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.

A Virtual Deadline Scheduler for Window-Constrained Service Guarantees

This paper presents a new approach to window-constrained scheduling, suitable for multimedia and weakly-hard real-time systems. We originally developed an algorithm, called Dynamic Window-Constrained Scheduling (DWCS), that attempts to guarantee no more than x out of y deadlines are missed for real-time jobs such as periodic CPU tasks, or delay-constrained packet streams. While DWCS is capable of generating a feasible window-constrained schedule that utilizes 100% of resources, it requires all jobs to have the same request periods (or intervals between successive service requests). We describe a new algorithm called Virtual Deadline Scheduling (VDS), that provides window-constrained service guarantees to jobs with potentially different request periods, while still maximizing resource utilization. VDS attempts to service m out of k job instances by their virtual deadlines, that may be some finite time after the corresponding real-time deadlines. Notwithstanding, VDS is capable of outperforming DWCS and similar algorithms, when servicing jobs with potentially different request periods. Additionally, VDS is able to limit the extent to which a fraction of all job instances are serviced late. Results from simulations show that VDS can provide better window-constrained service guarantees than other related algorithms, while still having as good or better delay bounds for all scheduled jobs. Finally, an implementation of VDS in the Linux kernel compares favorably against DWCS for a range of scheduling loads.