Petri Net Siphon Analysis and Network Centrality Measures for Identifying Combination Therapies in Signaling Pathways

Aberrant behavior of biological signaling pathways has been implicated in diseases such as cancers. Therapies have been developed to target proteins in these networks in the hope of curing the illness or bringing about remission. However, identifying targets for drug inhibition that exhibit good therapeutic index has proven to be challenging since signaling pathways have a large number of components and many interconnections such as feedback, crosstalk, and divergence. Unfortunately, some characteristics of these pathways such as redundancy, feedback, and drug resistance reduce the efficacy of single drug target therapy and necessitate the employment of more than one drug to target multiple nodes in the system. However, choosing multiple targets with high therapeutic index poses more challenges since the combinatorial search space could be huge. To cope with the complexity of these systems, computational tools such as ordinary differential equations have been used to successfully model some of these pathways. Regrettably, for building these models, experimentally-measured initial concentrations of the components and rates of reactions are needed which are difficult to obtain, and in very large networks, they may not be available at the moment. Fortunately, there exist other modeling tools, though not as powerful as ordinary differential equations, which do not need the rates and initial conditions to model signaling pathways. Petri net and graph theory are among these tools. In this thesis, we introduce a methodology based on Petri net siphon analysis and graph network centrality measures for identifying prospective targets for single and multiple drug therapies. In this methodology, first, potential targets are identified in the Petri net model of a signaling pathway using siphon analysis. Then, the graph-theoretic centrality measures are employed to prioritize the candidate targets. Also, an algorithm is developed to check whether the candidate targets are able to disable the intended outputs in the graph model of the system or not. We implement structural and dynamical models of ErbB1-Ras-MAPK pathways and use them to assess and evaluate this methodology. The identified drug-targets, single and multiple, correspond to clinically relevant drugs. Overall, the results suggest that this methodology, using siphons and centrality measures, shows promise in identifying and ranking drugs. Since this methodology only uses the structural information of the signaling pathways and does not need initial conditions and dynamical rates, it can be utilized in larger networks.

The centrality of groups and classes

This paper extends the standard network centrality measures of degree, closeness and betweenness to apply to groups and classes as well as individuals. The group centrality measures will enable researchers to answer such questions as ‘how central is the engineering department in the informal influence network of this company?’ or ‘among middle managers in a given organization, which are more central, the men or the women?’ With these measures we can also solve the inverse problem: given the network of ties among organization members, how can we form a team that is maximally central? The measures are illustrated using two classic network data sets. We also formalize a measure of group centrality efficiency, which indicates the extent to which a group's centrality is principally due to a small subset of its members.

Team Member’s Centrality, Cohesion, Conflict, and Performance in Multi-University Geographically Distributed Project Teams

This study examined team processes and outcomes among 12 multi-university distributed project teams from 11 universities during its early and late development stages over a 14-month project period. A longitudinal model of team interaction is presented and tested at the individual level to consider the extent to which both formal and informal network connections—measured as degree centrality—relate to changes in team members’ individual perceptions of cohesion and conflict in their teams, and their individual performance as a team member over time. The study showed a negative network centrality-cohesion relationship with significant temporal patterns, indicating that as team members perceive less degree centrality in distributed project teams, they report more team cohesion during the last four months of the project. We also found that changes in team cohesion from the first three months (i.e., early development stage) to the last four months (i.e., late development stage) of the project relate positively to changes in team member performance. Although degree centrality did not relate significantly to changes in team conflict over time, a strong inverse relationship was found between changes in team conflict and cohesion, suggesting that team conflict emphasizes a different but related aspect of how individuals view their experience with the team process. Changes in team conflict, however, did not relate to changes in team member performance. Ultimately, we showed that individuals, who are less central in the network and report higher levels of team cohesion, performed better in distributed teams over time.

Comparing China's city transportation and economic networks

The city system has been a prevailing research issue in the fields of urban geography and regional economics. Not only do the relationships between cities in the city system exist in the form of rankings, but also in a more general network form. Previous work has examined the spatial structure of the city system in terms of its separate industrial networks, such as in transportation and economic activity, but little has been done to compare different networks. To rectify this situation, this study analyzes and reveals the spatial structural features of China’s city system by comparing its transportation and economic urban networks, thus providing new avenues for research on China’s city network. The results indicate that these two networks relate with each other by sharing structural equivalence with a basic diamond structure and a layered intercity structure decreasing outwards from the national centers. A decoupling effect also exists between them as the transportation network contributes to a balanced regional development, while the economic network promotes agglomeration economies. The law of economic development and the government both play important roles in the articulation between these two networks, and the gap between them can be shortened by related policy reforms and the improvement of the transportation network.

Assessment of the EEE-4 oral test: a discourse analysis based on complex networks.

