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Villaverde A.F.,Bioprocess Engineering Group | Barreiro A.,University of Vigo | Raimundez C.,University of Vigo
Automatica | Year: 2010

During the last two decades, important advances have been made in the field of bilateral teleoperation. Different techniques for performing stable teleoperation in non-ideal conditions have been developed, especially in a passivity framework. Until recently, however, no robust solutions for addressing this problem with variable delays and other drawbacks of packet-switched networks have been developed. The requirement of maintaining passivity in these circumstances degrades performance, due to the loss of energy that it involves. In this paper an arrangement is proposed which is capable of eliminating position errors, while maintaining passivity of an Internet-like channel. The behaviour of this new controller is studied by Lyapunov analysis, compared to previous methods, and validated through numerical simulations. © 2010 Elsevier Ltd. All rights reserved.


Chis O.-T.,Bioprocess Engineering Group | Banga J.R.,Bioprocess Engineering Group | Balsa-Canto E.,Bioprocess Engineering Group
PLoS ONE | Year: 2011

Analysing the properties of a biological system through in silico experimentation requires a satisfactory mathematical representation of the system including accurate values of the model parameters. Fortunately, modern experimental techniques allow obtaining time-series data of appropriate quality which may then be used to estimate unknown parameters. However, in many cases, a subset of those parameters may not be uniquely estimated, independently of the experimental data available or the numerical techniques used for estimation. This lack of identifiability is related to the structure of the model, i.e. the system dynamics plus the observation function. Despite the interest in knowing a priori whether there is any chance of uniquely estimating all model unknown parameters, the structural identifiability analysis for general non-linear dynamic models is still an open question. There is no method amenable to every model, thus at some point we have to face the selection of one of the possibilities. This work presents a critical comparison of the currently available techniques. To this end, we perform the structural identifiability analysis of a collection of biological models. The results reveal that the generating series approach, in combination with identifiability tableaus, offers the most advantageous compromise among range of applicability, computational complexity and information provided. © 2011 Chis et al.


Balsa-Canto E.,Bioprocess Engineering Group | Alonso A.A.,Bioprocess Engineering Group | Banga J.R.,Bioprocess Engineering Group
BMC Systems Biology | Year: 2010

Background: Mathematical models provide abstract representations of the information gained from experimental observations on the structure and function of a particular biological system. Conferring a predictive character on a given mathematical formulation often relies on determining a number of non-measurable parameters that largely condition the model's response. These parameters can be identified by fitting the model to experimental data. However, this fit can only be accomplished when identifiability can be guaranteed.Results: We propose a novel iterative identification procedure for detecting and dealing with the lack of identifiability. The procedure involves the following steps: 1) performing a structural identifiability analysis to detect identifiable parameters; 2) globally ranking the parameters to assist in the selection of the most relevant parameters; 3) calibrating the model using global optimization methods; 4) conducting a practical identifiability analysis consisting of two (a priori and a posteriori) phases aimed at evaluating the quality of given experimental designs and of the parameter estimates, respectively and 5) optimal experimental design so as to compute the scheme of experiments that maximizes the quality and quantity of information for fitting the model.Conclusions: The presented procedure was used to iteratively identify a mathematical model that describes the NF-κB regulatory module involving several unknown parameters. We demonstrated the lack of identifiability of the model under typical experimental conditions and computed optimal dynamic experiments that largely improved identifiability properties. © 2010 Balsa-Canto et al; licensee BioMed Central Ltd.


de Hijas-Liste G.M.,Bioprocess Engineering Group | Klipp E.,Humboldt University of Berlin | Balsa-Canto E.,Bioprocess Engineering Group | Banga J.R.,Bioprocess Engineering Group
BMC Systems Biology | Year: 2014

