{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T15:24:19Z","timestamp":1764689059747},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2016,10,12]],"date-time":"2016-10-12T00:00:00Z","timestamp":1476230400000},"content-version":"vor","delay-in-days":336,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Biological systems are complex and challenging to model and therefore model reuse is highly desirable. To promote model reuse, models should include both information about the specifics of simulations and the underlying biology in the form of metadata. The availability of computationally tractable metadata is especially important for the effective automated interpretation and processing of models. Metadata are typically represented as machine-readable annotations which enhance programmatic access to information about models. Rule-based languages have emerged as a modelling framework to represent the complexity of biological systems. Annotation approaches have been widely used for reaction-based formalisms such as SBML. However, rule-based languages still lack a rich annotation framework to add semantic information, such as machine-readable descriptions, to the components of a model.<\/jats:p>\n               <jats:p>Results: We present an annotation framework and guidelines for annotating rule-based models, encoded in the commonly used Kappa and BioNetGen languages. We adapt widely adopted annotation approaches to rule-based models. We initially propose a syntax to store machine-readable annotations and describe a mapping between rule-based modelling entities, such as agents and rules, and their annotations. We then describe an ontology to both annotate these models and capture the information contained therein, and demonstrate annotating these models using examples. Finally, we present a proof of concept tool for extracting annotations from a model that can be queried and analyzed in a uniform way. The uniform representation of the annotations can be used to facilitate the creation, analysis, reuse and visualization of rule-based models. Although examples are given, using specific implementations the proposed techniques can be applied to rule-based models in general.<\/jats:p>\n               <jats:p>Availability and implementation: The annotation ontology for rule-based models can be found at http:\/\/purl.org\/rbm\/rbmo. The krdf tool and associated executable examples are available at http:\/\/purl.org\/rbm\/rbmo\/krdf.<\/jats:p>\n               <jats:p>Contact: \u00a0anil.wipat@newcastle.ac.uk \u00a0 or \u00a0vdanos@inf.ed.ac.uk<\/jats:p>","DOI":"10.1093\/bioinformatics\/btv660","type":"journal-article","created":{"date-parts":[[2015,11,12]],"date-time":"2015-11-12T02:10:31Z","timestamp":1447294231000},"page":"908-917","source":"Crossref","is-referenced-by-count":17,"title":["Annotation of rule-based models with formal semantics to enable creation, analysis, reuse and visualization"],"prefix":"10.1093","volume":"32","author":[{"given":"Goksel","family":"Misirli","sequence":"first","affiliation":[{"name":"1 Interdisciplinary Computing and Complex BioSystems Research Group, School of Computing Science and Centre for Synthetic Biology and the Bioeconomy, Newcastle University, Newcastle upon Tyne, UK,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Cavaliere","sequence":"additional","affiliation":[{"name":"2 School of Informatics, University of Edinburgh, Edinburgh, UK and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Waites","sequence":"additional","affiliation":[{"name":"2 School of Informatics, University of Edinburgh, Edinburgh, UK and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Pocock","sequence":"additional","affiliation":[{"name":"3 Turing Ate My Hamster Ltd., Newcastle upon Tyne, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Curtis","family":"Madsen","sequence":"additional","affiliation":[{"name":"1 Interdisciplinary Computing and Complex BioSystems Research Group, School of Computing Science and Centre for Synthetic Biology and the Bioeconomy, Newcastle University, Newcastle upon Tyne, UK,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Owen","family":"Gilfellon","sequence":"additional","affiliation":[{"name":"1 Interdisciplinary Computing and Complex BioSystems Research Group, School of Computing Science and Centre for Synthetic Biology and the Bioeconomy, Newcastle University, Newcastle upon Tyne, UK,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo","family":"Honorato-Zimmer","sequence":"additional","affiliation":[{"name":"2 School of Informatics, University of Edinburgh, Edinburgh, UK and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Zuliani","sequence":"additional","affiliation":[{"name":"1 Interdisciplinary Computing and Complex BioSystems Research Group, School of Computing Science and Centre for Synthetic Biology and the Bioeconomy, Newcastle University, Newcastle upon Tyne, UK,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent","family":"Danos","sequence":"additional","affiliation":[{"name":"2 School of Informatics, University of Edinburgh, Edinburgh, UK and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil","family":"Wipat","sequence":"additional","affiliation":[{"name":"1 