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Open Access Methodology article

Inference of complex biological networks: distinguishability issues and optimization-based solutions

Gábor Szederkényi12*, Julio R Banga1* and Antonio A Alonso1

Author Affiliations

1 (Bio)Process Engineering Group, IIM-CSIC, Spanish National Research Council, C/Eduardo Cabello, 6, 36208 Vigo, Spain

2 Process Control Research Group, MTA SZTAKI, Kende u. 13-17, H-1111 Budapest, Hungary

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BMC Systems Biology 2011, 5:177  doi:10.1186/1752-0509-5-177

Published: 28 October 2011

Abstract

Background

The inference of biological networks from high-throughput data has received huge attention during the last decade and can be considered an important problem class in systems biology. However, it has been recognized that reliable network inference remains an unsolved problem. Most authors have identified lack of data and deficiencies in the inference algorithms as the main reasons for this situation.

Results

We claim that another major difficulty for solving these inference problems is the frequent lack of uniqueness of many of these networks, especially when prior assumptions have not been taken properly into account. Our contributions aid the distinguishability analysis of chemical reaction network (CRN) models with mass action dynamics. The novel methods are based on linear programming (LP), therefore they allow the efficient analysis of CRNs containing several hundred complexes and reactions. Using these new tools and also previously published ones to obtain the network structure of biological systems from the literature, we find that, often, a unique topology cannot be determined, even if the structure of the corresponding mathematical model is assumed to be known and all dynamical variables are measurable. In other words, certain mechanisms may remain undetected (or they are falsely detected) while the inferred model is fully consistent with the measured data. It is also shown that sparsity enforcing approaches for determining 'true' reaction structures are generally not enough without additional prior information.

Conclusions

The inference of biological networks can be an extremely challenging problem even in the utopian case of perfect experimental information. Unfortunately, the practical situation is often more complex than that, since the measurements are typically incomplete, noisy and sometimes dynamically not rich enough, introducing further obstacles to the structure/parameter estimation process. In this paper, we show how the structural uniqueness and identifiability of the models can be guaranteed by carefully adding extra constraints, and that these important properties can be checked through appropriate computation methods.