Efficient simulation techniques for biochemical reaction networks

Discrete-state, continuous-time Markov models are becoming commonplace in the modelling of biochemical processes. The mathematical formulations that such models lead to are opaque, and, due to their complexity, are often considered analytically intractable. As such, a variety of Monte Carlo simulation algorithms have been developed to explore model dynamics empirically. Whilst well-known methods, such as the Gillespie Algorithm, can be implemented to investigate a given model, the computational demands of traditional simulation techniques remain a significant barrier to modern research. In order to further develop and explore biologically relevant stochastic models, new and efficient computational methods are required. In this thesis, high-performance simulation algorithms are developed to estimate summary statistics that characterise a chosen reaction network. The algorithms make use of variance reduction techniques, which exploit statistical properties of the model dynamics, to improve performance. The multi-level method is an example of a variance reduction technique. The method estimates summary statistics of well-mixed, spatially homogeneous models by using estimates from multiple ensembles of sample paths of different accuracies. In this thesis, the multi-level method is developed in three directions: firstly, a nuanced implementation framework is described; secondly, a reformulated method is applied to stiff reaction systems; and, finally, different approaches to variance reduction are implemented and compared. The variance reduction methods that underpin the multi-level method are then re-purposed to understand how the dynamics of a spatially-extended Markov model are affected by changes in its input parameters. By exploiting the inherent dynamics of spatially-extended models, an efficient finite difference scheme is used to estimate parametric sensitivities robustly.Comment: Doctor of Philosophy thesis submitted at the University of Oxford. This research was supervised by Prof Ruth E. Baker and Dr Christian A. Yate

Central limit theorems for multilevel Monte Carlo methods

In this work, we show that uniform integrability is not a necessary condition for central limit theorems (CLT) to hold for normalized multilevel Monte Carlo (MLMC) estimators and we provide near optimal weaker conditions under which the CLT is achieved. In particular, if the variance decay rate dominates the computational cost rate (i.e., $\beta > \gamma$), we prove that the CLT applies to the standard (variance minimizing) MLMC estimator. For other settings where the CLT may not apply to the standard MLMC estimator, we propose an alternative estimator, called the mass-shifted MLMC estimator, to which the CLT always applies. This comes at a small efficiency loss: the computational cost of achieving mean square approximation error $\mathcal{O}(\epsilon^2)$ is at worst a factor $\mathcal{O}(\log(1/\epsilon))$ higher with the mass-shifted estimator than with the standard one