Baseline Cumulative Hazard Research Articles

Imputing missing covariate values for the Cox model

Multiple imputation is commonly used to impute missing data, and is typically more efficient than complete cases analysis in regression analysis when covariates have missing values. Imputation may be performed using a regression model for the incomplete covariates on other covariates and, importantly, on the outcome. With a survival outcome, it is a common practice to use the event indicator D and the log of the observed event or censoring time T in the imputation model, but the rationale is not clear.We assume that the survival outcome follows a proportional hazards model given covariates X and Z. We show that a suitable model for imputing binary or Normal X is a logistic or linear regression on the event indicator D, the cumulative baseline hazard H0(T), and the other covariates Z. This result is exact in the case of a single binary covariate; in other cases, it is approximately valid for small covariate effects and/or small cumulative incidence. If we do not know H0(T), we approximate it by the Nelson–Aalen estimator of H(T) or estimate it by Cox regression.We compare the methods using simulation studies. We find that using log T biases covariate-outcome associations towards the null, while the new methods have lower bias. Overall, we recommend including the event indicator and the Nelson–Aalen estimator of H(T) in the imputation model. Copyright © 2009 John Wiley & Sons, Ltd.

Semiparametric estimation of a nested random effects model for the analysis of multi-level clustered failure time data

Multi-level clustered failure time data arise when the clustering of data occurs at more than one level. It is of interest to estimate the relative risks of covariates and clustering effect of failure times at each level. We consider a nested random effect proportional hazards model, where a subcluster-specific frailty operates multiplicatively on the conditional hazard model, and its distribution function depends on a cluster-specific random frailty. Under this model, we propose a Monte-Carlo EM-based semiparametric estimation procedure to estimate regression coefficients, nonparametric baseline cumulative hazard and the association parameters. In addition, we derive a covariance matrix of the parameter estimates. We illustrate the proposed method using clustered survival data collected from a vitamin A supplementation trial in Nepal, where it is of scientific interest to assess the clustering effect of mortality within households and within villages. We use simulations to study the performance of the proposed estimation procedure.

Bayesian Case Influence Diagnostics for Survival Models

We propose Bayesian case influence diagnostics for complex survival models. We develop case deletion influence diagnostics for both the joint and marginal posterior distributions based on the Kullback-Leibler divergence (K-L divergence). We present a simplified expression for computing the K-L divergence between the posterior with the full data and the posterior based on single case deletion, as well as investigate its relationships to the conditional predictive ordinate. All the computations for the proposed diagnostic measures can be easily done using Markov chain Monte Carlo samples from the full data posterior distribution. We consider the Cox model with a gamma process prior on the cumulative baseline hazard. We also present a theoretical relationship between our case-deletion diagnostics and diagnostics based on Cox's partial likelihood. A simulated data example and two real data examples are given to demonstrate the methodology.

CASE-CONTROL SURVIVAL ANALYSIS WITH A GENERAL SEMIPARAMETRIC SHARED FRAILTY MODEL - A PSEUDO FULL LIKELIHOOD APPROACH.

In this work we deal with correlated failure time (age at onset) data arising from population-based case-control studies, where case and control probands are selected by population-based sampling and an array of risk factor measures is collected for both cases and controls and their relatives. Parameters of interest are effects of risk factors on the failure time hazard function and within-family dependencies among failure times after adjusting for the risk factors. Due to the retrospective sampling scheme, large sample theory for existing methods has not been established. We develop a novel technique for estimating the parameters of interest under a general semiparametric shared frailty model. We also present a simple, easily computed, and non-iterative nonparametric estimator for the cumulative baseline hazard function. We provide rigorous large sample theory for the proposed method. We also present simulation results and a real data example for illustrating the utility of the proposed method.

