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Med."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Randomized clinical trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT enrollment. In simulated group sequential analyses of two large cardiovascular outcomes RCTs of (1) a therapeutic drug (pioglitazone versus placebo; Insulin Resistance Intervention after Stroke (IRIS) trial), and (2) a disease management strategy (intensive versus standard systolic blood pressure reduction in the Systolic Blood Pressure Intervention Trial (SPRINT)), we constructed dynamic phenotypic representations to infer response profiles during interim analyses and examined their association with study outcomes. Across three interim timepoints, our strategy learned dynamic phenotypic signatures predictive of individualized cardiovascular benefit. By conditioning a prospective candidate\u2019s probability of enrollment on their predicted benefit, we estimate that our approach would have enabled a reduction in the final trial size across ten simulations (IRIS: \u221214.8% \u00b1 3.1%, <jats:italic>p<\/jats:italic><jats:sub><jats:italic>one-sample t-test<\/jats:italic><\/jats:sub>\u2009=\u20090.001; SPRINT: \u221217.6% \u00b1 3.6%, <jats:italic>p<\/jats:italic><jats:sub><jats:italic>one-sample t-test<\/jats:italic><\/jats:sub>\u2009&lt;\u20090.001), while preserving the original average treatment effect (IRIS: hazard ratio of 0.73\u2009\u00b1\u20090.01 for pioglitazone vs placebo, vs 0.76 in the original trial; SPRINT: hazard ratio of 0.72\u2009\u00b1\u20090.01 for intensive vs standard systolic blood pressure, vs 0.75 in the original trial; all simulations with Cox regression-derived p value of \u2009&lt;\u20090.01 for the effect of the intervention on the respective primary outcome). This adaptive framework has the potential to maximize RCT enrollment efficiency.<\/jats:p>","DOI":"10.1038\/s41746-023-00963-z","type":"journal-article","created":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T04:22:04Z","timestamp":1700886124000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["An explainable machine learning-based phenomapping strategy for adaptive predictive enrichment in randomized clinical trials"],"prefix":"10.1038","volume":"6","author":[{"given":"Evangelos K.","family":"Oikonomou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phyllis M.","family":"Thangaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1278-6245","authenticated-orcid":false,"given":"Deepak L.","family":"Bhatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9218-3320","authenticated-orcid":false,"given":"Joseph S.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence H.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-127X","authenticated-orcid":false,"given":"Harlan M.","family":"Krumholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc A.","family":"Suchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9467-6199","authenticated-orcid":false,"given":"Rohan","family":"Khera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,25]]},"reference":[{"key":"963_CR1","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1056\/NEJMsb1901642","volume":"382","author":"R Collins","year":"2020","unstructured":"Collins, R., Bowman, L., Landray, M. & Peto, R. 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BMJ 335, 806\u2013808 (2007).","journal-title":"BMJ"}],"container-title":["npj Digital Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41746-023-00963-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41746-023-00963-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41746-023-00963-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T15:03:43Z","timestamp":1700924623000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41746-023-00963-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,25]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["963"],"URL":"https:\/\/doi.org\/10.1038\/s41746-023-00963-z","relation":{},"ISSN":["2398-6352"],"issn-type":[{"value":"2398-6352","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,25]]},"assertion":[{"value":"15 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 November 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"E.K.O. declares funding through the National Heart, Lung, and Blood Institute of the National Institutes of Health (1F32HL170592-01), is a co-inventor of the U.S. Patent Applications 63\/508,315 & 63\/177,117, and has previously served as a consultant to Caristo Diagnostics Ltd (outside the present work). R.K. is an Associate Editor of JAMA. He receives support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (under award K23HL153775) and the Doris Duke Charitable Foundation (under award, 2022060). He also receives research support, through Yale, from Bristol-Myers Squibb and Novo Nordisk. He is a coinventor of U.S. Provisional Patent Applications 63\/177,117, 63\/428,569, 63\/346,610, 63\/484,426, and 63\/508,315. E.K.O. and R.K. are co-founders of Evidence2Health, a precision health platform to improve evidence-based cardiovascular care. R.K. is also a co-founder of Ensight-AI, focusing on improving early disease diagnosis. D.L.B. discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures, Hims; Data Monitoring Committees: Acesion Pharma, Assistance Publique-H\u00f4pitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi\/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence\/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today\u2019s Intervention), Society of Cardiovascular Patient Care (Secretary\/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women\u2019s Hospital who assigned to Lexicon; neither I nor Brigham and Women\u2019s Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald\u2019s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. J.S.R. currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), and from Arnold Ventures; formerly received research support from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST) and from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644); and in addition, J.S.R. was an expert witness at the request of Relator\u2019s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. that was settled September 2022. L.H.Y. is the co-inventor of the U.S. patent US 9,308,255 B2. H.M.K. works under contract with the Centers for Medicare & Medicaid Services to support quality measurement programs, was a recipient of a research grant from Johnson & Johnson, through Yale University, to support clinical trial data sharing; was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; receives payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation, from the Martin Baughman Law Firm for work related to the Cook Celect IVC filter litigation, and from the Siegfried and Jensen Law Firm for work related to Vioxx litigation; chairs a Cardiac Scientific Advisory Board for UnitedHealth; was a member of the IBM Watson Health Life Sciences Board; is a member of the Advisory Board for Element Science, the Advisory Board for Facebook, and the Physician Advisory Board for Aetna; and is the co-founder of Hugo Health, a personal health information platform, and co-founder of Refactor Health, a healthcare AI-augmented data management company. M.A.S. reports institutional grant support from the US National Institutes of Health, US Food and Drug Administration, and US Department of Veteran Affairs; personal consulting fees from Janssen Research and Development and Private Health Management; and institutional grant support from Advanced Micro Devices, outside the scope of the submitted work. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The local ethics committee\/IRB (institutional review boards) of Yale University provided a determination of exemption and waived ethical approval for this work (under IRB protocol ID 2000029730, 1\/21\/2021).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"217"}}