This thesis focuses on development of spline-based hazard estimation models for cure rate data. Such data can be found in survival studies with long term survivors. Consequently, the population consists of the susceptible and non-susceptible sub-populations with the latter termed as "cured". The modeling of both the cure probability and the hazard function of the susceptible sub-population is of practical interest. Here we propose two smoothing-splines based models falling respectively into the popular classes of two component mixture cure rate models and promotion time cure rate models. Under the framework of two component mixture cure rate model, Wang, Du and Liang (2012) have developed a nonparametric model where the covariate effects on both the cure probability and the hazard component are estimated by smoothing splines. Our first development falls under the same framework but estimates the hazard component based on the accelerated failure time model, instead of the proportional hazards model in Wang, Du and Liang (2012). Our new model has better interpretation in practice. The promotion time cure rate model, motivated from a simplified biological interpretation of cancer metastasis, was first proposed only a few decades ago. Nonetheless, it has quickly become a competitor to the mixture models. Our second development aims to provide a nonparametric alternative to the existing parametric or semiparametric promotion time models. / Ph. D.

I have developed time-varying coefficient models for recurrent event data to evaluate the temporal profiles for recurrence rate and covariate effects. There are three major parts in this dissertation. The first two parts propose a mixed Poisson process model with gamma frailties for single type recurrent events. The third part proposes a Bayesian joint model based on multivariate log-normal frailties for multi-type recurrent events. In the first part, I propose an approach based on penalized B-splines to obtain smooth estimation for both time-varying coefficients and the log baseline intensity. An EM algorithm is developed for parameter estimation. One issue with this approach is that the estimating procedure is conditional on smoothing parameters, which have to be selected by cross-validation or optimizing certain performance criterion. The procedure can be computationally demanding with a large number of time-varying coefficients. To achieve objective estimation of smoothing parameters, I propose a mixed-model representation approach for penalized splines. Spline coefficients are treated as random effects and smoothing parameters are to be estimated as variance components. An EM algorithm embedded with penalized quasi-likelihood approximation is developed to estimate the model parameters. The third part proposes a Bayesian joint model with time-varying coefficients for multi-type recurrent events. Bayesian penalized splines are used to estimate time-varying coefficients and the log baseline intensity. One challenge in Bayesian penalized splines is that the smoothness of a spline fit is considerably sensitive to the subjective choice of hyperparameters. I establish a procedure to objectively determine the hyperparameters through a robust prior specification. A Markov chain Monte Carlo procedure based on Metropolis-adjusted Langevin algorithms is developed to sample from the high-dimensional distribution of spline coefficients. The procedure includes a joint sampling scheme to achieve better convergence and mixing properties. Simulation studies in the second and third part have confirmed satisfactory model performance in estimating time-varying coefficients under different curvature and event rate conditions. The models in the second and third part were applied to data from a commercial truck driver naturalistic driving study. The application results reveal that drivers with 7-hours-or-less sleep prior to a shift have a significantly higher intensity after 8 hours of on-duty driving and that their intensity remains higher after taking a break. In addition, the results also show drivers' self-selection on sleep time, total driving hours in a shift, and breaks. These applications provide crucial insight into the impact of sleep time on driving performance for commercial truck drivers and highlights the on-road safety implications of insufficient sleep and breaks while driving. This dissertation provides flexible and robust tools to evaluate the temporal profile of intensity for recurrent events. / PHD / The overall objective of this dissertation is to develop models to evaluate the time-varying profiles for event occurrences and the time-varying effects of risk factors upon event occurrences. There are three major parts in this dissertation. The first two parts are designed for single event type. They are based on approaches such that the whole model is conditional on a certain kind of tuning parameter. The value of this tuning parameter has to be pre-specified by users and is influential to the model results. Instead of pre-specifying the value, I develop an approach to achieve an objective estimate for the optimal value of tuning parameter and obtain model results simultaneously. The third part proposes a model for multi-type events. One challenge is that the model results are considerably sensitive to the subjective choice of hyperparameters. I establish a procedure to objectively determine the hyperparameters. Simulation studies have confirmed satisfactory model performance in estimating the temporal profiles for both event occurrences and effects of risk factors. The models were applied to data from a commercial truck driver naturalistic driving study. The results reveal that drivers with 7-hours-or-less sleep prior to a shift have a significantly higher intensity after 8 hours of on-duty driving and that their driving risk remains higher after taking a break. In addition, the results also show drivers’ self-selection on sleep time, total driving hours in a shift, and breaks. These applications provide crucial insight into the impact of sleep time on driving performance for commercial truck drivers and highlights the on-road safety implications of insufficient sleep and breaks while driving. This dissertation provides flexible and robust tools to evaluate the temporal profile of both event occurrences and effects of risk factors.

