Guidance on Genomics and Research in Sensitive Bioinformatics Data

The purpose of this revised guidance is to ensure that genomic research is conducted in accordance with the rules of the Committee Act concerning the self-determination, safety, and well-being of research subjects, which take precedence over the scientific interest in creating new knowledge, as per the Committee Act § 1 (Legal Notice No. 1338 of September 1, 2020, on the Ethical Treatment of Health Science Research Projects and Health Data Science Research Projects).

The analysis of the genome provides data regarding a person's genetic constitution, including constitutional (hereditary) and acquired (somatic) changes, which form the basis for health and diseases throughout life. Extensive mapping of an individual's genome can result in the identification of serious findings in research subjects, which they can be informed about according to the rules in the feedback notification ordinance (Ordinance No. 965 of May 21, 2021, on feedback about significant health-related findings from notification-required health science and health data science research projects, clinical trials of medical equipment, etc., and certain registry research projects). If there is a risk to the research subject's relatives, it is recommended to encourage the research subject to contact the relevant relatives for examination and treatment.

Requirements for information and consent raise special considerations in these projects: The main rule is that there should be informed or surrogate consent for mapping an individual's genome.

Broadly, extensive mapping of the genome is understood as: Analyses that provide detailed information about large parts of individuals' genomes, typically generating large amounts of information.

You can read more about the methods that fall under this concept in Appendix 1: Method List.

Reporting research, including genomic research on biological material, is described in NVK's Guide on the Use of Biological Material in Medical Research Projects. The Biobank Guide elaborates on how biological material should be managed if a project involves the extraction, storage, and/or use of biological material, including if biological material (and data) is sent to EU countries and countries outside the EU (third countries).

The project must be reported to the regional committee in the region where the responsible investigator has their main workplace. However, the report should be sent to NVK if the biological material has already been extracted from the participants and an exemption is sought from obtaining a new consent to conduct extensive mapping on biological material from a biobank.

See Guidelines on Biobanks.

If the research involves already created genomic data, which is generated by extensive genetic analyses, reporting must also be made to NVK. See section 7.

Analyzing the human genome with NGS involves many steps from the sequencing itself, i.e., generating DNA sequences as a copy of the participants' DNA or RNA, to the bioinformatic processing of data (alignment, variant calling, and variant annotation). To ensure maximum transparency, it is important that the research protocol contains sufficient information to assist in the assessment of the project, which takes place in the scientific ethics committee system.

The protocol should include information on:

• Which part of the genome is being studied (gene panels, exomes, the whole genome, epigenome, RNA).
• What type of sequences are to be studied (rare or common variants, structural variants, etc.).
• Which sequencing platform or high-density array is planned to be used.
• Which bioinformatic tools are planned to be used for variant calling, annotation, and validation, for example.
• The planned sequencing depth.
• How raw data storage is planned, where, and for how long.
• An assessment of the expected frequency of significant health-related secondary findings with justification.

Since the project's purpose is to produce new knowledge in a particular field of interest, it may focus on specific areas, so that, for example, bioinformatic data is preferentially generated from specific areas in the genome. In this context, data from other areas can be overlooked, for example, areas in the genome where certain variants are known to be of significant importance for the participant's health. This can be done, for instance, by not processing certain areas bioinformatically. For example, one might choose to ignore the clinically relevant genes on the ACMGs list (American College of Medical Genetics and Genomics) by not "calling" variants or filtering out all called variants in the genes on the list before further analysis. The project description should indicate that the selection is made in such a way that unwanted information is not generated or recorded.

Genomic research can be exploratory, where there is less emphasis on very specific hypotheses or endpoints. In some cases, the research is more hypothesis-generating. However, the committee law requires that it is a specific research project. The committee will focus on there being a purposeful or methodological delimitation with an overarching issue. The scientific purpose of the analyses must be described. It should be clear what is being searched for, and the methodological choices should be justified so that the committee can assess the scientific standard, including the scientific ethical justification of the project.

