A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> GeneMANIA (http://www.genemania.org) is a flexible, user-friendly web interface for generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Given a query list, GeneMANIA extends the list with functionally similar genes that it identifies using available genomics and proteomics data. GeneMANIA also reports weights that indicate the predictive value of each selected data set for the query. Six organisms are currently supported (Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Homo sapiens and Saccharomyces cerevisiae) and hundreds of data sets have been collected from GEO, BioGRID, Pathway Commons and I2D, as well as organism-specific functional genomics data sets. Users can select arbitrary subsets of the data sets associated with an organism to perform their analyses and can upload their own data sets to analyze. The GeneMANIA algorithm performs as well or better than other gene function prediction methods on yeast and mouse benchmarks. The high accuracy of the GeneMANIA prediction algorithm, an intuitive user interface and large database make GeneMANIA a useful tool for any biologist. <s> BIB001 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> Biomedical literature is traditionally used as a way to inform scientists of the relevance of genes in relation to a research topic. However many genes, especially from poorly studied organisms, are not discussed in the literature. Moreover, a manual and comprehensive summarization of the literature attached to the genes of an organism is in general impossible due to the high number of genes and abstracts involved. We introduce the novel Genie algorithm that overcomes these problems by eval- uating the literature attached to all genes in a genome and to their orthologs according to a selected topic. Genie showed high precision (up to 100%) and the best performance in comparison to other algorithms in most of the benchmarks, especially when high sensitivity was required. Moreover, the prioritization of zebrafish genes involved in heart development, using human and mouse orthologs, showed high en- richment in differentially expressed genes from microarray experiments. The Genie web server sup- ports hundreds of species, millions of genes and offers novel functionalities. Common run times below a minute, even when analyzing the human genome with hundreds of thousands of literature records, allows the use of Genie in routine lab work. Availability: http://cbdm.mdc-berlin.de/tools/genie/. <s> BIB002 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> Background ::: Answering questions such as "Which genes are related to breast cancer?" usually requires retrieving relevant publications through the PubMed search engine, reading these publications, and creating gene lists. This process is not only time-consuming, but also prone to errors. <s> BIB003 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> BackgroundPrioritization methods have become an useful tool for mining large amounts of data to suggest promising hypotheses in early research stages. Particularly, network-based prioritization tools use a network representation for the interactions between different biological entities to identify novel indirect relationships. However, current network-based prioritization tools are strongly tailored to specific domains of interest (e.g. gene-disease prioritization) and they do not allow to consider networks with more than two types of entities (e.g. genes and diseases). Therefore, the direct application of these methods to accomplish new prioritization tasks is limited.ResultsThis work presents ProphNet, a generic network-based prioritization tool that allows to integrate an arbitrary number of interrelated biological entities to accomplish any prioritization task. We tested the performance of ProphNet in comparison with leading network-based prioritization methods, namely rcNet and DomainRBF, for gene-disease and domain-disease prioritization, respectively. The results obtained by ProphNet show a significant improvement in terms of sensitivity and specificity for both tasks. We also applied ProphNet to disease-gene prioritization on Alzheimer, Diabetes Mellitus Type 2 and Breast Cancer to validate the results and identify putative candidate genes involved in these diseases.ConclusionsProphNet works on top of any heterogeneous network by integrating information of different types of biological entities to rank entities of a specific type according to their degree of relationship with a query set of entities of another type. Our method works by propagating information across data networks and measuring the correlation between the propagated values for a query and a target sets of entities. ProphNet is available at: http://genome2.ugr.es/prophnet. A Matlab implementation of the algorithm is also available at the website. <s> BIB004 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> PolySearch2 (http://polysearch.ca) is an online text-mining system for identifying relationships between biomedical entities such as human diseases, genes, SNPs, proteins, drugs, metabolites, toxins, metabolic pathways, organs, tissues, subcellular organelles, positive health effects, negative health effects, drug actions, Gene Ontology terms, MeSH terms, ICD-10 medical codes, biological taxonomies and chemical taxonomies. PolySearch2 supports a generalized ‘Given X, find all associated Ys’ query, where X and Y can be selected from the aforementioned biomedical entities. An example query might be: ‘Find all diseases associated with Bisphenol A’. To find its answers, PolySearch2 searches for associations against comprehensive collections of free-text collections, including local versions of MEDLINE abstracts, PubMed Central full-text articles, Wikipedia full-text articles and US Patent application abstracts. PolySearch2 also searches 14 widely used, text-rich biological databases such as UniProt, DrugBank and Human Metabolome Database to improve its accuracy and coverage. PolySearch2 maintains an extensive thesaurus of biological terms and exploits the latest search engine technology to rapidly retrieve relevant articles and databases records. PolySearch2 also generates, ranks and annotates associative candidates and present results with relevancy statistics and highlighted key sentences to facilitate user interpretation. <s> BIB005 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> Prior biological knowledge and phenotype information may help to identify disease genes from human whole-genome and whole-exome sequencing studies. We developed Phenolyzer (http://phenolyzer.usc.edu), a tool that uses prior information to implicate genes involved in diseases. Phenolyzer exhibits superior performance over competing methods for prioritizing Mendelian and complex disease genes, based on disease or phenotype terms entered as free text. <s> BIB006 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> The observation that disease associated proteins often interact with each other has fueled the development of network-based approaches to elucidate the molecular mechanisms of