title: Robustness analysis of stochastic biochemical systems.
abstract: We propose a new framework for rigorous robustness analysis of stochastic biochemical systems that is based on probabilistic model checking techniques. We adapt the general definition of robustness introduced by Kitano to the class of stochastic systems modelled as continuous time Markov Chains in order to extensively analyse and compare robustness of biological models with uncertain parameters. The framework utilises novel computational methods that enable to effectively evaluate the robustness of models with respect to quantitative temporal properties and parameters such as reaction rate constants and initial conditions. We have applied the framework to gene regulation as an example of a central biological mechanism where intrinsic and extrinsic stochasticity plays crucial role due to low numbers of DNA and RNA molecules. Using our methods we have obtained a comprehensive and precise analysis of stochastic dynamics under parameter uncertainty. Furthermore, we apply our framework to compare several variants of two-component signalling networks from the perspective of robustness with respect to intrinsic noise caused by low populations of signalling components. We have successfully extended previous studies performed on deterministic models (ODE) and showed that stochasticity may significantly affect obtained predictions. Our case studies demonstrate that the framework can provide deeper insight into the role of key parameters in maintaining the system functionality and thus it significantly contributes to formal methods in computational systems biology.
authors.affiliation: Systems Biology Laboratory at Faculty of Informatics, Masaryk University, Brno, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Ceska
authors.affiliation: Systems Biology Laboratory at Faculty of Informatics, Masaryk University, Brno, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Safránek
authors.affiliation: Systems Biology Laboratory at Faculty of Informatics, Masaryk University, Brno, Czech Republic.
authors.forename: Sven
authors.initials: S
authors.lastname: Dražan
authors.affiliation: Systems Biology Laboratory at Faculty of Informatics, Masaryk University, Brno, Czech Republic.
authors.forename: Luboš
authors.initials: L
authors.lastname: Brim
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008322:Mammals; D008954:Models, Biological; D015398:Signal Transduction; D013269:Stochastic Processes; D049490:Systems Biology
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19931-5
references.pmid: 18077424
references.citation: Bioinformatics. 2006 Dec 15;22(24):3067-74
references.pmid: 17032683
references.citation: Nat Genet. 2004 May;36(5):486-91
references.pmid: 15107854
references.citation: J Math Biol. 2014 Sep;69(3):687-735
references.pmid: 23918091
references.citation: Syst Biol (Stevenage). 2006 Jul;153(4):168-78
references.pmid: 16986618
references.citation: BMC Bioinformatics. 2012;13 Suppl 17:S15
references.pmid: 23282174
references.citation: Trends Biotechnol. 2001 Oct;19(10):401-6
references.pmid: 11587765
references.citation: IEEE/ACM Trans Comput Biol Bioinform. 2012 May-Jun;9(3):693-705
references.pmid: 21788679
references.citation: PLoS Comput Biol. 2011 Nov;7(11):e1002218
references.pmid: 22215991
references.citation: IET Syst Biol. 2010 Nov;4(6):441-52
references.pmid: 21073242
references.citation: PLoS One. 2011;6(9):e24246
references.pmid: 21980344
references.citation: IET Syst Biol. 2011 Jan;5(1):58
references.pmid: 21261403
references.citation: J Chem Phys. 2006 Jan 28;124(4):044104
references.pmid: 16460146
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):691-6
references.pmid: 12522261
references.citation: Brief Bioinform. 2010 May;11(3):301-12
references.pmid: 20478855
references.citation: IEEE Trans Biomed Circuits Syst. 2008 Jun;2(2):114-32
references.pmid: 23852758
references.citation: BMC Bioinformatics. 2012 May 01;13:68
references.pmid: 22548918
references.citation: Mol Syst Biol. 2007;3:137
references.pmid: 17882156
references.citation: Genome Res. 2003 Aug;13(8):1863-72
references.pmid: 12902380
references.citation: Nat Rev Genet. 2004 Nov;5(11):826-37
references.pmid: 15520792
references.citation: Int J Comput Biol Drug Des. 2009;2(2):134-48
references.pmid: 20090167
references.citation: Bioinformatics. 2004 Jul 10;20(10):1506-11
references.pmid: 15231543
references.citation: Biophys J. 2007 Jul 1;93(1):11-20
references.pmid: 17416630
references.citation: Bioinformatics. 2009 Jun 15;25(12):i169-78
references.pmid: 19477984
references.citation: Interface Focus. 2011 Dec 6;1(6):807-20
references.pmid: 23226583