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.
Quantile regression has become a widely used tool for analysing competing risk data. However, quantile regression for competing risk data with a continuous mark is still scarce. The mark variable is an extension of cause of failure in a classical competing risk model where cause of failure is replaced by a continuous mark only observed at uncensored failure times. An example of the continuous mark variable is the genetic distance that measures dissimilarity between the infecting virus and the virus contained in the vaccine construct. In this article, we propose a novel mark-specific quantile regression model. The proposed estimation method borrows strength from data in a neighbourhood of a mark and is based on an induced smoothed estimation equation, which is very different from the existing methods for competing risk data with discrete causes. The asymptotic properties of the resulting estimators are established across mark and quantile continuums. In addition, a mark-specific quantile-type vaccine efficacy is proposed and its statistical inference procedures are developed. Simulation studies are conducted to evaluate the finite sample performances of the proposed estimation and hypothesis testing procedures. An application to the first HIV vaccine efficacy trial is provided.
more » « less- Award ID(s):
- 1915829
- NSF-PAR ID:
- 10436930
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Biometrika
- ISSN:
- 0006-3444
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Censored quantile regression models, which offer great flexibility in assessing covariate effects on event times, have attracted considerable research interest. In this study, we consider flexible estimation and inference procedures for competing risks quantile regression, which not only provides meaningful interpretations by using cumulative incidence quantiles but also extends the conventional accelerated failure time model by relaxing some of the stringent model assumptions, such as global linearity and unconditional independence. Current method for censored quantile regressions often involves the minimization of the
L 1‐type convex function or solving the nonsmoothed estimating equations. This approach could lead to multiple roots in practical settings, particularly with multiple covariates. Moreover, variance estimation involves an unknown error distribution and most methods rely on computationally intensive resampling techniques such as bootstrapping. We consider the induced smoothing procedure for censored quantile regressions to the competing risks setting. The proposed procedure permits the fast and accurate computation of quantile regression parameter estimates and standard variances by using conventional numerical methods such as the Newton–Raphson algorithm. Numerical studies show that the proposed estimators perform well and the resulting inference is reliable in practical settings. The method is finally applied to data from a soft tissue sarcoma study. -
null (Ed.)In HIV vaccine efficacy trials, mark-specific hazards models have important applications and can be used to evaluate the strain-specific vaccine efficacy. Additive hazards models have been widely used in practice, especially when continuous covariates are present. In this article, we conduct variable selection for a mark-specific additive hazards model. The proposed method is based on an estimating equation with the first derivative of the adaptive LASSO penalty function. The asymptotic properties of the resulting estimators are established. The finite sample behavior of the proposed estimators is evaluated through simulation studies, and an application to a dataset from the first HIV vaccine efficacy trial is provided.more » « less
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Abstract Statistical analysis of longitudinal data often involves modeling treatment effects on clinically relevant longitudinal biomarkers since an initial event (the time origin). In some studies including preventive HIV vaccine efficacy trials, some participants have biomarkers measured starting at the time origin, whereas others have biomarkers measured starting later with the time origin unknown. The semiparametric additive time-varying coefficient model is investigated where the effects of some covariates vary nonparametrically with time while the effects of others remain constant. Weighted profile least squares estimators coupled with kernel smoothing are developed. The method uses the expectation maximization approach to deal with the censored time origin. The Kaplan–Meier estimator and other failure time regression models such as the Cox model can be utilized to estimate the distribution and the conditional distribution of left censored event time related to the censored time origin. Asymptotic properties of the parametric and nonparametric estimators and consistent asymptotic variance estimators are derived. A two-stage estimation procedure for choosing weight is proposed to improve estimation efficiency. Numerical simulations are conducted to examine finite sample properties of the proposed estimators. The simulation results show that the theory and methods work well. The efficiency gain of the two-stage estimation procedure depends on the distribution of the longitudinal error processes. The method is applied to analyze data from the Merck 023/HVTN 502 Step HIV vaccine study.
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Abstract We consider the proportional hazards model in which the covariates include the discretized categories of a continuous time‐dependent exposure variable measured with error. Naively ignoring the measurement error in the analysis may cause biased estimation and erroneous inference. Although various approaches have been proposed to deal with measurement error when the hazard depends linearly on the time‐dependent variable, it has not yet been investigated how to correct when the hazard depends on the discretized categories of the time‐dependent variable. To fill this gap in the literature, we propose a smoothed corrected score approach based on approximation of the discretized categories after smoothing the indicator function. The consistency and asymptotic normality of the proposed estimator are established. The observation times of the time‐dependent variable are allowed to be informative. For comparison, we also extend to this setting two approximate approaches, the regression calibration and the risk‐set regression calibration. The methods are assessed by simulation studies and by application to data from an HIV clinical trial.
