Orphanet

1. Resource facilitation to scientific research

a. Interoperability Resource: Briefly describe the function of the Interoperability Resource

Rare disease (RD) data is scattered in different countries, communities and contexts, in different silos, and often using different terminologies. Orphanet, the rare disease knowledge base, is an interoperability backbone for RD data, integrating genomics, phenomics (HPO) and functioning data around a standardised nomenclature of rare diseases in a structured, computable format. Orphanet provides a common language (the Orphanet nomenclature of RD) and resources (semantic alignments, ORDO – the Orphanet Rare Disease Ontology, and HOOM – the HPO-ORDO Ontological Module) that can render interoperable other data resources.

b. Scope statement: describe the scope , and the users of the resource. How is the Interoperability Resource positioned with respect to other similar Interoperability Resources ? Include the base URL and, if relevant, the introductory or “about” page URL.

Orphanet (established 1997) is a unique resource worldwide, gathering and improving knowledge on rare diseases (RD). Orphanet derives from its multi-lingual, manually curated, expert validated and quality controlled knowledge base an ontology of RD (Orphanet Rare Disease Ontology, ORDO), information on RD (www.orpha.net) and data (www.orphadata.org). Orphanet resources are used by medical professionals, researchers (public/private), political decision makers, patients and medical coders.

Orphanet maintains the Orphanet nomenclature, the only dedicated terminology for RD, aimed at improving the visibility of RD in health and research information systems, acting as an interoperability vector between healthcare and research. Each entity has a unique, stable ORPHA number, semantically aligned with: OMIM, ICD, SNOMED-CT, MedDRA, UMLS, MeSH, GARD. RD are annotated with curated epidemiological and natural history data, gene-disease qualified relationships, cross-references to databases (OMIM, UniProtKB, HGNC, ensembl, Reactome, IUPHAR, Genatlas), frequency of phenotypic features (using HPO), and International Classification of Functioning derived terms.

The two most-used catalogues of RD are Orphanet and OMIM. Entries in OMIM are genetically defined (including non-RD) whereas entries in Orphanet are clinically defined including all RD, genetic or not. Scientific annotations are not systematically captured by OMIM; they are in Orphanet. Only Orphanet provides an ontological representation of structured, machine-readable, re-usable RD data. The HPO-ORDO Ontological Module (HOOM) provides extra possibilities to co-analyse RD phenotype associations, or re-use integrated ontologies in genomic variant repositories/match-making tools. Orphanet supports FAIR Principles, providing its nomenclature as an ontology queriable via SPARQL Endpoint, Bioportal and EBI Ontology Lookup Service.

About Orphanet: http://www.orpha.net/consor/cgi-bin/Education_AboutOrphanet.php?lng=EN&…

c. Resource url

http://www.orphadata.org/cgi-bin/index.php/

d. Inter-organisational recognition: does the Interoperability Resource have community recognition? (e.g. demonstrated through a collaboration, geographical diversity in the source of the submissions, international diversity of delivery partners and/or funders)

Established in France at the initiative of INSERM and the Ministry of Health, the European Commission financially supports the project since 2000. Orphanet is a global Consortium of 41 countries in Europe and beyond (Argentina, Australia, Canada, Japan). The coordination is based at INSERM Unit 14. INSERM carries out the core scientific/technical activity, however a more distributed organisational model is being put into place in the scope of a sustainability plan. Nine Orphanet consortium teams translate the Orphanet nomenclature into their national languages (disseminated as official translations via Orphadata). A curation platform (https://curation.orphanet.org/) has been co-developed with the Garvan Institute (Australia) facilitating the curation of scientific annotations in a transparent manner by globally-sourced external experts. We use global data sources (literature, databases), and expert data reviewers are world-renowned.

