Governance and structure of U-IMD
With the aim of establishing the first European registry covering all known IMDs, the beneficiaries of U-IMD successfully applied for the call HP-PJ-06-2016 of the EU Executive Agency for Consumer, Health, Agriculture and Food (CHAFEA). The prerequisite for a successful application to this call was that the new established registry fully complies with the guidelines of the European Union Committee of Experts on Rare Diseases (EUCERD) and the European Commission Expert Group on Rare Diseases (CEG-RD), while at the same time fully implementing the ERDRI standard for rare disease registries.
The U-IMD beneficiaries are members of MetabERN as well as members of multiple IMD networks and are from experienced metabolic expert centres in four EU countries (Czech Republic, Germany, Italy and Spain), covering approximately 45% of the EU population. By including MetabERN and the established IMD networks E-IMD, E-HOD and iNTD as collaborating stakeholders the project further extended the geographical coverage. U-IMD furthermore invited non-MetabERN health care providers to become part of the project. Becoming part of U-IMD is possible for all health care providers by receiving a positive vote for the U-IMD study protocol by the responsible body and by the accepting the U-IMD consortium agreement. Patient involvement is secured through the patient advocacy groups organized within MetabERN.
U-IMD is coordinated by Heidelberg University Hospital and consists of the three bodies: (1) Members Board, (2) Steering Group, and (3) Work Packages, according to the CHAEFEA requirements.
1) The Members Board comprises all members of MetabERN that signed the U-IMD letter of agreement. This is a direct measure for assuring that U-IMD is fashioned according the requirements of MetabERN and for guaranteeing managerial continuity after the end of the funding period. The Members Board has an advisory function and is the principle decision making and arbitration body of the project, deciding by simple majority. By opening the Members Board to all MetabERN members, patient involvement is secured through the patient advocacy groups organized within MetabERN enjoying all obligations and privileges of a board member. The Members Board meets once a year in person, preferably during the annual Society for the Study of Inborn Errors of Metabolism (SSIEM) conference or annual MetabERN Members meeting receiving direct feedback on the proceedings of the project from the Work Package Leaders. Otherwise it is the obligation of the Steering Group to keep the Members Board informed. Members that use the registry for data entry are responsible for ensuring that their ethical authorization to collect data in the U-IMD registry is up to date and are responsible for applying the national guidelines and directives concerning patient consent. Beyond the major research aims of this project as specified in the grant agreement, any member may make an additional sufficiently elaborated request to the Members board to use the network’s data, which is the subject to voting rules as described above.
2) The Steering Group consists of the Work Package Leaders, one official representative from each of the three existing IMD networks (E-IMD, E-HOD, and iNTD), the MetabERN coordinator, and a member and/or representative of a patient advocacy group. The leader of Work Package 1 – Coordination is project leader and chair of the steering group. The Chair presides over the meetings of the Steering Group. The Steering Group coordinates and monitors the implementation of the project according to the milestones and deliverables laid out in the project plan. The Steering Group meets regularly and at each meeting Work Package Leaders are expected to provide a comprehensive progress report on new developments, opportunities and challenges encountered during their operational work creating transparency, accountability and early awareness of obstacles. If necessary the Steering Group takes prompt and adequate action to help in tackling challenges or to decide on the implementation of contingencies.
3) All specific tasks to be fulfilled to reach the project aims are thematically bundled in Work Packages (Coordination, Dissemination, Evaluation and Patient registry) forming the centres of the operational work within the project.
- Work Package 1 – Coordination (Centre for Child and Adolescent Medicine, Heidelberg University Hospital, Germany) is responsible for project management, including overall coordination of all scientific and non-scientific issues. It has to ensure that measures are implemented, milestones reached and deliverables achieved and is the central liaison for stakeholders seeking collaboration. Furthermore, it is responsible for the strategic planning of long-term sustainability.
- Work Packages 2 – Dissemination (General University Hospital Prague, Czech Republic) is responsible for the distribution of projects proceedings and results via various communication tools (including the website https://u-imd.org/) among all stakeholders, including other research networks, professional societies, clinicians and scientists, patient and parent organisations, policy makers, general public and industry.
- Work Package 3 – Evaluation (Bambino Gesù Children’s Hospital Rome, Italy) does a continuous evaluation of the project against indicators defined for the specific objectives within the given time frame and managing the process of preparing the evaluation report. The evaluation process is intended to promote learning from the project and ensure the achievement of intended impact. Indicators are reaching of defined milestones and deliverables, quality and quantity of data collected in the registries, completeness of geographical coverage, coverage of the MetabERN disease panel, acceptance of U-IMD within MetabERN and full implementation of the ERDRI standards.
- Work Package 4 – Patient registry (Centre for Child and Adolescent Medicine, Heidelberg University Hospital, Germany) will establish and maintain the Unified European registry for Inherited Metabolic Diseases (U-IMD), by building on other registry projects including E-IMD, E-HOD, and iNTD and fully implementing the ERDRI standards. It will make the existing iNTD registry interoperable with the new unified registry and develop a minimal core data set to be shared with the upgraded ERKNet registry.
U-IMD patient registry: set-up
The newly established Unified European Registry for Inherited Metabolic Diseases is the core of the U-IMD project. This registry is implemented as an observational, non-interventional natural history study, requiring members to obtain an ethics committee approval for the U-IMD study protocol and informed consent forms according to local standards. Patients are followed prospectively using a set of common data elements that are collected at baseline and standardized follow-up visits collecting longitudinal data. The data model of the registry includes a broad spectrum of basic information (e.g. disease name, date and mode of diagnosis, genotype, sex) as well as detailed information on the clinical presentation, laboratory test results, treatment modalities (including dietary management), follow-up investigations, results of standardized psychological and developmental tests (e.g. BSID-III, WPPSI-IV, WISC-V, WAIS-IV), patient and parent questionnaires on quality of life as well as on the level of disability for adult patients (Fig.1). The registry is web-based and accessible by password-protected user accounts via the internet using a secure encrypted connection.
