A family of multiplicative survival models incorporating a long-term survivorship parameter c as a function of covariates

A family of multiplicative survival models is obtained for the analysis of clinical trial data in which a substantial proportion c of patients respond favorably to treatment with longterm survivorship. The model (MWSM) representing the hazard function for all patients as a function of c and a Weibull density is developed in which the distributional parameters and c are regressed on covariates and estimated by the method of maximum likelihood. The MWSM hazard function is monotonically increasing, peaking, then decreasing thereafter if the shape parameter exceeds unity, and is monotonically decreasing otherwise. Mortality rates with similar behavior have been empirically observed in cancer clinical trial data. A nonproportional or proportional hazards model results depending upon whether or not any Weibull parameter is regressed on covariates. Tests of hypotheses and confidence intervals for c and p-quantiles are obtained.     

Incorporating Follow-up Time in M-Estimation for Survival Data

It has been approximately 30 years since D.R. Cox introduced the proportional hazards method to model the relationship between covariates and survival time. However, the proportional hazards model has limited value when the proportionality assumption is violated. Over the years, there have many been many alternative proposals to the proportional hazards regression model for the case of right censored survival data, but to date none have demonstrated widespread acceptance. In general, problems encountered in these methods include their computational algorithms or evaluation of their asymptotic properties. In this work, an estimating equation based on a U-statistic of degree 2 is proposed. It is easy to implement and the U-statistic framework provides a straightforward development of asymptotic inferential theory for the regression parameters.     

Covariate Selection for the Semiparametric Additive Risk Model

Abstract.  This paper considers covariate selection for the additive hazards model. This model is particularly simple to study theoretically and its practical implementation has several major advantages to the similar methodology for the proportional hazards model. One complication compared with the proportional model is, however, that there is no simple likelihood to work with. We here study a least squares criterion with desirable properties and show how this criterion can be interpreted as a prediction error. Given this criterion, we define ridge and Lasso estimators as well as an adaptive Lasso and study their large sample properties for the situation where the number of covariates p is smaller than the number of observations. We also show that the adaptive Lasso has the oracle property. In many practical situations, it is more relevant to tackle the situation with large p compared with the number of observations. We do this by studying the properties of the so-called Dantzig selector in the setting of the additive risk model. Specifically, we establish a bound on how close the solution is to a true sparse signal in the case where the number of covariates is large. In a simulation study, we also compare the Dantzig and adaptive Lasso for a moderate to small number of covariates. The methods are applied to a breast cancer data set with gene expression recordings and to the primary biliary cirrhosis clinical data.     

Confidence intervals for the difference between two median survival times for clustered survival data

Clustered survival data arise often in clinical trial design, where the correlated subunits from the same cluster are randomized to different treatment groups. Under such design, we consider the problem of constructing confidence interval for the difference of two median survival time given the covariates. We use Cox gamma frailty model to account for the within-cluster correlation. Based on the conditional confidence intervals, we can identify the possible range of covariates over which the two groups would provide different median survival times. The associated coverage probability and the expected length of the proposed interval are investigated via a simulation study. The implementation of the confidence intervals is illustrated using a real data set.     

Partial orders with respect to continuous covariates and tests for the proportional hazards model

Several omnibus tests of the proportional hazards assumption have been proposed in the literature. In the two-sample case, tests have also been developed against ordered alternatives like monotone hazard ratio and monotone ratio of cumulative hazards. Here we propose a natural extension of these partial orders to the case of continuous and potentially time varying covariates, and develop tests for the proportional hazards assumption against such ordered alternatives. The work is motivated by applications in biomedicine and economics where covariate effects often decay over lifetime. The proposed tests do not make restrictive assumptions on the underlying regression model, and are applicable in the presence of time varying covariates, multiple covariates and frailty. Small sample performance and an application to real data highlight the use of the framework and methodology to identify and model the nature of departures from proportionality.     

The proportional hazards model with covariate measurement error

The proportional hazards regression model is commonly used to evaluate the relationship between survival and covariates. Covariates are frequently measured with error. Substituting mismeasured values for the true covariates leads to biased estimation. Hu et al. (Biometrics 88 (1998) 447) have proposed to base estimation in the proportional hazards model with covariate measurement error on a joint likelihood for survival and the covariate variable. Nonparametric maximum likelihood estimation (NPMLE) was used and simulations were conducted to assess the asymptotic validity of this approach. In this paper, we derive a rigorous proof of asymptotic normality of the NPML estimators.     

