Description of work.
The ITHACA coordination team oversees WP1.
The general coordination of the project is ensured by the ITHACA Coordination Team (ITHACA WP1) under the supervision of the ITHACA Executive Committee (ExCom). General coordination covers the general monitoring of the project, interactions with other ERNs through meetings of the Coordinators' Group, the Project Managers’ Group, the Research WG and the "registry task force” established within the latter at the EC level.
Coordination will be done through monthly or bimonthly teleconferences in the 1st year, with the representatives of the WG involved in the development of the project and with the Groningen team.
• Implementation and maintenance of the management tools required for all partners and governance bodies to carry out their tasks within the project - a risk management plan, report template, tools for monitoring deliverables, milestones and project resource use.
• Project administration and logistics – notably the organisation and follow-up of all project meetings (agenda, minutes. etc.).
• Financial administration (monitoring of expenses against budget allocations, consolidation of financial summary sheets, etc.) and the consolidation and monitoring of the cost claims in line with contractual requirements, compliance with the work actually performed and certification of financial statements when required (in cooperation with the secondary beneficiaries’ financial supervisors for their part of the budget).
• Provision of assistance to individual project partners on specific administrative issues.
• Implementation, maintenance and dissemination of the project’s internal communication tools.
In close relationship with the IT WG, the coordination will support the regulatory issues related to national legislations of the Member States, and the constraints imposed by the GDPR, to allow interoperability between the components of the ILIAD network.
Sustainability
MOLGENIS, the tool chosen for the development of the registry, is open access and developed in an academic environment, which considerably reduces development and maintenance costs while increasing sustainability in an institutional/academic context. MOLGENIS has demonstrated continuous funding support via uptake in scientific projects, including EU projects such as GEN2PHEN, BioMedBridges, BioSHARE, RD-Connect, ADOPT, CORBEL and currently Solve-RD, EJP RD, EOSC-life, EUCAN-connect and CINECA. The ILIAD Coordinator has chosen to develop the registry with an academic partner with such a proven track record to increase the likelihood of the registry being maintained beyond the 3-year period of this grant, and reduce the risk of failure due to bankruptcy or price changes, which are significant risks when development and maintenance are entrusted to a private structure for a long-term project.
The project has foreseen sustainability for 4 years within the initial funding. If ERNs are maintained and renewed, further maintenance (which is obtained at a low cost thanks to mutualisation), will be budgeted and integrated into the ITHACA work plan.
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Description
This WP is led by the ITHACA coordination Team, with the help of the Patient Council.
Access to the registry will be made available to the clinical members of the ERN HCPs and collaborating ERNs through secured portals. The dissemination of information regarding the project will be ensured by the Coordination Team and supported by the communication manager of ITHACA through various means: information on the ITHACA website, announcements in the monthly newsletter upon request, systematic progress reports each trimester in the ITHACA Newsletter, emails or other targeted communications to the clinical coordinators and managers of the various HCPs, presentation of posters during the main scientific events (ESHG, ASHG). Research articles and other products making use of the registry as well as any websites mentioning the registry will acknowledge the ERN and EU co-funding.
The Patient Council will contribute to dissemination and drive use by specialists in their countries by informing the various ePAGs of the developments of this project and encouraging patients or their families to contribute to patient-fed registries. Presentations could also be made at meetings of EURORDIS and individual patient associations.
Wherever national patient databases exist (as for instance the French BAMARA registry) or are in development, the authorities responsible will be contacted to inform them about the registry and work to develop interoperability or automatic data uploads within the limits of national patient data protection laws. Limited access, for example to epidemiological data and statistics, could be made available to policy makers from the EU and Member States, since they are also stakeholders and target users.
• On the registry website, aggregated data about the content of the registry, the partner registries etc. will be publicly available. Technical innovations developed to respond to ITHACA-specific questions, such as the coding of diseases that are currently non-codable, will also be disseminated, as their wide use is the best guarantee of their perpetuation.
