论文标题

纵向临床试验中的灵敏度分析通过分布插补

Sensitivity analysis in longitudinal clinical trials via distributional imputation

论文作者

Liu, Siyi, Yang, Shu, Zhang, Yilong, Guanghan, Liu

论文摘要

在纵向临床试验中,丢失的数据是不可避免的。通常,假定丢失的随机假设可以处理丢失,但是在经验上是无法验证的。因此,敏感性分析对于评估研究结论对不可测试的假设的鲁棒性至关重要。为此,监管机构经常使用归纳模型,例如返回基础,基于控制和刷新的插图。多重插补在灵敏度分析中很受欢迎。但是,这可能是效率低下的,并且通过鲁宾的结合规则导致了不满意的间隔估计。我们在灵敏度分析中提出了分布插补(DI),鉴于观察到的数据,该敏感性分析中的每个缺失值都通过其目标插补模型的样本归积。 DI估计器根据蒙特卡洛整合的想法求解了估算数据集的平均估计方程。理论保证是完全有效的。此外,我们提出了加权引导程序以获得一致的方差估计器,并考虑了由于模型参数估计和目标参数估计而引起的变异性。在模拟研究中评估了DI推断的有限样本性能。我们将提出的框架应用于抗抑郁药纵向临床试验,涉及缺少数据以研究治疗效果的鲁棒性。我们提出的DI方法在某些预先指定的敏感性模型下,根据平均治疗效应,风险差异和较低反应的较低分位数的分数治疗效应,在某些预指定的敏感性模型下检测到具有统计学意义的治疗效应,从而发现了测试药物治疗抑郁症的益处。

Missing data is inevitable in longitudinal clinical trials. Conventionally, the missing at random assumption is assumed to handle missingness, which however is unverifiable empirically. Thus, sensitivity analysis is critically important to assess the robustness of the study conclusions against untestable assumptions. Toward this end, regulatory agencies often request using imputation models such as return-to-baseline, control-based, and washout imputation. Multiple imputation is popular in sensitivity analysis; however, it may be inefficient and result in an unsatisfying interval estimation by Rubin's combining rule. We propose distributional imputation (DI) in sensitivity analysis, which imputes each missing value by samples from its target imputation model given the observed data. Drawn on the idea of Monte Carlo integration, the DI estimator solves the mean estimating equations of the imputed dataset. It is fully efficient with theoretical guarantees. Moreover, we propose weighted bootstrap to obtain a consistent variance estimator, taking into account the variabilities due to model parameter estimation and target parameter estimation. The finite-sample performance of DI inference is assessed in the simulation study. We apply the proposed framework to an antidepressant longitudinal clinical trial involving missing data to investigate the robustness of the treatment effect. Our proposed DI approach detects a statistically significant treatment effect in both the primary analysis and sensitivity analysis under certain prespecified sensitivity models in terms of the average treatment effect, the risk difference, and the quantile treatment effect in lower quantiles of the responses, uncovering the benefit of the test drug for curing depression.

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