Background: During the last decade, a number of authors have shown that the genetic regulation of metabolic networks may follow optimality principles. Optimal control theory has been succesfully used to compute optimal enzyme profiles considering simple metabolic pathways. However, applying this optimal control framework to more general networks (e.g. branched networks, or networks incorporating enzyme production dynamics) yields problems that are analytically intractable and/or numerically very challenging. Further, these previous studies have only considered a single-objective framework.Results: In this work we consider a more general multi-objective formulation and we present solutions based on recent developments in global dynamic optimization techniques. We illustrate the performance and capabilities of these techniques considering two sets of problems. First, we consider a set of single-objective examples of increasing complexity taken from the recent literature. We analyze the multimodal character of the associated non linear optimization problems, and we also evaluate different global optimization approaches in terms of numerical robustness, efficiency and scalability. Second, we consider generalized multi-objective formulations for several examples, and we show how this framework results in more biologically meaningful results.Conclusions: The proposed strategy was used to solve a set of single-objective case studies related to unbranched and branched metabolic networks of different levels of complexity. All problems were successfully solved in reasonable computation times with our global dynamic optimization approach, reaching solutions which were comparable or better than those reported in previous literature. Further, we considered, for the first time, multi-objective formulations, illustrating how activation in metabolic pathways can be explained in terms of the best trade-offs between conflicting objectives. This new methodology can be applied to metabolic networks with arbitrary topologies, non-linear dynamics and constraints. © 2014 de Hijas-Liste et al.; licensee BioMed Central Ltd.


Otero-Muras I.,BioProcess Engineering Group | Banga J.R.,BioProcess Engineering Group
BMC Systems Biology | Year: 2014

Background: One of the challenges in Synthetic Biology is to design circuits with increasing levels of complexity. While circuits in Biology are complex and subject to natural tradeoffs, most synthetic circuits are simple in terms of the number of regulatory regions, and have been designed to meet a single design criterion.Results: In this contribution we introduce a multiobjective formulation for the design of biocircuits. We set up the basis for an advanced optimization tool for the modular and systematic design of biocircuits capable of handling high levels of complexity and multiple design criteria. Our methodology combines the efficiency of global Mixed Integer Nonlinear Programming solvers with multiobjective optimization techniques. Through a number of examples we show the capability of the method to generate non intuitive designs with a desired functionality setting up a priori the desired level of complexity.Conclusions: The methodology presented here can be used for biocircuit design and also to explore and identify different design principles for synthetic gene circuits. The presence of more than one competing objective provides a realistic design setting where every solution represents an optimal trade-off between different criteria. © 2014 Otero Muras and Banga; licensee BioMed Central Ltd.


Villaverde A.F.,BioProcess Engineering Group | Banga J.R.,BioProcess Engineering Group
Journal of the Royal Society Interface | Year: 2014

The interplay of mathematical modelling with experiments is one of the central elements in systems biology. The aim of reverse engineering is to infer, analyse and understand, through this interplay, the functional and regulatory mechanisms of biological systems. Reverse engineering is not exclusive of systems biology and has been studied in different areas, such as inverse problem theory, machine learning, nonlinear physics, (bio)chemical kinetics, control theory and optimization, among others. However, it seems that many of these areas have been relatively closed to outsiders. In this contribution, we aim to compare and highlight the different perspectives and contributions from these fields, with emphasis on two key questions: (i) why are reverse engineering problems so hard to solve, and (ii) what methods are available for the particular problems arising from systems biology? © 2013 The Authors. Published by the Royal Society.


Villaverde A.F.,Bioprocess Engineering Group | Egea J.A.,Technical University of Cartagena | Banga J.R.,Bioprocess Engineering Group
BMC Systems Biology | Year: 2012

Background: Mathematical models play a key role in systems biology: they summarize the currently available knowledge in a way that allows to make experimentally verifiable predictions. Model calibration consists of finding the parameters that give the best fit to a set of experimental data, which entails minimizing a cost function that measures the goodness of this fit. Most mathematical models in systems biology present three characteristics which make this problem very difficult to solve: they are highly non-linear, they have a large number of parameters to be estimated, and the information content of the available experimental data is frequently scarce. Hence, there is a need for global optimization methods capable of solving this problem efficiently.Results: A new approach for parameter estimation of large scale models, called Cooperative Enhanced Scatter Search (CeSS), is presented. Its key feature is the cooperation between different programs (" threads" ) that run in parallel in different processors. Each thread implements a state of the art metaheuristic, the enhanced Scatter Search algorithm (eSS). Cooperation, meaning information sharing between threads, modifies the systemic properties of the algorithm and allows to speed up performance. Two parameter estimation problems involving models related with the central carbon metabolism of E. coli which include different regulatory levels (metabolic and transcriptional) are used as case studies. The performance and capabilities of the method are also evaluated using benchmark problems of large-scale global optimization, with excellent results.Conclusions: The cooperative CeSS strategy is a general purpose technique that can be applied to any model calibration problem. Its capability has been demonstrated by calibrating two large-scale models of different characteristics, improving the performance of previously existing methods in both cases. The cooperative metaheuristic presented here can be easily extended to incorporate other global and local search solvers and specific structural information for particular classes of problems. © 2012 Villaverde et al.; licensee BioMed Central Ltd.


