Product-limit Estimators and Cox Regression with Missing Censoring Information

The Kaplan–Meier estimator of a survival function requires that the censoring indicator is always observed. A method of survival function estimation is developed when the censoring indicators are missing completely at random (MCAR). The resulting estimator is a smooth functional of the Nelson–Aalen estimators of certain cumulative transition intensities. The asymptotic properties of this estimator are derived. A simulation study shows that the proposed estimator has greater efficiency than competing MCAR-based estimators. The approach is extended to the Cox model setting for the estimation of a conditional survival function given a covariate.     

Non-parametric Estimation for the Location of a Change-point in an Otherwise Smooth Hazard Function under Random Censoring

A non-parametric wavelet based estimator is proposed for the location of a change-point in an otherwise smooth hazard function under non-informative random right censoring. The proposed estimator is based on wavelet coefficients differences via an appropriate parametrization of the time-frequency plane. The study of the estimator is facilitated by the strong representation theorem for the Kaplan–Meier estimator established by Lo and Singh (1986). The performance of the estimator is checked via simulations and two real examples conclude the paper.     

Non-parametric Estimation of a Survival Function with Two-stage Design Studies

Abstract.  The two-stage design is popular in epidemiology studies and clinical trials due to its cost effectiveness. Typically, the first stage sample contains cheaper and possibly biased information, while the second stage validation sample consists of a subset of subjects with accurate and complete information. In this paper, we study estimation of a survival function with right-censored survival data from a two-stage design. A non-parametric estimator is derived by combining data from both stages. We also study its large sample properties and derive pointwise and simultaneous confidence intervals for the survival function. The proposed estimator effectively reduces the variance and finite-sample bias of the Kaplan–Meier estimator solely based on the second stage validation sample. Finally, we apply our method to a real data set from a medical device postmarketing surveillance study.     

Estimation of the Average Survival Function Using a Censored Data Regression Model

In the presence of covariates information, assuming the linear relationship between a transformation of survival time and covariates, we propose a new estimator of survival function and show its consistency. In addition, a comparison of the proposed estimator with the product-limit estimator introduced by Kaplan and Meier (1958) is performed through Monte Carlo simulation studies. We illustrate the proposed estimator with the updated Stanford heart transplant data.     

Estimation of bivariate and marginal distributions with censored data

Summary. Consider a pair of random variables, both subject to random right censoring. New estimators for the bivariate and marginal distributions of these variables are proposed. The estimators of the marginal distributions are not the marginals of the corresponding estimator of the bivariate distribution. Both estimators require estimation of the conditional distribution when the conditioning variable is subject to censoring. Such a method of estimation is proposed. The weak convergence of the estimators proposed is obtained. A small simulation study suggests that the estimators of the marginal and bivariate distributions perform well relatively to respectively the Kaplan–Meier estimator for the marginal distribution and the estimators of Pruitt and van der Laan for the bivariate distribution. The use of the estimators in practice is illustrated by the analysis of a data set.     

Influence Function Based Variance Estimation and Missing Data Issues in Case-Cohort Studies

Recognizing that the efficiency in relative risk estimation for the Cox proportional hazards model is largely constrained by the total number of cases, Prentice (1986) proposed the case-cohort design in which covariates are measured on all cases and on a random sample of the cohort. Subsequent to Prentice, other methods of estimation and sampling have been proposed for these designs. We formalize an approach to variance estimation suggested by Barlow (1994), and derive a robust variance estimator based on the influence function. We consider the applicability of the variance estimator to all the proposed case-cohort estimators, and derive the influence function when known sampling probabilities in the estimators are replaced by observed sampling fractions. We discuss the modifications required when cases are missing covariate information. The missingness may occur by chance, and be completely at random; or may occur as part of the sampling design, and depend upon other observed covariates. We provide an adaptation of S-plus code that allows estimating influence function variances in the presence of such missing covariates. Using examples from our current case-cohort studies on esophageal and gastric cancer, we illustrate how our results our useful in solving design and analytic issues that arise in practice.     

Nonlinear Censored Regression Using Synthetic Data

Abstract.  The problem of estimating a nonlinear regression model, when the dependent variable is randomly censored, is considered. The parameter of the model is estimated by least squares using synthetic data. Consistency and asymptotic normality of the least squares estimators are derived. The proofs are based on a novel approach that uses i.i.d. representations of synthetic data through Kaplan–Meier integrals. The asymptotic results are supported by a small simulation study.     