Interdisciplinary Computing and Complex BioSystems Research Group, School of Computing Science and Centre for Synthetic Biology and the Bioeconomy, Newcastle University, Newcastle upon Tyne, UK,"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,11,11]]},"reference":[{"key":"2023020111562119900_btv660-B1","author":"Acuff","year":"1988"},{"key":"2023020111562119900_btv660-B2","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1093\/nar\/28.1.304","article-title":"The ENZYME database in 2000","volume":"28","author":"Bairoch","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2023020111562119900_btv660-B3","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1049\/iet-syb:20080092","article-title":"Complexity and modularity of intracellular networks: a systematic approach for modelling and simulation","volume":"2","author":"Blinov","year":"2008","journal-title":"IET Systems Biol."},{"key":"2023020111562119900_btv660-B4","first-page":"3","article-title":"Modeling without borders: creating and annotating VCell Models using the web","volume-title":"Bioinformatics Research and Applications, volume 6053 of Lecture Notes in Computer Science","author":"Blinov","year":"2010"},{"key":"2023020111562119900_btv660-B5","author":"Buneman","year":"2015"},{"key":"2023020111562119900_btv660-B6","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1039\/c1mb05077j","article-title":"Guidelines for visualizing and annotating rule-based models","volume":"7","author":"Chylek","year":"2011","journal-title":"Mol. BioSystems"},{"key":"2023020111562119900_btv660-B7","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/wsbm.1245","article-title":"Rule-based modeling: a computational approach for studying biomolecular site dynamics in cell signaling systems","volume":"6","author":"Chylek","year":"2014","journal-title":"Wiley Interdisc. Rev. Syst. Biol. Med."},{"key":"2023020111562119900_btv660-B8","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1093\/bioinformatics\/btq063","article-title":"Standard virtual biological parts: a repository of modular modeling components for synthetic biology","volume":"26","author":"Cooling","year":"2010","journal-title":"Bioinformatics"},{"key":"2023020111562119900_btv660-B9","doi-asserted-by":"crossref","DOI":"10.1038\/msb.2011.77","article-title":"Controlled vocabularies and semantics in systems biology","volume":"7","author":"Courtot","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"2023020111562119900_btv660-B10","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/1752-0509-6-107","article-title":"Specification, annotation, visualization and simulation of a large rule-based model for ERBB receptor signaling","volume":"6","author":"Creamer","year":"2012","journal-title":"BMC Syst. Biol."},{"key":"2023020111562119900_btv660-B11","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1177\/0037549703040939","article-title":"An Overview of CellML 1.1, a Biological Model Description Language","volume":"79","author":"Cuellar","year":"2003","journal-title":"Simulation"},{"key":"2023020111562119900_btv660-B12","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.tcs.2004.03.065","article-title":"Formal molecular biology","volume":"325","author":"Danos","year":"2004","journal-title":"Theor. Comput. Sci."},{"key":"2023020111562119900_btv660-B13","first-page":"139","article-title":"Scalable simulation of cellular signaling networks","volume-title":"APLAS, volume 4807 of Lecture Notes in Computer Science","author":"Danos","year":"2007"},{"key":"2023020111562119900_btv660-B14","first-page":"116","article-title":"Rule-based modelling and model perturbation","volume-title":"Transactions on Computational Systems Biology XI, volume 5750 of Lecture Notes in Computer Science","author":"Danos","year":"2009"},{"key":"2023020111562119900_btv660-B15","doi-asserted-by":"crossref","first-page":"D344","DOI":"10.1093\/nar\/gkm791","article-title":"Chebi: a database and ontology for chemical entities of biological interest","volume":"36","author":"Degtyarenko","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"2023020111562119900_btv660-B16","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nbt.1666","article-title":"The BioPAX community standard for pathway data sharing","volume":"28","author":"Demir","year":"2010","journal-title":"Nat Biotech."},{"key":"2023020111562119900_btv660-B17","doi-asserted-by":"crossref","first-page":"R44","DOI":"10.1186\/gb-2005-6-5-r44","article-title":"The Sequence Ontology: a tool for the unification of genome annotations","volume":"6","author":"Eilbeck","year":"2005","journal-title":"Genome Biol."},{"key":"2023020111562119900_btv660-B18","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/3-540-45848-4_57","article-title":"Graphvizopen source graph drawing tools","volume-title":"Graph Drawing","author":"Ellson","year":"2002"},{"key":"2023020111562119900_btv660-B19","doi-asserted-by":"crossref","DOI":"10.1098\/rsif.2009.0035.focus","article-title":"Designing and encoding models for synthetic biology","author":"Endler","year":"2009","journal-title":"J. R. Soc. Interface"},{"key":"2023020111562119900_btv660-B20","first-page":"113","article-title":"Rule-based modeling of biochemical systems with BioNetGen","volume-title":"Systems Biology, volume 500 of Methods in Molecular Biology","author":"Faeder","year":"2009"},{"key":"2023020111562119900_btv660-B21","first-page":"81","article-title":"Integration of CellDesigner and SABIO-RK","volume":"7","author":"Funahashi","year":"2007","journal-title":"In Silico Biol."