A Cox‐Aalen Model for Interval‐censored Data

The Cox‐Aalen model, obtained by replacing the baseline hazard function in the well‐known Cox model with a covariate‐dependent Aalen model, allows for both fixed and dynamic covariate effects. In this paper, we examine maximum likelihood estimation for a Cox‐Aalen model based on interval‐censored failure times with fixed covariates. The resulting estimator globally converges to the truth slower than the parametric rate, but its finite‐dimensional component is asymptotically efficient. Numerical studies show that estimation via a constrained Newton method performs well in terms of both finite sample properties and processing time for moderate‐to‐large samples with few covariates. We conclude with an application of the proposed methods to assess risk factors for disease progression in psoriatic arthritis.     

Estimation of odds of concordance based on the Aalen additive model

The Cox regression model is often used when analyzing survival data as it provides a convenient way of summarizing covariate effects in terms of relative risks. The proportional hazards assumption may not hold, however. A typical violation of the assumption is time-changing covariate effects. Under such scenarios one may use more flexible models but the results from such models may be complicated to communicate and it is desirable to have simple measures of a treatment effect, say. In this paper we focus on the odds-of-concordance measure that was recently studied by Schemper et al. (Stat Med 28:2473?C2489, 2009). They suggested to estimate this measure using weighted Cox regression (WCR). Although WCR may work in many scenarios no formal proof can be established. We suggest an alternative estimator of the odds-of-concordance measure based on the Aalen additive hazards model. In contrast to the WCR, one may derive the large sample properties for this estimator making formal inference possible. The estimator also allows for additional covariate effects.     

The Additive Nonparametric and Semiparametric Aalen Model as the Rate Function for a Counting Process

We use the additive risk model of Aalen (Aalen, 1980) as a model for the rate of a counting process. Rather than specifying the intensity, that is the instantaneous probability of an event conditional on the entire history of the relevant covariates and counting processes, we present a model for the rate function, i.e., the instantaneous probability of an event conditional on only a selected set of covariates. When the rate function for the counting process is of Aalen form we show that the usual Aalen estimator can be used and gives almost unbiased estimates. The usual martingale based variance estimator is incorrect and an alternative estimator should be used. We also consider the semi-parametric version of the Aalen model as a rate model (McKeague and Sasieni, 1994) and show that the standard errors that are computed based on an assumption of intensities are incorrect and give a different estimator. Finally, we introduce and implement a test-statistic for the hypothesis of a time-constant effect in both the non-parametric and semi-parametric model. A small simulation study was performed to evaluate the performance of the new estimator of the standard error.     

Estimation of Causal Odds of Concordance using the Aalen Additive Model

A simple summary of a treatment effect is attractive, which is part of the explanation of the success of the Cox model when analysing time‐to‐event data since the relative risk measure is such a convenient summary measure. In practice, however, the Cox model may fail to give a reasonable fit, very often because of time‐changing treatment effect. The Aalen additive hazards model may be a good alternative as time‐changing effects are easily modelled within this model, but results are then evidently more complicated to communicate. In such situations, the odds of concordance measure (OC) is a convenient way of communicating results, and recently Martinussen & Pipper (2012) showed how a variant of the OC measure may be estimated based on the Aalen additive hazards model. In this study, we propose an estimator that should be preferred in observational studies as it always estimates the causal effect on the chosen scale, only assuming that there are no un‐measured confounders. The resulting estimator is shown to be consistent and asymptotically normal, and an estimator of its limiting variance is provided. Two real applications are provided.     

Estimating Survival Curves Under Proportional Hazards Model with Covariate Measurement Errors

For the Cox proportional hazards model with additive covariate measurement errors, we propose a corrected cumulative baseline hazard estimator that reduces the bias of the na]ve Breslow estimator. We also derive corresponding modified estimators for the hazard functions and the survival functions of individuals with particular covariate values. Using a Monte Carlo technique developed by Lin et al . (1994), we construct confidence bands for such hazard and survival functions.     

The Cox–Aalen model for left-truncated and right-censored data

We analyze left-truncated and right-censored (LTRC) data using an additive-multiplicative Cox–Aalen model proposed by Scheike and Zhang (2002), which extends the Cox regression model as well as the additive Aalen model. Based on the conditional likelihood function, we derive the weighted least-squared (WLS) estimators for the regression parameters and cumulative intensity functions of the model. The estimators are shown to be consistent and asymptotically normal. A simulation study is conducted to investigate the performance of the proposed estimators.     

