Maximum likelihood is an ubiquitous method used in the estimation of generalized linear mixed model (GLMM). However, the method entails computational difficulties and relies on the normality assumption for random effects. We propose a second-order least squares (SLS) estimator based on the first two marginal moments of the response variables. The proposed estimator is computationally feasible and requires less distributional assumptions than the maximum likelihood estimator. To overcome the numerical difficulties of minimizing an objective function that involves multiple integrals, a simulation-based SLS estimator is proposed. We show that the SLS estimators are consistent and asymptotically normally distributed under fairly general conditions in the framework of GLMM. Missing data is almost inevitable in longitudinal studies. Problems arise if the missing data mechanism is related to the response process. This thesis develops the proposed estimators to deal with response data missing at random by either adapting the inverse probability weight method or applying the multiple imputation approach. In practice, some of the covariates are not directly observed but are measured with error. It is well-known that simply substituting a proxy variable for the unobserved covariate in the model will generally lead to biased and inconsistent estimates. We propose the instrumental variable method for the consistent estimation of GLMM with covariate measurement error. The proposed approach does not need any parametric assumption on the distribution of the unknown covariates. This makes the method less restrictive than other methods that rely on either a parametric distribution of the covariates, or to estimate the distribution using some extra information. In the presence of data outliers, it is a concern that the SLS estimators may be vulnerable due to the second-order moments. We investigated the robustness property of the SLS estimators using their influence functions. We showed that the proposed estimators have a bounded influence function and a redescending property so they are robust to outliers. The finite sample performance and property of the SLS estimators are studied and compared with other popular estimators in the literature through simulation studies and real world data examples.

Maximum likelihood is an ubiquitous method used in the estimation of generalized linear mixed model (GLMM). However, the method entails computational difficulties and relies on the normality assumption for random effects. We propose a second-order least squares (SLS) estimator based on the first two marginal moments of the response variables. The proposed estimator is computationally feasible and requires less distributional assumptions than the maximum likelihood estimator. To overcome the numerical difficulties of minimizing an objective function that involves multiple integrals, a simulation-based SLS estimator is proposed. We show that the SLS estimators are consistent and asymptotically normally distributed under fairly general conditions in the framework of GLMM. Missing data is almost inevitable in longitudinal studies. Problems arise if the missing data mechanism is related to the response process. This thesis develops the proposed estimators to deal with response data missing at random by either adapting the inverse probability weight method or applying the multiple imputation approach. In practice, some of the covariates are not directly observed but are measured with error. It is well-known that simply substituting a proxy variable for the unobserved covariate in the model will generally lead to biased and inconsistent estimates. We propose the instrumental variable method for the consistent estimation of GLMM with covariate measurement error. The proposed approach does not need any parametric assumption on the distribution of the unknown covariates. This makes the method less restrictive than other methods that rely on either a parametric distribution of the covariates, or to estimate the distribution using some extra information. In the presence of data outliers, it is a concern that the SLS estimators may be vulnerable due to the second-order moments. We investigated the robustness property of the SLS estimators using their influence functions. We showed that the proposed estimators have a bounded influence function and a redescending property so they are robust to outliers. The finite sample performance and property of the SLS estimators are studied and compared with other popular estimators in the literature through simulation studies and real world data examples.

