SENSITIVITY ANALYSIS FOR EVALUATING PRINCIPAL SURROGATE ENDPOINTS RELAXING THE EQUAL EARLY CLINICAL RISK ASSUMPTION.

IF 1.3 4区 数学 Q2 STATISTICS & PROBABILITY
Annals of Applied Statistics Pub Date : 2022-09-01 Epub Date: 2022-07-19 DOI:10.1214/21-aoas1566
Ying Huang, Yingying Zhuang, Peter Gilbert
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引用次数: 0

Abstract

This article addresses the evaluation of post-randomization immune response biomarkers as principal surrogate endpoints of a vaccine's protective effect, based on data from randomized vaccine trials. An important metric for quantifying a biomarker's principal surrogacy in vaccine research is the vaccine efficacy curve, which shows a vaccine's efficacy as a function of potential biomarker values if receiving vaccine, among an 'early-always-at-risk' principal stratum of trial participants who remain disease-free at the time of biomarker measurement whether having received vaccine or placebo. Earlier work in principal surrogate evaluation relied on an 'equal-early-clinical-risk' assumption for identifiability of the vaccine curve, based on observed disease status at the time of biomarker measurement. This assumption is violated in the common setting that the vaccine has an early effect on the clinical endpoint before the biomarker is measured. In particular, a vaccine's early protective effect observed in two phase III dengue vaccine trials (CYD14/CYD15) has motivated our current research development. We relax the 'equal-early-clinical-risk' assumption and propose a new sensitivity analysis framework for principal surrogate evaluation allowing for early vaccine efficacy. Under this framework, we develop inference procedures for vaccine efficacy curve estimators based on the estimated maximum likelihood approach. We then use the proposed methodology to assess the surrogacy of post-randomization neutralization titer in the motivating dengue application.

评估主要替代终点的灵敏度分析放松了早期临床风险相同的假设。
本文以随机疫苗试验的数据为基础,对作为疫苗保护效果主要替代终点的随机化后免疫反应生物标志物进行了评估。疫苗疗效曲线是疫苗研究中量化生物标志物主要代用性的一个重要指标,它显示了疫苗的疗效与接受疫苗时潜在生物标志物值的函数关系,而疫苗的疗效是由 "早期一直处于风险中 "的主要试验参与者组成的。早期的主要替代物评估工作依赖于 "早期临床风险相同 "的假设,根据生物标记物测量时观察到的疾病状态来确定疫苗曲线的可识别性。在生物标记物测量前疫苗对临床终点产生早期影响的常见情况下,这一假设就被打破了。特别是,在登革热疫苗 III 期试验(CYD14/CYD15)中观察到的疫苗早期保护效果激发了我们目前的研究发展。我们放宽了 "早期临床风险相等 "的假设,并提出了一个新的敏感性分析框架,用于主要替代物评估,允许早期疫苗疗效。在这一框架下,我们基于最大似然估计法开发了疫苗疗效曲线估计器的推断程序。然后,我们在登革热应用中使用所提出的方法来评估随机化后中和滴度的代用性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Annals of Applied Statistics
Annals of Applied Statistics 社会科学-统计学与概率论
CiteScore
3.10
自引率
5.60%
发文量
131
审稿时长
6-12 weeks
期刊介绍: Statistical research spans an enormous range from direct subject-matter collaborations to pure mathematical theory. The Annals of Applied Statistics, the newest journal from the IMS, is aimed at papers in the applied half of this range. Published quarterly in both print and electronic form, our goal is to provide a timely and unified forum for all areas of applied statistics.
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