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.     

Validation of A Heteroscedastic Hazards Regression Model

A Cox-type regression model accommodating heteroscedasticity, with a power factor of the baseline cumulative hazard, is investigated for analyzing data with crossing hazards behavior. Since the approach of partial likelihood cannot eliminate the baseline hazard, an overidentified estimating equation (OEE) approach is introduced in the estimation procedure. Its by-product, a model checking statistic, is presented to test for the overall adequacy of the heteroscedastic model. Further, under the heteroscedastic model setting, we propose two statistics to test the proportional hazards assumption. Implementation of this model is illustrated in a data analysis of a cancer clinical trial.     

On Estimation and Tests of Time-Varying Effects in the Proportional Hazards Model

Abstract.  Cox's proportional hazards model is routinely used in many applied fields, some times, however, with too little emphasis on the fit of the model. In this paper, we suggest some new tests for investigating whether or not covariate effects vary with time. These tests are a natural and integrated part of an extended version of the Cox model. An important new feature of the suggested test is that time constancy for a specific covariate is examined in a model, where some effects of other covariates are allowed to vary with time and some are constant; thus making successive testing of time-dependency possible. The proposed techniques are illustrated with the well-known Mayo liver disease data, and a small simulation study investigates the finite sample properties of the tests.     

Maximum Likelihood Estimation of Logistic Regression Parameters under Two-phase, Outcome-dependent Sampling

Outcome-dependent sampling increases the efficiency of studies of rare outcomes, examples being case—control studies in epidemiology and choice–based sampling in econometrics. Two-phase or double sampling is a standard technique for drawing efficient stratified samples. We develop maximum likelihood estimation of logistic regression coefficients for a hybrid two-phase, outcome–dependent sampling design. An algorithm is given for determining the estimates by repeated fitting of ordinary logistic regression models. Simulation results demonstrate the efficiency loss associated with alternative pseudolikelihood and weighted likelihood methods for certain data configurations. These results provide an efficient solution to the measurement error problem with validation sampling based on a discrete surrogate.     

Bayesian Inference from Case–cohort Data with Multiple End-points

Abstract.  In a case–cohort design a random sample from the study cohort, referred as a subcohort, and all the cases outside the subcohort are selected for collecting extra covariate data. The union of the selected subcohort and all cases are referred as the case–cohort set. Such a design is generally employed when the collection of information on an extra covariate for the study cohort is expensive. An advantage of the case–cohort design over more traditional case–control and the nested case–control designs is that it provides a set of controls which can be used for multiple end-points, in which case there is information on some covariates and event follow-up for the whole study cohort. Here, we propose a Bayesian approach to analyse such a case–cohort design as a cohort design with incomplete data on the extra covariate. We construct likelihood expressions when multiple end-points are of interest simultaneously and propose a Bayesian data augmentation method to estimate the model parameters. A simulation study is carried out to illustrate the method and the results are compared with the complete cohort analysis.     

Estimation Under the Lehmann Regression Model with Interval-Censored Data

We consider the estimation problem under the Lehmann model with interval-censored data, but focus on the computational issues. There are two methods for computing the semi-parametric maximum likelihood estimator (SMLE) under the Lehmann model (or called Cox model): the Newton-Raphson (NR) method and the profile likelihood (PL) method. We show that they often do not get close to the SMLE. We propose several approach to overcome the computational difficulty and apply our method to a breast cancer research data set.     

Semiparametric Efficient Estimation in the Generalized Odds-Rate Class of Regression Models for Right-Censored Time-to-Event Data

The generalized odds-rate class of regression models for time to event data is indexed by a non-negative constant and assumes thatg(S(t|Z)) = (t) + Zwhere g(s) = log(^-1(s-) for > 0, g₀(s) = log(- log s), S(t|Z) is the survival function of the time to event for an individual with qx1 covariate vector Z, is a qx1 vector of unknown regression parameters, and (t) is some arbitrary increasing function of t. When =0, this model is equivalent to the proportional hazards model and when =1, this model reduces to the proportional odds model. In the presence of right censoring, we construct estimators for and exp((t)) and show that they are consistent and asymptotically normal. In addition, we show that the estimator for is semiparametric efficient in the sense that it attains the semiparametric variance bound.     

