scholarly journals Silver: Forging almost Gold Standard Datasets

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1523
Author(s):  
Farhad Maleki ◽  
Katie Ovens ◽  
Ian McQuillan ◽  
Anthony J. Kusalik
Keyword(s):  
Gold Standard ◽  
Best Practice ◽  
Evaluation Studies ◽  
A Priori ◽  
Real Data ◽  
Gene Set Analysis ◽  
Gene Set ◽  
Analysis Methods ◽  
Gene Sets ◽  
New Gene

Gene set analysis has been widely used to gain insight from high-throughput expression studies. Although various tools and methods have been developed for gene set analysis, there is no consensus among researchers regarding best practice(s). Most often, evaluation studies have reported contradictory recommendations of which methods are superior. Therefore, an unbiased quantitative framework for evaluations of gene set analysis methods will be valuable. Such a framework requires gene expression datasets where enrichment status of gene sets is known a priori. In the absence of such gold standard datasets, artificial datasets are commonly used for evaluations of gene set analysis methods; however, they often rely on oversimplifying assumptions that make them biased in favor of or against a given method. In this paper, we propose a quantitative framework for evaluation of gene set analysis methods by synthesizing expression datasets using real data, without relying on oversimplifying or unrealistic assumptions, while preserving complex gene–gene correlations and retaining the distribution of expression values. The utility of the quantitative approach is shown by evaluating ten widely used gene set analysis methods. An implementation of the proposed method is publicly available. We suggest using Silver to evaluate existing and new gene set analysis methods. Evaluation using Silver provides a better understanding of current methods and can aid in the development of gene set analysis methods to achieve higher specificity without sacrificing sensitivity.

Measuring consistency among gene set analysis methods: A systematic study

2019 ◽  
Vol 17 (05) ◽  
pp. 1940010 ◽  
Author(s):  
Farhad Maleki ◽  
Katie L. Ovens ◽  
Daniel J. Hogan ◽  
Elham Rezaei ◽  
Alan M. Rosenberg ◽  
...  
Keyword(s):  
Gene Set Analysis ◽  
Rna Seq ◽  
Systematic Analysis ◽  
Gene Set ◽  
Large Gene ◽  
Analysis Methods ◽  
Gene Sets ◽  
Significant Gene ◽  
Biological Insight ◽  
Relevant Gene

Gene set analysis is a quantitative approach for generating biological insight from gene expression datasets. The abundance of gene set analysis methods speaks to their popularity, but raises the question of the extent to which results are affected by the choice of method. Our systematic analysis of 13 popular methods using 6 different datasets, from both DNA microarray and RNA-Seq origin, shows that this choice matters a great deal. We observed that the overall number of gene sets reported by each method differed by up to 2 orders of magnitude, and there was a bias toward reporting large gene sets with some methods. Furthermore, there was substantial disagreement between the 20 most statistically significant gene sets reported by the methods. This was also observed when expanding to the 100 most statistically significant reported gene sets. For different datasets of the same phenotype/condition, the top 20 and top 100 most significant results also showed little to no agreement even when using the same method. GAGE, PAGE, and ORA were the only methods able to achieve relatively high reproducibility when comparing the 20 and 100 most statistically significant gene sets. Biological validation on a juvenile idiopathic arthritis (JIA) dataset showed wide variation in terms of the relevance of the top 20 and top 100 most significant gene sets to known biology of the disease, where GAGE predicted the most relevant gene sets, followed by GSEA, ORA, and PAGE.

scholarly journals Gene Set Overlap: An Impediment to Achieving High Specificity in Over-representation Analysis

2018 ◽  
Author(s):  
Farhad Maleki ◽  
Anthony J. Kusalik
Keyword(s):  
Systematic Approach ◽  
False Positive Rate ◽  
High Specificity ◽  
Gene Set Analysis ◽  
Strong Negative Correlation ◽  
Gene Set ◽  
Analysis Methods ◽  
Positive Rate ◽  
New Gene ◽  
Analyze Data

AbstractGene set analysis methods are widely used to analyze data from high-throughput “omics” technologies. One drawback of these methods is their low specificity or high false positive rate. Over-representation analysis is one of the most commonly used gene set analysis methods. In this paper, we propose a systematic approach to investigate the hypothesis that gene set overlap is an underlying cause of low specificity in over-representation analysis. We quantify gene set overlap and show that it is a ubiquitous phenomenon across gene set databases. Statistical analysis indicates a strong negative correlation between gene set overlap and the specificity of over-representation analysis. We conclude that gene set overlap is an underlying cause of the low specificity. This result highlights the importance of considering gene set overlap in gene set analysis and explains the lack of specificity of methods that ignore gene set overlap. This research also establishes the direction for developing new gene set analysis methods.

