13,348 research outputs found
Hybrid framework for the simulation of stochastic chemical kinetics
Stochasticity plays a fundamental role in various biochemical processes, such
as cell regulatory networks and enzyme cascades. Isothermal, well-mixed systems
can be modelled as Markov processes, typically simulated using the Gillespie
Stochastic Simulation Algorithm (SSA). While easy to implement and exact, the
computational cost of using the Gillespie SSA to simulate such systems can
become prohibitive as the frequency of reaction events increases. This has
motivated numerous coarse-grained schemes, where the "fast" reactions are
approximated either using Langevin dynamics or deterministically. While such
approaches provide a good approximation when all reactants are abundant, the
approximation breaks down when one or more species exist only in small
concentrations and the fluctuations arising from the discrete nature of the
reactions becomes significant. This is particularly problematic when using such
methods to compute statistics of extinction times for chemical species, as well
as simulating non-equilibrium systems such as cell-cycle models in which a
single species can cycle between abundance and scarcity. In this paper, a
hybrid jump-diffusion model for simulating well- mixed stochastic kinetics is
derived. It acts as a bridge between the Gillespie SSA and the chemical
Langevin equation. For low reactant reactions the underlying behaviour is
purely discrete, while purely diffusive when the concentrations of all species
is large, with the two different behaviours coexisting in the intermediate
region. A bound on the weak error in the classical large volume scaling limit
is obtained, and three different numerical discretizations of the
jump-diffusion model are described. The benefits of such a formalism are
illustrated using computational examples.Comment: 37 pages, 6 figure
On the origins of approximations for stochastic chemical kinetics
This paper considers the derivation of approximations for stochastic chemical kinetics governed by the discrete master equation. Here, the concepts of (1) partitioning on the basis of fast and slow reactions as opposed to fast and slow species and (2) conditional probability densities are used to derive approximate, partitioned master equations, which are Markovian in nature, from the original master equation. Under different conditions dictated by relaxation time arguments, such approximations give rise to both the equilibrium and hybrid (deterministic or Langevin equations coupled with discrete stochastic simulation) approximations previously reported. In addition, the derivation points out several weaknesses in previous justifications of both the hybrid and equilibrium systems and demonstrates the connection between the original and approximate master equations. Two simple examples illustrate situations in which these two approximate methods are applicable and demonstrate the two methods' efficiencies
Switching and diffusion models for gene regulation networks
We analyze a hierarchy of three regimes for modeling gene regulation. The most complete model is a continuous time, discrete state space, Markov jump process. An intermediate 'switch plus diffusion' model takes the form of a stochastic differential equation driven by an independent continuous time Markov switch. In the third 'switch plus ODE' model the switch remains but the diffusion is removed. The latter two models allow for multi-scale simulation where, for the sake of computational efficiency, system components are treated differently according to their abundance. The 'switch plus ODE' regime was proposed by Paszek (Modeling stochasticity in gene regulation: characterization in the terms of the underlying distribution function, Bulletin of Mathematical Biology, 2007), who analyzed the steady state behavior, showing that the mean was preserved but the variance only approximated that of the full model. Here, we show that the tools of stochastic calculus can be used to analyze first and second moments for all time. A technical issue to be addressed is that the state space for the discrete-valued switch is infinite. We show that the new 'switch plus diffusion' regime preserves the biologically relevant measures of mean and variance, whereas the 'switch plus ODE' model uniformly underestimates the variance in the protein level. We also show that, for biologically relevant parameters, the transient behaviour can differ significantly from the steady state, justifying our time-dependent analysis. Extra computational results are also given for a protein dimerization model that is beyond the scope of the current analysis
Reduction of dynamical biochemical reaction networks in computational biology
Biochemical networks are used in computational biology, to model the static
and dynamical details of systems involved in cell signaling, metabolism, and
regulation of gene expression. Parametric and structural uncertainty, as well
as combinatorial explosion are strong obstacles against analyzing the dynamics
of large models of this type. Multi-scaleness is another property of these
networks, that can be used to get past some of these obstacles. Networks with
many well separated time scales, can be reduced to simpler networks, in a way
that depends only on the orders of magnitude and not on the exact values of the
kinetic parameters. The main idea used for such robust simplifications of
networks is the concept of dominance among model elements, allowing
hierarchical organization of these elements according to their effects on the
network dynamics. This concept finds a natural formulation in tropical
geometry. We revisit, in the light of these new ideas, the main approaches to
model reduction of reaction networks, such as quasi-steady state and
quasi-equilibrium approximations, and provide practical recipes for model
reduction of linear and nonlinear networks. We also discuss the application of
model reduction to backward pruning machine learning techniques
Hybrid Pathwise Sensitivity Methods for Discrete Stochastic Models of Chemical Reaction Systems
Stochastic models are often used to help understand the behavior of
intracellular biochemical processes. The most common such models are continuous
time Markov chains (CTMCs). Parametric sensitivities, which are derivatives of
expectations of model output quantities with respect to model parameters, are
useful in this setting for a variety of applications. In this paper, we
introduce a class of hybrid pathwise differentiation methods for the numerical
estimation of parametric sensitivities. The new hybrid methods combine elements
from the three main classes of procedures for sensitivity estimation, and have
a number of desirable qualities. First, the new methods are unbiased for a
broad class of problems. Second, the methods are applicable to nearly any
physically relevant biochemical CTMC model. Third, and as we demonstrate on
several numerical examples, the new methods are quite efficient, particularly
if one wishes to estimate the full gradient of parametric sensitivities. The
methods are rather intuitive and utilize the multilevel Monte Carlo philosophy
of splitting an expectation into separate parts and handling each in an
efficient manner.Comment: 30 pages. The numerical example section has been extensively
rewritte
Stochastic Representations of Ion Channel Kinetics and Exact Stochastic Simulation of Neuronal Dynamics
In this paper we provide two representations for stochastic ion channel
kinetics, and compare the performance of exact simulation with a commonly used
numerical approximation strategy. The first representation we present is a
random time change representation, popularized by Thomas Kurtz, with the second
being analogous to a "Gillespie" representation. Exact stochastic algorithms
are provided for the different representations, which are preferable to either
(a) fixed time step or (b) piecewise constant propensity algorithms, which
still appear in the literature. As examples, we provide versions of the exact
algorithms for the Morris-Lecar conductance based model, and detail the error
induced, both in a weak and a strong sense, by the use of approximate
algorithms on this model. We include ready-to-use implementations of the random
time change algorithm in both XPP and Matlab. Finally, through the
consideration of parametric sensitivity analysis, we show how the
representations presented here are useful in the development of further
computational methods. The general representations and simulation strategies
provided here are known in other parts of the sciences, but less so in the
present setting.Comment: 39 pages, 6 figures, appendix with XPP and Matlab cod
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