1. Raredis.eu Nordic database for rare diseases www.raredis.eu Dr. Ketil Heimdal, Medical genetics, Oslo Norway, Dr. Hanne Hove, Centre for Rare Diseases, Copenhagen, Denmark (curator of RAREDIS) Acknowledging: The Nordic working group

2. RAREDIS Raredis is a Nordic database for rare diseases supported by the Nordic Council of Ministers & The Norwegian Directorate of Health Today represented by Oslo Other participating centres: Aarhus, Helsinki, Uppsala, Gothenburg, and Reyjavik

3. Nordic database? 1: What are suitable aims for a Norwegian, a Nordic and a European RD database? 2: What should be the flow of data between these databases? Population 24 million – suitable for registries for rare diseases Large European countries often divided into regions of ~5 million The Nordic countries have a similiar social structure and health service

4. Raredis financing (1 euro=8 NOK) 2007/2008: DKK 500.000 2009: DKK 300.000 2011: NOK 500.000 2012+: Research project financing

5. The Nordic countries: a paradise for national medical registers For three reasons: 1)The structure of the health systems – National health insurance covers all citizens 2)The existence of nationwide registers 3)Systematic use of national registration numbers

6. National Reg number Birth Conscription Death certificates Primary Health service Hospital Discharge Abortion Malformations Drugs Psychiatric discharges Socio economic National registration numbers unique to each citizen widespread use in society

7. National health registries (Norway) 15 central health registries maintained by the central health authorities Cancer registry, Birth registry, Registry of cause of death... Ongoing project to coordinate registries (legal and political discussions) Mandatory reporting by health service No Rare Disease (RD) central registry

8. National health registries (Norway) 200 Medical quality registries 45 registries national coverage National central service of competency for all rare diseases established 2014 – planning project on coordinating existing rare disease registries and establishing registry for all rare diseases Established RD registries include NAPOS – national registry for porphyrias, planned and financed to establish European registry for porphyrias Aims: Describe diagnosis, natural course and existing treatment in Europe Investigate effect of treatments National neuromuscular disease registry Nordic collaboration RAREDIS 7 other Nordic registries (none i RD-area)

9. Raredis - the stepwise approach 2003: Local access database implementation – Copenhagen, Denmark– craniofacial diseases -> all rare diseases 2005-: Norway (Oslo University Hospital) joined the database 2007: Web based standard registration of patients (without patient identification) – SiteLab (commercial partner, technical solution) 2009: Research project protocol (for scaphocephaly) contained in standard registration system 2013: Implementation of login-procedures that overcome the legal differences in Nordic countries

10. Currently we have a database (the Nordic database) within a database (the Danish database for rare diseases with many more patients and diagnoses) Denmark Nordic

11. Raredis Principles We study selected rare diseases -Describe epidemiology, diagnosis, natural course and existing treatment, Investigate effect of treatments -Act as a resource to identify RD patients suitable for projects Diseases that are so rare one nationwide register is not sufficient and too common to necessitate a (pan-)European project Diseases that will benefit from long-time follow-up Future: Genetic disease for which treatments will become available One database for all rare diseases Core data = ID, age, sex, ICD10 Petals Specific to the diagnosis Specific to a project

12. CORE data

13. PETALS Diagnosis specific data

14. PETALS Project specific data

15. General principles for Raredis We have created the framework for a Nordic registry (legal, technical) Every institution own their data and may publish separately Raredis does not own the database The Nordic countries (governments) do not own the database Collaborators can apply to a board (representatives of all contributing countries for the use of Raredis data (on a project basis)

16. Raredis Principles (cont) Establish stable, fully functional networks of collaborating researchers This is essential to secure the full support for the Raredis effort from all the relevant scientific groups in the Nordic countries Raredis language = English Avoiding problems of translation

17. Raredis Principles (cont) Study selected rare diseases Define projects Intervention projects – prospective, long term Scaphocephaly (premature fusion of sagittal suture in the skull ) project 130 patients / 18 months Prospective evaluation of treatment effects – different centres use different operation techniques Complex craniosynostoses ~200 patients in Denmark and Norway (centralized treatment) - Several genetic subgroups Study natural course and effect of surgery (retrospective) Evaluation of new treatment (operation techniques)

18. General principles (cont) Data collection is in the health service Web based manual entry Automatic data transfer from local hospital database to Nordic database (Oslo only) Data flow should be (from the health service to) the local database to the central database

19. The successful implementation is challenging – lessons learned Things take time - Probably at least a 5 year perspective is needed General registration need dedicated resources at each center (secretarial support) Research initiatives must be managed by dedicated staff (phd-students or similar) The initiatives must be based on existing initiatives and existing databases instead of starting new One real challenge is defining good projects

20. Future developments Adding more diagnoses – project based Legal and political aspects: Nordic council 2010: Expert committee to report on how Nordic collaboration on highly specialized treatment may lead to improved quality in each country And how this may benefit the rare diseases 2012: Report prioritized 5 items including nordic registries for highly specialized treatment

21. Future developments(cont) Subcommittee report on registries – databases Lists existing Nordic registries (n=8) Recommending two Nordic databases as pilots Injuries to the spinal cord Prothesis for ankle and wrist Model (to be determined): Either expansion of existing local-national registries or the Nordic datase for rare diseases Both models build on existing research environments and infrastructure – databases are regarded as an essential part of a scientific collaboration within the health service (bottom up)

22. My thoughts on future developments - Raredis ”Data flow should be from local database to the central database” ? What about data flow from the Nordic database to European databases for rare diseases (diagnosis and/or project specific databases) Preparing for back transfer of data from the database to the patient Aim: Identify patients suitable for theraputic trials Therapies may become independent of diagnosis, may become mutation class specific (e.g. Therapy for nonsense mutations) In Raredis – contact via the submitting centre

23. My thoughts on future developments - Raredis ”Data flow should be from local database to the central database” Petal: Standardized Phenotype data ICD10, Orpha#, MIM, other? Human phenotype ontology? Petal: Standardized Genotype data HGDV format or similar

24. Status 2104: Databases of standardized Genotype data do exist for significant groups of RD patients Data originally collected for health service reasons (diagnostic activity) Genomic variation databases expanding into gene single gene variation detection by next generation sequencing Decipher, Ecaruca, ISCA Large projects aiming at collecting both genotype and phenotype UK: the DDD-project DDD=deciphering developmental disorders Computer tools for automatic funneling of data from local to central databases is in development Microarray – Cartagenia used by 120 labs – module to share data and export to central databases

25. How do we connect existing data sources (genotype-phenotype)? Building on existing scientific environments and infrastructure National databases starting with (clinical) phenotype – now expanding with genotype data Databases with results of (diagnostic) next generation sequencing ?

26. www.raredis.eu kheimdal@ous-hf.no