human disease. Such approaches build on the assumption that protein interaction networks can be viewed as maps in which diseases can be identified with localized perturbation within a certain neighborhood. The identification of these neighborhoods, or disease modules, is therefore a prerequisite of a detailed investigation of a particular pathophenotype. While numerous heuristic methods exist that successfully pinpoint disease associated modules, the basic underlying connectivity patterns remain largely unexplored. In this work we aim to fill this gap by analyzing the network properties of a comprehensive corpus of 70 complex diseases. We find that disease associated proteins do not reside within locally dense communities and instead identify connectivity significance as the most predictive quantity. This quantity inspires the design of a novel Disease Module Detection (DIAMOnD) algorithm to identify the full disease module around a set of known disease proteins. We study the performance of the algorithm using well-controlled synthetic data and systematically validate the identified neighborhoods for a large corpus of diseases. <s> BIB007 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> We have designed and developed a data integration and visualization platform that provides evidence about the association of known and potential drug targets with diseases. The platform is designed to support identification and prioritization of biological targets for follow-up. Each drug target is linked to a disease using integrated genome-wide data from a broad range of data sources. The platform provides either a target-centric workflow to identify diseases that may be associated with a specific target, or a disease-centric workflow to identify targets that may be associated with a specific disease. Users can easily transition between these target- and disease-centric workflows. The Open Targets Validation Platform is accessible at https://www.targetvalidation.org. <s> BIB008 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> The information about the genetic basis of human diseases lies at the heart of precision medicine and drug discovery. However, to realize its full potential to support these goals, several problems, such as fragmentation, heterogeneity, availability and different conceptualization of the data must be overcome. To provide the community with a resource free of these hurdles, we have developed DisGeNET (http://www.disgenet.org), one of the largest available collections of genes and variants involved in human diseases. DisGeNET integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. DisGeNET data are homogeneously annotated with controlled vocabularies and community-driven ontologies. Additionally, several original metrics are provided to assist the prioritization of genotype-phenotype relationships. The information is accessible through a web interface, a Cytoscape App, an RDF SPARQL endpoint, scripts in several programming languages and an R package. DisGeNET is a versatile platform that can be used for different research purposes including the investigation of the molecular underpinnings of specific human diseases and their comorbidities, the analysis of the properties of disease genes, the generation of hypothesis on drug therapeutic action and drug adverse effects, the validation of computationally predicted disease genes and the evaluation of text-mining methods performance. <s> BIB009 </s> A Survey of Gene Prioritization Tools for Mendelian and Complex Human Diseases <s> Overview of Gene Prioritization Tools <s> Motivation: Genome‐wide association studies have identified thousands of loci associated with human disease, but identifying the causal genes at these loci is often difficult. Several methods prioritize genes most likely to be disease causing through the integration of biological data, including protein‐protein interaction and phenotypic data. Data availability is not the same for all genes however, potentially influencing the performance of these methods. Results: We demonstrate that whilst disease genes tend to be associated with greater numbers of data, this may be at least partially a result of them being better studied. With this observation we develop PhenoRank, which prioritizes disease genes whilst avoiding being biased towards genes with more available data. Bias is avoided by comparing gene scores generated for the query disease against gene scores generated using simulated sets of phenotype terms, which ensures that differences in data availability do not affect the ranking of genes. We demonstrate that whilst existing prioritization methods are biased by data availability, PhenoRank is not similarly biased. Avoiding this bias allows PhenoRank to effectively prioritize genes with fewer available data and improves its overall performance. PhenoRank outperforms three available prioritization methods in cross‐validation (PhenoRank area under receiver operating characteristic curve [AUC]=0.89, DADA AUC = 0.87, EXOMISER AUC = 0.71, PRINCE AUC = 0.83, P < 2.2 × 10−16). Availability and implementation: PhenoRank is freely available for download at https://github.com/alexjcornish/PhenoRank. Supplementary information: Supplementary data are available at Bioinformatics online. <s> BIB010
Gene prioritization task could be formulated as follows: arrange candidate genes in order of their potential to be truly associated with the disease decreasing on the basis of prior knowledge about these genes and the disease. A typical gene prioritization tool is composed of two parts: a collection of evidence sources (i.e. databases of associations between genes, diseases and other biological entities) and a prioritization module ( Figure 1 ). Prioritization module takes two inputs: training data, which is used to define a phenotype of interest and testing data, a set of user-defined candidate genes to prioritize. After that, it extracts information about given genes or terms from evidence sources and calculates a score that reflects "likelihood" of each gene to be responsible for the phenotype. Training data could be represented either by genes, that were previously linked with a phenotype (seed genes). Alternatively to seed genes, some tools (PolySearch2 BIB005 , PhenoRank BIB010 , Open Targets BIB008 and others BIB004 , BIB006 , BIB009 , BIB002 , BIB003 ) require phenotype or disease terms defining relevant gene-disease associations. The second part of the input is a set of candidate genes to prioritize or in some cases, the whole genome BIB004 , BIB005 , BIB010 , BIB008 , BIB003 , BIB001 , BIB007 . Some tools, such as Génie BIB002 , Open Targets and Endeavour  , can automatically construct a set of candidate genes, belonging to a specific class, e.g. all protein-coding genes BIB002 , all receptors or enzymes BIB008 , or use GO or pathway terms to define a functional group of genes BIB005 ,  . The output of the program is a list of candidate genes arranged according to calculated scores or p-values. Every gene prioritization tool represents a unique combination of evidence sources, prioritization strategy and input requirements.