A validation phase may strengthen the scientific basis of the project. This can be included in the same project if it is the same responsible investigator, and it is specifically justified which participants, which material, and which methods will be used in the specific validation. Otherwise, the validation must be submitted as a new report.

4.1 Expert Committee for the Assessment of Secondary Findings

Genomic research, conducted using the methods described in NVK's list of "Methods that fall under the extensive mapping of the genome", is characterized by the possibility of significant health-related secondary findings emerging.

Significant health-related secondary findings are defined as information that arises as part of a health science or health data science research project, without being covered by the project's purpose. It indicates that the participant or research participant in data research (see section 7) unexpectedly suffers from or is certainly or highly likely predisposed to a life-threatening or clearly serious disease that can be treated, prevented, or alleviated.

In research projects where there is a predominant risk of significant health-related secondary findings, the responsible researcher or the responsible person in data research must describe their justified considerations about the likelihood of the emergence of significant health-related secondary findings. See the feedback regulation § 4, subsection 3.

Furthermore, the composition of the expert committee, which must be established upon the emergence of possible significant health-related secondary findings, and procedures for how the members of the expert committee are appointed, should be described. See the feedback regulation §§ 5 and 6. The protocol can also describe cooperation with a clinical genetic department in a hospital concerning the feedback of significant health-related secondary findings.

The expert committee must consist of an authorized health professional within the disease area being researched and must also consist of members who possess the necessary expertise to assess whether the criteria for feedback are met, according to the feedback regulation § 5 . See also below point 5.2 concerning the criteria for this.

4.2 Collaboration with External Partners on Genomic Data

In genomic research, the investigator may use an external laboratory or an external company to carry out the genetic, including bioinformatic, analyses. In such cases, the nature of the samples should be specified as well as the analysis method and the laboratory/company where the samples will be analyzed. It should be specified that a written data processing agreement will be entered into for this specific purpose, after which the laboratory or company may not use the provided information for anything other than the execution of the task for the data controller. For assistance in drafting a data processing agreement, refer to The Danish Data Protection Agency's website with guides and templates.

If the investigator further or additionally establishes an actual research collaboration with other researchers on the analysis and use of genomic data either in Denmark or within or outside the EU, the purpose and framework should be specified in the protocol. The protocol should clearly state:

• Which data will be passed on to specific collaborators.
• That data from the extensive sequencing is used only for research within the approved project's purpose.
• If raw data is intended to be made available to other researchers, for example, as required by journals, or if sequence data is not destroyed but stored after the project's completion, this is expected to be in accordance with the Data Protection Regulation and Data Protection Act.
• That the 4 criteria for feedback of significant health-related secondary findings, cf. below in section 5.2, must be followed by the partner.

Please note that in certain situations, The Danish Data Protection Agency's permission is required for disclosure to a third party outside the project, cf. the Data Protection Act § 10, subsection 3. See The Danish Data Protection Agency's  regulation no. 1509 of December 18, 2019, on the disclosure of personal information covered by the Data Protection Act § 10, subsections 1 and 2, and the Guide to regulation no. 1509 of December 18, 2019, on the disclosure of personal information covered by the Data Protection Act § 10, subsections 1 and 2.

4.3. Research with Minors

The Committee Act § 19 contains conditions that must be met when minors participate in research. Reference is also made to the notification regulation's §18 3 about the consent from minors.

A distinction should be made between the inclusion of healthy children and children where there is a suspicion of a genetic disorder. Both extensive mapping and targeted genetic analyses can be a burden to minors, especially healthy ones, if during their childhood or teenage years they might risk being confronted with incidental findings of a serious health nature that might only manifest in adulthood. This is especially true for the type of genetic investigations that neither have therapeutic nor preventive purposes in relation to the involved children. The right to an open future for these children should therefore be considered in the protocol for such research projects.

The written information provided to the participants should indicate that they are being asked to participate in a medical research project. This information should be presented in such a way that it enables the participant to decide whether they wish to participate in the research project. Emphasis must be placed on understandable information, as genomic research can be complex.

