Scalable nonlinear programming framework for parameter estimation in dynamic biological system models.

We 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 stiff 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. The proposed framework is flexible and easy-to-use, 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.