论文标题
对纵向临床试验的强大分析,缺失和非正常连续结局
Robust analyses for longitudinal clinical trials with missing and non-normal continuous outcomes
论文作者
论文摘要
在纵向临床试验中,丢失的数据是不可避免的,并且结果并不总是正态分布。在存在异常值或重尾分布的情况下,基于多变量正常假设的平均治疗效果(ATE)的混合模型的常规多重归档可能会产生偏差和功率损失。基于对照的插补(CBI)是一种假设,即测试组和对照组缺失结果数据的参与者具有与对照组相同病史的结果概况相似的方法。我们开发一个一般的鲁棒框架来处理CBI下的非正常结果,而无需施加任何参数建模假设。在提出的框架下,使用顺序加权的鲁棒回归来保护构造的插补模型免受协变量和响应变量的非正态性。伴随着随后的平均插补和健壮的模型分析,在一致性和渐近正态性方面,所得的估计量具有良好的理论特性。此外,我们提出的方法保证了ATE估计的分析模型的鲁棒性,即使分析模型被弄错了,即使其渐近结果仍然完好无损。综合模拟研究和AIDS临床试验数据应用证明了所提出的鲁棒方法的优势。
Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those with an identical history in the control group. We develop a general robust framework to handle non-normal outcomes under CBI without imposing any parametric modeling assumptions. Under the proposed framework, sequential weighted robust regressions are applied to protect the constructed imputation model against non-normality in both the covariates and the response variables. Accompanied by the subsequent mean imputation and robust model analysis, the resulting ATE estimator has good theoretical properties in terms of consistency and asymptotic normality. Moreover, our proposed method guarantees the analysis model robustness of the ATE estimation, in the sense that its asymptotic results remain intact even when the analysis model is misspecified. The superiority of the proposed robust method is demonstrated by comprehensive simulation studies and an AIDS clinical trial data application.