Among other things, the information should include that feedback can be given about significant health-related secondary findings, if the conditions in the feedback regulation are met, unless the participant has declined this. It should be stated that these conditions, among others, concern that an expert committee, in collaboration with the responsible investigator, has previously assessed the clinical relevance and safety of the findings. Additionally, it should be a life-threatening or clearly serious disease or disease predisposition that can significantly be prevented, alleviated, or treated and is of significant importance to the participant and their vital interests.

Reference is made to the researcher checklists, which also describe specific requirements for information in genome research.

The NVK has developed an optional standard text that represents best practice for informing participants in trials involving genomic research. This text can be incorporated into participant information solely concerning genomic research or in participant information where genomic research is included as an adjunct, e.g., in drug trials. See Appendix 2.

A new optional standard consent declaration has also been developed for use in projects that involve extensive mapping of the genetic heritage. The text is adapted to projects where the incapacitated or deceased are included. There is also a declaration for the very rare cases where a participant may refuse information about life-saving findings and the participant is still included in the project. The declaration concerns the right to refuse knowledge, cf. the feedback regulation's § 15, paragraph 3.

In projects where it is less likely that significant health-related secondary findings will emerge at the individual level, participants can be informed about this circumstance. This might be the case for exploratory analyzes of biomarkers in aggregated data, e.g., in drug trials. However, these trials are not exempt from the obligation to set up an expert committee. When participants are informed that there may be an insignificant risk of health findings, it can additionally be stated that the lack of feedback does not mean that the participant is healthy. The general rules about informing participants apply in addition.

5.1 Information and Involvement of Minors

Children cannot independently consent to having a blood sample taken for genome research. It is the parents who must be approached for a proxy consent. The Reporting Regulation § 18, section 3, deals with provisions regarding information to the participants and requires that consent is obtained from children when they participate in research. Children must be heard and the information should be adjusted according to the child's age. The requirements for the hearing increase in line with the child's age and mental maturity to understand the research.

5.2. Genetic Counseling

Participants should be offered qualified genetic counseling if findings emerge during the study about a genetic variation that has significant health implications for the participant.

Especially in projects investigating mutations in high-penetrance genes (e.g., in monogenic diseases), qualified genetic counseling should be offered before obtaining consent for participation in the study.

Genetic counseling is provided by a specialist physician with experience in the relevant disease group(s) or by other staff groups who are adequately trained and supervised. The researcher in charge can thus delegate to a professionally qualified individual to inform the participant about potential health findings.

5.3. Feedback on Significant Health-related Secondary Findings

The person responsible for the research or the person responsible for data research can relay significant health-related secondary findings to the study participant or research participant if there is certainty or high probability that this individual suffers from, or is predisposed to, a clearly serious disease and it is necessary for the vital interests of the study or research participant to provide feedback.

The expert committee must assess:

1. Whether the disease or disease predisposition can be significantly prevented, treated, or alleviated.
2. Whether the disease or disease predisposition is of significant importance to the study or research participant.
3. The clinical validity of the findings.
4. The reliability of the method used to identify the finding.

The decision on whether to provide feedback is made in collaboration with the expert committee or the clinical genetic department of a hospital. However, it's the responsibility of the researcher or person responsible for data research to make the final decision regarding feedback.

Note that only individuals with legally mandated confidentiality can inform the study or research participant. If the researcher or person responsible for data research is not covered by this legal confidentiality mandate, the information must be provided through a health professional bound by confidentiality, according to Section 3, paragraph 2 of the feedback regulation.

The researcher must ensure that personal information is only shared with the expert committee, the clinical genetic department, or involved health professionals in compliance with the data protection regulation rules.

However, feedback cannot be given if the study participant has declined this knowledge. Refer to the NVK's pre-printed declarations on the "Right Not to Know." Such a refusal should be an informed one, with current and relevant insight, adhering to the standard for good information practice.

