Non-parametric competing risks with multivariate frailty models

This research focuses on two theories: (i) competing risks and (ii) random eect (frailty) models. The theory of competing risks provides a structure for inference in problems where cases are subject to several types of failure. Random eects in competing risk models consist of two underlying distributions: the conditional distribution of the response variables, given the random eect, depending on the explanatory variables each with a failure type specic random eect; and the distribution of the random eect. In this situation, the distribution of interest is the unconditional distribution of the response variable, which may or may not have a tractable form. The parametric competing risk model, in which it is assumed that the failure times are coming from a known distribution, is widely used such as Weibull, Gamma and other distributions. The Gamma distribution has been widely used as a frailty distribution, perhaps due to its simplicity since it has a closed form expression of the unconditional hazard function. However, it is unrealistic to believe that a few parametric models are suitable for all types of failure time. This research focuses on a distribution free of the multivariate frailty models. Another approach used to overcome this problem is using nite mixture of parametric frailty especially those who have a closed form of unconditional survival function. In addition, the advantages and disadvantages of a parametric competing risk models with multivariate parametric and/or non-parametric frailty (correlated random eects) are investigated. In this research, four main models are proposed: rst, an application of a new computation and analysis of a multivariate frailty with competing risk model using Cholesky decomposition of the Lognormal frailty. Second, a correlated Inverse Gaussian frailty in the presence of competing risks model. Third, a non-parametric multivariate frailty with parametric competing risk model is proposed. Finally, a simulation study of nite mixture of Inverse Gaussian frailty showed the ability of this model to t dierent frailty distribution. One main issue in multivariate analysis is the time it needs to t the model. The proposed non-parametric model showed a signicant time decrease in estimating the model parameters (about 80% less time compared the Log-Normal frailty with nested loops). A real data of recurrence of breast cancer is used as the applications of these models

Inference in Mixed Proportional Hazard Models with K Random Effects

A general formulation of Mixed Proportional Hazard models with K random effects is provided. It enables to account for a population stratified at K different levels. We then show how to approximate the partial maximum likelihood estimator using an EM algorithm. In a Monte Carlo study, the behavior of the estimator is assessed and I provide an application to the ratification of ILO conventions. Compared to other procedures, the results indicate an important decrease in computing time, as well as improved convergence and stability.EM algorithm, penalized likelihood, partial likelihood, frailties.

Frailty multi-state models for the analysis of survival data from multicenter clinical trials

Proportional hazards models are among the most popular regression models in survival analysis. Multi-state models generalise them in the sense of jointly considering different types of events along with their interrelations, whereas frailty models introduce random effects to account for unobserved risk factors, possibly shared by groups of subjects. The integration of frailty and multi-state methodology is interesting to control for unobserved heterogeneity in presence of complex event history structures, particularly appealing in multicenter clinical trials applications. In the present thesis we propose the incorporation of nested frailties in the transition-specific hazard function; then, we develop and evaluate both parametric and semi-parametric inference. Simulation studies, performed thanks to an innovative method for generating dependent multi-state survival data, show that parametric inference is correct but extremely imprecise, whilst semiparametric methods are very competitive to evaluate the effect of covariates. Two case studies are presented, relative to cancer multicenter clinical trials. The multi-state nature of the models allows to study the treatment effect taking into account intermediate events, while the presence of frailties reduces the attenuation effect due to clustering. Finally, we present two new software tools, one to fit parametric frailty models with up to twenty possible combinations of baseline and frailty distributions, and one implementing semiparametric inference for multilevel frailty models, essential to fit the new nested frailty multi-state models

Semiparametric estimation with clustered right censored data via multivariate gaussian random fields

Consider a fixed number of clustered areas identified by their geographical coordinate that are monitored for the occurrences of an event such as pandemic, epidemic, migration to name a few. Data collected on units at all areas include time varying covariates and other environmental factors that may affect event occurrences. The event times in every area can be independent. They can also be correlated with correlation between two units induced by an unobservable frailty. In both cases, the collected data is considered pairwise to account for spatial correlation between all pair of areas. The pairwise right censored data is probit-transformed yielding a multivariate Gaussian random field preserving the spatial correlation function. The data is analyzed using counting process and geostatistical formulation that led to a class of weighted pairwise semiparametric estimating functions. In the independence case, estimators of models unknowns are shown to be consistent and asymptotically normally distributed under infill-type spatial statistics asymptotic. Detailed small sample numerical studies that are in agreement with the theoretical results are provided in the independence case. In the dependence case, the estimators are shown to be inefficiency when the dependence is ignored. The foregoing procedures are applied to Leukemia survival data in Northeast England--Abstract, page iv