Comorbidities in Childhood Celiac Disease: A Phenome Wide Association Study using the Electronic Health Record

Objectives: Celiac disease (CD) is associated with a variety of extraintestinal autoimmune and inflammatory findings that manifest clinically as symptoms and comorbidities. Understanding these comorbidities may improve identification of the disease and prevent sequelae. In this study, we use an unbiased electronic health record (EHR)-based Phenome Wide Association Study (PheWAS) method to confirm known comorbidities, discover novel associations and enhance characterization of the clinical presentation of CD in children. Methods: Data were extracted from the Nationwide Children's Hospital EHR. Confirmed CD cases (n = 433) were matched with 4330 randomly selected controls. Utilizing an EHR-based PheWAS method to analyze associations of phenotypes with CD, we conducted an unbiased screening of all ICD-10 diagnostic codes and examined significance by performing Fisher's Exact tests. We further tested for the association between CD and 14 previously-identified comorbidities in an a priori fashion. Results: We found 45 ICD-10 codes significantly associated with CD. Thirteen are known comorbidities and nine are expected symptoms of CD, thus validating our study methods. Further investigation found symptoms that characterized CD clinically and discovered a significant association between eosinophilic disorders of the esophagus and CD. Of 14 previously-identified comorbidities, 8 were significantly associated with CD. Conclusions: An EHR-based PheWAS method is a powerful, efficient, and cost-effective method to screen for possible CD comorbidities and validate associations at the population level. Ours is the first PheWAS of CD to confirm a significant association of eosinophilic disorders of the esophagus with CD in a controlled study. Address correspondence and reprint requests to Ariana Prinzbach, The Ohio State University College of Medicine, The Ohio State University, Columbus, OH (e-mail: ariana.prinzbach@osumc.edu); Simon Lin, MD, MBA, The Ohio State University College of Medicine, The Ohio State University, Columbus, OH, Research Information Solutions and Innovation, The Research Institute at Nationwide Children's Hospital, Columbus, OH (e-mail: simon.lin@nationwidehildrens.org). Received 24 February, 2017 Accepted 1 April, 2018 Grant support: Grant UL1TR001070 from Center for Clinical and Translational Science at the Ohio State University. Author Contributions to Manuscript: Ariana Prinzbach: Analysis and interpretation of data; clinical analysis; drafting of the manuscript. Soheil Moosavinasab: Acquisition of data; analysis and interpretation of data; statistical analysis. Steve Rust, PhD: Analysis and interpretation of data; statistical analysis; study supervision. Brendan Boyle, MD, MPH: Acquisition of data; clinical analysis and support. John A. Barnard, MD: Critical revision of the manuscript for important intellectual content; clinical analysis. Yungui Huang, PhD, MBA: Study concept and design; analysis and interpretation of data; study supervision. Simon Lin, MD, MBA: Study concept and design; analysis and interpretation of data; study supervision; critical revision for intellectual content. Disclosures: No Conflict of Interest to Disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org). © 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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