Secondary findings should be validated before feedback is provided to the study participant. The validity of the analysis methods used should be considered, including the frequency of false positives.

Feedback rules concern gene variants with high penetrance, predisposing to a serious disease that can be cured, treated, or prevented. Excluded from the feedback rules are feedbacks about risk variants with low or moderate penetrance or uncertain clinical significance. Clinically relevant findings can be those listed by ACMG.

Exemption from Renewed Consent from Participants When the Biological Material Comes from a Biobank

6.1. Exemptions Regarding Study Participants with Legal Capacity (Competent Participants)

Exemptions from the requirement for renewed consent can be granted if the experiment does not pose health risks, and the project otherwise cannot be burdensome for the study participant, or if it's impossible/disproportionately difficult to obtain consent.

When deciding on an exemption from the consent requirement, the NVK (National Committee on Health Research Ethics) emphasizes the following:

1. The project's purpose is related to the previous project/clinical area where the material was taken/collected.
2. The study participants were initially informed about genetic research if it's a prior research project.
3. A significant portion of the study participants have passed away.
4. Whether there's a search for high-penetrance variants significant for serious diseases, with derived consequences for the risk of significant health-related secondary findings.
5. The notifier adheres to NVK's genome guidelines concerning significant health-related secondary findings, including the use of an expert committee for evaluation.
6. The point in time when the consent was obtained. There's a particular need to be aware of the information and consent given many years ago.
7. The person responsible for the research/biobank will check if the study participants have declined research in the Tissue Usage Register.

In health science research projects where an exemption from the consent requirement has been granted, and in health data science research projects, the person responsible for the research is accountable for ensuring that feedback on significant health-related secondary findings to the study or research participant occurs, taking into account the individual's right not to receive this information. Refer to Section 9 of the feedback regulation.

6.2 Exemptions Regarding Minors

Research involving minors should primarily be conducted with informed consent from the parents. However, in projects where an exemption from consent is sought, the NVK (National Committee on Health Research Ethics) will especially focus on ensuring that exemption from parental consent is not burdensome for the minor. In this context, it's important to recognize that genome research can have specific implications for the entire family. Therefore, it's crucial to consider the significance of involving or not involving parents.

The NVK has denied an exemption for a research biobank due to the potential burden on children, especially the healthy ones, as they could later confront findings of a severe health-related nature, which might only become significant in adulthood. In this specific study, the genetic investigations had neither therapeutic nor preventative purposes in relation to the children.

However, the NVK has granted exemptions from consent for research on material from a clinical biobank containing samples from seriously ill children, some of whom have since passed away, where the research project pertained to the disease the children suffered from.

In some of the larger research projects set up over 18 years ago, and where the material is still stored, the study participants have become adults. If an exemption from consent is sought for material where parents previously approved research, it should be assessed whether there's a risk that the now-adult study participant might be burdened by it. If the committee in the original study stipulated a condition for renewed consent when the child becomes an adult, an exemption from consent cannot be granted. Even if no such condition exists, the NVK would be hesitant to grant an exemption and would prefer the now-adult study participant to independently consent to genome research.

6.2.1 Use of Material from the PKU Biobank

The PKU biobank, an essential research resource, holds a unique status. If material from this biobank is to be subjected to genetic research with exemption from consent, including targeted sequencing, attention is drawn to the fact that PKU samples were initially taken for specific therapeutic purposes, often significantly different from the purposes of new research projects later seeking exemption from consent. PKU samples are taken shortly after a child is born, at a time when it's debatable whether parents can anticipate future research uses concerning heredity investigations.

As of June 15, 2020, requirements were introduced for the reporting and processing of Research in Sensitive Bioinformatics Data, according to § 14 of the committee law. This concerns already existing genome data from extensive mapping of the genome or from imaging diagnostics without the use of biological material. Such research projects must be reported to the National Science Ethics Committee.

