Causal interactions from proteomic profiles: molecular data meets pathway knowledge

ABSTRACT Measurement of changes in protein levels and in post-translational modifications, such as phosphorylation, can be highly informative about the phenotypic consequences of genetic differences or about the dynamics of cellular processes. Typically, such proteomic profiles are interpreted intuitively or by simple correlation analysis. Here, we present a computational method to generate causal explanations for proteomic profiles using prior mechanistic knowledge in the literature, as recorded in cellular pathway maps. To demonstrate its potential, we use this method to analyze the cascading events after EGF stimulation of a cell line, to discover new pathways in platelet activation, to identify influential regulators of oncoproteins in breast cancer, to describe signaling characteristics in predefined subtypes of ovarian and breast cancers, and to highlight which pathway relations are most frequently activated across 32 cancer types. Causal pathway analysis, that combines molecular profiles with prior biological knowledge captured in computational form, may become a powerful discovery tool as the amount and quality of cellular profiling rapidly expands. The method is freely available at http://causalpath.org .