8,831 research outputs found
Simulation and inference algorithms for stochastic biochemical reaction networks: from basic concepts to state-of-the-art
Stochasticity is a key characteristic of intracellular processes such as gene
regulation and chemical signalling. Therefore, characterising stochastic
effects in biochemical systems is essential to understand the complex dynamics
of living things. Mathematical idealisations of biochemically reacting systems
must be able to capture stochastic phenomena. While robust theory exists to
describe such stochastic models, the computational challenges in exploring
these models can be a significant burden in practice since realistic models are
analytically intractable. Determining the expected behaviour and variability of
a stochastic biochemical reaction network requires many probabilistic
simulations of its evolution. Using a biochemical reaction network model to
assist in the interpretation of time course data from a biological experiment
is an even greater challenge due to the intractability of the likelihood
function for determining observation probabilities. These computational
challenges have been subjects of active research for over four decades. In this
review, we present an accessible discussion of the major historical
developments and state-of-the-art computational techniques relevant to
simulation and inference problems for stochastic biochemical reaction network
models. Detailed algorithms for particularly important methods are described
and complemented with MATLAB implementations. As a result, this review provides
a practical and accessible introduction to computational methods for stochastic
models within the life sciences community
Scalable Inference for Markov Processes with Intractable Likelihoods
Bayesian inference for Markov processes has become increasingly relevant in
recent years. Problems of this type often have intractable likelihoods and
prior knowledge about model rate parameters is often poor. Markov Chain Monte
Carlo (MCMC) techniques can lead to exact inference in such models but in
practice can suffer performance issues including long burn-in periods and poor
mixing. On the other hand approximate Bayesian computation techniques can allow
rapid exploration of a large parameter space but yield only approximate
posterior distributions. Here we consider the combined use of approximate
Bayesian computation (ABC) and MCMC techniques for improved computational
efficiency while retaining exact inference on parallel hardware
Data-driven modelling of biological multi-scale processes
Biological processes involve a variety of spatial and temporal scales. A
holistic understanding of many biological processes therefore requires
multi-scale models which capture the relevant properties on all these scales.
In this manuscript we review mathematical modelling approaches used to describe
the individual spatial scales and how they are integrated into holistic models.
We discuss the relation between spatial and temporal scales and the implication
of that on multi-scale modelling. Based upon this overview over
state-of-the-art modelling approaches, we formulate key challenges in
mathematical and computational modelling of biological multi-scale and
multi-physics processes. In particular, we considered the availability of
analysis tools for multi-scale models and model-based multi-scale data
integration. We provide a compact review of methods for model-based data
integration and model-based hypothesis testing. Furthermore, novel approaches
and recent trends are discussed, including computation time reduction using
reduced order and surrogate models, which contribute to the solution of
inference problems. We conclude the manuscript by providing a few ideas for the
development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and
Multiscale Dynamics (American Scientific Publishers
New Insights into History Matching via Sequential Monte Carlo
The aim of the history matching method is to locate non-implausible regions
of the parameter space of complex deterministic or stochastic models by
matching model outputs with data. It does this via a series of waves where at
each wave an emulator is fitted to a small number of training samples. An
implausibility measure is defined which takes into account the closeness of
simulated and observed outputs as well as emulator uncertainty. As the waves
progress, the emulator becomes more accurate so that training samples are more
concentrated on promising regions of the space and poorer parts of the space
are rejected with more confidence. Whilst history matching has proved to be
useful, existing implementations are not fully automated and some ad-hoc
choices are made during the process, which involves user intervention and is
time consuming. This occurs especially when the non-implausible region becomes
small and it is difficult to sample this space uniformly to generate new
training points. In this article we develop a sequential Monte Carlo (SMC)
algorithm for implementation which is semi-automated. Our novel SMC approach
reveals that the history matching method yields a non-implausible distribution
that can be multi-modal, highly irregular and very difficult to sample
uniformly. Our SMC approach offers a much more reliable sampling of the
non-implausible space, which requires additional computation compared to other
approaches used in the literature
Simulation based sequential Monte Carlo methods for discretely observed Markov processes
Parameter estimation for discretely observed Markov processes is a
challenging problem. However, simulation of Markov processes is straightforward
using the Gillespie algorithm. We exploit this ease of simulation to develop an
effective sequential Monte Carlo (SMC) algorithm for obtaining samples from the
posterior distribution of the parameters. In particular, we introduce two key
innovations, coupled simulations, which allow us to study multiple parameter
values on the basis of a single simulation, and a simple, yet effective,
importance sampling scheme for steering simulations towards the observed data.
These innovations substantially improve the efficiency of the SMC algorithm
with minimal effect on the speed of the simulation process. The SMC algorithm
is successfully applied to two examples, a Lotka-Volterra model and a
Repressilator model.Comment: 27 pages, 5 figure
Inference for reaction networks using the Linear Noise Approximation
We consider inference for the reaction rates in discretely observed networks
such as those found in models for systems biology, population ecology and
epidemics. Most such networks are neither slow enough nor small enough for
inference via the true state-dependent Markov jump process to be feasible.
Typically, inference is conducted by approximating the dynamics through an
ordinary differential equation (ODE), or a stochastic differential equation
(SDE). The former ignores the stochasticity in the true model, and can lead to
inaccurate inferences. The latter is more accurate but is harder to implement
as the transition density of the SDE model is generally unknown. The Linear
Noise Approximation (LNA) is a first order Taylor expansion of the
approximating SDE about a deterministic solution and can be viewed as a
compromise between the ODE and SDE models. It is a stochastic model, but
discrete time transition probabilities for the LNA are available through the
solution of a series of ordinary differential equations. We describe how a
restarting LNA can be efficiently used to perform inference for a general class
of reaction networks; evaluate the accuracy of such an approach; and show how
and when this approach is either statistically or computationally more
efficient than ODE or SDE methods. We apply the LNA to analyse Google Flu
Trends data from the North and South Islands of New Zealand, and are able to
obtain more accurate short-term forecasts of new flu cases than another
recently proposed method, although at a greater computational cost
Effective simulation techniques for biological systems
In this paper we give an overview of some very recent work on the stochastic simulation of systems involving chemical reactions. In many biological systems (such as genetic regulation and cellular dynamics) there is a mix between small numbers of key regulatory proteins, and medium and large numbers of molecules. In addition, it is important to be able to follow the trajectories of individual molecules by taking proper account of the randomness inherent in such a system. We describe different types of simulation techniques (including the stochastic simulation algorithm, Poisson Runge-Kutta methods and the Balanced Euler method) for treating simulations in the three different reaction regimes: slow, medium and fast. We then review some recent techniques on the treatment of coupled slow and fast reactions for stochastic chemical kinetics and discuss how novel computing implementations can enhance the performance of these simulations
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