A primary focus of wildlife research is to understand how habitat conditions and human activities impact the health of wild animals. External factors, both natural and anthropogenic that impact the ability of an animal to acquire food and build energy reserves have important implications for reproductive success, avoidance of predators, and the ability to withstand disease, and periods of food scarcity. In the analyses presented here, I quantify the impacts of habitat quality and anthropogenic disturbance on indicators of health for individuals in a threatened grizzly bear population in Alberta, Canada. The first analysis relates spatial patterns of hair cortisol concentrations, a promising indicator of long-term stress in mammals, measured from 304 grizzly bears to a variety of continuous environmental variables representative of habitat quality (e.g., crown closure, landcover, and vegetation productivity), topographic conditions (e.g., elevation and terrain ruggedness), and anthropogenic disturbances (e.g., roads, forest harvest blocks, and oil and gas well-sites). Hair cortisol concentration point data were integrated with continuous variables by creating a stress surface for male and female bears using kernel density estimation validated through bootstrapping. The relationships between hair cortisol concentrations for males and females and environmental variables were quantified using random forests, and landscape scale stress levels for both genders was predicted based on observed relationships. Low female stress levels were found to correspond with regions with high levels of anthropogenic disturbance and activity. High female stress levels were associated primarily with high-elevation parks and protected areas. Conversely, low male stress levels were found to correspond with parks and protected areas and spatially limited moderate to high stress levels were found in regions with greater anthropogenic disturbance. Of particular concern for conservation is the observed relationship between low female stress and sink habitats which have high mortality rates and high energetic costs. Extending the first analysis, the second portion of this research examined the impacts of scale-specific habitat selection and relationships between biology, habitat quality, and anthropogenic disturbance on body condition in 85 grizzly bears represented using a body condition index. Habitat quality and anthropogenic variables were represented at multiple scales using isopleths of a utilization distribution calculated using kernel density estimation for each bear. Several hypotheses regarding the influence of biology, habitat quality, and anthropogenic disturbance on body condition quantified using linear mixed-effects models were evaluated at each habitat selection scale using the small sample Aikake Information Criterion. Biological factors were influential at all scales as males had higher body condition than females, and body condition increased with age for both genders. At the scale of most concentrated habitat selection, the biology and habitat quality hypothesis had the greatest support and had a positive effect on body condition. A component of biology, the influence of long-term stress, which had a negative impact on body condition, was most pronounced within the biology and habitat quality hypothesis at this scale. As the scale of habitat selection was represented more broadly, support for the biology and anthropogenic disturbance hypothesis increased. Anthropogenic variables of particular importance were distance decay to roads, density of secondary linear features, and density of forest harvest areas which had a negative relationship with body condition. Management efforts aimed to promote landscape conditions beneficial to grizzly bear health should focus on promoting habitat quality in core habitat and limiting anthropogenic disturbance within larger grizzly bear home ranges. / Graduate / 0768 / 0463 / 0478 / mathieub@uvic.ca

Cette thèse est principalement consacrée au développement de méthodes de sélection de modèles par maximum de vraisemblance pénalisée dans le cadre de données complexes. Un premier travail porte sur la sélection des modèles linéaires généralisés dans le cadre de données stratifiées, caractérisées par la mesure d’observations ainsi que de covariables au sein de différents groupes (ou strates). Le but de l’analyse est alors de déterminer quelles covariables influencent de façon globale (quelque soit la strate) les observations mais aussi d’évaluer l’hétérogénéité de cet effet à travers les strates.Nous nous intéressons par la suite à la sélection des modèles non linéaires à effets mixtes utilisés dans l’analyse de données longitudinales comme celles rencontrées en pharmacocinétique de population. Dans un premier travail, nous décrivons un algorithme de type SAEM au sein duquel la pénalité est prise en compte lors de l’étape M en résolvant un problème de régression pénalisé à chaque itération. Dans un second travail, en s’inspirant des algorithmes de type gradient proximaux, nous simplifions l’étape M de l’algorithme SAEM pénalisé précédemment décrit en ne réalisant qu’une itération gradient proximale à chaque itération. Cet algorithme, baptisé Stochastic Approximation Proximal Gradient algorithm (SAPG), correspond à un algorithme gradient proximal dans lequel le gradient de la vraisemblance est approché par une technique d’approximation stochastique.Pour finir, nous présentons deux travaux de modélisation statistique, réalisés au cours de cette thèse. / This thesis is mainly devoted to the development of penalized maximum likelihood methods for the study of complex data.A first work deals with the selection of generalized linear models in the framework of stratified data, characterized by the measurement of observations as well as covariates within different groups (or strata). The purpose of the analysis is then to determine which covariates influence in a global way (whatever the stratum) the observations but also to evaluate the heterogeneity of this effect across the strata.Secondly, we are interested in the selection of nonlinear mixed effects models used in the analysis of longitudinal data. In a first work, we describe a SAEM-type algorithm in which the penalty is taken into account during step M by solving a penalized regression problem at each iteration. In a second work, inspired by proximal gradient algorithms, we simplify the M step of the penalized SAEM algorithm previously described by performing only one proximal gradient iteration at each iteration. This algorithm, called Stochastic Approximation Proximal Gradient Algorithm (SAPG), corresponds to a proximal gradient algorithm in which the gradient of the likelihood is approximated by a stochastic approximation technique.Finally, we present two statistical modeling works realized during this thesis.

