Integration of relational and hierarchical network information for protein function prediction

BACKGROUND:In the current climate of high-throughput computational biology, the inference of a protein's function from related measurements, such as protein-protein interaction relations, has become a canonical task. Most existing technologies pursue this task as a classification problem, on a term-by-term basis, for each term in a database, such as the Gene Ontology (GO) database, a popular rigorous vocabulary for biological functions. However, ontology structures are essentially hierarchies, with certain top to bottom annotation rules which protein function predictions should in principle follow. Currently, the most common approach to imposing these hierarchical constraints on network-based classifiers is through the use of transitive closure to predictions.RESULTS:We propose a probabilistic framework to integrate information in relational data, in the form of a protein-protein interaction network, and a hierarchically structured database of terms, in the form of the GO database, for the purpose of protein function prediction. At the heart of our framework is a factorization of local neighborhood information in the protein-protein interaction network across successive ancestral terms in the GO hierarchy. We introduce a classifier within this framework, with computationally efficient implementation, that produces GO-term predictions that naturally obey a hierarchical 'true-path' consistency from root to leaves, without the need for further post-processing.CONCLUSION:A cross-validation study, using data from the yeast Saccharomyces cerevisiae, shows our method offers substantial improvements over both standard 'guilt-by-association' (i.e., Nearest-Neighbor) and more refined Markov random field methods, whether in their original form or when post-processed to artificially impose 'true-path' consistency. Further analysis of the results indicates that these improvements are associated with increased predictive capabilities (i.e., increased positive predictive value), and that this increase is consistent uniformly with GO-term depth. Additional in silico validation on a collection of new annotations recently added to GO confirms the advantages suggested by the cross-validation study. Taken as a whole, our results show that a hierarchical approach to network-based protein function prediction, that exploits the ontological structure of protein annotation databases in a principled manner, can offer substantial advantages over the successive application of 'flat' network-based methods.

Exploiting the Transients of Adaptation for RoQ Attacks on Internet Resources

In this paper, we expose an unorthodox adversarial attack that exploits the transients of a system's adaptive behavior, as opposed to its limited steady-state capacity. We show that a well orchestrated attack could introduce significant inefficiencies that could potentially deprive a network element from much of its capacity, or significantly reduce its service quality, while evading detection by consuming an unsuspicious, small fraction of that element's hijacked capacity. This type of attack stands in sharp contrast to traditional brute-force, sustained high-rate DoS attacks, as well as recently proposed attacks that exploit specific protocol settings such as TCP timeouts. We exemplify what we term as Reduction of Quality (RoQ) attacks by exposing the vulnerabilities of common adaptation mechanisms. We develop control-theoretic models and associated metrics to quantify these vulnerabilities. We present numerical and simulation results, which we validate with observations from real Internet experiments. Our findings motivate the need for the development of adaptation mechanisms that are resilient to these new forms of attacks.

On the Geographic Location of Internet Resources

One relatively unexplored question about the Internet's physical structure concerns the geographical location of its components: routers, links and autonomous systems (ASes). We study this question using two large inventories of Internet routers and links, collected by different methods and about two years apart. We first map each router to its geographical location using two different state-of-the-art tools. We then study the relationship between router location and population density; between geographic distance and link density; and between the size and geographic extent of ASes. Our findings are consistent across the two datasets and both mapping methods. First, as expected, router density per person varies widely over different economic regions; however, in economically homogeneous regions, router density shows a strong superlinear relationship to population density. Second, the probability that two routers are directly connected is strongly dependent on distance; our data is consistent with a model in which a majority (up to 75-95%) of link formation is based on geographical distance (as in the Waxman topology generation method). Finally, we find that ASes show high variability in geographic size, which is correlated with other measures of AS size (degree and number of interfaces). Among small to medium ASes, ASes show wide variability in their geographic dispersal; however, all ASes exceeding a certain threshold in size are maximally dispersed geographically. These findings have many implications for the next generation of topology generators, which we envisage as producing router-level graphs annotated with attributes such as link latencies, AS identifiers and geographical locations.