• The Coordintion Team, helped by the Registry WG and the IT WG will produce Key Performance Indicators (KPIs). They will be disseminated by the Coordination Team among the ERN ITHACA HCPs (volume and trend).
• The Coordination Team will organize conference calls and WebEx meetings to present the new registry tool, why we use it, and how it works.
• The Coordination WG, helped by the Registry WG and the IT WG, will produce training documents, user guides etc., which will be circulated among ERN ITHACA HCPs.

Dissemination of information will happen through different means:
• Interoperability between registries that will feed the central EU database (ERDRI).
• Manual input into the Central Registry that will feed the EU database (ERDRI).
• Active communication with all members of ERN ITHACA to promote the use of the registry.
• Communication via articles and KPIs disseminated among the ERN ITHACA members (volume and trend) thanks to the ITHACA Newsletter and data posted on a dedicated page within ern-ithaca.eu and on the ILIAD webpage.
• Diffusion of information to the teams and associations of patients.
• Information via research networks such as EJP-RD.
• Information via the ESHG (European Society of Human Genetics) and other scientific societies linked to ITHACA.
• Publications in scientific journals and through posters at genetics meetings (ESHG, ASHG…).
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Description of work
This WP is led by the Coordination team, with the help of the Registry team, the Research team and the IT team.
The effectiveness of the registry can be measured by several KPI decided by the Steering committee and the Coordination Team, which will reflect the accessibility and the completeness of the uploaded records, and the general use of the website.
In order to ensure that the project is implemented as planned and reaches its objectives, user tests (UATs) will be performed to check that deliveries are in line with expectations, in collaboration with the IT team. UATs will be performed in the test environment through close collaboration with the IT WG (and thus in close functional connection with WP4). Then test interface will be delivered into the production environment. It will be up to the Users to indicate to the project manager if they notice any dysfunction or missing information.
Statistics will be regularly extracted from the registry to follow up on the number of contributions of centres, and the number of patients registered in the tool.
Internal evaluation of the project
Quality of the action. The UATs will determine if the deliveries are in line with specifications and will highlight the impact those actions have on the target group, as to the sharing of information and the quality of the information shared.
Evaluation methodology. It will include analysis of the data (for example, comparisons of extracts in Excel), some random checks on the platform, specific live cases during data entry (with an ERN ITHACA partner). This part will be done in close collaboration with the IT WG.
The IT WG will also need to ensure the quality of data (use of data curator) and compare previous extract to new one so as to avoid uploading an empty file (following technical issues such as server erreurs or failure).
Many of these tasks are in fact covered internally during the IT development supervised by WP4. The role of WP3 will be to echo the evaluation to the network.
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Description of work.
This WP is led by Pr Morris Swertz, head of the Genomics Coordination Center, the bioinformatics and genome diagnostics data science and support centre of the University Medical Centre of Groningen (UMCG), with the help of the Coordination team.
WP4 is the core WP of the call. It is responsible for the IT development of the Central Registry and the executables of the satellite application, respecting EU regulation, GDPR and FAIRification principles.
The development of the Central Registry will include a minimum of 4 steps:
Based on recommendations of the Steering Committee of the Registry and ad hoc subregistry task forces:
• Development of the core database common to all participating ERNs (which includes the common EU dataset and some other fields – see section 5.6).
• Development of ERN specific extensions of the common core dataset.
IT requirements:
• Development of user interfaces for partners to import, enter, query, share and use data.
• Development of programme interfaces for centres to automatically import/export data.
In collaboration with the Coordination group of ITHACA, the IT team will prepare the conventions between the hosting service in Groningen and each individual HCP, in order to allow interoperability of the Central Registry with the satellite registries. Depending on the degree of cooperation/synergy between the ERNs whose registries will be hosted in Groningen, this WP will largely be shared with one or several other ERNs, for some or all of its/their patients.
