In Mathematical Biology, many dynamical models of biochemical reaction systems are presented with Ordinary Differential Equations (ODE). Once kinetic parameter values are fixed, this simple mathematical formalism completely defines the dynamical behavior of a system of biochemical reactions and provides powerful tools for deterministic simulations, parameter sensitivity analysis, bifurcation analysis, etc. However, without requiring any information on the reaction kinetics and parameter values, various qualitative analyses can be performed using the structure of the reactions, provided the reactants, products and modifiers of each reaction are precisely defined. In order to apply these structural methods to parametric ODE models, we study a mathematical condition for expressing the consistency between the structure and the kinetics of a reaction, without restricting to Mass Action law kinetics. This condition, satisfied in particular by standard kinetic laws, entails a remarkable property of independence of the influence graph from the kinetics of the reactions. We derive from this study a heuristic algorithm which, given a system of ODEs as input, computes a system of reactions with the same ODE semantics, by inferring well-formed reactions whenever possible. We show how this strategy is capable of automatically curating the writing of ODE models in SBML, and present some statistics obtained on the model repository biomodels.net. 1 .
Motivation: In Systems Biology, an increasing collection of models of various biological processes is currently developed and made available in publicly accessible repositories, such as biomodels.net for instance, through common exchange formats such as SBML. To date, however, there is no general method to relate different models to each other by abstraction or reduction relationships, and this task is left to the modeler for re-using and coupling models. In mathematical biology, model reduction techniques have been studied for a long time, mainly in the case where a model exhibits different time scales, or different spatial phases, which can be analyzed separately. These techniques are however far too restrictive to be applied on a large scale in systems biology, and do not take into account abstractions other than time or phase decompositions. Our purpose here is to propose a general computational method for relating models together, by considering primarily the structure of the interactions and abstracting from their dynamics in a first step.Results: We present a graph-theoretic formalism with node merge and delete operations, in which model reductions can be studied as graph matching problems. From this setting, we derive an algorithm for deciding whether there exists a reduction from one model to another, and evaluate it on the computation of the reduction relations between all SBML models of the biomodels.net repository. In particular, in the case of the numerous models of MAPK signalling, and of the circadian clock, biologically meaningful mappings between models of each class are automatically inferred from the structure of the interactions. We conclude on the generality of our graphical method, on its limits with respect to the representation of the structure of the interactions in SBML, and on some perspectives for dealing with the dynamics.Availability: The algorithms described in this article are implemented in the open-source software modeling platform BIOCHAM available at http://contraintes.inria.fr/biocham The models used in the experiments are available from http://www.biomodels.net/Contact: francois.fages@inria.fr
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