Training signaling pathway maps to biochemical data with constrained fuzzy logic: quantitative analysis of liver cell responses to inflammatory stimuli.

TitleTraining signaling pathway maps to biochemical data with constrained fuzzy logic: quantitative analysis of liver cell responses to inflammatory stimuli.
Publication TypeJournal Article
Year of Publication2011
AuthorsMorris, MK, Saez-Rodriguez, J, Clarke, DC, Sorger, PK, Lauffenburger, DA
JournalPLoS Comput Biol
Volume7
Issue3
Paginatione1001099
Date Published2011 Mar
ISSN1553-7358
KeywordsAlgorithms, Animals, Computational Biology, Computer Simulation, Cytokines, Fuzzy Logic, Hep G2 Cells, Humans, Inflammation Mediators, Liver, Models, Biological, Phosphorylation, Proteins, Rats, Reproducibility of Results, Signal Transduction
Abstract

Predictive understanding of cell signaling network operation based on general prior knowledge but consistent with empirical data in a specific environmental context is a current challenge in computational biology. Recent work has demonstrated that Boolean logic can be used to create context-specific network models by training proteomic pathway maps to dedicated biochemical data; however, the Boolean formalism is restricted to characterizing protein species as either fully active or inactive. To advance beyond this limitation, we propose a novel form of fuzzy logic sufficiently flexible to model quantitative data but also sufficiently simple to efficiently construct models by training pathway maps on dedicated experimental measurements. Our new approach, termed constrained fuzzy logic (cFL), converts a prior knowledge network (obtained from literature or interactome databases) into a computable model that describes graded values of protein activation across multiple pathways. We train a cFL-converted network to experimental data describing hepatocytic protein activation by inflammatory cytokines and demonstrate the application of the resultant trained models for three important purposes: (a) generating experimentally testable biological hypotheses concerning pathway crosstalk, (b) establishing capability for quantitative prediction of protein activity, and (c) prediction and understanding of the cytokine release phenotypic response. Our methodology systematically and quantitatively trains a protein pathway map summarizing curated literature to context-specific biochemical data. This process generates a computable model yielding successful prediction of new test data and offering biological insight into complex datasets that are difficult to fully analyze by intuition alone.

DOI10.1371/journal.pcbi.1001099
Alternate JournalPLoS Comput. Biol.
PubMed ID21408212
PubMed Central IDPMC3048376
Grant ListP50 GM068762-08 / GM / NIGMS NIH HHS / United States
P50-GM68762 / GM / NIGMS NIH HHS / United States
U54-CA112967 / CA / NCI NIH HHS / United States