Les paramètres de croissance de poissons pélagiques et démersaux ont été étudiés durant la période de 1990 à 2015 dans le but d’examiner l’impact de facteurs biotiques comme la densité-dépendance, le recrutement, la mortalité totale et de facteurs abiotiques tels que l’intensité d’upwelling, la température et la concentration en chlorophylle a. Les paramètres d’histoire de vie des espèces peuvent varier selon les espèces, d’une région à l’autre, et dans le temps au sein d’une même région en raison de leur plasticité et de la pression de la pêche. Une comparaison inter-espèces et inter-régions a été réalisée. Le modèle non linéaire à effets mixtes a été utilisé pour différentes populations de l’Océan Atlantique afin d’établir les paramètres de croissance aux niveaux individuel et de la population. Les variations des paramètres de croissance d’une sélection d’espèces ont été mises en corrélation avec des facteurs biotiques et abiotiquesLes espèces (Sardinella aurita, sardinelle ronde, Atherinella brasiliensis, tinicalo, Merlangius merlangus, merlan, Melanogrammus aeglefinus, églefin et Solea solea, sole) montrent des réponses différentes aux facteurs biotiques et abiotiques. Au niveau spatial pour le merlan et l’églefin, la croissance est affectée par la latitude et la température, tandis qu’au niveau temporel la croissance du merlan est affectée par la température et la densité. Il y avait un intérêt pour savoir si les variables morphométriques et le diamètre de l’otolithe de tinicalo étaient de bons indicateurs de la croissance : c’est la longueur standard qui a présenté / The impact of biotic factors such as density-dependent processes, recruitment, total mortality, and abiotic factors such as upwelling intensity, temperature and chlorophyll a concentration on the variation of growth parameters of pelagic and demersal fish were studied during the periods 1990 - 2008 (pelagic) and 1971 - 2015 (demersal). Life history parameters vary according to the species and from one region to another and over time within a given area because of their plasticity and the high fishing pressure. Interspecies and inter-regional comparison were carried out. Non-linear mixed effects models were used on different fish species of the Atlantic Ocean in order to estimate the growth parameters at the individual and population levels. Variations in growth parameters of selected species were correlated with biotic and abiotic factors.Selected species (Sardinella aurita, round sardinella, Xenomelaniris brasiliensis, tinicalo, Merlangus merlangus, whiting, Melanogrammus aeglefinus, haddock and Solea solea, sole) showed different responses to biotic and abiotic factors. Regardind the spatial component for whiting and haddock, the variation of growth parameters was affected by latitude and temperature. Concerning the temporal component, whiting was affected by temperature and density-dependent processes. There was also an interest to know if the morphometric variables and the diameter of the otolith of Atherinella brasilensis were good growth indicators. Among the morphometric parameters examined, the standard length-Age relationship showed the best fit (r2 = 0.90), foll

La radiothérapie externe (EBRT en anglais pour External Beam Radiotherapy) est l'un des traitements référence du cancer de prostate. Les objectifs de la radiothérapie sont, premièrement, de délivrer une haute dose de radiations dans la cible tumorale (prostate et vésicules séminales) afin d'assurer un contrôle local de la maladie et, deuxièmement, d'épargner les organes à risque voisins (principalement le rectum et la vessie) afin de limiter les effets secondaires. Des modèles de probabilité de complication des tissus sains (NTCP en anglais pour Normal Tissue Complication Probability) sont nécessaires pour estimer sur les risques de présenter des effets secondaires au traitement. Dans le contexte de la radiothérapie externe, les objectifs de cette thèse étaient d'identifier des paramètres prédictifs de complications rectales et vésicales secondaires au traitement; de développer de nouveaux modèles NTCP permettant l'intégration de paramètres dosimétriques et de paramètres propres aux patients; de comparer les capacités prédictives de ces nouveaux modèles à celles des modèles classiques et de développer de nouvelles méthodologies d'identification de motifs de dose corrélés à l'apparition de complications. Une importante base de données de