Inference for Stochastic Chemical Kinetics Using Moment Equations and System Size Expansion

Quantitative mechanistic models are valuable tools for disentangling biochemical pathways and for achieving a comprehensive understanding of biological systems. However, to be quantitative the parameters of these models have to be estimated from experimental data. In the presence of significant stochastic fluctuations this is a challenging task as stochastic simulations are usually too time-consuming and a macroscopic description using reaction rate equations (RREs) is no longer accurate. In this manuscript, we therefore consider moment-closure approximation (MA) and the system size expansion (SSE), which approximate the statistical moments of stochastic processes and tend to be more precise than macroscopic descriptions. We introduce gradient-based parameter optimization methods and uncertainty analysis methods for MA and SSE. Efficiency and reliability of the methods are assessed using simulation examples as well as by an application to data for Epo-induced JAK/STAT signaling. The application revealed that even if merely population-average data are available, MA and SSE improve parameter identifiability in comparison to RRE. Furthermore, the simulation examples revealed that the resulting estimates are more reliable for an intermediate volume regime. In this regime the estimation error is reduced and we propose methods to determine the regime boundaries. These results illustrate that inference using MA and SSE is feasible and possesses a high sensitivity.Author Summary: In this manuscript, we introduce efficient methods for parameter estimation for stochastic processes. The stochasticity of chemical reactions can influence the average behavior of the considered system. For some biological systems, a microscopic, stochastic description is computationally intractable but a macroscopic, deterministic description too inaccurate. This inaccuracy manifests itself in an error in parameter estimates, which impede the predictive power of the proposed model. Until now, no rigorous analysis on the magnitude of the estimation error exists. We show by means of two simulation examples that using mesoscopic descriptions based on the system size expansions and moment-closure approximations can reduce this estimation error compared to inference using a macroscopic description. This reduction is most pronounced in an intermediate volume regime where the influence of stochasticity on the average behavior is moderately strong. For the JAK/STAT pathway where experimental data is available, we show that one parameter that was not structurally identifiable when using a macroscopic description becomes structurally identifiable when using a mesoscopic description for parameter estimation.