This story was originally published May 20.
The questions surrounding incidental findings in clinical sequencing — whether to return them, which variants to return, how to return them, and who should be involved in that decision — have been some of the most hotly debated questions as next-gen sequencing is increasingly being used to provide diagnoses or guide treatment decisions.
Last week, a pair of articles published online in Science, debated the pros and cons of the American College of Medical Genetics and Genomics' recommendations on incidental findings from clinical sequencing.
ACMG issued the recommendations at its annual meeting in March, in which it laid out a minimum list of pathogenic variants on 57 genes corresponding to 24 disorders that the organization felt should always be analyzed and returned to the ordering physician, regardless of patient preference.
In an article supporting the ACMG guidelines, researchers from Baylor College of Medicine; Harvard Medical School; the University of California, San Francisco; the National Human Genome Research Institute; the University of Alberta; and Brigham and Women's Hospital argued that laboratories "have an obligation to report clinically beneficial incidental findings."
Countering that argument, researchers from the University of Minnesota, Boston University, and Northwestern University make the case that "returning genetic incidental findings without patient consent is misguided."
The recommendations are a "big departure from the pre-existing consensus, both on the patient's right not to know and also on testing children during childhood for genetic disorders of adult onset," Susan Wolf, lead author of the paper arguing against the recommendations and the McKnight Presidential professor of law, medicine and public policy at the University of Minnesota, told Clinical Sequencing News.
Immediately following the release of the recommendations, some laboratories were concerned that the guidelines were at odds with their current practices (CSN 3/27/2013). In the months since, ACMG issued a clarification further explaining its rationale, and several clinical sequencing providers have adopted the recommendations but only in part, including an opt-out option for patients (CSN 5/8/2013).
Making the case in support of the ACMG guidelines, the researchers wrote that the recommendations "represent an initial attempt to set a professional standard for best laboratory practices that will responsibly minimize variation in laboratory analysis and reporting of clinically beneficial incidental findings."
Currently, there are no standards guiding the reporting and analysis of incidental findings from clinical sequencing. So, clinicians may receive different results depending on which laboratory performs the sequencing. Additionally, the recommendations restrict the list of incidental findings to variants that are "unequivocally pathogenic," that have a very high probability of leading to disease, and where "evidence strongly supports the benefits of early intervention."
Patient autonomy
While most agree that there needs to be standards for clinical sequencing, detractors say that the recommendations run afoul of patient autonomy.
The group in favor of the recommendations argued in the paper that even though ACMG suggests that patients must consent to receiving results regarding the genes on the minimum list in order to obtain clinical sequencing, patients still have autonomy in that they can choose not to be sequenced.
"From our perspective, the recommendations are clear that you need informed consent and pre- and post-test counseling," Amy McGuire, lead author of the paper and director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine, told Clinical Sequencing News.
"The scope of analysis and what is clinically relevant is a matter of expert judgment," she said, adding that this has "been misunderstood by some to say [it means there is] no patient autonomy."
Test counseling should describe the types of incidental findings that could be uncovered as well as their risks and benefits, and patients always have the right to refuse testing, she said.
However, Wolf counters that it's critical "for the adoption of this important technology, that patients' rights be respected, that patients feel they can trust their clinicians to respect their decisions. Patients have to be confident that they retain some control over what's being analyzed, the information that's being returned to them, and that their privacy interests are being protected."
She said there are a number of legitimate reasons why a patient would not want that extra information. For instance, she said that late-stage cancer patients may not want the extra burden of obtaining such results. Patients also may be concerned that such information may impact their ability to obtain health insurance.
While the researchers that argue that the recommendations are consistent with current practices with regards to informed consent and patient autonomy — saying that an exome or whole-genome sequencing test is one broad test — Wolf and her colleagues view each of the 57 genes that are analyzed as discrete tests.
While the sequencing itself may be one act, "to interpret it, to analyze it, you actually have to take the affirmative step of interrogating that data," asking, for instance, "what do the data tell me about BRCA 1 and 2?," she said. "It is a further interrogation of the raw data that requires consent."
The ACMG's list of genes "includes mutations in genes that patients have long been able to refuse testing for, including cancer risk mutations (such as BRCA1) and cardiovascular risk mutations," the authors wrote.
Testing in children
Another contentious issue has been ACMG's decision to apply its recommendations to children and adults alike.
According to Wolf, the recommendations go against a "longstanding position … that children should not be tested for adult onset disorders unless there is a direct benefit to the child," she said.
On the other side, McGuire and co-authors argued that applying these guidelines to children as well as to adults makes sense because the alternative "withholds information that is potentially life-saving for the child, one of the parents, and potentially other family members — information that they would otherwise have no reason to suspect."
This recommendation does not go against ACMG's general guideline about genetic testing in children, which says that children should not be tested for adult-onset conditions. Instead, the current recommendations "address a very different context," in which both the child and the family's interests should be considered.
However, Wolf argues that longstanding medical practice, legal, and ethical guidelines have said that "medical treatment of children should be guided by the best interest of the child, not secondary benefit to the family."
Next steps
Going forward, both Wolf and McGuire said there will likely be significant discussion and debate of the guidelines.
"There will be a very robust dialog both in the literature and in meetings," said Wolf.
Aside from the two recent Science articles, researchers from Stanford University recently expressed their opinions on the guidelines in an article in Trends in Biotechnology, writing that the recommendations are "challenging from both an ethical and a practical perspective" because "the implication that individual autonomy should be over-ridden by physicians for the patient's 'own good' is weakly supported in modern clinical ethics."
McGuire said that ACMG will gather input about the list itself and what should be included on the list, but noted that it will unlikely change the overall principles of the guidelines.
"I think the recommendations did kind of move this discussion forward in a very productive way," she said.
For her part, Wolf would like to see ACMG revisit the guidelines and "re-issue a new statement that restores [its] commitment to patient autonomy, informed consent, … and the absolute priority of a child's best interest," she said.
"ACMG has an important and valuable role to play in articulating standards and promoting dialog," she said, and "it's a genuinely hard topic."
So far, both Ambry Genetics and GeneDx have said that they will adopt the recommendations, but only in part, giving patients the ability to opt-out of receiving results. Even Wayne Grody, former ACMG president and member of the working group that developed the guidelines, said that his institution, University of California, Los Angeles, would consider letting patients opt-out of receiving results from its clinical exome sequencing test.