scholarly journals A Biological Evaluation of Six Gene Set Analysis Methods for Identification of Differentially Expressed Pathways in Microarray Data

2008 ◽  
Vol 6 ◽  
pp. CIN.S867 ◽  
Author(s):  
Irina Dinu ◽  
Qi Liu ◽  
John D. Potter ◽  
Adeniyi J. Adewale ◽  
Gian S. Jhangri ◽  
...  
Keyword(s):  
Differential Expression ◽  
Microarray Data ◽  
Biological Evaluation ◽  
Gene Set Enrichment Analysis ◽  
The Other ◽  
Differentially Expressed ◽  
Gene Set Analysis ◽  
Gene Set ◽  
Analysis Methods ◽  
Gene Sets

Gene-set analysis of microarray data evaluates biological pathways, or gene sets, for their differential expression by a phenotype of interest. In contrast to the analysis of individual genes, gene-set analysis utilizes existing biological knowledge of genes and their pathways in assessing differential expression. This paper evaluates the biological performance of five gene-set analysis methods testing “self-contained null hypotheses” via subject sampling, along with the most popular gene-set analysis method, Gene Set Enrichment Analysis (GSEA). We use three real microarray analyses in which differentially expressed gene sets are predictable biologically from the phenotype. Two types of gene sets are considered for this empirical evaluation: one type contains “truly positive” sets that should be identified as differentially expressed; and the other type contains “truly negative” sets that should not be identified as differentially expressed. Our evaluation suggests advantages of SAM-GS, Global, and ANCOVA Global methods over GSEA and the other two methods.

scholarly journals Enhancing gene set enrichment using networks

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 129 ◽  
Author(s):  
Michael Prummer
Keyword(s):  
Biological Function ◽  
Automated Analysis ◽  
Gene Set Analysis ◽  
Molecular Pathways ◽  
Human Intervention ◽  
Gene Set Enrichment ◽  
Topological Information ◽  
Gene Set ◽  
Gene Sets ◽  
Differential Gene

Differential gene expression (DGE) studies often suffer from poor interpretability of their primary results, i.e., thousands of differentially expressed genes. This has led to the introduction of gene set analysis (GSA) methods that aim at identifying interpretable global effects by grouping genes into sets of common context, such as, molecular pathways, biological function or tissue localization. In practice, GSA often results in hundreds of differentially regulated gene sets. Similar to the genes they contain, gene sets are often regulated in a correlative fashion because they share many of their genes or they describe related processes. Using these kind of neighborhood information to construct networks of gene sets allows to identify highly connected sub-networks as well as poorly connected islands or singletons. We show here how topological information and other network features can be used to filter and prioritize gene sets in routine DGE studies. Community detection in combination with automatic labeling and the network representation of gene set clusters further constitute an appealing and intuitive visualization of GSA results. The RICHNET workflow described here does not require human intervention and can thus be conveniently incorporated in automated analysis pipelines.

scholarly journals Comparative evaluation of gene-set analysis methods

2007 ◽  
Vol 8 (1) ◽  
pp. 431 ◽  
Author(s):  
Qi Liu ◽  
Irina Dinu ◽  
Adeniyi J Adewale ◽  
John D Potter ◽  
Yutaka Yasui
Keyword(s):  
Comparative Evaluation ◽  
Gene Set Analysis ◽  
Gene Set ◽  
Analysis Methods

scholarly journals PhenoExam: an R package and Web application for the examination of phenotypes linked to genes and gene sets

2021 ◽  
Author(s):  
Alejandro Cisterna García ◽  
Aurora González-Vidal ◽  
Daniel Ruiz Villa ◽  
Jordi Ortiz Murillo ◽  
Alicia Gómez-Pascual ◽  
...  
Keyword(s):  
Web Application ◽  
Enrichment Analysis ◽  
R Package ◽  
Web Interface ◽  
Gene Set ◽  
New Genes ◽  
Gene Sets ◽  
Phenotype Analysis ◽  
New Gene ◽  
Early Onset Parkinson’S Disease