Dynamic path analysis for event time data: large sample properties and inference

We consider the situation with a survival or more generally a counting process endpoint for which we wish to investigate the effect of an initial treatment. Besides the treatment indicator we also have information about a time-varying covariate that may be of importance for the survival endpoint. The treatment may possibly influence both the endpoint and the time-varying covariate, and the concern is whether or not one should correct for the effect of the dynamic covariate. Recently Fosen et al. (Biometrical J 48:381–398, 2006a) investigated this situation using the notion of dynamic path analysis and showed under the Aalen additive hazards model that the total effect of the treatment indicator can be decomposed as a sum of what they termed a direct and an indirect effect. In this paper, we give large sample properties of the estimator of the cumulative indirect effect that may be used to draw inferences. Small sample properties are investigated by Monte Carlo simulation and two applications are provided for illustration. We also consider the Cox model in the situation with recurrent events data and show that a similar decomposition of the total effect into a sum of direct and indirect effects holds under certain assumptions.     

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.     

The additive hazards model with high-dimensional regressors

This paper considers estimation and prediction in the Aalen additive hazards model in the case where the covariate vector is high-dimensional such as gene expression measurements. Some form of dimension reduction of the covariate space is needed to obtain useful statistical analyses. We study the partial least squares regression method. It turns out that it is naturally adapted to this setting via the so-called Krylov sequence. The resulting PLS estimator is shown to be consistent provided that the number of terms included is taken to be equal to the number of relevant components in the regression model. A standard PLS algorithm can also be constructed, but it turns out that the resulting predictor can only be related to the original covariates via time-dependent coefficients. The methods are applied to a breast cancer data set with gene expression recordings and to the well known primary biliary cirrhosis clinical data.     

Estimation of average causal effect using the restricted mean residual lifetime as effect measure

Although mean residual lifetime is often of interest in biomedical studies, restricted mean residual lifetime must be considered in order to accommodate censoring. Differences in the restricted mean residual lifetime can be used as an appropriate quantity for comparing different treatment groups with respect to their survival times. In observational studies where the factor of interest is not randomized, covariate adjustment is needed to take into account imbalances in confounding factors. In this article, we develop an estimator for the average causal treatment difference using the restricted mean residual lifetime as target parameter. We account for confounding factors using the Aalen additive hazards model. Large sample property of the proposed estimator is established and simulation studies are conducted in order to assess small sample performance of the resulting estimator. The method is also applied to an observational data set of patients after an acute myocardial infarction event.     

The Cox-Aalen model for left-truncated and mixed interval-censored data

Scheike and Zhang [An additive-multiplicative Cox-Aalen regression model. Scand J Stat. 2002;29:75–88] proposed a flexible additive-multiplicative hazard model, called the Cox-Aalen model, by replacing the baseline hazard function in the well-known Cox model with a covariate-dependent Aalen model, which allows for both fixed and dynamic covariate effects. In this paper, based on left-truncated and mixed interval-censored (LT-MIC) data, we consider maximum likelihood estimation for the Cox-Aalen model with fixed covariates. We propose expectation-maximization (EM) algorithms for obtaining the conditional maximum likelihood estimators (cMLE) of the regression coefficients for the Cox-Aalen model. We establish the consistency of the cMLE. Numerical studies show that estimation via the EM algorithms performs well.     

A study of regression calibration in a partially observed stratified Cox model

Regression calibration is a simple method for estimating regression models when covariate data are missing for some study subjects. It consists in replacing an unobserved covariate by an estimator of its conditional expectation given available covariates. Regression calibration has recently been investigated in various regression models such as the linear, generalized linear, and proportional hazards models. The aim of this paper is to investigate the appropriateness of this method for estimating the stratified Cox regression model with missing values of the covariate defining the strata. Despite its practical relevance, this problem has not yet been discussed in the literature. Asymptotic distribution theory is developed for the regression calibration estimator in this setting. A simulation study is also conducted to investigate the properties of this estimator.     

