论文标题
在具有外部观察数据的临床试验中,鉴定和估计治疗对长期结局的影响
Identification and estimation of treatment effects on long-term outcomes in clinical trials with external observational data
论文作者
论文摘要
在生物医学研究中,估计药物对慢性疾病的影响需要长期随访期,这在随机临床试验(RCT)中很难满足。使用短期替代物来替代评估药物效应的长期结局的使用取决于严格的假设,即经验研究通常无法满足。在一项肾脏疾病研究的激励中,我们通过将RCT结合在一起而没有观察到长期结局和一项观察性研究,其中观察到了长期结局,但可能存在未衡量的混淆,从而研究了药物对长期结局的影响。在平均交换性假设较弱的情况下,我们确定了RCT中的平均治疗效果,并得出相关的有效影响函数和半参数效率结合。此外,我们提出了一个局部有效的双重稳健估计器和一个反概率加权(IPW)估计器。如果正确指定了所有工作模型,前者将达到半参数效率。后者的形式更简单,需要更少的模型规格。使用估计倾向得分的IPW估计器比使用真实倾向得分并在离散协变量和具有有限支持的替代物的情况下实现了半参数效率的估计量更有效。两种估计量均显示一致且渐近地正态分布。进行了广泛的模拟,以评估所提出的估计器的有限样本性能。我们应用提出的方法来估计口服羟基氯喹对肾衰竭的疗效,在现实世界中的数据分析中。
In biomedical studies, estimating drug effects on chronic diseases requires a long follow-up period, which is difficult to meet in randomized clinical trials (RCTs). The use of a short-term surrogate to replace the long-term outcome for assessing the drug effect relies on stringent assumptions that empirical studies often fail to satisfy. Motivated by a kidney disease study, we investigate the drug effects on long-term outcomes by combining an RCT without observation of long-term outcome and an observational study in which the long-term outcome is observed but unmeasured confounding may exist. Under a mean exchangeability assumption weaker than the previous literature, we identify the average treatment effects in the RCT and derive the associated efficient influence function and semiparametric efficiency bound. Furthermore, we propose a locally efficient doubly robust estimator and an inverse probability weighted (IPW) estimator. The former attains the semiparametric efficiency bound if all the working models are correctly specified. The latter has a simpler form and requires much fewer model specifications. The IPW estimator using estimated propensity scores is more efficient than that using true propensity scores and achieves the semiparametric efficient bound in the case of discrete covariates and surrogates with finite support. Both estimators are shown to be consistent and asymptotically normally distributed. Extensive simulations are conducted to evaluate the finite-sample performance of the proposed estimators. We apply the proposed methods to estimate the efficacy of oral hydroxychloroquine on renal failure in a real-world data analysis.