},{"key":"2023020111562119900_btv660-B22","author":"Galdzicki","year":"2012"},{"key":"2023020111562119900_btv660-B23","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nbt.2891","article-title":"SBOL: a community standard for communicating designs in synthetic biology","volume":"32","author":"Galdzicki","year":"2014","journal-title":"Nat. Biotechnol"},{"key":"2023020111562119900_btv660-B24","article-title":"BioNetGen 2.2: Advances in Rule-Based Modeling","author":"Harris","year":"2015","journal-title":"ArXiv e-prints."},{"key":"2023020111562119900_btv660-B25","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1098\/rsta.2001.0817","article-title":"A short introduction to CellML","volume":"359","author":"Hedley","year":"2001","journal-title":"Philos. Trans. R. Soc. Lond. Ser. A: Math. Phys. Eng. Sci."},{"key":"2023020111562119900_btv660-B26","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1093\/bioinformatics\/btg015","article-title":"The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models","volume":"19","author":"Hucka","year":"2003","journal-title":"Bioinformatics"},{"key":"2023020111562119900_btv660-B27","doi-asserted-by":"crossref","first-page":"D580","DOI":"10.1093\/nar\/gkr1097","article-title":"Identifiers.org and miriam registry: community resources to provide persistent identification","volume":"40","author":"Juty","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2023020111562119900_btv660-B28","first-page":"227","article-title":"Controlled annotations for systems biology","volume-title":"In Silico Systems Biology, volume 1021 of Methods in Molecular Biology","author":"Juty","year":"2013"},{"key":"2023020111562119900_btv660-B29","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkm882","article-title":"KEGG for linking genomes to life and the environment","volume":"36","author":"Kanehisa","year":"2008","journal-title":"Nucl. Acids Res."},{"key":"2023020111562119900_btv660-B30","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.entcs.2014.06.013","article-title":"Biochemical space: a framework for systemic annotation of biological models","volume":"306","author":"Klement","year":"2014","journal-title":"Electronic Notes in Theoretical Computer Science"},{"key":"2023020111562119900_btv660-B31","first-page":"173","article-title":"A rule-based model of base excision repair","volume-title":"Computational Methods in Systems Biology - 12th International Conference, CMSB 2014, Manchester, UK, November 17\u201319, 2014, Proceedings, volume 8859 of Lecture Notes in Computer Science","author":"K\u00f6hler","year":"2014"},{"key":"2023020111562119900_btv660-B32","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1093\/bioinformatics\/btp642","article-title":"Annotation and merging of SBML models with semanticSBML","volume":"26","author":"Krause","year":"2010","journal-title":"Bioinformatics"},{"key":"2023020111562119900_btv660-B33","article-title":"A simple scheme for annotating SBML with references to controlled vocabularies and database entries","author":"Le Nov\u00e8re","year":"2005"},{"key":"2023020111562119900_btv660-B57","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1038\/nbt1156","article-title":"Minimum information requested in the annotation of biochemical models (MIRIAM)","volume":"23","author":"Le Novere","year":"2005","journal-title":"Nat Biotech."},{"key":"2023020111562119900_btv660-B34","article-title":"BioModels.net Web Services, a free and integrated toolkit for computational modelling software","author":"Li","year":"2009","journal-title":"Brief Bioinf."},{"key":"2023020111562119900_btv660-B35","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/1752-0509-4-92","article-title":"BioModels Database: an enhanced, curated and annotated resource for published quantitative kinetic models","volume":"4","author":"Li","year":"2010","journal-title":"BMC Syst. Biol."},{"key":"2023020111562119900_btv660-B36","doi-asserted-by":"crossref","first-page":"3026","DOI":"10.1093\/bioinformatics\/btp523","article-title":"Saint: a lightweight integration environment for model annotation","volume":"25","author":"Lister","year":"2009","journal-title":"Bioinformatics"},{"key":"2023020111562119900_btv660-B37","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1186\/2041-1480-1-S1-S3","article-title":"Annotation of SBML models through rule-based semantic integration","volume":"1","author":"Lister","year":"2010","journal-title":"J. Biomed. Sem."},{"key":"2023020111562119900_btv660-B38","doi-asserted-by":"crossref","DOI":"10.1038\/msb.2013.1","article-title":"Programming biological models in Python using PySB","volume":"9","author":"Lopez","year":"2013","journal-title":"Mol. Syst. Biol."