Two models are proposed to describe interactions among genes, transcription factors, and signaling cascades involved in regulating a cellular sub-system. These models fall within the class of Markovian regulatory networks, and can accommodate for different biological time scales. These regulatory networks are used to study pathological cellular dynamics and discover treatments that beneficially alter those dynamics. The salient translational goal is to design effective therapeutic actions that desirably modify a pathological cellular behavior via external treatments that vary the expressions of targeted genes. The objective of therapeutic actions is to reduce the likelihood of the pathological phenotypes related to a disease. The task of finding effective treatments is formulated as sequential decision making processes that discriminate the gene-expression profiles with high pathological competence versus those with low pathological competence. Thereby, the proposed computational frameworks provide tools that facilitate the discovery of effective drug targets and the design of potent therapeutic actions on them. Each of the proposed system-based therapeutic methods in this dissertation is motivated by practical and analytical considerations. First, it is determined how asynchronous regulatory models can be used as a tool to search for effective therapeutic interventions. Then, a constrained intervention method is introduced to incorporate the side-effects of treatments while searching for a sequence of potent therapeutic actions. Lastly, to bypass the impediment of model inference and to mitigate the numerical challenges of exhaustive search algorithms, a heuristic method is proposed for designing system-based therapies. The presentation of the key ideas in method is facilitated with the help of several case studies.

The development of cDNA microarray technology has made it possible to simultaneously monitor the expression status of thousands of genes. A natural use for this vast amount of information would be to try and figure out inter-gene relationships by studying the gene expression patterns across different experimental conditions and to build Gene Regulatory Networks from these data. In this thesis, we study some of the issues involved in Genetic Regulatory Networks. One of them is to discover and elucidate multivariate logical predictive relations among gene expressions and to demonstrate how these logical relations based on coarse quantization closely reflect corresponding relations in the continuous data. The other issue involves construction of synthetic Probabilistic Boolean Networks with particular attractor structures. These synthetic networks help in testing of various algorithms like Bayesian Connectivity based approach for design of Probabilistic Boolean Networks.

Genetic regulatory network (GRN) is a fundamental research area in systems biology. This thesis studies the stability of a class of GRN models. First, a condition is proposed to ensure the robust stability of uncertain GRNs with SUM regulatory functions. It is assumed that the uncertainties are in the form of a parameter vector that determines the coefficients of the model via given functions. Then, the global asymptotic stability conditions of uncertain GRNs affected by disturbances and time delays are further explored. The conditions are obtained by solving a convex optimization problem by exploring the sum of squares (SOS) of matrix polynomials and by introducing polynomially parameter-dependent Lyapunov-Krasovskii functionals (LKFs). Moreover, based on the uncertain GRNs with guaranteed disturbance attenuation, it is shown that estimates of the sought stable uncertainty sets can be obtained through a recursive strategy based on parameter-dependent Lyapunov functions and the SOS. Second, the stability conditions of GRNs described by piecewise models are considered. Depending on whether the state partitions and mode transitions are known or unknown as priori, the proposed networks are divided into two categories, i.e., switched GRNs and hybrid GRNs. It is shown that, by using common polynomial Lyapunov functions and piecewise polynomial Lyapunov functions, two conditions are established to ensure the global asymptotic stability for switched and hybrid GRNs, respectively. In addition, it is shown that, by using the SOS techniques, stability conditions in the form of LMIs for both models can be obtained. Third, the multi-stability of uncertain GRNs with multivariable regulation functions is investigated. It is shown that, by using the Lyapunov functional method and LMI technology, a criterion is established to ensure the robust asymptotical stability of the uncertain GRNs, and such condition can be extended to deal with the multi-stability problem. Moreover, it is shown that by using the square matrix representation (SMR) and by adopting polynomially parameter-dependent Lyapunov functions, a condition in the form of LMIs for robust stability for all admissible uncertainties can be obtained. Examples with synthetic and real biological models are presented in each section to illustrate the applicability and effectiveness of the theoretical results. / published_or_final_version / Electrical and Electronic Engineering / Doctoral / Doctor of Philosophy

