A Proportional Hazards Regression Model for the Subdistribution with Covariates‐adjusted Censoring Weight for Competing Risks Data

With competing risks data, one often needs to assess the treatment and covariate effects on the cumulative incidence function. Fine and Gray proposed a proportional hazards regression model for the subdistribution of a competing risk with the assumption that the censoring distribution and the covariates are independent. Covariate‐dependent censoring sometimes occurs in medical studies. In this paper, we study the proportional hazards regression model for the subdistribution of a competing risk with proper adjustments for covariate‐dependent censoring. We consider a covariate‐adjusted weight function by fitting the Cox model for the censoring distribution and using the predictive probability for each individual. Our simulation study shows that the covariate‐adjusted weight estimator is basically unbiased when the censoring time depends on the covariates, and the covariate‐adjusted weight approach works well for the variance estimator as well. We illustrate our methods with bone marrow transplant data from the Center for International Blood and Marrow Transplant Research. Here, cancer relapse and death in complete remission are two competing risks.     

Stratified proportional subdistribution hazards model with covariate-adjusted censoring weight for case-cohort studies

The case-cohort study design is widely used to reduce cost when collecting expensive covariates in large cohort studies with survival or competing risks outcomes. A case-cohort study dataset consists of two parts: (a) a random sample and (b) all cases or failures from a specific cause of interest. Clinicians often assess covariate effects on competing risks outcomes. The proportional subdistribution hazards model directly evaluates the effect of a covariate on the cumulative incidence function under the non-covariate-dependent censoring assumption for the full cohort study. However, the non-covariate-dependent censoring assumption is often violated in many biomedical studies. In this article, we propose a proportional subdistribution hazards model for case-cohort studies with stratified data with covariate-adjusted censoring weight. We further propose an efficient estimator when extra information from the other causes is available under case-cohort studies. The proposed estimators are shown to be consistent and asymptotically normal. Simulation studies show (a) the proposed estimator is unbiased when the censoring distribution depends on covariates and (b) the proposed efficient estimator gains estimation efficiency when using extra information from the other causes. We analyze a bone marrow transplant dataset and a coronary heart disease dataset using the proposed method.     

Multiple event times in the presence of informative censoring: modeling and analysis by copulas

Motivated by a breast cancer research program, this paper is concerned with the joint survivor function of multiple event times when their observations are subject to informative censoring caused by a terminating event. We formulate the correlation of the multiple event times together with the time to the terminating event by an Archimedean copula to account for the informative censoring. Adapting the widely used two-stage procedure under a copula model, we propose an easy-to-implement pseudo-likelihood based procedure for estimating the model parameters. The approach yields a new estimator for the marginal distribution of a single event time with semicompeting-risks data. We conduct both asymptotics and simulation studies to examine the proposed approach in consistency, efficiency, and robustness. Data from the breast cancer program are employed to illustrate this research.

     

Composite Estimating Equation Method for the Accelerated Failure Time Model with Length‐biased Sampling Data

Length‐biased sampling data are often encountered in the studies of economics, industrial reliability, epidemiology, genetics and cancer screening. The complication of this type of data is due to the fact that the observed lifetimes suffer from left truncation and right censoring, where the left truncation variable has a uniform distribution. In the Cox proportional hazards model, Huang & Qin (Journal of the American Statistical Association, 107, 2012, p. 107) proposed a composite partial likelihood method which not only has the simplicity of the popular partial likelihood estimator, but also can be easily performed by the standard statistical software. The accelerated failure time model has become a useful alternative to the Cox proportional hazards model. In this paper, by using the composite partial likelihood technique, we study this model with length‐biased sampling data. The proposed method has a very simple form and is robust when the assumption that the censoring time is independent of the covariate is violated. To ease the difficulty of calculations when solving the non‐smooth estimating equation, we use a kernel smoothed estimation method (Heller; Journal of the American Statistical Association, 102, 2007, p. 552). Large sample results and a re‐sampling method for the variance estimation are discussed. Some simulation studies are conducted to compare the performance of the proposed method with other existing methods. A real data set is used for illustration.     