Gabor A.,BioProcess Engineering Group | Banga J.R.,BioProcess Engineering Group
BMC Systems Biology | Year: 2015

Background: Dynamic modelling provides a systematic framework to understand function in biological systems. Parameter estimation in nonlinear dynamic models remains a very challenging inverse problem due to its nonconvexity and ill-conditioning. Associated issues like overfitting and local solutions are usually not properly addressed in the systems biology literature despite their importance. Results: We illustrate the performance of the presented method with seven case studies of different nature and increasing complexity, considering several scenarios of data availability, measurement noise and prior knowledge. We show how our method ensures improved estimations with faster and more stable convergence. We also show how the calibrated models are more generalizable. Finally, we give a set of simple guidelines to apply this strategy to a wide variety of calibration problems. Conclusions: Here we provide a parameter estimation strategy which combines efficient global optimization with a regularization scheme. This method is able to calibrate dynamic models in an efficient and robust way, effectively fighting overfitting and allowing the incorporation of prior information. © 2015 Gábor and Banga.


Villaverde A.F.,Bioprocess Engineering Group | Ross J.,Stanford University | Moran F.,Complutense University of Madrid | Banga J.R.,Bioprocess Engineering Group
PLoS ONE | Year: 2014

The prediction of links among variables from a given dataset is a task referred to as network inference or reverse engineering. It is an open problem in bioinformatics and systems biology, as well as in other areas of science. Information theory, which uses concepts such as mutual information, provides a rigorous framework for addressing it. While a number of information-theoretic methods are already available, most of them focus on a particular type of problem, introducing assumptions that limit their generality. Furthermore, many of these methods lack a publicly available implementation. Here we present MIDER, a method for inferring network structures with information theoretic concepts. It consists of two steps: first, it provides a representation of the network in which the distance among nodes indicates their statistical closeness. Second, it refines the prediction of the existing links to distinguish between direct and indirect interactions and to assign directionality. The method accepts as input time-series data related to some quantitative features of the network nodes (such as e.g. concentrations, if the nodes are chemical species). It takes into account time delays between variables, and allows choosing among several definitions and normalizations of mutual information. It is general purpose: it may be applied to any type of network, cellular or otherwise. A Matlab implementation including source code and data is freely available (http://www.iim.csic.es/∼gingproc/mider.html). The performance of MIDER has been evaluated on seven different benchmark problems that cover the main types of cellular networks, including metabolic, gene regulatory, and signaling. Comparisons with state of the art information-theoretic methods have demonstrated the competitive performance of MIDER, as well as its versatility. Its use does not demand any a priori knowledge from the user; the default settings and the adaptive nature of the method provide good results for a wide range of problems without requiring tuning. © 2014 Villaverde et al.


Balsa-Canto E.,Bioprocess Engineering Group | Banga J.R.,Bioprocess Engineering Group
Bioinformatics | Year: 2011

Motivation: Mathematical models of complex biological systems usually consist of sets of differential equations which depend on several parameters which are not accessible to experimentation. These parameters must be estimated by fitting the model to experimental data. This estimation problem is very challenging due to the non-linear character of the dynamics, the large number of parameters and the frequently poor information content of the experimental data (poor practical identifiability). The design of optimal (more informative) experiments is an associated problem of the highest interest. Results: This work presents AMIGO, a toolbox which facilitates parametric identification by means of advanced numerical techniques which cover the full iterative identification procedure putting especial emphasis on robust methods for parameter estimation and practical identifiability analyses, plus flexible capabilities for optimal experimental design. © The Author(s) 2011. Published by Oxford University Press.

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