With the advent of high throughput measurement technologies, large scale gene expression data are available for analysis. Various computational methods have been introduced to analyze and predict meaningful molecular interactions from gene expression data. Such patterns can provide an understanding of the regulatory mechanisms in the cells. In the past, system identification algorithms have been extensively developed for engineering systems. These methods capture the dynamic input/output relationship of a system, provide a deterministic model of its function, and have reasonable computational requirements. In this work, two system identification methods are applied for reverse engineering of gene regulatory networks. The first method is based on an orthogonal search; it selects terms from a predefined set of gene expression profiles to best fit the expression levels of a given output gene. The second method consists of a few cascades, each of which includes a dynamic component and a static component. Multiple cascades are added in a parallel to reduce the difference of the estimated expression profiles with the actual ones. Gene regulatory networks can be constructed by defining the selected inputs as the regulators of the output. To assess the performance of the approaches, a temporal synthetic dataset is developed. Methods are then applied to this dataset as well as the Brainsim dataset, a popular simulated temporal gene expression data. Furthermore, the methods are also applied to a biological dataset in yeast Saccharomyces Cerevisiae. This dataset includes 14 cell-cycle regulated genes; their known cell cycle pathway is used as the target network structure, and the criteria sensitivity, precision, and specificity are calculated to evaluate the inferred networks through these two methods. Resulting networks are also compared with two previous studies in the literature on the same dataset. / Thesis (Master, Computing) -- Queen's University, 2010-10-18 20:47:36.458

Gene regulatory networks analyze the relationships between genes allowing us to un- derstand the gene regulatory interactions in systems biology. Gene expression data from the microarray experiments is used to obtain the gene regulatory networks. How- ever, the microarray data is discrete, noisy and non-linear which makes learning the networks a challenging problem and existing gene network inference methods do not give consistent results. Current state-of-the-art study uses the average-ranking-based consensus method to combine and average the ranked predictions from individual methods. However each individual method has an equal contribution to the consen- sus prediction. We have developed a linear programming-based consensus approach which uses learned weights from linear programming among individual methods such that the methods have di↵erent weights depending on their performance. Our result reveals that assigning di↵erent weights to individual methods rather than giving them equal weights improves the performance of the consensus. The linear programming- based consensus method is evaluated and it had the best performance on in silico and Saccharomyces cerevisiae networks, and the second best on the Escherichia coli network outperformed by Inferelator Pipeline method which gives inconsistent results across a wide range of microarray data sets.

Stochastic modeling to represent intrinsic and extrinsic noise is an important challenge in molecular systems biology. There are numerous ways to model intrinsic noise. One framework for intrinsic noise in gene regulatory networks was recently proposed within the discrete setting. In contrast, extrinsic perturbations were rarely modeled due to the complex mechanisms that contribute to its emergence. Here a discrete framework to model extrinsic noise is proposed. The interacting species of the model are represented by discrete variables and are perturbed to represent extrinsic noise. In particular, they are subject to a discretized lognormal distribution. Additionally, a delay is imposed on the update with a certain probability. These two perturbations represent global extrinsic noise and pathway-specic extrinsic noise. It leads to large variations in the concentration of proteins, which is consistent with an existing continuous way of modeling extrinsic fluctuations. The framework is applied to three different published discrete models: the cell fate of lambda phage infection of bacteria, the lactose utilization system in E. coli, and a signaling network in melanoma cells. The framework captures factors that signicantly contribute to the random decision between lysis and lysogeny as well as explains the bistable switch in the model of the lac operon. Finally, a feed-forward loop analysis is conducted by measuring and comparing the noise level in the target protein of feed-forward loops. This analysis reveals the ability of certain feed-forward loops to attenuate or amplify fluctuations, dependent upon various levels of noise. In conclusion, this thesis aims to resolve the question of how the extrinsic noise can be modeled and how biological systems are able to maintain functionality in the wake of such large variations. / Master of Science

