Q&A: Susan Wolf on Recommendations for Returning Genomic Results to Families of Study Participants

NEW YORK (GenomeWeb) – Over the last several years, as research programs evaluating the clinical utility of genome sequencing have blossomed, so have questions about how results discovered through broad analysis of the human genome should be communicated to participants of these studies.

Ethicists, lawyers, and genetic researchers have applied themselves to constructing consensus guidelines and recommendations for best practices, for example a statement published by members of the Return of Results committees of the Clinical Sequencing Exploratory Research (CSER) Consortium in the American Journal of Human Genetics last year.

But as the wellspring of data collected in genomic research has grown, so has the scope of these ethical and practical questions, for example, whether to include not only research participants- but also their family members in the return or results — for whom the genome of a relative could hold information with implications for their own health.

To tackle this question, researchers from the University of Minnesota, the Mayo Clinic, and the University of California, San Francisco have been working under a five-year grant from the National Human Genome Research Institute to develop recommendations for how investigators should share patients' genomic data with family members.

This month, the group published a series of articles as part of a special issue of the Journal of Law, Medicine & Ethics, reporting on various empiric studies of attitudes among research participants, researchers, and ethics governing bodies to the return of genomic results to families, as well as a consensus report with a list of specific recommendations for when and how results should be communicated.

My group began working on return of results and incidental findings a decade ago. In fact, to my knowledge, we received the first NIH-funded grant dedicated to these issues, which was a grant funded by NHGRI in order to look comparatively at how imaging researchers were approaching incidental findings, and to look at the lessons for genomics researchers.

Imaging was further along as a field in addressing the issue than genomics, so our comparative approach was to look at what imaging researchers were doing and then bring that into the genetics and genomics sphere to consider what lessons that held, and to make adjustments as needed. We published on that in 2008 — a set of consensus recommendations on managing incidental findings — as part of another big symposium issue in the Journal of Law, Medicine & Ethics.

We then got a subsequent grant to look at how this should be managed in the context of biobanks. Biobanks collecting specimens and genomic data are at the center now of genomic research. It's very common for specimens and data to be archived for long-term secondary research, and so we needed to move beyond the simple model of an investigator executing a protocol to consider what should happen when multiple investigators deposit samples or data in a central biobank or repository, and then those materials go out to secondary researchers. That project resulted in consensus guidelines published in Genetics in Medicine in 2012 —  again as part of a special issue.

Can you fill me in briefly on how the project that yielded this new set of articles and insights was designed and implemented?

The grant that produced this new issue of the Journal of Law, Medicine & Ethics on the return of results to family, and this new consensus set of recommendations, is an ongoing collaborative grant between the University of Minnesota, the Mayo Clinic, and the University of California, San Francisco. Three of us are PIs: myself, Gloria Peterson at Mayo, and Barbara Koenig at UCSF.

The goal of this project is to deal with the reality that genomic results may have implications for other family members who are biologically related to a particular proband. We have been hearing from the Clinical Sequencing Exploratory Research (CSER) consortium — of which we are a part — that the issue of family implications and when, if ever, an individual participant's results should be offered to family is a big issue.

As you might expect, cancer genomics projects are encountering this problem with special force because depending on the cancer, quite a few, if not the great majority of participants, may die during the course of the project. In fact, the empirical piece of our own project — our laboratory for testing out these approaches for return of results to family — is based at Mayo Clinic in a pancreatic cancer biobank. Pancreatic cancer unfortunately remains a swiftly lethal cancer. Median survival from diagnosis is only about six months, so it's a strong test case for this question of when results should be returned to family, including after the death of the proband.

The project that produced this symposium issue is both empirical and normative, with four aims and [running over] five years. We are in the fifth year now. What you are seeing in this special issue of the journal is primarily the product of one aim, which is to develop normative recommendations. But this issue also included reports on some of our empirical findings, as we surveyed individuals and family members to try to get information on their thinking and preferences on sharing results in the family.

But the main result of this is the group's consensus paper or statement?

The centerpiece of the journal issue is the article on returning results to relatives, presenting our consensus recommendations. This is a very challenging subject with complex ethics, law, and research design aspects, and it took us three years to study, considering empirical findings, and ultimately negotiating with each other in order to devise these recommendations. In addition, a year ago we held a public conference here at the University of Minnesota and invited key experts to come and publicly critique what was then our late-stage draft. So we were able to take into account the views of others, criticism, and recommendations in order to crystallize and now publish this final article.

Trying to draw out some of the main takeaways, one aspect that seems to strike an important note comes right at the beginning of the recommendations: that researchers should anticipate the potential for requests by relatives for participant results by communicating the project’s policy ahead of time. You also state that researchers aren't required to design their studies to allow return of results to families. Despite that, do you think it's more ethical to design studies so this is possible?

First of all, you are right in that in some ways the biggest punchline here is that it's time to recognize this problem, and researchers really should be thinking ahead and planning ahead and be open with participants in the enrollment process about what the project's policy and plan is on sharing with relatives. One policy would be not to share at all. Another could be to defer to participants' judgment on whether to share. A third could be something more detailed, for instance following our ten recommendations that are summarized in the article.

So the first big message is, "Plan ahead and talk to your participants." They may have preferences about if and when results should be shared, perhaps allowing sharing only after their death. Then, equally important, is the question of who is it that they trust to make decisions as their representative about family member access to their genomic results, including after death.

Another thing you talk about is a "passive disclosure policy." Can you explain a little more what that means?

