The Community Structure of R&D Cooperation in Europe. Evidence from a social network perspective

The focus of this paper is on pre-competitive R&D cooperation across Europe, as captured by R&D joint ventures funded by the European Commission in the time period 1998-2002, within the 5th Framework Program. The cooperations in this Framework Program give rise to a bipartite network with 72,745 network edges between 25,839 actors (representing organizations that include firms, universities, research organizations and public agencies) and 9,490 R&D projects. With this construction, participating actors are linked only through joint projects. In this paper we describe the community identification problem based on the concept of modularity, and use the recently introduced label-propagation algorithm to identify communities in the network, and differentiate the identified communities by developing community-specific profiles using social network analysis and geographic visualization techniques. We expect the results to enrich our picture of the European Research Area by providing new insights into the global and local structures of R&D cooperation across Europe

Twin subgraphs and core-semiperiphery-periphery structures

A standard approach to reduce the complexity of very large networks is to group together sets of nodes into clusters according to some criterion which reflects certain structural properties of the network. Beyond the well-known modularity measures defining communities, there are criteria based on the existence of similar or identical connection patterns of a node or sets of nodes to the remainder of the network. A key notion in this context is that of structurally equivalent or twin nodes, displaying exactly the same connection pattern to the remainder of the network. The first goal of this paper is to extend this idea to subgraphs of arbitrary order of a given network, by means of the notions of T-twin and F-twin subgraphs. This is motivated by the need to provide a systematic approach to the analysis of core-semiperiphery-periphery (CSP) structures, a notion which somehow lacks a formal treatment in the literature. The goal is to provide an analytical framework accommodating and extending the idea that the unique (ideal) core-periphery (CP) structure is a 2-partitioned K2. We provide a formal definition of CSP structures in terms of core eccentricities and periphery degrees, with semiperiphery vertices acting as intermediaries. The T-twin and F-twin notions then make it possible to reduce the large number of resulting structures by identifying isomorphic substructures which share the connection pattern to the remainder of the graph, paving the way for the decomposition and enumeration of CSP structures. We compute the resulting CSP structures up to order six. We illustrate the scope of our results by analyzing a subnetwork of the network of 1994 metal manufactures trade. Our approach can be further applied in complex network theory and seems to have many potential extensions

Computational Methods for the Integration of Biological Activity and Chemical Space

One general aim of medicinal chemistry is the understanding of structure-activity relationships of ligands that bind to biological targets. Advances in combinatorial chemistry and biological screening technologies allow the analysis of ligand-target relationships on a large-scale. However, in order to extract useful information from biological activity data, computational methods are needed that link activity of ligands to their chemical structure. In this thesis, it is investigated how fragment-type descriptors of molecular structure can be used in order to create a link between activity and chemical ligand space. First, an activity class-dependent hierarchical fragmentation scheme is introduced that generates fragmentation pathways that are aligned using established methodologies for multiple alignment of biological sequences. These alignments are then used to extract consensus fragment sequences that serve as a structural signature for individual biological activity classes. It is also investigated how defined, chemically intuitive molecular fragments can be organized based on their topological environment and co-occurrence in compounds active against closely related targets. Therefore, the Topological Fragment Index is introduced that quantifies the topological environment complexity of a fragment in a given molecule, and thus goes beyond fragment frequency analysis. Fragment dependencies have been established on the basis of common topological environments, which facilitates the identification of activity class-characteristic fragment dependency pathways that describe fragment relationships beyond structural resemblance. Because fragments are often dependent on each other in an activity class-specific manner, the importance of defined fragment combinations for similarity searching is further assessed. Therefore, Feature Co-occurrence Networks are introduced that allow the identification of feature cliques characteristic of individual activity classes. Three differently designed molecular fingerprints are compared for their ability to provide such cliques and a clique-based similarity searching strategy is established. For molecule- and activity class-centric fingerprint designs, feature combinations are shown to improve similarity search performance in comparison to standard methods. Moreover, it is demonstrated that individual features can form activity-class specific combinations. Extending the analysis of feature cliques characteristic of individual activity classes, the distribution of defined fragment combinations among several compound classes acting against closely related targets is assessed. Fragment Formal Concept Analysis is introduced for flexible mining of complex structure-activity relationships. It allows the interactive assembly of fragment queries that yield fragment combinations characteristic of defined activity and potency profiles. It is shown that pairs and triplets, rather than individual fragments distinguish between different activity profiles. A classifier is built based on these fragment signatures that distinguishes between ligands of closely related targets. Going beyond activity profiles, compound selectivity is also analyzed. Therefore, Molecular Formal Concept Analysis is introduced for the systematic mining of compound selectivity profiles on a whole-molecule basis. Using this approach, structurally diverse compounds are identified that share a selectivity profile with selected template compounds. Structure-selectivity relationships of obtained compound sets are further analyzed

Revealing cytotoxic substructures in molecules using deep learning

In drug development, late stage toxicity issues of a compound are the main cause of failure in clinical trials. In silico meth ods are therefore of high importance to guide the early design process to reduce time, costs and animal testing. Technical advances and the ever growing amount of available toxicity data enabled machine learning, especially neural networks, to impact the feld of predictive toxicology. In this study, cytotoxicity prediction, one of the earliest handles in drug discovery, is investigated using a deep learning approach trained on a highly consistent in-house data set of over 34,000 compounds with a share of less than 5% of cytotoxic molecules. The model reached a balanced accuracy of over 70%, similar to previ ously reported studies using Random Forest. Albeit yielding good results, neural networks are often described as a black box lacking deeper mechanistic understanding of the underlying model. To overcome this absence of interpretability, a Deep Taylor Decomposition method is investigated to identify substructures that may be responsible for the cytotoxic efects, the so-called toxicophores. Furthermore, this study introduces cytotoxicity maps which provide a visual structural interpretation of the relevance of these substructures. Using this approach could be helpful in drug development to predict the potential toxicity of a compound as well as to generate new insights into the toxic mechanism. Moreover, it could also help to de-risk and optimize compounds

On the Shapley value and its application to the Italian VQR research assessment exercise

Research assessment exercises have now become common evaluation tools in a number of countries. These exercises have the goal of guiding merit-based public funds allocation, stimulating improvement of research productivity through competition and assessing the impact of adopted research support policies. One case in point is Italy's most recent research assessment effort, VQR 2011–2014 (Research Quality Evaluation), which, in addition to research institutions, also evaluated university departments, and individuals in some cases (i.e., recently hired research staff and members of PhD committees). However, the way an institution's score was divided, according to VQR rules, between its constituent departments or its staff members does not enjoy many desirable properties well known from coalitional game theory (e.g., budget balance, fairness, marginality). We propose, instead, an alternative score division rule that is based on the notion of Shapley value, a well known solution concept in coalitional game theory, which enjoys the desirable properties mentioned above. For a significant test case (namely, Sapienza University of Rome, the largest university in Italy), we present a detailed comparison of the scores obtained, for substructures and individuals, by applying the official VQR rules, with those resulting from Shapley value computations. We show that there are significant differences in the resulting scores, making room for improvements in the allocation rules used in research assessment exercises