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            "8": {
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                "title": "Unknown function",
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                        "*": "==Alleles with unknown biochemical function==\n''Unknown funtion'' means that the biochemical function of the allele is unknown or uncertain.\nThere are at least four kind of alleles that have unknown biochemical function\n* PGx alleles that are classified with ''Unknown function'' status by PharmGKB\n* PGx alleles that are listed by PharmGKB, but has no functional status\n* Unknown alleles with variants that cause changes to the protein, but which are not classified by PharmGKB\n* Unknown alleles with variants that do not cause changes to the protein, and which are not classified by PharmGKB\n\nThere is no explicit dosing recommendation for patients with an unknown biochemical function allele on at least one chromatid. This means that there is no special medication recommendation '''even if the sister-chromatid has ''No function'' or ''Increased function'''''.\n\nThis dosing recommendation is very conservative, and the question is whether the allele with ''Unknown function'' should rather be treated as a ''Normal function'' allele (thereby assigning modified dosing recommendations to e.g. ''Unknown function''/''No function''-patients).\n\n==Alleles with normal biochemical function==\nNormal function means that the biochemical function of the allele is sufficiently close to the average that a normal medication recommendation can be used.\nAlleles with normal biochemical function are\n* PGx alleles that are classified with ''Normal function'' status by PharmGKB\n* alleles with no variants (these \"wildtype\" alleles are usually explicitly classified as ''Normal function'' by PharmGKB, but not always)\nIn addition, at least in the world of SNP-arrays, the definition of ''Normal function'' alleles and ''Unknown function'' alleles are overlapping\n* Alleles that are '''not''' classified (by PharmGKB) have ''Normal function''\n\nIn other words: the definitions ''Normal function'' and ''Unknown function'' are overlapping.\n\nIf we replace the ''Unknown function'' classification with ''Normal function'', dosing recommendations for these patients have to be changed accordingly."
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            "21": {
                "pageid": 21,
                "ns": 0,
                "title": "WebProtege",
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                        "*": "This tutorial gives an introduction to using [https://www.pgx.no/webprotege WebProt\u00e9g\u00e9] for curating PGx recommendations.\n\nProt\u00e9g\u00e9 is developed by Stanford University. And general-puropose tutorials can be found at the [https://protegewiki.stanford.edu/wiki/Main_Page Stanford Prot\u00e9g\u00e9 Wiki].\n\n==User interface of Pharmacoracle's WebProt\u00e9g\u00e9==\n[[File:Webprotege main screen.png|thumb|Default ''Classes'' tab with views ''Class Hierarchy'', ''Class'', ''Comments'' and ''Project Feed'' is shown when opening a new OWL file or creating a new OWL ontology]]\n\nWhen opening an PGx guideline in WebProt\u00e9g\u00e9 for the first time, we are presented to the ''Classes'' tab, containing four so-called views (frames)\n* ''Class Hierarchy'' (a tree of all class entities of this ontology)\n* ''Class'' (for description and editing of each class entity)\n* ''Comments'' (for chatting with other curators)\n* ''Project Feed'' (to see changes to the project.)\n\n[[File:WebProtege choose view and arrow lowres.png|thumb|Add a view by clicking the three horizontal bars, and chose appropriate view that will appear as a box that can be placed as desired]]\n\nThe user interface of WebProt\u00e9g\u00e9 can be modified. We suggest to replace the view ''Project Feed'' with the view ''OWL Entity Description Editor''. In this way the editor/curator can inspect semantic properties of the class entities that are not shown in the default view. We suggest to remove the ''Project Feed'' in order to make the interface cleaner. The user can modify the interface as she or he pleases. Available views can be browsed by clicking on the three-bar symbol next to the ''Classes'' tab.\n\n==Using WebProt\u00e9g\u00e9 for curation of PGx recommendations==\nWe suppose that the user has modified the ''Classes'' tab as explained above. We will use the drug voriconazole as an example. We have downloaded the CPIC guideline from the PharmGKB API and converted the PharmGKB JSON-LD file to the OWL format that can be edited in WebProt\u00e9g\u00e9.\n\n===Curation of the functional status of star alleles===\n[[File:WebProtege user interface func status.png|thumb|Inspection of the gene function element ''Voriconazole CYP2C19: Decreased function'' in the ''Class Hierarchy'' shows which star alleles that have this functional status]]\n\nBy navigating in the ''Class Hierachy'' view, the curator can e.g. view the class element ''Voriconazole CYP2C19:Decreased function''. (The naming is based on the functional status that is provided by PharmGKB's API, and the drug and gene name is added because functional status is gene specific and possibly drug specific.)