title: Understanding disease mechanisms with models of signaling pathway activities.
abstract: BACKGROUND
  Understanding 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.
  
  
  RESULTS
  Here 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. psebastian@cipf.es.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sebastian-Leon
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. evidalo@idibell.cat.|BIER, CIBER de Enfermedades Raras (CIBERER), Valencia, 46012, Spain. evidalo@idibell.cat.|Present Address: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. evidalo@idibell.cat.
authors.forename: Enrique
authors.initials: E
authors.lastname: Vidal
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. pablo.minguez@embl.de.|Present Address: Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, 69117, Germany. pablo.minguez@embl.de.
authors.forename: Pablo
authors.initials: P
authors.lastname: Minguez
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. aconesa@cipf.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Conesa
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. starazona@cipf.es.
authors.forename: Sonia
authors.initials: S
authors.lastname: Tarazona
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. aamadoz@cipf.es.
authors.forename: Alicia
authors.initials: A
authors.lastname: Amadoz
authors.affiliation: Department of Statistics and Operations Research, University of Valencia, Valencia, 46100, Spain. Carmen.Armero@uv.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Armero
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. fsalavert@cipf.es.|BIER, CIBER de Enfermedades Raras (CIBERER), Valencia, 46012, Spain. fsalavert@cipf.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Salavert
authors.affiliation: Institute of Metabolic Science - Metabolic Research Laboratories and Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. ajv22@medschl.cam.ac.uk.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. dmontaner@cipf.es.
authors.forename: David
authors.initials: D
authors.lastname: Montaner
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. jdopazo@cipf.es.|BIER, CIBER de Enfermedades Raras (CIBERER), Valencia, 46012, Spain. jdopazo@cipf.es.|Functional Genomics Node, (INB) at CIPF, Valencia, Spain. jdopazo@cipf.es.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D003198:Computer Simulation; D004194:Disease; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D020407:Internet; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*; D012984:Software; D013045:Species Specificity
chemical_list: D015415:Biomarkers