Defining the female pragmatic language profile of autism and the broad autism phenotype - Summary Pragmatic (i.e., social) language impairments are a defining feature of autism spectrum disorder (ASD), which can impose significant burden on individuals throughout the lifespan. Strong evidence also suggests that this clinical domain is influenced by genetic markers associated with ASD in clinically unaffected relatives, constituting a principal component of the broad autism phenotype (BAP). Although sex differences in the development of pragmatic language have been repeatedly demonstrated in the general population, sex-specific differences in pragmatics in ASD and the BAP are woefully understudied, despite mounting evidence of a distinct clinical phenotype among autistic females, and the strong impact of pragmatic skills on clinical outcomes and well-being. Most studies of pragmatics in ASD have included only males or included so few females that they were insufficiently powered to address the potential of sex-specific patterns of pragmatic skills in conversation, narrative, or other crucial social-communication contexts where pragmatic skills play an essential role in social functioning (including vocational success) across the lifespan. In this project, we will apply an armamentarium of deep phenotyping methods to dissect the key features and contributors to the hypothesized sex-specific pragmatic language profiles of ASD and the BAP that extend beyond traditional, categorically-defined diagnostic boundaries, using a family-study design and including a representative ASD cohort enriched for females, ASD parents, and respective control groups. Aim 1 will characterize the pragmatic language profile of females with ASD and related, potentially sex-specific neurocognitive mechanistic skills and psychosocial outcomes. Aim 2 will conduct parallel questions in the BAP. Finally, Aim 3 will estimate the incidence of sex-specific pragmatic profiles of ASD and BAP in the general population via crowdsourced pragmatic phenotyping. Our preliminary studies demonstrate strong evidence for complex sex-specific patterns of pragmatic abilities in ASD that may be comprehensively and sensitively measured with the complement of gold-standard hand-coding methods and advanced fine-grained computational- and machine-learning-based approaches proposed in this project. Together, the rich and extensive data produced will contribute to our understanding of the fine-grained skills underlying the sex-based heterogeneity in ASD, and the mechanistic, potentially sex-specific origins of pragmatics as an important clinical domain. Our findings will move us closer to achieving long-term translational goals to advance understanding of the sex-specific differences in pragmatic language impairment in ASD in order to improve the prediction of clinical outcomes and help guide future interventions and treatment in ASD.
