{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T07:31:06Z","timestamp":1767079866446,"version":"3.48.0"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA206465"],"award-info":[{"award-number":["R01CA206465"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["P01 AA029545"],"award-info":[{"award-number":["P01 AA029545"]}],"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":["U24AA020794"],"award-info":[{"award-number":["U24AA020794"]}],"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":["U01AA020790"],"award-info":[{"award-number":["U01AA020790"]}],"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":["U24AA022001"],"award-info":[{"award-number":["U24AA022001"]}],"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":["U01AA013566"],"award-info":[{"award-number":["U01AA013566"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacoepidemiology and Drug"],"published-print":{"date-parts":[[2025,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Medications associated with acute liver injury (ALI) are primarily identified by case reports. High\u2010throughput screening of real\u2010world data could be leveraged to detect hepatotoxicity signals.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To apply tree\u2010based scan statistics in real\u2010world data to identify drugs associated with hospitalization for severe ALI among patients without liver\/biliary disease and with chronic liver disease (CLD).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We implemented a self\u2010controlled case\u2010crossover design in Veterans Health Administration data (2000\u20132023) among patients hospitalized for laboratory\u2010confirmed severe ALI. We identified all newly dispensed drugs within 365\u2009days prior to their hospitalization and used conditional Bernoulli tree\u2010based scan statistics to identify potential associations (\n p<\/jats:italic>\n \u2009<\u20090.3). We performed analyses separately in patients without liver\/biliary disease and with CLD.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 12\u2009860 patients without liver\/biliary disease and 17\u2009512 with CLD hospitalized for severe ALI, we evaluated associations with 450 and 543 drugs, respectively. Drugs associated with severe ALI among patients without liver\/biliary disease included: acid\u2010suppressives (ranitidine [\n p<\/jats:italic>\n \u2009<\u20090.001], omeprazole [\n p<\/jats:italic>\n \u2009=\u20090.004]), antiemetics (ondansetron [\n p<\/jats:italic>\n \u2009<\u20090.001], promethazine [\n p<\/jats:italic>\n \u2009=\u20090.06]), antibiotics (amoxicillin\/clavulanate [\n p<\/jats:italic>\n \u2009=\u20090.008], ciprofloxacin [\n p<\/jats:italic>\n \u2009=\u20090.02], mupirocin [\n p<\/jats:italic>\n \u2009=\u20090.032], ethambutol [\n p<\/jats:italic>\n \u2009=\u20090.275]), anticoagulants (heparin [\n p<\/jats:italic>\n \u2009=\u20090.015]), and chemotherapy (pazopanib [\n p<\/jats:italic>\n \u2009=\u20090.275]). Drugs associated with severe ALI among CLD patients were: diuretics (spironolactone, furosemide [both\n p<\/jats:italic>\n \u2009<\u20090.001]), antiemetics (ondansetron, metoclopramide, promethazine [all\n p<\/jats:italic>\n \u2009<\u20090.001]), appetite stimulants (\n p<\/jats:italic>\n \u2009<\u20090.001), analgesics (morphine, oxycodone, fentanyl [all\n p<\/jats:italic>\n \u2009<\u20090.001]), chemotherapy (sorafenib [\n p<\/jats:italic>\n \u2009<\u20090.001]), antibiotics (ciprofloxacin [\n p<\/jats:italic>\n \u2009=\u20090.011], metronidazole [\n p<\/jats:italic>\n \u2009=\u20090.020]), antipsychotics (prochlorperazine [\n p<\/jats:italic>\n \u2009=\u20090.105]), vitamins (\n p<\/jats:italic>\n \u2009=\u20090.134), acid\u2010suppressives (omeprazole [\n p<\/jats:italic>\n \u2009=\u20090.164]), and gastrointestinal\/liver disease treatments (lactulose, senna, docusate, silicones, antiflatulents [all\n p<\/jats:italic>\n \u2009<\u20090.001]; sucralfate [\n p<\/jats:italic>\n \u2009=\u20090.005], albumin [\n p<\/jats:italic>\n \u2009=\u20090.228]).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n High\u2010throughput screening using tree\u2010based scan statistics detected potentially hepatotoxic drugs for investigation in future pharmacoepidemiology studies.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/pds.70275","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T05:25:52Z","timestamp":1764912352000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High\u2010Throughput Screening Using the Self\u2010Controlled Tree\u2010Based Scan Statistic to Identify Medications Associated With Hospitalization for Severe Acute Liver Injury"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-0600","authenticated-orcid":false,"suffix":"III","given":"Vincent","family":"Lo Re","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Center for Clinical Epidemiology and Biostatistics, Center for Real\u2010World Effectiveness and Safety of Therapeutics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig W.","family":"Newcomb","sequence":"additional","affiliation":[{"name":"Center for Clinical Epidemiology and Biostatistics, Center for Real\u2010World Effectiveness and Safety of Therapeutics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0310-270X","authenticated-orcid":false,"given":"Dean M.","family":"Carbonari","sequence":"additional","affiliation":[{"name":"Center for Clinical Epidemiology and Biostatistics, Center for Real\u2010World Effectiveness and Safety of Therapeutics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles E.","family":"Leonard","sequence":"additional","affiliation":[{"name":"Center for Clinical Epidemiology and Biostatistics, Center for Real\u2010World Effectiveness and Safety of Therapeutics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Leonard Davis Institute of Health Economics University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1408-7907","authenticated-orcid":false,"given":"Christopher T.","family":"Rentsch","sequence":"additional","affiliation":[{"name":"Department of Non\u2010communicable Disease Epidemiology London School of Hygiene & Tropical Medicine London UK"},{"name":"VA Connecticut Healthcare System, US Department of Veterans Affairs West Haven Connecticut USA"},{"name":"Department of Medicine, Yale School of Medicine New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9900-2142","authenticated-orcid":false,"given":"Judith C.","family":"Maro","sequence":"additional","affiliation":[{"name":"Department of Population Medicine Harvard Medical School and Harvard Pilgrim Healthcare Institute Boston Massachusetts 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