Partially Linear Additive Hazards Regression With Varying Coefficients

Please see the supplementary materials for a correction to this article.To explore the nonlinear interactions between some covariates and an exposure variable, we propose the partially linear additive hazards model for survival data. In a semiparametric setting, we construct a local pseudoscore function to estimate the varying and constant coefficients and establish the asymptotic normality of the proposed estimators. Moreover, we develop the weak convergence property for the local estimator of the baseline cumulative hazard function. We conduct simulation studies to empirically examine the finite-sample performance of the proposed methods and use real data from a breast cancer study for illustration.

Inference in the additive risk model with time-varying covariates subject to measurement errors

For the additive risk model with time-varying covariates which are subject to measurement errors, we study the estimation of both regression parameters and cumulative baseline hazard function. We first develop a procedure to estimate the regression parameters by correcting the bias of the naive estimator, and provide the large-sample properties of the bias-adjusted estimators. The procedure can be repeated to further improve the accuracy of the estimator. We then construct a corresponding estimator for the cumulative baseline hazard function and derive its asymptotic properties. Based on these results, confidence bands are constructed for the cumulative hazard function as well as the survival function. Monte Carlo studies are conducted to evaluate the performance of these estimators.

A semiparametric shock model for a pair of event-related dependent censored failure times

In this paper, we propose a semiparametric shock model for two dependent failure times where the risk indicator of one failure time plays the part of a time-varying covariate for the other one. According to Hougaard [2000. Analysis of Multivariate Survival Data. Springer, New York], the dependence between the two failure times is therefore of event-related type. To derive our results, we define a joint distribution for the pair of failure times by means of a pair of parameters and a pair of baseline hazard rates. We then construct the associated counting processes and their compensators: in particular, we exhibit a special form of the risk indicators. We then propose a maximal partial likelihood estimator for the pair of parameters and Breslow estimators for the pair of baseline cumulative hazard rates. We establish the large sample properties of our estimators, following Andersen et al. [1993. Statistical Models based on Counting Processes. Springer, New York] and we illustrate our results by a short simulation study and an application to a real data set in demography.

Proportional hazards models based on biased samples and estimated selection probabilities

AbstractIn non‐randomized biomedical studies using the proportional hazards model, the data often constitute an unrepresentative sample of the underlying target population, which results in biased regression coefficients. The bias can be avoided by weighting included subjects by the inverse of their respective selection probabilities, as proposed by Horvitz & Thompson (1952) and extended to the proportional hazards setting for use in surveys by Binder (1992) and Lin (2000). In practice, the weights are often estimated and must be treated as such in order for the resulting inference to be accurate. The authors propose a two‐stage weighted proportional hazards model in which, at the first stage, weights are estimated through a logistic regression model fitted to a representative sample from the target population. At the second stage, a weighted Cox model is fitted to the biased sample. The authors propose estimators for the regression parameter and cumulative baseline hazard. They derive the asymptotic properties of the parameter estimators, accounting for the difference in the variance introduced by the randomness of the weights. They evaluate the accuracy of the asymptotic approximations in finite samples through simulation. They illustrate their approach in an analysis of renal transplant patients using data obtained from the Scientific Registry of Transplant Recipients

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.

Bayesian Survival Analysis in Proportional Hazard Models with Logistic Relative Risk

Abstract. The traditional Cox proportional hazards regression model uses an exponential relative risk function. We argue that under various plausible scenarios, the relative risk part of the model should be bounded, suggesting also that the traditional model often might overdramatize the hazard rate assessment for individuals with unusual covariates. This motivates our working with proportional hazards models where the relative risk function takes a logistic form. We provide frequentist methods, based on the partial likelihood, and then go on to semiparametric Bayesian constructions. These involve a Beta process for the cumulative baseline hazard function and any prior with a density, for example that dictated by a Jeffreys‐type argument, for the regression coefficients. The posterior is derived using machinery for Lévy processes, and a simulation recipe is devised for sampling from the posterior distribution of any quantity. Our methods are illustrated on real data. A Bernshteĭn–von Mises theorem is reached for our class of semiparametric priors, guaranteeing asymptotic normality of the posterior processes.

