Technology advances at a faster pace than our ability to determine how to handle the many complex issues that can emerge around its uses. One example of this relates to the obligations researchers have to people who have been sequenced as part of a study and new findings about their genes arise.
The American Society of Human Genetics this month published a set of guidelines in The American Journal of Human Genetics to address this issue. It established them through a working group it led with a number of other organizations. The guidelines are meant to serve as a minimum set of principles intended to guide researchers as to what their responsibilities to recontact research participants about the reclassification gene variants they were found to have.
The question as to whether there is a responsibility to recontact research participants to update them about reinterpretations of genetic variants after an initial analysis is a complex one that extends across ethical, legal, and financial considerations. The question has been a concern to both researchers and clinicians. But while there has been an emergence of clinical guidance (and a belief that there is a shared responsibility between patients, clinicians and clinical laboratories), there has not been guidance for researchers as to their responsibilities to inform participants of updated findings.
“While clinical recommendations on this topic have begun to emerge, there is a lack of guidance on the responsibility of researchers to inform participants of reinterpreted results,” said Yvonne Bombard, former chair of the ASHG Social Issues Committee and co-lead author of the statement. “Because the research and clinical contexts have different goals, priorities, timelines, and restrictions, we need to consider them separately.”
The understanding of gene variants is constantly evolving. When an individual is sequenced, researchers may find variants with unknown significance at the time of the analysis, but new information may later identify a given variant as pathogenic. At the same time there are cases where patients were told they had a variant that was either pathogenic or probably pathogenic that was later determined to be benign.
The creation of guidelines is not an abstract exercise. The groups found that there is what they called a “relatively high rate of reclassification of variants.” Many of those reclassifications have been downgrades from “pathogenic,” “likely pathogenic,” or “variants of unknown significance” to “likely benign” or “benign” as a greater number of people and a more diverse population of people have been sequenced and their data has been documented.
New findings may not only result from the reclassification of a variant, but also because a specimen was resequenced or reanalyzed using new technology or new methods that may detect a variant that was previously missed.
The authors note that evidence suggests most stakeholders think it would be “ethically desirable although practically difficult” to recontact patients or research participants with new findings. Those practical issues include concerns about liability, funding, and the ability to track participants among others.
To create the guidance, the working group started with well-established ethical principles that have long been used to guide modern research regulations. These foundational principles include the belief that research with human participants should be guided by respect for participants, beneficence (maximizing benefit and minimizing risks), and justice (in recruiting, funding, and the protection of the scientific aims of a study).
The working group concluded that a broad range of approaches to returning updated results would be permissible, but that an institutional review board would need to review them to see that they adhere to ethical standards and would need to be included in the informed consent process to ensure participants have adequate information to voluntarily agree to the plan.
The working group said researchers have a stronger obligation to recontact research participants when:
- Research is active, ongoing, and has funding and the participants’ contact information is up to date
- Informed consent set the expectation for potential recontact
- There is a high degree of certainty about the new interpretation and / or implications of a changed interpretation
- The reinterpretation would be relevant to the condition under study or, in the case of an actionable incidental finding, likely to change medical management.
If the interpretation of a given variant is related to the condition under study or reasonably expected to affect participants’ medical management, the guidelines strongly recommend that researchers make reasonable attempts to recontact participants to offer updated results.
If the reinterpretation is not expected to affect medical management, recontact is advised rather than strongly recommended.
The statement also suggests that there is no responsibility for researchers to hunt or scan the genomic literature for changes in variant interpretation, and that any responsibility to recontact should be limited to the duration of research funding.
Other recommendations made in the statement address the practicalities of informed consent, involvement of institutional review boards, timeliness and protocol of recontact, and structuring of future research studies.
The statement was supported by the other members of the working group including Genetic Alliance, European Society of Human Genetics, Canadian Association of Genetic Counsellors, American Association of Anthropological Genetics, Executive Committee of the American Association of Physical Anthropologists, Canadian College of Medical Genetics, Humana Genetics Society of Australasia, and National Society of Genetic Counselors.
“Technological advances could help ease the practical challenges of recontacting participants, improving its feasibility for researchers,” said Howard Levy, co-lead on the statement. “Efforts to cross-reference and integrate research databases, as well as to create lay-friendly information and automated notifications of variant reinterpretation, could enable a more self-service model of educating research participants about continued research progress.”
Though the guidelines are for researchers, they should also serve as a reminder to research participants about the need to pay attention to the informed consent process, to ask questions about their rights and the obligations of researchers, whether they will receive results of a study, whether they have obligations to update their contact information and how they could do so.
Researcher have an obligation to manage the expectations of participants, but participants should also be careful about making assumptions about what they will and will not get from their participation.