{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:50:07Z","timestamp":1753890607031,"version":"3.41.2"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T00:00:00Z","timestamp":1689120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at <jats:ext-link>https:\/\/gitlab.lcsb.uni.lu\/minerva\/automap\/<\/jats:ext-link>.<\/jats:p>","DOI":"10.3389\/fbinf.2023.1101505","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T23:41:35Z","timestamp":1689205295000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Visualization of automatically combined disease maps and pathway diagrams for rare diseases"],"prefix":"10.3389","volume":"3","author":[{"given":"Piotr","family":"Gawron","sequence":"first","affiliation":[]},{"given":"David","family":"Hoksza","sequence":"additional","affiliation":[]},{"given":"Janet","family":"Pi\u00f1ero","sequence":"additional","affiliation":[]},{"given":"Maria","family":"Pe\u00f1a-Chilet","sequence":"additional","affiliation":[]},{"given":"Marina","family":"Esteban-Medina","sequence":"additional","affiliation":[]},{"given":"Jose Luis","family":"Fernandez-Rueda","sequence":"additional","affiliation":[]},{"given":"Vincenza","family":"Colonna","sequence":"additional","affiliation":[]},{"given":"Ewa","family":"Smula","sequence":"additional","affiliation":[]},{"given":"Laurent","family":"Heirendt","sequence":"additional","affiliation":[]},{"given":"Fran\u00e7ois","family":"Ancien","sequence":"additional","affiliation":[]},{"given":"Valentin","family":"Groues","sequence":"additional","affiliation":[]},{"given":"Venkata P.","family":"Satagopam","sequence":"additional","affiliation":[]},{"given":"Reinhard","family":"Schneider","sequence":"additional","affiliation":[]},{"given":"Joaquin","family":"Dopazo","sequence":"additional","affiliation":[]},{"given":"Laura I.","family":"Furlong","sequence":"additional","affiliation":[]},{"given":"Marek","family":"Ostaszewski","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2023,7,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1080\/13816810701537424","article-title":"The retinal ciliopathies","volume":"28","author":"Adams","year":"2007","journal-title":"Ophthalmic Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/gm155","article-title":"Retinitis pigmentosa and allied conditions today: A paradigm of translational research","volume":"2","author":"Ayuso","year":"2010","journal-title":"Genome Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1093\/bioinformatics\/btaa850","article-title":"Newt: A comprehensive web-based tool for viewing, constructing and analyzing biological maps","volume":"37","author":"Balci","year":"2021","journal-title":"Bioinformatics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.exer.2015.11.007","article-title":"Aberrant protein trafficking in retinal degenerations: The initial phase of retinal remodeling","volume":"150","author":"Bales","year":"2016","journal-title":"Exp. Eye Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.ceca.2018.01.002","article-title":"A critical appraisal of the role of intracellular Ca2+-signaling pathways in Kawasaki disease","volume":"71","author":"Bijnens","year":"2018","journal-title":"Cell Calcium"},{"key":"B6","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/s11926-021-01028-4","article-title":"Current understanding of multisystem inflammatory syndrome (MIS-C) following COVID-19 and its distinction from Kawasaki disease","volume":"23","author":"Bukulmez","year":"2021","journal-title":"Curr. Rheumatol. Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"D1056","DOI":"10.1093\/nar\/gky1133","article-title":"Open targets platform: New developments and updates two years on","volume":"47","author":"Carvalho-Silva","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1096\/fj.201901888r","article-title":"Novel molecular mechanisms for Prph2-associated pattern dystrophy","volume":"34","author":"Chakraborty","year":"2020","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"W155","DOI":"10.1093\/nar\/gkq331","article-title":"The Ontology Lookup service: Bigger and better","volume":"38","author":"C\u00f4t\u00e9","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B10","first-page":"1","article-title":"The igraph software package for complex network research","volume":"1695","author":"Csardi","year":"2006","journal-title":"InterJournal Complex Syst."