title: Discrete Logic Modelling Optimization to Contextualize Prior Knowledge Networks Using PRUNET.
abstract: High-throughput technologies have led to the generation of an increasing amount of data in different areas of biology. Datasets capturing the cell's response to its intra- and extra-cellular microenvironment allows such data to be incorporated as signed and directed graphs or influence networks. These prior knowledge networks (PKNs) represent our current knowledge of the causality of cellular signal transduction. New signalling data is often examined and interpreted in conjunction with PKNs. However, different biological contexts, such as cell type or disease states, may have distinct variants of signalling pathways, resulting in the misinterpretation of new data. The identification of inconsistencies between measured data and signalling topologies, as well as the training of PKNs using context specific datasets (PKN contextualization), are necessary conditions to construct reliable, predictive models, which are current challenges in the systems biology of cell signalling. Here we present PRUNET, a user-friendly software tool designed to address the contextualization of a PKNs to specific experimental conditions. As the input, the algorithm takes a PKN and the expression profile of two given stable steady states or cellular phenotypes. The PKN is iteratively pruned using an evolutionary algorithm to perform an optimization process. This optimization rests in a match between predicted attractors in a discrete logic model (Boolean) and a Booleanized representation of the phenotypes, within a population of alternative subnetworks that evolves iteratively. We validated the algorithm applying PRUNET to four biological examples and using the resulting contextualized networks to predict missing expression values and to simulate well-characterized perturbations. PRUNET constitutes a tool for the automatic curation of a PKN to make it suitable for describing biological processes under particular experimental conditions. The general applicability of the implemented algorithm makes PRUNET suitable for a variety of biological processes, for instance cellular reprogramming or transitions between healthy and disease states.
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
authors.forename: Isaac
authors.initials: I
authors.lastname: Crespo
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
authors.forename: Anna
authors.initials: A
authors.lastname: Fournier
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
authors.forename: Antonio
authors.initials: A
authors.lastname: del Sol
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D058750:Epithelial-Mesenchymal Transition; D000066449:Human Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D019359:Knowledge; D008128:Logic; D032383:Myocytes, Cardiac / Q000166:cytology; D012984:Software; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology; D014584:User-Computer Interface