Li Xiaozhou, Yang Zhenyu, Yuan Chuanji, Liu Jiaqing, Li Zuojing
Department of Pharmaceutical informatics, School of Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
Department of Biostatistics and Data Analysis, Liaoning Yidu Medical Data Technology Co., Ltd., Shenyang, Liaoning, China.
PLoS One. 2025 May 29;20(5):e0323496. doi: 10.1371/journal.pone.0323496. eCollection 2025.
Currently, various methods have been proposed to handle missing data in clinical trials. Some methods assume that the missing data are missing at random (MAR), which means that it is assumed that subjects who stopped treatment would still maintain the treatment effect. In many cases, however, researchers often assume that the missing data are missing not at random (MNAR) to conduct additional sensitivity analyses. Under the MNAR assumption, whether using some conservative imputation methods such as RTB (return to baseline) method, J2R (jump to reference) method, and CR (copy reference) method, or optimistic imputation methods like multiple imputation (MI) and its derivative RD (retrieved dropout) method, biases compared to the true treatment effect can occur in some scenarios. This paper aims to propose a method that can impute results while considering the occurrence of intercurrent events, thereby reducing the bias compared to the true treatment effect. This method combines the RD method with the RTB formula, reducing the biases and standard errors associated with using either method alone. Considering the differing treatment effects between RD subjects and non-RD subjects, our imputation results often align more closely with the true drug efficacy.
目前,已经提出了各种方法来处理临床试验中的缺失数据。一些方法假定缺失数据是随机缺失(MAR),这意味着假定停止治疗的受试者仍会保持治疗效果。然而,在许多情况下,研究人员经常假定缺失数据是非随机缺失(MNAR),以便进行额外的敏感性分析。在MNAR假设下,无论是使用一些保守的插补方法,如RTB(回归基线)法、J2R(跳跃至对照)法和CR(复制对照)法,还是乐观的插补方法,如多重插补(MI)及其衍生的RD(检索失访者)法,在某些情况下与真实治疗效果相比都可能出现偏差。本文旨在提出一种能够在考虑并发事件发生的情况下插补结果的方法,从而减少与真实治疗效果相比的偏差。该方法将RD方法与RTB公式相结合,减少了单独使用任何一种方法时相关的偏差和标准误差。考虑到RD受试者和非RD受试者之间不同的治疗效果,我们的插补结果通常更接近真实的药物疗效。
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