Choice of parametric models in survival analysis: applications to monotherapy for epilepsy and cerebral palsy

Summary. In the analysis of medical survival data, semiparametric proportional hazards models are widely used. When the proportional hazards assumption is not tenable, these models will not be suitable. Other models for covariate effects can be useful. In particular, we consider accelerated life models, in which the effect of covariates is to scale the quantiles of the base-line distribution. Solomon and Hutton have suggested that there is some robustness to misspecification of survival regression models. They showed that the relative importance of covariates is preserved under misspecification with assumptions of small coefficients and orthogonal transformation of covariates. We elucidate these results by applications to data from five trials which compare two common anti-epileptic drugs (carbamazepine versus sodium valporate monotherapy for epilepsy) and to survival of a cohort of people with cerebral palsy. Results on the robustness against model misspecification depend on the assumptions of small coefficients and on the underlying distribution of the data. These results hold in cerebral palsy but do not hold in epilepsy data which have early high hazard rates. The orthogonality of coefficients is not important. However, the choice of model is important for an estimation of the magnitude of effects, particularly if the base-line shape parameter indicates high initial hazard rates.     

Local Linear Regression in Proportional Hazards Model with Censored Data

In this article we study the method of nonparametric regression based on a transformation model, under which an unknown transformation of the survival time is nonlinearly, even more, nonparametrically, related to the covariates with various error distributions, which are parametrically specified with unknown parameters. Local linear approximations and locally weighted least squares are applied to obtain estimators for the effects of covariates with censored observations. We show that the estimators are consistent and asymptotically normal. This transformation model, coupled with local linear approximation techniques, provides many alternatives to the more general proportional hazards models with nonparametric covariates.     

Dynamic Random Effects Models for Times Between Repeated Events

We consider recurrent event data when the duration or gap times between successive event occurrences are of intrinsic interest. Subject heterogeneity not attributed to observed covariates is usually handled by random effects which result in an exchangeable correlation structure for the gap times of a subject. Recently, efforts have been put into relaxing this restriction to allow non-exchangeable correlation. Here we consider dynamic models where random effects can vary stochastically over the gap times. We extend the traditional Gaussian variance components models and evaluate a previously proposed proportional hazards model through a simulation study and some examples. Besides, semiparametric estimation of the proportional hazards models is considered. Both models are easily used. The Gaussian models are easily interpreted in terms of the variance structure. On the other hand, the proportional hazards models would be more appropriate in the context of survival analysis, particularly in the interpretation of the regression parameters. They can be sensitive to the choice of model for random effects but not to the choice of the baseline hazard function.     

Estimation of Main Effect When Covariates Have Non-Proportional Hazards

The Cox proportional hazards (PH) regression model has been widely used to analyze survival data in clinical trials and observational studies. In addition to estimating the main treatment or exposure group effect, it is common to adjust for additional covariates using the Cox model. It is well known that violation of the PH assumption can lead to estimates that are biased and difficult to interpret, and model checking has become a routine procedure. However, such checking might focus on the primary group comparisons, and the assumption can still be violated when adjusting for many of the potential covariates. We study the effect of violation of the PH assumption of the covariates on the estimation of the main group effect in the Cox model. The results are summarized in terms of the bias and the coverage properties of the confidence intervals. Overall in randomized clinical trials, the bias caused by misspecifying the PH assumption on the covariates is no more than 15% in absolute value regardless of sample size. In observational studies where the covariates are likely correlated with the group variable, however, the bias can be very severe. The coverage properties largely depend on sample size, as expected, as bias becomes dominating with increasing sample size. These findings should serve as cautionary notes when adjusting for potential confounders in observational studies, as the violation of PH assumption on the confounders can lead to erroneous results.     

Estimating Regression Parameters in an Extended Proportional Odds Model

The proportional odds model may serve as a useful alternative to the Cox proportional hazards model to study association between covariates and their survival functions in medical studies. In this article, we study an extended proportional odds model that incorporates the so-called "external" time-varying covariates. In the extended model, regression parameters have a direct interpretation of comparing survival functions, without specifying the baseline survival odds function. Semiparametric and maximum likelihood estimation procedures are proposed to estimate the extended model. Our methods are demonstrated by Monte-Carlo simulations, and applied to a landmark randomized clinical trial of a short course Nevirapine (NVP) for mother-to-child transmission (MTCT) of human immunodeficiency virus type-1 (HIV-1). Additional application includes analysis of the well-known Veterans Administration (VA) Lung Cancer Trial.     