Orphanet (ORPHA nomenclature and annotations) is an internationally recognised RD standard: the International Rare Disease Research Consortium (IRDiRC) awarded Orphanet and ORDO IRDiRC Recognized Resource (http://www.irdirc.org/activities/irdirc-recognized-resources/) status. These resources are also Human Variome Project Recommended Systems (http://www.humanvariomeproject.org/solutions/recommended-systems.html), and EC JRC Common Data Elements for RD registration (http://www.erare.eu/sites/default/files/SetCommonData-EU%20RD%20Platfor…). The European Commission Expert Group on Rare Diseases has promoted the inclusion of ORPHA codes in health information systems (“Recommendation on Ways to Improve Codification for RD in Health Information Systems (2014)” https://ec.europa.eu/health/sites/health/files/rare_diseases/docs/recom…). Orphanet is committed to improving the visibility of RD in other international terminologies, and has established partnerships with SNOMED International, NIH-NCATS (GARD), and WHO (ICD-11 revision).

2. Community

a. Community impact: If applicable, provide documented evidence of community impact (e.g., publication citations, API calls, projects using the resource, etc.)

The www.orpha.net website is accessed by users in 235 countries. Www.orphadata.org is accessed by users in 73 countries. Over the past year over 9 million unique users visited www.orpha.net, and over 21,000 unique users accessed www.orphadata.org, downloading over 200,000 datasets. ORDO was downloaded over 7,000 times last year. The accessibility of Orphanet resources is facilitated by Orphanet’s multilingual approach: the Orphanet nomenclature of RD is available in English, French, Spanish, Portuguese, Dutch, German, Italian, Polish and Czech.

Orphanet resources were cited in 121 peer-reviewed publications in 2017. The Orphanet nomenclature and associated interoperability resources are already recommended to the international RD and genetic research communities as International Rare Disease Research Consortium (IRDiRC) recognised resource and Human Variome Project recommended system.

The Orphanet nomenclature is now recognised by the European Commission and in an increasing number of European Member States as the standard nomenclature for medical coding of RD: a European Joint Action and Project Grant have been launched in the EU Health Programme to support the adoption of this coding system (ORPHAcodes) in European countries. Current use of ORPHAcodes in EU countries is described here: http://www.rd-action.eu/wp-content/uploads/2017/09/2017-09_RD-ACTION-im….

In 2016 in the scope of ELIXIR-EXCELERATE, a report was issued on Orphanet resources as interoperability backbone components for RD: https://drive.google.com/file/d/1dsfAAdxF4USmsKK9YQ4IpDW44OqNIZ--/view?….

Orphanet interoperability resources are keystones of the ongoing H2020 project Solve-RD that aims to solve unsolved RD cases by exploiting ORDO and HOOM to calculate similarities to phenotypic and genotypic descriptions of known RD.

b. Potential usage: Describe other systems that could use this candidate resource, but currently do not.

Orphanet is already globally-used, recommended as an interoperability resource by the International Rare Disease Research Consortium and Human Variome Project. The EC JRC’s Common Data Elements for RD registration (http://www.erare.eu/sites/default/files/SetCommonData-EU%20RD%20Platfor…) also promote ORPHAcodes. Orphanet’s interoperability resources (useful for professionals, industry, researchers and political decision makers) are potentially valuable for millions worldwide, considering the benefit to patients of improved visibility in healthcare systems.

Ten European countries (and Western Australia) use ORPHA codes in health information systems alongside existing terminologies: any country worldwide could implement ORPHAcodes to promote interoperability between the spheres of health and research data, to better understand the natural history of rare diseases, plan healthcare resources, and constitute patient cohorts for treatment development. Registries, biobanks and variant repositories could more widely use ORPHAcodes to ensure interoperability with other RD data sources, this will be implemented in Europe in the European Joint Co-fund Programme for RD research if funded.

c. Outreach & support: Provide resource support publication(s)/user documentation(s) describing the Interoperability Resource (e.g. scientific journal publications, community preprints, resource user’s documentations etc.), resource dissemination plan (e.g. workshops, conference presentations), and other equal-opportunity research support (if applicable).

Orphanet interoperability resources are presented in “Representation of rare diseases in health information systems: The Orphanet approach to serve a wide range of end users” (A. Rath et al, Hum Mutat 33:803–808, 2012), and in “Harmonising phenomics information for a better interoperability in the rare disease field” (S. Maiella et al, European Journal of Medical Genetics, Available online 7 February 2018).

