Identifying Interventional and Pathogenic Mechanisms by Generative Inverse Modeling of Gene Expression Profiles

Abstract

Motivation: The characterization of genetic mechanisms underlying normal cellular function, cancer development, pathogenesis, and the effect of drug treatment is one of the most challenging topics for cancer research and molecular biology. Existing methods for inferring genetic regulatory networks from genomewide expression profiles provide important information about gene interactions and regulatory relationships. However, these methods do not provide information about the impact of possible interventions or changes on such regulatory networks to study cause–effect relationships at a systems-biology level. Results: We present a data-driven method called generative inverse modeling, which simulates the effect of local genetic changes on the global cellular state, as reflected by an altered genomewide expression profile. For each genetic change we define a pathogenic score by calculating to what extent it transforms the simulated expression patterns into patterns measured for pathologically altered tissues. The method can be used to estimate the relevance of genes for disease-specific genetic mechanisms, e.g., as presented here for pathogenesis. Generative inverse modeling is based on a Bayesian probability density estimation from a set of measured gene-expression patterns.