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The 1+ Million Genomes (1+MG) initiative aims to enable secure access to genomics and the corresponding clinical data across Europe for better research, personalised healthcare and health policy making. The Beyond 1 Million Genomes (B1MG) project was funded under the Horizon 2020 Framework Programme (duration: June 2020-May 2023) with the objective to establish the support and coordination structure for the 1+MG initiative. More recently (November 2022), the Genomic Data Infrastructure (GDI) project was funded to build upon the work carried out in 1+MG and B1MG and provide the data infrastructure that will enable secure access to genomics and corresponding clinical data across Europe. A major challenge for 1+MG, B1MG and GDI is addressing adequately the Ethical, Legal, and Social Implications (ELSI) of genomic and health research and translating them into technical specifications and implementation guidelines that capture European best practice. Stakeholders, defined as individuals, groups or organisations who may affect, be affected by or perceive themselves to be affected by a decision, activity, or outcome of a project can play a crucial role in the success of a scientific project for reasons such as helping to solve arising problems, achieving goals, increasing the availability of resources and improving the quality of products, services or outcomes. The B1MG project since its kick-off involved different groups of key stakeholders (patient organisations, HTA bodies, academics, national policy and decision makers, Research Infrastructures, clinicians and medical specialists, medicines authorities, industry, funders, EU Joint Actions) through annual B1MG Stakeholder Forum meetings, the creation of an interactive B1MG stakeholder portal, expert stakeholder consultation through regular meetings and workshops etc. The present report describes the identification and prioritisation of stakeholders from the B1MG WP2 “ELSI” perspective and summarises the different meetings and consultations that took place for the period June 2020-December 2022. The mapping exercise of WP2 resulted in an internal project inventory of more than 100 ELSI stakeholders, several of which were invited to engage with the project through the WP2 sessions in the annual B1MG Stakeholder Forum meetings, thematic workshops or their inclusion to the monthly B1MG WP2/ 1+MG WG2 meetings. In addition, several members of the B1MG WP2/1+MG WG2 have participated in meetings of other European projects and initiatives as stakeholders, advisory board members or invited speakers, ensuring knowledge transfer and alignment.

Supplemental material, sj-docx-1-jre-10.1177_15562646231181439 for Health Research with Data in a Time of Privacy: Which Information do Patients Want? by Miriam Beusink, Folkert Koetsveld, Sonja van Scheijen, Tomas Janssen, Maarten Buiter, Marjanka K Schmidt and Susanne Rebers in Journal of Empirical Research on Human Research Ethics

Supplemental material, sj-docx-4-jre-10.1177_15562646231181439 for Health Research with Data in a Time of Privacy: Which Information do Patients Want? by Miriam Beusink, Folkert Koetsveld, Sonja van Scheijen, Tomas Janssen, Maarten Buiter, Marjanka K Schmidt and Susanne Rebers in Journal of Empirical Research on Human Research Ethics

Supplemental material, sj-docx-3-jre-10.1177_15562646231181439 for Health Research with Data in a Time of Privacy: Which Information do Patients Want? by Miriam Beusink, Folkert Koetsveld, Sonja van Scheijen, Tomas Janssen, Maarten Buiter, Marjanka K Schmidt and Susanne Rebers in Journal of Empirical Research on Human Research Ethics

Supplemental material, sj-docx-2-jre-10.1177_15562646231181439 for Health Research with Data in a Time of Privacy: Which Information do Patients Want? by Miriam Beusink, Folkert Koetsveld, Sonja van Scheijen, Tomas Janssen, Maarten Buiter, Marjanka K Schmidt and Susanne Rebers in Journal of Empirical Research on Human Research Ethics

Analysis of whole genome sequence data can reveal information of clinical relevance to data subjects and their family members (incidental findings (IFs), broadly defined here to include any individual finding of clinical relevance, whether related or unrelated to the aims of secondary use (e.g. research project or healthcare diagnosis)). Clinicians and researchers have legal and ethical obligations to appropriately handle IFs in a manner that shows due concern for the welfare of data subjects and their family members. The likelihood of IFs in healthcare and research contexts, as well as the benefits, risks, and costs of reporting them, are not fully understood. European healthcare and research organisations tend to handle IFs cautiously. 1+MG aims to facilitate the secondary use of pseudonymised genomic and related-health data for the purposes of research, health-care and policy-making. The scope of this policy therefore focuses on genomic IFs revealed in secondary use contexts. The uncertainties surrounding IFs are greater still in secondary use contexts compared to (both clinical and research) primary contexts. Secondary use contexts may be very distant from a patient care context. It is not clear if distant 1+MG data users, especially researchers, have legal and ethical duties of care towards data subjects. Practically speaking, it is also difficult for 1+MG data users to assess if a potential IF is (still) clinically actionable. Secondary use may occur many years after sequencing. The health and familial situation of a 1+MG data subject are not fully known to the data user, and become more uncertain with the passage of time. 1+MG minimum data standards ensure sufficient data quality to enable secondary use, but the data may not be suitable for informing diagnosis of the original data subjects or their family members. A key practical difficulty in cross-border, secondary use contexts is that the data user does not know what IF policy applied in the initial healthcare or research context. Efforts to communicate an IF from secondary use may be undermined if the IF has already been returned to the data subject or family members. Another practical difficulty in cross-border secondary use contexts is that reporting IFs requires dedicated coordination and collaboration between data users, 1+MG coordinating bodies, data submitters, and (designated) healthcare professionals. Because of this context, reporting of IFs should be handled cautiously.

