Lumpability abstractions of rule-based systems

Theoretical Computer Science (Impact Factor: 0.52). 05/2012; 431:137--164. DOI: 10.1016/j.tcs.2011.12.059
Source: OAI

ABSTRACT The induction of a signaling pathway is characterized by transient complex formation and mutual posttranslational modification of proteins. To faithfully capture this combinatorial process in a mathematical model is an important challenge in systems biology. Exploiting the limited context on which most binding and modification events are conditioned, attempts have been made to reduce the combinatorial complexity by quotienting the reachable set of molecular species, into species aggregates while preserving the deterministic semantics of the thermodynamic limit. Recently we proposed a quotienting that also preserves the stochastic semantics and that is complete in the sense that the semantics of individual species can be recovered from the aggregate semantics.
In this paper we prove that this quotienting yields a sufficient condition for \emph{weak lumpability} and that it gives rise to a backward Markov bisimulation between the original and aggregated transition system. We illustrate the framework on a case study of the EGF/insulin receptor crosstalk.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Biochemical networks are used in computational biology, to model mechanistic details of systems involved in cell signaling, metabolism, and regulation of gene expression. Parametric and structural uncertainty, as well as combinatorial explosion are strong obstacles against analyzing the dynamics of large models of this type. Multiscaleness, an important property of these networks, can be used to get past some of these obstacles. Networks with many well separated time scales, can be reduced to simpler models, in a way that depends only on the orders of magnitude and not on the exact values of the kinetic parameters. The main idea used for such robust simplifications of networks is the concept of dominance among model elements, allowing hierarchical organization of these elements according to their effects on the network dynamics. This concept finds a natural formulation in tropical geometry. We revisit, in the light of these new ideas, the main approaches to model reduction of reaction networks, such as quasi-steady state (QSS) and quasi-equilibrium approximations (QE), and provide practical recipes for model reduction of linear and non-linear networks. We also discuss the application of model reduction to the problem of parameter identification, via backward pruning machine learning techniques.
    Frontiers in Genetics 05/2012; 3:131.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this paper, we present a method for reducing a regular, discrete-time Markov chain (DTMC) to another DTMC with a given, typically much smaller number of states. The cost of reduction is defined as the Kullback-Leibler divergence rate between a projection of the original process through a partition function and the a DTMC on the correspondingly partitioned state space. Finding the reduced model with minimal cost is computationally expensive, as it requires exhaustive search among all state space partitions, and exact evaluation of the reduction cost for each candidate partition. In our approach, we optimize an upper bound on the reduction cost instead of the exact cost; The proposed upper bound is easy to compute and it is tight in the case when the original chain is lumpable with respect to the partition. Then, we express the problem in form of information bottleneck optimization, and we propose the agglomerative information bottleneck algorithm for finding a locally optimal solution. The theory is illustrated with examples and one application scenario in the context of modeling bio-molecular interactions.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this paper, we discuss a method for decomposition, abstraction and reconstruction of the stochastic semantics of rule-based systems with conserved number of agents. Abstraction is induced by counting fragments instead of the species, which are the standard entities of information in molecular signaling. The rule-set can be decomposed to smaller rule-sets, so that the fragment-based dynamics of the whole rule-set is exactly a composition of species-based dynamics of smaller rule-sets. The reconstruction of the transient species-based dynamics is possible for certain initial distributions. We show that, if all the rules in a rule set are reversible, the reconstruction of the species-based dynamics is always possible at the stationary distribution. We use a case study of colloidal aggregation to demonstrate that the method can reduce the state space exponentially with respect to the standard, species-based description.
    Electronic Notes in Theoretical Computer Science 284:105–124.

Full-text (2 Sources)

Available from
Jun 1, 2014