The average person carries more than 500,000 rare or novel genetic variants, thousands of which might be identified during a genomics research study. The question is whether, and how, people should be told about any of these findings.
“The vast majority would be variants of uncertain significance [VUS] and would not cause health problems,” explains Gail Jarvik, MD, PhD, professor of medicine and genome sciences and head of the division of medical genetics at the University of Washington. In clinical testing, only a small number of VUS relevant to a condition for which patient is under evaluation are returned.
“Even in that case, most VUS will prove to not be associated with disease,” Jarvik reports. “We do not use VUS to determine a patient’s treatment for that reason.”
Of course, additional studies might give more clarity on the significance, or lack thereof, of VUS. “With further research, VUS can rise to being called pathogenics or be downgraded to completely benign,” says Charis Eng, MD, PhD, FACP, chair of the Genomic Medicine Institute and director of the Center for Personalized Genetic Healthcare at the Cleveland Clinic. A researcher informing individual research subjects about all VUS is not realistic — and it is unethical, too, Eng says. In exome and genome sequencing research, there typically are thousands of variants of unknown significance. “It’s also very impractical. It’s not very beneficent to tell research subjects something like ‘You have thousands of VUS,’” Eng explains.
Eng says best practice in research is for a genetic counselor or research coordinator to make two things clear to study participants: only clinically actionable findings will be returned, and results will be confirmed in a clinical-grade lab in the setting of pre- and post-test genetic counseling. “This is exactly why genomics research should be performed with appropriate informed consent given by knowledgeable people,” Eng stresses.
Attitudes about sharing information with study participants is changing. Historically, subjects did not even find out aggregate results of research to which they had contributed.
“People have started to advocate that individual research results should be returned to participants, to honor their participation, so we are not just using them as a means to an end,” says Liza-Marie Johnson, MD, MPH, MSB, a pediatric oncologist and vice chair of the ethics committee at St. Jude Children’s Research Hospital in Memphis, TN.
As for findings of unknown clinical significance, “the landscape is mixed about whether or not information should be returned,” says Johnson, who co-authored a recently published paper on this topic.1 This ethical dilemma is a hot topic in genomics, but can come up in any kind of study.
Ethicists recently studied the question of whether research participants should be told if they carried gadolinium deposits in the liver or brain from contrast agents used during previous MRIs. The deposits are of unknown clinical significance, but could influence future decision-making if that changes. If someone was not told about the finding, “in the event that later we find it wasn’t safe, you may be upset,” Johnson notes.
The children’s oncology group directed a committee to work specifically on return of results for an ongoing research study called Genomes for Kids. Investigators will reanalyze results over a period. “As it gets into the public sector, we are ramping up the return of results plan for our study participants,” Johnson reports.
Returning results requires considerable resources. Many studies take years to complete, and researchers must stay in contact with participants the entire time. Exactly how long is something to consider, since more information about VUS is coming to light.
“If you are going to return results, there needs to be a time limit set,” Johnson suggests. “Is it until the grant ends, indefinitely, or until the participants asks you to stop?”
The ability to adequately educate participants about the meaning of all these findings is another consideration. “If you can’t do adequate pretest counseling or follow-up, it could be harmful if people don’t understand the significance of the results returned,” Johnson explains.
Generally, people want more information about their health rather than less. That does not mean it is in their best interest to hear about every single finding. For instance, a study participant may want to know if they carry a gene for a cardiac condition for which there is an intervention to prevent sudden death. However, that same study participant might not want to know if they carry a gene for early onset Alzheimer’s disease.
For researchers, “it’s all about having a plan and managing expectations, and communicating from the beginning,” Johnson stresses.
At the time of informed consent, investigators should be clear on what will, and will not, be returned to study participants. “If you enroll in a study on migraine headaches and got an MRI, you would hope if they thought you had a brain tumor that they would share that information to you,” Johnson says.
While ethical obligations in that case seem pretty clear, there can be additional complexities. For one thing, MRI images are not always viewed in real time. Instead, data are collected and reviewed months later. Perhaps the person reviewing the MRI is not a board-certified radiologist; therefore, this person is not qualified to interpret results on behalf of an individual.
“It’s not just about one discussion when you are getting participants to sign a form,” Johnson explains. “There should be ongoing discussions over the course of a study, if appropriate.”
To meet ethical obligations, more than one conversation may be necessary. “What is comes down to is recognizing that most participants would want to receive information that’s important for their future health,” Johnson adds.
- Johnson LM, Zabrowski J, Wilfond BS. Should research participants be notified about results of currently unknown but potential significance? Am J Bioeth 2019;19:73-74.