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Should Researchers Warn Their Subjects About Genetic Danger?

It seems like an easy question, but the indirect correlation between genetic mutations and disease risk muddles up the ethics.
(Photo: winui/Shutterstock)

(Photo: winui/Shutterstock)

If you were aware that someone was in grave danger but didn't know it, would you warn them? Most of us would. These days, medical researchers are often confronted with people who may be in danger: unsuspecting human research subjects who carry mutations that could cause a devastating disease. It seems obvious that medical scientists should warn their study subjects when they stumble across a potentially dangerous mutation. But as it turns out, the ethics involved aren't so simple, and warning people about a possible risk may not always be the right thing to do.

DNA analysis is becoming a routine part of most biomedical research, and that means researchers are now very likely to stumble across "incidental findings" in their human subjects. “Incidental findings” is the technical term for potentially pathogenic mutations that have nothing to do with the focus of the research, but which put those who carry them at risk for major health problems. Researchers studying diabetes may find that some of their subjects are carriers of cystic fibrosis, or have a mutation with a high risk for breast cancer. This genetic information is clearly important to pass on, since it could have a big influence on their study subjects’ decisions about their medical care or about having children who might inherit a genetic disorder.

How common are incidental findings? Last fall, scientists at the University of Washington examined a population of 1,000 randomly selected subjects whose genes had been sequenced as part of a large study by the National Heart Lung and Blood Institute. The researchers looked for mutations in 114 "medically actionable" genes for which there are specific, evidence-supported treatment recommendations. Mutations in these genes showed up remarkably often. Over half of the study subjects carried a mutation that was classified as disease-causing in a leading database of human mutations.

But this initial result was misleading. The researchers had a panel of experts in medical genetics review the mutations, and found that only a handful of the mutations were likely to be pathogenic and clinically actionable. In the end, only 18 out of the 1,000 human participants had serious incidental genetic findings that would be important to share with the study participants.

These results pose a dilemma for well-intentioned researchers who would warn their study subjects about harmful mutations: without careful review by clinical experts, they’re overwhelmingly likely to do more harm than good by telling subjects about them. If researchers aren't careful, they could lead people to undergo expensive and unnecessary follow-up testing, and leave subjects with anxiety over their health that may never go away.

So what seems like a straightforward ethical decision—to warn someone of potential harm—is, like most other areas of biomedical ethics, not so simple. Because validating incidental findings involves more than checking a database of known mutations, and because many research teams don't have the resources or the clinical expertise to pick out medically actionable mutations, it’s not clear when researchers are ethically obligated to warn their subjects of possibly dangerous mutations.

As genetic research develops, this issue is growing more urgent, and research organizations are trying to formulate sensible and workable guidelines. Writing last week in the American Journal of Human Genetics, a committee made up of members of two medical research consortia reported their recommendations and identified questions that are still unresolved.

The committee argued that a crucial principle is that research is distinctly different from clinical care "in both its goals and procedures." The point of research is to gain knowledge, not to provide patient care. To do their jobs effectively, researchers can't always follow established clinical standards for, say, sample handling or methods analysis. For example, the expensive safeguards against mislabeled samples in clinically certified diagnostic labs are impractical in research labs. And perhaps most importantly, the relationship between researchers and study subjects is not the same as the doctor-patient relationship. Researchers certainly have an ethical obligation to minimize any danger that their subjects are exposed to in the study. But because most researchers aren't trained as physicians, and because of the nature of research itself, they can't assume the legal obligations that a physician has toward a patient.

The distinction between medical research and medical care is helpful, but it leaves some important questions unanswered. Should we spend research funds to ensure that incidental findings meet rigorous clinical standards? And if the data are on hand, should researchers always check for known disease mutations, even if that analysis wasn't part of the research?

In their report, the committee argues that requiring researchers to spend much money or effort hunting and validating incidental findings would be "a low-yield preventive health screening," and, given the cost, "one could think of many interventions that would most likely yield a higher benefit." But when researchers do discover "analytically and clinically valid" mutations, they should tell their study subjects, and research budgets should include the funds to do this properly.

While the biomedical research community is still struggling to explore this ethical ground, the legal landscape is almost completely uncharted. The distinction between medical research and medical care is important, but in practice it’s hard to maintain, because the whole point of research is to improve medical care. With incidental findings, research spills over into medical practice, with legal questions that are hard to avoid. If researchers discover that a subject carries a severe breast cancer mutation, but fail to tell her, should they be legally liable? What if a researcher warns you that you are a carrier for cystic fibrosis, but turns out to be wrong?

Reviewing these questions, a group of bioethicists found that "there is very little legal precedent to determine the parameters of researchers’ risk of liability at this point in time." In the near future, this could get very messy: "Absent clearly defined and agreed upon standards, and given that there is still fervent debate about how to interpret variants and what, if any, results ought to be returned and how, it will be extremely difficult to prove what the standard of care is or that it has clearly been breached by a researcher acting in good faith."

In other words, if biomedical researchers don't establish their own standards for incidental findings, the courts may soon do it for them.