Documentation for users is available via www.orphadata.org, as well as procedures describing the curation process (bottom of page https://www.orpha.net/consor/cgi-bin/Education.php?lng=EN), and video tutorials (https://www.youtube.com/channel/UCKMLSL9hlrxz6zKFod5IlnA).

Orphanet promotes its interoperability resources at booths at the European Society of Human Genetics, American Society of Human Genetics, IRDiRC Conferences, European Conference on Rare Diseases, International Conference on Rare Diseases, and at expert workshops, at BYOD sessions, at biobanks and registries summer schools, and at an ELIXIR SME Forum (/events/elixir-innovation-and-sme-forum-data-driven-innovation-rare-diseases-and-personalised).

The European Joint Action for RD, RD-ACTION, coordinated by INSERM US14, has organised a workshop and published toolkits for ERNs for data sharing (http://www.rd-action.eu/european-reference-networks-erns/rd-action-work…). Guidelines to implement ORPHAcodes are published (http://www.rd-action.eu/leaflet-and-documents/).

d. Dependency of other resources: How is this resource critical to the user(s)? Do other resources depend on the resource described here to provide downstream service? Please list, or provide a link to a diagram.

The use of Orphanet interoperability resources derives from it being the only nomenclature specific to RD: it is essential in helping to identify patients for clinical research, and to improve interoperability between healthcare and research. The Orphanet Nomenclature and Orphanet Rare Disease Ontology, derives added-value and generates knowledge from curated annotations with genes, phenotypes and functional consequences in the Orphanet database, as well as with other terminologies/databases: a diagram of interactions is available : https://docs.google.com/presentation/d/19_cFupASMvZ6JAzE35raH1U4ex7SYmP…

ORDO is already integrated with EBI’s Experimental Factor Ontology (EFO). HOOM: The HPO-ORDO Ontological Module has been developed in order to bridge the two ontologies. HOOM enriches ORDO with HPO annotations for diseases, including semantic relations such as diagnostic criteria, clinical signs frequencies for a disease, provenance and evidence for annotations. Orphanet helps improve HPO, providing suggestions on lacking terms needed to describe RD: 970 requests for new terms have been made.

A large number of resources have incorporated Orphanet nomenclature or ORDO: ClinVar, MedGen, NIH-NCATS Genetic and Rare Disease Information Center, OMIM, GenAtlas, Uniprot, HGNC, LOVD, Reactome, Ensembl, IUPHAR/BPS Guide to Pharmacology, RD-Connect. Integration of the Orphanet nomenclature into UMLS is planned.

European resources that structure the European RD landscape (the clinical patient management system (CPMS) for case data sharing amongst ERNs, and the JRC’s Common Data Elements for RD registration (http://www.erare.eu/sites/default/files/SetCommonData-EU%20RD%20Platfor… ) use/promote the Orphanet nomenclature. The Orphanet nomenclature is used for codification purposes in more than 10 European countries, as well as in Western Australia, with other countries planning implementation.

3. Quality of resource

a. Uptime: Average percentage uptime/month during the last 12 months, response time of the resource. In case of ontology/standards production, interval of update/release, adaptability of ontology design patterns to evolving data. Provide information where applicable: uptime of resource, software release cycle (please state week/month etc), update frequency.

The resources are available for query by disease or gene via www.orpha.net (daily update): the site has a 99.434% uptime. As Orphanet has a Plan for Continuous Activity during maintenance sessions: we never cut access for technical maintenance. Technical blackouts, power outages, network failures may occur, but we use two separate hosting centers to minimise risks.

Aggregated Orphadata datasets (nomenclature, cross-referenced terminologies, disease-gene relationships, disease-phenotype relations, classifications, linearisation) are updated at the start of every month on www.orphadata.org. A Github is available https://github.com/Orphanet/Orphadata.org to track changes.