Fitting Cox Models with Doubly Censored Data Using Spline‐Based Sieve Marginal Likelihood

In some applications, the failure time of interest is the time from an originating event to a failure event while both event times are interval censored. We propose fitting Cox proportional hazards models to this type of data using a spline‐based sieve maximum marginal likelihood, where the time to the originating event is integrated out in the empirical likelihood function of the failure time of interest. This greatly reduces the complexity of the objective function compared with the fully semiparametric likelihood. The dependence of the time of interest on time to the originating event is induced by including the latter as a covariate in the proportional hazards model for the failure time of interest. The use of splines results in a higher rate of convergence of the estimator of the baseline hazard function compared with the usual non‐parametric estimator. The computation of the estimator is facilitated by a multiple imputation approach. Asymptotic theory is established and a simulation study is conducted to assess its finite sample performance. It is also applied to analyzing a real data set on AIDS incubation time.     

A note on the asymptotic relative efficiency of estimators from the additive hazards model

In this note, the asymptotic variance formulas are explicitly derived and compared between the parametric and semiparametric estimators of a regression parameter and survival probability under the additive hazards model. To obtain explicit formulas, it is assumed that the covariate term including a regression coefficient follows a gamma distribution and the baseline hazard function is constant. The results show that the semiparametric estimator of the regression coefficient parameter is fully efficient relative to the parametric counterpart when the survival time and a covariate are independent, as in the proportional hazards model. Relative to a more realistic case of the parametric additive hazards model with a Weibull baseline, the loss of efficiency of the semiparametric estimator of survival probability is moderate.     

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.     

Shape Constrained Non‐parametric Estimators of the Baseline Distribution in Cox Proportional Hazards Model

Abstract. We investigate non‐parametric estimation of a monotone baseline hazard and a decreasing baseline density within the Cox model. Two estimators of a non‐decreasing baseline hazard function are proposed. We derive the non‐parametric maximum likelihood estimator and consider a Grenander type estimator, defined as the left‐hand slope of the greatest convex minorant of the Breslow estimator. We demonstrate that the two estimators are strongly consistent and asymptotically equivalent and derive their common limit distribution at a fixed point. Both estimators of a non‐increasing baseline hazard and their asymptotic properties are obtained in a similar manner. Furthermore, we introduce a Grenander type estimator for a non‐increasing 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. We show that this estimator is strongly consistent and derive its asymptotic distribution at a fixed point.     

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.     

A Spline‐Based Semiparametric Maximum Likelihood Estimation Method for the Cox Model with Interval‐Censored Data

Abstract. We propose a spline‐based semiparametric maximum likelihood approach to analysing the Cox model with interval‐censored data. With this approach, the baseline cumulative hazard function is approximated by a monotone B‐spline function. We extend the generalized Rosen algorithm to compute the maximum likelihood estimate. We show that the estimator of the regression parameter is asymptotically normal and semiparametrically efficient, although the estimator of the baseline cumulative hazard function converges at a rate slower than root‐n. We also develop an easy‐to‐implement method for consistently estimating the standard error of the estimated regression parameter, which facilitates the proposed inference procedure for the Cox model with interval‐censored data. The proposed method is evaluated by simulation studies regarding its finite sample performance and is illustrated using data from a breast cosmesis study.     

Checking a Semiparametric Additive Risk Model

McKeague and Sasieni [A partly parametric additive risk model. Biometrika 81 (1994) 501] propose a restriction of Aalen’s additive risk model by the additional hypothesis that some of the covariates have time-independent influence on the intensity of the observed counting process. We introduce goodness-of-fit tests for this semiparametric Aalen model. The asymptotic distribution properties of the test statistics are derived by means of martingale techniques. The tests can be adjusted to detect particular alternatives. As one of the most important alternatives we consider Cox’s proportional hazards model. We present simulation studies and an application to a real data set.     

A risk set calibration method for failure time regression by using a covariate reliability sample

Regression parameter estimation in the Cox failure time model is considered when regression variables are subject to measurement error. Assuming that repeat regression vector measurements adhere to a classical measurement model, we can consider an ordinary regression calibration approach in which the unobserved covariates are replaced by an estimate of their conditional expectation given available covariate measurements. However, since the rate of withdrawal from the risk set across the time axis, due to failure or censoring, will typically depend on covariates, we may improve the regression parameter estimator by recalibrating within each risk set. The asymptotic and small sample properties of such a risk set regression calibration estimator are studied. A simple estimator based on a least squares calibration in each risk set appears able to eliminate much of the bias that attends the ordinary regression calibration estimator under extreme measurement error circumstances. Corresponding asymptotic distribution theory is developed, small sample properties are studied using computer simulations and an illustration is provided.