AbstractsComputer Science

Modeling and learning realistic genetic interactions using dynamic Bayesian network and information theory

by Nizamul Morshed

Institution: Monash University
Department: Gippsland School of IT
Year: 2013
Keywords: Gene regulatory network; Dynamic Bayesian network; DNA microarray data
Record ID: 1041973
Full text PDF: http://arrow.monash.edu.au/hdl/1959.1/915637


Deciphering genetic interactions is of fundamental importance in computational systems biology, with wide applications in a number of other associated areas. Realistic modeling of these interactions poses novel challenges while dealing with the problem. Further, learning these interactions using computational methods becomes increasingly complex with the adoption of advanced and more realistic modeling techniques. In this thesis, we propose methods to address this challenge using a graphical model having sound probabilistic underpinnings, commonly known as dynamic Bayesian networks. Inference of genetic interactions is usually carried out using DNA microarray data. This data provides snapshots of mRNA expression levels of a large number of genes from a single experiment. However, the number of samples from such experiments is small, and additionally, they contain missing values and noise. Bayesian networks are considered as one of the most promising ways by which these issues can be tackled. However, traditional Bayesian networks have their own limitations; for example, they neither take time information into account nor can they capture feedback. Further, accurate determination of the direction of regulation requires a significant number of tests to be performed. Dynamic Bayesian networks (DBN) are extensions of Bayesian networks that can effectively address these limitations. In this thesis, we develop novel techniques for gene regulatory network reconstruction using DBN based modeling approach. We start with a basic DBN based model, and improve it so that it can represent and model both instantaneous and time-delayed genetic interactions. Initially, we aim to detect the occurrence of instantaneous and single-step time-delayed interactions, and subsequently this approach is further extended to model the instantaneous and multi-step time-delayed interactions. This approach of modeling both instantaneous and multi-step time-delayed genetic interactions is superior to traditional DBN based GRN reconstruction techniques, where only the time delayed interactions are learnt.%, thereby advancing the state of the art for modeling genetic regulations using DBNs. In addition to modeling interactions, one needs a learning mechanism for inferring genetic interactions. To facilitate detection of nonlinear gene to gene interactions (in addition to linear interactions), which are prevalent in all genetic networks, we propose using well known properties, including fundamental results related to information theoretic measures for testing conditional independence relations in a DBN. This enables us to formulate efficient learning techniques for reconstructing GRNs. Using these theoretical underpinnings, we first implement simple hill-climbing techniques that enable detection of various types of interactions among genes. Subsequently, we use these results to devise novel score and search based evolutionary computation techniques, which can effectively explore a significantly larger search space. We carry out investigations using both…