Clinical recruitment and enrolment
The Recon4IMD clinical recruitment team shall acquire biosamples from diagnosed and exome sequenced patients, for the generation of additional metabolomic and proteomic data to train personalised computational models to diagnose a broad range of IMDs. In parallel, clinical experts shall enrol patients from established cohorts to initiate personalised disease management. Proactive patient engagement will encourage recruitment and enrolment by MetabERN healthcare providers via established registries.
IMD patient recruitment and enrolment
There are ~1,450 IMDs, with patients distributed across Europe, varying national healthcare policies and legal constraints as well as varying institutional ethical assessment procedures and electronic health record formats. Therefore, it is a communication, administrative, logistical, and information technology challenge to recruit, enrol, and obtain biofluid samples of sufficient IMD patients, for a metabolically diverse collection of IMDs, which are required to train the classification algorithms so that they can diagnose a broad collection of IMDs. This challenge remains even when one assumes relatively large effect sizes typical of most IMD metabolite biomarkers. However, the Recon4IMD consortium is optimally structured to address these recruitment and enrolment challenges with an ambitious yet tractable campaign. First, we introduce several key consortium components, then we explain how they come together.
UNIAMO
UNIAMO is an umbrella patient organisation, representing more than 170 federated associations, accounting for over two million people with rare diseases in Italy. UNIAMO is the designated national alliance and member of the board of directors of EURORDIS-Rare Diseases Europe, a unique, non-profit alliance of over 1,000 rare disease patient organisations from 74 countries that work together to improve the lives of over 300 million people living with a rare disease globally.
MetabERN
The European Reference Network for Rare Inherited Metabolic Diseases (MetabERN) was launched by the European Commission in 2017, after the Directive 2011/24/EU and is coordinated by Recon4IMD partner Prof. Maurizio Scarpa, Director, Coordinating Center for Rare Diseases, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy. MetabERN aims to facilitate access to the best available diagnosis and care, improve quality of life, provide equal access to therapies, and address the needs across borders for all patients and their families affected by IMDs. MetabERN is Europe’s largest organised network of healthcare providers (HCPs) specialised in treating IMD patients, has the most complete database of patients affected by IMDs, and works closely with many international patient organisations, including UNIAMO and EURORDIS. Specifically: 101 HCPs, ~3,000 multidisciplinary professionals, ~80,000 patients, and 44 patient organisations.
U-IMD & GENOMIT
The Unified European Registry for Inherited Metabolic Diseases (U-IMD), led by Recon4IMD partner Prof. Stefan Kölker, is a large registry of IMD patients (n >= 2,641). U-IMD was established under the auspices of MetabERN and is actively used by 21 MetabERN members. The GENOMIT Registry for Inherited Mitochondrial Diseases (GENOMIT) led by Prof. Holger Prokisch, is a registry focused on mitochondrial IMD patients (n >= 3,000). GENOMIT was established as a collaboration of national networks for mitochondrial disorders from Germany, Austria, Italy, UK, USA, Japan and Paris and is actively used by 40 clinical centres specialising in mitochondrial disease. Together, U-IMD and GENOMIT represent the most comprehensive IMD registry as they have a high level of semantic interoperability, and both can record in either a cross-sectional or longitudinal manner.
Solve-RD
Solving the unsolved Rare Diseases (Solve-RD, 2018-2023) is a Horizon 2020-funded EU flagship project, coordinated by Recon4IMD partners Prof. Olaf Riess and Prof. Holm Graessner, which aims to diagnose rare diseases in patients with an inconclusive diagnosis. Solve-RD involves >300 clinicians, scientists, and patient representatives from 51 sites in 15 countries, based on a core group of four European Reference Networks (ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS). Up to now, Solve-RD has collected or newly generated 22,374 exome, whole genome, epigenome, transcriptome datasets, or combinations thereof, from a cohort of 21,492 individuals (13,010 RD patients and 8,482 unaffected family members). Solve-RD has established administrative, logistical, and data stewardship infrastructure to enable patient recruitment, data submission, data sharing, and archiving of clinical and multi-omics data from large numbers of clinical sites. In Solve-RD, genomic data analysis is in conjunction with the diagnostic service of the University Hospital Tübingen, led by Recon4IMD partner Prof. Tobias Haack, which is one of the leading laboratories in the field of clinical whole genome sequencing in Europe, with >2,500 analyses per year.
Recruitment and enrolment strategy
We will leverage the capacity of MetabERN to coordinate healthcare providers, the experience of Solve-RD in multi-institutional clinical data stewardship, the data management infrastructure of U-IMD and GENOMIT, and the experience of UNIAMO, in collaboration with EURORDIS, of representing and communicating with patients across Europe.
MetabERN maintains a database with the number of each type of IMD patient that each of the 101 HCPs sees for follow-up clinical visits. Using this database, we are able to identify IMD patients which are accessible to MetabERN HCPs. The Recon4IMD clinical recruitment team has been established from a subset of MetabERN HCPs. In parallel, UNIAMO, in collaboration with EURORDIS, will reach out to patients among the affiliated associations and inform them of the opportunity to be recruited. Patients will be enrolled into Recon4IMD by the HCPs in charge of their follow-up, with clinical data entered into the aforementioned, and biofluid samples (blood, urine) shipped to the Leiden University for metabolomic analysis and fibroblast samples shipped to Helmholtz Zentrum Munich for proteomic analysis.
Established registry patients and patients newly enrolled will serve as positive controls. If necessary, this sample can be enhanced by the inclusion of disease-specific phenotypic patterns and biochemical markers used as disease-specific sets in the IEMbase (www.iembase.org), the most comprehensive knowledge base for IMDs, and included as modifiable pre-sets within U-IMD. Solve-RD patients with a diagnosis that is not an IMD (80%) and without secondary metabolic dysfunction, will act as negative controls. Solve-RD patients with symptoms suggestive of an IMD and with exomic variants of unknown significance in metabolic genes, together with new undiagnosed patients recruited by MetabERN clinicians will be considered at risk of an IMD. Clinical data stewardship will follow the approach already successfully implemented in Solve-RD. Ethical issues regarding the involvement of patients will be assessed by a multi-stakeholder working group. All data processing steps will be set up in accordance with applicable regulations.
To train and test algorithms to accelerate diagnosis we will enrol a cross-section of patients for a diverse range of IMDs, where the focus is the acquisition of data to personalise models. Developing computational classification tools for a broad range of IMDs ensures that the resulting software is applicable to IMDs in general. In parallel, we will enrol an established longitudinal cohort of GD patients, where our focus is on the demonstration of personalised disease modelling for an exemplary IMD.