Computational biology is an interdisciplinary field that focuses on developing mathematical models and algorithms to interpret biological data so as to understand biological problems. With current high-throughput technology development, different types of biological data can be measured in a large scale, which calls for more sophisticated computational methods to analyze and interpret the data. In this dissertation research work, we propose novel methods to integrate, model and analyze multiple biological data, including microarray gene expression data, protein-DNA interaction data and protein-protein interaction data. These methods will help improve our understanding of biological systems. First, we propose a knowledge-guided multi-scale independent component analysis (ICA) method for biomarker identification on time course microarray data. Guided by a knowledge gene pool related to a specific disease under study, the method can determine disease relevant biological components from ICA modes and then identify biologically meaningful markers related to the specific disease. We have applied the proposed method to yeast cell cycle microarray data and Rsf-1-induced ovarian cancer microarray data. The results show that our knowledge-guided ICA approach can extract biologically meaningful regulatory modes and outperform several baseline methods for biomarker identification. Second, we propose a novel method for transcriptional regulatory network identification by integrating gene expression data and protein-DNA binding data. The approach is built upon a multi-level analysis strategy designed for suppressing false positive predictions. With this strategy, a regulatory module becomes increasingly significant as more relevant gene sets are formed at finer levels. At each level, a two-stage support vector regression (SVR) method is utilized to reduce false positive predictions by integrating binding motif information and gene expression data; a significance analysis procedure is followed to assess the significance of each regulatory module. The resulting performance on simulation data and yeast cell cycle data shows that the multi-level SVR approach outperforms other existing methods in the identification of both regulators and their target genes. We have further applied the proposed method to breast cancer cell line data to identify condition-specific regulatory modules associated with estrogen treatment. Experimental results show that our method can identify biologically meaningful regulatory modules related to estrogen signaling and action in breast cancer. Third, we propose a bootstrapping Markov Random Filed (MRF)-based method for subnetwork identification on microarray data by incorporating protein-protein interaction data. Methodologically, an MRF-based network score is first derived by considering the dependency among genes to increase the chance of selecting hub genes. A modified simulated annealing search algorithm is then utilized to find the optimal/suboptimal subnetworks with maximal network score. A bootstrapping scheme is finally implemented to generate confident subnetworks. Experimentally, we have compared the proposed method with other existing methods, and the resulting performance on simulation data shows that the bootstrapping MRF-based method outperforms other methods in identifying ground truth subnetwork and hub genes. We have then applied our method to breast cancer data to identify significant subnetworks associated with drug resistance. The identified subnetworks not only show good reproducibility across different data sets, but indicate several pathways and biological functions potentially associated with the development of breast cancer and drug resistance. In addition, we propose to develop network-constrained support vector machines (SVM) for cancer classification and prediction, by taking into account the network structure to construct classification hyperplanes. The simulation study demonstrates the effectiveness of our proposed method. The study on the real microarray data sets shows that our network-constrained SVM, together with the bootstrapping MRF-based subnetwork identification approach, can achieve better classification performance compared with conventional biomarker selection approaches and SVMs. We believe that the research presented in this dissertation not only provides novel and effective methods to model and analyze different types of biological data, the extensive experiments on several real microarray data sets and results also show the potential to improve the understanding of biological mechanisms related to cancers by generating novel hypotheses for further study. / Ph. D.

Our intention is to find similarity among the time series expressions of the genes in microarray experiments. It is hypothesized that at a given time point the concentration of one gene’s mRNA is directly affected by the concentration of other gene’s mRNA, and may have biological significance. We define dissimilarity between two time-series data set as the variance of Euclidean distances of each time points. The large numbers of gene expressions make the calculation of variance of distance in each point computationally expensive and therefore computationally challenging in terms of execution time. For this reason we use autoregressive model which estimates nineteen points gene expression to a three point vector. It allows us to find variance of difference between two data sets without point-to-point matching. Previous analysis from the microarray experiments data found that 62 genes are regulated following EGF (Epidermal Growth Factor) and HRG (Heregulin) treatment of the MCF-7 breast cancer cells. We have chosen these suspected cancer-related genes as our reference and investigated which additional set of genes has similar time point expression profiles. Keeping variance of difference as a measure of distance, we have used several methods for clustering the gene expression data, such as our own maximum clique finding heuristics and hierarchical clustering. The results obtained were validated through a text mining study. New predictions from our study could be a basis for further investigations in the genesis of breast cancer. Overall in 84 new genes are found in which 57 genes are related to cancer among them 35 genes are associated with breast cancer.

