Epistemology of computational biology: Mathematical models and experimental prediction as the basis of their validity

Knowing the roles of mathematics and computation in experimental science is important for computational biology because these roles determine to a great extent how research in this field should be pursued and how it should relate to biology in general. The present paper examines the epistemology of computational biology from the perspective of modern science, the underlying principle of which is that a scientific theory must have two parts: (1) a structural model, which is a mathematical construct that aims to represent a selected portion of physical reality and (2) a well-defined procedure for relating consequences of the model to quantifiable observations. We also explore the contingency and creative nature of a scientific theory. Among the questions considered are: Can computational biology form the theoretical core of biology? What is the basis, if any, for choosing one particular model over another? And what is the role of computation in science, and in biology in particular? We examine how this broad epistemological framework applies to important statistical methodologies pertaining to computational biology, such as expression-based phenotype classification, gene regulatory networks, and clustering. We consider classification in detail, as the epistemological issues raised by classification are related to all computational-biology topics in which statistical prediction plays a key role. We pay particular attention to classifier-model validity and its relation to estimation rules.