INTRODUCTION. Note that KEGG IDs are the same as Entrez Gene IDs for most species anyway. Examples of widely used statistical A wide range of databases and resources have been built (KEGG (), Reactome (), Wikipathways (), MetaCyc (), PANTHER (), Pathway Commons etc.) The default goana and kegga methods accept a vector prior.prob giving the prior probability that each gene in the universe appears in a gene set. Which KEGG pathways are over-represented in the differentially expressed genes from the leukemia study? To visualise the changes on the pathway diagram from KEGG, one can use the package pathview. Ignored if gene.pathway and pathway.names are not NULL. following uses the keegdb and reacdb lists created above as annotation systems. Determine how functions are attributed to genes using Gene Ontology terms. keyType one of kegg, ncbi-geneid, ncib-proteinid or uniprot. In this case, the subset is your set of under or over expressed genes. Well use these KEGG pathway IDs downstream for plotting. The final video in the pipeline! Set the species to "Hs" for Homo sapiens. kegg.gs and go.sets.hs. The data may also be a single-column of gene IDs (example). for pathway analysis. Examples of KEGG format are "hsa" for human, "mmu" for mouse of "dme" for fly. kegga requires an internet connection unless gene.pathway and pathway.names are both supplied.. However, gage is tricky; note that by default, it makes a [] The KEGG database contains curated sets of genes that are known to interact in the same biological pathway. Next, get results for the HoxA1 knockdown versus control siRNA, and reorder them by p-value. This more time consuming step needs to be performed only once. Using GOstats to test gene lists for GO term association. Bioinformatics 23 (2): 25758. The knowl-edge from KEGG has proven of great value by numerous work in a wide range of fields [Kanehisaet al., 2008]. https://doi.org/10.1093/bioinformatics/btl567. To perform GSEA analysis of KEGG gene sets, clusterProfiler requires the genes to be . are organized and how to access them. Emphasizes the genes overlapping among different gene sets. First, the package requires a vector or a matrix with, respectively, names or rownames that are ENTREZ IDs. Both the absolute or original expression levels and the relative expression levels (log2 fold changes, t-statistics) can be visualized on pathways. 1 Overview. systemPipeR package. In contrast to this, Gene Set How to perform KEGG pathway analysis in R? Palombo, V., Milanesi, M., Sferra, G. et al. KEGG pathways. https://doi.org/10.1186/s12859-020-3371-7, DOI: https://doi.org/10.1186/s12859-020-3371-7. logical, should the universe be restricted to gene identifiers found in at least one pathway in gene.pathway? If you have suggestions or recommendations for a better way to perform something, feel free to let me know! The goseq package provides an alternative implementation of methods from Young et al (2010). This tutorial shows an example of RNA-seq data analysis with DESeq2, followed by KEGG pathway analysis using GAGE.Using data from GSE37704, with processed data available on Figshare DOI: 10.6084/m9.figshare.1601975.This dataset has six samples from GSE37704, where expression was quantified by either: (A) mapping to to GRCh38 using STAR then counting reads mapped to genes with featureCounts . trend=FALSE is equivalent to prior.prob=NULL. provided by Bioconductor packages. A very useful query interface for Reactome is the ReactomeContentService4R package. Mariasilvia DAndrea. Examples of widely used statistical enrichment methods are introduced as well. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. For more information please see the full documentation here: https://bioconductor.org/packages/release/bioc/vignettes/clusterProfiler/inst/doc/clusterProfiler.html, Follow along interactively with the R Markdown Notebook: It works with: 1) essentially all types of biological data mappable to pathways, 2) over 10 types of gene or protein IDs, and 20 types of compound or metabolite IDs, 3) pathways for over 2000 species as well as KEGG orthology, 4) varoius data attributes and formats, i.e. In addition, this work also attempts to preliminarily estimate the impact direction of each KEGG pathway by a gradient analysis method from principal component analysis (PCA). Figure 1: Fireworks plot depicting genome-wide view of reactome pathways. The following provide sample code for using GO.db as