With the development of information technology, the theory and methodology of complex network has been introduced to the language research, which transforms the system of language in a complex networks composed of nodes and edges for the quantitative analysis about the language structure. The development of dependency grammar provides theoretical support for the construction of a treebank corpus, making possible a statistic analysis of complex networks. This paper introduces the theory and methodology of the complex network and builds dependency syntactic networks based on the treebank of speeches from the EEE-4 oral test. According to the analysis of the overall characteristics of the networks, including the number of edges, the number of the nodes, the average degree, the average path length, the network centrality and the degree distribution, it aims to find in the networks potential difference and similarity between various grades of speaking performance. Through clustering analysis, this research intends to prove the network parameters’ discriminating feature and provide potential reference for scoring speaking performance.

A new betweenness centrality measure based on an algorithm for ranking the nodes of a network

We propose and discuss a new centrality index for urban street patterns represented as networks in geographical space. This centrality measure, that we call ranking-betweenness centrality, combines the idea behind the random-walk betweenness centrality measure and the idea of ranking the nodes of a network produced by an adapted PageRank algorithm. We initially use a PageRank algorithm in which we are able to transform some information of the network that we want to analyze into numerical values. Numerical values summarizing the information are associated to each of the nodes by means of a data matrix. After running the adapted PageRank algorithm, a ranking of the nodes is obtained, according to their importance in the network. This classification is the starting point for applying an algorithm based on the random-walk betweenness centrality. A detailed example of a real urban street network is discussed in order to understand the process to evaluate the ranking-betweenness centrality proposed, performing some comparisons with other classical centrality measures.

Using complex network metrics to predict the persistence of metapopulations with asymmetric connectivity patterns

Almost all metapopulation modelling assumes that connectivity between patches is only a function of distance, and is therefore symmetric. However, connectivity will not depend only on the distance between the patches, as some paths are easy to traverse, while others are difficult. When colonising organisms interact with the heterogeneous landscape between patches, connectivity patterns will invariably be asymmetric. There have been few attempts to theoretically assess the effects of asymmetric connectivity patterns on the dynamics of metapopulations. In this paper, we use the framework of complex networks to investigate whether metapopulation dynamics can be determined by directly analysing the asymmetric connectivity patterns that link the patches. Our analyses focus on “patch occupancy” metapopulation models, which only consider whether a patch is occupied or not. We propose three easily calculated network metrics: the “asymmetry” and “average path strength” of the connectivity pattern, and the “centrality” of each patch. Together, these metrics can be used to predict the length of time a metapopulation is expected to persist, and the relative contribution of each patch to a metapopulation’s viability. Our results clearly demonstrate the negative effect that asymmetry has on metapopulation persistence. Complex network analyses represent a useful new tool for understanding the dynamics of species existing in fragmented landscapes, particularly those existing in large metapopulations.

The application of social network analysis in the construction industry of Hong Kong

The Hong Kong construction industry is currently facing ageing problem and labour shortage. There are opportunities for employing ethnic minority construction workers to join this hazardous industry. These ethnic minority workers are prone to accidents due to communication barriers. Safety communication is playing an important role for avoiding the accidents on construction sites. However, the ethnic minority workers are not very fluent in the local language and facing safety communication problems while working with local workers. Social network analysis (SNA), being an effective tool to identify the safety communication flow on the construction site, is used to attain the measures of safety communication like centrality, density and betweenness within the ethnic minorities and local workers, and to generate sociograms that visually represent communication pattern within the effective and ineffective safety networks. The aim of this paper is to present the application of SNA for improving the safety communication of ethnic minorities in the construction industry of Hong Kong. The paper provides the theoretical background of SNA approaches for the data collection and analysis using the software UCINET and NetDraw, to determine the predominant safety communication network structure and pattern of ethnic minorities on site.

A linear programming approach for estimating the structure of a sparse linear genetic network from transcript profiling data

Background: A genetic network can be represented as a directed graph in which a node corresponds to a gene and a directed edge specifies the direction of influence of one gene on another. The reconstruction of such networks from transcript profiling data remains an important yet challenging endeavor. A transcript profile specifies the abundances of many genes in a biological sample of interest. Prevailing strategies for learning the structure of a genetic network from high-dimensional transcript profiling data assume sparsity and linearity. Many methods consider relatively small directed graphs, inferring graphs with up to a few hundred nodes. This work examines large undirected graphs representations of genetic networks, graphs with many thousands of nodes where an undirected edge between two nodes does not indicate the direction of influence, and the problem of estimating the structure of such a sparse linear genetic network (SLGN) from transcript profiling data. Results: The structure learning task is cast as a sparse linear regression problem which is then posed as a LASSO (l1-constrained fitting) problem and solved finally by formulating a Linear Program (LP). A bound on the Generalization Error of this approach is given in terms of the Leave-One-Out Error. The accuracy and utility of LP-SLGNs is assessed quantitatively and qualitatively using simulated and real data. The Dialogue for Reverse Engineering Assessments and Methods (DREAM) initiative provides gold standard data sets and evaluation metrics that enable and facilitate the comparison of algorithms for deducing the structure of networks. The structures of LP-SLGNs estimated from the INSILICO1, INSILICO2 and INSILICO3 simulated DREAM2 data sets are comparable to those proposed by the first and/or second ranked teams in the DREAM2 competition. The structures of LP-SLGNs estimated from two published Saccharomyces cerevisae cell cycle transcript profiling data sets capture known regulatory associations. In each S. cerevisiae LP-SLGN, the number of nodes with a particular degree follows an approximate power law suggesting that its degree distributions is similar to that observed in real-world networks. Inspection of these LP-SLGNs suggests biological hypotheses amenable to experimental verification. Conclusion: A statistically robust and computationally efficient LP-based method for estimating the topology of a large sparse undirected graph from high-dimensional data yields representations of genetic networks that are biologically plausible and useful abstractions of the structures of real genetic networks. Analysis of the statistical and topological properties of learned LP-SLGNs may have practical value; for example, genes with high random walk betweenness, a measure of the centrality of a node in a graph, are good candidates for intervention studies and hence integrated computational – experimental investigations designed to infer more realistic and sophisticated probabilistic directed graphical model representations of genetic networks. The LP-based solutions of the sparse linear regression problem described here may provide a method for learning the structure of transcription factor networks from transcript profiling and transcription factor binding motif data.