In collaboration with the Coordination Team, the Registry WG and Research WG, the Groningen team will establish an interface to interact with patient databases, registries and biobanks that wish to join the ITHACA Central Registry. This will require regulatory expertise and audits. Hopefully, these tasks will be shared among ERNs to reduce workload and avoid duplicating processes.
The IT workgroup will use a modern ‘agile’ approach, using the scrum method to deliver early working prototypes of the above systems and then iteratively improve these systems, driven by the needs of the ITHACA community, according to the ‘release early, release often’ principle. A dedicated software developer and data manager will be assigned to be the standard liaisons to the project, and this staff will be part of larger teams of software developers (8 people) and data managemenet (4 people) to ensure that the best expertise and support is available. All software will be developed as open source using Github to version the software. Each software component will be reviewed by a second developer before it is added to the system. In addition, we will provide 80%+ automated test coverage on all software code and employ continuous automated quality control (i.e. ‘continuous integration’) to ensure that all these tests are checked at every change. After the first delivery of the system, most effort will be spent on data management support to facilitate data entry and produce user evaluation reports.
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Description of work
The first task is to set up the Steering Committee and to issue a consensus statement about data access and usage for ILIAD, in collaboration with all ITHACA WGs and the Patient Council. Final validation by the Ethics committee (see WP8) is necessary.
Besides this early task, which should be delivered within 6 months, the main task within this WP is monitoring the usage of the registry.
This monitoring includes:
● Collecting and following registry activity, producing KPIs to be disseminated (WP2) through the ERN community and other relevant external registries.
● Establishing and supervising a Registry steering committee in charge of analysing and validating requests to access the registry for non-aggregated data. Different levels of access to information stored in the Central Registry can be hypothesized in order to comply with patients’ preferences and applicable local legal rules. This steering committee will be built as a trans-ERN instance if other ERNs are involved in ILIAD.
● Establishing regular monitoring of project activities during web meetings in order to ensure constant periodic evaluation of the project development and to identify any problems or delays to the planned schedule.
● Establishing a checklist of scheduled objectives/tasks to be circulated among the participants before each web meetings asking them to confirm completion. During the meeting, checklists will be reviewed and discussed in order to find appropriate solutions.
● Establishing and supervising task force groups dedicated to specific subregistries that have specific datasets and external registries that share access with ILIAD.
● Establishing the coordination of relationships with external registries interoperating with ILIAD.
● Establishing a set of aggregated data to be organized in a graphical and/or table format, and that will be automatically updated every 6 months. This dataset will show the number of patients included in the registry according to the syndrome, the involved gene and the countries of origin. Moreover, syndrome-specific graphical cohort overview will show patient distributions according to different clinical signs.

KPIs will be collected on a semestrial basis and reported to the ExCom and the Board, and contribute to the deliverables of WP3.
The Coordination Team will establish its functioning rules, set up a procedure to deal with requests, and track publications that rely on data extracted from the registry or obtained through its querying facilities.
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Description of work.
As a proof of principle we want to link two different registries: one Disease specific registry made by professionnals, and a patient-driven registry. Because of earlier connections with ITHACA, we will begin with 2 registries: RETT (Task1) and GenIDA (Task2). Other registries may follow (task 4).
Task 1 : Link the Rett Database Network (assigned to AOUS)
The Rett Database Network was founded in 2008 by merging 4 different databases in Italy, France, UK and Spain, after a long process of harmonisation. It now contains more than 2000 patients and more than 300 clinical items, in addition to genetic items. A group of items that could be of major interest to families and researchers will be selected and chosen to be represented as both numeric data and graphics in ILIAD. These data and graphics will be live so that the addition of a single patient will result in the immediate modification of data and graphs.
