{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:09:04Z","timestamp":1740136144096,"version":"3.37.3"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["BD2K","U54HG007963"],"award-info":[{"award-number":["BD2K","U54HG007963"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stichting de Drie Lichten and Stichting Sophia Kinderziekenhuis Fonds"},{"DOI":"10.13039\/100006691","name":"Harvard Medical School","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 27 different comorbidities that appeared significantly more frequently in females with ASD. The comorbidities were mostly neurological (eg, epilepsy, odds ratio [OR]\u2009&amp;gt;\u20091.8, 3-18 years of age), congenital (eg, chromosomal anomalies, OR\u2009&amp;gt;\u20092, 3-18 years of age), and mental disorders (eg, intellectual disability, OR\u2009&amp;gt;\u20091.7, 6-18 years of age). Novel comorbidities included endocrine metabolic diseases (eg, failure to thrive, OR\u2009=\u20092.5, ages 0-2), digestive disorders (gastroesophageal reflux disease: OR\u2009=\u20091.7, 6-11 years of age; and constipation: OR\u2009&amp;gt;\u20091.6, 3-11 years of age), and sense organs (strabismus: OR\u2009&amp;gt;\u20091.8, 3-18 years of age).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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).<\/jats:p><\/jats:sec>","DOI":"10.1093\/jamia\/ocab144","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T19:18:32Z","timestamp":1624907912000},"page":"230-238","source":"Crossref","is-referenced-by-count":5,"title":["Multi-PheWAS intersection approach to identify sex differences across comorbidities in 59 140 pediatric patients with autism spectrum disorder"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1245-198X","authenticated-orcid":false,"given":"Alba","family":"Guti\u00e9rrez-Sacrist\u00e1n","sequence":"first","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2678-8249","authenticated-orcid":false,"given":"Carlos","family":"S\u00e1ez","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Biomedical Data Science Lab, Instituto Universitario de Tecnolog\u00edas de la Informaci\u00f3n y Comunicaciones, Universitat Polit\u00e8cnica de Val\u00e8ncia, Valencia, Spain"}]},{"given":"Carlos","family":"De Niz","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"}]},{"given":"Niloofar","family":"Jalali","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"}]},{"given":"Thomas N","family":"DeSain","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"}]},{"given":"Ranjay","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"}]},{"given":"Joany M","family":"Zachariasse","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Department of General Paediatrics, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands"}]},{"given":"Kathe P","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"}]},{"given":"Nathan","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"}]},{"given":"Isaac","family":"Kohane","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0235-7543","authenticated-orcid":false,"given":"Paul","family":"Avillach","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Computational Health Informatics Program, Boston Children's Hospital, Boston, Massachusetts, USA"}]}],"member":"286","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"2022011313561584900_ocab144-B1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13229-015-0019-y","article-title":"Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority","volume":"6","author":"Halladay","year":"2015","journal-title":"Mol Autism"},{"issue":"2","key":"2022011313561584900_ocab144-B2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s11920-018-0874-2","article-title":"Sex differences in autism spectrum disorder: a review","volume":"20","author":"Ferri","year":"2018","journal-title":"Curr Psychiatry Rep"},{"issue":"2","key":"2022011313561584900_ocab144-B3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1001\/jamapediatrics.2018.4208","article-title":"Prevalence and treatment patterns of autism spectrum disorder in the United States, 2016","volume":"173","author":"Xu","year":"2019","journal-title":"JAMA Pediatr"},{"issue":"6","key":"2022011313561584900_ocab144-B4","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.jaac.2017.03.013","article-title":"What is the male-to-female ratio in autism spectrum disorder? 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