Assessing the potential of surrogate markers and surrogate outcomes for replacing a long term outcome is an active area of research. The interest in this topic is partly motivated by increasing pressure from stakeholders to shorten the time required to evaluate the safety and/or efficacy of a treatment or intervention such that treatments deemed safe and effective can be made available to those in need more quickly. Most existing methods in surrogacy evaluation either require strict model assumptions or that primary outcome and surrogate outcome information is available for all study participants. In this paper, we focus on a setting where the primary outcome is subject to censoring and the aim is to quantify the surrogacy of an intermediate outcome, which is also subject to censoring. We define the surrogacy as the proportion of treatment effect on the primary outcome that is explained by the intermediate surrogate outcome information and propose two robust methods to estimate this quantity. We propose both a nonparametric approach that uses a kernel smoothed Nelson–Aalen estimator of conditional survival, and a semiparametric method that derives conditional survival estimates from a landmark Cox proportional hazards model. Simulation studies demonstrate that both approaches perform well in finite samples. Our methodological development is motivated by our interest in investigating the use of a composite cardiovascular endpoint as a surrogate outcome in a randomized study of the effectiveness of angiotensin-converting enzyme inhibitors on survival. We apply the proposed methods to quantify the surrogacy of this potential surrogate outcome for the primary outcome, time to death.

中文翻译：

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评估审查的替代结果的价值。

评估替代标志物和替代结局替代长期结果的潜力是一个活跃的研究领域。对这一主题的兴趣部分是由于利益相关者的压力越来越大，他们需要缩短评估治疗或干预措施的安全性和/或功效所需的时间，以便可以更快地向需要的人提供被认为安全有效的治疗方法。代孕评估中大多数现有方法要么要求严格的模型假设，要么要求所有研究参与者都可获得主要结果和替代结果信息。在本文中，我们专注于主要结果受到审查的设置，目的是量化代孕中间结果的结果，也应进行审查。我们定义代孕作为由中间替代结果信息解释的治疗效果对主要结果的比例，并提出了两种可靠的方法来估计该量。我们提出了一种非参数方法，该方法使用了核平滑的条件生存率的Nelson-Aalen估计量，还提出了一种半参数方法，该方法从具有里程碑意义的Cox比例风险模型中得出条件生存率估计值。仿真研究表明，这两种方法在有限样本中均表现良好。我们的方法学发展受到了我们对研究使用复合心血管终点作为替代结果的兴趣的推动，该结果是对血管紧张素转化酶抑制剂对生存的有效性进行的随机研究。