Task 2 : Link GenIDA (assigned to Coordination Team in APHP)
GenIDA is a registry collecting all forms of ID, due to either single gene mutations or CNVs in the genome (see section 5.10.3.1)
Working with the GenIDA team, ITHACA’s objectives are:
• to strengthen GenIDA's recruitment capabilities at the EU level by enhancing the website, notably its ergonomics for registration of participating families, translating it into at least 5 more major EU languages (it is currently available only in English and French) and increasing the number of available translations of the questionnaire (currently available in 5 languages, adding Italian and Spanish are our first priorities),
• Streamlining access of professionals from ITHACA HCPs to the anonymised data in GenIDA, allowing interpretation in terms of findings pertinent for improved healthcare of concerned patients (comorbidities, major aspects concerning health and quality of life of patients concerned by a given genetic form of neurodevelopmental disorder). This will require IT upgrades of the GenIDA website and database (in collaboration with the Insecable IT Company (www.insecable.com)) to work towards interoperability of GenIDA with ILIAD. This will necessitate the approval of the Ethics Evaluation Committee of the INSERM, the CNIL and permission from individual EU families registered in GenIDA, with the use of the EUPID pseudonymisation tool, to ensure interoperablity between data concerning a given patient in the minimal dataset in ILIAD and the family-entered and often rich complementary information in GenIDA.
• Indexing the clinical data in GenIDA to the Human Phenotype Ontology, following the FAIR data principle.
Task 3: Set the process to avoid duplication (AOUS)
We are planning on setting up a registry in which both direct importation from ITHACA HCPs as well as data transfer from specific or non-specific preexisting registries will be possible. One of the main issues in such a complex scenario is how to avoid patient duplication. For this purpose a specific but unrecognisable identification code will be generated for each patient based on anagraphic characteristics. The system will register and block any attempt to insert the same patient a second time.
Task 4: Create a manual for connecting other databases in the future (AOUS)
Other registries e.g. WaihonaPedia, have manifested their interest in being connected with ILIAD. In order to ensure a virtuous cycle of growth, a detailed manual including procedures useful for linking ILIAD to any registry will be created. Through this instrument, the linking of an unlimited number of registries will be possible without any need for additional resources. The manual will also resolve the issue of FAIRification of the single registry structure (declared in ERDRI and compliant with RGPD) before the linking step.
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Description of work
In strict interaction with WP4, the core dataset of the ILIAD registry will be connected with the OPBG Research Biobank collection and storage interface through a dedicated FAIRification process. Roles for data sharing and data access will be strictly defined. The availability of biological specimens of single patients/specific cohorts will be made visible through ILIAD dissemination channels. After obtaining informed consent, the OPBG Research Biobank will offer the collection and storage of biological specimens for sub-cohorts of ILIAD patients. Access to the samples will be regulated in a coordinated way with the contributing clinician/researcher, following applicable laws and ethical principles, by a Steering Committee headed by ILIAD and OPBG Research Biobank representatives.
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Description of work.
The ILIAD registry will organize an Ethics Committee that will provide ethical advice and oversight on registry developments and will support and ensure that the registry policies and procedures meet the needs of the patients and families concerned.
The ePAG patient representative’s role is to ensure that the patient perspective is considered. The ILIAD registry will draw on the structured involvement of patients in ERN ITHACA through its Patient Council and their formal representation in the ERN ITHACA Research, Registry and ID WGs to inform the development of a consensus on the rules of data sharing and data protection under WP8 (Patients, Parents & Ethics).
One representative of the ERN ITHACA Patient Council will be part of the Registry Steering Committee (WP1) and two representatives of the Ethics Committee (WP8); they will allocate patient representation to each of the Project's WPs.
The ILIAD Registry Ethics Committee shall meet, at a minimum, twice every year. The Ethics Committee will comprise five external advisors, including its Chair.
The Patient Council will be involved in each step, to ensure that the patients’ wishes and rights are scrupulously respected during the implementation of the registry.
The Patient Council will interact with WP5.
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