well as a organism 161, doi: 10.1186/1471-2105-10-161, Pathway based data integration and visualization, Example Gene Data These include among many other The California Privacy Statement, is a generic concept, including multiple types of The first part shows how to generate the proper catdb Policy. Data The mapping against the KEGG pathways was performed with the pathview R package v1.36. Over-representation (or enrichment) analysis is a statistical method that determines whether genes from pre-defined sets (ex: those beloging to a specific GO term or KEGG pathway) are present more than would be expected (over-represented) in a subset of your data. PATH PMID REFSEQ SYMBOL UNIGENE UNIPROT. ADD COMMENT link 5.4 years ago by Fabio Marroni 2.9k. Please consider contributing to my Patreon where I may do merch and gather ideas for future content:https://www.patreon.com/AlexSoupir Sept 28, 2022: In ShinyGO 0.76.2, KEGG is now the default pathway database. Bug fix: results from kegga with trend=TRUE or with non-NULL covariate were incorrect prior to limma 3.32.3. Getting Genetics Done by Stephen Turner is licensed under a Creative Commons Attribution-ShareAlike 3.0 Unported License. Now, lets process the results to pull out the top 5 upregulated pathways, then further process that just to get the IDs. When users select "Sort by Fold Enrichment", the minimum pathway size is raised to 10 to filter out noise from tiny gene sets. Use of this site constitutes acceptance of our User Agreement and Privacy You need to specify a few extra options(NOT needed if you just want to visualize the input data as it is): For examples of gene data, check: Example Gene Data Pathways are stored and presented as graphs on the KEGG server side, where nodes are Note. First column should be gene IDs, continuous/discrete data, matrices/vectors, single/multiple samples etc. Commonly used gene sets include those derived from KEGG pathways, Gene Ontology terms, MSigDB, Reactome, or gene groups that share some other functional annotations, etc. ADD COMMENT link 5.4 years ago by roy.granit 880. hsa, ath, dme, mmu, ). Enrichment map organizes enriched terms into a network with edges connecting overlapping gene sets. The following introduces gene and protein annotation systems that are widely used for functional enrichment analysis (FEA). To aid interpretation of differential expression results, a common technique is to test for enrichment in known gene sets. I currently have 10 separate FASTA files, each file is from a different species. /Length 2105 Unlike the goseq package, the gene identifiers here must be Entrez Gene IDs and the user is assumed to be able to supply gene lengths if necessary. The network graph visualization helps to interpret functional profiles of . Set up the DESeqDataSet, run the DESeq2 pipeline. 2018. https://doi.org/10.3168/jds.2018-14413. We previously developed an R/BioConductor package called Pathview, which maps, integrates and visualizes a wide range of data onto KEGG pathway graphs.Since its publication, Pathview has been widely used in omics studies and data analyses, and has become the leading tool in its category. U. S. A. Falcon, S, and R Gentleman. This tutorial shows an example of RNA-seq data analysis with DESeq2, followed by KEGG pathway analysis using. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The resulting list object can be used transcript or protein IDs, for example ENTREZ Gene, Symbol, RefSeq, GenBank Accession Number, GO.db is a data package that stores the GO term information from the GO SS Testing and manuscript review. I wrote an R package for doing this offline the dplyr way (, Now, lets run the pathway analysis. 2005. systemPipeR: NGS workflow and report generation environment. BMC Bioinformatics 17 (September): 388. https://doi.org/10.1186/s12859-016-1241-0. to its speed, it is very flexible in adopting custom annotation systems since it It organizes data in several overlapping ways, including pathway, diseases, drugs, compounds and so on. Springer Nature. 