L'incidence de l'infection par le VIH, définie comme le nombre de sujets nouvellement infectés par le VIH au cours du temps, est le seul indicateur permettant réellement d'appréhender la dynamique de l'épidémie du VIH/SIDA. Sa connaissance permet de prévoir les conséquences démographiques de l'épidémie et les besoins futurs de prise en charge, mais également d'évaluer l'efficacité des programmes de prévention. Jusqu'à très récemment, l'idée de base pour estimer l'incidence de l'infection par le VIH a été d'utiliser la méthode de rétro-calcul à partir des données de l'incidence du SIDA et de la connaissance de la distribution de la durée d'incubation du SIDA. L'avènement, à partir de 1996, de nouvelles combinaisons thérapeutiques très efficaces contre le VIH a contribué à modifier la durée d'incubation du SIDA et, par conséquent, à augmenter la difficulté d'utilisation de la méthode de rétro-calcul sous sa forme classique. Plus récemment, l'idée d'intégrer des informations sur les dates de diagnostic VIH a permis d'améliorer la précision des estimations. La plupart des pays occidentaux ont mis en place depuis quelques années un système de surveillance de l'infection à VIH. En France, la notification obligatoire des nouveaux diagnostics d'infection VIH, couplée à la surveillance virologique permettant de distinguer les contaminations récentes des plus anciennes a été mise en place en mars 2003. L'objectif de ce travail de thèse est de développer de nouvelles méthodes d'estimation de l'incidence de l'infection par le VIH capables de combiner les données de surveillance des diagnostics VIH et SIDA et d'utiliser les marqueurs sérologiques recueillis dans la surveillance virologique dans le but de mieux saisir l'évolution de l'épidémie dans les périodes les plus récentes. / The knowledge of the dynamics of the HIV/AIDS epidemic is crucial for planning current and future health care needs. The HIV incidence, i.e. the number of new HIV infections over time, determines the trajectory and the extent of the epidemic but is difficult to measure. The backcalculation method has been widely developed and used to estimate the past pattern of HIV infections and to project future incidence of AIDS from information on the incubation period distribution and AIDS incidence data. In recent years the incubation period from HIV infection to AIDS has changed dramatically due to increased use of antiretroviral therapy, which lengthens the time from HIV infection to the development of AIDS. Therefore, it has become more difficult to use AIDS diagnosis as the basis for back-calculation. More recently, the idea of integrating information on the dates of HIV diagnosis has improved the precision of estimates. In recent years, most western countries have set up a system for monitoring HIV infection. In France, the mandatory reporting of newly diagnosed HIV infection, coupled with virological surveillance to distinguish recent infections from older, was introduced in March 2003. The goal of this PhD thesis is to develop new methods for estimating the HIV incidence able to combine data from monitoring HIV and AIDS diagnoses and use of serologic markers collected in the virological surveillance in order to better understand the evolution of the epidemic in the most recent periods.

In this dissertation, we approach three different contributions in measurement error model (MEM). Initially, we carry out maximum penalized likelihood inference in MEMs under the normality assumption. The methodology is based on the method proposed by Firth (1993), which can be used to improve some asymptotic properties of the maximum likelihood estimators. In the second contribution, we develop two new estimation methods based on generalized fiducial inference for the precision parameters and the variability product under the Grubbs model considering the two-instrument case. One method is based on a fiducial generalized pivotal quantity and the other one is built on the method of the generalized fiducial distribution. Comparisons with two existing approaches are reported. Finally, we propose to study inference in a heteroscedastic MEM with known error variances. Instead of the normal distribution for the random components, we develop a model that assumes a skew-t distribution for the true covariate and a centered Students t distribution for the error terms. The proposed model enables to accommodate skewness and heavy-tailedness in the data, while the degrees of freedom of the distributions can be different. We use the maximum likelihood method to estimate the model parameters and compute them via an EM-type algorithm. All proposed methodologies are assessed numerically through simulation studies and illustrated with real datasets extracted from the literature. / Neste trabalho abordamos três contribuições diferentes em modelos com erros de medição (MEM). Inicialmente estudamos inferência pelo método de máxima verossimilhança penalizada em MEM sob a suposição de normalidade. A metodologia baseia-se no método proposto por Firth (1993), o qual pode ser usado para melhorar algumas propriedades assintóticas de os estimadores de máxima verossimilhança. Em seguida, propomos construir dois novos métodos de estimação baseados na inferência fiducial generalizada para os parâmetros de precisão e a variabilidade produto no modelo de Grubbs para o caso de dois instrumentos. O primeiro método é baseado em uma quantidade pivotal generalizada fiducial e o outro é baseado no método da distribuição fiducial generalizada. Comparações com duas abordagens existentes são reportadas. Finalmente, propomos estudar inferência em um MEM heterocedástico em que as variâncias dos erros são consideradas conhecidas. Nós desenvolvemos um modelo que assume uma distribuição t-assimétrica para a covariável verdadeira e uma distribuição t de Student centrada para os termos dos erros. O modelo proposto permite acomodar assimetria e cauda pesada nos dados, enquanto os graus de liberdade das distribuições podem ser diferentes. Usamos o método de máxima verossimilhança para estimar os parâmetros do modelo e calculá-los através de um algoritmo tipo EM. Todas as metodologias propostas são avaliadas numericamente em estudos de simulação e são ilustradas com conjuntos de dados reais extraídos da literatura