patients traités par radiothérapie conformationnelle, construite à partir de plusieurs études cliniques prospectives françaises, a été utilisée pour ces travaux. Dans un premier temps, la fréquence des symptômes gastro-Intestinaux et génito-Urinaires a été décrite par une estimation non paramétrique de Kaplan-Meier. Des prédicteurs de complications gastro-Intestinales et génito-Urinaires ont été identifiés via une autre approche classique : la régression logistique. Les modèles de régression logistique ont ensuite été utilisés dans la construction de nomogrammes, outils graphiques permettant aux cliniciens d'évaluer rapidement le risque de complication associé à un traitement et d'informer les patients. Nous avons proposé l'utilisation de la méthode d'apprentissage de machine des forêts aléatoires (RF en anglais pour Random Forests) pour estimer le risque de complications. Les performances de ce modèle incluant des paramètres cliniques et patients, surpassent celles des modèle NTCP de Lyman-Kutcher-Burman (LKB) et de la régression logistique. Enfin, la dose 3D a été étudiée. Une méthode de décomposition en valeurs populationnelles (PVD en anglais pour Population Value Decomposition) en 2D a été généralisée au cas tensoriel et appliquée à l'analyse d'image 3D. L'application de cette méthode à une analyse de population a été menée afin d'extraire un motif de dose corrélée à l'apparition de complication après EBRT. Nous avons également développé un modèle non paramétrique d'effets mixtes spatio-Temporels pour l'analyse de population d'images tridimensionnelles afin d'identifier une région anatomique dans laquelle la dose pourrait être corrélée à l'apparition d'effets secondaires. / External beam radiotherapy (EBRT) is one of the cornerstones of prostate cancer treatment. The objectives of radiotherapy are, firstly, to deliver a high dose of radiation to the tumor (prostate and seminal vesicles) in order to achieve a maximal local control and, secondly, to spare the neighboring organs (mainly the rectum and the bladder) to avoid normal tissue complications. Normal tissue complication probability (NTCP) models are then needed to assess the feasibility of the treatment and inform the patient about the risk of side effects, to derive dose-Volume constraints and to compare different treatments. In the context of EBRT, the objectives of this thesis were to find predictors of bladder and rectal complications following treatment; to develop new NTCP models that allow for the integration of both dosimetric and patient parameters; to compare the predictive capabilities of these new models to the classic NTCP models and to develop new methodologies to identify dose patterns correlated to normal complications following EBRT for prostate cancer treatment. A large cohort of patient treated by conformal EBRT for prostate caner under several prospective French clinical trials was used for the study. In a first step, the incidence of the main genitourinary and gastrointestinal symptoms have been described. With another classical approach, namely logistic regression, some predictors of genitourinary and gastrointestinal complications were identified. The logistic regression models were then graphically represented to obtain nomograms, a graphical tool that enables clinicians to rapidly assess the complication risks associated with a treatment and to inform patients. This information can be used by patients and clinicians to select a treatment among several options (e.g. EBRT or radical prostatectomy). In a second step, we proposed the use of random forest, a machine-Learning technique, to predict the risk of complications following EBRT for prostate cancer. The superiority of the random forest NTCP, assessed by the area under the curve (AUC) of the receiving operative characteristic (ROC) curve, was established. In a third step, the 3D dose distribution was studied. A 2D population value decomposition (PVD) technique was extended to a tensorial framework to be applied on 3D volume image analysis. Using this tensorial PVD, a population analysis was carried out to find a pattern of dose possibly correlated to a normal tissue complication following EBRT. Also in the context of 3D image population analysis, a spatio-Temporal nonparametric mixed-Effects model was developed. This model was applied to find an anatomical region where the dose could be correlated to a normal tissue complication following EBRT.

