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Signals of ADEs from three\u2010drug combinations could be identified from real\u2010world data, and the risks of ADEs from single drug exposure to three\u2010drug combination exposure could be illustrated by a graphic model. We used a US nationwide insurance claim database. We explored the relationship between drug exposure (from single drugs to three\u2010drug combinations) and risks of ADEs (acute kidney injury, gastrointestinal bleeding, and opioid\u2010related ADE). We used a conditional logistic regression model to estimate the odds ratios (ORs), the posterior probability of null hypothesis to control false discovery rate (FDR), and a graphic model to illustrate the ORs from single drug exposure to three\u2010drug combination exposure. We derived approximately 1.7 million covariate\u2010matched ADE\u2010case\u2013control pairs and investigated approximately 0.25 million three\u2010drug combinations. We identified 3412 signals of adverse three\u2010drug combinations (FDR &lt;\u20090.01 and OR &gt;\u20092). For the signals, we observed the medians and interquartile ranges (IQRs) of ORs increased from single drug exposure (median\u2009=\u20091.03, IQR: 0.95\u20131.15), through two\u2010drug combination exposure (median\u2009=\u20091.45, IQR: 1.23\u20131.75), to three\u2010drug combination exposure (median\u2009=\u20092.95, IQR: 2.43\u20133.91). We built a webpage\u2010based tool to illustrate the ORs from single drug exposure to three\u2010drug combination exposure. In conclusion, certain three\u2010drug combinations are associated with an increased risk of ADE, and the risks of ADE could increase from single drug exposure to three\u2010drug combination exposure.<\/jats:p>","DOI":"10.1111\/cts.70672","type":"journal-article","created":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T03:06:38Z","timestamp":1784430398000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring Risks of Adverse Drug Events From Single Drug to Three\u2010Drug Combination"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0145-2968","authenticated-orcid":false,"given":"Yi","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Health Data Science Indiana University  Indianapolis Indiana 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