Comparison Between Two Partial Likelihood Approaches for the Competing Risks Model with Missing Cause of Failure

In many clinical studies where time to failure is of primary interest, patients may fail or die from one of many causes where failure time can be right censored. In some circumstances, it might also be the case that patients are known to die but the cause of death information is not available for some patients. Under the assumption that cause of death is missing at random, we compare the Goetghebeur and Ryan (1995, Biometrika, 82, 821–833) partial likelihood approach with the Dewanji (1992, Biometrika, 79, 855–857)partial likelihood approach. We show that the estimator for the regression coefficients based on the Dewanji partial likelihood is not only consistent and asymptotically normal, but also semiparametric efficient. While the Goetghebeur and Ryan estimator is more robust than the Dewanji partial likelihood estimator against misspecification of proportional baseline hazards, the Dewanji partial likelihood estimator allows the probability of missing cause of failure to depend on covariate information without the need to model the missingness mechanism. Tests for proportional baseline hazards are also suggested and a robust variance estimator is derived.     

Generating data from improper distributions: application to Cox proportional hazards models with cure

Cure rate models are survival models characterized by improper survivor distributions which occur when the cumulative distribution function, say F, of the survival times does not sum up to 1 (i.e. F(+∞)<1). The first objective of this paper is to provide a general approach to generate data from any improper distribution. An application to times to event data randomly drawn from improper distributions with proportional hazards is investigated using the semi-parametric proportional hazards model with cure obtained as a special case of the nonlinear transformation models in [Tsodikov, Semiparametric models: A generalized self-consistency approach, J. R. Stat. Soc. Ser. B 65 (2003), pp. 759–774]. The second objective of this paper is to show by simulations that the bias, the standard error and the mean square error of the maximum partial likelihood (PL) estimator of the hazard ratio as well as the statistical power based on the PL estimator strongly depend on the proportion of subjects in the whole population who will never experience the event of interest.     

Local Linear Estimation for Time-Dependent Coefficients in Cox's Regression Models

This article develops a local partial likelihood technique to estimate the time-dependent coefficients in Cox's regression model. The basic idea is a simple extension of the local linear fitting technique used in the scatterplot smoothing. The coefficients are estimated locally based on the partial likelihood in a window around each time point. Multiple time-dependent covariates are incorporated in the local partial likelihood procedure. The procedure is useful as a diagnostic tool and can be used in uncovering time-dependencies or departure from the proportional hazards model. The programming involved in the local partial likelihood estimation is relatively simple and it can be modified with few efforts from the existing programs for the proportional hazards model. The asymptotic properties of the resulting estimator are established and compared with those from the local constant fitting. A consistent estimator of the asymptotic variance is also proposed. The approach is illustrated by a real data set from the study of gastric cancer patients and a simulation study is also presented.     

On Local Polynomial Modelling of the Additive Risk Model

The additive risk model provides an alternative modelling technique for failure time data to the proportional hazards model. In this article, we consider the additive risk model with a nonparametric risk effect. We study estimation of the risk function and its derivatives with a parametric and an unspecified baseline hazard function respectively. The resulting estimators are the local likelihood and the local score estimators. We establish the asymptotic normality of the estimators and show that both methods have the same formula for asymptotic bias but different formula for variance. It is found that, in some special cases, the local score estimator is of the same efficiency as the local likelihood estimator though it does not use the information about the baseline hazard function. Another advantage of the local score estimator is that it has a closed form and is easy to implement. Some simulation studies are conducted to evaluate and compare the performance of the two estimators. A numerical example is used for illustration.     

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.     

A risk set adjustment for proportional hazards modeling of combined cohort data

Sporting careers observed over a preset time interval can be partitioned into two distinct subsamples. These samples consist of individuals whose careers had already commenced at the start of the time interval (prevalent subsample) and individuals whose careers began during the time interval (incident subsample) as well the respective individual-level covariate data such as salary, height, weight, performance statistics, draft position, etc. Under the assumption of a proportional hazards model, we propose a partial likelihood estimator to model the effect of covariates on survival via an adjusted risk set sampling procedure for when the incident cohort data is used in conjunction with the prevalent cohort data. We use simulated failure time data to validate the combined cohort proportional hazards methodology and illustrate our model using an NBA data set for career durations measured between 1990 and 2008.     

