Analysis of molecular expression patterns and integration with other knowledge bases using probabilistic Bayesian network models

How can molecular expression experiments be interpreted with greater than ten to the fourth measurements per chip? How can one get the most quantitative information possible from the experimental data with good confidence? These are important questions whose solutions require an interdisciplinary combination of molecular and cellular biology, computer science, statistics, and complex systems analysis. The explosion of data from microarray techniques present the problem of interpreting the experiments. The availability of large-scale knowledge bases provide the opportunity to maximize the information extracted from these experiments. We have developed new methods of discovering biological function, metabolic pathways, and regulatory networks from these data and knowledge bases. These techniques are applicable to analyses for biomedical engineering, clinical, and fundamental cell and molecular biology studies. Our approach uses probabilistic, computational methods that give quantitative interpretations of data in a biological context. We have selected Bayesian statistical models with graphical network representations as a framework for our methods. As a first step, we use a nave Bayesian classifier to identify statistically significant patterns in gene expression data. We have developed methods which allow us to (a) characterize which genes or experiments distinguish each class from the others, (b) cross-index the resulting classes with other databases to assess biological meaning of the classes, and (c) display a gross overview of cellular dynamics. We have developed a number of visualization tools to convey the results. We report here our methods of classification and our first attempts at integrating the data and other knowledge bases together with new visualization tools. We demonstrate the utility of these methods and tools by analysis of a series of yeast cDNA microarray data and to a set of cancerous/normal sample data from colon cancer patients. We discuss extending our methods to inferring biological pathways and networks using more complex dynamic Bayesian networks