The population-wise error rate (PWER) is a type I error rate for clinical trials with multiple target populations. In such trials, one treatment is tested for its efficacy in each population. The PWER is defined as the probability that a randomly selected, future patient will be exposed to an inefficient treatment based on the study results. The PWER can be understood and computed as an average of strata-specific family-wise error rates and involves the prevalences of these strata. A major issue of this concept is that the prevalences are usually not known in practice, so that the PWER cannot be directly controlled. Instead, one could use an estimator based on the given sample, like their maximum-likelihood estimator under a multinomial distribution. In this paper we show in simulations that this does not substantially inflate the true PWER. We differentiate between the expected PWER, which is almost perfectly controlled, and study-specific values of the PWER which are conditioned on all subgroup sample sizes and vary within a narrow range. Thereby, we consider up to eight different overlapping patient populations and moderate to large sample sizes. In these settings, we also consider the maximum strata-wise family-wise error rate, which is found to be, on average, at least bounded by twice the significance level used for PWER control. Finally, we introduce an adjustment of the PWER that could be made when, by chance, no patients are recruited from a stratum, so that this stratum is not counted in PWER control. We would then reduce the PWER in order to control for multiplicity in this stratum as well.

翻译：总体错误率（PWER）是针对具有多个目标人群的临床试验所定义的一种第一类错误率。在此类试验中，一种治疗方法需在各个人群中检验其有效性。PWER定义为：基于研究结果，随机选取的未来患者将暴露于无效治疗的概率。PWER可理解为各分层特定家族错误率的加权平均值，其计算涉及这些分层的患病率。该概念的一个主要问题是，实际中患病率通常未知，因此无法直接控制PWER。一种替代方案是使用基于给定样本的估计量，例如在多项分布假设下的极大似然估计量。本文通过模拟实验表明，这种方法不会显著增加真实PWER值。我们区分了两种情形：期望PWER几乎能完美控制，而基于各亚组样本量条件化的研究特定PWER值变化范围狭窄。研究中我们考虑了多达八个重叠的患者人群，以及中等至较大的样本量。在这些设定下，我们还考察了最大分层家族错误率，发现其平均值至少被限制在用于PWER控制的显著性水平的两倍以内。最后，我们引入一种PWER调整方法：当某分层偶然未被招募患者时（即不纳入PWER控制），通过降低PWER值以控制该分层内的多重比较问题。