ORDO is updated/released twice a year, and is available on Bioportal, EBI Ontologies Lookup Service and Orphadata.

b. Accessibility: what are resource retrieval mechanisms? Does the resource provide web-based user interface, application programmable interface (API), containers, and/or other channels? Please list resource access mechanism, provide URLs as applicable.

Orphanet interoperability resources can be retrieved using one of the following mechanisms:

• Individual query: web-based by disease or gene via the Orphanet website www.orpha.net
• Aggregated datasets: XML, JSON via www.orphadata.org
• API: Sparql queries exemple via via www.orphadata.org and Sparql Endpoint: www.orpha.net/sparql
• Ontologies: ORDO and HOOM via www.orphadata.org, files available and blazegraph docker container, preloaded with booth ORDO and HOOM. ORDO is also available and can be queried from Bioportal (http://bioportal.bioontology.org/ontologies/ORDO) and EBI OLS tool (https://www.ebi.ac.uk/ols/ontologies/ordo).

c. Maintenance quality: Is there a maintenance SOP or plan, reflecting sustainability and scalability? Does it align with guidelines for sustainable software development? Please include a resource commitment statement (description text or URL).

Orphanet data is manually curated, based on a twice-monthly scientific survey of the literature and reference databases based on published standard operating procedures (Bottom of page: https://www.orpha.net/consor/cgi-bin/Education.php?lng=EN).

Established in 1997, Orphanet is co-funded by the European Commission since 2000, with the coordinating/core team in France financed by the Ministries of Health and Research. This resource is intended to remain in operation in the long-term, with sustainability plans being currently discussed in both France and at the level of the European Commission (Steering Group on Promotion and Prevention).

As Orphanet is not technically software, but a data resource, the guidelines for sustainable software development do not apply to this application.

d. Support quality: Please list support mechanisms (e.g., point of contact, request ticketing, resource’s response time where a solution is identified, etc.), and methods to collect user feedback. If available, list tutorial documentations or tutorial materials and format, including linking on the ELIXIR’s Training Portal (TeSS) (or other training platforms) where applicable.

A number of channels are available to help users wishing to use Orphanet interoperability resources. A contact form (http://www.orphadata.org/cgi-bin/contact.php) and dedicated address data.orphanet@inserm.fr are available, with a 24 hour first response time during office days. A FAQ and user guide is also available on www.orphadata.org. Orphanet also publishes its Standard Operating Procedures and Curation Procedures (bottom of page: https://www.orpha.net/consor/cgi-bin/Education.php?lng=EN). In addition, there is an ORDO user mailing list (ordo-users.orphanet) to deliver updates concerning the ontology.

Orphanet conducts an annual users’ survey (https://www.orpha.net/orphacom/cahiers/docs/GB/Orphanet_survey2017.pdf) at the start of each year to gather feedback concerning the utility and ease of use of Orphanet resources. The results of this survey are analysed and feedback is forwarded to the Quality Manager and the Orphanet Strategy Committee (twice a year) for integration into future developments.

Orphanet is committed to continuous improvement, and introduced a Quality Management System in 2015. In the scope of the future ISO 9001 certification of Orphanet nomenclature, user feedback will be sought and acted on in a systematic manner.

Orphanet also organises regular rounds of training sessions on Orphanet resources for information scientists working in the Orphanet Consortium on the collection of information concerning expert services in their country. They then communication on these resources in their country. Orphanet is invited to present at BYOD RD-Connect/Excelerate sessions, has run workshops on its resources for European Reference Networks for RD, has presented resources at the 2017 ELIXIR SME Forum, and has launched a Orphanet Tutorials YouTube channel (https://www.youtube.com/channel/UCKMLSL9hlrxz6zKFod5IlnA).

4. Legal framework, funding, and governance

a. Legal framework: What are the resource’s license/terms of use? Can the license facilitate Open Science? Please include the url for the license the resource uses.

