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

Alba Gutiérrez-Sacristán*, Carlos Sáez, Carlos De Niz, Niloofar Jalali, Thomas N. DeSain, Ranjay Kumar, Joany M. Zachariasse, Kathe P. Fox, Nathan Palmer, Isaac Kohane, Paul Avillach

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
81 Downloads (Pure)


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 (

Original languageEnglish
Pages (from-to)230-238
Number of pages9
JournalJournal of the American Medical Informatics Association : JAMIA
Issue number2
Early online date18 Aug 2021
Publication statusPublished - 1 Feb 2022

Bibliographical note

Funding Information:
This work has been supported by the National Institutes of Health BD2K grant U54HG007963.

Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the American Medical Informatics Association.


Dive into the research topics of 'Multi-PheWAS intersection approach to identify sex differences across comorbidities in 59 140 pediatric patients with autism spectrum disorder'. Together they form a unique fingerprint.

Cite this