Dans cette thèse, nous nous sommes focalisés sur le modèle statistique linéaire à effets mixtes. Nous nous sommes d'abord intéressés à l'estimation consistante des paramètres du modèle dans sa version multidimensionnelle, puis à de la sélection d'effets fixes en dimension un. En ce qui concerne l'estimation des paramètres du modèle linéaire à effets mixtes multidimensionnel, nous avons proposé des estimateurs du maximum de vraisemblance par utilisation de l'algorithme EM, mais avec des expressions plus générales que celles de la littérature classique, permettant d'analyser non seulement des données longitudinales multivariées mais aussi des données multidimensionnelles multi-niveaux. Ici, en s'appuyant sur ces EM-estimateurs, nous avons introduit un test de rapport de vraisemblance permettant de tester la significativité globale des corrélations entre les effets aléatoires de deux dimensions du modèle. Ce qui permettrait de construire un modèle multidimensionnel plus parcimonieux en terme de paramètres de variance des effets aléatoires, par une procédure de selection pas-à-pas ascendante. Cette démarche a été suscitée par le fait que la dimension du vecteur de tous les effets aléatoires du modèle peut très rapidement croitre avec le nombre de variables à analyser, entrainant facilement des problèmes numériques dans l'optimisation du critère choisi (ML ou REML). Nous avons ensuite proposé une procédure d'estimation consistante des paramètres du modèle qui passe par la résolution d'un problème de moindres carrés pénalisés pour fournir une expression explicite de la déviance à minimiser. La procédure de sélection d'effets fixes proposée ici est de type adaptive ridge itérative et permet d'approximer les performances de sélection d'une pénalité de type L0 de la vraisemblance des paramètres du modèle. Nos résultats ont été appuyés par des études de simulation à plusieurs niveaux, mais aussi par l'analyse de plusieurs jeux de données réelles. / This thesis focuses on the statistical linear mixed-effects model, where we have been interested in its multivariate version's parameters estimation but also in the unidimensional selection of fixed effects. Concerning the parameters estimation of the multivariate linear mixed-effects model, we have first introduced more general expressions of the EM algorithm-based estimators which fit the multivariate longitudinal data analysis framework but also the framework of the multivariate multilevel data analysis. Since the dimensionality of the total vector of random effects in the multivariate model can grow with the number of the outcome variables leading often to computational problems in the likelihood optimization, we introduced a likelihood ratio test for testing the global effect of the correlations between the random effects of two dimensions of the model. This bivariate correlation test is intended to help in constructing a more parsimonious model regarding the variance components of the random effects, using a stepwise procedure. Secondly, we have introduced another estimation procedure that yields to consistent estimates for all the model parameters. This procedure is based on the Cholesky factorization of the random effects covariance matrix and the resolution of a preliminary penalized means square problem, and leads to an explicite expression of the profiled deviance of the model. For selecting fixed effects in the one dimensional mixed-effects model, we introduce an iterative adaptive ridge procedure for approximating sL0 penalty selection performances. All the results in this manuscript have been accompanied by extensive simulation studies along with real data analysis examples.