Gene set based phenotype enrichment analysis (detecting phenotypic terms that emerge as significant in a set of genes) can improve the rate of genetic diagnoses amongst other research purposes. To facilitate diverse phenotype analysis, we developed PhenoExam, a freely available R package for tool developers and a web interface for users, which performs: (1) phenotype and disease enrichment analysis on a gene set; (2) measures statistically significant phenotype similarities between gene sets and (3) detects significant differential phenotypes or disease terms across different databases. PhenoExam achieves these tasks by integrating databases or resources such as the HPO, MGD, CRISPRbrain, CTD, ClinGen, CGI, OrphaNET, UniProt, PsyGeNET, and Genomics England Panel App. PhenoExam accepts both human and mouse genes as input. We developed PhenoExam to assist a variety of users, including clinicians, computational biologists and geneticists. It can be used to support the validation of new gene-to-disease discoveries, and in the detection of differential phenotypes between two gene sets (a phenotype linked to one of the gene set but no to the other) that are useful for differential diagnosis and to improve genetic panels. We validated PhenoExam performance through simulations and its application to real cases. We demonstrate that PhenoExam is effective in distinguishing gene sets or Mendelian diseases with very similar phenotypes through projecting the disease-causing genes into their annotation-based phenotypic spaces. We also tested the tool with early onset Parkinson's disease and dystonia genes, to show phenotype-level similarities but also potentially interesting differences. More specifically, we used PhenoExam to validate computationally predicted new genes potentially associated with epilepsy. Therefore, PhenoExam effectively discovers links between phenotypic terms across annotation databases through effective integration. The R package is available at https://github.com/alexcis95/PhenoExam and the Web tool is accessible at https://snca.atica.um.es/PhenoExamWeb/.

scholarly journals GSAn: an alternative to enrichment analysis for annotating gene sets

2019 ◽  
Author(s):  
Aaron Ayllon-Benitez ◽  
Romain Bourqui ◽  
Patricia Thébaut ◽  
Fleur Mougin
Keyword(s):  
A Priori ◽  
Similarity Measures ◽  
Enrichment Analysis ◽  
Biological Information ◽  
New Approach ◽  
Gene Set ◽  
Multi Scale ◽  
Sequencing Technologies ◽  
Gene Sets ◽  
Limited Coverage

AbstractThe revolution in new sequencing technologies, by strongly improving the production of omics data, is greatly leading to new understandings of the relations between genotype and phenotype. To interpret and analyze these massive data that are grouped according to a phenotype of interest, methods based on statistical enrichment became a standard in biology. However, these methods synthesize the biological information by a priori selecting the over-represented terms and may suffer from focusing on the most studied genes that represent a limited coverage of annotated genes within the gene set.To address these limitations, we developed GSAn, a novel gene set annotation Web server that uses semantic similarity measures to reduce a priori Gene Ontology annotation terms. The originality of this new approach is to identify the best compromise between the number of retained annotation terms that has to be drastically reduced and the number of related genes that has to be as large as possible. Moreover, GSAn offers interactive visualization facilities dedicated to the multi-scale analysis of gene set annotations. GSAn is available at: https://gsan.labri.fr.

scholarly journals GeneSetCluster: a tool for summarizing and integrating gene-set analysis results

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ewoud Ewing ◽  
Nuria Planell-Picola ◽  
Maja Jagodic ◽  
David Gomez-Cabrero
Keyword(s):  
Gene Content ◽  
Gene Set Analysis ◽  
Gene Set ◽  
Overlapping Gene ◽  
Analysis Tools ◽  
Novel Approach ◽  
Gene Sets ◽  
Distance Score ◽  
Significant Gene ◽  
Similar Gene

Abstract Background Gene-set analysis tools, which make use of curated sets of molecules grouped based on their shared functions, aim to identify which gene-sets are over-represented in the set of features that have been associated with a given trait of interest. Such tools are frequently used in gene-centric approaches derived from RNA-sequencing or microarrays such as Ingenuity or GSEA, but they have also been adapted for interval-based analysis derived from DNA methylation or ChIP/ATAC-sequencing. Gene-set analysis tools return, as a result, a list of significant gene-sets. However, while these results are useful for the researcher in the identification of major biological insights, they may be complex to interpret because many gene-sets have largely overlapping gene contents. Additionally, in many cases the result of gene-set analysis consists of a large number of gene-sets making it complicated to identify the major biological insights. Results We present GeneSetCluster, a novel approach which allows clustering of identified gene-sets, from one or multiple experiments and/or tools, based on shared genes. GeneSetCluster calculates a distance score based on overlapping gene content, which is then used to cluster them together and as a result, GeneSetCluster identifies groups of gene-sets with similar gene-set definitions (i.e. gene content). These groups of gene-sets can aid the researcher to focus on such groups for biological interpretations. Conclusions GeneSetCluster is a novel approach for grouping together post gene-set analysis results based on overlapping gene content. GeneSetCluster is implemented as a package in R. The package and the vignette can be downloaded at https://github.com/TranslationalBioinformaticsUnit

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