Therapeutic target discovery using Boolean network attractors: avoiding pathological phenotypes

Target identification, one of the steps of drug discovery, aims at identifying biomolecules whose function should be therapeutically altered in order to cure the considered pathology. This work proposes an algorithm for in silico target identification using Boolean network attractors. It assumes that attractors of dynamical systems, such as Boolean networks, correspond to phenotypes produced by the modeled biological system. Under this assumption, and given a Boolean network modeling a pathophysiology, the algorithm identifies target combinations able to remove attractors associated with pathological phenotypes. It is tested on a Boolean model of the mammalian cell cycle bearing a constitutive inactivation of the retinoblastoma protein, as seen in cancers, and its applications are illustrated on a Boolean model of Fanconi anemia. The results show that the algorithm returns target combinations able to remove attractors associated with pathological phenotypes and then succeeds in performing the proposed in silico target identification. However, as with any in silico evidence, there is a bridge to cross between theory and practice, thus requiring it to be used in combination with wet lab experiments. Nevertheless, it is expected that the algorithm is of interest for target identification, notably by exploiting the inexpensiveness and predictive power of computational approaches to optimize the efficiency of costly wet lab experiments.Comment: Since the publication of this article and among the possible improvements mentioned in the Conclusion, two improvements have been done: extending the algorithm for multivalued logic and considering the basins of attraction of the pathological attractors for selecting the therapeutic bullet

Probabilistic Graphical Models on Multi-Core CPUs using Java 8

In this paper, we discuss software design issues related to the development of parallel computational intelligence algorithms on multi-core CPUs, using the new Java 8 functional programming features. In particular, we focus on probabilistic graphical models (PGMs) and present the parallelisation of a collection of algorithms that deal with inference and learning of PGMs from data. Namely, maximum likelihood estimation, importance sampling, and greedy search for solving combinatorial optimisation problems. Through these concrete examples, we tackle the problem of defining efficient data structures for PGMs and parallel processing of same-size batches of data sets using Java 8 features. We also provide straightforward techniques to code parallel algorithms that seamlessly exploit multi-core processors. The experimental analysis, carried out using our open source AMIDST (Analysis of MassIve Data STreams) Java toolbox, shows the merits of the proposed solutions.Comment: Pre-print version of the paper presented in the special issue on Computational Intelligence Software at IEEE Computational Intelligence Magazine journa

Competent Program Evolution, Doctoral Dissertation, December 2006

Heuristic optimization methods are adaptive when they sample problem solutions based on knowledge of the search space gathered from past sampling. Recently, competent evolutionary optimization methods have been developed that adapt via probabilistic modeling of the search space. However, their effectiveness requires the existence of a compact problem decomposition in terms of prespecified solution parameters. How can we use these techniques to effectively and reliably solve program learning problems, given that program spaces will rarely have compact decompositions? One method is to manually build a problem-specific representation that is more tractable than the general space. But can this process be automated? My thesis is that the properties of programs and program spaces can be leveraged as inductive bias to reduce the burden of manual representation-building, leading to competent program evolution. The central contributions of this dissertation are a synthesis of the requirements for competent program evolution, and the design of a procedure, meta-optimizing semantic evolutionary search (MOSES), that meets these requirements. In support of my thesis, experimental results are provided to analyze and verify the effectiveness of MOSES, demonstrating scalability and real-world applicability