Landmark estimation of survival and treatment effects in observational studies

Clinical studies aimed at identifying effective treatments to reduce the risk of disease or death often require long term follow-up of participants in order to observe a sufficient number of events to precisely estimate the treatment effect. In such studies, observing the outcome of interest during follow-up may be difficult and high rates of censoring may be observed which often leads to reduced power when applying straightforward statistical methods developed for time-to-event data. Alternative methods have been proposed to take advantage of auxiliary information that may potentially improve efficiency when estimating marginal survival and improve power when testing for a treatment effect. Recently, Parast et al. (J Am Stat Assoc 109(505):384–394, 2014) proposed a landmark estimation procedure for the estimation of survival and treatment effects in a randomized clinical trial setting and demonstrated that significant gains in efficiency and power could be obtained by incorporating intermediate event information as well as baseline covariates. However, the procedure requires the assumption that the potential outcomes for each individual under treatment and control are independent of treatment group assignment which is unlikely to hold in an observational study setting. In this paper we develop the landmark estimation procedure for use in an observational setting. In particular, we incorporate inverse probability of treatment weights (IPTW) in the landmark estimation procedure to account for selection bias on observed baseline (pretreatment) covariates. We demonstrate that consistent estimates of survival and treatment effects can be obtained by using IPTW and that there is improved efficiency by using auxiliary intermediate event and baseline information. We compare our proposed estimates to those obtained using the Kaplan–Meier estimator, the original landmark estimation procedure, and the IPTW Kaplan–Meier estimator. We illustrate our resulting reduction in bias and gains in efficiency through a simulation study and apply our procedure to an AIDS dataset to examine the effect of previous antiretroviral therapy on survival.     

Ordered Tests for Right–Censored Survival Data

In comparative clinical trials or animal carcinogenesis studies, the effect of increasing dose levels of an agent or an increasing number of additional modalities are frequently evaluated on the prolonged survival time of patients with a particular disease. It is of particular interest to test the ordered alternative that a treatment level increase leads to better survival. This paper considers an ordered test based on the two–sample weighted Kaplan–Meier statistics (Pepe & Fleming, 1989, 1991). It evaluates asymptotic relative efficiencies of the proposed ordered weighted Kaplan–Meier test, the competing ordered weighted logrank test (Liu et al., 1993) and modified ordered logrank test (Liu & Tsai, 1999) under Lehmann alternatives, for various piecewise exponential survival distributions. Finally, it demonstrates the proposed test on an appropriate dataset.     

Semiparametric estimation of treatment effect with time-lagged response in the presence of informative censoring

In many randomized clinical trials, the primary response variable, for example, the survival time, is not observed directly after the patients enroll in the study but rather observed after some period of time (lag time). It is often the case that such a response variable is missing for some patients due to censoring that occurs when the study ends before the patient’s response is observed or when the patients drop out of the study. It is often assumed that censoring occurs at random which is referred to as noninformative censoring; however, in many cases such an assumption may not be reasonable. If the missing data are not analyzed properly, the estimator or test for the treatment effect may be biased. In this paper, we use semiparametric theory to derive a class of consistent and asymptotically normal estimators for the treatment effect parameter which are applicable when the response variable is right censored. The baseline auxiliary covariates and post-treatment auxiliary covariates, which may be time-dependent, are also considered in our semiparametric model. These auxiliary covariates are used to derive estimators that both account for informative censoring and are more efficient then the estimators which do not consider the auxiliary covariates.     

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.

     

Estimation with Interval Censored Data and Covariates

In biostatistical applications interest often focuses on the estimation of the distribution of time T between two consecutive events. If the initial event time is observed and the subsequent event time is only known to be larger or smaller than an observed monitoring time C, then the data conforms to the well understood singly-censored current status model, also known as interval censored data, case I. Additional covariates can be used to allow for dependent censoring and to improve estimation of the marginal distribution of T. Assuming a wrong model for the conditional distribution of T, given the covariates, will lead to an inconsistent estimator of the marginal distribution. On the other hand, the nonparametric maximum likelihood estimator of FT requires splitting up the sample in several subsamples corresponding with a particular value of the covariates, computing the NPMLE for every subsample and then taking an average. With a few continuous covariates the performance of the resulting estimator is typically miserable. In van der Laan, Robins (1996) a locally efficient one-step estimator is proposed for smooth functionals of the distribution of T, assuming nothing about the conditional distribution of T, given the covariates, but assuming a model for censoring, given the covariates. The estimators are asymptotically linear if the censoring mechanism is estimated correctly. The estimator also uses an estimator of the conditional distribution of T, given the covariates. If this estimate is consistent, then the estimator is efficient and if it is inconsistent, then the estimator is still consistent and asymptotically normal. In this paper we show that the estimators can also be used to estimate the distribution function in a locally optimal way. Moreover, we show that the proposed estimator can be used to estimate the distribution based on interval censored data (T is now known to lie between two observed points) in the presence of covariates. The resulting estimator also has a known influence curve so that asymptotic confidence intervals are directly available. In particular, one can apply our proposal to the interval censored data without covariates. In Geskus (1992) the information bound for interval censored data with two uniformly distributed monitoring times at the uniform distribution (for T has been computed. We show that the relative efficiency of our proposal w.r.t. this optimal bound equals 0.994, which is also reflected in finite sample simulations. Finally, the good practical performance of the estimator is shown in a simulation study. This revised version was published online in July 2006 with corrections to the Cover Date.     