Estimation in a competing risks proportional hazards model under length-biased sampling with censoring

What population does the sample represent? The answer to this question is of crucial importance when estimating a survivor function in duration studies. As is well-known, in a stationary population, survival data obtained from a cross-sectional sample taken from the population at time $t_0$ represents not the target density $f(t)$ but its length-biased version proportional to $tf(t)$ , for $t>0$ . The problem of estimating survivor function from such length-biased samples becomes more complex, and interesting, in presence of competing risks and censoring. This paper lays out a sampling scheme related to a mixed Poisson process and develops nonparametric estimators of the survivor function of the target population assuming that the two independent competing risks have proportional hazards. Two cases are considered: with and without independent censoring before length biased sampling. In each case, the weak convergence of the process generated by the proposed estimator is proved. A well-known study of the duration in power for political leaders is used to illustrate our results. Finally, a simulation study is carried out in order to assess the finite sample behaviour of our estimators.     

Adjusted Hazard Rate Estimator Based on a Known Censoring Probability

In most reliability studies involving censoring, one assumes that censoring probabilities are unknown. We derive a nonparametric estimator for the survival function when information regarding censoring frequency is available. The estimator is constructed by adjusting the Nelson–Aalen estimator to incorporate censoring information. Our results indicate significant improvements can be achieved if available information regarding censoring is used. We compare this model to the Koziol–Green model, which is also based on a form of proportional hazards for the lifetime and censoring distributions. Two examples of survival data help to illustrate the differences in the estimation techniques.     

Non parametric hazard estimation with dependent censoring using penalized likelihood and an assumed copula

This article introduces a novel non parametric penalized likelihood hazard estimation when the censoring time is dependent on the failure time for each subject under observation. More specifically, we model this dependence using a copula, and the method of maximum penalized likelihood (MPL) is adopted to estimate the hazard function. We do not consider covariates in this article. The non negatively constrained MPL hazard estimation is obtained using a multiplicative iterative algorithm. The consistency results and the asymptotic properties of the proposed hazard estimator are derived. The simulation studies show that our MPL estimator under dependent censoring with an assumed copula model provides a better accuracy than the MPL estimator under independent censoring if the sign of dependence is correctly specified in the copula function. The proposed method is applied to a real dataset, with a sensitivity analysis performed over various values of correlation between failure and censoring times.     

Estimation of the joint survival function for successive duration times under double-truncation and right-censoring

ABSTRACT

In incident cohort studies, survival data often include subjects who have had an initiate event at recruitment and may potentially experience two successive events (first and second) during the follow-up period. When disease registries or surveillance systems collect data based on incidence occurring within a specific calendar time interval, the initial event is usually subject to double truncation. Furthermore, since the second duration process is observable only if the first event has occurred, double truncation and dependent censoring arise. In this article, under the two sampling biases with an unspecified distribution of truncation variables, we propose a nonparametric estimator of the joint survival function of two successive duration times using the inverse-probability-weighted (IPW) approach. The consistency of the proposed estimator is established. Based on the estimated marginal survival functions, we also propose a two-stage estimation procedure for estimating the parameters of copula model. The bootstrap method is used to construct confidence interval. Numerical studies demonstrate that the proposed estimation approaches perform well with moderate sample sizes.     

Comparing waiting times in a multi-stage model: A log-rank approach

A proper log-rank test for comparing two waiting (i.e. sojourn, gap) times under right censored data has been absent in the survival literature. The classical log-rank test provides a biased comparison even under independent right censoring since the censoring induced on the time since state entry depends on the entry time unless the hazards are semi-Markov. We develop test statistics for comparing K waiting time distributions from a multi-stage model in which censoring and waiting times may be dependent upon the transition history in the multi-stage model. To account for such dependent censoring, the proposed test statistics utilize an inverse probability of censoring weighted (IPCW) approach previously employed to define estimators for the cumulative hazard and survival function for waiting times in multi-stage models. We develop the test statistics as analogues to K-sample log-rank statistics for failure time data, and weak convergence to a Gaussian limit is demonstrated. A simulation study demonstrates the appropriateness of the test statistics in designs that violate typical independence assumptions for multi-stage models, under which naive test statistics for failure time data perform poorly, and illustrates the superiority of the test under proportional hazards alternatives to a Mann–Whitney type test. We apply the test statistics to an existing data set of burn patients.     

