Shape Constrained Nonparametric Estimation in the Cox Model

Abstract

The events of interest in any survival analysis study are regularly subject to censoring. There are various censoring schemes, including right or left censoring, and interval censoring. The most frequent censoring scheme is the right censoring, where subjects might drop out of the study or simply because not all events of interest occur before the end of the study. Moreover, for each subject, additional information referred to as covariates is registered at the beginning or throughout the study, such as age, sex, undergoing treatment, etc. The classical model to study the distribution of the events of interest, while accounting for additional information, is the Cox model. The Cox model expresses the hazard function of a subject given a set of covariates in terms of a baseline hazard, for which all covariates are zero, and an exponential function of the covariates and corresponding regression parameters. The baseline hazard can be left completely unspecified while estimating the regression parameters. Nonetheless, in practice, there are numerous studies in which the baseline hazard appears to be monotone. Time to death or to the onset of a disease are observed to have a nondecreasing baseline hazard, while the survival or recovery time after a successful medical treatment usually exhibit a nonincreasing baseline hazard. The aim of this thesis is to study the behavior of nonparametric baseline hazard and baseline density estimators in the Cox model under monotonicity constraints. The event times are assumed to be right censored and the censoring mechanism is assumed to be independent of the event of interest and non-informative. The covariates are assumed to be time-independent, usually recorded at the beginning of the study. In addition to point estimates, interval estimates of a monotone baseline hazard will be provided, based on a likelihood ratio method, along with testing at a fixed point. Furthermore, kernel smoothed estimates of a monotone baseline hazard will be defined and their behavior will be investigated. In Chapter 2, we propose several nonparametric monotone estimators of a baseline hazard or a baseline density within the Cox model. We derive the nonparametric maximum likelihood estimator of a nondecreasing baseline hazard and we consider a Grenander-type estimator, defined as the left-hand slope of the greatest convex minorant of the Breslow estimator. The two estimators are then shown to be strongly consistent and asymptotically equivalent. Moreover, we derive their common limit distribution at a fixed point. The two equivalent estimators of a nonincreasing baseline hazard and their asymptotic properties are acquired similarly. Furthermore, we introduce a Grenander-type estimator of a nonincreasing baseline density, defined as the left-hand slope of the least concave majorant of an estimator of the baseline cumulative distribution function derived from the Breslow estimator. This estimator is proven to be strongly consistent and its asymptotic distribution at a fixed point is derived. Chapter 3 provides an asymptotic linear representation of the Breslow estimator of the baseline cumulative hazard function in the Cox model. This representation can be used to derive the asymptotic distribution of the Grenander type estimator of a monotone baseline hazard estimator. The representation consists of an average of independent random variables and a term involving the difference between the maximum partial likelihood estimator and the underlying regression parameter. The order of the remainder term is arbitrarily close to n^-1. Chapter 4 focuses on interval estimation and on testing whether a monotone baseline hazard function in the Cox model has a particular value at a fixed point, via a likelihood ratio method. Nonparametric maximum likelihood estimators under the null hypothesis are defined for both nondecreasing and nonincreasing baseline hazard functions. These characterizations, along with those of the monotone nonparametric maximum likelihood estimators provide the asymptotic distribution of the likelihood ratio test. This asymptotic distribution enables, via inversion, the construction of pointwise confidence intervals. This method of constructing confidence intervals avoids the issue of estimating the nuisance parameters, as in the case of confidence intervals based on the asymptotic distribution of the estimators. Simulations indicate that the two methods yield confidence intervals with comparable coverage probabilities. Nonetheless, the confidence intervals based on the likelihood ratio are smaller, on average. Finally, in chapter 5 we consider smooth baseline hazard estimators. The estimators are obtained by kernel smoothing the maximum likelihood and Grenander-type estimators of a monotone baseline hazard function. Three different estimators are proposed for a nondecreasing baseline hazard, which are provided by the interchange of the smoothing and isotonization step. With this respect, we define a smoothed maximum likelihood estimator (SMLE), as well as a smoothed Grenander type (SG) estimator and a Grenander type smoothed (GS) estimator. All estimators are shown to be strongly pointwise or uniformly consistent.