A Geometric Index Reduction Method for Implicit Systems of Differential Algebraic Equations

This paper deals with the index reduction problem for the class of quasi-regular DAE systems. It is shown that any of these systems can be transformed to a generically equivalent first order DAE system consisting of a single purely algebraic (polynomial) equation plus an under-determined ODE (a differential Kronecker representation) in as many variables as the order of the input system. This can be done by means of a Kronecker-type algorithm with bounded complexity.Fil: D'alfonso, L.. Universidad de Buenos Aires; ArgentinaFil: Jeronimo, Gabriela Tali. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Matemática; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Investigaciones Matemáticas "Luis A. Santaló"; ArgentinaFil: Ollivier, F.. Centre National de la Recherche Scientifique; FranciaFil: Sedoglavic. A.. Centre National de la Recherche Scientifique; FranciaFil: Solernó, Pablo Luis. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Matemática; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Investigaciones Matemáticas "Luis A. Santaló"; Argentin

Structural identifiability of dynamic systems biology models

22 páginas, 5 figuras, 2 tablas.-- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.A powerful way of gaining insight into biological systems is by creating a nonlinear differential equation model, which usually contains many unknown parameters. Such a model is called structurally identifiable if it is possible to determine the values of its parameters from measurements of the model outputs. Structural identifiability is a prerequisite for parameter estimation, and should be assessed before exploiting a model. However, this analysis is seldom performed due to the high computational cost involved in the necessary symbolic calculations, which quickly becomes prohibitive as the problem size increases. In this paper we show how to analyse the structural identifiability of a very general class of nonlinear models by extending methods originally developed for studying observability. We present results about models whose identifiability had not been previously determined, report unidentifiabilities that had not been found before, and show how to modify those unidentifiable models to make them identifiable. This method helps prevent problems caused by lack of identifiability analysis, which can compromise the success of tasks such as experiment design, parameter estimation, and model-based optimization. The procedure is called STRIKE-GOLDD (STRuctural Identifiability taKen as Extended-Generalized Observability with Lie Derivatives and Decomposition), and it is implemented in a MATLAB toolbox which is available as open source software. The broad applicability of this approach facilitates the analysis of the increasingly complex models used in systems biology and other areasAFV acknowledges funding from the Galician government (Xunta de Galiza, Consellería de Cultura, Educación e Ordenación Universitaria http://www.edu.xunta.es/portal/taxonomy/term/206) through the I2C postdoctoral program, fellowship ED481B2014/133-0. AB and AFV were partially supported by grant DPI2013-47100-C2-2-P from the Spanish Ministry of Economy and Competitiveness (MINECO). AFV acknowledges additional funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 686282 (CanPathPro). AP was partially supported through EPSRC projects EP/M002454/1 and EP/J012041/1.Peer reviewe

Quantification of Circadian Rhythms in Single Cells

Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber)

Au Sujet des Approches Symboliques des Équations Intégro-Différentielles

International audienceRecent progress in computer algebra has opened new opportunities for the parameter estimation problem in nonlinear control theory, by means of integro-differential input-output equations. This paper recalls the origin of integro-differential equations. It presents new opportunities in nonlinear control theory. Finally, it reviews related recent theoretical approaches on integro-differential algebras, illustrating what an integro-differential elimination method might be and what benefits the parameter estimation problem would gain from it.Un résultat récent en calcul formel a ouvert de nouvelles opportunités pour l'estimation de paramètres en théorie du contrôle non linéaire, via des équations entrée-sortie intégro-différentielles. Ce chapitre rappelle les origines des équations intégro-différentielles. Il présente de nouvelles opportunités en théorie du contrôle non linéaire. Finalement, il passe en revue des approches théoriques récentes sur les algèbres intégro-différentielles, illustrant ce qu'une méthode d'élimination intégro-différentielle pourrait être et les bénéfices que le problème de l'estimation de paramètres pourrait en tirer

Fast Computation of Discrete Invariants Associated to a Differential Rational Mapping

We exhibit probabilistic algorithms which compute the differentiation index, the differential Hilbert function and an algebraic parametric set associated to a differential rational mapping. These algorithms are based on a process of linearization and specialization in a generic solution, and have polynomial time complexity

Inverse Problems in Systems Biology: A Critical Review

Systems Biology may be assimilated to a symbiotic cyclic interplaying between the forward and inverse problems. Computational models need to be continuously refined through experiments and in turn they help us to make limited experimental resources more efficient. Every time one does an experiment we know that there will be some noise that can disrupt our measurements. Despite the noise certainly is a problem, the inverse problems already involve the inference of missing information, even if the data is entirely reliable. So the addition of a certain limited noise does not fundamentally change the situation but can be used to solve the so-called ill-posed problem, as defined by Hadamard. It can be seen as an extra source of information. Recent studies have shown that complex systems, among others the systems biology, are poorly constrained and ill-conditioned because it is difficult to use experimental data to fully estimate their parameters. For these reasons was born the concept of sloppy models, a sequence of models of increasing complexity that become sloppy in the limit of microscopic accuracy. Furthermore the concept of sloppy models contains also the concept of un-identifiability, because the models are characterized by many parameters that are poorly constrained by experimental data. Then a strategy needs to be designed to infer, analyze, and understand biological systems. The aim of this work is to provide a critical review to the inverse problems in systems biology defining a strategy to determine the minimal set of information needed to overcome the problems arising from dynamic biological models that generally may have many unknown, non-measurable parameters