{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:03:26Z","timestamp":1780621406023,"version":"3.54.1"},"reference-count":10,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"publisher","award":["R01-HL168202"],"award-info":[{"award-number":["R01-HL168202"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Adaptive platform trials enrolling heterogeneous populations face a critical challenge: when treatment effects differ across subgroups and enrollment is non-concurrent, pooled analyses can produce misleading results due to shifting patient composition over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To quantify treatment effect heterogeneity in the RENOVATE trial using evidential methods and e-processes, and to demonstrate how temporal shifts in enrollment composition can create statistical artifacts in sequential monitoring.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Secondary analysis of the RENOVATE trial, which randomized 1766 adults with acute respiratory failure to high-flow nasal oxygen (HFNO) versus noninvasive ventilation (NIV) across five populations: non-immunocompromised hypoxemia (n = 485), immunocompromised hypoxemia (n = 50), COPD exacerbation (n = 77), cardiogenic pulmonary edema (n = 272), and COVID-19 (n = 882). We computed sequential likelihood ratio (SLR) processes within each group for the primary outcome (death or intubation at 7\u2009days), testing a 5% absolute risk reduction hypothesis. We compared group-specific trajectories with pooled analysis to visualize how enrollment composition influenced evidence accumulation. Sensitivity analyses used conditional e-processes (which eliminate the baseline rate parameter) and randomization-based e-processes (assumption-free).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Treatment effects varied substantially across populations. Cardiogenic edema showed strong evidence of HFNO benefit (absolute risk difference \u221211.0%; S-3 interval \u221215.8% to \u22123.8%; final support S = 3.36). COVID-19 showed a point estimate suggesting harm (+4.3%; S-3 interval \u22121.3% to + 9.8%; S = \u22123.23). The pooled SLR displayed a V-shaped artifact, with support dropping to S = \u22125.5 during the COVID-dominated enrollment period, then reversing to S = +5.6 as lower-risk patients entered. Alternative analyses were aligned with SLR but did not suffer from artifact interpretation due to baseline risk change.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Sequential evidential analysis reveals substantial treatment effect heterogeneity, which is masked by pooled analysis, with enrollment composition mechanistically driving the evidence trajectories. E-processes provide a diagnostic tool for platform trials, making visible the interaction between enrollment dynamics and treatment heterogeneity that conventional pooled estimates cannot reveal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>NCT03643939<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Primary Source of Funding<\/jats:title>\n                    <jats:p>Brazilian Ministry of Health<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/annalsats\/aaoag042","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T16:46:11Z","timestamp":1771951571000},"page":"941-950","source":"Crossref","is-referenced-by-count":0,"title":["Sequential likelihood ratios and e-processes in the analysis of the RENOVATE trial"],"prefix":"10.1093","volume":"23","author":[{"given":"Fernando G","family":"Zampieri","sequence":"first","affiliation":[{"name":"Research Institute, Hospital do Coracao (HCor) , Sao Paulo,","place":["Brazil"]},{"name":"Department of Critical Care Medicine, University of Alberta , Edmonton,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre B","family":"Cavalcanti","sequence":"additional","affiliation":[{"name":"Research Institute, Hospital do Coracao (HCor) , Sao Paulo,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4976-2834","authenticated-orcid":false,"given":"Peter M B","family":"Cahusac","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Biostatistics, College of Medicine, Alfaisal University , Riyadh,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Kawano-Dourado","sequence":"additional","affiliation":[{"name":"Research Institute, Hospital do Coracao (HCor) , Sao Paulo,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0553-674X","authenticated-orcid":false,"given":"Michael O","family":"Harhay","sequence":"additional","affiliation":[{"name":"Pulmonary, Allergy, and Critical Care Medicine Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA,","place":["United States"]},{"name":"Center for Clinical Trials Innovation, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA,","place":["United States"]},{"name":"Department of Statistics and Data Science, Wharton School, University of Pennsylvania , Philadelphia, PA,","place":["United States"]},{"name":"MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel S","family":"Maia","sequence":"additional","affiliation":[{"name":"Research Institute, Hospital do Coracao (HCor) , Sao Paulo,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"2026060420443303100_aaoag042-B1","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1002\/pst.2093","article-title":"Assessing efficacy in important subgroups in confirmatory trials: an example using Bayesian dynamic borrowing","volume":"20","author":"Best","year":"2021","journal-title":"Pharm Stat"},{"key":"2026060420443303100_aaoag042-B2","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1177\/1740774513497539","article-title":"Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase II oncology clinical trials","volume":"10","author":"Berry","year":"2013","journal-title":"Clin Trials"},{"key":"2026060420443303100_aaoag042-B3","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1001\/jama.2024.26244","article-title":"High-flow nasal oxygen vs noninvasive ventilation in patients with acute respiratory failure: the RENOVATE randomized clinical trial","volume":"333","author":"Maia","year":"2025","journal-title":"JAMA"},{"key":"2026060420443303100_aaoag042-B4","doi-asserted-by":"publisher","first-page":"1610","DOI":"10.1164\/rccm.202504-0809TR","article-title":"Trial analysis and interpretation in critical care using the evidential (likelihood) approach: rationale and practical considerations","volume":"211","author":"Zampieri","year":"2025","journal-title":"Am J Respir Crit Care Med"},{"key":"2026060420443303100_aaoag042-B5","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1080\/03610920701713336","article-title":"How often likelihood ratios are misleading in sequential trials","volume":"37","author":"Blume","year":"2008","journal-title":"Commun Stat Theory Methods"},{"key":"2026060420443303100_aaoag042-B6","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1111\/rssa.12647","article-title":"Testing by betting: a strategy for statistical and scientific communication","volume":"184","author":"Shafer","year":"2021","journal-title":"J R Stat Soc Ser A Stat Soc"},{"key":"2026060420443303100_aaoag042-B7","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1214\/20-AOS2020","article-title":"E-values: calibration, combination and applications","volume":"49","author":"Vovk","year":"2021","journal-title":"Ann Statist"},{"key":"2026060420443303100_aaoag042-B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1561\/3600000002","article-title":"Hypothesis testing with e-values","volume":"1","author":"Ramdas","year":"2025","journal-title":"Found Trends Stat"},{"key":"2026060420443303100_aaoag042-B9","doi-asserted-by":"publisher","author":"Zampieri","DOI":"10.48550\/arXiv.2512.04366"},{"key":"2026060420443303100_aaoag042-B10","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1136\/bmj.309.6967.1480","article-title":"Confounding and Simpson\u2019s paradox","volume":"309","author":"Julious","year":"1994","journal-title":"BMJ"}],"container-title":["Annals of the American Thoracic Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/annalsats\/advance-article-pdf\/doi\/10.1093\/annalsats\/aaoag042\/67092084\/aaoag042.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/annalsats\/article-pdf\/23\/6\/941\/67092084\/aaoag042.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/annalsats\/article-pdf\/23\/6\/941\/67092084\/aaoag042.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:44:39Z","timestamp":1780620279000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/annalsats\/article\/23\/6\/941\/8496146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,24]]},"references-count":10,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,2,24]]},"published-print":{"date-parts":[[2026,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/annalsats\/aaoag042","relation":{},"ISSN":["2329-6933","2325-6621"],"issn-type":[{"value":"2329-6933","type":"print"},{"value":"2325-6621","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,6]]},"published":{"date-parts":[[2026,2,24]]}}}