Cox regression analysis in presence of collinearity: an application to assessment of health risks associated with occupational radiation exposure

This paper considers the analysis of time to event data in the presence of collinearity between covariates. In linear and logistic regression models, the ridge regression estimator has been applied as an alternative to the maximum likelihood estimator in the presence of collinearity. The advantage of the ridge regression estimator over the usual maximum likelihood estimator is that the former often has a smaller total mean square error and is thus more precise. In this paper, we generalized this approach for addressing collinearity to the Cox proportional hazards model. Simulation studies were conducted to evaluate the performance of the ridge regression estimator. Our approach was motivated by an occupational radiation study conducted at Oak Ridge National Laboratory to evaluate health risks associated with occupational radiation exposure in which the exposure tends to be correlated with possible confounders such as years of exposure and attained age. We applied the proposed methods to this study to evaluate the association of radiation exposure with all-cause mortality.     

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.     

Cox regression of clustered event times with covariates missing not at random

Motivated by a recent tuberculosis (TB) study, this paper is concerned with covariates missing not at random (MNAR) and models the potential intracluster correlation by a frailty. We consider the regression analysis of right‐censored event times from clustered subjects under a Cox proportional hazards frailty model and present the semiparametric maximum likelihood estimator (SPMLE) of the model parameters. An easy‐to‐implement pseudo‐SPMLE is then proposed to accommodate more realistic situations using readily available supplementary information on the missing covariates. Algorithms are provided to compute the estimators and their consistent variance estimators. We demonstrate that both the SPMLE and the pseudo‐SPMLE are consistent and asymptotically normal by the arguments based on the theory of modern empirical processes. The proposed approach is examined numerically via simulation and illustrated with an analysis of the motivating TB study data.     

Semiparametric Likelihood Estimation in the Clayton–Oakes Failure Time Model

Multivariate failure time data arise when the sample consists of clusters and each cluster contains several possibly dependent failure times. The Clayton–Oakes model (Clayton, 1978; Oakes, 1982) for multivariate failure times characterizes the intracluster dependence parametrically but allows arbitrary specification of the marginal distributions. In this paper, we discuss estimation in the Clayton–Oakes model when the marginal distributions are modeled to follow the Cox (1972) proportional hazards regression model. Parameter estimation is based on an approximate generalized maximum likelihood estimator. We illustrate the model's application with example datasets.     

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.     

On the Breslow estimator

In his discussion of Cox’s (1972) paper on proportional hazards regression, Breslow (1972) provided the maximum likelihood estimator for the cumulative baseline hazard function. This estimator is commonly used in practice. The estimator has also been highly valuable in the further development of Cox regression and semiparametric inference with censored data. The present paper describes the Breslow estimator and its tremendous impact on the theory and practice of survival analysis.     

A New Estimator for Cox Proportional Hazard Regression Model in Presence of Collinearity

We propose a new approach to estimate the parameters of the Cox proportional hazards model in the presence of collinearity. Generally, a maximum partial likelihood estimator is used to estimate parameters for the Cox proportional hazards model. However, the maximum partial likelihood estimators can be seriously affected by the presence of collinearity since the parameter estimates result in large variances.

In this study, we develop a Liu-type estimator for Cox proportional hazards model parameters and compare it with a ridge regression estimator based on the scalar mean squared error (MSE). Finally, we evaluate its performance through a simulation study.     

Analysis of transformation models with right-truncated data

In many applications, statistical data are frequently observed subject to a retrospective sampling criterion resulting in right-truncated data. In this article, a general class of semiparametric transformation models that include proportional hazards model and proportional odds model as special cases is studied for the analysis of right-truncated data. We proposed two estimators for regression coefficients. The first estimator is based on martingale estimating equations. The second estimator is based on the conditional likelihood function given the truncation times. The asymptotic properties of both estimators are derived. The finite sample performance is examined through a simulation study.     

