Abstract
BACKGROUND: Parameter estimation is often the bottlenecking step in biological system modeling. For ordinary differential equation (ODE) models, the challenge in this estimation has been attributed to not only the lack of parameter identifiability, but also computational issues such as finding globally optimal parameter estimates over highly multidimensional search space. Recent methods using incremental estimation approach could alleviate the computational difficulty by performing the parameter estimation one-reaction-at-a-time. However, incremental estimation strategies usually require data smoothing and are known to produce biased parameter estimates. RESULTS: In this article, we presented a new parameter estimation method called integrated flux parameter estimation (IFPE). We employed the integral form of the ODE such that we could compute the integral of reaction fluxes from time-series concentration data without data smoothing. Here, we formulated the parameter estimation as a nested optimization problem. In the outer optimization, we performed a minimization of model prediction errors over parameters associated with a subset of reactions labeled as independent. The dimension of the independent reaction subset was equal to the degrees of freedom in the calculation of integrated fluxes (IF) from concentration data. We selected the independent reactions such that given their IF values, the IFs of the remaining (dependent) reactions could be uniquely determined. Meanwhile, in the inner optimization, we estimated the model parameters associated with the dependent reactions, one-reaction-at-a-time, by minimizing the dependent IF prediction errors. We demonstrated the performance of the IFPE method using two case studies: a generalized mass action model of a branched pathway and a lin-log ODE model of Lactococcus lactis glycolytic pathway. CONCLUSIONS: The IFPE significantly outperformed standard simultaneous parameter estimation in terms of computational efficiency and scaling. In comparison to incremental parameter estimation (IPE) method, the IFPE produced parameter estimates with significantly lower bias and did not require time-series data smoothing. The advantages of IFPE over the IPE however came at the cost of a small increase in the computational time.