Computational systems biology is an inter-disciplinary field that aims to develop computational approaches for a system-level understanding of biological systems. Advances in high-throughput biotechnology offer broad scope and high resolution in multiple disciplines. However, it is still a major challenge to extract biologically meaningful information from the overwhelming amount of data generated from biological systems. Effective computational approaches are of pressing need to reveal the functional components. Thus, in this dissertation work, we aim to develop computational approaches for differential analysis of RNA-seq and methylation data to detect aberrant events associated with cancers. We develop a novel Bayesian approach, BayesIso, to identify differentially expressed isoforms from RNA-seq data. BayesIso features a joint model of the variability of RNA-seq data and the differential state of isoforms. BayesIso can not only account for the variability of RNA-seq data but also combines the differential states of isoforms as hidden variables for differential analysis. The differential states of isoforms are estimated jointly with other model parameters through a sampling process, providing an improved performance in detecting isoforms of less differentially expressed. We propose to develop a novel probabilistic approach, DM-BLD, in a Bayesian framework to identify differentially methylated genes. The DM-BLD approach features a hierarchical model, built upon Markov random field models, to capture both the local dependency of measured loci and the dependency of methylation change. A Gibbs sampling procedure is designed to estimate the posterior distribution of the methylation change of CpG sites. Then, the differential methylation score of a gene is calculated from the estimated methylation changes of the involved CpG sites and the significance of genes is assessed by permutation-based statistical tests. We have demonstrated the advantage of the proposed Bayesian approaches over conventional methods for differential analysis of RNA-seq data and methylation data. The joint estimation of the posterior distributions of the variables and model parameters using sampling procedure has demonstrated the advantage in detecting isoforms or methylated genes of less differential. The applications to breast cancer data shed light on understanding the molecular mechanisms underlying breast cancer recurrence, aiming to identify new molecular targets for breast cancer treatment. / Ph. D.

Liquid chromatography coupled with mass spectrometry (LC-MS) has been widely used in various omic studies for biomarker discovery. Appropriate LC-MS data preprocessing steps are needed to detect true differences between biological groups. Retention time alignment is one of the most important yet challenging preprocessing steps, in order to ensure that ion intensity measurements among multiple LC-MS runs are comparable. In this dissertation, we propose a Bayesian alignment model (BAM) for analysis of LC-MS data. BAM uses Markov chain Monte Carlo (MCMC) methods to draw inference on the model parameters and provides estimates of the retention time variability along with uncertainty measures, enabling a natural framework to integrate information of various sources. From methodology development to practical application, we investigate the alignment problem through three research topics: 1) development of single-profile Bayesian alignment model, 2) development of multi-profile Bayesian alignment model, and 3) application to biomarker discovery research. Chapter 2 introduces the profile-based Bayesian alignment using a single chromatogram, e.g., base peak chromatogram from each LC-MS run. The single-profile alignment model improves on existing MCMC-based alignment methods through 1) the implementation of an efficient MCMC sampler using a block Metropolis-Hastings algorithm, and 2) an adaptive mechanism for knot specification using stochastic search variable selection (SSVS). Chapter 3 extends the model to integrate complementary information that better captures the variability in chromatographic separation. We use Gaussian process regression on the internal standards to derive a prior distribution for the mapping functions. In addition, a clustering approach is proposed to identify multiple representative chromatograms for each LC-MS run. With the Gaussian process prior, these chromatograms are simultaneously considered in the profile-based alignment, which greatly improves the model estimation and facilitates the subsequent peak matching process. Chapter 4 demonstrates the applicability of the proposed Bayesian alignment model to biomarker discovery research. We integrate the proposed Bayesian alignment model into a rigorous preprocessing pipeline for LC-MS data analysis. Through the developed analysis pipeline, candidate biomarkers for hepatocellular carcinoma (HCC) are identified and confirmed on a complementary platform. / Ph. D.

