Behavioral and Cognitive Characteristics of Females and Males with Autism in the Simons Simplex Collection

Background:  Being male is one of the most powerful and well-established risk factors for autism spectrum disorders (ASD). Sex ratio estimates have indicated 3-4 males per female across the diagnostic spectrum. Even more severe ratios (as high as 9:1) are observed in cognitively higher functioning cases. Consequently, original descriptions, subsequent diagnostic criteria, and the vast majority of phenotypic data are from males with ASD. Yet, recent data suggest that females may be under-identified or, at minimum, show a different behavioral expression of autism. Unfortunately, studies of sex differences in the ASD phenotype have often included modest female sample sizes and/or focused on a limited number of domains (e.g. symptoms or cognition). The Simons Simplex Collection affords the advantage of simultaneously evaluating an array of phenotypic measures, including core ASD symptoms, cognitive and language measures, adaptive functions, and associated behavior problems in a large number of females and males with ASD.

Objectives:  The primary aim was examine differences in behavioral symptoms and cognitive functioning between males and females with ASD. The secondary aim was to determine whether sex differences in IQ explained sex differences in other domains. The tertiary aim was to evaluate whether measurement differences between sexes for autism symptoms may be driving sex ratios for ASD diagnosis.

Methods:  We analyzed data from 2418 probands with autism (304 females, 2114 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 multi-group confirmatory factor models of autism symptom measurements. 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 significantly greater social communication impairment, lower levels of restricted interests, lower cognitive ability, weaker adaptive skills, and greater externalizing problems relative to males. All effect sizes were small to moderate (Cohen's d<=.22) but still potentially clinically meaningful. Sex differences tended to be larger at older ages (largest p=.045). 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. Symptom differences could not be accounted for by measurement differences, indicating that diagnostic instruments captured autism similarly in males and females.

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.