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Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program |
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PLoS One. 2020 Aug 25;15(8):e0237430.doi: 10.1371/journal.pone.0237430. eCollection 2020.
Marina Serper 1 2 3, Marijana Vujkovic 1, David E Kaplan 1 2, Rotonya M Carr 1 2, Kyung Min Lee 4 5 6, Qing Shao 4, Donald R Miller 4, Peter D Reaven 7, Lawrence S Phillips 8 9, Christopher J O'Donnell 10 11, James B Meigs 12, Peter W F Wilson 8 9, Rachel Vickers-Smith 13, Henry R Kranzler 13 14, Amy C Justice 15 16 17, John M Gaziano 10 18, Sumitra Muralidhar 19, Saiju Pyarajan 10 11, Scott L DuVall 6 20, Themistocles L Assimes 21 22, Jennifer S Lee 21 22, Philip S Tsao 21 22, Daniel J Rader 2 23 24 25, Scott M Damrauer 1 26, Julie A Lynch 6 27, Danish Saleheen 1 28, Benjamin F Voight 1 23 29, Kyong-Mi Chang 1 2, VA Million Veteran Program
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Author information
- 1Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States of America.
- 2Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
- 3Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
- 4Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts, United States of America.
- 5Department of Health Law, Policy and Management, Boston University School of Public Health, Boston, Massachusetts, United States of America.
- 6VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, Utah, United States of America.
- 7Phoenix VA Health Care System, Phoenix, Arizona, United States of America.
- 8Department of Veterans Affairs, Atlanta Health Care System, Decatur, Georgia, United States of America.
- 9Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
- 10Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts, United States of America.
- 11Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
- 12Massachusetts General Hospital, Harvard Medical School and the Broad Institute, Boston, Massachusetts, United States of America.
- 13University of Louisville, Louisville, Kentucky, United States of America.
- 14Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
- 15Yale School of Medicine, New Haven, Connecticut, United States of America.
- 16Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States of America.
- 17Yale School of Public Health, New Haven, Connecticut, United States of America.
- 18Boston University School of Public Health, Boston, Massachusetts, United States of America.
- 19Office of Research and Development, Veterans Health Administration, Washington, DC, United States of America.
- 20Department of Internal Medicine Division of Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
- 21Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
- 22VA Palo Alto Health Care System, Palo Alto, California, United States of America.
- 23Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
- 24Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
- 25Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
- 26Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
- 27College of Nursing and Health Sciences, University of Massachusetts, Boston, Massachusetts, United States of America.
- 28Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
- 29Department of Systems Pharmacology and Translational Therapeutics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Abstract
Background & aims: Given ongoing challenges in non-invasive non-alcoholic liver disease (NAFLD) diagnosis, we sought to validate an ALT-based NAFLD phenotype using measures readily available in electronic health records (EHRs) and population-based studies by leveraging the clinical and genetic data in the Million Veteran Program (MVP), a multi-ethnic mega-biobank of US Veterans.
Methods: MVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for women without other causes of liver disease were compared to controls with normal ALT. Genetic variants spanning eight NAFLD risk or ALT-associated loci (LYPLAL1, GCKR, HSD17B13, TRIB1, PPP1R3B, ERLIN1, TM6SF2, PNPLA3) were tested for NAFLD associations with sensitivity analyses adjusting for metabolic risk factors and alcohol consumption. A manual EHR review assessed performance characteristics of the NAFLD phenotype with imaging and biopsy data as gold standards. Genetic associations with advanced fibrosis were explored using FIB4, NAFLD Fibrosis Score and platelet counts.
Results: Among 322,259 MVP participants, 19% met non-invasive criteria for NAFLD. Trans-ethnic meta-analysis replicated associations with previously reported genetic variants in all but LYPLAL1 and GCKR loci (P<6x10-3), without attenuation when adjusted for metabolic risk factors and alcohol consumption. At the previously reported LYPLAL1 locus, the established genetic variant did not appear to be associated with NAFLD, however the regional association plot showed a significant association with NAFLD 279kb downstream. In the EHR validation, the ALT-based NAFLD phenotype yielded a positive predictive value 0.89 and 0.84 for liver biopsy and abdominal imaging, respectively (inter-rater reliability (Cohen's kappa = 0.98)). HSD17B13 and PNPLA3 loci were associated with advanced fibrosis.
Conclusions: We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.
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