Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program.
<h4>Background & aims</h4>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 cli...
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Public Library of Science (PLoS)
2020
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oai:doaj.org-article:6b22e0279c39480fb539751b81449be22021-12-02T20:05:46ZValidating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program.1932-620310.1371/journal.pone.0237430https://doaj.org/article/6b22e0279c39480fb539751b81449be22020-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0237430https://doaj.org/toc/1932-6203<h4>Background & aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.Marina SerperMarijana VujkovicDavid E KaplanRotonya M CarrKyung Min LeeQing ShaoDonald R MillerPeter D ReavenLawrence S PhillipsChristopher J O'DonnellJames B MeigsPeter W F WilsonRachel Vickers-SmithHenry R KranzlerAmy C JusticeJohn M GazianoSumitra MuralidharSaiju PyarajanScott L DuVallThemistocles L AssimesJennifer S LeePhilip S TsaoDaniel J RaderScott M DamrauerJulie A LynchDanish SaleheenBenjamin F VoightKyong-Mi ChangVA Million Veteran ProgramPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 15, Iss 8, p e0237430 (2020) |
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| collection |
DOAJ |
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Medicine R Science Q |
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Medicine R Science Q Marina Serper Marijana Vujkovic David E Kaplan Rotonya M Carr Kyung Min Lee Qing Shao Donald R Miller Peter D Reaven Lawrence S Phillips Christopher J O'Donnell James B Meigs Peter W F Wilson Rachel Vickers-Smith Henry R Kranzler Amy C Justice John M Gaziano Sumitra Muralidhar Saiju Pyarajan Scott L DuVall Themistocles L Assimes Jennifer S Lee Philip S Tsao Daniel J Rader Scott M Damrauer Julie A Lynch Danish Saleheen Benjamin F Voight Kyong-Mi Chang VA Million Veteran Program Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program. |
| description |
<h4>Background & aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms. |
| format |
article |
| author |
Marina Serper Marijana Vujkovic David E Kaplan Rotonya M Carr Kyung Min Lee Qing Shao Donald R Miller Peter D Reaven Lawrence S Phillips Christopher J O'Donnell James B Meigs Peter W F Wilson Rachel Vickers-Smith Henry R Kranzler Amy C Justice John M Gaziano Sumitra Muralidhar Saiju Pyarajan Scott L DuVall Themistocles L Assimes Jennifer S Lee Philip S Tsao Daniel J Rader Scott M Damrauer Julie A Lynch Danish Saleheen Benjamin F Voight Kyong-Mi Chang VA Million Veteran Program |
| author_facet |
Marina Serper Marijana Vujkovic David E Kaplan Rotonya M Carr Kyung Min Lee Qing Shao Donald R Miller Peter D Reaven Lawrence S Phillips Christopher J O'Donnell James B Meigs Peter W F Wilson Rachel Vickers-Smith Henry R Kranzler Amy C Justice John M Gaziano Sumitra Muralidhar Saiju Pyarajan Scott L DuVall Themistocles L Assimes Jennifer S Lee Philip S Tsao Daniel J Rader Scott M Damrauer Julie A Lynch Danish Saleheen Benjamin F Voight Kyong-Mi Chang VA Million Veteran Program |
| author_sort |
Marina Serper |
| title |
Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program. |
| title_short |
Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program. |
| title_full |
Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program. |
| title_fullStr |
Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program. |
| title_full_unstemmed |
Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program. |
| title_sort |
validating a non-invasive, alt-based non-alcoholic fatty liver phenotype in the million veteran program. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2020 |
| url |
https://doaj.org/article/6b22e0279c39480fb539751b81449be2 |
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