A regularized variable selection procedure in additive hazards model with stratified case-cohort design

Case-cohort designs are commonly used in large epidemiological studies to reduce the cost associated with covariate measurement. In many such studies the number of covariates is very large. An efficient variable selection method is needed for case-cohort studies where the covariates are only observed in a subset of the sample. Current literature on this topic has been focused on the proportional hazards model. However, in many studies the additive hazards model is preferred over the proportional hazards model either because the proportional hazards assumption is violated or the additive hazards model provides more relevent information to the research question. Motivated by one such study, the Atherosclerosis Risk in Communities (ARIC) study, we investigate the properties of a regularized variable selection procedure in stratified case-cohort design under an additive hazards model with a diverging number of parameters. We establish the consistency and asymptotic normality of the penalized estimator and prove its oracle property. Simulation studies are conducted to assess the finite sample performance of the proposed method with a modified cross-validation tuning parameter selection methods. We apply the variable selection procedure to the ARIC study to demonstrate its practical use.     

Mixture cure rate models with accelerated failures and nonparametric form of covariate effects

Two-component mixture cure rate model is popular in cure rate data analysis with the proportional hazards and accelerated failure time (AFT) models being the major competitors for modelling the latency component. [Wang, L., Du, P., and Liang, H. (2012), ‘Two-Component Mixture Cure Rate Model with Spline Estimated Nonparametric Components’, Biometrics, 68, 726–735] first proposed a nonparametric mixture cure rate model where the latency component assumes proportional hazards with nonparametric covariate effects in the relative risk. Here we consider a mixture cure rate model where the latency component assumes AFTs with nonparametric covariate effects in the acceleration factor. Besides the more direct physical interpretation than the proportional hazards, our model has an additional scalar parameter which adds more complication to the computational algorithm as well as the asymptotic theory. We develop a penalised EM algorithm for estimation together with confidence intervals derived from the Louis formula. Asymptotic convergence rates of the parameter estimates are established. Simulations and the application to a melanoma study shows the advantages of our new method.     

A fully nonparametric approach in survival models with explanatory variables

The most widely used model for multidimensional survival analysis is the Cox model. This model is semi-parametric, since its hazard function is the product of an unspecified baseline hazard, and a parametric functional form relating the hazard and the covariates. We consider a more flexible and fully nonparametric proportional hazards model, where the functional form of the covariates effect is left unspecified. In this model, estimation is based on the maximum likelihood method. Results obtained from a Monte-Carlo experiment and from real data are presented. Finally, the advantages and the limitations of the approacha are discussed.     

Confidence Bands for the Difference of Two Survival Curves Under Proportional Hazards Model

A common approach to testing for differences between the survival rates of two therapies is to use a proportional hazards regression model which allows for an adjustment of the two survival functions for any imbalance in prognostic factors in the comparison. When the relative risk of one treatment to the other is not constant over time the question of which therapy has a survival advantage is difficult to determine from the Cox model. An alternative approach to this problem is to plot the difference between the two predicted survival functions with a confidence band that provides information about when these two treatments differ. Such a band will depend on the covariate values of a given patient. In this paper we show how to construct a confidence band for the difference of two survival functions based on the proportional hazards model. A simulation approach is used to generate the bands. This approach is used to compare the survival probabilities of chemotherapy and allogeneic bone marrow transplants for chronic leukemia.     

Extended Hazard Regression Model for Reliability and Survival Analysis

We propose an extended hazard regression model which allows the spread parameter to be dependent on covariates. This allows a broad class of models which includes the most common hazard models, such as the proportional hazards model, the accelerated failure time model and a proportional hazards/accelerated failure time hybrid model with constant spread parameter. Simulations based on sub-classes of this model suggest that maximum likelihood performs well even when only small or moderate-size data sets are available and the censoring pattern is heavy. The methodology provides a broad framework for analysis of reliability and survival data. Two numerical examples illustrate the results.     