Health data science research projects, therefore, involve research in sensitive bioinformatics data, such as:

1. Genome data from a previous health science research project with extensive mapping.
2. Genome data from patient treatment with extensive mapping.
3. Data from imaging diagnostics from a prior health science research project.
4. Data from imaging diagnostics from patient treatment.

These projects are referred to as health data science research projects, and the person responsible for the trial is termed the research manager. Similarly, individuals whose data are processed are referred to as research participants.

In delineating the research from quality assurance, emphasis is placed on whether the knowledge generated is generalizable. That is, whether the study's findings benefit multiple treatment locations or if the knowledge acquired is consolidated in one place for internal use. Therefore, whether the results are for internal or external use becomes significant. For instance, if researchers have considered publishing, it suggests that it is research.

7.1. Purpose of the Rules

The overarching purpose of these rules is to enhance the trust and confidence of citizens in research while creating improved frameworks for health research. The rules aim to protect the rights, integrity, and privacy of research participants.

There will be a focus on ensuring that data is legally collected and assessing the societal utility, that is, the therapeutic purpose of the research. There will also be an emphasis on ensuring high scientific quality of the research while ensuring that research participants are not burdened, upholding their integrity and right to privacy.

It is crucial that there is an ethically appropriate handling of secondary findings, including bioinformatics data, see sections 4-6, but not section 5 on information for research participants. Therefore, be aware that the committee can only evaluate the research and cannot stipulate conditions that informed consent must be obtained.

When reporting, the research manager must submit the documents outlined in the researcher checklists for health data science research projects.

7.2. Delineation from Research in Patient Records

Especially concerning data originating from a patient's record, it is essential to determine when the project should be reported to the region as a request for access to research in patient records and when the project is a health data science research project that needs to be reported to the NVK. Concerning research in journal data stemming from comprehensive mapping of the genome in the clinic, this will always be a health data science research project, and an application for access to research these data will not need to be submitted to the region but to the NVK.

Regarding imaging diagnostic data, imaging diagnostics refer to the treatment of patients using and/or guided by imaging techniques – X-ray, CT scans, MR scans, PET scans, and UL scans - solely or in combination. The specialty is "Diagnostic Radiology", but it also includes many micro-invasive treatments and samplings where, guided by ultrasound scanning, X-ray, or CT scanning etc., patients can be treated. However, imaging diagnostics can also be conducted within specialties other than radiology, e.g., nuclear medicine or oncology. These are projects explicitly focusing on research in the images, meaning that the image as a medium is the primary focus and specific subject of the research project. Additionally, secondary data from the rest of the patient record or data from health registries may be included.

The primary consideration for the reporting obligation has been the specific risk of secondary findings when the image medium is specifically and intrinsically the subject of renewed research.

Thus, health data science research projects are those where there is a need to establish a specific preparedness for the emergence of secondary findings since the image medium itself is the focal point of the research. In contrast, the "classic" projects, where access to a range of health information from the patient record is requested, e.g., residence, age, diagnoses, laboratory or blood test results, medication prescriptions, discharge letters, X-rays, anesthesia records, etc., where the X-ray image can more be characterized as an "add on", should not be subjected to the new procedure applicable to complex health data science projects. These projects should be reported to the region, thereby requesting access to research in patient records.

Also, refer to the researcher checklist's "Special Requirements: Research in Genomes".

Appendix 1: Method List

Appendix 2: Best Practice for Informing Participants in Genome Research.

• LBK no. 1338 of 01/09/2020 - Announcement of the law on the scientific ethical treatment of health science research projects and health data science research projects.
• BEK no. 825 of 04/06/2020 - Notification on reportable health science and health data science research projects.
• BEK no. 829 of 08/06/2020 - Notification on feedback about significant health-related findings from reportable health science and health data science research projects, as well as certain registry research projects.
• LAW no. 502 of 23/05/2018 - Law on supplementary provisions to the regulation on the protection of natural persons in connection with the processing of personal data and the free exchange of such information (Data Protection Act).