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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.
Answer Set Programming faces an increasing popularity for problem solving in various domains. While its modeling language allows us to express many complex problems in an easy way, its solving technology enables their effective resolution. In what follows, we detail some of the key factors of its success. Answer Set Programming [ASP; Brewka et al. Commun ACM 54(12):92–103, (2011)] is seeing a rapid proliferation in academia and industry due to its easy and flexible way to model and solve knowledge-intense combinatorial (optimization) problems. To this end, ASP offers a high-level modeling language paired with high-performance solving technology. As a result, ASP systems provide out-off-the-box, general-purpose search engines that allow for enumerating (optimal) solutions. They are represented as answer sets, each being a set of atoms representing a solution. The declarative approach of ASP allows a user to concentrate on a problem’s specification rather than the computational means to solve it. This makes ASP a prime candidate for rapid prototyping and an attractive tool for teaching key AI techniques since complex problems can be expressed in a succinct and elaboration tolerant way. This is eased by the tuning of ASP’s modeling language to knowledge representation and reasoning (KRR). The resulting impact is nicely reflected by a growing range of successful applications of ASP [Erdem et al. AI Mag 37(3):53–68, 2016; Falkner et al. Industrial applications of answer set programming. K++nstliche Intelligenz (2018)]
Preferred well-founded semantics for logic programming by alternating fixpoints : preliminary report
(2002)
The family of default logics
(1998)
A polynomial translation of logic programs with nested expressions into disjunctive logic programs
(2002)
We present the hybrid ASP solver clingcon, combining the simple modeling language and the high performance Boolean solving capacities of Answer Set Programming (ASP) with techniques for using non-Boolean constraints from the area of Constraint Programming (CP). The new clingcon system features an extended syntax supporting global constraints and optimize statements for constraint variables. The major technical innovation improves the interaction between ASP and CP solver through elaborated learning techniques based on irreducible inconsistent sets. A broad empirical evaluation shows that these techniques yield a performance improvement of an order of magnitude.
Boolean networks (and more general logic models) are useful frameworks to study signal transduction across multiple pathways. Logic models can be learned from a prior knowledge network structure and multiplex phosphoproteomics data. However, most efficient and scalable training methods focus on the comparison of two time-points and assume that the system has reached an early steady state. In this paper, we generalize such a learning procedure to take into account the time series traces of phosphoproteomics data in order to discriminate Boolean networks according to their transient dynamics. To that end, we identify a necessary condition that must be satisfied by the dynamics of a Boolean network to be consistent with a discretized time series trace. Based on this condition, we use Answer Set Programming to compute an over-approximation of the set of Boolean networks which fit best with experimental data and provide the corresponding encodings. Combined with model-checking approaches, we end up with a global learning algorithm. Our approach is able to learn logic models with a true positive rate higher than 78% in two case studies of mammalian signaling networks; for a larger case study, our method provides optimal answers after 7 min of computation. We quantified the gain in our method predictions precision compared to learning approaches based on static data. Finally, as an application, our method proposes erroneous time-points in the time series data with respect to the optimal learned logic models. (C) 2016 Elsevier Ireland Ltd. All rights reserved.