Joint modeling of longitudinal and survival data has received much attention and is becoming increasingly useful. In clinical studies, longitudinal biomarkers are used to monitor disease progression and to predict survival. These longitudinal measures are often missing at failure times and may be prone to measurement errors. In previous studies these two types of data are frequently analyzed separately where a mixed effects model is used for longitudinal data and a survival model is applied to event outcomes. The argument in favor of a joint model has been the efficient use of the data as the survival information goes into modeling the longitudinal process and vice versa. In this thesis, we present joint maximum likelihood methods, a two stage approach and time dependent covariate methods that link longitudinal data to survival data. First, we use simulation studies to explore and assess the performance of these methods with bias, accuracy and coverage probabilities. Then, we focus on four time dependent methods considering models that are unadjusted and adjusted for time. Finally, we consider mediation analysis for longitudinal and survival data. Mediation analysis is introduced and applied in a research framework based on genetic variants, longitudinal measures and disease risk. We implement accelerated failure time regression using the joint maximum likelihood approach (AFT-joint) and an accelerated failure time regression model using the observed longitudinal measures as time dependent covariates (AFT-observed) to assess the mediated effect. We found that the two stage approach (TSA) performed best at estimating the link parameter. The joint maximum likelihood methods that used the predicted values of the longitudinal measures, similar to the TSA, provided larger estimates. The time dependent covariate methods that used the observed longitudinal measures in the survival analysis underestimated the true estimates. The mediation results showed that the AFT-joint and the AFT-observed underestimated the mediated effect. Comparison of the methods in Framingham Heart Study data revealed similar patterns. We recommend adjusting for time when estimating the association parameter in time dependent Cox and logistic models. Additional work is needed for estimating the mediated effect with longitudinal and survival data.

Generalized estimating equations (GEE) are popularly utilized for the marginal analysis of longitudinal data. In order to obtain consistent regression parameter estimates, these estimating equations must be unbiased. However, when certain types of time-dependent covariates are presented, these equations can be biased unless an independence working correlation structure is employed. Moreover, in this case regression parameter estimation can be very inefficient because not all valid moment conditions are incorporated within the corresponding estimating equations. Therefore, approaches using the generalized method of moments or quadratic inference functions have been proposed for utilizing all valid moment conditions. However, we have found that such methods will not always provide valid inference and can also be improved upon in terms of finite-sample regression parameter estimation. Therefore, we propose a modified GEE approach and a selection method that will both ensure the validity of inference and improve regression parameter estimation. In addition, these modified approaches assume the data analyst knows the type of time-dependent covariate, although this likely is not the case in practice. Whereas hypothesis testing has been used to determine covariate type, we propose a novel strategy to select a working covariate type in order to avoid potentially high type II error rates with these hypothesis testing procedures. Parameter estimates resulting from our proposed method are consistent and have overall improved mean squared error relative to hypothesis testing approaches. Finally, for some real-world examples the use of mean regression models may be sensitive to skewness and outliers in the data. Therefore, we extend our approaches from their use with marginal quantile regression to modeling the conditional quantiles of the response variable. Existing and proposed methods are compared in simulation studies and application examples.

Dans le contexte de la modélisation aléatoire des événements récurrents, un modèle statistique particulier est exploré. Ce modèle est fondé sur la théorie des processus de comptage et est construit dans le cadre d'analyse de défaillances dans les réseaux d'eau. Dans ce domaine nous disposons de données sur de nombreux systèmes observés durant une certaine période de temps. Les systèmes étant posés à des instants différents, leur âge est utilisé en tant qu'échelle temporelle dans la modélisation. Le modèle tient compte de l'historique incomplet d'événements, du vieillissement des systèmes, de l'impact négatif des défaillances précédentes sur l'état des systèmes et des covariables. Le modèle est positionné parmi d'autres approches visant à l'analyse d'événements récurrents utilisées en biostatistique et en fiabilité. Les paramètres du modèle sont estimés par la méthode du Maximum de Vraisemblance (MV). Une covariable dépendante du temps est intégrée au modèle. Il est supposé qu'elle est extérieure au processus de défaillance et constante par morceaux. Des méthodes heuristiques sont proposées afin de tenir compte de cette covariable lorsqu'elle n'est pas observée. Des méthodes de simulation de données artificielles et des estimations en présence de la covariable temporelle sont proposées. Les propriétés de l'estimateur (la normalité, le biais, la variance) sont étudiées empiriquement par la méthode de Monte Carlo. L'accent est mis sur la présence de deux directions asymptotiques : asymptotique en nombre de systèmes n et asymptotique en durée d'observation T. Le comportement asymptotique de l'estimateur MV constaté empiriquement est conforme aux résultats théoriques classiques. Il s'agit de l'asymptotique en n. Le comportement T-asymptotique constaté empiriquement n'est pas classique. L'analyse montre également que les deux directions asymptotiques n et T peuvent être combinées en une unique direction : le nombre d'événements observés. Cela concerne les paramètres classiques du modèle (les coefficients associés aux covariables fixes et le paramètre caractérisant le vieillissement des systèmes). Ce n'est en revanche pas le cas pour le coefficient associé à la covariable temporelle et pour le paramètre caractérisant l'impact négatif des défaillances précédentes sur le comportement futur du système. La méthodologie développée est appliquée à l'analyse des défaillances des réseaux d'eau. L'influence des variations climatiques sur l'intensité de défaillance est prise en compte par une covariable dépendante du temps. Les résultats montrent globalement une amélioration des prédictions du comportement futur du processus lorsque la covariable temporelle est incluse dans le modèle. / In the context of stochastic modeling of recurrent events, a particular model is explored. This model is based on the counting process theory and is built to analyze failures in water distribution networks. In this domain the data on a large number of systems observed during a certain time period are available. Since the systems are installed at different dates, their age is used as a time scale in modeling. The model accounts for incomplete event history, aging of systems, negative impact of previous failures on the state of systems and for covariates.The model is situated among other approaches to analyze the recurrent events, used in biostatistics and in reliability. The model parameters are estimated by the Maximum Likelihood method (ML). A method to integrate a time-dependent covariate into the model is developed. The time-dependent covariate is assumed to be external to the failure process and to be piecewise constant. Heuristic methods are proposed to account for influence of this covariate when it is not observed. Methods for data simulation and for estimations in presence of the time-dependent covariate are proposed. A Monte Carlo study is carried out to empirically assess the ML estimator's properties (normality, bias, variance). The study is focused on the doubly-asymptotic nature of data: asymptotic in terms of the number of systems n and in terms of the duration of observation T. The asymptotic behavior of the ML estimator, assessed empirically agrees with the classical theoretical results for n-asymptotic behavior. The T-asymptotics appears to be less typical. It is also revealed that the two asymptotic directions, n and T can be combined into one unique direction: the number of observed events. This concerns the classical model parameters (the coefficients associated to fixed covariates, the parameter characterizing aging of systems). The presence of one unique asymptotic direction is not obvious for the time-dependent covariate coefficient and for a parameter characterizing the negative impact of previous events on the future behavior of a system.The developed methodology is applied to the analysis of failures of water networks. The influence of climatic variations on failure intensity is assessed by a time-dependent covariate. The results show a global improvement in predictions of future behavior of the process when the time-dependent covariate is included into the model.