The U-IMD registry follows the recommendations of ERDRI on rare disease patient registration. The key guiding principle of ERDRI is the usage of systematic and controlled vocabularies for coding diagnosis and describing phenotypic abnormalities as well as the usage of core data sets that are similar across multiple platforms. It hereby aims at increasing the interoperability of European rare disease registries and reducing the fragmentation of data sources (https://eu-rd-platform.jrc.ec.europa.eu/). The applied set of tools consists of four major elements:
Common Data Elements (CDE): A set of variables and guiding principles that should be adhered by each rare disease registry in the EU, allowing to describe patients identically at least on the level of this core data set.
European Patient Identity Service (EUPID): GDPR-compliant pseudonymization tool for patient registration, providing distinct pseudonyms for patients in different contexts while retaining a protected link between the different pseudonyms. The EUPID services acts as trusted third party supporting the creation of merged datasets.
European Directory of Registries (ERDRI.dor): “Registry of registries” for European rare disease registries, searchable by up to 27 characteristics, like name of registry, disease panel, operating institution, etc.
Central Metadata Repository (ERDRI.mdr): Collects the metadata of all data elements used by participating registries, like variable names, definition of variables, value domains, etc.
The U-IMD registry is designed in a modular fashion and integrates the ERDRI recommendations as follows (Fig.1):
Common Data Elements (CDE)
The registry contains a module of common data elements that is uniform across all diseases. The module contains all data elements recommended by ERDRI and additional variables specific to the context of IMDs. Cases are defined using the nosology of the IEMbase which is mapped to ORPHA codes and OMIM gene codes (see additional table 1). Disease-causing mutations are recorded according to the systematics of the ClinVar, Human Gene Mutation Database (HGMD) and the Single Nucleotide Polymorphism database (dbSNP). Biochemical markers at diagnosis are collected according to the disease specific sets developed by the IEMbase which are mapped to the coding system of the Human Metabolome Database (HMDB; http://www.hmdb.ca/).
Clinical phenotype and patient perspective
The clinical phenotype is recorded using the structured and controlled vocabulary of the Human Phenotype Ontology (http://human-phenotype-ontology.github.io/), ensuring interoperability with other registries using the same vocabulary for phenotyping and comparability of phenotypes across all diseases in the registry.
Patient perspective
The registry also contains a module for adequately capturing the patient perspective that is uniform across all diseases. PedsQL (http://www.pedsql.org/) and WHOQOL-BREF questionnaires (http://www.who.int/mental_health/publications/whoqol/en/) can be filled in by the patients directly and have been translated and validated in multiple languages. Disability is measured by the World Health Organization Disability Assessment Schedule (WHODAS 2.0).
Biochemical phenotype
The evolving biochemical phenotype is recorded according to the disease specific sets of biochemical markers developed by the IEMbase which are mapped to the coding system of the Human Metabolome Database (HMDB; http://www.hmdb.ca/). The Human Metabolome Database is a freely available electronic database containing detailed information about small molecule metabolites found in the human body.
Treatment
The registry comprises also a module for capturing drug treatment that is uniform across all diseases. For this purpose, the World Health Organization Anatomical Therapeutic Chemical Classification (WHO ATC) classification system (https://www.whocc.no/atc_ddd_index/) is used representing an established, controlled and standardized vocabulary. WHO ATC codes drugs with a five-tiered classification system, from the treated organ system down to the respective chemical substance. Off-label or orphan drug usage is recorded as recommended by EUCERD. Some patients with IMDs require special diet and the most common dietary treatments have been added to the data model.
U-IMD patient registry: current status of recruitment
The patient registry was successfully launched in February 2019, after being approved by the local ethics committee of the coordinating centre (i.e. University Hospital Heidelberg, application no. S-387/2018) on 5th July, 2018 and then approved by the ethics committees of clinical partners contributing to the registry. Fourteen MetabERN partners and one non-MetabERN partner from nine European countries [8 EU member states (MS)], have so far contributed to the registry (Fig. 2).
By October 2020, 1193 individuals with a confirmed IMD from 13 different European centers have been registered. The distribution of the 25 most frequently documented IMDs in the registry is shown in Fig. 3. A detailed overview of all in the U-IMD registry documented IMDs, the corresponding number of patients as well as the IEM codes can be found in the additional tables 1 and 2.
Upgrade of existing IMD registries
To improve semantic interoperability and ERDRI conformity of all patient records coming from the various IMD registries, it is our strategy to upgrade existing IMD registries to the standard of data collection developed for U-IMD. In the framework of the project, the iNTD registry serves as a pilot for this adaptation process and was enhanced by the inclusion of the ERDRI CDEs, IEMbase nosology for case definition and HPO terms of description of the phenotype. Until today 34 iNTD patients records from the University Children’s Hospital Heidelberg have been updated using new functions.
Collaboration with ERKNet
To facilitate the collaboration between MetabERN and ERKNet, the ERNs developed a shared minimal core data set. The ERKNet registry has been upgraded and U-IMD programmed using this core dataset, ensuring that metabolic nephropathies are described alike in both registries. As of June 2020, 14 patients have been registered in U-IMD using the shared core dataset.