31 research outputs found
Approximation and inference methods for stochastic biochemical kinetics-a tutorial review
Stochastic fluctuations of molecule numbers are ubiquitous in biological systems. Important examples include gene expression and enzymatic processes in living cells. Such systems are typically modelled as chemical reaction networks whose dynamics are governed by the chemical master equation. Despite its simple structure, no analytic solutions to the chemical master equation are known for most systems. Moreover, stochastic simulations are computationally expensive, making systematic analysis and statistical inference a challenging task. Consequently, significant effort has been spent in recent decades on the development of efficient approximation and inference methods. This article gives an introduction to basic modelling concepts as well as an overview of state of the art methods. First, we motivate and introduce deterministic and stochastic methods for modelling chemical networks, and give an overview of simulation and exact solution methods. Next, we discuss several approximation methods, including the chemical Langevin equation, the system size expansion, moment closure approximations, time-scale separation approximations and hybrid methods. We discuss their various properties and review recent advances and remaining challenges for these methods. We present a comparison of several of these methods by means of a numerical case study and highlight some of their respective advantages and disadvantages. Finally, we discuss the problem of inference from experimental data in the Bayesian framework and review recent methods developed the literature. In summary, this review gives a self-contained introduction to modelling, approximations and inference methods for stochastic chemical kinetics
Probabilistic Model Checking for Continuous-Time Markov Chains via Sequential Bayesian Inference
Probabilistic model checking for systems with large or unbounded state space
is a challenging computational problem in formal modelling and its
applications. Numerical algorithms require an explicit representation of the
state space, while statistical approaches require a large number of samples to
estimate the desired properties with high confidence. Here, we show how model
checking of time-bounded path properties can be recast exactly as a Bayesian
inference problem. In this novel formulation the problem can be efficiently
approximated using techniques from machine learning. Our approach is inspired
by a recent result in statistical physics which derived closed form
differential equations for the first-passage time distribution of stochastic
processes. We show on a number of non-trivial case studies that our method
achieves both high accuracy and significant computational gains compared to
statistical model checking
Bounding Mean First Passage Times in Population Continuous-Time Markov Chains
We consider the problem of bounding mean first passage times and reachability probabilities for the class of population continuous-time Markov chains, which capture stochastic interactions between groups of identical agents. The quantitative analysis of such models is notoriously difficult since typically neither state-based numerical approaches nor methods based on stochastic sampling give efficient and accurate results. Here, we propose a novel approach that leverages techniques from martingale theory and stochastic processes to generate constraints on the statistical moments of first passage time distributions. These constraints induce a semi-definite program that can be used to compute exact bounds on reachability probabilities and mean first passage times without numerically solving the transient probability distribution of the process or sampling from it. We showcase the method on some test examples and tailor it to models exhibiting multimodality, a class of particularly challenging scenarios from biology
Parameter estimation for biochemical reaction networks using Wasserstein distances
We present a method for estimating parameters in stochastic models of
biochemical reaction networks by fitting steady-state distributions using
Wasserstein distances. We simulate a reaction network at different parameter
settings and train a Gaussian process to learn the Wasserstein distance between
observations and the simulator output for all parameters. We then use Bayesian
optimization to find parameters minimizing this distance based on the trained
Gaussian process. The effectiveness of our method is demonstrated on the
three-stage model of gene expression and a genetic feedback loop for which
moment-based methods are known to perform poorly. Our method is applicable to
any simulator model of stochastic reaction networks, including Brownian
Dynamics.Comment: 22 pages, 8 figures. Slight modifications/additions to the text;
added new section (Section 4.4) and Appendi
Linear mapping approximation of gene regulatory networks with stochastic dynamics
The intractability of most stochastic models of gene regulatory networks (GRNs) limits their utility. Here, the authors present a linear-mapping approximation mapping models onto simpler ones, giving approximate but accurate analytic or semi- analytic solutions for a wide range of model GRNs
Expectation propagation for continuous time stochastic processes
We consider the inverse problem of reconstructing the posterior measure over
the trajec- tories of a diffusion process from discrete time observations and
continuous time constraints. We cast the problem in a Bayesian framework and
derive approximations to the posterior distributions of single time marginals
using variational approximate inference. We then show how the approximation can
be extended to a wide class of discrete-state Markov jump pro- cesses by making
use of the chemical Langevin equation. Our empirical results show that the
proposed method is computationally efficient and provides good approximations
for these classes of inverse problems
Single-cell variability in multicellular organisms
While gene expression noise in single-celled organisms is well understood, it is less so in the context of tissues. Here the authors show that coupling between cells in tissues can increase or decrease cell-to-cell variability depending on the level of noise intrinsic to the regulatory networks
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