Properties of Added Variable Plots in Cox's Regression Model

The added variable plot is useful for examining the effect of a covariate in regression models. The plot provides information regarding the inclusion of a covariate, and is useful in identifying influential observations on the parameter estimates. Hall et al. (1996) proposed a plot for Cox's proportional hazards model derived by regarding the Cox model as a generalized linear model. This paper proves and discusses properties of this plot. These properties make the plot a valuable tool in model evaluation. Quantities considered include parameter estimates, residuals, leverage, case influence measures and correspondence to previously proposed residuals and diagnostics.     

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.     

Comparison of goodness of fit tests for the cox proportional hazards model

The proportional hazards regression model of Cox(1972) is widely used in analyzing survival data. We examine several goodness of fit tests for checking the proportionality of hazards in the Cox model with two-sample censored data, and compare the performance of these tests by a simulation study. The strengths and weaknesses of the tests are pointed out. The effects of the extent of random censoring on the size and power are also examined. Results of a simulation study demonstrate that Gill and Schumacher's test is most powerful against a broad range of monotone departures from the proportional hazards assumption, but it may not perform as well fail for alternatives of nonmonotone hazard ratio. For the latter kind of alternatives, Andersen's test may detect patterns of irregular changes in hazards.     

An Exact Corrected Log-Likelihood Function for Cox's Proportional Hazards Model under Measurement Error and Some Extensions

Abstract.  This paper studies Cox's proportional hazards model under covariate measurement error. Nakamura's [ Biometrika 77 (1990) 127] methodology of corrected log-likelihood will be applied to the so-called Breslow likelihood, which is, in the absence of measurement error, equivalent to partial likelihood. For a general error model with possibly heteroscedastic and non-normal additive measurement error, corrected estimators of the regression parameter as well as of the baseline hazard rate are obtained. The estimators proposed by Nakamura [Biometrics 48 (1992) 829], Kong et al. [ Scand. J. Statist. 25 (1998) 573] and Kong & Gu [ Statistica Sinica 9 (1999) 953] are re-established in the special cases considered there. This sheds new light on these estimators and justifies them as exact corrected score estimators. Finally, the method will be extended to some variants of the Cox model.     

A Note on the Estimate of Treatment Effect from a Cox Regression Model When the Proportionality Assumption Is Violated

ABSTRACT

Cox proportional hazards regression model has been widely used to estimate the effect of a prognostic factor on a time-to-event outcome. In a survey of survival analyses in cancer journals, it was found that only 5% of studies using Cox proportional hazards model attempted to verify the underlying assumption. Usually an estimate of the treatment effect from fitting a Cox model was reported without validation of the proportionality assumption. It is not clear how such an estimate should be interpreted if the proportionality assumption is violated. In this article, we show that the estimate of treatment effect from a Cox regression model can be interpreted as a weighted average of the log-scaled hazard ratio over the duration of study. A hypothetic example is used to explain the weights.     

Strategies for Cohort Sampling Under the Cox Proportional Hazards Model,Application to an AIDS Clinical Trial

In some studies that relate covariates to times of failure it is not feasible to observe all covariates for all subjects. For example, some covariates may be too costly in terms of time, money, or effect on the subject to record for all subjects. This paper considers the relative efficiencies of several designs for sampling a portion of the cohort on which the costly covariates will be observed. Such designs typically measure all covariates for each failure and control for covariates of lesser interest. Control subjects are sampled either from risk sets at times of observed failures or from the entire cohort. A new design in which the sampling probability for each individual depends on the amount of information that the individual can contribute to estimated coefficients is shown to be superior to other sampling designs under certain conditions. Primary focus of our designs is on time-invariant covariates, but some methods easily generalize to the time-varying setting. Data from a study conducted by the AIDS Clinical Trials Group are used to illustrate the new sampling procedure and to explore the relative efficiency of several sampling schemes.     

