Morris Tim P, Walker A Sarah, Williamson Elizabeth J, White Ian R
MRC Clinical Trials Unit at UCL, London, UK.
Department of Medical Statistics, LSHTM, London, UK.
Trials. 2022 Apr 18;23(1):328. doi: 10.1186/s13063-022-06097-z.
BACKGROUND: It has long been advised to account for baseline covariates in the analysis of confirmatory randomised trials, with the main statistical justifications being that this increases power and, when a randomisation scheme balanced covariates, permits a valid estimate of experimental error. There are various methods available to account for covariates but it is not clear how to choose among them. METHODS: Taking the perspective of writing a statistical analysis plan, we consider how to choose between the three most promising broad approaches: direct adjustment, standardisation and inverse-probability-of-treatment weighting. RESULTS: The three approaches are similar in being asymptotically efficient, in losing efficiency with mis-specified covariate functions and in handling designed balance. If a marginal estimand is targeted (for example, a risk difference or survival difference), then direct adjustment should be avoided because it involves fitting non-standard models that are subject to convergence issues. Convergence is most likely with IPTW. Robust standard errors used by IPTW are anti-conservative at small sample sizes. All approaches can use similar methods to handle missing covariate data. With missing outcome data, each method has its own way to estimate a treatment effect in the all-randomised population. We illustrate some issues in a reanalysis of GetTested, a randomised trial designed to assess the effectiveness of an electonic sexually transmitted infection testing and results service. CONCLUSIONS: No single approach is always best: the choice will depend on the trial context. We encourage trialists to consider all three methods more routinely.
背景:长期以来,在确证性随机试验的分析中一直建议考虑基线协变量,主要的统计学依据是这会提高检验效能,并且当随机化方案使协变量平衡时,能够对实验误差进行有效估计。有多种方法可用于考虑协变量,但尚不清楚如何在它们之间进行选择。 方法:从撰写统计分析计划的角度出发,我们考虑如何在三种最有前景的主要方法之间进行选择:直接调整、标准化和治疗逆概率加权。 结果:这三种方法在渐近效率、因协变量函数指定错误而导致效率损失以及处理设计平衡方面相似。如果目标是边际估计量(例如,风险差或生存差),则应避免直接调整,因为它涉及拟合存在收敛问题的非标准模型。IPTW最有可能实现收敛。IPTW使用的稳健标准误在小样本量时是反保守的。所有方法都可以使用类似的方法来处理协变量数据缺失的情况。对于结局数据缺失的情况,每种方法都有自己在所有随机分组人群中估计治疗效果的方式。我们在对GetTested(一项旨在评估电子性传播感染检测及结果服务有效性的随机试验)的重新分析中阐述了一些问题。 结论:没有一种方法总是最佳的:选择将取决于试验背景。我们鼓励试验者更常规地考虑所有这三种方法。
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