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Introduction: The current development strategy of population pharmacokinetic models is a complex and iterative process that is manually performed by modellers. Such a strategy is time-demanding, subjective, and dependent on the modellers’ experience. This thesis presents a novel model building tool that automates the development process of pharmacokinetic (PK) structural models. Methods: Modelsearch is a tool in Pharmpy library, an open-source package for pharmacometrics modelling, that searches for the best structural model using an exhaustive stepwise search algorithm. Given a dataset, a starting model and a pre-specified model search space of structural model features, the tool creates and fits a series of candidate models that are then ranked based on a selection criterion, leading to the selection of the best model. The Modelsearch tool was used to develop structural models for 10 clinical PK datasets (5 orally and 5 i.v. administered drugs). A starting model for each dataset was generated using the assemblerr package in R, which included a first-order (FO) absorption without any absorption delay for oral drugs, one-compartment disposition, FO elimination, a proportional residual error model, and inter-individual variability on the starting model parameters with a correlation between clearance (CL) and central volume of distribution (VC). The model search space included aspects of absorption and absorption delay (for oral drugs), distribution and elimination. In order to understand the effects of different IIV structures on structural model selection, five model search approaches were investigated that differ in the IIV structure of candidate models: 1. naïve pooling, 2. IIV on starting model parameters only, 3. additional IIV on mean delay time parameter, 4. additional diagonal IIVs on newly added parameters, and 5. full block IIVs. Additionally, the implementation of structural model selection in the workflow of the fully automatic model development was investigated. Three strategies were evaluated: SIR, SRI, and RSI depending on the development order of structural model (S), IIV model (I) and residual error model (R). Moreover, the NONMEM errors encountered when using the tool were investigated and categorized in order to be handled in the automatic model building workflow. Results: Differences in the final selected structural models for each drug were observed between the five different model search approaches. The same distribution components were selected through Approaches 1 and 2 for 6/10 drugs. Approach 2 has also identified an absorption delay component in 4/5 oral drugs, whilst the naïve pooling approach only identified an absorption delay model in 2 drugs. Compared to Approaches 1 and 2, Approaches 3, 4 and 5 tended to select more complex models and more often resulted in minimization errors during the search. For the SIR, SRI and RSI investigations, the same structural model was selected in 9/10 drugs with a significant higher run time in RSI strategy compared to the other strategies. The NONMEM errors were categorized into four categories based on the handling suggestions which is valuable to further improve the tool in its automatic error handling. Conclusions: The Modelsearch tool was able to automatically select a structural model with different strategies of setting the IIV model structure. This novel tool enables the evaluation of numerous combinations of model components, which would not be possible using a traditional manual model building strategy. Furthermore, the tool is flexible and can support multiple research investigations for how to best implement structural model selection in a fully automatic model development workflow.

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.

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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.

Reliability analysis plays an important role in keeping manufacturers in a competitive position. It can be applied in many areas such as warranty predictions, maintenance scheduling, spare parts provisioning, and risk assessment. This dissertation focuses on statistical modeling and predictions based on lifetime data, degradation data, and recurrent event data. The datasets used in this dissertation come from the field, and have complicated structures. The dissertation consists of three main chapters, in addition to Chapter 1 which is the introduction chapter, and Chapter 5 which is the general conclusion chapter. Chapter 2 consists of the traditional time-to-failure data analysis. We propose a statistical method to address the failure data from an appliance used at home with the consideration of retirement times and delayed reporting time. We also develop a prediction method based on the proposed model. Using the information of retirement-time distribution and delayed reporting time, the predictions are more accurate and useful in the decision making. In Chapter 3, we introduce a nonlinear mixed-effects general path model to incorporate dynamic covariates into degradation data analysis. Dynamic covariates include time-varying environmental variables and usage condition. The shapes of the effect functions of covariates may be constrained to be, for example, monotonically increasing (i.e., higher temperature is likely to cause more damage). Incorporating dynamic covariates with shape restrictions is challenging. A modified alternative algorithm and the corresponding prediction method are proposed. In Chapter 4, we introduce a multi-level trend-renewal process (MTRP) model to describe component-level events in multi-level repairable systems. In particular, we consider two-level repairable systems in which events can occur at the subsystem level, or the component (within the subsystem) level. The main goal is to develop a method for estimation of model parameters and a procedure for prediction of the future replacement events at component level with the consideration of the effects from the subsystem replacement events. To explain unit-to-unit variability, time-dependent covariates as well as random effects are introduced into the heterogeneous MTRP model (HMTRP). A Metropolis-within-Gibbs algorithm is used to estimate the unknown parameters in the HMTRP model. The proposed method is illustrated by a simulated dataset. / Ph. D.

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In longitudinal studies, data collected within a subject or cluster are somewhat correlated by their very nature and special cares are needed to account for such correlation in the analysis of data. Under the framework of longitudinal studies, three topics are being discussed in this thesis. In chapter 2, the joint modelling of multivariate longitudinal process consisting of different types of outcomes are discussed. In the large cohort study of UK north Stafforshire osteoarthritis project, longitudinal trivariate outcomes of continuous, binary and ordinary data are observed at baseline, year 3 and year 6. Instead of analysing each process separately, joint modelling is proposed for the trivariate outcomes to account for the inherent association by introducing random effects and the covariance matrix G. The influence of covariance matrix G on statistical inference of fixed-effects parameters has been investigated within the Bayesian framework. The study shows that by joint modelling the multivariate longitudinal process, it can reduce the bias and provide with more reliable results than it does by modelling each process separately. Together with the longitudinal measurements taken intermittently, a counting process of events in time is often being observed as well during a longitudinal study. It is of interest to investigate the relationship between time to event and longitudinal process, on the other hand, measurements taken for the longitudinal process may be potentially truncated by the terminated events, such as death. Thus, it may be crucial to jointly model the survival and longitudinal data. It is popular to propose linear mixed-effects models for the longitudinal process of continuous outcomes and Cox regression model for survival data to characterize the relationship between time to event and longitudinal process, and some standard assumptions have been made. In chapter 3, we try to investigate the influence on statistical inference for survival data when the assumption of mutual independence on random error of linear mixed-effects models of longitudinal process has been violated. And the study is conducted by utilising conditional score estimation approach, which provides with robust estimators and shares computational advantage. Generalised sufficient statistic of random effects is proposed to account for the correlation remaining among the random error, which is characterized by the data-driven method of modified Cholesky decomposition. The simulation study shows that, by doing so, it can provide with nearly unbiased estimation and efficient statistical inference as well. In chapter 4, it is trying to account for both the current and past information of longitudinal process into the survival models of joint modelling. In the last 15 to 20 years, it has been popular or even standard to assume that longitudinal process affects the counting process of events in time only through the current value, which, however, is not necessary to be true all the time, as recognised by the investigators in more recent studies. An integral over the trajectory of longitudinal process, along with a weighted curve, is proposed to account for both the current and past information to improve inference and reduce the under estimation of effects of longitudinal process on the risk hazards. A plausible approach of statistical inference for the proposed models has been proposed in the chapter, along with real data analysis and simulation study.