Deployment of the recently licensed tetravalent dengue vaccine based on a chimeric yellow fever virus, CYD‐TDV, requires understanding of how the risk of dengue disease in vaccine recipients depends jointly on a host biomarker measured after vaccination (neutralization titre—neutralizing antibodies) 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 neutralizing antibodies 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 neighbourhood hot deck multiple imputation. The two approaches differ in how the imputed marks are pooled in estimation. Our investigation shows that nearest neighbourhood hot deck imputation can lead to biased estimation without properly selected neighbourhoods. Simulations show that the hybrid methods developed perform well with unbiased nearest neighbourhood hot deck imputations from proper neighbourhood selection. The new methods applied to CYD14 show that neutralizing antibody level is strongly inversely associated with the risk of dengue disease in vaccine recipients, more strongly against dengue viruses with shorter distances.

中文翻译：

---

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，应用于疫苗功效试验

部署最近获得许可的基于嵌合黄热病病毒 CYD-TDV 的四价登革热疫苗需要了解疫苗接种者的登革热风险如何共同取决于疫苗接种后测量的宿主生物标志物（中和滴度 - 中和抗体）和登革热失败事件的“标志”特征（登革病毒与疫苗中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和登革热失败事件中的标记测量中和抗体，大约有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理程序来解决感兴趣的问题。研究了两种混合方法，它们利用了增强逆概率加权和最近邻域热甲板多重插补。这两种方法的不同之处在于如何在估计中汇集估算标记。我们的调查表明，如果没有正确选择邻域，最近邻域热甲板插补会导致估计有偏差。模拟表明，所开发的混合方法在通过适当的邻域选择进行无偏最近邻域热甲板插补的情况下表现良好。应用于 CYD14 的新方法表明，中和抗体水平与疫苗接种者的登革热风险呈负相关，对距离较短的登革热病毒更强烈。