},{"key":"2023020111562119900_btv660-B39","doi-asserted-by":"crossref","DOI":"10.1093\/database\/bar009","article-title":"UniProt Knowledgebase: a hub of integrated protein data","author":"Magrane","year":"2011","journal-title":"Database"},{"key":"2023020111562119900_btv660-B40","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1093\/bioinformatics\/btr048","article-title":"Model annotation for synthetic biology: automating model to nucleotide sequence conversion","volume":"27","author":"Misirli","year":"2011","journal-title":"Bioinformatics"},{"key":"2023020111562119900_btv660-B41","first-page":"22:1","article-title":"Composable modular models for synthetic biology","volume":"11","author":"Misirli","year":"2014","journal-title":"ACM J. Emer. Technol. Comput. Syst."},{"key":"2023020111562119900_btv660-B42","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/nbt0808-864","article-title":"The PSI-MOD community standard for representation of protein modification data","volume":"26","author":"Montecchi-Palazzi","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"2023020111562119900_btv660-B43","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1049\/iet-syb:20080102","article-title":"Virtual cell modelling and simulation software environment","volume":"2","author":"Moraru","year":"2008","journal-title":"IET Syst. Biol."},{"key":"2023020111562119900_btv660-B44","doi-asserted-by":"crossref","DOI":"10.1002\/0471250953.bi0207s21","volume-title":"The InterPro Database and Tools for Protein Domain Analysis","author":"Mulder","year":"2008"},{"key":"2023020111562119900_btv660-B45","doi-asserted-by":"crossref","first-page":"D539","DOI":"10.1093\/nar\/gkq907","article-title":"The protein ontology: a structured representation of protein forms and complexes","volume":"39","author":"Natale","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2023020111562119900_btv660-B46","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1093\/bioinformatics\/btt567","article-title":"A C library for retrieving specific reactions from the BioModels database","volume":"30","author":"Neal","year":"2014","journal-title":"Bioinformatics"},{"key":"2023020111562119900_btv660-B47","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1021\/sb400066m","article-title":"A methodology to annotate systems biology markup language models with the synthetic biology open language","volume":"3","author":"Roehner","year":"2013","journal-title":"ACS Synth. Biol."},{"key":"2023020111562119900_btv660-B48","first-page":"91","article-title":"Hermit: a highly-efficient owl reasoner","volume":"432","author":"Shearer","year":"2008","journal-title":"OWLED"},{"key":"2023020111562119900_btv660-B49","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.websem.2007.03.004","article-title":"Pellet: A practical owl-dl reasoner","volume":"5","author":"Sirin","year":"2007","journal-title":"Web Seman. Sci. Serv. Agents World Wide Web"},{"key":"2023020111562119900_btv660-B50","doi-asserted-by":"crossref","first-page":"R46","DOI":"10.1186\/gb-2005-6-5-r46","article-title":"Relations in biomedical ontologies","volume":"6","author":"Smith","year":"2005","journal-title":"Genome Biol."},{"key":"2023020111562119900_btv660-B51","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1099\/mic.0.C0124-0","article-title":"JWS online cellular systems modelling and microbiology","volume":"149","author":"Snoep","year":"2003","journal-title":"Microbiology"},{"key":"2023020111562119900_btv660-B52","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1093\/bioinformatics\/btp392","article-title":"libAnnotationSBML: a library for exploiting SBML annotations","volume":"25","author":"Swainston","year":"2009","journal-title":"Bioinformatics"},{"key":"2023020111562119900_btv660-B53","doi-asserted-by":"crossref","DOI":"10.1145\/2506583.2512389","article-title":"The atomizer: extracting implicit molecular structure from reaction network models","author":"Tapia","year":"2013"},{"key":"2023020111562119900_btv660-B54","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1101\/gr.180801","article-title":"Creating the gene ontology resource: design and implementation","volume":"11","author":"The Gene Ontology Consortium","year":"2001","journal-title":"Genome Res."},{"key":"2023020111562119900_btv660-B55","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1093\/bioinformatics\/btr197","article-title":"RuleBender: a visual interface for rule-based modeling","volume":"27","author":"Xu","year":"2011","journal-title":"Bioinformatics"},{"key":"2023020111562119900_btv660-B56","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1093\/bioinformatics\/btq723","article-title":"The physiome model repository 2","volume":"27","author":"Yu","year":"2011","journal-title":"Bioinformatics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/6\/908\/49018422\/bioinformatics_32_6_908.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/6\/908\/49018422\/bioinformatics_32_6_908.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T22:19:57Z","timestamp":1675289997000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/32\/6\/908\/1743798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,11]]},"references-count":57,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016,3,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btv660","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2016,3,15]]},"published":{"date-parts":[[2015,11,11]]}}}