Proportional hazards estimate of the conditional survival function

We introduce a new estimator of the conditional survival function given some subset of the covariate values under a proportional hazards regression. The new estimate does not require estimating the base-line cumulative hazard function. An estimate of the variance is given and is easy to compute, involving only those quantities that are routinely calculated in a Cox model analysis. The asymptotic normality of the new estimate is shown by using a central limit theorem for Kaplan–Meier integrals. We indicate the straightforward extension of the estimation procedure under models with multiplicative relative risks, including non-proportional hazards, and to stratified and frailty models. The estimator is applied to a gastric cancer study where it is of interest to predict patients' survival based only on measurements obtained before surgery, the time at which the most important prognostic variable, stage, becomes known.     

Finite-sample properties of the maximum likelihood estimator for the binary logit model with random covariates

We examine the finite sample properties of the maximum likelihood estimator for the binary logit model with random covariates. Previous studies have either relied on large-sample asymptotics or have assumed non-random covariates. Analytic expressions for the first-order bias and second-order mean squared error function for the maximum likelihood estimator in this model are derived, and we undertake numerical evaluations to illustrate these analytic results for the single covariate case. For various data distributions, the bias of the estimator is signed the same as the covariate’s coefficient, and both the absolute bias and the mean squared errors increase symmetrically with the absolute value of that parameter. The behaviour of a bias-adjusted maximum likelihood estimator, constructed by subtracting the (maximum likelihood) estimator of the first-order bias from the original estimator, is examined in a Monte Carlo experiment. This bias-correction is effective in all of the cases considered, and is recommended for use when this logit model is estimated by maximum likelihood using small samples.     

Estimation in a General Repair Model Based on Left-truncated Data

We consider a repairable system with general repairs introduced by Last & Szekli (1998a ). Apart from simple special cases this model leads to a strong dependency among the observed failure times. Our aim is to estimate the underlying failure time distribution and its cumulative hazard given that the failure process has been observed up to the n th failure. We use non-parametric estimators of Kaplan–Meier and Nelson–Aalen type. We prove strong uniform consistency of the estimators as n tends to infinity. Further results on weak convergence are derived. Neither stationarity nor mixing conditions are required.     

Comparison of Regression Curves with Censored Responses

Abstract.  In this article, we introduce a procedure to test the equality of regression functions when the response variables are censored. The test is based on a comparison of Kaplan–Meier estimators of the distribution of the censored residuals. Kolmogorov–Smirnov- and Cramér–von Mises-type statistics are considered. Some asymptotic results are proved: weak convergence of the process of interest, convergence of the test statistics and behaviour of the process under local alternatives. We also describe a bootstrap procedure in order to approximate the critical values of the test. A simulation study and an application to a real data set conclude the paper.     

Finite-Sample Properties of the Maximum Likelihood Estimator for the Poisson Regression Model With Random Covariates

We examine the small-sample behaviour of the maximum likelihood estimator for the Poisson regression model with random covariates. Analytic expressions for the second-order bias and mean squared error are derived, and we undertake some numerical evaluations to illustrate these results for the single covariate case. The properties of the bias-adjusted maximum likelihood estimator are investigated in a Monte Carlo experiment. Correcting the estimator for its second-order bias is found to be effective in the cases considered, and we recommend its use when the Poisson regression model is estimated by maximum likelihood with small samples.     

Form and selection of covariance adjusted estimators in repeated measures models

The GMANOVA model is considered when one characteristic is measured at q time points. The covariance adjusted estimator is the OLS estimator adjusted using analysis of covariance. The covariates are obtained from the space vertical to that derived from the design matrix. Its form is obtained as a GLS estimator using a weight matrix of reduced rank unless all available covariates are used. The choice of the appropriate covariate combination is made by introducing a method based on cross validation (CV). A comparison is made with two other methods that appeared in statistical literature using simulation.     

The Jackknife estimate of covariance of two Kaplan–Meier integrals with covariables

In this paper the Jackknife estimate of covariance of two Kaplan–Meier integrals with covariates is introduced. Its strong consistency is established under mild conditions. Several applications of the estimator are discussed.     

Generalized Concept of Relative Risk and Wider Applications of the Proportional Hazards Model and the Kaplan–Meier Estimator

The concepts of relative risk and hazard ratio are generalized for ordinary ordinal and continuous response variables, respectively. Under the generalized concepts, the Cox proportional hazards model with the Breslow's and Efron's methods can be regarded as generalizations of the Mantel–Haenszel estimator for dealing with broader types of covariates and responses. When ordinal responses can be regarded as discretized observations of a hypothetical continuous variable, the estimated relative risks from the Cox model reflect the associations between the responses and covariates. Examples are given to illustrate the generalized concepts and wider applications of the Cox model and the Kaplan–Meier estimator.