An application of the Krylov-FSP-SSA method to parameter fitting with maximum likelihood.

Monte Carlo methods such as the stochastic simulation algorithm (SSA) have traditionally been employed in gene regulation problems. However, there has been increasing interest to directly obtain the probability distribution of the molecules involved by solving the chemical master equation (CME). This requires addressing the curse of dimensionality that is inherent in most gene regulation problems. The finite state projection (FSP) seeks to address the challenge and there have been variants that further reduce the size of the projection or that accelerate the resulting matrix exponential. The Krylov-FSP-SSA variant has proved numerically efficient by combining, on one hand, the SSA to adaptively drive the FSP, and on the other hand, adaptive Krylov techniques to evaluate the matrix exponential. Here we apply this Krylov-FSP-SSA to a mutual inhibitory gene network synthetically engineered in Saccharomyces cerevisiae, in which bimodality arises. We show numerically that the approach can efficiently approximate the transient probability distribution, and this has important implications for parameter fitting, where the CME has to be solved for many different parameter sets. The fitting scheme amounts to an optimization problem of finding the parameter set so that the transient probability distributions fit the observations with maximum likelihood. We compare five optimization schemes for this difficult problem, thereby providing further insights into this approach of parameter estimation that is often applied to models in systems biology where there is a need to calibrate free parameters.