|Title||Understanding disease mechanisms with models of signaling pathway activities.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Sebastián-Leon, P, Vidal, E, Minguez, P, Conesa, A, Tarazona, S, Amadoz, A, Armero, C, Salavert, F, Vidal-Puig, A, Montaner, D, Dopazo, J|
|Journal||BMC systems biology|
|Date Published||2014 Oct 25|
|Keywords||Disease mechanism; pathway; signalling; Systems biology|
BackgroundUnderstanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine.ResultsHere we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets.ConclusionsThe proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.