2020). Which KEGG pathways are over-represented in the differentially expressed genes from the leukemia study? The final video in the pipeline! Privacy Enrichment Analysis (GSEA) algorithms use as query a score ranked list (e.g. The yellow and the blue diamonds represent the second (2L) and third-levels (3L) pathways connected with candidate genes, respectively. Correspondence to Incidentally, we can immediately make an analysis using gage. This vector can be used to correct for unwanted trends in the differential expression analysis associated with gene length, gene abundance or any other covariate (Young et al, 2010). I define this as kegg_organism first, because it is used again below when making the pathview plots. statement and The cnetplot depicts the linkages of genes and biological concepts (e.g. expression levels or differential scores (log ratios or fold changes). developed for pathway analysis. If trend=TRUE or a covariate is supplied, then a trend is fitted to the differential expression results and this is used to set prior.prob. By default this is obtained automatically by getGeneKEGGLinks(species.KEGG). In this case, the subset is your set of under or over expressed genes. These functions perform over-representation analyses for Gene Ontology terms or KEGG pathways in one or more vectors of Entrez Gene IDs. If TRUE, then de$Amean is used as the covariate. The goana default method produces a data frame with a row for each GO term and the following columns: ontology that the GO term belongs to. View the top 20 enriched KEGG pathways with topKEGG. Unlike the limma functions documented here, goseq will work with a variety of gene identifiers and includes a database of gene length information for various species. Terms and Conditions, Frequently, you also need to the extra options: Control/reference, Case/sample, optional numeric vector of the same length as universe giving the prior probability that each gene in the universe appears in a gene set. By default this is obtained automatically using getKEGGPathwayNames(species.KEGG, remove=TRUE). Understand the theory of how functional enrichment tools yield statistically enriched functions or interactions. Pathway Selection set to Auto on the New Analysis page. systemPipeR: Workflow Design and Reporting Environment, Environments dplyr, tidyr and some SQLite, https://doi.org/10.1093/bioinformatics/btl567, https://doi.org/10.1186/s12859-016-1241-0, Many additional packages can be found under Biocs KEGG View page. Gene Data accepts data matrices in tab- or comma-delimited format (txt or csv). PubMedGoogle Scholar. Genome-wide association study of milk fatty acid composition in Italian Simmental and Italian Holstein cows using single nucleotide polymorphism arrays. . Not adjusted for multiple testing. p-value for over-representation of GO term in down-regulated genes. Customize the color coding of your gene and compound data. KEGG ortholog IDs are also treated as gene IDs This will create a PNG and different PDF of the enriched KEGG pathway. We also see the importance of exploring the results a little further when P53 pathway is upregulated as a whole but P53, while having higher levels in the P53+/+ samples, didn't show as much of an increase by treatment than did P53-/-.Creating DESeq2 object:https://www.youtube.com/watch?v=5z_1ziS0-5wCalculating Differentially Expressed genes:https://www.youtube.com/watch?v=ZjMfiPLuwN4Series github with the subsampled data so the whole pipeline can be done on most computers.https://github.com/ACSoupir/Bioinformatics_YouTubeI use these videos to practice speaking and teaching others about processes. For simplicity, the term gene sets is used Sergushichev, Alexey. If NULL then all Entrez Gene IDs associated with any gene ontology term will be used as the universe. VP Project design, implementation, documentation and manuscript writing. either the standard Hypergeometric test or a conditional Hypergeometric test that uses the In this case, the universe is all the genes found in the fit object. in the vignette of the fgsea package here. You can generate up-to-date gene set data using kegg.gsetsand go.gsets. However, conventional methods for pathway analysis do not take into account complex protein-protein interaction information, resulting in incomplete conclusions. The default for kegga with species="Dm" changed from convert=TRUE to convert=FALSE in limma 3.27.8. Data 2. Bioinformatics, 2013, 29(14):1830-1831, doi: Luo W, Pant G, Bhavnasi YK, Blanchard SG, Brouwer C. Pathview Web: user friendly pathway visualization and data integration. in using R in general, you may use the Pathview Web server: pathview.uncc.edu and its comprehensive pathway analysis workflow. The top five were photosynthesis, phenylpropanoid biosynthesis, metabolism of starch and sucrose, photosynthesis-antenna proteins, and zeatin biosynthesis (Figure 4B, Table S5). In the "FS3 vs. FS0" group, 937 DEGs were enriched in 111 KEGG pathways. 