Bayesian methods are often criticized on the grounds of subjectivity. Furthermore, misspecified priors can have a deleterious effect on Bayesian inference. Noting that model selection is effectively a test of many hypotheses, Dr. Valen E. Johnson sought to eliminate the need of prior specification by computing Bayes' factors from frequentist test statistics. In his pioneering work that was published in the year 2005, Dr. Johnson proposed using so-called local priors for computing Bayes? factors from test statistics. Dr. Johnson and Dr. Jianhua Hu used Bayes' factors for model selection in a linear model setting. In an independent work, Dr. Johnson and another colleage, David Rossell, investigated two families of non-local priors for testing the regression parameter in a linear model setting. These non-local priors enable greater separation between the theories of null and alternative hypotheses. In this dissertation, I extend model selection based on Bayes' factors and use nonlocal priors to define Bayes' factors based on test statistics. With these priors, I have been able to reduce the problem of prior specification to setting to just one scaling parameter. That scaling parameter can be easily set, for example, on the basis of frequentist operating characteristics of the corresponding Bayes' factors. Furthermore, the loss of information by basing a Bayes' factors on a test statistic is minimal. Along with Dr. Johnson and Dr. Hu, I used the Bayes' factors based on the likelihood ratio statistic to develop a method for clustering gene expression data. This method has performed well in both simulated examples and real datasets. An outline of that work is also included in this dissertation. Further, I extend the clustering model to a subclass of the decomposable graphical model class, which is more appropriate for genotype data sets, such as single-nucleotide polymorphism (SNP) data. Efficient FORTRAN programming has enabled me to apply the methodology to hundreds of nodes. For problems that produce computationally harder probability landscapes, I propose a modification of the Markov chain Monte Carlo algorithm to extract information regarding the important network structures in the data. This modified algorithm performs well in inferring complex network structures. I use this method to develop a prediction model for disease based on SNP data. My method performs well in cross-validation studies.

Genetic regulatory networks can model dynamics of cells. They also allow for studying the effect of internal or external interventions. Selectively applying interventions towards a certain objective is known as controlling network dynamics. In this thesis work, the issue of how the external interventions af fect the network is studied. The effects are determined using differential gene expression analysis. The differential gene expression problem is further studied to improve the power of the given method. Control problem for dynamic discrete regulatory networks is formulated. This also addresses the needs for various control strategies, e.g., finite horizon, infinite horizon, and various accounting of state and intervention costs. Control schemes for small to large networks are proposed and experimented. A case study is provided to show how the proposals are exploited / also given is the need for and effectiveness of various control schemes.