In this thesis, a dynamic spatial model for the spread of Chronic Wasting Disease in Colorado mule deer is derived from a system of differential equations that captures the qualitative spatial and temporal behaviour of the disease. These differential equations are incorporated into an empirical Bayesian hierarchical model through the unusual step of deterministic autoregressive updates. Spatial effects in the model are described directly in the differential equations rather than through the use of correlations in the data. The use of deterministic updates is a simplification that reduces the number of parameters that must be estimated, yet still provides a flexible model that gives reasonable predictions for the disease. The posterior distribution generated by the data model hierarchy possesses characteristics that are atypical for many Markov chain Monte Carlo simulation techniques. To address these difficulties, a new MCMC technique is developed that has qualities similar to recently introduced tempered Langevin type algorithms. The methodology is used to fit the CWD model, and posterior parameter estimates are then used to obtain predictions about Chronic Wasting Disease.

The rapid development of biotechnology has enabled researchers to collect high-throughput data for studying various biological processes at the genomic level, transcriptomic level, and proteomic level. Due to the large noise in the data and the high complexity of diseases (such as cancer), it is a challenging task for researchers to extract biologically meaningful information that can help reveal the underlying molecular mechanisms. The challenges call for more efforts in developing efficient and effective computational methods to analyze the data at different levels so as to understand the biological systems in different aspects. In this dissertation research, we have developed novel Bayesian approaches to infer alternative splicing mechanisms in biological systems using RNA sequencing data. Specifically, we focus on two research topics in this dissertation: isoform identification and phenotype-specific transcript assembly. For isoform identification, we develop a computational approach, SparseIso, to jointly model the existence and abundance of isoforms in a Bayesian framework. A spike-and-slab prior is incorporated into the model to enforce the sparsity of expressed isoforms. A Gibbs sampler is developed to sample the existence and abundance of isoforms iteratively. For transcript assembly, we develop a Bayesian approach, IntAPT, to assemble phenotype-specific transcripts from multiple RNA sequencing profiles. A two-layer Bayesian framework is used to model the existence of phenotype-specific transcripts and the transcript abundance in individual samples. Based on the hierarchical Bayesian model, a Gibbs sampling algorithm is developed to estimate the joint posterior distribution for phenotype-specific transcript assembly. The performances of our proposed methods are evaluated with simulation data, compared with existing methods and benchmarked with real cell line data. We then apply our methods on breast cancer data to identify biologically meaningful splicing mechanisms associated with breast cancer. For the further work, we will extend our methods for de novo transcript assembly to identify novel isoforms in biological systems; we will incorporate isoform-specific networks into our methods to better understand splicing mechanisms in biological systems. / Ph. D. / The next-generation sequencing technology has significantly improved the resolution of the biomedical research at the genomic level and transcriptomic level. Due to the large noise in the data and the high complexity of diseases (such as cancer), it is a challenging task for researchers to extract biologically meaningful information that can help reveal the underlying molecular mechanisms. In this dissertation, we have developed two novel Bayesian approaches to infer alternative splicing mechanisms in biological systems using RNA sequencing data. We have demonstrated the advantages of our proposed approaches over existing methods on both simulation data and real cell line data. Furthermore, the application of our methods on real breast cancer data and glioblastoma tissue data has further shown the efficacy of our methods in real biological applications.

Doctor of Philosophy / With the fast development of artificial intelligence (AI) technology, the reliability of AI needs to be investigated for confidently using AI products in our daily lives. This dissertation includes three projects introducing the statistical models and model estimation methods that can be used in the reliability analysis of AI systems. The first project analyzes the recurrent events data from autonomous vehicles (AVs). A nonparametric model is proposed to study the reliability of AI systems in AVs, and a statistical framework is introduced to evaluate the adequacy of using traditional parametric models in the analysis. The proposed model and framework are then applied to analyze AV data from four manufacturers that participated in an AV driving testing program overseen by the California Department of Motor Vehicles. The second project develops a survival model to investigate the failure times of graphics processing units (GPUs) used in supercomputers. The model considers several covariates, the spatial correlation, and the correlation among multiple types of failures. In addition, unique spatial correlation functions and a special distance function are introduced to quantify the spatial correlation inside supercomputers. The model is applied to explore the GPU failure times in the Titan supercomputer. The third project proposes a new Markov chain Monte Carlo sampler that can be used in the estimation and inference of spatial survival models. The sampler can generate a reasonable amount of samples within a shorter computing time compared with existing popular samplers. Important factors that can influence the performance of the proposed sampler are explored, and the sampler is used to analyze the Titan GPU failures to illustrate its usefulness in solving real-world problems.

