{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T16:00:52Z","timestamp":1747152052143,"version":"3.40.5"},"reference-count":24,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Statistics in Medicine"],"published-print":{"date-parts":[[2021,4,15]]},"abstract":"<jats:p>Parallel\u2010group thorough QT\/QTc studies focus on the change of QT\/QTc values at several time\u2010matched points from a pretreatment day (baseline) to a posttreatment day for different groups of treatment. The International Council for Harmonisation E14 stresses that QTc prolongation beyond a threshold represents high cardiac risk and calls for a test on the largest time\u2010matched treatment effect (QTc prolongation). QT\/QTc analysis usually assumes a jointly multivariate normal (MVN) distribution of pretreatment and posttreatment QT\/QTc values, with a blocked compound symmetry covariance matrix. Existing methods use an analysis of covariance (ANCOVA) model including day\u2010averaged baseline as a covariate to deal with the MVN model. However, the ANCOVA model tends to underestimate the variation of the estimator for treatment effects, resulting in the inflation of empirical type I error rate when testing whether the largest QTc prolongation is beyond a threshold. In this article, we propose two new methods to estimate the time\u2010matched treatment effects under the MVN model, including maximum likelihood estimation and ordinary\u2010least\u2010square\u2010based two\u2010stage estimation. These two methods take advantage of the covariance structure and are asymptotically efficient. Based on these estimators, powerful tests for QT\/QTc prolongation are constructed. Simulation shows that the proposed estimators have smaller mean square error, and the tests can control the type I error rate with high power. The proposed methods are applied on testing the carryover effect of diltiazem to inhibit dofetilide in a randomized phase 1 trial.<\/jats:p>","DOI":"10.1002\/sim.8881","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T11:52:29Z","timestamp":1611057149000},"page":"1947-1959","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A powerful test for the maximum treatment effect in thorough QT\/QTc studies"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0331-6070","authenticated-orcid":false,"given":"Yuhao","family":"Deng","sequence":"first","affiliation":[{"name":"School of Mathematical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Statistics Columbia University New York City USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Academy for Advanced Interdisciplinary Studies Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaihuan","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao\u2010Hua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health Peking University Beijing China"},{"name":"Beijing International Center for Mathematical Research Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_9_2_1","DOI":"10.1161\/JAHA.116.003264"},{"unstructured":"TempleR. 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