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非比例风险下联合检验的样本量计算

Sample size calculation for the combination test under nonproportional hazards.

作者信息

Cheng Huan, He Jianghua

机构信息

Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, United States.

出版信息

Biom J. 2023 Apr;65(4):e2100403. doi: 10.1002/bimj.202100403. Epub 2023 Feb 15.

Abstract

For sample size calculation in clinical trials with survival endpoints, the logrank test, which is the optimal method under the proportional hazard (PH) assumption, is predominantly used. In reality, the PH assumption may not hold. For example, in immuno-oncology trials, delayed treatment effects are often expected. The sample size without considering the potential violation of the PH assumption may lead to an underpowered study. In recent years, combination tests such as the maximum weighted logrank test have received great attention because of their robust performance in various hazards scenarios. In this paper, we propose a flexible simulation-free procedure to calculate the sample size using combination tests. The procedure extends the Lakatos' Markov model and allows for complex situations encountered in a clinical trial, like staggered entry, dropouts, etc. We evaluate the procedure using two maximum weighted logrank tests, one projection-type test, and three other commonly used tests under various hazards scenarios. The simulation studies show that the proposed method can achieve the target power for all compared tests in most scenarios. The combination tests exhibit robust performance under correct specification and misspecification scenarios and are highly recommended when the hazard-changing patterns are unknown beforehand. Finally, we demonstrate our method using two clinical trial examples and provide suggestions about the sample size calculations under nonproportional hazards.

摘要

在具有生存终点的临床试验中进行样本量计算时,主要使用对数秩检验,它是比例风险(PH)假设下的最优方法。实际上,PH假设可能不成立。例如,在免疫肿瘤学试验中,常常预期会有延迟治疗效果。不考虑PH假设潜在违背情况的样本量可能会导致研究效能不足。近年来,诸如最大加权对数秩检验等组合检验因其在各种风险情形下的稳健性能而备受关注。在本文中,我们提出一种灵活的无需模拟的程序,使用组合检验来计算样本量。该程序扩展了拉卡托斯的马尔可夫模型,并考虑了临床试验中遇到的复杂情况,如交错入组、失访等。我们在各种风险情形下,使用两种最大加权对数秩检验、一种投影型检验以及其他三种常用检验来评估该程序。模拟研究表明,所提出的方法在大多数情形下能为所有比较的检验实现目标效能。组合检验在正确设定和错误设定情形下均表现出稳健性能,并且当风险变化模式事先未知时,强烈推荐使用。最后,我们用两个临床试验实例展示了我们的方法,并提供了关于非比例风险下样本量计算的建议。

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