Title: Resilience Measures for the Surrogate Paradox Show Chinese title

Title: 代理悖论的韧性措施

Abstract: Surrogate markers are often used in clinical trials to evaluate treatment effects when primary outcomes are costly, invasive, or take a long time to observe. However, reliance on surrogates can lead to the surrogate paradox, where a treatment appears beneficial based on the surrogate but is actually harmful with respect to the primary outcome. In this paper, we propose formal measures to assess resilience against the surrogate paradox. Our setting assumes an existing study in which the surrogate marker and primary outcome have been measured (Study A) and a new study (Study B) in which only the surrogate is measured. Rather than assuming transportability of the conditional mean functions across studies, we consider a class of functions for Study B that deviate from those in Study A. Using these, we estimate the distribution of potential treatment effects on the unmeasured primary outcome and define resilience measures including a resilience probability, resilience bound, and resilience set. Our approach complements traditional surrogate validation methods by quantifying the plausibility of the surrogate paradox under controlled deviations from what is known from Study A. We investigate the performance of our proposed measures via a simulation study and application to two distinct HIV clinical trials. Show Chinese abstract

Abstract: 替代标志物常用于临床试验中以评估治疗效果，特别是在主要结局成本高昂、侵入性强或需要很长时间才能观察到的情况下。 然而，过度依赖替代标志物可能导致替代悖论，即基于替代标志物显示治疗有益，但与主要结局相比实际上是有害的。 本文提出了一些正式的度量方法来评估对替代悖论的抗性。 我们的设定假设一个已经存在的研究（研究A），其中替代标志物和主要结局已被测量，并且一个新的研究（研究B）中仅测量了替代标志物。 我们考虑了一类偏离研究A函数的研究B函数，而不是假设条件均值函数在不同研究间的可传递性。 利用这些函数，我们估计未测量的主要结局潜在治疗效果的分布，并定义了抗性度量，包括抗性概率、抗性界限和抗性集合。 我们的方法通过量化在已知研究A的基础上可控偏差下替代悖论的可能性，补充了传统的替代验证方法。 我们通过模拟研究以及对两个不同的HIV临床试验的应用，调查了所提出的度量方法的表现。