The need for re-contact. Genotype-driven research recruitment refers to the inclusion of research participants in future genetic studies based on the findings from previous studies. For example, deep sequencing efforts within the EuroEPINOMICS Consortium may generate potentially interesting novel variants that warrant further investigation. In some cases, it might be necessary to obtain more phenotypic information, in other cases, segregation in the family might be of interest. Since many variants are rare in the general population, genotype-driven approaches are particularly attractive, i.e. research participants are selected based on genetic findings. This so-called “bottom up” approach allows for targeted studies without the time-consuming and expensive step of re-screening large patient cohorts. In the future, genotype-driven research efforts will likely become increasingly common, since it is unlikely that large-scale genomic studies alone will be able to sufficiently characterize rare genetic variants. However, approaching patients based on genetic research data raises important questions.
Uncharted ethical territory. Genotype-driven research presents a wide array of ethical concerns. How much do researchers need to inform participants about why they’re being asked to participate in a follow-up study? How can we avoid revealing unwanted genetic information? How do we strike a balance that allows participants to make an informed decision about participation in future research but also allows the participant to decide for him/herself what information is personally meaningful? This field is an ethical gray zone and was completely uncharted.
Recently however, Beskow and colleagues published the results of a multi-disciplinary workshop convened to establish recommendations and ethical guidelines regarding genotype-driven research recruitment. This workshop generated seven practical recommendations:
Recommendation 1 – Disclose the possibility of future contact during the initial study. Even if re-contact for follow-up studies is not initially envisioned, it is likely to become more and more common. During the initial consent process, it should be made clear to participants in common language that they may be contacted in the future for additional research. Regarding existing consent forms, if the option of re-contact was not mentioned, it is still ethically possible to re-contact participants. The participant then must decide how and if he/she responds to the request for further contact. What should be avoided in consent forms are statements that prohibit any future contact. If the consent form explicitly states that participants will not be contacted in the future, this must be honored.
Recommendation 2 – Offer the participant the choice about future contact during initial recruitment. This is not an ethical requirement, although it should be considered. While too many options in consent forms may be overwhelming for participants, this question can be posed as a simple “yes/no” question (i.e. May we contact you in the future regarding participation in additional research?).
Recommendation 3 – A person already known to the participant should make contact. Ideally the researcher or member of the research team who conducted the initial study should be the one to contact participants regarding follow-up studies. Otherwise this may leave participants wondering how an unknown researcher received their contact data.
Recommendation 4 – The re-contact process should be specific to study question. Some situations require a more conservative approach to participant re-contact. Some examples:
- The follow-up study is being conducted by a different researcher than the original study.
- The follow-up study is investigating a different medical condition than the original study.
- The research involves a potentially sensitive or stigmatizing issue (which may in some cases include epilepsy or intellectual disability).
In these circumstances, an “opt-in” approach might be more favorable than an “opt-out” approach. For example, researchers should only contact participants who, after receiving a general initial letter about the follow-up study, explicitly indicate that they would like to learn more.
Recommendation 5 – Established criteria for disclosure should not be used. The disclosure of research results is a hotly debated topic, with a broad range of opinions, spanning from no disclosure of any findings to routine disclosure. The generally accepted criteria require clinical validity, clinical utility, and the possibility of therapeutic or preventative intervention. However, these stringent criteria are not applicable in the context of genotype-driven research recruitment, as the purpose of such research is to characterize the clinical utility and validity of the variants under investigation.
Recommendation 6 – Results should be offered. To avoid deception, participants should be appropriately informed about why they’re being contacted to participate in a follow-up study, but this must be balanced with the right not to know unwanted genetic information. Information must be revealed carefully and incrementally by well-trained staff. The figure below outlines a proposed approach to disclosing research results. The decision whether or not to receive research results must be made by the participant. Researchers and ethics committees must decide in advance if a participant who does not want to know this information can still be included in subsequent studies.
Recommendation 7 – Each individual study requires a unique approach. There is no “one-size-fits-all” approach to genotype-driven recruitment. Factors to consider when determining an appropriate approach include:
- The nature of the relationship between the participant and researcher. Is the researcher also the participant’s physician?
- The nature of the research findings. Do they relate to a previously diagnosed condition? Do they indicate anything about future prognosis or risk assessment?
- The nature of the study population. Are participants unaffected individuals or have they already been diagnosed with the condition being studied? Is the study population comprised of minors or other vulnerable individuals, such as those with intellectual disability?
- The nature of the follow-up study design. Will family members be recruited?
Unanswered questions. Beskow and colleagues have undertaken a great challenge by addressing a previously ignored area of research ethics, and their recommendations are a helpful and positive first step. However, some questions remain unanswered.
- Who should disclose the results of the first study? Is it sufficient if a well-trained member of the research team provides this information? Should formal genetic counseling be offered?
- How should the information be disclosed? Should participants receive this information face to face? By telephone? By letter?
- What exceptions apply to children? Should this population be treated any differently than an adult population? Should minors be re-contacted at age 18 to be re-consented or to opt out of future research?
Implications for EuroEPINOMICS. Despite some ambiguous issues, Beskow and colleagues offer sound recommendations that should be followed when undertaking genotype-driven research. Researchers within the EuroEPINOMICS Consortium may keep these recommendations in mind when pursuing follow-up studies of rare variants identified within a research context.