Mitigating sex-related biases to elucidate the autism phenotype

Autism spectrum disorder (ASD) is commonly considered a male-dominant condition, with epidemiological estimates finding that approximately 3-4 males are diagnosed for every female. An overwhelming majority of studies used to establish this sex ratio were conducted with participants ascertained based on having first met clinical criteria, which may obscure qualitative differences between males and females, and omits females who do not meet male-biased criteria. Our recently published data, which used a prospectively-identified sample of children at high-familial likelihood for ASD, corrected for sex-based measurement bias, and used data-driven groupings of behavior over time, were well-suited to address this issue and suggest the male-to-female ratio of autism-related concerns is closer to 1:1. In this review, we propose that research is needed that characterizes the autism phenotype, or behavioral expression of underlying genetic variation in autism-relevant traits. We describe shifts in sample ascertainment, methodological rigor, and scope of traits examined that may help elucidate the autism phenotype. A research program focusing on delineating the genetically-related, biological determinants of clinical disorders has the potential to reveal the full expression of underlying genetic liability for ASD and improve early identification of ASD-related concerns in females.