Quantification of biological network perturbations for mechanistic insight and diagnostics using two-layer causal models

Background: High-throughput measurement technologies such as microarrays provide complex datasets reflecting mechanisms perturbed in an experiment, typically a treatment vs. control design. Analysis of these information rich data can be guided based on a priori knowledge, such as networks or set of related proteins or genes. Among those, cause-and-effect network models are becoming increasingly popular and more than eighty such models, describing processes involved in cell proliferation, cell fate, cell stress, and inflammation have already been published. A meaningful systems toxicology approach to study the response of a cell system, or organism, exposed to bio-active substances requires a quantitative measure of dose-response at network level, to go beyond the differential expression of single genes. Results: We developed a method that quantifies network response in an interpretable manner. It fully exploits the (signed graph) structure of cause-and-effect networks models to integrate and mine transcriptomics measurements. The presented approach also enables the extraction of network-based signatures for predicting a phenotype of interest. The obtained signatures are coherent with the underlying network perturbation and can lead to more robust predictions across independent studies. The value of the various components of our mathematically coherent approach is substantiated using several in vivo and in vitro transcriptomics datasets. As a proof-of-principle, our methodology was applied to unravel mechanisms related to the efficacy of a specific anti-inflammatory drug in patients suffering from ulcerative colitis. A plausible mechanistic explanation of the unequal efficacy of the drug is provided. Moreover, by utilizing the underlying mechanisms, an accurate and robust network-based diagnosis was built to predict the response to the treatment. Conclusion: The presented framework efficiently integrates transcriptomics data and "cause and effect" network models to enable a mathematically coherent framework from quantitative impact assessment and data interpretation to patient stratification for diagnosis purposes.