Marginal Analysis of Correlated Failure Time Data with Informative Cluster Sizes

We consider modeling correlated survival data when cluster sizes may be informative to the outcome of interest based on a within-cluster resampling (WCR) approach and a weighted score function (WSF) method. We derive the large sample properties for the WCR estimators under the Cox proportional hazards model. We establish consistency and asymptotic normality of the regression coefficient estimators, and the weak convergence property of the estimated baseline cumulative hazard function. The WSF method is to incorporate the inverse of cluster sizes as weights in the score function. We conduct simulation studies to assess and compare the finite-sample behaviors of the estimators and apply the proposed methods to a dental study as an illustration.

Posterior propriety and computation for the Cox regression model with applications to missing covariates

In this paper, we carry out an in-depth theoretical investigation of Bayesian inference for the Cox regression model. We establish necessary and sufficient conditions for posterior propriety of the regression coefficient, β, in Cox's partial likelihood, which can be obtained as the limiting marginal posterior distribution of β through the specification of a gamma process prior for the cumulative baseline hazard and a uniform improper prior for β. We also examine necessary and sufficient conditions for posterior propriety of the regression coefficients, β, using full likelihood Bayesian approaches in which a gamma process prior is specified for the cumulative baseline hazard. We examine characterisation of posterior propriety under completely observed data settings as well as for settings involving missing covariates. Latent variables are introduced to facilitate a straightforward Gibbs sampling scheme in the Bayesian computation. A real dataset is presented to illustrate the proposed methodology.

A relaxation of the gamma frailty (Burr) model

Frailty models are used in univariate data to account for individual heterogeneity. In the popular gamma frailty model the marginal hazard has the form of a Burr model. Although the Burr model is very useful and can offer insight on the data, it is far from perfect. The estimation of the covariate effects is linked to the baseline hazard and this makes the model coefficients hard to interpret. At the same time, the frailties are assumed constant over time, while biological reasoning in some cases may indicate that frailties may be time dependent. In this paper we present a relaxation of the Burr model which is based on loosening the link between the estimation of the covariate effects and the baseline hazard. This can be achieved by replacing the cumulative baseline hazard in the Burr model by a set of time functions, and the frailty variance by a vector of coefficients directly estimated from the data using a partial likelihood. We illustrate the similarities of the model with the Burr model and a further extension of the latter, a model with an autoregressive stochastic process for the frailty. We compare the models on simulated data sets with constant and time-dependent frailties and show how the relaxed Burr models performs on two different real data sets. We show that the relaxed Burr model serves as a good approximation to the Burr model when the frailty is constant, and furthermore it gives better results when the frailty is time dependent.

The Bernstein–von Mises theorem for the proportional hazard model

We study large sample properties of Bayesian analysis of the proportional hazard model with neutral to the right process priors on the baseline hazard function. We show that the posterior distribution of the baseline cumulative hazard function and regression coefficients centered at the maximum likelihood estimator is jointly asymptotically equivalent to the sampling distribution of the maximum likelihood estimator.

A Pseudo–Partial Likelihood Method for Semiparametric Survival Regression With Covariate Errors

This article presents an estimator for the regression coefficient vector in the Cox proportional hazards model with covariate error. The estimator is obtained by maximizing a likelihood-type function similar to the Cox partial likelihood. The likelihood function involves the cumulative baseline hazard function, for which a simple estimator is substituted. The method is capable of handling general covariate error structures; it is not restricted to the independent additive error model. It can be applied to studies with either an external or internal validation sample, and also to studies with replicate measurements of the surrogate covariate. The estimator is shown to be consistent and asymptotically normal, and an estimate of the asymptotic covariance matrix is derived. Some extensions to general transformation survival models are indicated. Simulation studies are presented for a setup with a single error-prone binary covariate and a setup with a single error-prone normally distributed covariate. These simulation studies show that the method typically produces estimates with low bias and confidence intervals with accurate coverage rates. Efficiency results relative to fully parametric maximum likelihood are also presented. The method is applied to data from the Framingham Heart Study.

