Robustness analysis of stochastic biochemical systems

PLoS One. 2014 Apr 21;9(4):e94553. doi: 10.1371/journal.pone.0094553. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / genetics
  • Gene Expression Regulation
  • Humans
  • Mammals
  • Models, Biological
  • Signal Transduction
  • Stochastic Processes
  • Systems Biology*

Grants and funding

This work has been supported by the Czech Science Foundation grant No. GAP202/11/0312. Milan Češka has been partially supported by the Ministry of Education, Youth, and Sport project No.∼CZ.1.07/2.3.00/30.0009 - Employment of Newly Graduated Doctors of Science for Scientific Excellence. David Šafránek has been partially supported by EC OP project No. CZ.1.07/2.3.00/20.0256. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.