En raison des relations complexes entre les variables des systèmes biologiques, l’hétérogénéité des données biologiques pose un défi pour leur modélisation par des modèles mathématiques et statistiques. En réponse, étant conçus pour traiter des données multiniveaux et bruitées, les modèles à effets mixtes deviennent de plus en plus populaires en modélisation quantitative de systèmes biologiques. L'objectif de cette thèse est de présenter l’application de modèles à effets mixtes à différents systèmes biologiques. Le deuxième chapitre de ce mémoire vise à déterminer la relation entre la cote de qualité du sirop d'érable, divers indicateurs de qualité couramment obtenus par les producteurs ainsi qu'un nouvel indicateur, le COLORI, et la concentration en acides aminés (AA). Pour cela, nous avons créé deux modèles à effets mixtes : le premier est un modèle ordinal qui prédit directement la cote de qualité du sirop d'érable en utilisant la transmittance, COLORI et AA ; le deuxième modèle est un modèle non linéaire qui prédit la concentration en AA en utilisant COLORI avec le pH comme approximation temporelle. Nos résultats montrent que la concentration en AA est un bon prédicteur de la qualité du sirop d'érable et que COLORI est un bon prédicteur de la concentration en AA. Le troisième chapitre traite de l’utilisation d’un modèle de la pharmacocinétique de population (PopPK) pour décrire la dynamique de l'estradiol dans un modèle de pharmacologie quantitative des systèmes (QSP) de la différenciation des cellules mammaires en cellules myoépithéliales afin de capturer l'hétérogénéité de la population de patients. Nous avons trouvé que la composante PopPK du modèle QSP n’a pas ajoutée de grande variation dans la dynamique de patients virtuels, ce qui suggère que le modèle QSP inclut intrinsèquement l'hétérogénéité. Dans l'ensemble, ce mémoire démontre l'application de modèles à effets mixtes au systèmes biologiques pour comprendre l'hétérogénéité des données biologiques. / Modelling biological systems with mathematical models has been a challenge due to the tendency for biological data to be heavily heterogeneous with complex relationships between the variables. Mixed effects models are an increasingly popular choice as a statistical model for biological systems since it is designed for multilevel data and noisy data. The aim of this thesis is to showcase the range of usage of mixed effects modelling for different biological systems. The second chapter aims to determine the relationship between maple syrup quality rating and various quality indicator commonly obtained by producers as well as a new indicator, COLORI, and amino acid (AA) concentration. For this, we created two mixed effects models: the first is an ordinal model that directly predicts maple syrup quality rating using transmittance, COLORI and AA; the second model is a nonlinear model that predicts AA concentration using COLORI with pH as a time proxy. Our models show that AA concentration is a good predictor for maple syrup quality, and COLORI is a good predictor for AA concentration. The third chapter involves using a population pharmacokinetics (PopPK) model to estimate estradiol dynamics in a quantitative systems pharmacokinetics (QSP) model for mammary cell differentiation into myoepithelial cells in order to capture population heterogeneity among patients. Our results show that the QSP model inherently includes heterogeneity in its structure since the added PopPK estradiol portion of the model does not add large variation in the estimated virtual patients. Overall, this thesis demonstrates the application of mixed effects models in biology as a way to understand heterogeneity in biological data.

