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.

Spatiotemporal Gesture Segmentation

Spotting patterns of interest in an input signal is a very useful task in many different fields including medicine, bioinformatics, economics, speech recognition and computer vision. Example instances of this problem include spotting an object of interest in an image (e.g., a tumor), a pattern of interest in a time-varying signal (e.g., audio analysis), or an object of interest moving in a specific way (e.g., a human's body gesture). Traditional spotting methods, which are based on Dynamic Time Warping or hidden Markov models, use some variant of dynamic programming to register the pattern and the input while accounting for temporal variation between them. At the same time, those methods often suffer from several shortcomings: they may give meaningless solutions when input observations are unreliable or ambiguous, they require a high complexity search across the whole input signal, and they may give incorrect solutions if some patterns appear as smaller parts within other patterns. In this thesis, we develop a framework that addresses these three problems, and evaluate the framework's performance in spotting and recognizing hand gestures in video. The first contribution is a spatiotemporal matching algorithm that extends the dynamic programming formulation to accommodate multiple candidate hand detections in every video frame. The algorithm finds the best alignment between the gesture model and the input, and simultaneously locates the best candidate hand detection in every frame. This allows for a gesture to be recognized even when the hand location is highly ambiguous. The second contribution is a pruning method that uses model-specific classifiers to reject dynamic programming hypotheses with a poor match between the input and model. Pruning improves the efficiency of the spatiotemporal matching algorithm, and in some cases may improve the recognition accuracy. The pruning classifiers are learned from training data, and cross-validation is used to reduce the chance of overpruning. The third contribution is a subgesture reasoning process that models the fact that some gesture models can falsely match parts of other, longer gestures. By integrating subgesture reasoning the spotting algorithm can avoid the premature detection of a subgesture when the longer gesture is actually being performed. Subgesture relations between pairs of gestures are automatically learned from training data. The performance of the approach is evaluated on two challenging video datasets: hand-signed digits gestured by users wearing short sleeved shirts, in front of a cluttered background, and American Sign Language (ASL) utterances gestured by ASL native signers. The experiments demonstrate that the proposed method is more accurate and efficient than competing approaches. The proposed approach can be generally applied to alignment or search problems with multiple input observations, that use dynamic programming to find a solution.