Semiparametric censorship model with covariates

In real applications, we may be confronted with the problem of informative censoring. Koziol-Green model is commonly used to model the possible information contained in the informative censoring. However the proportionality assumption cast by Koziol-Green model (see (1.2) below) is "too restrictive in that it limits the scope of the Cox model in practice" (Subramanian, 2000). In this paper, we try to relax the proportionality condition of Koziol-Green model by modeling the censorship semiparametrically. It is shown that our suggested semiparametric censoring model is an applicable extension of the Koziol-Green model. Through a close connection with the logistic regression, our model assumptions are readily to be checked in practice. We also propose estimation for both the regression parameter and the cumulative baseline hazard function which can incorporate the additional information contained in the semiparametric censorship model. Simulations and the analysis of a real dataset confirm the applicability of the suggested model and estimation.

Competing risk and the Cox proportional hazard model

We propose a heuristic for evaluating model adequacy for the Cox proportional hazard model by comparing the population cumulative hazard with the baseline cumulative hazard. We illustrate how recent results from the theory of competing risk can contribute to analysis of data with the Cox proportional hazard model. A classical theorem on independent competing risks allows us to assess model adequacy under the hypothesis of random right censoring, and a recent result on mixtures of exponentials predicts the patterns of the conditional subsurvival functions of random right censored data if the proportional hazard model holds.

Haplotype‐Based Association Analysis in Cohort and Nested Case–Control Studies

Genetic epidemiologic studies often collect genotype data at multiple loci within a genomic region of interest from a sample of unrelated individuals. One popular method for analyzing such data is to assess whether haplotypes, i.e., the arrangements of alleles along individual chromosomes, are associated with the disease phenotype or not. For many study subjects, however, the exact haplotype configuration on the pair of homologous chromosomes cannot be derived with certainty from the available locus-specific genotype data (phase ambiguity). In this article, we consider estimating haplotype-specific association parameters in the Cox proportional hazards model, using genotype, environmental exposure, and the disease endpoint data collected from cohort or nested case-control studies. We study alternative Expectation-Maximization algorithms for estimating haplotype frequencies from cohort and nested case-control studies. Based on a hazard function of the disease derived from the observed genotype data, we then propose a semiparametric method for joint estimation of relative-risk parameters and the cumulative baseline hazard function. The method is greatly simplified under a rare disease assumption, for which an asymptotic variance estimator is also proposed. The performance of the proposed estimators is assessed via simulation studies. An application of the proposed method is presented, using data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.

Cox's Regression Model Under Partially Informative Censoring

ABSTRACT We extend Cox's classical regression model to accomodate partially informative censored data. In this type of data, each observation is the minimum of one lifetime and two censoring times. The survival function of one of these censoring times is a power of the survival function of the lifetime. We call this the informative censoring time. The distribution of the other censoring time has no relation with the distribution of the lifetime. It is called the non informative censoring time. In this model we specify a semiparametric relation between the lifetime and a covariate where we take into account that also informatively censored observations contribute to this relation. We introduce an estimator for the cumulative baseline hazard function and use maximum likelihood techniques for the estimation of the parameters in the model. Our main results are strong consistency and asymptotic normality of these estimators. The proof uses the general theory of Murphy and van der Vaart (2000) on profile likelihoods. Finally, the method is applied to simulated data and to real data examples on survival with malignant melanoma and survival after bone marrow transplantation.

Estimating Load-Sharing Properties in a Dynamic Reliability System

An estimator for the load-share parameters in an equal load-share model is derived based on observing k-component parallel systems of identical components that have a continuous distribution function F (˙) and failure rate r (˙). In an equal load-share model, after the first of k components fails, failure rates for the remaining components change from r (t) to γ1r (t), then to γ2r (t) after the next failure, and so on. On the basis of observations on n independent and identical systems, a semiparametric estimator of the component baseline cumulative hazard function R = –log(1 – F) is presented, and its asymptotic limit process is established to be a Gaussian process. The effect of estimation of the load-share parameters is considered in the derivation of the limiting process. Potential applications can be found in diverse areas, including materials testing, software reliability, and power plant safety assessment.