TY - JOUR A1 - Guziolowski, Carito A1 - Videla, Santiago A1 - Eduati, Federica A1 - Thiele, Sven A1 - Cokelaer, Thomas A1 - Siegel, Anne A1 - Saez-Rodriguez, Julio T1 - Exhaustively characterizing feasible logic models of a signaling network using Answer Set Programming JF - Bioinformatics N2 - Motivation: Logic modeling is a useful tool to study signal transduction across multiple pathways. Logic models can be generated by training a network containing the prior knowledge to phospho-proteomics data. The training can be performed using stochastic optimization procedures, but these are unable to guarantee a global optima or to report the complete family of feasible models. This, however, is essential to provide precise insight in the mechanisms underlaying signal transduction and generate reliable predictions. Results: We propose the use of Answer Set Programming to explore exhaustively the space of feasible logic models. Toward this end, we have developed caspo, an open-source Python package that provides a powerful platform to learn and characterize logic models by leveraging the rich modeling language and solving technologies of Answer Set Programming. We illustrate the usefulness of caspo by revisiting a model of pro-growth and inflammatory pathways in liver cells. We show that, if experimental error is taken into account, there are thousands (11 700) of models compatible with the data. Despite the large number, we can extract structural features from the models, such as links that are always (or never) present or modules that appear in a mutual exclusive fashion. To further characterize this family of models, we investigate the input-output behavior of the models. We find 91 behaviors across the 11 700 models and we suggest new experiments to discriminate among them. Our results underscore the importance of characterizing in a global and exhaustive manner the family of feasible models, with important implications for experimental design. Y1 - 2013 U6 - https://doi.org/10.1093/bioinformatics/btt393 SN - 1367-4803 VL - 29 IS - 18 SP - 2320 EP - 2326 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Kaminski, Roland A1 - Schaub, Torsten H. A1 - Siegel, Anne A1 - Videla, Santiago T1 - Minimal intervention strategies in logical signaling networks with ASP JF - Theory and practice of logic programming N2 - Proposing relevant perturbations to biological signaling networks is central to many problems in biology and medicine because it allows for enabling or disabling certain biological outcomes. In contrast to quantitative methods that permit fine-grained (kinetic) analysis, qualitative approaches allow for addressing large-scale networks. This is accomplished by more abstract representations such as logical networks. We elaborate upon such a qualitative approach aiming at the computation of minimal interventions in logical signaling networks relying on Kleene's three-valued logic and fixpoint semantics. We address this problem within answer set programming and show that it greatly outperforms previous work using dedicated algorithms. Y1 - 2013 U6 - https://doi.org/10.1017/S1471068413000422 SN - 1471-0684 VL - 13 SP - 675 EP - 690 PB - Cambridge Univ. Press CY - New York ER - TY - JOUR A1 - Videla, Santiago A1 - Guziolowski, Carito A1 - Eduati, Federica A1 - Thiele, Sven A1 - Gebser, Martin A1 - Nicolas, Jacques A1 - Saez-Rodriguez, Julio A1 - Schaub, Torsten H. A1 - Siegel, Anne T1 - Learning Boolean logic models of signaling networks with ASP JF - Theoretical computer science N2 - Boolean networks provide a simple yet powerful qualitative modeling approach in systems biology. However, manual identification of logic rules underlying the system being studied is in most cases out of reach. Therefore, automated inference of Boolean logical networks from experimental data is a fundamental question in this field. This paper addresses the problem consisting of learning from a prior knowledge network describing causal interactions and phosphorylation activities at a pseudo-steady state, Boolean logic models of immediate-early response in signaling transduction networks. The underlying optimization problem has been so far addressed through mathematical programming approaches and the use of dedicated genetic algorithms. In a recent work we have shown severe limitations of stochastic approaches in this domain and proposed to use Answer Set Programming (ASP), considering a simpler problem setting. Herein, we extend our previous work in order to consider more realistic biological conditions including numerical datasets, the presence of feedback-loops in the prior knowledge network and the necessity of multi-objective optimization. In order to cope with such extensions, we propose several discretization schemes and elaborate upon our previous ASP encoding. Towards real-world biological data, we evaluate the performance of our approach over in silico numerical datasets based on a real and large-scale prior knowledge network. The correctness of our encoding and discretization schemes are dealt with in Appendices A-B. (C) 2014 Elsevier