Nesta dissertação apresentamos métodos de diagnóstico em modelos semiparamétricos sob erros normais, em especial os modelos semiparamétricos com uma variável explicativa não paramétrica, conhecidos como modelos lineares parciais. São utilizados splines cúbicos para o ajuste da variável resposta e são aplicadas funções de verossimilhança penalizadas para a obtenção dos estimadores de máxima verossimilhança com os respectivos erros padrão aproximados. São derivadas também as propriedades da matriz hat para esse tipo de modelo, com o objetivo de utilizá-la como ferramenta na análise de diagnóstico. Gráficos normais de probabilidade com envelope gerado também foram adaptados para avaliar a adequabilidade do modelo. Finalmente, são apresentados dois exemplos ilustrativos em que os ajustes são comparados com modelos lineares normais usuais, tanto no contexto do modelo aditivo normal simples como no contexto do modelo linear parcial. / In this master dissertation we present diagnostic methods in semiparametric models under normal errors, specially in semiparametric models with one nonparametric explanatory variable, also known as partial linear model. We use cubic splines for the nonparametric fitting, and penalized likelihood functions are applied for obtaining maximum likelihood estimators with their respective approximate standard errors. The properties of the hat matrix are also derived for this kind of model, aiming to use it as a tool for diagnostic analysis. Normal probability plots with simulated envelope graphs were also adapted to evaluate the model suitability. Finally, two illustrative examples are presented, in which the fits are compared with usual normal linear models, such as simple normal additive and partially linear models.

Neste trabalho estendemos os modelos mistos semiparamétricos propostos por Zhang et al. (1998) para uma classe mais geral de modelos, a qual denominamos modelos mistos aditivos semiparamétricos com erros de contornos elípticos. Com essa nova abordagem, flexibilizamos a curtose da distribuição dos erros possibilitando a escolha de distribuições com caudas mais leves ou mais pesadas do que as caudas da distribuição normal padrão. Funções de verossimilhança penalizadas são aplicadas para a obtenção das estimativas de máxima verossimilhança com os respectivos erros padrão aproximados. Essas estimativas, sob erros de caudas pesadas, são robustas no sentido da distância de Mahalanobis contra observações aberrantes. Curvaturas de influência local são obtidas segundo alguns esquemas de perturbação e gráficos de diagnóstico são propostos. Exemplos ilustrativos são apresentados em que ajustes sob erros normais são comparados, através das metodologias de sensibilidade desenvolvidas no trabalho, com ajustes sob erros de contornos elípticos. / In this work we extend the models proposed by Zhang et al. (1998) to a more general class of models, know as semiparametric additive mixed models with elliptical errors in order to allow distributions with heavier or lighter tails than the normal ones. Penalized likelihood equations are applied to derive the maximum likelihood estimates which appear to be robust against outlying observations in the sense of the Mahalanobis distance. In order to study the sensitivity of the penalized estimates under some usual perturbation schemes in the model or data, the local influence curvatures are derived and some diagnostic graphics are proposed. Motivating examples preliminary analyzed under normal errors are reanalyzed under some appropriate elliptical errors. The local influence approach is used to compare the sensitivity of the model estimates.

Neste trabalho estendemos os modelos mistos semiparamétricos propostos por Zhang et al. (1998) para uma classe mais geral de modelos, a qual denominamos modelos mistos aditivos semiparamétricos com erros de contornos elípticos. Com essa nova abordagem, flexibilizamos a curtose da distribuição dos erros possibilitando a escolha de distribuições com caudas mais leves ou mais pesadas do que as caudas da distribuição normal padrão. Funções de verossimilhança penalizadas são aplicadas para a obtenção das estimativas de máxima verossimilhança com os respectivos erros padrão aproximados. Essas estimativas, sob erros de caudas pesadas, são robustas no sentido da distância de Mahalanobis contra observações aberrantes. Curvaturas de influência local são obtidas segundo alguns esquemas de perturbação e gráficos de diagnóstico são propostos. Exemplos ilustrativos são apresentados em que ajustes sob erros normais são comparados, através das metodologias de sensibilidade desenvolvidas no trabalho, com ajustes sob erros de contornos elípticos. / In this work we extend the models proposed by Zhang et al. (1998) to a more general class of models, know as semiparametric additive mixed models with elliptical errors in order to allow distributions with heavier or lighter tails than the normal ones. Penalized likelihood equations are applied to derive the maximum likelihood estimates which appear to be robust against outlying observations in the sense of the Mahalanobis distance. In order to study the sensitivity of the penalized estimates under some usual perturbation schemes in the model or data, the local influence curvatures are derived and some diagnostic graphics are proposed. Motivating examples preliminary analyzed under normal errors are reanalyzed under some appropriate elliptical errors. The local influence approach is used to compare the sensitivity of the model estimates.