Estimation of treatment effects based on possibly misspecified Cox regression

In randomized clinical trials, a treatment effect on a time-to-event endpoint is often estimated by the Cox proportional hazards model. The maximum partial likelihood estimator does not make sense if the proportional hazard assumption is violated. Xu and O'Quigley (Biostatistics 1:423-439, 2000) proposed an estimating equation, which provides an interpretable estimator for the treatment effect under model misspecification. Namely it provides a consistent estimator for the log-hazard ratio among the treatment groups if the model is correctly specified, and it is interpreted as an average log-hazard ratio over time even if misspecified. However, the method requires the assumption that censoring is independent of treatment group, which is more restricted than that for the maximum partial likelihood estimator and is often violated in practice. In this paper, we propose an alternative estimating equation. Our method provides an estimator of the same property as that of Xu and O'Quigley under the usual assumption for the maximum partial likelihood estimation. We show that our estimator is consistent and asymptotically normal, and derive a consistent estimator of the asymptotic variance. If the proportional hazards assumption holds, the efficiency of the estimator can be improved by applying the covariate adjustment method based on the semiparametric theory proposed by Lu and Tsiatis (Biometrika 95:679-694, 2008).     

Quantile estimation in the proportional hazards model of random censorship

The asymptotic theory is given for quantile estimation in the proportional hazards model of random censorship. In this model, the tail of the censoring distribution function is some power of the tail of the survival distribution function. The quantile estimator is based on the maximum likelihood estimator for the survival time distribution, due to Abdushukurov, Cheng and Lin.     

Small-area estimation by combining time-series and cross-sectional data

A model involving autocorrelated random effects and sampling errors is proposed for small-area estimation, using both time-series and cross-sectional data. The sampling errors are assumed to have a known block-diagonal covariance matrix. This model is an extension of a well-known model, due to Fay and Herriot (1979), for cross-sectional data. A two-stage estimator of a small-area mean for the current period is obtained under the proposed model with known autocorrelation, by first deriving the best linear unbiased prediction estimator assuming known variance components, and then replacing them with their consistent estimators. Extending the approach of Prasad and Rao (1986, 1990) for the Fay-Herriot model, an estimator of mean squared error (MSE) of the two-stage estimator, correct to a second-order approximation for a small or moderate number of time points, T, and a large number of small areas, m, is obtained. The case of unknown autocorrelation is also considered. Limited simulation results on the efficiency of two-stage estimators and the accuracy of the proposed estimator of MSE are présentés.     

Estimation of Survival Function Subject to Time-Dependent Covariates and Left Truncation

Abstract

Satten et al. [Satten, G. A., Datta, S., Robins, J. M. (2001). Estimating the marginal survival function in the presence of time dependent covariates. Statis. Prob. Lett. 54: 397--403] proposed an estimator [denoted by ?(t)] of survival function of failure times that is in the class of survival function estimators proposed by Robins [Robins, J. M. (1993). Information recovery and bias adjustment in proportional hazards regression analysis of randomized trials using surrogate markers. In: Proceedings of the American Statistical Association-Biopharmaceutical Section. Alexandria, VA: ASA, pp. 24--33]. The estimator is appropriate when data are subject to dependent censoring. In this article, it is demonstrated that the estimator ?(t) can be extended to estimate the survival function when data are subject to dependent censoring and left truncation. In addition, we propose an alternative estimator of survival function [denoted by ? _w (t)] that is represented as an inverse-probability-weighted average Satten and Datta [Satten, G. A., Datta, S. (2001). The Kaplan–Meier estimator as an inverse-probability-of-censoring weighted average. Amer. Statist. Ass. 55: 207--210]. Simulation results show that when truncation is not severe the mean squared error of ?(t) is smaller than that of ? _w (t), except for the case when censoring is light. However, when truncation is severe, ? _w (t) has the advantage of less bias and the situation can be reversed.     

Improved precision in the analysis of randomized trials with survival outcomes,without assuming proportional hazards

We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the Kaplan–Meier and inverse probability weighted estimators, under identifiability conditions; (iii) it remains consistent under violations of independent censoring (unlike the Kaplan–Meier estimator) when either the censoring or survival distributions, conditional on covariates, are estimated consistently; and (iv) it achieves the nonparametric efficiency bound when both of these distributions are consistently estimated. We illustrate the performance of our method using simulations based on resampling data from a completed, phase 3 randomized clinical trial of a new surgical treatment for stroke; the proposed estimator achieves a 12% gain in relative efficiency compared to the Kaplan–Meier estimator. The proposed estimator has potential advantages over existing approaches for randomized trials with time-to-event outcomes, since existing methods either rely on model assumptions that are untenable in many applications, or lack some of the efficiency and consistency properties (i)–(iv). We focus on estimation of the restricted mean survival time, but our methods may be adapted to estimate any treatment effect measure defined as a smooth contrast between the survival curves for each study arm. We provide R code to implement the estimator.

