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Background  To infer gene regulatory networks from time series gene profiles, two important tasks that are related to biological systems must be undertaken. One task is to determine a valid network structure that has topological properties that can influence the network dynamics profoundly. The other task is to optimize the network parameters to minimize the accumulated discrepancy between the gene expression data and the values produced by the inferred network model. Though the above two tasks must be conducted simultaneously, most existing work addresses only one of the tasks.    Results  We propose an iterative approach that couples parameter identification and parameter optimization techniques, to address the two tasks simultaneously during network inference. This approach first identifies the most influential parameters against internal perturbations; this identification is based on sensitivity measurements. Then, a hybrid GA-PSO optimization method infers parameters in accordance with their criticalities. The proposed approach has been applied to several datasets, including subsets of the SOS DNA repair system in  E. coli , the Rat central nervous system (CNS), and the protein glycosylation system of yeast  S. cerevisiae . The result and analysis show that our approach can infer solutions to satisfy both the requirements of network structure and network behavior.    Conclusions  Network structure is an important though challenging issue to address in inferring sophisticated networks with biological details. In need of prior structural knowledge, we turn to measure parameter sensitivity instead to account for the network structure in an indirect way. By developing an integrated approach for considering both the network structure and behavior in the inference process, we can successfully infer critical gene interactions as well as valid time expression profiles.

Reverse engineering gene regulatory networks: Coupling an optimization algorithm with a parameter identification technique