WebProtege

This tutorial gives an introduction to using WebProtégé for curating PGx recommendations.

A general tutorial for Protégé (desktop and web-version) can be found at the Protégé Wiki.

The best Protégé tool for looking at OWL semantics is the desktop version of Protégé, which is a visual front-end to the OWLAPI.

However, for collaborative curation of OWLs it is better to use the WebProtégé. We host our own copy of WebProtégé.

User interface of Pharmacoracle's WebProtégé

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

When opening an OUS adapted PharmGKB OWL file in WebProtégé for the first time, we are presented to the Classes tab, containing four views

• Class Hierarchy (a tree of all class entities of this ontology)
• Class (for description and editing of each class entity)
• Comments (for chatting with other curators)
• Project Feed (to see changes to the project.)

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

The user interface of WebProtégé 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.

Using WebProtégé for curation of PGx recommendations

We suppose that the user has modified the Classes tab as explained above. We will use the drug voriconazole as an example.

Curation of the functional status of star alleles

Inspection of the gene function element Voriconazole CYP2C19: Decreased function in the Class Hierarchy shows which star alleles that have this functional status

By 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.) In 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.

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.

Although 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.

Curation of the Phenotype of patient diplotypes

CPIC 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.

A model of the CPIC Phenotype by combination of pairs of Functional Statuses

As 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.

Curation of the Recommendation

Finally, the WebProtégé 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 language:

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)

Using Desktop Protégé for curation of PGx recommendations

Collaborative curation of PGx recommendations can quite easily be performed in WebProtégé, as explained above (of course, as with any tool, curators have to get used to it).

By running the reasoner in the Desktop Protégé, we can ensure that the OUS guidelines and the CPIC guidelines are sematnically equivalent

When 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. Consistency 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.