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. This article is protected by copyright. All rights reserved.

中文翻译：

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纵向替代标记的评估

使用替代标记来检查治疗的有效性有可能缩短研究时间并更快地确定有效的治疗。调查替代标记有用性的大多数可用方法都涉及限制性参数假设，并且倾向于关注在单个时间点测量替代标记的设置。然而，在许多临床环境中，潜在的替代标记经常随时间重复测量，因此，替代标记信息是测量的轨迹。此外，在实践中通常很难正确指定治疗、主要结果和替代标记轨迹之间的关系。在本文中，我们提出了一个无模型定义，即治疗效果对主要结果的比例，由对纵向替代指标的治疗效果来解释。我们提出了三种新颖的灵活方法来估计这个比例，开发我们估计量的渐近特性，并通过模拟研究研究估计量在多种设置下的稳健性。我们将我们提出的程序应用于 AIDS 临床试验数据集，以检查 CD4 计数作为潜在替代物的轨迹。本文受版权保护。版权所有。我们将我们提出的程序应用于 AIDS 临床试验数据集，以检查 CD4 计数作为潜在替代物的轨迹。本文受版权保护。版权所有。我们将我们提出的程序应用于 AIDS 临床试验数据集，以检查 CD4 计数作为潜在替代物的轨迹。本文受版权保护。版权所有。