Approximate parameter inference in systems biology using gradient matching: a comparative evaluation

Background: A challenging problem in current systems biology is that of parameter inference in biological pathways expressed as coupled ordinary differential equations (ODEs). Conventional methods that repeatedly numerically solve the ODEs have large associated computational costs. Aimed at reducing this cost, new concepts using gradient matching have been proposed, which bypass the need for numerical integration. This paper presents a recently established adaptive gradient matching approach, using Gaussian processes, combined with a parallel tempering scheme, and conducts a comparative evaluation with current state of the art methods used for parameter inference in ODEs. Among these contemporary methods is a technique based on reproducing kernel Hilbert spaces (RKHS). This has previously shown promising results for parameter estimation, but under lax experimental settings. We look at a range of scenarios to test the robustness of this method. We also change the approach of inferring the penalty parameter from AIC to cross validation to improve the stability of the method. Methodology: Methodology for the recently proposed adaptive gradient matching method using Gaussian processes, upon which we build our new method, is provided. Details of a competing method using reproducing kernel Hilbert spaces are also described here. Results: We conduct a comparative analysis for the methods described in this paper, using two benchmark ODE systems. The analyses are repeated under different experimental settings, to observe the sensitivity of the techniques. Conclusions: Our study reveals that for known noise variance, our proposed method based on Gaussian processes and parallel tempering achieves overall the best performance. When the noise variance is unknown, the RKHS method proves to be more robust

Fifty Years of Stiffness

The notion of stiffness, which originated in several applications of a different nature, has dominated the activities related to the numerical treatment of differential problems for the last fifty years. Contrary to what usually happens in Mathematics, its definition has been, for a long time, not formally precise (actually, there are too many of them). Again, the needs of applications, especially those arising in the construction of robust and general purpose codes, require nowadays a formally precise definition. In this paper, we review the evolution of such a notion and we also provide a precise definition which encompasses all the previous ones.Comment: 24 pages, 11 figure

Differential-Algebraic Equations and Beyond: From Smooth to Nonsmooth Constrained Dynamical Systems

The present article presents a summarizing view at differential-algebraic equations (DAEs) and analyzes how new application fields and corresponding mathematical models lead to innovations both in theory and in numerical analysis for this problem class. Recent numerical methods for nonsmooth dynamical systems subject to unilateral contact and friction illustrate the topicality of this development.Comment: Preprint of Book Chapte

Extrapolation-based implicit-explicit general linear methods

For many systems of differential equations modeling problems in science and engineering, there are natural splittings of the right hand side into two parts, one non-stiff or mildly stiff, and the other one stiff. For such systems implicit-explicit (IMEX) integration combines an explicit scheme for the non-stiff part with an implicit scheme for the stiff part. In a recent series of papers two of the authors (Sandu and Zhang) have developed IMEX GLMs, a family of implicit-explicit schemes based on general linear methods. It has been shown that, due to their high stage order, IMEX GLMs require no additional coupling order conditions, and are not marred by order reduction. This work develops a new extrapolation-based approach to construct practical IMEX GLM pairs of high order. We look for methods with large absolute stability region, assuming that the implicit part of the method is A- or L-stable. We provide examples of IMEX GLMs with optimal stability properties. Their application to a two dimensional test problem confirms the theoretical findings

Travelling waves in a tissue interaction model for skin pattern formation

Tissue interaction plays a major role in many morphogenetic processes, particularly those associated with skin organ primordia. We examine travelling wave solutions in a tissue interaction model for skin pattern formation which is firmly based on the known biology. From a phase space analysis we conjecture the existence of travelling waves with specific wave speeds. Subsequently, analytical approximations to the wave profiles are derived using perturbation methods. We then show numerically that such travelling wave solutions do exist and that they are in good agreement with our analytical results. Finally, the biological implications of our analysis are discussed