161, doi. The multi-types and multi-groups expression data can be visualized in one pathway map. Could anyone please suggest me any good R package? Young, M. D., Wakefield, M. J., Smyth, G. K., Oshlack, A. Description: PANEV is an R package set for pathway-based network gene visualization. lookup data structure for any organism supported by BioMart (H Backman and Girke 2016). Data 2, Example Compound https://doi.org/10.1073/pnas.0506580102. You can also do that using edgeR. Immunology. The goseq package has additional functionality to convert gene identifiers and to provide gene lengths. species Same as organism above in gseKEGG, which we defined as kegg_organism gene.idtype The index number (first index is 1) correspoding to your keytype from this list gene.idtype.list, Next-Generation Sequencing Analysis Resources, NGS Sequencing Technology and File Formats, Gene Set Enrichment Analysis with ClusterProfiler, Over-Representation Analysis with ClusterProfiler, Salmon & kallisto: Rapid Transcript Quantification for RNA-Seq Data, Instructions to install R Modules on Dalma, Prerequisites, data summary and availability, Deeptools2 computeMatrix and plotHeatmap using BioSAILs, Exercise part4 Alternative approach in R to plot and visualize the data, Seurat part 3 Data normalization and PCA, Loading your own data in Seurat & Reanalyze a different dataset, JBrowse: Visualizing Data Quickly & Easily, https://bioconductor.org/packages/release/bioc/vignettes/clusterProfiler/inst/doc/clusterProfiler.html, https://github.com/gencorefacility/r-notebooks/blob/master/ora.Rmd, http://bioconductor.org/packages/release/BiocViews.html#___OrgDb, https://www.genome.jp/kegg/catalog/org_list.html. Frequently, you also need to the extra options: Control/reference, Case/sample, and Compare in the dialogue box. kegga can be used for any species supported by KEGG, of which there are more than 14,000 possibilities. under the org argument (e.g. These include among many other annotation systems: Gene Ontology (GO), Disease Ontology (DO) and pathway annotations, such as KEGG and Reactome. rankings (Subramanian et al. For Drosophila, the default is FlyBase CG annotation symbol. KEGG MODULE is a collection of manually defined functional units, called KEGG modules and identified by the M numbers, used for annotation and biological interpretation of sequenced genomes. annotations, such as KEGG and Reactome. The plotEnrichment can be used to create enrichment plots. << If you supply data as original expression levels, but you want to visualize the relative expression levels (or differences) between two states. That's great, I didn't know very useful if you are already using edgeR! Its P-value Luo W, Friedman M, etc. The following introduceds a GOCluster_Report convenience function from the pathway.id The user needs to enter this. Its vignette provides many useful examples, see here. by fgsea. PANEV: an R package for a pathway-based network visualization. used for functional enrichment analysis (FEA). Alternatively one can supply the required pathway annotation to kegga in the form of two data.frames. . See alias2Symbol for other possible values for species. Part of /Length 691 But, our pathway analysis downstream will use KEGG pathways, and genes in KEGG pathways are annotated with Entrez gene IDs. For KEGG pathway enrichment using the gseKEGG() function, we need to convert id types. if TRUE, the species qualifier will be removed from the pathway names. The mRNA expression of the top 10 potential targets was verified in the brain tissue. The ability to supply data.frame annotation to kegga means that kegga can in principle be used in conjunction with any user-supplied set of annotation terms. The options vary for each annotation. If this is done, then an internet connection is not required. #ok, so most variation is in the first 2 axes for pathway # 3-4 axes for kegg p=plot_ordination(pw,ord_pw,type="samples",color="Facility",shape="Genotype") p=p+geom . package for a species selected under the org argument (e.g. If 260 genes are categorized as axon guidance (2.6% of all genes have category axon guidance), and in an experiment we find 1000 genes are differentially expressed and 200 of those genes are in the category axon guidance (20% of DE genes have category axon guidance), is that significant? BMC Bioinformatics, 2009, 10, pp. Policy. The results were biased towards significant Down p-values and against significant Up p-values. Genome Biology 11, R14. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. and Compare in the dialogue box. We can also do a similar procedure with gene ontology. concordance:KEGGgraph.tex:KEGGgraph.Rnw:1 22 1 1 0 35 1 1 2 4 0 1 2 18 1 1 2 1 0 1 1 3 0 1 2 6 1 1 3 5 0 2 2 1 0 1 1 8 0 1 2 1 1 1 2 1 0 1 1 17 0 2 1 8 0 1 2 10 1 1 2 1 0 1 1 5 0 2 1 7 0 1 2 3 1 1 2 1 0 1 1 12 0 1 2 1 1 1 2 13 0 1 2 3 1 1 2 1 0 1 1 13 0 2 2 14 0 1 2 7 1 1 2 1 0 4 1 6 0 1 1 7 0 1 2 4 1 1 2 1 0 4 1 8 0 1 2 5 1 1 17 2 1 1 2 1 0 2 1 1 8 6 0 1 1 1 2 2 1 1 4 7 0 1 2 4 1 1 2 1 0 4 1 8 0 1 2 29 1 1 2 1 0 4 1 7 0 1 2 6 1 1 2 1 0 4 1 1 2 5 1 1 2 4 0 1 2 7 1 1 2 4 0 1 2 14 1 1 2 1 0 2 1 17 0 2 1 11 0 1 2 4 1 1 2 1 0 1 2 1 1 1 2 5 1 4 0 1 2 5 1 1 2 4 0 1 2 1 1 1 2 1 0 1 1 7 0 2 1 8 0 1 2 2 1 1 2 1 0 3 1 3 0 1 2 2 1 1 9 12 0 1 2 2 1 1 2 1 0 2 1 1 3 5 0 1 2 12 1 1 2 42 0 1 2 11 1 organism KEGG Organism Code: The full list is here: https://www.genome.jp/kegg/catalog/org_list.html (need the 3 letter code). MM Implementation, testing and validation, manuscript review. AnntationHub. Please check the Section Basic Analysis and the help info on the function for details. https://doi.org/10.1093/nar/gkaa878. I would suggest KEGGprofile or KEGGrest. stream check ClusterProfiler http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html and document link http://bioconductor.org/packages/release/bioc/vignettes/clusterProfiler/inst/doc/clusterProfiler.html. For human and mouse, the default (and only choice) is Entrez Gene ID. GENENAME GO GOALL MAP ONTOLOGY ONTOLOGYALL Numerous pathway analysis methods and data types are implemented in R/Bioconductor, yet there has not been a dedicated and established tool for pathway-based data integration and visualization. Ignored if universe is NULL. Posted on August 28, 2014 by January in R bloggers | 0 Comments. Please cite our paper if you use this website. The row names of the data frame give the GO term IDs. See 10.GeneSetTests for a description of other functions used for gene set testing. Possible values include "Hs" (human), "Mm" (mouse), "Rn" (rat), "Dm" (fly) or "Pt" (chimpanzee), but other values are possible if the corresponding organism package is available. The output from kegga is the same except that row names become KEGG pathway IDs, Term becomes Pathway and there is no Ont column.. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. any other arguments in a call to the MArrayLM methods are passed to the corresponding default method. Nucleic Acids Res, 2017, Web Server issue, doi: Luo W, Brouwer C. Pathview: an R/Biocondutor package for pathway-based data integration Acad. number of down-regulated differentially expressed genes. 2016. column number or column name specifying for which coefficient or contrast differential expression should be assessed. vector specifying the set of Entrez Gene identifiers to be the background universe. PANEV (PAthway NEtwork Visualizer) is an R package set for gene/pathway-based network visualization. 5. Test for enriched KEGG pathways with kegga. In the case of org.Dm.eg.db, none of those 4 types are available, but ENTREZID are the same as ncbi-geneid for org.Dm.eg.db so we use this for toType. Compared to other GESA implementations, fgsea is very fast. H Backman, Tyler W, and Thomas Girke. The last two column names above assume one gene set with the name DE. Please also cite GAGE paper if you are doing pathway analysis besides visualization, i.e. GAGE: generally applicable gene set enrichment for pathway analysis. As a result, the advantage of the KEGG-PATH model is demonstrated through the functional analysis of the bovine mammary transcriptome during lactation. gene.data This is kegg_gene_list created above Organism specific gene to GO annotations are provied by I have a couple hundred nucleotide sequences from a Fungus genome. 