There isn't a very big literature yet on this problem of what to do about sharing results with family members in a genomic research context. But in the literature that exists, there is a division of view about whether researchers should initiate contact with family members and say, "Hey, we've found something in your loved one or your loved one's data that has potential importance for you, do you want to know about it?" That would be an active disclosure policy, where researchers initiate the process.

The alternative is a more passive policy where researchers are not duty-bound to reach out in that active way, but are ready and know what their plan is in the event that relatives come to them or communicate with them and say, "We would like to know more about what you found." What we recommended was dominantly a passive disclosure policy, for a lot of reasons, including the fact that the goal of research is really to seek generalizable knowledge, not to provide clinical care. Because of that, even return of results to probands themselves has been debated, with some researchers feeling that it goes too far in transforming the research enterprise into something more clinical. I think the dominant view now, and I agree with this, is that researchers have limited duties — more limited than clinicians, but still some duties — to offer back to participants themselves at least a subset of information that is of high clinical importance. That said, if you start expanding those duties and now you include all the relatives, you really have transformed the role of the researcher and greatly enlarged the universe of people they have to worry about in a clinical way.

That's part of why we cabined that responsibility. However, as you see in our fourth recommendation, we created an exception — a safety valve — although this was hotly debated in our group, and this is one place where you can see in the paper that we did not achieve consensus. The majority of the group ended up concluding that researchers may be ethically justified in actively reaching out to relatives in the exceptional circumstance where they discovery a highly pathogenic and actionable variant that the relative is also likely to carry and whose disclosure is highly likely to avert imminent harm.

That is going to be a very small set of findings. And even in those circumstances, we say that ethics consultation is warranted.

It's a tough one, because there seems to be a natural squeamishness around the idea that a researcher could have information that might have disastrous implications for someone's health, and they wouldn't share that.

Sitting behind this recommendation of ours is a series of other recommendations, beginning, as I recall, in the 1990s, from [a variety of professional organizations], about the clinical question of when a physician is privileged to breach the confidentiality of a proband's genetic information and offer it to family members because of a potential health threat. The basic recommendation — mind you, in a clinical, not a research context — is that those should be very rare case, but if the physician concludes that disclosure has the likelihood of averting very significant and imminent harm, the physician doesn't have to, but could reach out to a relative. They may do that without incurring liability or ethical condemnation as a consequence.

We were very aware of that history and debate in the clinical context, and that resolution of the clinical debate, I think, to a great extent informed our thinking.

Anything else in the details here that you would highlight, either in the recommendations or some of the other studies published in this special issue that represent that backbone of research that informed the recommendations?

I think this symposium publication moves the ball forward. With this in print and a great deal of discussion being engendered among investigators, I really expect to see a shift in practice toward considering these issues ahead of time. I would also expect to see IRBs expecting these issues to be considered ahead of time. And I think there is a relationship between this and some of the discussion going on now on the Notice of Proposed Rulemaking (NPRM) that is out for comment now about changes to the Common Rule.

The NPRM proposes a big change on biospecimens, acknowledging that there is a lot of evidence now that people care about what happens to their biospecimens, and that there are potential privacy risks attached to sequencing and other research. So it moves in the direction of urging investigators to get at least broad consent from specimen sources for future research on their specimens.

That is a move toward transparency, toward empowering people to make decisions in advance. And I think that we are seeing a sea change in the relationship between investigators and participants toward greater partnership and greater transparency. Thinking about relatives' access, including after death, is very much a part of that.

A lot of focus is given in the associated articles to issues specifically around research on children or infants. I imagine that's not a coincidence as we see more studies focused on the clinical potential of genomic analysis of children.

One thing we did that is very much in keeping with current trends is to strongly encourage consideration of a child's preferences if the child is old enough and able to express preferences about access to their information. In most cases, it's still going to be up to parents and guardians, and it's complicated in pediatrics research because honestly, the parents may already have the information, as they are often the ones giving permission for the child to be in research. Nonetheless, we took seriously this question of when a child's information should be available. There are circumstances in which there may be a preference to not share data, or in which family members may be making incorrect assumptions about genetics, like in cases of misattributed paternity or undisclosed adoption.

I think it's important to recognize that even though the empirical data show a lot of support for families to have access, it's not unanimous. We need to do much more research in diverse populations and family settings in order to really understand the range of preferences that policy should respond to. I think there is wonderful empirical work on this in this issue, but I think all the authors would agree that we really need to replicate those findings in a more diverse setting that is attentive to the full spectrum of views on sharing.

With more and more genomic analysis going on, I imagine there is growing diversity in how individual projects approach all of these issues. Do you think that there is benefit in or an ethical mandate for standardization, and do you hope that the recommendations you and your colleagues have put forth may help draw things together?

I'm not sure I would use the world “standardization,” but I think there is great benefit to developing best practices that are grounded on evidence and on careful consensus-building. I do think the worst way to approach these issues of return of results is with no guidance at all.

And I think there is a growing convergence on policy, even though there is much important research to be done.

You mentioned that you and your colleagues are in the fifth year of this project. Now that you've put out this document and the associated empirical studies, where do you go from here?

There are two big things that we are doing. One is, we are trying this out in a subset of families, which is extremely exciting, actually collecting all sorts of data and measures to see how this works. Many projects work long and hard to devise recommendations and don't have the opportunity to test them, but we are testing these [in a Mayo Clinic pancreatic cancer biobank cohort]. That is an important next step and may lead to further refinements.

The other thing we are doing is trying to develop a toolkit, including consent language and biobank policy — the nuts and bolts of what would be needed by investigators, biobanks, and institutions to really make our recommendations work.