Candidate gene prioritization with Endeavour.
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ABSTRACT:
SUBMITTER: Tranchevent LC
PROVIDER: S-EPMC4987917 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Endeavour (http://www.esat.kuleuven.be/endeavourweb; this web site is free and open to all users and there is no login requirement) is a web resource for the prioritization of candidate genes. Using a training set of genes known to be involved in a biological process of interest, our approach consists of (i) inferring several models (based on various genomic data sources), (ii) applying each model to the candidate genes to rank those candidates against the profile of the known genes and (iii) merging the several rankings into a global ranking of the candidate genes. In the present article, we describe the latest developments of Endeavour. First, we provide a web-based user interface, besides our Java client, to make Endeavour more universally accessible. Second, we support multiple species: in addition to Homo sapiens, we now provide gene prioritization for three major model organisms: Mus musculus, Rattus norvegicus and Caenorhabditis elegans. Third, Endeavour makes use of additional data sources and is now including numerous databases: ontologies and annotations, protein-protein interactions, cis-regulatory information, gene expression data sets, sequence information and text-mining data. We tested the novel version of Endeavour on 32 recent disease gene associations from the literature. Additionally, we describe a number of recent independent studies that made use of Endeavour to prioritize candidate genes for obesity and Type II diabetes, cleft lip and cleft palate, and pulmonary fibrosis.
| S-EPMC2447805 | biostudies-other
Project description:The majority of common diseases are multi-factorial and modified by genetically and mechanistically complex polygenic interactions and environmental factors. High-throughput genome-wide studies like linkage analysis and gene expression profiling, tend to be most useful for classification and characterization but do not provide sufficient information to identify or prioritize specific disease causal genes.Extending on an earlier hypothesis that the majority of genes that impact or cause disease share membership in any of several functional relationships we, for the first time, show the utility of mouse phenotype data in human disease gene prioritization. We study the effect of different data integration methods, and based on the validation studies, we show that our approach, ToppGene http://toppgene.cchmc.org, outperforms two of the existing candidate gene prioritization methods, SUSPECTS and ENDEAVOUR.The incorporation of phenotype information for mouse orthologs of human genes greatly improves the human disease candidate gene analysis and prioritization.
| S-EPMC2194797 | biostudies-other
Project description:BackgroundGenes that are co-expressed tend to be involved in the same biological process. However, co-expression is not a very reliable predictor of functional links between genes. The evolutionary conservation of co-expression between species can be used to predict protein function more reliably than co-expression in a single species. Here we examine whether co-expression across multiple species is also a better prioritizer of disease genes than is co-expression between human genes alone.ResultsWe use co-expression data from yeast (S. cerevisiae), nematode worm (C. elegans), fruit fly (D. melanogaster), mouse and human and find that the use of evolutionary conservation can indeed improve the predictive value of co-expression. The effect that genes causing the same disease have higher co-expression than do other genes from their associated disease loci, is significantly enhanced when co-expression data are combined across evolutionarily distant species. We also find that performance can vary significantly depending on the co-expression datasets used, and just using more data does not necessarily lead to better prioritization. Instead, we find that dataset quality is more important than quantity, and using a consistent microarray platform per species leads to better performance than using more inclusive datasets pooled from various platforms.ConclusionWe find that evolutionarily conserved gene co-expression prioritizes disease candidate genes better than human gene co-expression alone, and provide the integrated data as a new resource for disease gene prioritization tools.
| S-EPMC2383918 | biostudies-literature
Project description:BackgroundRegions of interest identified through genetic linkage studies regularly exceed 30 centimorgans in size and can contain hundreds of genes. Traditionally this number is reduced by matching functional annotation to knowledge of the disease or phenotype in question. However, here we show that disease genes share patterns of sequence-based features that can provide a good basis for automatic prioritization of candidates by machine learning.ResultsWe examined a variety of sequence-based features and found that for many of them there are significant differences between the sets of genes known to be involved in human hereditary disease and those not known to be involved in disease. We have created an automatic classifier called PROSPECTR based on those features using the alternating decision tree algorithm which ranks genes in the order of likelihood of involvement in disease. On average, PROSPECTR enriches lists for disease genes two-fold 77% of the time, five-fold 37% of the time and twenty-fold 11% of the time.ConclusionPROSPECTR is a simple and effective way to identify genes involved in Mendelian and oligogenic disorders. It performs markedly better than the single existing sequence-based classifier on novel data. PROSPECTR could save investigators looking at large regions of interest time and effort by prioritizing positional candidate genes for mutation detection and case-control association studies.
