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.     

Evolution of recurrent asthma event rate over time in frailty models

Summary. To model the time evolution of the event rate in recurrent event data a crucial role is played by the timescale that is used. Depending on the timescale selected the interpretation of the time evolution will be entirely different, both in parametric and semiparametric frailty models. The gap timescale is more appropriate when studying the recurrent event rate as a function of time since the last event, whereas the calendar timescale keeps track of actual time. We show both timescales in action on data from an asthma prevention trial in young children. The frailty model is further extended to include both timescales simultaneously as this might be most relevant in practice.     

Modelling conditional distributions in bivariate survival

Conditional distributions for bivariate survival can be obtained via a model for the joint distribution, or, as has sometimes been suggested, by modelling the conditioned variable directly, with the conditioning variable included as a covariate. A quantitative comparison of estimated covariate effects and predictive distributions under the two approaches is given. The results are illustrated in a novel frailty application.     

Exploring the Clustering Effect of the Frailty Survival Model by Means of the Brier Score

In this article, the Brier score is used to investigate the importance of clustering for the frailty survival model. For this purpose, two versions of the Brier score are constructed, i.e., a “conditional Brier score” and a “marginal Brier score.” Both versions of the Brier score show how the clustering effects and the covariate effects affect the predictive ability of the frailty model separately. Using a Bayesian and a likelihood approach, point estimates and 95% credible/confidence intervals are computed. The estimation properties of both procedures are evaluated in an extensive simulation study for both versions of the Brier score. Further, a validation strategy is developed to calculate an internally validated point estimate and credible/confidence interval. The ensemble of the developments is applied to a dental dataset.     

Bayesian Versus Frequentist Approach of the Frailty Cox Model,Application to Calf Gastroenteritis

In the frailty Cox model, frequentist approaches often present problems of numerical resolution, convergence, and variance calculation. The Bayesian approach offers an alternative. The goal of this study was to compare, using real (calf gastroenteritis) and simulated data, the results obtained with the MCMC method used in the Bayesian approach versus two frequentist approaches: the Newton–Raphson algorithm to solve a penalized likelihood and the EM algorithm. The results obtained showed that when the number of groups in the population decreases, the Bayesian approach gives a less biased estimation of the frailty variance and of the group fixed effect than the frequentist approaches.     

Comparative Studies on Frailties in Survival Analysis

A mixed survival function is derived through proportional hazards model assuming Gamma or Inverse Gaussian frailty under Weibull baseline via Bayesian approach, and the maximum likelihood estimation (MLE) is proposed to estimate the parameters in the population. Through intensive simulations designed to generate right-censored data from the proposed survival function, we compare the MLE in this article with Cox estimates (in many different versions) for the covariate coefficient. Finally, the proposed survival model is applied to fit Leukemia data from Cox and Oakes (1992 Cox , D. R. , Oakes , D. ( 1992 ). Analysis of Survival Data . London : Chapman & Hall . [Google Scholar]).     

Validation of prognostic indices using the frailty model

A major issue when proposing a new prognostic index is its generalisibility to daily clinical practice. Validation is therefore required. Most validation techniques assess whether “on average” the results obtained by the prognostic index in classifying patients in a new sample of patients are similar to the results obtained in the construction set. We introduce a new important aspect of the generalisibility of a prognostic index: the heterogeneity of the prognostic index risk group hazard ratios over different centers. If substantial variability between centers exists, the prognostic index may have no discriminatory capability in some of the centers. To model such heterogeneity, we use a frailty model including a random center effect and a random prognostic index by center interaction. Statistical inference is based on a Bayesian approach using a Laplacian approximation for the marginal posterior distribution of the variances of the random effects. We investigate different ways to summarize the information available from this marginal posterior distribution. Our approach is applied to a real bladder cancer database for which we demonstrate how to investigate and interpret heterogeneity in prognostic index effect over centers.     

Semiparametric inference for a general class of models for recurrent events

Procedures for estimating the parameters of the general class of semiparametric models for recurrent events proposed by Peña and Hollander [(2004). Models for recurrent events in reliability and survival analysis. In: Soyer R., Mazzuchi T., Singpurwalla N. (Eds.), Mathematical Reliability: An Expository Perspective. Kluwer Academic Publishers, Dordrecht, pp. 105–123 (Chapter 6)] are developed. This class of models incorporates an effective age function encoding the effect of changes after each event occurrence such as the impact of an intervention, it models the impact of accumulating event occurrences on the unit, it admits a link function in which the effect of possibly time-dependent covariates are incorporated, and it allows the incorporation of unobservable frailty components which induce dependencies among the inter-event times for each unit. The estimation procedures are semiparametric in that a baseline hazard function is nonparametrically specified. The sampling distribution properties of the estimators are examined through a simulation study, and the consequences of mis-specifying the model are analyzed. The results indicate that the flexibility of this general class of models provides a safeguard for analyzing recurrent event data, even data possibly arising from a frailty-less mechanism. The estimation procedures are applied to real data sets arising in the biomedical and public health settings, as well as from reliability and engineering situations. In particular, the procedures are applied to a data set pertaining to times to recurrence of bladder cancer and the results of the analysis are compared to those obtained using three methods of analyzing recurrent event data.