across measures and sub-samples. Empirical classifications from this hybrid model closely mirrored clinical ASD diagnoses (90% overlap), implying a broad ASD category distinct from non-ASD. DSM-5 criteria had superior specificity relative to DSM-IV-TR criteria (.97 vs. .86), however sensitivity was lower (.81 vs. .95). Relaxing DSM-5 criteria by requiring one less symptom criterion increased sensitivity (.93 vs. .81), with minimal reduction in specificity (.95 vs. .97). Conclusions Results supported the validity of proposed DSM-5 criteria for ASD as provided in Phase I field trials criteria. Increased specificity of DSM-5 relative to DSM-IV-TR may reduce false positive diagnoses, a particularly relevant consideration for low base rate clinical settings. Phase II testing of DSM-5 should consider a relaxed algorithm, without which as many as 12% of ASD-affected individuals, particularly females, will be missed. Relaxed DSM-5 criteria may improve identification of ASD, decreasing societal costs through appropriate early diagnosis and maximizing intervention resources.

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.A utism spectrum disorder (ASD) is a brain disorder of early childhood onset. ASD is characterized by core social communication impairments as well as restricted, repetitive behaviors, which jeopardize the development of appropriate social skills and the maintenance of social relationships (1). Despite being one of the most devastating childhood disorders in terms of prevalence [1 in 68 US children (2)] and societal cost [$236 billion expended annually in the United States (3)], ASD pathophysiology remains poorly understood. Consequently, there are no approved medications that enhance social abilities in individuals with ASD.

Objective Numerous studies have identified abnormal gaze in individuals with autism. Yet only a limited number of findings have been replicated, the magnitude of effects is unclear, and the pattern of gaze differences across stimuli remains poorly understood. To address these gaps, we conducted a comprehensive meta-analysis of autism eye tracking studies. Method PubMed and manual search of 1,132 publications were used to identify studies comparing looking behavior to social and/or nonsocial stimuli between individuals with autism and controls. Sample characteristics, eye tracking methods, stimulus features, and regions-of-interest (ROI) were coded for each comparison within each study. Multivariate mixed-effects meta-regression analyses examined the impact of study methodology, stimulus features, and ROI on effect sizes derived from comparisons using gaze fixation metrics. Results The search revealed 122 independent studies with 1,155 comparisons. Estimated effect sizes tended to be small-to-medium, but varied substantially across stimuli and ROI. Overall, nonsocial ROIs yielded larger effect sizes than social ROIs; however, eye and whole face regions from stimuli with human interaction produced the largest effects (Hedge’s g=.47 and .50, respectively). Studies with weaker study designs/reporting yielded larger effects, but key effects remained significant and medium-sized, even for high-rigor designs. Conclusion Individuals with autism show a reliable pattern of gaze abnormalities that suggests a basic problem with selecting socially-relevant versus irrelevant information for attention and that is persistent across age and worsens during perception of human interactions. Aggregation of gaze abnormalities across stimuli and ROI could yield clinically useful risk assessment and quantitative, objective outcome measures.

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