B.V. All rights reserved. KW - Answer set programming KW - Signaling transduction networks KW - Boolean logic models KW - Combinatorial multi-objective optimization KW - Systems biology Y1 - 2015 U6 - https://doi.org/10.1016/j.tcs.2014.06.022 SN - 0304-3975 SN - 1879-2294 VL - 599 SP - 79 EP - 101 PB - Elsevier CY - Amsterdam ER - TY - THES A1 - Videla, Santiago T1 - Reasoning on the response of logical signaling networks with answer set programming T1 - Modellierung Logischer Signalnetzwerke mittels Antwortmengenprogrammierung N2 - Deciphering the functioning of biological networks is one of the central tasks in systems biology. In particular, signal transduction networks are crucial for the understanding of the cellular response to external and internal perturbations. Importantly, in order to cope with the complexity of these networks, mathematical and computational modeling is required. We propose a computational modeling framework in order to achieve more robust discoveries in the context of logical signaling networks. More precisely, we focus on modeling the response of logical signaling networks by means of automated reasoning using Answer Set Programming (ASP). ASP provides a declarative language for modeling various knowledge representation and reasoning problems. Moreover, available ASP solvers provide several reasoning modes for assessing the multitude of answer sets. Therefore, leveraging its rich modeling language and its highly efficient solving capacities, we use ASP to address three challenging problems in the context of logical signaling networks: learning of (Boolean) logical networks, experimental design, and identification of intervention strategies. Overall, the contribution of this thesis is three-fold. Firstly, we introduce a mathematical framework for characterizing and reasoning on the response of logical signaling networks. Secondly, we contribute to a growing list of successful applications of ASP in systems biology. Thirdly, we present a software providing a complete pipeline for automated reasoning on the response of logical signaling networks. N2 - Deciphering the functioning of biological networks is one of the central tasks in systems biology. In particular, signal transduction networks are crucial for the understanding of the cellular response to external and internal perturbations. Importantly, in order to cope with the complexity of these networks, mathematical and computational modeling is required. We propose a computational modeling framework in order to achieve more robust discoveries in the context of logical signaling networks. More precisely, we focus on modeling the response of logical signaling networks by means of automated reasoning using Answer Set Programming (ASP). ASP provides a declarative language for modeling various knowledge representation and reasoning problems. Moreover, available ASP solvers provide several reasoning modes for assessing the multitude of answer sets. Therefore, leveraging its rich modeling language and its highly efficient solving capacities, we use ASP to address three challenging problems in the context of logical signaling networks: learning of (Boolean) logical networks, experimental design, and identification of intervention strategies. Overall, the contribution of this thesis is three-fold. Firstly, we introduce a mathematical framework for characterizing and reasoning on the response of logical signaling networks. Secondly, we contribute to a growing list of successful applications of ASP in systems biology. Thirdly, we present a software providing a complete pipeline for automated reasoning on the response of logical signaling networks. KW - Systembiologie KW - logische Signalnetzwerke KW - Antwortmengenprogrammierung KW - systems biology KW - logical signaling networks KW - answer set programming Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus-71890 ER - TY - GEN A1 - Kaminski, Roland A1 - Schaub, Torsten H. A1 - Siegel, Anne A1 - Videla, Santiago T1 - Minimal intervention strategies in logical signaling networks with ASP T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - Proposing relevant perturbations to biological signaling networks is central to many problems in biology and medicine because it allows for enabling or disabling certain biological outcomes. In contrast to quantitative methods that permit fine-grained (kinetic) analysis, qualitative approaches allow for addressing large-scale networks. This is accomplished by more abstract representations such as logical networks. We elaborate upon such a qualitative approach aiming at the computation of minimal interventions in logical signaling networks relying on Kleene's three-valued logic and fixpoint semantics. We address this problem within answer set programming and show that it greatly outperforms previous work using dedicated algorithms. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 596 KW - systems biology KW - transduction KW - circuits KW - models KW - sets Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-415704 SN - 1866-8372 IS - 4-5 SP - 675 EP - 690 ER -