| S-EPMC1274252 | biostudies-literature
Project description:BackgroundAlthough most of the current disease candidate gene identification and prioritization methods depend on functional annotations, the coverage of the gene functional annotations is a limiting factor. In the current study, we describe a candidate gene prioritization method that is entirely based on protein-protein interaction network (PPIN) analyses.ResultsFor the first time, extended versions of the PageRank and HITS algorithms, and the K-Step Markov method are applied to prioritize disease candidate genes in a training-test schema. Using a list of known disease-related genes from our earlier study as a training set ("seeds"), and the rest of the known genes as a test list, we perform large-scale cross validation to rank the candidate genes and also evaluate and compare the performance of our approach. Under appropriate settings - for example, a back probability of 0.3 for PageRank with Priors and HITS with Priors, and step size 6 for K-Step Markov method - the three methods achieved a comparable AUC value, suggesting a similar performance.ConclusionEven though network-based methods are generally not as effective as integrated functional annotation-based methods for disease candidate gene prioritization, in a one-to-one comparison, PPIN-based candidate gene prioritization performs better than all other gene features or annotations. Additionally, we demonstrate that methods used for studying both social and Web networks can be successfully used for disease candidate gene prioritization.
| S-EPMC2657789 | biostudies-literature
Project description:MotivationThe identification of genes involved in specific phenotypes, such as human hereditary diseases, often requires the time-consuming and expensive examination of a large number of positional candidates selected by genome-wide techniques such as linkage analysis and association studies. Even considering the positive impact of next-generation sequencing technologies, the prioritization of these positional candidates may be an important step for disease-gene identification.ResultsHere, we report a large-scale analysis of spatial, i.e. 3D, gene-expression data from an entire organ (the mouse brain) for the purpose of evaluating and ranking positional candidate genes, showing that the spatial gene-expression patterns can be successfully exploited for the prediction of gene-phenotype associations not only for mouse phenotypes, but also for human central nervous system-related Mendelian disorders. We apply our method to the case of X-linked mental retardation, compare the predictions to the results obtained from a previous large-scale resequencing study of chromosome X and discuss some promising novel candidates.
| S-EPMC2935433 | biostudies-literature
Project description:BackgroundFeature selection is a critical step for translating advances afforded by systems-scale molecular profiling into actionable clinical insights. While data-driven methods are commonly utilized for selecting candidate genes, knowledge-driven methods must contend with the challenge of efficiently sifting through extensive volumes of biomedical information. This work aimed to assess the utility of large language models (LLMs) for knowledge-driven gene prioritization and selection.MethodsIn this proof of concept, we focused on 11 blood transcriptional modules associated with an Erythroid cells signature. We evaluated four leading LLMs across multiple tasks. Next, we established a workflow leveraging LLMs. The steps consisted of: (1) Selecting one of the 11 modules; (2) Identifying functional convergences among constituent genes using the LLMs; (3) Scoring candidate genes across six criteria capturing the gene's biological and clinical relevance; (4) Prioritizing candidate genes and summarizing justifications; (5) Fact-checking justifications and identifying supporting references; (6) Selecting a top candidate gene based on validated scoring justifications; and (7) Factoring in transcriptome profiling data to finalize the selection of the top candidate gene.ResultsOf the four LLMs evaluated, OpenAI's GPT-4 and Anthropic's Claude demonstrated the best performance and were chosen for the implementation of the candidate gene prioritization and selection workflow. This workflow was run in parallel for each of the 11 erythroid cell modules by participants in a data mining workshop. Module M9.2 served as an illustrative use case. The 30 candidate genes forming this module were assessed, and the top five scoring genes were identified as BCL2L1, ALAS2, SLC4A1, CA1, and FECH. Researchers carefully fact-checked the summarized scoring justifications, after which the LLMs were prompted to select a top candidate based on this information. GPT-4 initially chose BCL2L1, while Claude selected ALAS2. When transcriptional profiling data from three reference datasets were provided for additional context, GPT-4 revised its initial choice to ALAS2, whereas Claude reaffirmed its original selection for this module.ConclusionsTaken together, our findings highlight the ability of LLMs to prioritize candidate genes with minimal human intervention. This suggests the potential of this technology to boost productivity, especially for tasks that require leveraging extensive biomedical knowledge.