1. Scope Recommendations for the responsible inclusion of special groups of data subjects in 1+MG such as minors, persons not able to consent, minorities, vulnerable persons and groups, and deceased persons. The recommendations are directed towards researchers, research ethics committees (RECs), and 1+MG data centres and oversight bodies. 2. Objectives − To identify existing approaches and best practices for inclusion of special groups. − To develop 1+MG minimal requirements for inclusion of special subjects. 3. Background The term ‘special subjects’ in the context of 1+MG project applies to a diverse set of potential research subjects: minors, persons with diminished capacity to consent, persons not able to consent, other vulnerable groups, deceased persons etc. These special subjects in at least some respects are incapable of deliberating or acting based on their own plans or are controlled by others. To respect a person representing special group means to protect him/her to ensure that the person is not subjected to abuse, exploitation, or discrimination. Usually, definitions of vulnerability combine two aspects: (1) lack of ability, capacity, means and/or willingness to protect one's own interests, and (2) exposure to the possibility of being harmed, especially through exploitation. As outlined in the Declaration of Helsinki, vulnerable groups and individuals “may have an increased likelihood of being wronged or of incurring additional harm” (WMA, 2013). In case of involving vulnerable persons and groups in research “specific protections should be provided for vulnerable subjects and vulnerable populations, based on the general principle of acting in their best interest” (ESHG, 2003). There is ongoing discussion in the field of research ethics regarding the usefulness of the concept of vulnerable groups. CIOMS Guidelines advise to “avoid considering members of entire classes of individuals as vulnerable” (CIOMS, 2016) and instead suggest looking at specific characteristics and situations that may render persons vulnerable, as this can “aid in identifying the special protections needed” (CIOMS, 2016). CIOMS Guidelines also remind that different characteristics and situations generating vulnerability may co-exist, making some individuals more vulnerable than others. Evaluating vulnerability of research subjects or groups before involving them in research is a duty of researchers and respective research ethics committees (RECs). For initial identification of vulnerability, a useful tool is Kipnis's taxonomy of vulnerability in research

B1MG Project Milestone - M2.2Draft policies and best practice guidelines

This background document supports the 1+MG Incidental Findings Policy - Summary and Recommendations. The task described in the grant proposal was to develop recommendations for minimal standards for 1+MG on how to deal with incidental findings (IFs). The recommendations are based on a review of current best practices and guidelines, summarised here.

This policy recommendation covers general feedback of the results of research studies conducted with data provided through 1+MG to data subjects. The 1+MG policy covers: ● what information should and should not (necessarily) be shared with data subjects (and potentially other people interested in 1+MG); ● how this information should be shared (e.g. through which medium and in which language(s)). The 1+MG policy only applies to analyses conducted in the context of 1+MG data sharing. Data uses addressed in the primary data collection context should be covered by local policies. In an analysis of current guidelines and best practices, we identified three important principles to provide feedback of general research results to data subjects: transparency, accountability, and the fair distribution of benefits. Providing feedback towards data subjects about general research results contributes to transparency, and as a result, accountability, about conducted studies with health data. Factors that contribute to the need for transparency and accountability, both towards data subjects and the general public, are the use of public funding to set up the infrastructure, collect the data, and conduct the studies, and the fact that in observational research, it is often difficult to provide a detailed account of the exact studies that will be conducted with the data at the moment the data subject is informed about participation. In the long run, providing feedback may add to the (prolonged) trust of data subjects and the broader society in 1+MG and health research in general. The third principle, fair distribution of benefits from the data infrastructure, should not only be seen as the fair distribution of the resulting clinical progress, but also as the fair distribution of knowledge gained from the use of data. Sharing general research results adds to this knowledge sharing. Based on these three principles, a recommendation to provide feedback of general research results to data subjects is set up. Other considerations are taken into account when determining how to provide this feedback. In the 1+MG federated infrastructure, the responsibility to engage with data subjects lies with the signatories. It is therefore presumed that feedback is organised by the national nodes. Practical issues, such as restricted time and expertise available to develop information that is clear to data subjects, are taken into account. Below we summarise the recommendations and provide a short list of best practices.

The increase in personal genome data generated in diagnostics and research holds great promise for advancing personalized prevention and medicine. However, valuable genomic and associated clinical data is fragmented across many healthcare providers and research organizations, making it difficult to reuse due to lack of findability, accessibility and interoperability. This prohibits us from exploiting the potential information contained in these genomes for health benefit. FAIR Genomes aims to provide guidelines that should increase reuse of genomic data while considering the needs of all stakeholders and addressing ELSI issues. We present a standardized meta-data schema to harmonize genomic data workflows and their reporting practices. This schema is broadly segmented into five categories: general information; informed consent; personal and clinical information; material information and technical information. In face-to-face and videoconference meetings, we work towards defining the schema, which is a list of common and optional data elements with relationships and values mapped to existing ontologies such as SNOMED, DUO, HPO, UMLS and EDAM. This project aims to make all data and meta-data elements findable and interoperable to increase FAIRness and standardization in capturing genomic data. This meta-data schema provides a strong basis for digital twin data in Dutch hospitals, development of personal genetic lockers, and active Dutch participation in the European '1+ Million Genomes' Initiative. The scope of this schema goes beyond to next-generation DNA sequencing data. We expect to expand into various *omics varieties, as well as capturing analysis pipelines in FAIR terms. Hence, the FAIR Genomes meta-data framework could be used to develop other research-based infrastructures such as X-omics, BBMRI, ELIXIR, Solve-RD and European Joint Programme on Rare Diseases. The FAIR Genomes meetings are open to receive input from anyone to achieve the highest quality and usability of the resulting meta-data framework. Join us at: https://github.com/fairgenomes. &nbsp