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.

Some Considerations on a Calculus with Weak References

Weak references are references that do not prevent the object they point to from being garbage collected. Most realistic languages, including Java, SML/NJ, and OCaml to name a few, have some facility for programming with weak references. Weak references are used in implementing idioms like memoizing functions and hash-consing in order to avoid potential memory leaks. However, the semantics of weak references in many languages are not clearly specified. Without a formal semantics for weak references it becomes impossible to prove the correctness of implementations making use of this feature. Previous work by Hallett and Kfoury extends λgc, a language for modeling garbage collection, to λweak, a similar language with weak references. Using this previously formalized semantics for weak references, we consider two issues related to well-behavedness of programs. Firstly, we provide a new, simpler proof of the well-behavedness of the syntactically restricted fragment of λweak defined previously. Secondly, we give a natural semantic criterion for well-behavedness much broader than the syntactic restriction, which is useful as principle for programming with weak references. Furthermore we extend the result, proved in previously of λgc, which allows one to use type-inference to collect some reachable objects that are never used. We prove that this result holds of our language, and we extend this result to allow the collection of weakly-referenced reachable garbage without incurring the computational overhead sometimes associated with collecting weak bindings (e.g. the need to recompute a memoized function). Lastly we use extend the semantic framework to model the key/value weak references found in Haskell and we prove the Haskell is semantics equivalent to a simpler semantics due to the lack of side-effects in our language.