},{"key":"B11","doi-asserted-by":"publisher","first-page":"D988","DOI":"10.1093\/nar\/gkab1049","article-title":"Ensembl 2022","volume":"50","author":"Cunningham","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2710","DOI":"10.3390\/biomedicines10112710","article-title":"Pathogenesis of vascular retinal manifestations in COVID-19 patients: A review","volume":"10","author":"D\u2019Alessandro","year":"2022","journal-title":"Biomedicines"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1846","DOI":"10.1093\/bioinformatics\/btm254","article-title":"GEOquery: A bridge between the gene expression Omnibus (GEO) and BioConductor","volume":"23","author":"Davis","year":"2007","journal-title":"Bioinformatics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"238","DOI":"10.2174\/138920211795860107","article-title":"Retinitis pigmentosa: Genes and disease mechanisms","volume":"12","author":"Ferrari","year":"2011","journal-title":"Curr. Genomics"},{"key":"B15","unstructured":"Pre-mRNA processing factors and retinitis pigmentosa: RNA splicing and beyond\n            Frontiers\n          2021"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.3390\/ijms21041503","article-title":"Targeting neurovascular interaction in retinal disorders","volume":"21","author":"Fu","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1007\/s12035-013-8489-4","article-title":"Integrating pathways of Parkinson\u2019s disease in a molecular interaction map","volume":"49","author":"Fujita","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"16020","DOI":"10.1038\/npjsba.2016.20","article-title":"MINERVA-a platform for visualization and curation of molecular interaction networks","volume":"2","author":"Gawron","year":"2016","journal-title":"NPJ Syst. Biol. Appl."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e4565","DOI":"10.1002\/pro.4565","article-title":"Exploration and comparison of molecular mechanisms across diseases using MINERVA Net","volume":"32","author":"Gawron","year":"2023","journal-title":"Protein Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"D687","DOI":"10.1093\/nar\/gkab1028","article-title":"The reactome pathway knowledgebase 2022","volume":"50","author":"Gillespie","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"103240","DOI":"10.1016\/j.autrev.2022.103240","article-title":"Immune and non-immune mechanisms that determine vasculitis and coronary artery aneurysm topography in Kawasaki disease and MIS-C","volume":"22","author":"Giryes","year":"2023","journal-title":"Autoimmun. Rev."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbz067","article-title":"Closing the gap between formats for storing layout information in systems biology","volume":"21","author":"Hoksza","year":"2019","journal-title":"Brief. Bioinform"},{"key":"B23","doi-asserted-by":"publisher","first-page":"4127","DOI":"10.1093\/bioinformatics\/bty489","article-title":"MolArt: A molecular structure annotation and visualization tool","volume":"34","author":"Hoksza","year":"2018","journal-title":"Bioinforma. Oxf Engl."},{"key":"B24","doi-asserted-by":"publisher","first-page":"4496","DOI":"10.1093\/bioinformatics\/btz286","article-title":"MINERVA API and plugins: Opening molecular network analysis and visualization to the community","volume":"35","author":"Hoksza","year":"2019","journal-title":"Bioinforma. Oxf Engl."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.3390\/vaccines10111879","article-title":"COVID-19 vaccine-associated ocular adverse effects: An overview","volume":"10","author":"Ichhpujani","year":"2022","journal-title":"Vaccines"},{"key":"B26","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1038\/nbt1111","article-title":"Using process diagrams for the graphical representation of biological networks","volume":"23","author":"Kitano","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"D1207","DOI":"10.1093\/nar\/gkaa1043","article-title":"The human phenotype Ontology in 2021","volume":"49","author":"K\u00f6hler","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1007\/s12016-020-08783-9","article-title":"Immunogenetics of Kawasaki disease","volume":"59","author":"Kumrah","year":"2020","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"746856","DOI":"10.3389\/fped.2021.746856","article-title":"Increased risk of asthma and allergic rhinitis in patients with a past history of Kawasaki disease: A systematic review and meta-analyses","volume":"9","author":"Lei","year":"2021","journal-title":"Front. Pediatr."},{"key":"B32","doi-asserted-by":"publisher","first-page":"W551","DOI":"10.1093\/nar\/gkac352","article-title":"PaintOmics 4: New tools for the integrative analysis of multi-omics datasets supported by multiple pathway databases","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res. gkac352"},{"key":"B33","doi-asserted-by":"publisher","first-page":"W312","DOI":"10.1093\/nar\/gkac399","article-title":"ExpressVis: A biologist-oriented interactive web server for exploring multi-omics data","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res. gkac399"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1093\/bioinformatics\/btq099","article-title":"Modeling sample variables with an experimental factor Ontology","volume":"26","author":"Malone","year":"2010","journal-title":"Bioinforma. Oxf Engl."