During the past decade, many successful deterministic models of macromolecular regulatory networks have been built. Deterministic simulations of these models can show only average dynamics of the systems. However, stochastic simulations of macromolecular regulatory models can account for behaviors that are introduced by the noisy nature of the systems but not revealed by deterministic simulations. Thus, converting an existing model of value from the most common deterministic formulation to one suitable for stochastic simulation enables further investigation of the regulatory network. Although many different stochastic models can be developed and evolved from deterministic models, a direct conversion is the first step in practice. This conversion process is tedious and error-prone, especially for complex models. Thus, we seek to automate as much of the conversion process as possible. However, deterministic models often omit key information necessary for a stochastic formulation. Specifically, values in the model have to be scaled before a complete conversion, and the scaling factors are typically not given in the deterministic model. Several functionalities helping model scaling and converting are introduced and implemented in the JigCell modeling environment. Our tool makes it easier for the modeler to include complete details as well as to convert the model. Stochastic simulations are known for being computationally intensive, and thus require high performance computing facilities to be practical. With parallel computation on Virginia Tech's System X supercomputer, we are able to obtain the first stochastic simulation results for realistic cell cycle models. Stochastic simulation results for several mutants, which are thought to be biologically significant, are presented. Successful deployment of the enhanced modeling environment demonstrates the power of our techniques. / Master of Science

Zhang, Qing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 129-148). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

In spite of many efforts in the past, inference or reverse engineering of regulatory networks from microarray data remains an unsolved problem in the area of systems biology. Such regulatory networks play a critical role in cellular function and organization and are of interest in the study of a variety of disease areas and ecotoxicology to name a few. This dissertation proposes information theoretic methods/algorithms for inferring regulatory networks from microarray data. Most of the algorithms proposed in this dissertation can be implemented both on time series and multifactorial microarray data sets. The work proposed here infers regulatory networks considering the following six factors: (i) computational efficiency to infer genome-scale networks, (ii) incorporation of prior biological knowledge, (iii) choosing the optimal network that minimizes the joint network entropy, (iv) impact of higher order structures (specifically 3-node structures) on network inference (v) effects of the time sensitivity of regulatory interactions and (vi) exploiting the benefits of existing/proposed metrics and algorithms for reverse engineering using the concept of consensus of consensus networks. Specifically, this dissertation presents an approach towards incorporating knock-out data sets. The proposed method for incorporating knock-out data sets is flexible so that it can be easily adapted in existing/new approaches. While most of the information theoretic approaches infer networks based on pair-wise interactions this dissertation discusses inference methods that consider scoring edges from complex structures. A new inference method for building consensus networks based on networks inferred by multiple popular information theoretic approaches is also proposed here. For time-series datasets, new information theoretic metrics were proposed considering the time-lags of regulatory interactions estimated from microarray datasets. Finally, based on the scores predicted for each possible edge in the network, a probabilistic minimum description length based approach was proposed to identify the optimal network (minimizing the joint network entropy). Comparison analysis on in-silico and/or real time data sets have shown that the proposed algorithms achieve better inference accuracy and/or higher computational efficiency as compared with other state-of-the-art schemes such as ARACNE, CLR and Relevance Networks. Most of the methods proposed in this dissertation are generalized and can be easily incorporated into new methods/algorithms for network inference.

High-throughput technologies for measuring gene expression made inferring of the genome-wide Gene Regulatory Networks an active field of research. Reverse-engineering of systems of transcriptional regulations became an important challenge in molecular and computational biology. Because such systems model dependencies between genes, they are important in understanding of cell behavior, and can potentially turn observed expression data into the new biological knowledge and practical applications. In this dissertation we introduce a set of algorithms, which infer networks of transcriptional regulations from variety of expression profiles with superior accuracy compared to the state-of-the-art techniques. The proposed methods make use of ensembles of trees, which became popular in many scientific fields, including genetics and bioinformatics. However, originally they were motivated from the perspective of classification, regression, and feature selection theory. In this study we exploit their relative variable importance measure as an indication of the presence or absence of a regulatory interaction between genes. We further analyze their predictions on a set of the universally recognized benchmark expression data sets, and achieve favorable results in compare with the state-of-the-art algorithms.