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.

Efficient Support for Common Relations in Lightweight Formal Reasoning Systems

In work that involves mathematical rigor, there are numerous benefits to adopting a representation of models and arguments that can be supplied to a formal reasoning or verification system: reusability, automatic evaluation of examples, and verification of consistency and correctness. However, accessibility has not been a priority in the design of formal verification tools that can provide these benefits. In earlier work [Lap09a], we attempt to address this broad problem by proposing several specific design criteria organized around the notion of a natural context: the sphere of awareness a working human user maintains of the relevant constructs, arguments, experiences, and background materials necessary to accomplish the task at hand. This work expands one aspect of the earlier work by considering more extensively an essential capability for any formal reasoning system whose design is oriented around simulating the natural context: native support for a collection of mathematical relations that deal with common constructs in arithmetic and set theory. We provide a formal definition for a context of relations that can be used to both validate and assist formal reasoning activities. We provide a proof that any algorithm that implements this formal structure faithfully will necessary converge. Finally, we consider the efficiency of an implementation of this formal structure that leverages modular implementations of well-known data structures: balanced search trees and transitive closures of hypergraphs.