{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T15:42:43Z","timestamp":1785339763555,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T00:00:00Z","timestamp":1718064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:p>The global rise in polypharmacy has increased both the necessity and complexity of drug\u2013drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large\u2010scale healthcare claims data, we piloted a semi\u2010automated, high\u2010throughput case\u2010crossover\u2010based approach for drug\u2013drug\u2013drug interaction (3DI) screening. Cases were direct\u2010acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme\u2010inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme\u2010inducing antiseizure medications (ASMs) (Study 2). 3DI detection was based on screening for additional drug exposures that served as acute outcome triggers. To mitigate direct effects and confounding by concomitant drugs, self\u2010controlled estimates were adjusted using negative cases (external \u201ccontrol\u201d DOAC users with the same outcomes but co\u2010dispensings for non\u2010interacting AHDs or ASMs). Signal thresholds were set based on <jats:italic>P<\/jats:italic>\u2010values and false discovery rate <jats:italic>q<\/jats:italic>\u2010values to address multiple comparisons. Study 1: 285 drugs were examined among 3,306 episodes. Self\u2010controlled assessments with <jats:italic>q<\/jats:italic>\u2010value thresholds yielded 9 3DI signals (cases) and 40 DDI signals (negative cases). External adjustment generated 10 3DI signals from the <jats:italic>P<\/jats:italic>\u2010value threshold and no signals from the <jats:italic>q<\/jats:italic>\u2010value threshold. Study 2: 126 drugs were examined among 604 episodes. Assessments with <jats:italic>P<\/jats:italic>\u2010value thresholds yielded 3 3DI and 26 DDI signals following self\u2010control, as well as 4 3DI signals following adjustment. No 3DI signals met the <jats:italic>q<\/jats:italic>\u2010value threshold. The presented self\u2010 and externally\u2010controlled approach aimed to advance paradigms for real\u2010world higher order drug interaction screening among high\u2010susceptibility populations with pre\u2010existent DDI risk.<\/jats:p>","DOI":"10.1002\/cpt.3310","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T09:07:32Z","timestamp":1718096852000},"page":"448-459","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Thinking Three\u2010Dimensionally: A Self\u2010 and Externally\u2010Controlled Approach to Screening for Drug\u2013Drug\u2013Drug Interactions Among High\u2010Risk Populations"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5150-5995","authenticated-orcid":false,"given":"Emily K.","family":"Acton","sequence":"first","affiliation":[{"name":"Center for Real\u2010World Effectiveness and Safety of Therapeutics, Department of 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