     

Quantile regression methods for left-truncated and right-censored data

Left-truncated and right-censored (LTRC) data are encountered frequently due to a prevalent cohort sampling in follow-up studies. Because of the skewness of the distribution of survival time, quantile regression is a useful alternative to the Cox's proportional hazards model and the accelerated failure time model for survival analysis. In this paper, we apply the quantile regression model to LTRC data and develops an unbiased estimating equation for regression coefficients. The proposed estimation methods use the inverse probabilities of truncation and censoring weighting technique. The resulting estimator is uniformly consistent and asymptotically normal. The finite-sample performance of the proposed estimation methods is also evaluated using extensive simulation studies. Finally, analysis of real data is presented to illustrate our proposed estimation methods.     

Survival estimation through the cumulative hazard function with monotone natural cubic splines

In this paper we explore the estimation of survival probabilities via a smoothed version of the survival function, in the presence of censoring. We investigate the fit of a natural cubic spline on the cumulative hazard function under appropriate constraints. Under the proposed technique the problem reduces to a restricted least squares one, leading to convex optimization. The approach taken in this paper is evaluated and compared via simulations to other known methods such as the Kaplan Meier and the logspline estimator. Our approach is easily extended to address estimation of survival probabilities in the presence of covariates when the proportional hazards model assumption holds. In this case the method is compared to a restricted cubic spline approach that involves maximum likelihood. The proposed approach can be also adjusted to accommodate left censoring.     

Weak convergence for the conditional distribution function in a Koziol–Green model under dependent censoring

In this paper we consider the conditional Koziol–Green model of Braekers and Veraverbeke [2008. A conditional Koziol–Green model under dependent censoring. Statist. Probab. Lett., accepted for publication] in which they generalized the Koziol–Green model of Veraverbeke and Cadarso Suárez [2000. Estimation of the conditional distribution in a conditional Koziol–Green model. Test 9, 97–122] by assuming that the association between a censoring time and a time until an event is described by a known Archimedean copula function. They got in this way, an informative censoring model with two different types of informative censoring. Braekers and Veraverbeke [2008. A conditional Koziol–Green model under dependent censoring. Statist. Probab. Lett., accepted for publication] derived in this model a non-parametric Koziol–Green estimator for the conditional distribution function of the time until an event, for which they showed the uniform consistency and the asymptotic normality. In this paper we extend their results and prove the weak convergence of the process associated to this estimator. Furthermore we show that the conditional Koziol–Green estimator is asymptotically more efficient in this model than the general copula-graphic estimator of Braekers and Veraverbeke [2005. A copula-graphic estimator for the conditional survival function under dependent censoring. Canad. J. Statist. 33, 429–447]. As last result, we construct an asymptotic confidence band for the conditional Koziol–Green estimator. Through a simulation study, we investigate the small sample properties of this asymptotic confidence band. Afterwards we apply this estimator and its confidence band on a practical data set.     

Interval estimation of the joint survival function for successive duration times under left truncation and right censoring

In incident cohort studies, survival data often include subjects who have had an initiate event at recruitment and may potentially experience two successive events (first and second) during the follow-up period. Since the second duration process becomes observable only if the first event has occurred, left truncation and dependent censoring arise if the two duration times are correlated. To confront the two potential sampling biases, we propose two inverse-probability-weighted (IPW) estimators for the estimation of the joint survival function of two successive duration times. One of them is similar to the estimator proposed by Chang and Tzeng [Nonparametric estimation of sojourn time distributions for truncated serial event data – a weight adjusted approach, Lifetime Data Anal. 12 (2006), pp. 53–67]. The other is the extension of the nonparametric estimator proposed by Wang and Wells [Nonparametric estimation of successive duration times under dependent censoring, Biometrika 85 (1998), pp. 561–572]. The weak convergence of both estimators are established. Furthermore, the delete-one jackknife and simple bootstrap methods are used to estimate standard deviations and construct interval estimators. A simulation study is conducted to compare the two IPW approaches.