AbstractWe present a nonlinear programming (NLP) framework for the scalable solution of parameter estimation problems that arise in dynamic modeling of biological systems. Such problems are computationally challenging because they often involve highly nonlinear and stif differential equations as well as many experimental data sets and parameters. The proposed framework uses cutting-edge modeling and solution tools which are computationally efficient, robust, and easy-to-use. Specifically, our framework uses a time discretization approach that: i) avoids repetitive simulations of the dynamic model, ii) enables fully algebraic model implementations and computation of derivatives, and iii) enables the use of computationally efficient nonlinear interior point solvers that exploit sparse and structured linear algebra techniques. We demonstrate these capabilities by solving estimation problems for synthetic human gut microbiome community models. We show that an instance with 156 parameters, 144 differential equations, and 1,704 experimental data points can be solved in less than 3 minutes using our proposed framework (while an off-the-shelf simulation-based solution framework requires over 7 hours). We also create large instances to show that the proposed framework is scalable and can solve problems with up to 2,352 parameters, 2,304 differential equations, and 20,352 data points in less than 15 minutes. Competing methods reported in the computational biology literature cannot address problems of this level of complexity. The proposed framework is flexible, can be broadly applied to dynamic models of biological systems, and enables the implementation of sophisticated estimation techniques to quantify parameter uncertainty, to diagnose observability/uniqueness issues, to perform model selection, and to handle outliers.Author summaryConstructing and validating dynamic models of biological systems spanning biomolecular networks to ecological systems is a challenging problem. Here we present a scalable computational framework to rapidly infer parameters in complex dynamic models of biological systems from large-scale experimental data. The framework was applied to infer parameters of a synthetic microbial community model from large-scale time series data. We also demonstrate that this framework can be used to analyze parameter uncertainty, to diagnose whether the experimental data are sufficient to uniquely determine the parameters, to determine the model that best describes the data, and to infer parameters in the face of data outliers.
The unraveling of balanced complexes in metabolic networks
