{"title":"改进重复测量的混合模型,显著提高随机试验的精度。","authors":"Bingkai Wang, Yu Du","doi":"10.1515/ijb-2022-0101","DOIUrl":null,"url":null,"abstract":"<p><p>In randomized trials, repeated measures of the outcome are routinely collected. The mixed model for repeated measures (MMRM) leverages the information from these repeated outcome measures, and is often used for the primary analysis to estimate the average treatment effect at the primary endpoint. MMRM, however, can suffer from bias and precision loss when it models intermediate outcomes incorrectly, and hence fails to use the post-randomization information harmlessly. This paper proposes an extension of the commonly used MMRM, called IMMRM, that improves the robustness and optimizes the precision gain from covariate adjustment, stratified randomization, and adjustment for intermediate outcome measures. Under regularity conditions and missing completely at random, we prove that the IMMRM estimator for the average treatment effect is robust to arbitrary model misspecification and is asymptotically equal or more precise than the analysis of covariance (ANCOVA) estimator and the MMRM estimator. Under missing at random, IMMRM is less likely to be misspecified than MMRM, and we demonstrate via simulation studies that IMMRM continues to have less bias and smaller variance. Our results are further supported by a re-analysis of a randomized trial for the treatment of diabetes.</p>","PeriodicalId":50333,"journal":{"name":"International Journal of Biostatistics","volume":" ","pages":"585-598"},"PeriodicalIF":1.2000,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Improving the mixed model for repeated measures to robustly increase precision in randomized trials.\",\"authors\":\"Bingkai Wang, Yu Du\",\"doi\":\"10.1515/ijb-2022-0101\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>In randomized trials, repeated measures of the outcome are routinely collected. The mixed model for repeated measures (MMRM) leverages the information from these repeated outcome measures, and is often used for the primary analysis to estimate the average treatment effect at the primary endpoint. MMRM, however, can suffer from bias and precision loss when it models intermediate outcomes incorrectly, and hence fails to use the post-randomization information harmlessly. This paper proposes an extension of the commonly used MMRM, called IMMRM, that improves the robustness and optimizes the precision gain from covariate adjustment, stratified randomization, and adjustment for intermediate outcome measures. Under regularity conditions and missing completely at random, we prove that the IMMRM estimator for the average treatment effect is robust to arbitrary model misspecification and is asymptotically equal or more precise than the analysis of covariance (ANCOVA) estimator and the MMRM estimator. Under missing at random, IMMRM is less likely to be misspecified than MMRM, and we demonstrate via simulation studies that IMMRM continues to have less bias and smaller variance. Our results are further supported by a re-analysis of a randomized trial for the treatment of diabetes.</p>\",\"PeriodicalId\":50333,\"journal\":{\"name\":\"International Journal of Biostatistics\",\"volume\":\" \",\"pages\":\"585-598\"},\"PeriodicalIF\":1.2000,\"publicationDate\":\"2023-11-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Biostatistics\",\"FirstCategoryId\":\"100\",\"ListUrlMain\":\"https://doi.org/10.1515/ijb-2022-0101\",\"RegionNum\":4,\"RegionCategory\":\"数学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Biostatistics","FirstCategoryId":"100","ListUrlMain":"https://doi.org/10.1515/ijb-2022-0101","RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
Improving the mixed model for repeated measures to robustly increase precision in randomized trials.
In randomized trials, repeated measures of the outcome are routinely collected. The mixed model for repeated measures (MMRM) leverages the information from these repeated outcome measures, and is often used for the primary analysis to estimate the average treatment effect at the primary endpoint. MMRM, however, can suffer from bias and precision loss when it models intermediate outcomes incorrectly, and hence fails to use the post-randomization information harmlessly. This paper proposes an extension of the commonly used MMRM, called IMMRM, that improves the robustness and optimizes the precision gain from covariate adjustment, stratified randomization, and adjustment for intermediate outcome measures. Under regularity conditions and missing completely at random, we prove that the IMMRM estimator for the average treatment effect is robust to arbitrary model misspecification and is asymptotically equal or more precise than the analysis of covariance (ANCOVA) estimator and the MMRM estimator. Under missing at random, IMMRM is less likely to be misspecified than MMRM, and we demonstrate via simulation studies that IMMRM continues to have less bias and smaller variance. Our results are further supported by a re-analysis of a randomized trial for the treatment of diabetes.
期刊介绍:
The International Journal of Biostatistics (IJB) seeks to publish new biostatistical models and methods, new statistical theory, as well as original applications of statistical methods, for important practical problems arising from the biological, medical, public health, and agricultural sciences with an emphasis on semiparametric methods. Given many alternatives to publish exist within biostatistics, IJB offers a place to publish for research in biostatistics focusing on modern methods, often based on machine-learning and other data-adaptive methodologies, as well as providing a unique reading experience that compels the author to be explicit about the statistical inference problem addressed by the paper. IJB is intended that the journal cover the entire range of biostatistics, from theoretical advances to relevant and sensible translations of a practical problem into a statistical framework. Electronic publication also allows for data and software code to be appended, and opens the door for reproducible research allowing readers to easily replicate analyses described in a paper. Both original research and review articles will be warmly received, as will articles applying sound statistical methods to practical problems.