A successful partnership. Making progress in understanding the genetics of the epilepsies requires a successful partnership involving many players. Researchers, clinicians, patients, and families must work together in order to advance scientific goals. Since the first genetic etiology was discovered in a large family with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy nearly 20 years ago, we have made many strides scientifically, in terms of technologies, our clinical classifications, and our knowledge of genetics. Our views on how we approach research from an ethical perspective is also continuing to evolve. Genetic research hinges on the participation of patients and families, and returning results to participants is increasingly viewed as imperative. A recent paper has used the Epilepsy Phenome/Genome Project (EPGP) and Epi4K studies as a case example of the challenges and opportunities regarding returning genetic results to research participants.
Historical context. The context of the publication by Ottman and colleagues is the situation that arose after the publication of the Epi4K study, which was the first major exome sequencing study in the epilepsies. Within this study, there were clearly diagnostic findings identified in a substantial proportion of individuals who had undergone exome sequencing. However, the study had no way to return these results to participants, as the consent forms initially developed for this project did not include the ability to return results and re-contact patients. It should be emphasized that the timeframe of EPGP and subsequent Epi4K study spanned more than a decade – a decade in which our understanding of informed consent of research participation and return of results has evolved. Given this evolution of the current standards regarding return of results, the EPGP/Epi4K team held a workshop about this topic in July 2016 sponsored by Ron and Sanne Higgins Epilepsy Research Fund, which I was invited to attend. The current publication by Ottman and collaborators now summarizes the conclusions that we arrived at during this workshop.
What should be returned? Within the July 2016 workshop, we established the following criteria that would dictate on whether a research finding should be returned. First, the finding needs to be clinically valid, representing a pathogenic or likely pathogenic variant in an established disease gene. There should not be a return of genes without sufficient evidence or variants that are known to be benign. Second, the findings need to have clinical utility, which refers to the fact that the return of results should impact patient management, but does not have to be confined to treatment changes. In fact, the proverbial end of the diagnostic odyssey due to an explanatory finding also represents clinical utility. Finally, the return process should consider the personal utility of findings, a finding that is meaningful for a patient or family, but may not strictly fall under the category of clinical utility. Ideally, these three components would also be mentioned in the consent process.
Who should return it and how? This question was relatively easy to answer within our workshop. We overwhelmingly felt that results should be returned through the healthcare professionals who initially consented the patients, ideally with the involvement of a genetic counselor, and that this mechanism should be outlined in the informed consent process. We acknowledged that this may pose difficulties in scenarios when patients were recruited through other mechanisms such as recruitment drives. However, in these situations, similar mechanisms may be put into place to ensure that all patients who would like to have results returned have a healthcare professional who would be a contact person.
CLIA validation. The panel was split with regards to the need to validate findings by a laboratory that is CLIA (Clinical Laboratory Improvements Amendment)-certified. In reality, this process is frequently dictated by local IRB rules and may not be up to the individual researcher. Arguments in favor of CLIA validation emphasize the need for a formal validation, as research samples may not have been analyzed or stored in a way that could completely exclude sample mix-up or false positive findings. Opponents of CLIA validation discussed the additional costs and effort that the research study would be burdened with.
Participant preferences. In the context of Epi4K, honoring patient preferences regarding return of individual genetic results was challenging, since participants were not asked upfront whether or not they would like to receive findings from the research study. However, multiple studies have consistently indicated that research participants overwhelmingly opt to have results returned when given the option. Importantly, research participants should be given the choice whether or not to receive individual research results.
Financial considerations. If results to research participants are returned, this will financially burden someone somehow. Who should this person be? Should this be the researcher or should this be a public responsibility that should be covered by the researcher’s institutions or funding bodies. Clinical validation of research findings and research-based genetic counseling could easily result in significant costs. We did not arrive at a conclusion about what the best mechanism for this should be, but there is one thing to consider. While it is tempting to postulate that the costs for return of results should be on the researcher, these costs may be difficult to shoulder for smaller groups or even for larger consortia. Put differently, EPGP and Epi4K could only be carried out in the way they were conceptualized because there was no return of results – if a significant proportion of the budget had been allocated to return of results, the project in itself may have likely been smaller in scope. Likewise, would the EPGP and Epi4K researchers also be responsible for any variant identified in a secondary analysis, as this dataset can be accessed through dbgap by many research groups?
The opportunities. Within the era of large-scale clinical testing, making diagnoses through return of research results may seem obsolete. However, nothing is further from the truth. Research-based sequencing and data analysis will continue to provide opportunities to give back meaningful results to research participants, and we need to think about feasible mechanisms to enable this. Furthermore, the general expectation for data to be returned may increase. It is not uncommon for us to have families request their full genetic data such as BAM and VCF files that were generated clinically, and we need to consider that the general expectations for the researcher’s obligation to return results may shift. Maybe there will be a consensus in the near future that this return of results should also include secondary findings such as variant predisposing to cancer or cardiac diseases. How can we continue meaningful genetic research or is the era of research sequencing over?
What you need to know. The publication by Ottman and collaborators discussed the return of research results to study participants, emphasizing that the general opinion on return of results has shifted and that there is a generally emerging consensus that study participants should be given the opportunity to have clinically relevant results returned. This shift in attitude has several expected and unexpected consequences, including the question of who should carry the responsibility for this type of validation. Research-based identification of genetic etiologies will remain an important component of epilepsy genetics, with the ability to identify diagnoses in a significant number of patients. We therefore need to think about and plan for a framework for a return of individual results at the initiation of a research project, when writing study protocols and when obtaining informed consent from patients and families.