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Open Access Highly Accessed Methodology article

A cooperative strategy for parameter estimation in large scale systems biology models

Alejandro F Villaverde1, Jose A Egea2 and Julio R Banga1*

Author Affiliations

1 Bioprocess Engineering Group, IIM-CSIC, Eduardo Cabello 6, Vigo 36208Spain

2 Department of Applied Mathematics and Statistics, Universidad Politécnica de Cartagena, Avenida Dr. Fleming s/n, 30202, Cartagena, Spain

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BMC Systems Biology 2012, 6:75  doi:10.1186/1752-0509-6-75

Published: 22 June 2012



Mathematical models play a key role in systems biology: they summarize the currently available knowledge in a way that allows to make experimentally verifiable predictions. Model calibration consists of finding the parameters that give the best fit to a set of experimental data, which entails minimizing a cost function that measures the goodness of this fit. Most mathematical models in systems biology present three characteristics which make this problem very difficult to solve: they are highly non-linear, they have a large number of parameters to be estimated, and the information content of the available experimental data is frequently scarce. Hence, there is a need for global optimization methods capable of solving this problem efficiently.


A new approach for parameter estimation of large scale models, called Cooperative Enhanced Scatter Search (CeSS), is presented. Its key feature is the cooperation between different programs (“threads”) that run in parallel in different processors. Each thread implements a state of the art metaheuristic, the enhanced Scatter Search algorithm (eSS). Cooperation, meaning information sharing between threads, modifies the systemic properties of the algorithm and allows to speed up performance. Two parameter estimation problems involving models related with the central carbon metabolism of E. coli which include different regulatory levels (metabolic and transcriptional) are used as case studies. The performance and capabilities of the method are also evaluated using benchmark problems of large-scale global optimization, with excellent results.


The cooperative CeSS strategy is a general purpose technique that can be applied to any model calibration problem. Its capability has been demonstrated by calibrating two large-scale models of different characteristics, improving the performance of previously existing methods in both cases. The cooperative metaheuristic presented here can be easily extended to incorporate other global and local search solvers and specific structural information for particular classes of problems.