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BMC Syst Biol. 2014 Oct 25;8:121. doi: 10.1186/s12918-014-0121-3.

Understanding disease mechanisms with models of signaling pathway activities.

Author information

1
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. psebastian@cipf.es.
2
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. evidalo@idibell.cat.
3
BIER, CIBER de Enfermedades Raras (CIBERER), Valencia, 46012, Spain. evidalo@idibell.cat.
4
Present Address: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. evidalo@idibell.cat.
5
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. pablo.minguez@embl.de.
6
Present Address: Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, 69117, Germany. pablo.minguez@embl.de.
7
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. aconesa@cipf.es.
8
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. starazona@cipf.es.
9
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. aamadoz@cipf.es.
10
Department of Statistics and Operations Research, University of Valencia, Valencia, 46100, Spain. Carmen.Armero@uv.es.
11
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. fsalavert@cipf.es.
12
BIER, CIBER de Enfermedades Raras (CIBERER), Valencia, 46012, Spain. fsalavert@cipf.es.
13
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.
14
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. dmontaner@cipf.es.
15
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Avda. Autopista del Saler, 16, 46012, Valencia, Spain. jdopazo@cipf.es.
16
BIER, CIBER de Enfermedades Raras (CIBERER), Valencia, 46012, Spain. jdopazo@cipf.es.
17
Functional Genomics Node, (INB) at CIPF, Valencia, Spain. jdopazo@cipf.es.

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.

PMID:
25344409
PMCID:
PMC4213475
DOI:
10.1186/s12918-014-0121-3
[Indexed for MEDLINE]
Free PMC Article

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