Multi-PheWAS intersection approach to identify sex differences across comorbidities in 59 140 pediatric patients with autism spectrum disorder

• Main Authors: Avillach, P. (Author), De Niz, C. (Author), DeSain, T.N (Author), Fox, K.P (Author), Gutiérrez-Sacristán, A. (Author), Jalali, N. (Author), Kohane, I. (Author), Kumar, R. (Author), Palmer, N. (Author), Sáez, C. (Author), Zachariasse, J.M (Author)
• Format: Article
• Language: English
• Published: NLM (Medline) 2022
• Subjects: autism; autism spectrum disorder; Autism Spectrum Disorder; child; Child; Child, Preschool; comorbidity; Comorbidity; female; Female; human; Humans; infant; Infant; Infant, Newborn; large-scale; male; Male; newborn; odds ratio; Odds Ratio; preschool child; prevalence; Prevalence; sex characteristics; Sex Characteristics; sexual characteristics
• Online Access: View Fulltext in Publisher

 OBJECTIVE: To identify differences related to sex and define autism spectrum disorder (ASD) comorbidities female-enriched through a comprehensive multi-PheWAS intersection approach on big, real-world data. Although sex difference is a consistent and recognized feature of ASD, additional clinical correlates could help to identify potential disease subgroups, based on sex and age. MATERIALS AND METHODS: We performed a systematic comorbidity analysis on 1860 groups of comorbidities exploring all spectrum of known disease, in 59 140 individuals (11 440 females) with ASD from 4 age groups. We explored ASD sex differences in 2 independent real-world datasets, across all potential comorbidities by comparing (1) females with ASD vs males with ASD and (2) females with ASD vs females without ASD. RESULTS: We identified 27 different comorbidities that appeared significantly more frequently in females with ASD. The comorbidities were mostly neurological (eg, epilepsy, odds ratio [OR] > 1.8, 3-18 years of age), congenital (eg, chromosomal anomalies, OR > 2, 3-18 years of age), and mental disorders (eg, intellectual disability, OR > 1.7, 6-18 years of age). Novel comorbidities included endocrine metabolic diseases (eg, failure to thrive, OR = 2.5, ages 0-2), digestive disorders (gastroesophageal reflux disease: OR = 1.7, 6-11 years of age; and constipation: OR > 1.6, 3-11 years of age), and sense organs (strabismus: OR > 1.8, 3-18 years of age). DISCUSSION: A multi-PheWAS intersection approach on real-world data as presented in this study uniquely contributes to the growing body of research regarding sex-based comorbidity analysis in ASD population. CONCLUSIONS: Our findings provide insights into female-enriched ASD comorbidities that are potentially important in diagnosis, as well as the identification of distinct comorbidity patterns influencing anticipatory treatment or referrals. The code is publicly available (https://github.com/hms-dbmi/sexDifferenceInASD). © The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association.