Self-adaptive exploration in evolutionary search

We address a primary question of computational as well as biological research on evolution: How can an exploration strategy adapt in such a way as to exploit the information gained about the problem at hand? We first introduce an integrated formalism of evolutionary search which provides a unified view on different specific approaches. On this basis we discuss the implications of indirect modeling (via a ``genotype-phenotype mapping'') on the exploration strategy. Notions such as modularity, pleiotropy and functional phenotypic complex are discussed as implications. Then, rigorously reflecting the notion of self-adaptability, we introduce a new definition that captures self-adaptability of exploration: different genotypes that map to the same phenotype may represent (also topologically) different exploration strategies; self-adaptability requires a variation of exploration strategies along such a ``neutral space''. By this definition, the concept of neutrality becomes a central concern of this paper. Finally, we present examples of these concepts: For a specific grammar-type encoding, we observe a large variability of exploration strategies for a fixed phenotype, and a self-adaptive drift towards short representations with highly structured exploration strategy that matches the ``problem's structure''.Comment: 24 pages, 5 figure

Hypothesis testing near singularities and boundaries

The likelihood ratio statistic, with its asymptotic $\chi^2$ distribution at regular model points, is often used for hypothesis testing. At model singularities and boundaries, however, the asymptotic distribution may not be $\chi^2$, as highlighted by recent work of Drton. Indeed, poor behavior of a $\chi^2$ for testing near singularities and boundaries is apparent in simulations, and can lead to conservative or anti-conservative tests. Here we develop a new distribution designed for use in hypothesis testing near singularities and boundaries, which asymptotically agrees with that of the likelihood ratio statistic. For two example trinomial models, arising in the context of inference of evolutionary trees, we show the new distributions outperform a $\chi^2$.Comment: 32 pages, 12 figure

Petri nets for systems and synthetic biology

We give a description of a Petri net-based framework for modelling and analysing biochemical pathways, which uni¯es the qualita- tive, stochastic and continuous paradigms. Each perspective adds its con- tribution to the understanding of the system, thus the three approaches do not compete, but complement each other. We illustrate our approach by applying it to an extended model of the three stage cascade, which forms the core of the ERK signal transduction pathway. Consequently our focus is on transient behaviour analysis. We demonstrate how quali- tative descriptions are abstractions over stochastic or continuous descrip- tions, and show that the stochastic and continuous models approximate each other. Although our framework is based on Petri nets, it can be applied more widely to other formalisms which are used to model and analyse biochemical networks

Computational models for inferring biochemical networks

Biochemical networks are of great practical importance. The interaction of biological compounds in cells has been enforced to a proper understanding by the numerous bioinformatics projects, which contributed to a vast amount of biological information. The construction of biochemical systems (systems of chemical reactions), which include both topology and kinetic constants of the chemical reactions, is NP-hard and is a well-studied system biology problem. In this paper, we propose a hybrid architecture, which combines genetic programming and simulated annealing in order to generate and optimize both the topology (the network) and the reaction rates of a biochemical system. Simulations and analysis of an artificial model and three real models (two models and the noisy version of one of them) show promising results for the proposed method.The Romanian National Authority for Scientific Research, CNDI–UEFISCDI, Project No. PN-II-PT-PCCA-2011-3.2-0917

Towards a Theory of Scale-Free Graphs: Definition, Properties, and Implications (Extended Version)

Although the ``scale-free'' literature is large and growing, it gives neither a precise definition of scale-free graphs nor rigorous proofs of many of their claimed properties. In fact, it is easily shown that the existing theory has many inherent contradictions and verifiably false claims. In this paper, we propose a new, mathematically precise, and structural definition of the extent to which a graph is scale-free, and prove a series of results that recover many of the claimed properties while suggesting the potential for a rich and interesting theory. With this definition, scale-free (or its opposite, scale-rich) is closely related to other structural graph properties such as various notions of self-similarity (or respectively, self-dissimilarity). Scale-free graphs are also shown to be the likely outcome of random construction processes, consistent with the heuristic definitions implicit in existing random graph approaches. Our approach clarifies much of the confusion surrounding the sensational qualitative claims in the scale-free literature, and offers rigorous and quantitative alternatives.Comment: 44 pages, 16 figures. The primary version is to appear in Internet Mathematics (2005

Representing Conversations for Scalable Overhearing

Open distributed multi-agent systems are gaining interest in the academic community and in industry. In such open settings, agents are often coordinated using standardized agent conversation protocols. The representation of such protocols (for analysis, validation, monitoring, etc) is an important aspect of multi-agent applications. Recently, Petri nets have been shown to be an interesting approach to such representation, and radically different approaches using Petri nets have been proposed. However, their relative strengths and weaknesses have not been examined. Moreover, their scalability and suitability for different tasks have not been addressed. This paper addresses both these challenges. First, we analyze existing Petri net representations in terms of their scalability and appropriateness for overhearing, an important task in monitoring open multi-agent systems. Then, building on the insights gained, we introduce a novel representation using Colored Petri nets that explicitly represent legal joint conversation states and messages. This representation approach offers significant improvements in scalability and is particularly suitable for overhearing. Furthermore, we show that this new representation offers a comprehensive coverage of all conversation features of FIPA conversation standards. We also present a procedure for transforming AUML conversation protocol diagrams (a standard human-readable representation), to our Colored Petri net representation

Protein-Ligand Binding Affinity Directed Multi-Objective Drug Design Based on Fragment Representation Methods

Drug discovery is a challenging process with a vast molecular space to be explored and numerous pharmacological properties to be appropriately considered. Among various drug design protocols, fragment-based drug design is an effective way of constraining the search space and better utilizing biologically active compounds. Motivated by fragment-based drug search for a given protein target and the emergence of artificial intelligence (AI) approaches in this field, this work advances the field of in silico drug design by (1) integrating a graph fragmentation-based deep generative model with a deep evolutionary learning process for large-scale multi-objective molecular optimization, and (2) applying protein-ligand binding affinity scores together with other desired physicochemical properties as objectives. Our experiments show that the proposed method can generate novel molecules with improved property values and binding affinities

Automatic Analysis and Validation of the Chemical Literature

ThesisMethods to automatically extract and validate data from the chemical literature in legacy formats to machine-understandable forms are examined. The work focuses of three types of data: analytical data reported in articles, computational chemistry output files and crystallographic information files (CIFs). It is shown that machines are capable of reading and extracting analytical data from the current legacy formats with high recall and precision. Regular expressions cannot identify chemical names with high precision or recall but non-deterministic methods perform significantly better. The lack of machine-understandable connection tables in the literature has been identified as the major issue preventing molecule-based data-driven science being performed in the area. The extraction of data from computational chemistry output files using parser-like approaches is shown to be not generally possible although such methods work well for input files. A hierarchical regular expression based approach can parse > 99:9% of the output files correctly although significant human input is required to prepare the templates. CIFs may be parsed with extremely high recall and precision, contain connection tables and the data is of high quality. The comparison of bond lengths calculated by two computational chemistry programs show good agreement in general but structures containing specific moieties cause discrepancies. An initial protocol for the high-throughput geometry optimisation of molecules extracted from the CIFs is presented and the refinement of this protocol is discussed. Differences in bond length between calculated and experimentally determined values from the CIFs of less than 0.03 Angstrom are shown to be expected by random error. The final protocol is used to find high-quality structures from crystallography which can be reused for further science.Unilever Centre for Molecular Science Informatic