Efficient parametric analysis of the chemical master equation through model order reduction

Background: Stochastic biochemical reaction networks are commonly modelled by the chemical master equation, and can be simulated as first order linear differential equations through a finite state projection. Due to the very high state space dimension of these equations, numerical simulations are computationally expensive. This is a particular problem for analysis tasks requiring repeated simulations for different parameter values. Such tasks are computationally expensive to the point of infeasibility with the chemical master equation. Results: In this article, we apply parametric model order reduction techniques in order to construct accurate low-dimensional parametric models of the chemical master equation. These surrogate models can be used in various parametric analysis task such as identifiability analysis, parameter estimation, or sensitivity analysis. As biological examples, we consider two models for gene regulation networks, a bistable switch and a network displaying stochastic oscillations. Conclusions: The results show that the parametric model reduction yields efficient models of stochastic biochemical reaction networks, and that these models can be useful for systems biology applications involving parametric analysis problems such as parameter exploration, optimization, estimation or sensitivity analysis.Comment: 23 pages, 8 figures, 2 table

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

An overview of the proper generalized decomposition with applications in computational rheology

We review the foundations and applications of the proper generalized decomposition (PGD), a powerful model reduction technique that computes a priori by means of successive enrichment a separated representation of the unknown field. The computational complexity of the PGD scales linearly with the dimension of the space wherein the model is defined, which is in marked contrast with the exponential scaling of standard grid-based methods. First introduced in the context of computational rheology by Ammar et al. [3] and [4], the PGD has since been further developed and applied in a variety of applications ranging from the solution of the Schrödinger equation of quantum mechanics to the analysis of laminate composites. In this paper, we illustrate the use of the PGD in four problem categories related to computational rheology: (i) the direct solution of the Fokker-Planck equation for complex fluids in configuration spaces of high dimension, (ii) the development of very efficient non-incremental algorithms for transient problems, (iii) the fully three-dimensional solution of problems defined in degenerate plate or shell-like domains often encountered in polymer processing or composites manufacturing, and finally (iv) the solution of multidimensional parametric models obtained by introducing various sources of problem variability as additional coordinates

Targeting Conservation Investments in Heterogeneous Landscapes: A distance function approach and application to watershed management

To achieve a given level of an environmental amenity at least cost, decision-makers must integrate information about spatially variable biophysical and economic conditions. Although the biophysical attributes that contribute to supplying an environmental amenity are often known, the way in which these attributes interact to produce the amenity is often unknown. Given the difficulty in converting multiple attributes into a unidimensional physical measure of an environmental amenity (e.g., habitat quality), analyses in the academic literature tend to use a single biophysical attribute as a proxy for the environmental amenity (e.g., species richness). A narrow focus on a single attribute, however, fails to consider the full range of biophysical attributes that are critical to the supply of an environmental amenity. Drawing on the production efficiency literature, we introduce an alternative conservation targeting approach that relies on distance functions to cost-efficiently allocate conservation funds across a spatially heterogeneous landscape. An approach based on distance functions has the advantage of not requiring a parametric specification of the amenity function (or cost function), but rather only requiring that the decision-maker identify important biophysical and economic attributes. We apply the distance-function approach empirically to an increasingly common, but little studied, conservation initiative: conservation contracting for water quality objectives. The contract portfolios derived from the distance-function application have many desirable properties, including intuitive appeal, robust performance across plausible parametric amenity measures, and the generation of ranking measures that can be easily used by field practitioners in complex decision-making environments that cannot be completely modeled. Working Paper # 2002-01

Stochastic focusing coupled with negative feedback enables robust regulation in biochemical reaction networks

Nature presents multiple intriguing examples of processes which proceed at high precision and regularity. This remarkable stability is frequently counter to modelers' experience with the inherent stochasticity of chemical reactions in the regime of low copy numbers. Moreover, the effects of noise and nonlinearities can lead to "counter-intuitive" behavior, as demonstrated for a basic enzymatic reaction scheme that can display stochastic focusing (SF). Under the assumption of rapid signal fluctuations, SF has been shown to convert a graded response into a threshold mechanism, thus attenuating the detrimental effects of signal noise. However, when the rapid fluctuation assumption is violated, this gain in sensitivity is generally obtained at the cost of very large product variance, and this unpredictable behavior may be one possible explanation of why, more than a decade after its introduction, SF has still not been observed in real biochemical systems. In this work we explore the noise properties of a simple enzymatic reaction mechanism with a small and fluctuating number of active enzymes that behaves as a high-gain, noisy amplifier due to SF caused by slow enzyme fluctuations. We then show that the inclusion of a plausible negative feedback mechanism turns the system from a noisy signal detector to a strong homeostatic mechanism by exchanging high gain with strong attenuation in output noise and robustness to parameter variations. Moreover, we observe that the discrepancy between deterministic and stochastic descriptions of stochastically focused systems in the evolution of the means almost completely disappears, despite very low molecule counts and the additional nonlinearity due to feedback. The reaction mechanism considered here can provide a possible resolution to the apparent conflict between intrinsic noise and high precision in critical intracellular processes

A literature survey of low-rank tensor approximation techniques

During the last years, low-rank tensor approximation has been established as a new tool in scientific computing to address large-scale linear and multilinear algebra problems, which would be intractable by classical techniques. This survey attempts to give a literature overview of current developments in this area, with an emphasis on function-related tensors

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