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一种针对具有缺失协变量和缺失标记的分层标记特定比例风险模型的混合方法及其在疫苗效力试验中的应用

A Hybrid Approach for the Stratified Mark-Specific Proportional Hazards Model with Missing Covariates and Missing Marks, with Application to Vaccine Efficacy Trials.

作者信息

Sun Yanqing, Qi Li, Heng Fei, Gilbert Peter B

机构信息

University of North Carolina at Charlotte, Charlotte, U.S.A.

Sanofi, Bridgewater, U.S.A.

出版信息

J R Stat Soc Ser C Appl Stat. 2020 Aug;69(4):791-814. doi: 10.1111/rssc.12417. Epub 2020 May 22.

Abstract

Deployment of the recently licensed CYD-TDV dengue vaccine requires understanding of how the risk of dengue disease in vaccine recipients depends jointly on a host biomarker measured after vaccination (neutralization titer - NAb) and on a "mark" feature of the dengue disease failure event (the amino acid sequence distance of the dengue virus to the dengue sequence represented in the vaccine). The CYD14 phase 3 trial of CYD-TDV measured NAb via case-cohort sampling and the mark in dengue disease failure events, with about a third missing marks. We addressed the question of interest by developing inferential procedures for the stratified mark-specific proportional hazards model with missing covariates and missing marks. Two hybrid approaches are investigated that leverage both augmented inverse probability weighting and nearest neighborhood hot deck multiple imputation. The two approaches differ in how the imputed marks are pooled in estimation. Our investigation shows that NNHD imputation can lead to biased estimation without properly selected neighborhood. Simulations show that the developed hybrid methods perform well with unbiased NNHD imputations from proper neighborhood selection. The new methods applied to CYD14 show that NAb is strongly inversely associated with risk of dengue disease in vaccine recipients, more strongly against dengue viruses with shorter distances.

摘要

最近获批的CYD - TDV登革热疫苗的部署需要了解疫苗接种者中登革热疾病风险如何共同取决于接种后测量的宿主生物标志物(中和滴度 - NAb)以及登革热疾病失败事件的“标记”特征(登革热病毒与疫苗中所代表的登革热序列的氨基酸序列距离)。CYD - TDV的CYD14 3期试验通过病例队列抽样测量NAb以及登革热疾病失败事件中的标记,约三分之一的标记缺失。我们通过为具有缺失协变量和缺失标记的分层标记特定比例风险模型开发推断程序来解决感兴趣的问题。研究了两种混合方法,它们利用增强逆概率加权和最近邻热卡多重插补。这两种方法在估计中合并插补标记的方式上有所不同。我们的研究表明,如果没有正确选择邻域,最近邻热卡插补可能导致有偏估计。模拟表明,通过正确选择邻域进行无偏最近邻热卡插补,所开发的混合方法表现良好。应用于CYD14的新方法表明,NAb与疫苗接种者中登革热疾病风险呈强烈负相关,对距离较短的登革热病毒的相关性更强。

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