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Les microorganismes constituent la plus grande diversité du monde vivant. Ils jouent un rôle clef dans tous les processus biologiques grâce à leurs capacités d’adaptation et à la diversité de leurs capacités métaboliques. Le développement de nouvelles approches de génomique permet de mieux explorer les populations microbiennes. Dans ce contexte, les biopuces à ADN représentent un outil à haut débit de choix pour l'étude de plusieurs milliers d’espèces en une seule expérience. Cependant, la conception et l’analyse des biopuces à ADN, avec leurs formats de haute densité actuels ainsi que l’immense quantité de données à traiter, représentent des étapes complexes mais cruciales. Pour améliorer la qualité et la performance de ces deux étapes, nous avons proposé de nouvelles approches bioinformatiques pour la conception et l’analyse des biopuces à ADN en environnements parallèles. Ces approches généralistes et polyvalentes utilisent le calcul haute performance (HPC) et les nouvelles approches du génie logiciel inspirées de la modélisation, notamment l’ingénierie dirigée par les modèles (IDM) pour contourner les limites actuelles. Nous avons développé PhylGrid 2.0, une nouvelle approche distribuée sur grilles de calcul pour la sélection de sondes exploratoires pour biopuces phylogénétiques. Ce logiciel a alors été utilisé pour construire PhylOPDb: une base de données complète de sondes oligonucléotidiques pour l’étude des communautés procaryotiques. MetaExploArrays qui est un logiciel parallèle pour la détermination de sondes sur différentes architectures de calcul (un PC, un multiprocesseur, un cluster ou une grille de calcul), en utilisant une approche de méta-programmation et d’ingénierie dirigée par les modèles a alors été conçu pour apporter une flexibilité aux utilisateurs en fonction de leurs ressources matériel. PhylInterpret, quant à lui est un nouveau logiciel pour faciliter l’analyse des résultats d’hybridation des biopuces à ADN. PhylInterpret utilise les notions de la logique propositionnelle pour déterminer la composition en procaryotes d’échantillons métagénomiques. Enfin, une démarche d’ingénierie dirigée par les modèles pour la parallélisation de la traduction inverse d’oligopeptides pour le design des biopuces à ADN fonctionnelles a également été mise en place. / Microorganisms represent the largest diversity of the living beings. They play a crucial rôle in all biological processes related to their huge metabolic potentialities and their capacity for adaptation to different ecological niches. The development of new genomic approaches allows a better knowledge of the microbial communities involved in complex environments functioning. In this context, DNA microarrays represent high-throughput tools able to study the presence, or the expression levels of several thousands of genes, combining qualitative and quantitative aspects in only one experiment. However, the design and analysis of DNA microarrays, with their current high density formats as well as the huge amount of data to process, are complex but crucial steps. To improve the quality and performance of these two steps, we have proposed new bioinformatics approaches for the design and analysis of DNA microarrays in parallel and distributed environments. These multipurpose approaches use high performance computing (HPC) and new software engineering approaches, especially model driven engineering (MDE), to overcome the current limitations. We have first developed PhylGrid 2.0, a new distributed approach for the selection of explorative probes for phylogenetic DNA microarrays at large scale using computing grids. This software was used to build PhylOPDb: a comprehensive 16S rRNA oligonucleotide probe database for prokaryotic identification. MetaExploArrays, which is a parallel software of oligonucleotide probe selection on different computing architectures (a PC, a multiprocessor, a cluster or a computing grid) using meta-programming and a model driven engineering approach, has been developed to improve flexibility in accordance to user’s informatics resources. Then, PhylInterpret, a new software for the analysis of hybridization results of DNA microarrays. PhylInterpret uses the concepts of propositional logic to determine the prokaryotic composition of metagenomic samples. Finally, a new parallelization method based on model driven engineering (MDE) has been proposed to compute a complete backtranslation of short peptides to select probes for functional microarrays.

Dizertační práce se zabývá predikcí vysokodimenzionálních dat genových expresí. Množství dostupných genomických dat významně vzrostlo v průběhu posledního desetiletí. Kombinování dat genových expresí s dalšími daty nachází uplatnění v mnoha oblastech. Například v klinickém řízení rakoviny (clinical cancer management) může přispět k přesnějšímu určení prognózy nemocí. Hlavní část této dizertační práce je zaměřena na kombinování dat genových expresí a klinických dat. Používáme logistické regresní modely vytvořené prostřednictvím různých regularizačních technik. Generalizované lineární modely umožňují kombinování modelů s různou strukturou dat. V dizertační práci je ukázáno, že kombinování modelu dat genových expresí a klinických dat může vést ke zpřesnění výsledku predikce oproti vytvoření modelu pouze z dat genových expresí nebo klinických dat. Navrhované postupy přitom nejsou výpočetně náročné.  Testování je provedeno nejprve se simulovanými datovými sadami v různých nastaveních a následně s~reálnými srovnávacími daty. Také se zde zabýváme určením přídavné hodnoty microarray dat. Dizertační práce obsahuje porovnání příznaků vybraných pomocí klasifikátoru genových expresí na pěti různých sadách dat týkajících se rakoviny prsu. Navrhujeme také postup výběru příznaků, který kombinuje data genových expresí a znalosti z genových ontologií.