We consider the statistical inverse problem of estimating a background flow field (e.g., of air or water) from the partial and noisy observation of a passive scalar (e.g., the concentration of a pollutant). Here the unknown is a vector field that is specified by large or infinite number of degrees of freedom. We show that the inverse problem is ill-posed, i.e., there may be many or no background flows that match a given set of observations. We therefore adopt a Bayesian approach, incorporating prior knowledge of background flows and models of the observation error to develop probabilistic estimates of the fluid flow. In doing so, we leverage frameworks developed in recent years for infinite-dimensional Bayesian inference. We provide conditions under which the inference is consistent, i.e., the posterior measure converges to a Dirac measure on the true background flow as the number of observations of the solute concentration grows large. We also define several computationally-efficient algorithms adapted to the problem. One is an adjoint method for computation of the gradient of the log likelihood, a key ingredient in many numerical methods. A second is a particle method that allows direct computation of point observations of the solute concentration, leveraging the structure of the inverse problem to avoid approximation of the full infinite-dimensional scalar field. Finally, we identify two interesting example problems with very different posterior structures, which we use to conduct a large-scale benchmark of the convergence of several Markov Chain Monte Carlo methods that have been developed in recent years for infinite-dimensional settings. / Ph. D. / We consider the problem of estimating a fluid flow (e.g., of air or water) from partial and noisy observations of the concentration of a solute (e.g., a pollutant) dissolved in the fluid. Because of observational noise, and because there are cases where the fluid flow will not affect the movement of the pollutant, the fluid flow cannot be uniquely determined from the observations. We therefore adopt a statistical (Bayesian) approach, developing probabilistic estimates of the fluid flow using models of observation error and our understanding of the flow before measurements are taken. We provide conditions under which, as the number of observations grows large, the approach is able to identify the fluid flow that generated the observations. We define several efficient algorithms for computing statistics of the fluid flow, one of which involves approximating the movement of individual solute particles to estimate concentrations only where required by the inverse problem. We identify two interesting example problems for which the statistics of the fluid flow are very different. The first case produces an approximately normal distribution. The second example exhibits highly nonGaussian structure, where several different classes of fluid flows match the data very well. We use these examples to test the functionality and efficiency of several numerical (Markov Chain Monte Carlo) methods developed in recent years to compute the solution to similar problems.

Les séquences protéiques naturelles sont le résultat net de l’interaction entre les mécanismes de mutation, de sélection naturelle et de dérive stochastique au cours des temps évolutifs. Les modèles probabilistes d’évolution moléculaire qui tiennent compte de ces différents facteurs ont été substantiellement améliorés au cours des dernières années. En particulier, ont été proposés des modèles incorporant explicitement la structure des protéines et les interdépendances entre sites, ainsi que les outils statistiques pour évaluer la performance de ces modèles. Toutefois, en dépit des avancées significatives dans cette direction, seules des représentations très simplifiées de la structure protéique ont été utilisées jusqu’à présent. Dans ce contexte, le sujet général de cette thèse est la modélisation de la structure tridimensionnelle des protéines, en tenant compte des limitations pratiques imposées par l’utilisation de méthodes phylogénétiques très gourmandes en temps de calcul. Dans un premier temps, une méthode statistique générale est présentée, visant à optimiser les paramètres d’un potentiel statistique (qui est une pseudo-énergie mesurant la compatibilité séquence-structure). La forme fonctionnelle du potentiel est par la suite raffinée, en augmentant le niveau de détails dans la description structurale sans alourdir les coûts computationnels. Plusieurs éléments structuraux sont explorés : interactions entre pairs de résidus, accessibilité au solvant, conformation de la chaîne principale et flexibilité. Les potentiels sont ensuite inclus dans un modèle d’évolution et leur performance est évaluée en termes d’ajustement statistique à des données réelles, et contrastée avec des modèles d’évolution standards. Finalement, le nouveau modèle structurellement contraint ainsi obtenu est utilisé pour mieux comprendre les relations entre niveau d’expression des gènes et sélection et conservation de leur séquence protéique. / Protein sequences are the net result of the interplay of mutation, natural selection and stochastic variation. Probabilistic models of molecular evolution accounting for these processes have been substantially improved over the last years. In particular, models that explicitly incorporate protein structure and site interdependencies have recently been developed, as well as statistical tools for assessing their performance. Despite major advances in this direction, only simple representations of protein structure have been used so far. In this context, the main theme of this dissertation has been the modeling of three-dimensional protein structure for evolutionary studies, taking into account the limitations imposed by computationally demanding phylogenetic methods. First, a general statistical framework for optimizing the parameters of a statistical potential (an energy-like scoring system for sequence-structure compatibility) is presented. The functional form of the potential is then refined, increasing the detail of structural description without inflating computational costs. Always at the residue-level, several structural elements are investigated: pairwise distance interactions, solvent accessibility, backbone conformation and flexibility of the residues. The potentials are then included into an evolutionary model and their performance is assessed in terms of model fit, compared to standard evolutionary models. Finally, this new structurally constrained phylogenetic model is used to better understand the selective forces behind the differences in conservation found in genes of very different expression levels.

