Insights about disease risks gleaned from a person's genome sequence can be relevant not only to that individual but also to his or her relatives. People participating in studies that yield clinically important information therefore often decide to share their results with family members. But what if the participant dies before he or she receives the results?
A study published last month in the American Journal of Bioethics by members of the ClinSeq study of the National Human Genome Research Institute addresses this issue.
ClinSeq, a large-scale medical sequencing study, analyzes the exomes or genomes of participants and returns clinically significant results to them (CSN 5/24/2011). Currently, about 1,000 individuals are enrolled in the study, each of whom is "highly likely to have clinically actionable variants," according to the authors.
So far, ClinSeq investigators have become aware of three cases where participants have died, prompting them to consider whether to return results to their relatives.
The first case came to light in 2010, when the ClinSeq team tried to follow up with a participant who had enrolled two years earlier but had since died. At the time of his enrollment, he was 64 years old and had suffered from early-age elevated cholesterol, hypertension, and coronary artery disease, resulting in quintuple bypass surgery in his 40s. He had four biological adult children as well as a sister. At the time of the follow-up, exome sequencing and a partial analysis of his genome had been performed but he had not received any results.
After talking to the NIH Clinical Center's Bioethics Consultation Service, the ClinSeq team contacted one of the participant's sons, the executor of his estate, who they decided would serve as their point of contact for the family. He expressed "much interest" in learning about his father's results and said that his sister would also be interested.
The research team concluded that there was good reason to return certain results to this participant's family, as they might have a bearing on their health and as family members had expressed an interest in receiving them. But it was not immediately clear which results should be returned, and to whom and how they should be disclosed.
With regard to the nature of information to be returned, the ClinSeq team decided that they should only include variants with well-established clinical significance, meaning variants "linked to a significant harm" where "there are measures that one can take to prevent or treat the potential harm."
To actual ClinSeq participants, the researchers might return a wider range of results because they are interested in their preferences and responses to them, explained Les Biesecker, ClinSeq's principal investigator and chief of the genetic disease research branch at NHGRI. But when a research subject dies, "we shift more to a mode of clinical utility and say to ourselves, 'What are the variants that are of the highest potential utility, medically actionable things that would be prudent to disclose to a person, whether they were a research subject or not?' And of course that's a much smaller set of results than the larger set that the research subject probands would get."
Which specific results would be returned to relatives would be decided on a case-by-case basis, he said.
The team further decided that a single member of the deceased participant's family — usually the executor of his or her estate — should decide on obtaining results and receive them on behalf of the family.
This family member would then receive the information in the same way that ClinSeq participants currently do, which involves making a separate decision on each clinically significant finding and a face-to-face consultation with a genetic counselor.
ClinSeq would not be involved in testing or follow-up treatment of relatives.
The sequencing data of the deceased patient would continue to be annotated and analyzed, so additional results could be disclosed for months or years to come.
In two other cases, the argument for returning results to relatives was less clear cut, the researchers reported in their article. A second participant whose death the ClinSeq team became aware of did not have any biological siblings or children, though his wife expressed an interest in receiving his results, especially if they could explain his history of early-onset heart disease. His sample, however, had not been sequenced yet.
In the case of a third participant whose death came to the team's attention, the participant's wife, who was the executor of his estate, said that their two adult daughters would probably not be interested in learning about clinically relevant results from their father's genome. In the past, she said, they had not been interested in being tested for a gene that was implicated in a disease on their paternal family's side.
So far, the ClinSeq team has not returned results to any of the three participants' families. "The families have not followed up with us," said Biesecker. "They may be overwhelmed by a number of things they may have to do, so this may not be that high of a priority."
In future cases, the ClinSeq investigators plan to contact the executor of the deceased participant's estate in order to find out whether the family has an interest in receiving clinically significant results. They also made existing ClinSeq participants aware of this disclosure process and encouraged them to discuss the study with their family.
However, they did not change the ClinSeq consent form to give a participant the option to shield their results from family members after their death, arguing that he or she "does not have the ethical authority to preemptively prevent relatives from obtaining information that could be of clinical benefit to them after his or her death."
"One of the things that we think is important is to maintain some flexibility about how to handle this," Biesecker said. People's life circumstances may change over the course of the study, "so while some people argue for being extremely specific in telling people exactly what you will do, and asking them to tell you what they want you to do when they originally sign the consent form, we don't agree with that."
Beyond the ClinSeq study, the authors argued in their paper that "at a minimum, researchers should enact a passive disclosure policy so as to enable relatives to obtain results that are of potentially significant medical benefit."
It is unclear whether other research studies that sequence the exomes or genomes of individuals have implemented policies for disclosing results after a participant's death, but the issue has come up.
For example, researchers at Washington University's Genome Institute last year published a study in the Journal of the American Medical Association in which the sequencing of a woman with a highly aggressive form of breast cancer who developed chemotherapy-induced acute myeloid leukemia and had consented to being part of the research study identified a de novo mutation predictive of familial predisposition to cancer. The woman passed away before the study was completed, but the Wash U team has a "movable firewall" in place that allows them to return medically actionable results to the patient's physician (CSN 4/26/2011).
Speaking at the Personal Genomes conference at Cold Spring Harbor Laboratory last year, Wash U genetic counselor Jennifer Ivanovich said that even with the moveable firewall, situations such as these are tricky. Legally, results should be shared with the next of kin, but doing so can also pose challenges, especially if a significant amount of time has passed since the patient has died. Additionally, ethical responsibility to children, siblings, and other family members, whose medical care could be impacted by the results, should be taken into consideration, Ivanovich said at the time (CSN 10/12/2011).
23andMe provides results to relatives if the customer has designated this in his or her will. "If the account holder leaves his or her 23andMe account to you or another family member in a will, trust or some other legal documentation, that person will continue to have uninterrupted access to the account," a company representative told a customer in an email that was obtained by CSN. "In the absence of an estate or will we are not able to transfer ownership of an account to another person."