Functional data analysis for identifying nonlinear models of gene regulatory networks

BACKGROUND: A key problem in systems biology is estimating dynamical models of gene regulatory networks. Traditionally, this has been done using regression or other ad-hoc methods when the model is linear. More detailed, realistic modeling studies usually employ nonlinear dynamical models, which lead to computationally difficult parameter estimation problems. Functional data analysis methods, however, offer a means to simplify fitting by transforming the problem from one of matching modeled and observed dynamics to one of matching modeled and observed time derivatives–a regression problem, albeit a nonlinear one. RESULTS: We formulate a functional data analysis approach for estimating the parameters of nonlinear dynamical models and evaluate this approach on data from two real systems, the gap gene system of Drosophila melanogaster and the synthetic IRMA network, which was created expressly as a test case for genetic network inference. We also evaluate the approach on simulated data sets generated by the GeneNetWeaver program, the basis for the annual DREAM reverse engineering challenge. We assess the accuracy with which the correct regulatory relationships within the networks are extracted, and consider alternative methods of regularization for the purpose of overfitting avoidance. We also show that the computational efficiency of the functional data analysis approach, and the decomposability of the resulting regression problem, allow us to explicitly enumerate and evaluate all possible regulator combinations for every gene. This gives deeper insight into the the relevance of different regulators or regulator combinations, and lets one check for alternative regulatory explanations. CONCLUSIONS: Functional data analysis is a powerful approach for estimating detailed nonlinear models of gene expression dynamics, allowing efficient and accurate estimation of regulatory architecture.