\nIn the definition of the ''Voriconazole CYP2C19:Decreased function'', pay attention to the ''OWL Entity Description Editor'' where we see that the ''Voriconazole CYP2C19:Decreased function'' is equivalent to a gene that has haplotype either CYP2C19*10, CYP2C19*16, CYP2C19*19, CYP2C19*25, CYP2C19*26 or CYP2C19*9.\n\n[[File:WebProtege user interface func status discussion.png|thumb|Comments can be added on a per-element basis to highlighted class elements in the Class Hierarchy, and the comment is by default sent by email to all curators.]]\n\nAlthough the Functional Status can be manually modified by the curator, we believe that it is better to edit the Functional Status programmatically, based on the current PharmGKB functional status. By starting a discussion in the ''Comment'' view, suggestions can be included in the next version of the ontology.\n\n===Curation of the ''Phenotype'' of patient diplotypes===\nCPIC has recommended to use the term Phenotype for the metabolization status, transportation function or presence of a particular trait. Currently, this Phenotype is not a independent entity in the PharmGKB API. This means that for a drug that is affected by two genes, the Phenotype is aggregated for the two genes. We suggest to make a phenotype per gene, and make a recommendation for the combination of phenotypes. If more genes are added later, then it may be easier to expand the guideline. Another reason for modelling phenotypes on a per gene basis is that we want to make a guideline that is not drug-dependent, but rather made for families of drugs for Psychopharmaca or Cancer, and involving very many different genes. \n\n[[File:WebProtege user interface phen.png|thumb|A model of the CPIC Phenotype by combination of pairs of Functional Statuses]]\n\nAs an example, we see that the phenotype ''Voriconazole CYP2C19:Intermediate Metabolizer'' is either a heterozygote Voriconazole CYP2C19:Increased function/No function or a Voriconazole CYP2C19:No function/Normal function. As for the functional status, we suggest that curators start a discussion if definitions of Phenotypes should be changed.\n\n===Curation of the ''Recommendation''===\nFinally, the WebProt\u00e9g\u00e9 can be used for writing the actual prose of the recommendations. For instance, if the curator wants to translate the CPIC recommendations into another language, in the ''Class'' view, she can enter a property ''Recommendations'', a recommendation text and tagging it with the appropriate language.\n[[File:WebProtege user interface guideline language.png|thumb|Translating a CPIC recommendation into another language can be achieved by adding a new property Recommendations with a recommendation text and a language (here ''no'')]]\n\n===Downloading the guideline in OWL format===\n[[File:WebProtege download owl ontology.png|thumb|A new revision of the OWL PGx guideline can be downloded from the ''History'' tab]]\n\nOne way to download a new revision of the guideline, is to go to the ''History'' tab, click on the revision number that you want to download, and download this as a .zip-file.  \n\n===Try the Pharmacoracle WebProt\u00e9g\u00e9 yourself===\nEither contact us to [https://www.pgx.no/webprotege register a new account at the WebProt\u00e9g\u00e9], and for access to test ontologies\n\nor try the Tutorial account:\n\nuser: Tutorial\n\npassword: Tutorial2018\n\nThe Tutorial account contains definitions of PGx alleles, PGx variants, functional status, phenotype and recommendations for the drug azathioprine.\n\n==Using Desktop Prot\u00e9g\u00e9 for curation of PGx recommendations==\nCollaborative curation of PGx recommendations can quite easily be performed in WebProt\u00e9g\u00e9, as explained above (of course, as with any tool, curators have to get used to it).\n\nHowever, for quality assurance of PGx guideline semantics, we still need to use the desktop version of Prot\u00e9g\u00e9<ref>Support for semantic reasoning may be introduced in WebProtege at a later stage</ref>.\n\n[[File:Protege compare guideline structure.png|thumb|By running the reasoner in the Desktop Prot\u00e9g\u00e9, we can ensure that the OUS guidelines and the CPIC guidelines are sematnically equivalent]]\n\nWhen changing the semantic structure of the guidelines, as explained for Phenotype in the section above, we need to be sure that our new guideline structure is equivalent to the structure we get from PharmGKB. \nConsistency can be checked automatically in the Desktop Protege by running a reasoner (e.g. keyboard shortcut Ctrl-r). We then see if our structurally different OUS guidelines give the same recommendations as the CPIC guidelines."
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