2023 BioMed Central Ltd unless otherwise stated. See http://www.kegg.jp/kegg/catalog/org_list.html or http://rest.kegg.jp/list/organism for possible values. kegga reads KEGG pathway annotation from the KEGG website. Ignored if universe is NULL. consortium in an SQLite database. Approximate time: 120 minutes. The resulting list object can be used for various ORA or GSEA methods, e.g. Manage cookies/Do not sell my data we use in the preference centre. If you intend to do a full pathway analysis plus data visualization (or integration), you need to set GS Testing and manuscript review. Now, some filthy details about the parameters for gage. a character vector of Entrez Gene IDs, or a list of such vectors, or an MArrayLM fit object. Pathway analysis is often the first choice for studying the mechanisms underlying a phenotype. (2014) study and considering three levels for the investigation. Note we use the demo gene set data, i.e. KEGGprofile is an annotation and visualization tool which integrated the expression profiles and the function annotation in KEGG pathway maps. However, these options are NOT needed if your data is already relative The GOstats package allows testing for both over and under representation of GO terms using Luo W, Pant G, Bhavnasi YK, Blanchard SG, Brouwer C. Pathview Web: user friendly pathway visualization and data integration. In addition BMC Bioinformatics, 2009, 10, pp. That's great, I didn't know. Extract the entrez Gene IDs from the data frame fit2$genes. Dipartimento Agricoltura, Ambiente e Alimenti, Universit degli Studi del Molise, 86100, Campobasso, Italy, Department of Support, Production and Animal Health, School of Veterinary Medicine, So Paulo State University, Araatuba, So Paulo, 16050-680, Brazil, Istituto di Zootecnica, Universit Cattolica del Sacro Cuore, 29122, Piacenza, Italy, Dipartimento di Bioscienze e Territorio, Universit degli Studi del Molise, 86090, Pesche, IS, Italy, Dipartimento di Medicina Veterinaria, Universit di Perugia, 06126, Perugia, Italy, Dipartimento di Scienze Agrarie ed Ambientali, Universit degli Studi di Udine, 33100, Udine, Italy, You can also search for this author in Cookies policy. Sci. http://genomebiology.com/2010/11/2/R14. Duan, Yuzhu, Daniel S Evans, Richard A Miller, Nicholas J Schork, Steven R Cummings, and Thomas Girke. goana uses annotation from the appropriate Bioconductor organism package. The species can be any character string XX for which an organism package org.XX.eg.db is installed. Nucleic Acids Res, 2017, Web Server issue, doi: 10.1093/ nar/gkx372 Ontology Options: [BP, MF, CC] Examples are "Hs" for human for "Mm" for mouse. KEGGprofile facilitated more detailed analysis about the specific function changes inner pathway or temporal correlations in different genes and samples. KEGG pathway are divided into seven categories. Here gene ID The gene ID system used by kegga for each species is determined by KEGG. This includes code to inspect how the annotations 1, Example Gene Params: Several accessor functions are provided to While tricubeMovingAverage does not enforce monotonicity, it has the advantage of numerical stability when de contains only a small number of genes. KEGG stands for, Kyoto Encyclopedia of Genes and Genomes. estimation is based on an adaptive multi-level split Monte-Carlo scheme. The fgsea function performs gene set enrichment analysis (GSEA) on a score ranked if TRUE then KEGG gene identifiers will be converted to NCBI Entrez Gene identifiers. for ORA or GSEA methods, e.g. There are many options to do pathway analysis with R and BioConductor. First column gives pathway IDs, second column gives pathway names. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. bioRxiv. This is . The format of the IDs can be seen by typing head(getGeneKEGGLinks(species)), for examplehead(getGeneKEGGLinks("hsa")) or head(getGeneKEGGLinks("dme")). 3. Provided by the Springer Nature SharedIt content-sharing initiative. PANEV: an R package for a pathway-based network visualization, https://doi.org/10.1186/s12859-020-3371-7, https://cran.r-project.org/web/packages/visNetwork, https://cran.r-project.org/package=devtools, https://bioconductor.org/packages/release/bioc/html/KEGGREST.html, https://github.com/vpalombo/PANEV/tree/master/vignettes, https://doi.org/10.1371/journal.pcbi.1002375, https://doi.org/10.1016/j.tibtech.2005.05.011, https://doi.org/10.1093/bioinformatics/bti565, https://doi.org/10.1093/bioinformatics/btt285, https://doi.org/10.1016/j.csbj.2015.03.009, https://doi.org/10.1093/bioinformatics/bth456, https://doi.org/10.1371/journal.pcbi.1002820, https://doi.org/10.1038/s41540-018-0055-2, https://doi.org/10.1371/journal.pone.0032455, https://doi.org/10.1371/journal.pone.0033624, https://doi.org/10.1016/S0198-8859(02)00427-5, https://doi.org/10.1111/j.1365-2567.2005.02254.x, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/.
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