Nesta dissertação apresentamos métodos de diagnóstico em modelos semiparamétricos sob erros normais, em especial os modelos semiparamétricos com uma variável explicativa não paramétrica, conhecidos como modelos lineares parciais. São utilizados splines cúbicos para o ajuste da variável resposta e são aplicadas funções de verossimilhança penalizadas para a obtenção dos estimadores de máxima verossimilhança com os respectivos erros padrão aproximados. São derivadas também as propriedades da matriz hat para esse tipo de modelo, com o objetivo de utilizá-la como ferramenta na análise de diagnóstico. Gráficos normais de probabilidade com envelope gerado também foram adaptados para avaliar a adequabilidade do modelo. Finalmente, são apresentados dois exemplos ilustrativos em que os ajustes são comparados com modelos lineares normais usuais, tanto no contexto do modelo aditivo normal simples como no contexto do modelo linear parcial. / In this master dissertation we present diagnostic methods in semiparametric models under normal errors, specially in semiparametric models with one nonparametric explanatory variable, also known as partial linear model. We use cubic splines for the nonparametric fitting, and penalized likelihood functions are applied for obtaining maximum likelihood estimators with their respective approximate standard errors. The properties of the hat matrix are also derived for this kind of model, aiming to use it as a tool for diagnostic analysis. Normal probability plots with simulated envelope graphs were also adapted to evaluate the model suitability. Finally, two illustrative examples are presented, in which the fits are compared with usual normal linear models, such as simple normal additive and partially linear models.

<p>This thesis concerns different aspects of dating divergence times in phylogenetic trees, using molecular data and multiple fossil age constraints.</p><p>Datings of phylogenetically basal eudicots, monocots and modern birds (Neoaves) are presented. Large phylograms and multiple fossil constraints were used in all these studies. Eudicots and monocots are suggested to be part of a rapid divergence of angiosperms in the Early Cretaceous, with most families present at the Cretaceous/Tertiary boundary. Stem lineages of Neoaves were present in the Late Cretaceous, but the main divergence of extant families took place around the Cre-taceous/Tertiary boundary.</p><p>A novel method and computer software for dating large phylogenetic trees, PATHd8, is presented. PATHd8 is a nonparametric smoothing method that smoothes one pair of sister groups at a time, by taking the mean of the added branch lengths from a terminal taxon to a node. Because of the local smoothing, the algorithm is simple, hence providing stable and very fast analyses, allowing for thousands of taxa and an arbitrary number of age constraints.</p><p>The importance of fossil constraints and their placement are discussed, and concluded to be the most important factor for obtaining reasonable age estimates.</p><p>Different dating methods are compared, and it is concluded that differences in age estimates are obtained from penalized likelihood, PATHd8, and the Bayesian autocorrelation method implemented in the multidivtime program. In the Bayesian method, prior assumptions about evolutionary rate at the root, rate variance and the level of rate smoothing between internal edges, are suggested to influence the results.</p>

This thesis concerns different aspects of dating divergence times in phylogenetic trees, using molecular data and multiple fossil age constraints. Datings of phylogenetically basal eudicots, monocots and modern birds (Neoaves) are presented. Large phylograms and multiple fossil constraints were used in all these studies. Eudicots and monocots are suggested to be part of a rapid divergence of angiosperms in the Early Cretaceous, with most families present at the Cretaceous/Tertiary boundary. Stem lineages of Neoaves were present in the Late Cretaceous, but the main divergence of extant families took place around the Cre-taceous/Tertiary boundary. A novel method and computer software for dating large phylogenetic trees, PATHd8, is presented. PATHd8 is a nonparametric smoothing method that smoothes one pair of sister groups at a time, by taking the mean of the added branch lengths from a terminal taxon to a node. Because of the local smoothing, the algorithm is simple, hence providing stable and very fast analyses, allowing for thousands of taxa and an arbitrary number of age constraints. The importance of fossil constraints and their placement are discussed, and concluded to be the most important factor for obtaining reasonable age estimates. Different dating methods are compared, and it is concluded that differences in age estimates are obtained from penalized likelihood, PATHd8, and the Bayesian autocorrelation method implemented in the multidivtime program. In the Bayesian method, prior assumptions about evolutionary rate at the root, rate variance and the level of rate smoothing between internal edges, are suggested to influence the results.