RAND Corporation.
Biometrics. 2021 Jun;77(2):477-489. doi: 10.1111/biom.13310. Epub 2020 Jun 22.
The use of surrogate markers to examine the effectiveness of a treatment has the potential to decrease study length and identify effective treatments more quickly. Most available methods to investigate the usefulness of a surrogate marker involve restrictive parametric assumptions and tend to focus on settings where the surrogate is measured at a single point in time. However, in many clinical settings, the potential surrogate marker is often measured repeatedly over time, and thus, the surrogate marker information is a trajectory of measurements. In addition, it is often difficult in practice to correctly specify the relationship between a treatment, primary outcome, and surrogate marker trajectory. In this paper, we propose a model-free definition for the proportion of the treatment effect on the primary outcome that is explained by the treatment effect on the longitudinal surrogate markers. We propose three novel flexible methods to estimate this proportion, develop the asymptotic properties of our estimators, and investigate the robustness of the estimators under multiple settings via a simulation study. We apply our proposed procedures to an AIDS clinical trial dataset to examine a trajectory of CD4 counts as a potential surrogate.
使用替代标志物来检验治疗效果具有缩短研究时间和更快确定有效治疗方法的潜力。大多数现有的调查替代标志物有用性的方法都涉及到限制性参数假设，并且往往侧重于在替代标志物在一个时间点被测量的情况下。然而，在许多临床情况下，潜在的替代标志物通常是随时间多次重复测量的，因此，替代标志物信息是一个测量轨迹。此外，在实践中，通常很难正确指定治疗、主要结局和替代标志物轨迹之间的关系。在本文中，我们提出了一种无模型定义，用于定义治疗对主要结局的效果中，由治疗对纵向替代标志物的效果所解释的比例。我们提出了三种新的灵活方法来估计这个比例，发展了我们的估计量的渐近性质，并通过模拟研究在多种设置下研究了估计量的稳健性。我们将我们提出的程序应用于艾滋病临床试验数据集，以研究 CD4 计数作为潜在替代标志物的轨迹。