Semi-parametric survival analysis via Dirichlet process mixtures of the First Hitting Time model

Time-to-event data often violate the proportional hazards assumption inherent in the popular Cox regression model. Such violations are especially common in the sphere of biological and medical data where latent heterogeneity due to unmeasured covariates or time varying effects are common. A variety of parametric survival models have been proposed in the literature which make more appropriate assumptions on the hazard function, at least for certain applications. One such model is derived from the First Hitting Time (FHT) paradigm which assumes that a subject’s event time is determined by a latent stochastic process reaching a threshold value. Several random effects specifications of the FHT model have also been proposed which allow for better modeling of data with unmeasured covariates. While often appropriate, these methods often display limited flexibility due to their inability to model a wide range of heterogeneities. To address this issue, we propose a Bayesian model which loosens assumptions on the mixing distribution inherent in the random effects FHT models currently in use. We demonstrate via simulation study that the proposed model greatly improves both survival and parameter estimation in the presence of latent heterogeneity. We also apply the proposed methodology to data from a toxicology/carcinogenicity study which exhibits nonproportional hazards and contrast the results with both the Cox model and two popular FHT models.

     

Model diagnostics for the proportional hazards model with length-biased data

Length-biased data are frequently encountered in prevalent cohort studies. Many statistical methods have been developed to estimate the covariate effects on the survival outcomes arising from such data while properly adjusting for length-biased sampling. Among them, regression methods based on the proportional hazards model have been widely adopted. However, little work has focused on checking the proportional hazards model assumptions with length-biased data, which is essential to ensure the validity of inference. In this article, we propose a statistical tool for testing the assumed functional form of covariates and the proportional hazards assumption graphically and analytically under the setting of length-biased sampling, through a general class of multiparameter stochastic processes. The finite sample performance is examined through simulation studies, and the proposed methods are illustrated with the data from a cohort study of dementia in Canada.

     

IMPORTANCE BOOTSTRAP RESAMPLING FOR PROPORTIONAL HAZARDS REGRESSION

Importance resampling is an approach that uses exponential tilting to reduce the resampling necessary for the construction of nonparametric bootstrap confidence intervals. The properties of bootstrap importance confidence intervals are well established when the data is a smooth function of means and when there is no censoring. However, in the framework of survival or time-to-event data, the asymptotic properties of importance resampling have not been rigorously studied, mainly because of the unduly complicated theory incurred when data is censored. This paper uses extensive simulation to show that, for parameter estimates arising from fitting Cox proportional hazards models, importance bootstrap confidence intervals can be constructed if the importance resampling probabilities of the records for the n individuals in the study are determined by the empirical influence function for the parameter of interest. Our results show that, compared to uniform resampling, importance resampling improves the relative mean-squared-error (MSE) efficiency by a factor of nine (for n = 200). The efficiency increases significantly with sample size, is mildly associated with the amount of censoring, but decreases slightly as the number of bootstrap resamples increases. The extra CPU time requirement for calculating importance resamples is negligible when compared to the large improvement in MSE efficiency. The method is illustrated through an application to data on chronic lymphocytic leukemia, which highlights that the bootstrap confidence interval is the preferred alternative to large sample inferences when the distribution of a specific covariate deviates from normality. Our results imply that, because of its computational efficiency, importance resampling is recommended whenever bootstrap methodology is implemented in a survival framework. Its use is particularly important when complex covariates are involved or the survival problem to be solved is part of a larger problem; for instance, when determining confidence bounds for models linking survival time with clusters identified in gene expression microarray data.     

Parameter Orthogonality in Mixed Regression Models for Survival Data

The implications of parameter orthogonality for the robustness of survival regression models are considered. The question of which of the proportional hazards or the accelerated life families of models would be more appropriate for analysis is usually ignored, and the proportional hazards family is applied, particularly in medicine, for convenience. Accelerated life models have conventionally been used in reliability applications. We propose a one-parameter family mixture survival model which includes both the accelerated life and the proportional hazards models. By orthogonalizing relative to the mixture parameter, we can show that, for small effects of the covariates, the regression parameters under the alternative families agree to within a constant. This recovers a known misspecification result. We use notions of parameter orthogonality to explore robustness to other types of misspecification including misspecified base-line hazards. The results hold in the presence of censoring. We also study the important question of when proportionality matters.