Orphanet’s nomenclature, cross-referencing with terminologies, classifications, phenotypic features annotaitons, diseases with associated genes/qualified relationships, Orphanet Rare Disease Ontology (ORDO), HPO-ORDO Ontological Module, are available via www.orphadata.org through Creative Commons Attibution-NoDerivs 3.0 (CC BY-ND 3.0) (http://www.orphadata.org/cgi-bin/inc/legal.inc.php).

CC BY-ND was chosen to distribute the nomenclature as it is used as a standard for medical codification. Translations adhere to procedures and are medically validated. Commercial integration of Orphanet interoperability resources is allowed to facilitate integration of this standard in health information systems and CPMS (Computerised Patient Management Systems); modifications are not permitted because of its use in medical codification for diagnosis.

b. Privacy/Ethics policy: If applicable, is there a publicly available privacy policy in which use and security around personal data are described (e.g. the EU General Data Protection Regulation (GDPR), ELIXIR Ethics Policy, other relevant ELIXIR Policies)? Please include the url of the privacy/ethics policy, if applicable.

The perimeter of the resource as described in this document does not include personal data. Orphanet is working to comply with the GDPR in the parts of the database that include the name and activity of professionals, out of the scope of this application.

c. Funding & sustainability plan: List of funding sources supporting the resource, and sustainability plan.

The Orphanet activities described in this application, namely the maintenance of the Orphanet nomenclature of RD and annotated scientific data, as well as the Orphanet Rare Disease Ontology and HPO-ORDO Ontological Module, are carried out by the Orphanet coordinating team at the INSERM. INSERM provides permanent public officials for these core activities. Orphanet’s core interoperability resources are currently principally funded by the INSERM (French Ministry of Health, French Ministry of Research) and European Commission Direct Grant (3rd EU Health Programme).

Further details concerning the financing of the resource described in this application, and other resources provided by Orphanet can be found on the Orphanet website (http://www.orpha.net/consor/cgi-bin/Education_AboutOrphanet.php?lng=EN&…) and in each annual Orphanet activity report (http://www.orpha.net/orphacom/cahiers/docs/GB/ActivityReport2016.pdf).

Given the strategic importance of the Orphanet nomenclature of RD and associated resources as the only standard terminology for RD, a solution for the sustainability of Orphanet is essential. Discussions are currently underway at both European Commission and INSERM level in order to implement a sustainability plan for Orphanet. Indeed, the European Commission in the 2018 Health Programme Work Plan recognised Orphanet as having a de facto monopoly in its field.

d. Governance: Describe the Resource’s QA/QC plan that guarantees similar quality governance to that of ELIXIR. Please link SAB members, if applicable.

Orphanet data is collected and curated according to published procedures (http://www.orpha.net/consor/cgi-bin/Education_Home.php?lng=EN), and undergoes pre- and post-publication quality control processes. Orphanet introduced a complete Quality Management System in 2015 and is working towards obtaining ISO 9001 certification of the Orphanet nomenclature of RD.

The governance of Orphanet includes the following Boards:

The Management Board (http://www.orpha.net/orphacom/cahiers/docs/GB/Orphanet_MB_members_2017…) , composed of country coordinators, is in charge of identifying funding opportunities, guiding the project to provide an optimum service for the end-users, and considering the inclusion of new teams as well as ensuring the continuity of the project.

The Orphanet International Advisory Board (http://www.orpha.net/orphacom/cahiers/docs/GB/Orphanet_IAB_members_2015…) , composed of international experts is in charge of peer-reviewing the Orphanet project, reports to the Orphanet Management Board (MB) and issues comments and recommendations on an annual basis which will enable the MB to define changes to be introduced to the project. The International Advisory Board rules of procedures are available : http://www.orpha.net/orphacom/cahiers/docs/GB/eproc_IAB_V02.pdf.

The Genetic Advisory Board (http://www.orpha.net/orphacom/cahiers/docs/GB/Orphanet_GAB_members_2017…), is in charge of advising Orphanet on topics related to the gene database and the database of genetic tests and laboratories. The rules of procedure are available: http://www.orpha.net/orphacom/cahiers/docs/GB/eproc_GAB_V01.pdf .