},{"key":"B35","first-page":"275","article-title":"Retinal phototransduction","volume":"19","author":"Mannu","year":"2014","journal-title":"Retin. Phototransduction. Neurosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"D613","DOI":"10.1093\/nar\/gkaa1024","article-title":"WikiPathways: Connecting communities","volume":"49","author":"Martens","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.jaci.2020.11.032","article-title":"AsthmaMap: An interactive knowledge repository for mechanisms of asthma","volume":"147","author":"Mazein","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41540-018-0059-y","article-title":"Systems medicine disease maps: Community-driven comprehensive representation of disease mechanisms","volume":"4","author":"Mazein","year":"2018","journal-title":"NPJ Syst. Biol. Appl."},{"key":"B39","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"B40","unstructured":"Orphanet: An online database of rare diseases and orphan drugs copyright INSERM\n            Orpha\n          1997"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.3390\/pharmaceutics13111935","article-title":"Neuroinflammation as a therapeutic target in retinitis pigmentosa and quercetin as its potential modulator","volume":"13","author":"Ortega","year":"2021","journal-title":"Pharmaceutics"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e10387","DOI":"10.15252\/msb.202110387","article-title":"COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms","volume":"17","author":"Ostaszewski","year":"2021","journal-title":"Mol. Syst. Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"D845","DOI":"10.1093\/nar\/gkz1021","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Pi\u00f1ero","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1001\/jamapediatrics.2022.3756","article-title":"Incidence of Kawasaki disease before and after the COVID-19 pandemic in Japan: Results of the 26th nationwide survey, 2019 to 2020","volume":"176","author":"Makino","year":"2022","journal-title":"JAMA Pediatr."},{"key":"B45","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"B46","doi-asserted-by":"publisher","first-page":"D489","DOI":"10.1093\/nar\/gkz946","article-title":"Pathway commons 2019 update: Integration, analysis and exploration of pathway data","volume":"48","author":"Rodchenkov","year":"2019","journal-title":"Nucleic Acids Res. gkz946"},{"key":"B47","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/s41536-022-00235-6","article-title":"Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue","volume":"7","author":"Rodrigues","year":"2022","journal-title":"Npj Regen. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"4681","DOI":"10.1038\/s41598-021-84098-9","article-title":"A case of retinitis pigmentosa homozygous for a rare CNGA1 causal variant","volume":"11","author":"Saito","year":"2021","journal-title":"Sci. Rep."},{"key":"B49","doi-asserted-by":"publisher","first-page":"251","DOI":"10.18176\/jiaci.0300","article-title":"Autoimmune aspects of Kawasaki disease","volume":"29","author":"Sakurai","year":"2019","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"baaa017","DOI":"10.1093\/database\/baaa017","article-title":"RA-Map: Building a state-of-the-art interactive knowledge base for rheumatoid arthritis","volume":"2020","author":"Singh","year":"2020","journal-title":"Database J. Biol. Databases Curation"},{"key":"B51","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1038\/nmeth.4077","article-title":"OmniPath: Guidelines and gateway for literature-curated signaling pathway resources","volume":"13","author":"T\u00fcrei","year":"2016","journal-title":"Nat. Methods"},{"key":"B53","doi-asserted-by":"publisher","first-page":"2378","DOI":"10.1093\/bioinformatics\/btw167","article-title":"pileup.js: a JavaScript library for interactive and in-browser visualization of genomic data","volume":"32","author":"Vanderkam","year":"2016","journal-title":"Bioinforma. Oxf Engl."},{"key":"B54","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s13023-021-01741-4","article-title":"RDmap: A map for exploring rare diseases","volume":"16","author":"Yang","year":"2021","journal-title":"Orphanet J. Rare Dis."}],"container-title":["Frontiers in Bioinformatics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbinf.2023.1101505\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T23:41:42Z","timestamp":1689205302000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbinf.2023.1101505\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,12]]},"references-count":54,"alternative-id":["10.3389\/fbinf.2023.1101505"],"URL":"https:\/\/doi.org\/10.3389\/fbinf.2023.1101505","relation":{},"ISSN":["2673-7647"],"issn-type":[{"type":"electronic","value":"2673-7647"}],"subject":[],"published":{"date-parts":[[2023,7,12]]},"article-number":"1101505"}}