All living organisms are built from DNA. It is made from four blocks of chemicals called adenine (A), cytosine (C), guanine (G) and thymine (T). In humans, when an embryo is developing, the order of these letters are read to produce proteins, which are the building blocks of the the cells and tissues that make up various parts of the body.

Gene network information is believed to be beneficial for disease module and pathway identification, but has not been explicitly utilized in the standard random forest (RF) algorithm for gene expression data analysis. We investigate the performance of a network-guided RF where the network information is summarized into a sampling probability of predictor variables which is further used in the construction of the RF. Our results suggest that network-guided RF does not provide better disease prediction than the standard RF. In terms of disease gene discovery, if disease genes form module(s), network-guided RF identifies them more accurately. In addition, when disease status is independent from genes in the given network, spurious gene selection results can occur when using network information, especially on hub genes. Our empirical analysis on two balanced microarray and RNA-Seq breast cancer datasets from The Cancer Genome Atlas (TCGA) for classification of progesterone receptor (PR) status also demonstrates that network-guided RF can identify genes from PGR-related pathways, which leads to a better connected module of identified genes.

Motivation: Gene-disease associations are fundamental for understanding disease etiology and developing effective interventions and treatments. Identifying genes not yet associated with a disease due to a lack of studies is a challenging task in which prioritization based on prior knowledge is an important element. The computational search for new candidate disease genes may be eased by positive-unlabeled learning, the machine learning setting in which only a subset of instances are labeled as positive while the rest of the data set is unlabeled. In this work, we propose a set of effective network-based features to be used in a novel Markov diffusion-based multi-class labeling strategy for putative disease gene discovery. Results: The performances of the new labeling algorithm and the effectiveness of the proposed features have been tested on ten different disease data sets using three machine learning algorithms. The new features have been compared against classical topological and functional/ontological features and a set of network-and biological-derived features already used in gene discovery tasks. The predictive power of the integrated methodology in searching for new disease genes has been found to be competitive against state-of-the-art algorithms. Availability and implementation: The source code of NIAPU can be accessed at https://github.

This work proposes a unified framework to leverage biological information in network propagation-based gene prioritization algorithms. Preliminary results on breast cancer data show significant improvements over state-of-the-art baselines, such as the prioritization of genes that are not identified as potential candidates by interactome-based algorithms, but that appear to be involved in/or potentially related to breast cancer, according to a functional analysis based on recent literature.

Motivation: The rapid growth of diverse biological data allows us to consider interactions between a variety of objects, such as genes, chemicals, molecular signatures, diseases, pathways and environmental exposures. Often, any pair of objects--such as a gene and a disease--can be related in different ways, for example, directly via gene-disease associations or indirectly via functional annotations, chemicals and pathways. Different ways of relating these objects carry different semantic meanings. However, traditional methods disregard these semantics and thus cannot fully exploit their value in data modeling. Results: We present Medusa, an approach to detect size-k modules of objects that, taken together, appear most significant to another set of objects. Medusa operates on large-scale collections of heterogeneous data sets and explicitly distinguishes between diverse data semantics. It advances research along two dimensions: it builds on collective matrix factorization to derive different semantics, and it formulates the growing of the modules as a submodular optimization program. Medusa is flexible in choosing or combining semantic meanings and provides theoretical guarantees about detection quality. In a systematic study on 310 complex diseases, we show the effectiveness of Medusa in associating genes with diseases and detecting disease modules. We demonstrate that in predicting gene-disease associations Medusa compares favorably to methods that ignore diverse semantic meanings. We find that the utility of different semantics depends on disease categories and that, overall, Medusa recovers disease modules more accurately when combining different semantics.

Background: Predictive, stable and interpretable gene signatures are generally seen as an important step towards a better personalized medicine. During the last decade various methods have been proposed for that purpose. However, one important obstacle for making gene signatures a standard tool in clinics is the typical low reproducibility of these signatures combined with the difficulty to achieve a clear biological interpretation. For that purpose in the last years there has been a growing interest in approaches that try to integrate information from molecular interaction networks. Results: We propose a novel algorithm, called FrSVM, which integrates protein-protein interaction network information into gene selection for prognostic biomarker discovery. Our method is a simple filter based approach, which focuses on central genes with large differences in their expression. Compared to several other competing methods our algorithm reveals a significantly better prediction performance and higher signature stability. More- over, obtained gene lists are highly enriched with known disease genes and drug targets. We extendd our approach further by integrating information on candidate disease genes and targets of disease associated Transcript Factors (TFs).

Elucidating the genetic basis of human diseases is a central goal of genetics and molecular biology. While traditional linkage analysis and modern high-throughput techniques often provide long lists of tens or hundreds of disease gene candidates, the identification of disease genes among the candidates remains time-consuming and expensive. Efficient computational methods are therefore needed to prioritize genes within the list of candidates, by exploiting the wealth of information available about the genes in various databases. Here we propose ProDiGe, a novel algorithm for Prioritization of Disease Genes. ProDiGe implements a novel machine learning strategy based on learning from positive and unlabeled examples, which allows to integrate various sources of information about the genes, to share information about known disease genes across diseases, and to perform genome-wide searches for new disease genes. Experiments on real data show that ProDiGe outperforms state-of-the-art methods for the prioritization of genes in human diseases.

A computational challenge to validate the candidate disease genes identified in a high-throughput genomic study is to elucidate the associations between the set of candidate genes and disease phenotypes. The conventional gene set enrichment analysis often fails to reveal associations between disease phenotypes and the gene sets with a short list of poorly annotated genes, because the existing annotations of disease causative genes are incomplete. We propose a network-based computational approach called rcNet to discover the associations between gene sets and disease phenotypes. Assuming coherent associations between the genes ranked by their relevance to the query gene set, and the disease phenotypes ranked by their relevance to the hidden target disease phenotypes of the query gene set, we formulate a learning framework maximizing the rank coherence with respect to the known disease phenotype-gene associations. An efficient algorithm coupling ridge regression with label propagation, and two variants are introduced to find the optimal solution of the framework. We evaluated the rcNet algorithms and existing baseline methods with both leave-one-out cross-validation and a task of predicting recently discovered disease-gene associations in OMIM. The experiments demonstrated that the rcNet algorithms achieved the best overall rankings compared to the baselines. To further validate the reproducibility of the performance, we applied the algorithms to identify the target diseases of novel candidate disease genes obtained from recent studies of GWAS, DNA copy number variation analysis, and gene expression profiling. The algorithms ranked the target disease of the candidate genes at the top of the rank list in many cases across all the three case studies. The rcNet algorithms are available as a webtool for disease and gene set association analysis at http://compbio.cs.umn.edu/dgsa_rcNet.