Accelerated Sensitivity Analysis in High-Dimensional Stochastic Reaction Networks

PLoS One. 2015 Jul 10;10(7):e0130825. doi: 10.1371/journal.pone.0130825. eCollection 2015.

Abstract

Existing sensitivity analysis approaches are not able to handle efficiently stochastic reaction networks with a large number of parameters and species, which are typical in the modeling and simulation of complex biochemical phenomena. In this paper, a two-step strategy for parametric sensitivity analysis for such systems is proposed, exploiting advantages and synergies between two recently proposed sensitivity analysis methodologies for stochastic dynamics. The first method performs sensitivity analysis of the stochastic dynamics by means of the Fisher Information Matrix on the underlying distribution of the trajectories; the second method is a reduced-variance, finite-difference, gradient-type sensitivity approach relying on stochastic coupling techniques for variance reduction. Here we demonstrate that these two methods can be combined and deployed together by means of a new sensitivity bound which incorporates the variance of the quantity of interest as well as the Fisher Information Matrix estimated from the first method. The first step of the proposed strategy labels sensitivities using the bound and screens out the insensitive parameters in a controlled manner. In the second step of the proposed strategy, a finite-difference method is applied only for the sensitivity estimation of the (potentially) sensitive parameters that have not been screened out in the first step. Results on an epidermal growth factor network with fifty parameters and on a protein homeostasis with eighty parameters demonstrate that the proposed strategy is able to quickly discover and discard the insensitive parameters and in the remaining potentially sensitive parameters it accurately estimates the sensitivities. The new sensitivity strategy can be several times faster than current state-of-the-art approaches that test all parameters, especially in "sloppy" systems. In particular, the computational acceleration is quantified by the ratio between the total number of parameters over the number of the sensitive parameters.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms*
  • Biostatistics / methods*
  • ErbB Receptors / metabolism
  • Feedback, Physiological
  • Heat-Shock Proteins / metabolism
  • Homeostasis
  • Humans
  • Mathematical Computing
  • Models, Biological*
  • Reproducibility of Results
  • Stochastic Processes*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Heat-Shock Proteins
  • Tumor Suppressor Protein p53
  • ErbB Receptors

Grants and funding

The work of GA, MAK, and YP was supported in part by the Office of Advanced Scientific Computing Research, U.S. Department of Energy under Contract No. DE-SC0010723 as well as in part by the European Union (European Social Fund) and Greece (National Strategic Reference Framework), under the THALES Program, grant AMOSICSS.