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.

Programming Examples Needing Polymorphic Recursion

Inferring types for polymorphic recursive function definitions (abbreviated to polymorphic recursion) is a recurring topic on the mailing lists of popular typed programming languages. This is despite the fact that type inference for polymorphic recursion using for all-types has been proved undecidable. This report presents several programming examples involving polymorphic recursion and determines their typability under various type systems, including the Hindley-Milner system, an intersection-type system, and extensions of these two. The goal of this report is to show that many of these examples are typable using a system of intersection types as an alternative form of polymorphism. By accomplishing this, we hope to lay the foundation for future research into a decidable intersection-type inference algorithm. We do not provide a comprehensive survey of type systems appropriate for polymorphic recursion, with or without type annotations inserted in the source language. Rather, we focus on examples for which types may be inferred without type annotations.

Hidden Type Variables and Conditional Extension for More Expressive Generic Programs

Generic object-oriented programming languages combine parametric polymorphism and nominal subtype polymorphism, thereby providing better data abstraction, greater code reuse, and fewer run-time errors. However, most generic object-oriented languages provide a straightforward combination of the two kinds of polymorphism, which prevents the expression of advanced type relationships. Furthermore, most generic object-oriented languages have a type-erasure semantics: instantiations of type parameters are not available at run time, and thus may not be used by type-dependent operations. This dissertation shows that two features, which allow the expression of many advanced type relationships, can be added to a generic object-oriented programming language without type erasure: 1. type variables that are not parameters of the class that declares them, and 2. extension that is dependent on the satisfiability of one or more constraints. We refer to the first feature as hidden type variables and the second feature as conditional extension. Hidden type variables allow: covariance and contravariance without variance annotations or special type arguments such as wildcards; a single type to extend, and inherit methods from, infinitely many instantiations of another type; a limited capacity to augment the set of superclasses after that class is defined; and the omission of redundant type arguments. Conditional extension allows the properties of a collection type to be dependent on the properties of its element type. This dissertation describes the semantics and implementation of hidden type variables and conditional extension. A sound type system is presented. In addition, a sound and terminating type checking algorithm is presented. Although designed for the Fortress programming language, hidden type variables and conditional extension can be incorporated into other generic object-oriented languages. Many of the same problems would arise, and solutions analogous to those we present would apply.

Type Inference for Variant Object Types

Existing type systems for object calculi are based on invariant subtyping. Subtyping invariance is required for soundness of static typing in the presence of method overrides, but it is often in the way of the expressive power of the type system. Flexibility of static typing can be recovered in different ways: in first-order systems, by the adoption of object types with variance annotations, in second-order systems by resorting to Self types. Type inference is known to be P-complete for first-order systems of finite and recursive object types, and NP-complete for a restricted version of Self types. The complexity of type inference for systems with variance annotations is yet unknown. This paper presents a new object type system based on the notion of Split types, a form of object types where every method is assigned two types, namely, an update type and a select type. The subtyping relation that arises for Split types is variant and, as a result, subtyping can be performed both in width and in depth. The new type system generalizes all the existing first-order type systems for objects, including systems based on variance annotations. Interestingly, the additional expressive power does not affect the complexity of the type inference problem, as we show by presenting an O(n^3) inference algorithm.

Constraint-based Mining of Frequent Arrangements of Temporal Intervals

The problem of discovering frequent arrangements of temporal intervals is studied. It is assumed that the database consists of sequences of events, where an event occurs during a time-interval. The goal is to mine temporal arrangements of event intervals that appear frequently in the database. The motivation of this work is the observation that in practice most events are not instantaneous but occur over a period of time and different events may occur concurrently. Thus, there are many practical applications that require mining such temporal correlations between intervals including the linguistic analysis of annotated data from American Sign Language as well as network and biological data. Two efficient methods to find frequent arrangements of temporal intervals are described; the first one is tree-based and uses depth first search to mine the set of frequent arrangements, whereas the second one is prefix-based. The above methods apply efficient pruning techniques that include a set of constraints consisting of regular expressions and gap constraints that add user-controlled focus into the mining process. Moreover, based on the extracted patterns a standard method for mining association rules is employed that applies different interestingness measures to evaluate the significance of the discovered patterns and rules. The performance of the proposed algorithms is evaluated and compared with other approaches on real (American Sign Language annotations and network data) and large synthetic datasets.