| S-EPMC10580627 | biostudies-literature
Project description:BACKGROUND:Refinement of candidate gene lists to select the most promising candidates for further experimental verification remains an essential step between high-throughput exploratory analysis and the discovery of specific causal genes. Given the qualitative and semantic complexity of biological data, successfully addressing this challenge requires development of flexible and interoperable solutions for making the best possible use of the largest possible fraction of all available data. RESULTS:We have developed an easily accessible framework that links two established network-based gene prioritization approaches with a supporting isolation forest-based integrative ranking method. The defining feature of the method is that both topological information of the biological networks and additional sources of evidence can be considered at the same time. The implementation was realized as an app extension for the Cytoscape graph analysis suite, and therefore can further benefit from the synergy with other analysis methods available as part of this system. CONCLUSIONS:We provide efficient reference implementations of two popular gene prioritization algorithms - DIAMOnD and random walk with restart for the Cytoscape system. An extension of those methods was also developed that allows outputs of these algorithms to be combined with additional data. To demonstrate the utility of our software, we present two example disease gene prioritization application cases and show how our tool can be used to evaluate these different approaches.
| S-EPMC5501438 | biostudies-literature
Project description:Down's syndrome (DS), or trisomy 21, is a complex developmental disorder that exhibits many clinical signs that vary in occurrence and severity among patients. The molecular mechanisms responsible for DS have thus far remained elusive. We argue here that normal variation in gene expression in the population contributes to the heterogeneous clinical picture of DS, and we estimated the amplitude of this variation in 50 mouse orthologs of chromosome 21 genes in brain regions of Ts65Dn (a mouse model of DS). We analyzed the RNAs of eight Ts65Dn and eight euploid mice by real-time polymerase chain reaction.In pooled RNAs, we confirmed that trisomic/euploid gene expression ratios were close to 1.5. However, we observed that inter-individual gene expression levels spanned a broad range of values. We identified three categories of genes: genes with expression levels consistently higher in Ts65Dn than in euploids (9, 17, and 7 genes in cerebellum, cortex, and midbrain, respectively); genes whose expression levels partially overlap between the two groups (10, 9, and 14 genes); and genes with intermingled expression, which cannot be used to differentiate trisomics from euploids (12, 5 and 9 genes). Of the genes in the first category, App, Cbr1, and Mrps6 exhibited tight regulation in the three tissues and are therefore attractive candidates for further research.This is the first analysis addressing inter-individual gene expression levels as a function of trisomy. We propose a strategy allowing discrimination between candidates for the constant features of DS and those genes that may contribute to the partially penetrant signs of DS.
| S-EPMC1929163 | biostudies-literature
Project description:MotivationIn attempts to determine the genetic causes of human disease, researchers are often faced with a large number of candidate genes. Linkage studies can point to a genomic region containing hundreds of genes, while the high-throughput sequencing approach will often identify a great number of non-synonymous genetic variants. Since systematic experimental verification of each such candidate gene is not feasible, a method is needed to decide which genes are worth investigating further. Computational gene prioritization presents itself as a solution to this problem, systematically analyzing and sorting each gene from the most to least likely to be the disease-causing gene, in a fraction of the time it would take a researcher to perform such queries manually.ResultsHere, we present Gene TIssue Expression Ranker (GeneTIER), a new web-based application for candidate gene prioritization. GeneTIER replaces knowledge-based inference traditionally used in candidate disease gene prioritization applications with experimental data from tissue-specific gene expression datasets and thus largely overcomes the bias toward the better characterized genes/diseases that commonly afflict other methods. We show that our approach is capable of accurate candidate gene prioritization and illustrate its strengths and weaknesses using case study examples.Availability and implementationFreely available on the web at http://dna.leeds.ac.uk/GeneTIER/.Contactumaan@leeds.ac.ukSupplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC4528628 | biostudies-literature