Die vier in der vorliegenden Dissertation enthaltenen Studien beschäftigen sich vorwiegend mit dem dynamischen Verhalten makroökonomischer Zeitreihen. Diese Dynamiken werden sowohl im Kontext eines einfachen DSGE Modells, als auch aus der Sichtweise reiner Zeitreihenmodelle untersucht. / The four studies of this thesis are concerned predominantly with the dynamics of macroeconomic time series, both in the context of a simple DSGE model, as well as from a pure time series modeling perspective.

Cette thèse travaille principalement sur trois sujets. Le premier concentre sur le clustering en ligne dans lequel nous présentons un nouvel algorithme stochastique adaptatif pour regrouper des ensembles de données en ligne. Cet algorithme repose sur l'approche quasi-bayésienne, avec une estimation dynamique (i.e., dépendant du temps) du nombre de clusters. Nous prouvons que cet algorithme atteint une borne de regret de l'ordre et que cette borne est asymptotiquement minimax sous la contrainte sur le nombre de clusters. Nous proposons aussi une implémentation par RJMCMC. Le deuxième sujet est lié à l'apprentissage séquentiel des courbes principales qui cherche à résumer une séquence des données par une courbe continue. Pour ce faire, nous présentons une procédure basée sur une approche maximum a posteriori pour le quasi-posteriori de Gibbs. Nous montrons que la borne de regret de cet algorithme et celui de sa version adaptative est sous-linéaire en l'horizon temporel T. En outre, nous proposons une implémentation par un algorithme glouton local qui intègre des éléments de sleeping experts et de bandit à plusieurs bras. Le troisième concerne les travaux qui visent à accomplir des tâches pratiques au sein d'iAdvize, l'entreprise qui soutient cette thèse. Il inclut l'analyse des sentiments pour les messages textuels et l'implémentation de chatbot dans lesquels la première est réalisé par les méthodes classiques dans la fouille de textes et les statistiques et la seconde repose sur le traitement du langage naturel et les réseaux de neurones artificiels. / This thesis works mainly on three subjects. The first one is online clustering in which we introduce a new and adaptive stochastic algorithm to cluster online dataset. It relies on a quasi-Bayesian approach, with a dynamic (i.e., time-dependent) estimation of the (unknown and changing) number of clusters. We prove that this algorithm has a regret bound of the order of and is asymptotically minimax under the constraint on the number of clusters. A RJMCMC-flavored implementation is also proposed. The second subject is related to the sequential learning of principal curves which seeks to represent a sequence of data by a continuous polygonal curve. To this aim, we introduce a procedure based on the MAP of Gibbs-posterior that can give polygonal lines whose number of segments can be chosen automatically. We also show that our procedure is supported by regret bounds with sublinear remainder terms. In addition, a greedy local search implementation that incorporates both sleeping experts and multi-armed bandit ingredients is presented. The third one concerns about the work which aims to fulfilling practical tasks within iAdvize, the company which supports this thesis. It includes sentiment analysis for textual messages by using methods in both text mining and statistics, and implementation of chatbot based on nature language processing and neural networks.

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