The biological characteristics of fisheries stocks that are assessed for management considerations are rarely homogeneous over time or space. However, stock assessment scientists largely ignore this heterogeneity in their models. This thesis addresses the effects of spatial and temporal heterogeneity on stock assessment models using Atlantic Weakfish (Cynoscion regalis) as a case study. First, spatial and temporal variation was incorporated into length-, weight-, and maturity-at-age estimates using mixed-effects models (Chapter Two). The resulting heterogeneous weight and maturity parameters then were applied to per-recruit analyses to examine the sensitivity of biological reference points to spatial and temporal variation in life history attributes (Chapter Three). Mixed-effects life history models incorporating spatial and temporal variation revealed distinct regional and annual trends that were not visible from standard homogeneous models. In several instances, the homogeneous modelling approach produced life history estimates that varied significantly from the spatial and temporal means produced by the heterogeneous models. In some cases, this difference was so great that the homogeneous means were much higher or lower than the heterogeneous means for all regions or years. Minimized AIC statistics revealed that spatially and temporally integrated mixed-effects models were more robust and descriptive of Atlantic Weakfish life history than the standard homogeneous models. Per-recruit and biological reference points derived from these life history estimates in Chapter Three were found to be highly sensitive to spatial and temporal variations in weight parameters. In several cases, reference points used as management targets were so significantly different that ignoring spatial and temporal heterogeneity in Atlantic Weakfish life history would likely cause overfishing and decline of Weakfish in certain regions and years. / Master of Science / Many stocks of commercially and recreationally harvested marine fish have displayed a declining trend in recent years. Marine fisheries are a vital component of the global economy, and, as such, sophisticated management measures have been developed to reduce and reverse this trend. These management strategies are based on regular reports from fisheries stock assessment scientists, who evaluate the status of fish stocks by modelling life history and productivity trends. One of the greatest challenges to stock assessments is the identification and incorporation of variability in fish populations. There is an inherent variation in fish growth, maturity, and productivity among geographical locations and over time. To produce the most effective management strategies, stock assessments must incorporate this spatial (regional) and temporal (annual) variation. In this thesis, I used mixed effects models to integrate spatial and temporal variation in life history and productivity using Atlantic Weakfish (Cynoscion regalis) as a case study. Distinct trends were observed in fishery-independent data for this species that were reflected in spatially and temporally incorporated models. However, these trends were masked in the standard models which incorporated neither spatial nor temporal variation. This oversight could cause weakfish to be overfished in certain regions and years and underfished in others. To maximize the effectiveness of management and the sustainable fisheries yield in all regions and years for Atlantic Weakfish and other harvested species, I highly recommend using spatially and temporally incorporated life history and productivity models such as the ones developed in this thesis.

Treatment of patients with multiple sclerosis (MS) and development of new therapies have been challenging due to the disease complexity and slow progression, and the limited sensitivity of available clinical outcomes. Modeling and simulation has become an increasingly important component in drug development and in post-marketing optimization of use of medication. This thesis focuses on development of pharmacometric models for characterization and quantification of the relationships between drug exposure, biomarkers and clinical endpoints in relapse-remitting MS (RRMS) following cladribine treatment. A population pharmacokinetic model of cladribine and its main metabolite, 2-chloroadenine, was developed using plasma and urine data. The renal clearance of cladribine was close to half of total elimination, and was found to be a linear function of creatinine clearance (CRCL). Exposure-response models could quantify a clear effect of cladribine tablets on absolute lymphocyte count (ALC), burden of disease (BoD), expanded disability status scale (EDSS) and relapse rate (RR) endpoints. Moreover, they gave insight into disease progression of RRMS. This thesis further demonstrates how integrated modeling framework allows an understanding of the interplay between ALC and clinical efficacy endpoints. ALC was found to be a promising predictor of RR. Moreover, ALC and BoD were identified as predictors of EDSS time-course. This enables the understanding of the behavior of the key outcomes necessary for the successful development of long-awaited MS therapies, as well as how these outcomes correlate with each other. The item response theory (IRT) methodology, an alternative approach for analysing composite scores, enabled to quantify the information content of the individual EDSS components, which could help improve this scale. In addition, IRT also proved capable of increasing the detection power of potential drug effects in clinical trials, which may enhance drug development efficiency. The developed nonlinear mixed-effects models offer a platform for the quantitative understanding of the biomarker(s)/clinical endpoint relationship, disease progression and therapeutic response in RRMS by integrating a significant amount of knowledge and data.