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1. Analysis of the time-varying Cox model for the cause-specific hazard functions with missing causes

   https://doi.org/10.1007/s10985-020-09497-y  

   Heng, Fei; Sun, Yanqing; Hyun, Seunggeun; Gilbert, Peter B. (January 2020, Lifetime Data Analysis)

   This paper studies theCox model with time-varying coefficients for cause-specific hazard functions when the causes of failure are subject to missingness. Inverse probability weighted and augmented inverse probability weighted estimators are investigated. The latter is considered as a two-stage estimator by directly utilizing the inverse probability weighted estimator and through modeling available auxiliary variables to improve efficiency. The asymptotic properties of the two estimators are investigated. Hypothesis testing procedures are developed to test the null hypotheses that the covariate effects are zero and that the covariate effects are constant. We conduct simulation studies to examine the finite sample properties of the proposed estimation and hypothesis testing procedures under various settings of the auxiliary variables and the percentages of the failure causes that are missing. These simulation results demonstrate that the augmented inverse probability weighted estimators are more efficient than the inverse probability weighted estimators and that the proposed testing procedures have the expected satisfactory results in sizes and powers. The proposed methods are illustrated using the Mashi clinical trial data for investigating the effect of randomization to formula-feeding versus breastfeeding plus extended infant zidovudine prophylaxis on death due to mother-to-child HIV transmission in Botswana. 

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2. A Semiparametric Cox–Aalen Transformation Model with Censored Data

   https://doi.org/10.1111/biom.13895  

   Ning, Xi; Pan, Yinghao; Sun, Yanqing; Gilbert, Peter_B (July 2023, Biometrics)

   Abstract We propose a broad class of so-called Cox–Aalen transformation models that incorporate both multiplicative and additive covariate effects on the baseline hazard function within a transformation. The proposed models provide a highly flexible and versatile class of semiparametric models that include the transformation models and the Cox–Aalen model as special cases. Specifically, it extends the transformation models by allowing potentially time-dependent covariates to work additively on the baseline hazard and extends the Cox–Aalen model through a predetermined transformation function. We propose an estimating equation approach and devise an expectation-solving (ES) algorithm that involves fast and robust calculations. The resulting estimator is shown to be consistent and asymptotically normal via modern empirical process techniques. The ES algorithm yields a computationally simple method for estimating the variance of both parametric and nonparametric estimators. Finally, we demonstrate the performance of our procedures through extensive simulation studies and applications in two randomized, placebo-controlled human immunodeficiency virus (HIV) prevention efficacy trials. The data example shows the utility of the proposed Cox–Aalen transformation models in enhancing statistical power for discovering covariate effects. 

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3. Semiparametric Additive Time-Varying Coefficients Model for Longitudinal Data with Censored Time Origin

   https://doi.org/10.1111/biom.13610  

   Sun, Yanqing; Shou, Qiong; Gilbert, Peter B.; Heng, Fei; Qian, Xiyuan (December 2021, Biometrics)

   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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4. Semiparametric regression analysis of partly interval‐censored failure time data with application to an AIDS clinical trial

   https://doi.org/10.1002/sim.9035  

   Zhou, Qingning; Sun, Yanqing; Gilbert, Peter B. (May 2021, Statistics in Medicine)

   Failure time data subject to various types of censoring commonly arise in epidemiological and biomedical studies. Motivated by an AIDS clinical trial, we consider regression analysis of failure time data that include exact and left‐, interval‐, and/or right‐censored observations, which are often referred to as partly interval‐censored failure time data. We study the effects of potentially time‐dependent covariates on partly interval‐censored failure time via a class of semiparametric transformation models that includes the widely used proportional hazards model and the proportional odds model as special cases. We propose an EM algorithm for the nonparametric maximum likelihood estimation and show that it unifies some existing approaches developed for traditional right‐censored data or purely interval‐censored data. In particular, the proposed method reduces to the partial likelihood approach in the case of right‐censored data under the proportional hazards model. We establish that the resulting estimator is consistent and asymptotically normal. In addition, we investigate the proposed method via simulation studies and apply it to the motivating AIDS clinical trial. 

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5. Improving Trial Generalizability Using Observational Studies

   https://doi.org/10.1111/biom.13609  

   Lee, Dasom; Yang, Shu; Dong, Lin; Wang, Xiaofei; Zeng, Donglin; Cai, Jianwen (December 2021, Biometrics)

   Abstract Complementary features of randomized controlled trials (RCTs) and observational studies (OSs) can be used jointly to estimate the average treatment effect of a target population. We propose a calibration weighting estimator that enforces the covariate balance between the RCT and OS, therefore improving the trial-based estimator's generalizability. Exploiting semiparametric efficiency theory, we propose a doubly robust augmented calibration weighting estimator that achieves the efficiency bound derived under the identification assumptions. A nonparametric sieve method is provided as an alternative to the parametric approach, which enables the robust approximation of the nuisance functions and data-adaptive selection of outcome predictors for calibration. We establish asymptotic results and confirm the finite sample performances of the proposed estimators by simulation experiments and an application on the estimation of the treatment effect of adjuvant chemotherapy for early-stage non-small-cell lung patients after surgery. 

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