Altruism in the (Social) Network

This paper explores the role of social integration on altruistic behavior. To this aim, we develop a two-stage experimental protocol based on the classic Dictator Game. In the first stage, we ask a group of 77 undergraduate students in Economics to elicit their social network; in the second stage, each of them has to unilaterally decide over the division of a fixed amount of money to be shared with another anonymous member in the group. Our experimental design allows to control for other variables known to be relevant for altruistic behavior: framing and friendship/acquaintance relations. Consistently with previous research, we find that subjects favor their friends and that framing enhances altruistic behavior. Once we control for these effects, social integration (measured by betweenness, a standard centrality measure in network theory) has a positive effect on giving: the larger social isolation within the group, the more likely it is the emergence of selfish behavior. These results suggest that information on the network structure in which subjects are embedded is crucial to account for their behavior.

Analysis of Spanish text-thesaurus as a complex network

[EN]Based on the theoretical tools of Complex Networks, this work provides a basic descriptive study of a synonyms dictionary, the Spanish Open Thesaurus represented as a graph. We study the main structural measures of the network compared with those of a random graph. Numerical results show that Open-Thesaurus is a graph whose topological properties approximate a scale-free network, but seems not to present the small-world property because of its sparse structure. We also found that the words of highest betweenness centrality are terms that suggest the vocabulary of psychoanalysis: placer (pleasure), ayudante (in the sense of assistant or worker), and regular (to regulate).

Determinants of port centrality in maritime container transportation.

This paper adapts Freeman’s measures of degree, closeness and betweenness centrality and applies them to assessing: port centrality in relation to direct connectivity; accessibility to all ports in the network (direct and indirect routes) and; as an intermediary between other ports. An additional parameter added to the formulae ensures that the relative importance of available shipping capacity and foreland market coverage are also accounted for. Validation of this adapted measure is provided by the results obtained from an empirical application. These reveal that foreland market coverage exerts a particularly strong influence on a port’s demand and closeness centrality

Network analysis of 2-mode data

Network analysis is distinguished from traditional social science by the dyadic nature of the standard data set. Whereas in traditional social science we study monadic attributes of individuals, in network analysis we study dyadic attributes of pairs of individuals. These dyadic attributes (e.g. social relations) may be represented in matrix form by a square 1-mode matrix. In contrast, the data in traditional social science are represented as 2-mode matrices. However, network analysis is not completely divorced from traditional social science, and often has occasion to collect and analyze 2-mode matrices. Furthermore, some of the methods developed in network analysis have uses in analysing non-network data. This paper presents and discusses ways of applying and interpreting traditional network analytic techniques to 2-mode data, as well as developing new techniques. Three areas are covered in detail: displaying 2-mode data as networks, detecting clusters and measuring centrality.

Betweenness Centrality in Some Classes of Graphs

There are several centrality measures that have been introduced and studied for real world networks. They account for the different vertex characteristics that permit them to be ranked in order of importance in the network. Betweenness centrality is a measure of the influence of a vertex over the flow of information between every pair of vertices under the assumption that information primarily flows over the shortest path between them. In this paper we present betweenness centrality of some important classes of graphs.

Semantic network analysis of ontologies

A key argument for modeling knowledge in ontologies is the easy re-use and re-engineering of the knowledge. However, beside consistency checking, current ontology engineering tools provide only basic functionalities for analyzing ontologies. Since ontologies can be considered as (labeled, directed) graphs, graph analysis techniques are a suitable answer for this need. Graph analysis has been performed by sociologists for over 60 years, and resulted in the vivid research area of Social Network Analysis (SNA). While social network structures in general currently receive high attention in the Semantic Web community, there are only very few SNA applications up to now, and virtually none for analyzing the structure of ontologies. We illustrate in this paper the benefits of applying SNA to ontologies and the Semantic Web, and discuss which research topics arise on the edge between the two areas. In particular, we discuss how different notions of centrality describe the core content and structure of an ontology. From the rather simple notion of degree centrality over betweenness centrality to the more complex eigenvector centrality based on Hermitian matrices, we illustrate the insights these measures provide on two ontologies, which are different in purpose, scope, and size.