Assessing Low-Intensity Relationships in Complex Networks.

Many large network data sets are noisy and contain links representing low-intensity relationships that are difficult to differentiate from random interactions. This is especially relevant for high-throughput data from systems biology, large-scale ecological data, but also for Web 2.0 data on human interactions. In these networks with missing and spurious links, it is possible to refine the data based on the principle of structural similarity, which assesses the shared neighborhood of two nodes. By using similarity measures to globally rank all possible links and choosing the top-ranked pairs, true links can be validated, missing links inferred, and spurious observations removed. While many similarity measures have been proposed to this end, there is no general consensus on which one to use. In this article, we first contribute a set of benchmarks for complex networks from three different settings (e-commerce, systems biology, and social networks) and thus enable a quantitative performance analysis of classic node similarity measures. Based on this, we then propose a new methodology for link assessment called z* that assesses the statistical significance of the number of their common neighbors by comparison with the expected value in a suitably chosen random graph model and which is a consistently top-performing algorithm for all benchmarks. In addition to a global ranking of links, we also use this method to identify the most similar neighbors of each single node in a local ranking, thereby showing the versatility of the method in two distinct scenarios and augmenting its applicability. Finally, we perform an exploratory analysis on an oceanographic plankton data set and find that the distribution of microbes follows similar biogeographic rules as those of macroorganisms, a result that rejects the global dispersal hypothesis for microbes.

A network-based method to assess the statistical significance of mild co-regulation effects.

Recent development of high-throughput, multiplexing technology has initiated projects that systematically investigate interactions between two types of components in biological networks, for instance transcription factors and promoter sequences, or microRNAs (miRNAs) and mRNAs. In terms of network biology, such screening approaches primarily attempt to elucidate relations between biological components of two distinct types, which can be represented as edges between nodes in a bipartite graph. However, it is often desirable not only to determine regulatory relationships between nodes of different types, but also to understand the connection patterns of nodes of the same type. Especially interesting is the co-occurrence of two nodes of the same type, i.e., the number of their common neighbours, which current high-throughput screening analysis fails to address. The co-occurrence gives the number of circumstances under which both of the biological components are influenced in the same way. Here we present SICORE, a novel network-based method to detect pairs of nodes with a statistically significant co-occurrence. We first show the stability of the proposed method on artificial data sets: when randomly adding and deleting observations we obtain reliable results even with noise exceeding the expected level in large-scale experiments. Subsequently, we illustrate the viability of the method based on the analysis of a proteomic screening data set to reveal regulatory patterns of human microRNAs targeting proteins in the EGFR-driven cell cycle signalling system. Since statistically significant co-occurrence may indicate functional synergy and the mechanisms underlying canalization, and thus hold promise in drug target identification and therapeutic development, we provide a platform-independent implementation of SICORE with a graphical user interface as a novel tool in the arsenal of high-throughput screening analysis.