Protein Function Prediction by Integrating Multiple Kernels ∗

Determining protein function constitutes an exercise in integrating information derived from several heterogeneous high-throughput experiments. To utilize the information spread across multiple sources in a combined fashion, these data sources are transformed into kernels. Several protein function prediction methods follow a two-phased approach: they first optimize the weights on individual kernels to produce a composite kernel, and then train a classifier on the composite kernel. As such, these methods result in an optimal composite kernel, but not necessarily in an optimal classifier. On the other hand, some methods optimize the loss of binary classifiers, and learn weights for the different kernels iteratively. A protein has multiple functions, and each function can be viewed as a label. These methods solve the problem of optimizing weights on the input kernels for each of the labels. This is computationally expensive and ignores inter-label correlations. In this paper, we propose a method called Protein Function Prediction by Integrating Multiple Kernels (ProMK). ProMK iteratively optimizes the phases of learning optimal weights and reducing the empirical loss of a multi-label classifier for each of the labels simultaneously, using a combined objective function. ProMK can assign larger weights to smooth kernels and downgrade the weights on noisy kernels. We evaluate the ability of ProMK to predict the function of proteins using several standard benchmarks. We show that our approach performs better than previously proposed protein function prediction approaches that integrate data from multiple networks, and multi-label multiple kernel learning methods.

Disease gene prioritization by integrating tissue-specific molecular networks using a robust multi-network model

abstract: Background Accurately prioritizing candidate disease genes is an important and challenging problem. Various network-based methods have been developed to predict potential disease genes by utilizing the disease similarity network and molecular networks such as protein interaction or gene co-expression networks. Although successful, a common limitation of the existing methods is that they assume all diseases share the same molecular network and a single generic molecular network is used to predict candidate genes for all diseases. However, different diseases tend to manifest in different tissues, and the molecular networks in different tissues are usually different. An ideal method should be able to incorporate tissue-specific molecular networks for different diseases. Results In this paper, we develop a robust and flexible method to integrate tissue-specific molecular networks for disease gene prioritization. Our method allows each disease to have its own tissue-specific network(s). We formulate the problem of candidate gene prioritization as an optimization problem based on network propagation. When there are multiple tissue-specific networks available for a disease, our method can automatically infer the relative importance of each tissue-specific network. Thus it is robust to the noisy and incomplete network data. To solve the optimization problem, we develop fast algorithms which have linear time complexities in the number of nodes in the molecular networks. We also provide rigorous theoretical foundations for our algorithms in terms of their optimality and convergence properties. Extensive experimental results show that our method can significantly improve the accuracy of candidate gene prioritization compared with the state-of-the-art methods. Conclusions In our experiments, we compare our methods with 7 popular network-based disease gene prioritization algorithms on diseases from Online Mendelian Inheritance in Man (OMIM) database. The experimental results demonstrate that our methods recover true associations more accurately than other methods in terms of AUC values, and the performance differences are significant (with paired t-test p-values less than 0.05). This validates the importance to integrate tissue-specific molecular networks for studying disease gene prioritization and show the superiority of our network models and ranking algorithms toward this purpose. The source code and datasets are available at http://nijingchao.github.io/CRstar/.The electronic version of this article is the complete one and can be found online at: https://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-016-1317-

Hierarchical ensemble methods for protein function prediction

Protein function prediction is a complex multiclass multilabel classification problem, characterized by multiple issues such as the incompleteness of the available annotations, the integration of multiple sources of high dimensional biomolecular data, the unbalance of several functional classes, and the difficulty of univocally determining negative examples. Moreover, the hierarchical relationships between functional classes that characterize both the Gene Ontology and FunCat taxonomies motivate the development of hierarchy-aware prediction methods that showed significantly better performances than hierarchical-unaware \u201cflat\u201d prediction methods. In this paper, we provide a comprehensive review of hierarchical methods for protein function prediction based on ensembles of learning machines. According to this general approach, a separate learning machine is trained to learn a specific functional term and then the resulting predictions are assembled in a \u201cconsensus\u201d ensemble decision, taking into account the hierarchical relationships between classes. The main hierarchical ensemble methods proposed in the literature are discussed in the context of existing computational methods for protein function prediction, highlighting their characteristics, advantages, and limitations. Open problems of this exciting research area of computational biology are finally considered, outlining novel perspectives for future research

Toward Robust Group-Wise eQTL Mapping via Integrating Multi-Domain Heterogeneous Data

As a promising tool for dissecting the genetic basis of common diseases, expression quantitative trait loci (eQTL) study has attracted increasing research interest. Traditional eQTL methods focus on testing the associations between individual single-nucleotide polymorphisms (SNPs) and gene expression traits. A major drawback of this approach is that it cannot model the joint effect of a set of SNPs on a set of genes, which may correspond to biological pathways. This thesis studies the problem of identifying group-wise associations in eQTL mapping. Based on the intuition of group-wise association, we examine how the integration of heterogeneous prior knowledge on the correlation structures between SNPs, and between genes can improve the robustness and the interpretability of eQTL mapping. To obtain a more accurate knowledgebase on the interactions among SNPs and genes, we developed a robust and flexible approach that can incorporate multiple data sources and automatically identify noisy sources. Extensive experiments demonstrate the effectiveness of the proposed algorithms.Doctor of Philosoph