{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T16:35:44Z","timestamp":1787589344736,"version":"build-2736575974"},"reference-count":23,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,4,10]],"date-time":"2017-04-10T00:00:00Z","timestamp":1491782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["U01 AA020790"],"award-info":[{"award-number":["U01 AA020790"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["U10 AA013566"],"award-info":[{"award-number":["U10 AA013566"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["U24 AA020794"],"award-info":[{"award-number":["U24 AA020794"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Alcoholism Clin &amp;amp; Exp Res"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Although alcohol risk is heritable, few genetic risk variants have been identified. Longitudinal electronic health record (EHR) data offer a largely untapped source of phenotypic information for genetic studies, but <jats:styled-content style=\"fixed-case\">EHR<\/jats:styled-content>\u2010derived phenotypes for harmful alcohol exposure have yet to be validated. Using a variant of known effect, we used <jats:styled-content style=\"fixed-case\">EHR<\/jats:styled-content> data to develop and validate a phenotype for harmful alcohol exposure that can be used to identify unknown genetic variants in large samples. Herein, we consider the validity of 3 approaches using the 3\u2010item Alcohol Use Disorders Identification Test consumption measure (<jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C) as a phenotype for harmful alcohol exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>First, using longitudinal <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C data from the Veterans Aging Cohort Biomarker Study Cohort (<jats:styled-content style=\"fixed-case\">VACS<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">BC<\/jats:styled-content>), we compared 3 metrics of <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C using correlation coefficients: (i) <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C closest to blood sampling (closest <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C), (ii) the highest value (highest <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C), (iii) and longitudinal trajectories generated using joint trajectory modeling (<jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C trajectory). Second, we compared the associations of the 3 <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C metrics with phosphatidylethanol (<jats:styled-content style=\"fixed-case\">PE<\/jats:styled-content>th), a direct, quantitative biomarker for alcohol in the overall sample using chi\u2010square tests for trend. Last, in the subsample of African Americans (<jats:styled-content style=\"fixed-case\">AA<\/jats:styled-content>s; <jats:italic>n<\/jats:italic>\u00a0=\u00a01,503), we compared the associations of the 3 <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C metrics with rs2066702 a common missense (Arg369Cys) polymorphism of the <jats:italic><jats:styled-content style=\"fixed-case\">ADH<\/jats:styled-content>1B<\/jats:italic> gene, which encodes an alcohol dehydrogenase isozyme.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The sample (<jats:italic>n<\/jats:italic>\u00a0=\u00a01,851, 94.5% male, 65% <jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content>+, mean age 52\u00a0years) had a median of 7 <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C scores over a median of 6.1\u00a0years. Highest <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C and <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C trajectory were correlated <jats:italic>r<\/jats:italic>\u00a0=\u00a00.86. The closest <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C was obtained a median of 2.26\u00a0years after the <jats:styled-content style=\"fixed-case\">VACS<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">BC<\/jats:styled-content> blood draw. Overall and among <jats:styled-content style=\"fixed-case\">AA<\/jats:styled-content>s, all 3 <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C metrics were associated with <jats:styled-content style=\"fixed-case\">PE<\/jats:styled-content>th (all <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05), but the gradient was steepest with <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C trajectory. Among <jats:styled-content style=\"fixed-case\">AA<\/jats:styled-content>s (36% with the protective <jats:italic><jats:styled-content style=\"fixed-case\">ADH<\/jats:styled-content>1B<\/jats:italic> allele), the association of rs2066702 with <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C trajectory and highest <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C was statistically significant (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05), and the gradient was steeper for the <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C trajectory than for the highest <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C. The closest <jats:styled-content style=\"fixed-case\">AUDIT<\/jats:styled-content>\u2010C was not statistically significantly associated with rs2066702.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">EHR<\/jats:styled-content> data can be used to identify complex phenotypes such as harmful alcohol use. The validity of the phenotype may be enhanced through the use of longitudinal trajectories.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.13373","type":"journal-article","created":{"date-parts":[[2017,3,11]],"date-time":"2017-03-11T08:03:28Z","timestamp":1489219408000},"page":"998-1003","source":"Crossref","is-referenced-by-count":17,"title":["Validating Harmful Alcohol Use as a Phenotype for Genetic Discovery Using Phosphatidylethanol and a Polymorphism in <i><scp>ADH<\/scp>1B<\/i>"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-5502","authenticated-orcid":false,"given":"Amy C.","family":"Justice","sequence":"first","affiliation":[{"name":"Yale School of Medicine New Haven Connecticut"},{"name":"Veterans Affairs Connecticut Healthcare System West Haven Connecticut"},{"name":"Yale School of Public Health New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"McGinnis","sequence":"additional","affiliation":[{"name":"Veterans Affairs Connecticut Healthcare System West Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet P.","family":"Tate","sequence":"additional","affiliation":[{"name":"Yale School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Xu","sequence":"additional","affiliation":[{"name":"Yale School of Medicine New Haven Connecticut"},{"name":"Veterans Affairs Connecticut Healthcare System West Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Becker","sequence":"additional","affiliation":[{"name":"Yale School of Medicine New Haven Connecticut"},{"name":"Veterans Affairs Connecticut Healthcare System West Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Yale School of Medicine New Haven Connecticut"},{"name":"Yale School of Public Health New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Gelernter","sequence":"additional","affiliation":[{"name":"Yale School of Medicine New Haven Connecticut"},{"name":"Veterans Affairs Connecticut Healthcare System West Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry R.","family":"Kranzler","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine and VISN 4 MIRECC, Crescenz VAMC Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,4,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/alcalc\/agl027"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis406"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11606-010-1341-x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2011.124"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2007.00403.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.158.16.1789"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00414-012-0799-y"},{"key":"e_1_2_7_9_1","first-page":"64","article-title":"Genetic research: who is at risk for alcoholism","volume":"33","author":"Foroud T","year":"2010","journal-title":"Alcohol Res Health"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0152588"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2013.145"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/acer.12792"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2008.120923"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/0049124101029003005"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir989"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2011.02.024"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2014.12.023"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2012.01937.x"},{"key":"e_1_2_7_19_1","unstructured":"McGinnisK JusticeAC SaitzR KraemerK BryantK FiellinD(2010)Measures of unhealthy alcohol use among HIV infected and uninfected patients in the Veterans Aging Cohort Study. 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