Weighted Likelihood for Semiparametric Models and Two-phase Stratified Samples, with Application to Cox Regression

Abstract.  We consider semiparametric models for which solution of Horvitz–Thompson or inverse probability weighted (IPW) likelihood equations with two-phase stratified samples leads to consistent and asymptotically Gaussian estimators of both Euclidean and non-parametric parameters. For Bernoulli (independent and identically distributed) sampling, standard theory shows that the Euclidean parameter estimator is asymptotically linear in the IPW influence function. By proving weak convergence of the IPW empirical process, and borrowing results on weighted bootstrap empirical processes, we derive a parallel asymptotic expansion for finite population stratified sampling. Several of our key results have been derived already for Cox regression with stratified case–cohort and more general survey designs. This paper is intended to help interpret this previous work and to pave the way towards a general Horvitz–Thompson approach to semiparametric inference with data from complex probability samples.     

A Study of Suicide Risk Using a Cox Cure Model via a Retrospective Sampling and Multiple Imputation

The incidence of suicide is an example of rare event. A Cox cure model is adopted to examine the suicide risk of a cohort study of a sample of 65,000 Personal Emergency Link users over a 10-year observation period. Our objective is to investigate the effect of personal covariates on the failure time to suicide as well as the long-term survival from suicide. Based on the Cox cure model, a new and efficient estimation approach using retrospective sampling and multiple imputation was used. Compared with the standard Cox proportional hazards model, the Cox cure model provides a new perspective on analyzing the suicide data.     

Maximum Penalized Likelihood Estimation in a Gamma-Frailty Model

The shared frailty models allow for unobserved heterogeneity or for statistical dependence between observed survival data. The most commonly used estimation procedure in frailty models is the EM algorithm, but this approach yields a discrete estimator of the distribution and consequently does not allow direct estimation of the hazard function. We show how maximum penalized likelihood estimation can be applied to nonparametric estimation of a continuous hazard function in a shared gamma-frailty model with right-censored and left-truncated data. We examine the problem of obtaining variance estimators for regression coefficients, the frailty parameter and baseline hazard functions. Some simulations for the proposed estimation procedure are presented. A prospective cohort (Paquid) with grouped survival data serves to illustrate the method which was used to analyze the relationship between environmental factors and the risk of dementia.     

Penalized Empirical Likelihood via Bridge Estimator in Cox's Proportional Hazard Model

We propose the penalized empirical likelihood method via bridge estimator in Cox's proportional hazard model for parameter estimation and variable selection. Under reasonable conditions, we show that penalized empirical likelihood in Cox's proportional hazard model has oracle property. A penalized empirical likelihood ratio for the vector of regression coefficients is defined and its limiting distribution is a chi-square distributions. The advantage of penalized empirical likelihood as a nonparametric likelihood approach is illustrated in testing hypothesis and constructing confidence sets. The method is illustrated by extensive simulation studies and a real example.     

A multicollinearity diagnostic for models fit to censored data

A multicollinearity diagnostic is discussed for parametric models fit to censored data. The models considered include the Weibull, exponential and lognormal models as well as the Cox proportional hazards model. This diagnostic is an extension of the diagnostic proposed by Belsley, Kuh, and Welsch (1980). The diagnostic is based on the condition indicies and variance proportions of the variance covariance matrix. Its use and properties are studied through a series of examples. The effect of centering variables included in model is also discussed.     

Analyzing Cohort Mortality Data

Several methods for analyzing data from mortality studies of occupationally or environmentally exposed cohorts are shown to be special cases of a single procedure. The procedure assumes a proportional hazards model for exposure effects and represents the log-likelihood kernel for the data as that of N independent Poisson variates, where N is the total number of person-units of mortality observation time in the study. It formalizes and justifies the epidemiological techniques of classifying deaths and person-months of study time into categories defined by exposure and other covariates, and of computing standardized mortality ratios and indirectly standardized death rates. Parameters representing exposure effects can be estimated by using standard software packages. Special cases and applications are described in the context of lung cancer mortality among U.S. uranium miners.     

Maximum Likelihood Estimation of the Log-Binomial Model

Maximum likelihood estimation of prevalence ratios using the log-binomial model is problematic when the estimates are on the boundary of the parameter space. When the model is correct, maximum likelihood is often the method of choice. The authors provide a theorem, formulas, and methodology for obtaining maximum likelihood estimators of the log-binomial model and their estimated standard errors when the solution is on the boundary of the parameter space. Examples are given to illustrate the method.