Maximum Likelihood Estimation for Cox's Regression Model Under Case–Cohort Sampling

Abstract.  Case–cohort sampling aims at reducing the data sampling and costs of large cohort studies. It is therefore important to estimate the parameters of interest as efficiently as possible. We present a maximum likelihood estimator (MLE) for a case–cohort study based on the proportional hazards assumption. The estimator shows finite sample properties that improve on those by the Self & Prentice [Ann. Statist. 16 (1988)] estimator. The size of the gain by the MLE varies with the level of the disease incidence and the variability of the relative risk over the considered population. The gain tends to be small when the disease incidence is low. The MLE is found by a simple EM algorithm that is easy to implement. Standard errors are estimated by a profile likelihood approach based on EM-aided differentiation.     

Global Partial Likelihood for Nonparametric Proportional Hazards Models

As an alternative to the local partial likelihood method of Tibshirani and Hastie and Fan, Gijbels, and King, a global partial likelihood method is proposed to estimate the covariate effect in a nonparametric proportional hazards model, λ(t|x) = exp{ψ(x)}λ(0)(t). The estimator, ψ?(x), reduces to the Cox partial likelihood estimator if the covariate is discrete. The estimator is shown to be consistent and semiparametrically efficient for linear functionals of ψ(x). Moreover, Breslow-type estimation of the cumulative baseline hazard function, using the proposed estimator ψ?(x), is proved to be efficient. The asymptotic bias and variance are derived under regularity conditions. Computation of the estimator involves an iterative but simple algorithm. Extensive simulation studies provide evidence supporting the theory. The method is illustrated with the Stanford heart transplant data set. The proposed global approach is also extended to a partially linear proportional hazards model and found to provide efficient estimation of the slope parameter. This article has the supplementary materials online.     

Estimation in the Cox cure model with covariates missing not at random,with application to disease screening/prediction

In an attempt to provide a statistical tool for disease screening and prediction, we propose a semiparametric approach to analysis of the Cox proportional hazards cure model in situations where the observations on the event time are subject to right censoring and some covariates are missing not at random. To facilitate the methodological development, we begin with semiparametric maximum likelihood estimation (SPMLE) assuming that the (conditional) distribution of the missing covariates is known. A variant of the EM algorithm is used to compute the estimator. We then adapt the SPMLE to a more practical situation where the distribution is unknown and there is a consistent estimator based on available information. We establish the consistency and weak convergence of the resulting pseudo-SPMLE, and identify a suitable variance estimator. The application of our inference procedure to disease screening and prediction is illustrated via empirical studies. The proposed approach is used to analyze the tuberculosis screening study data that motivated this research. Its finite-sample performance is examined by simulation.     

A class of semiparametric cure models with current status data

Current status data occur in many biomedical studies where we only know whether the event of interest occurs before or after a particular time point. In practice, some subjects may never experience the event of interest, i.e., a certain fraction of the population is cured or is not susceptible to the event of interest. We consider a class of semiparametric transformation cure models for current status data with a survival fraction. This class includes both the proportional hazards and the proportional odds cure models as two special cases. We develop efficient likelihood-based estimation and inference procedures. We show that the maximum likelihood estimators for the regression coefficients are consistent, asymptotically normal, and asymptotically efficient. Simulation studies demonstrate that the proposed methods perform well in finite samples. For illustration, we provide an application of the models to a study on the calcification of the hydrogel intraocular lenses.

     

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).     

Maximum likelihood estimation in the proportional hazards model of random censorship

The maximum likelihood estimator (MLE) for the survival function S_Tunder the proportional hazards model of censorship is derived and shown to differ from the Abdushukurov-Cheng-Lin estimator when the class of allowable distributions includes all continuous and discrete distributions. The estimators are compared via an example. The MLE is calculated using a Newton-Raphson iterative procedure and implemented via a FORTRAN algorithm.