Recently, the ACMG released recommendations for return of incidental findings following genome or exome sequencing, garnering a great deal of attention in the science media and some in the popular media as well – most of it stressing two points: the fact that the guidelines call for certain results to be returned regardless of patient preferences, and that they call for the same results to be returned regardless of patient age. These are big departures from current practice, and they have drawn a lot of fire for going too far (or for not going far enough).
The reasons for the paradigm change were explained at length in the ACMG report, which is well written and worth reading in it’s entirety. I am going to discuss a few of those reasons here, but first let me emphasize one thing I believe was often obscured in the first-reaction coverage: the report does not suggest that all incidental findings should be reported. Not even close. The list of conditions is relatively short (about 35, although the authors acknowledge that it will inevitably get longer) and strictly curated. In each case the result in question has a well-established risk of likely and serious harm, at least potentially amenable to intervention. Likely, serious, preventable: the criteria echo the language of duty to warn, stemming from the famous Tarasoff case in the 1970’s. In duty to warn cases, the danger is such that it demands action even when that action violates a patient’s right of confidentiality – a serious breach, and as such the bar is set high. In this case, the competing right, as it were, is the right not to know – or to state one’s preferences – and the danger is to oneself and one’s family rather than to a stranger. But the model is the same, as is the commitment to reserving this option for circumstances where the risk is compelling.
One difference between a duty to warn scenario and incidental findings is that with IF’s, you have the option, theoretically, of asking the individual for his or her preferences in advance, and then using that as a guide. That has always been our default recommendation, and the ACMG report explains several reasons why they deviated from this standard:
1. The information is THAT important.
Driving the issue of incidental findings is a better understanding of what certain gene changes mean – not perfect, but better. Mutations of significant prognostic value used to be the exception and not the rule – okay, they still are. A lot of the information we have about genetic variation is suggestive rather than diagnostic. Only a limited number of known gene changes produce risks in the manner of, say, BRCA 1/2 mutations. But some things do. Hypertrophic cardiomyopathy. MEN2. Familial hypercholesterolemia. Remember, the right not to know – the acknowledgement that someone might reasonably assume they were better off not knowing – is predicated on the inherent uncertainty of genetic information, and our inability to change the outcome. And while I would be the last person to suggest that is no longer the case as a rule, we have made some progress on both of those fronts.
We still have a way to go to understand the relationship between genotype and phenotype, especially where medical or family history are uninformative. For some if not most of genetic variation, I personally doubt we will ever reach the point of acceptable or compelling certainty. But we have come to the point where BRCA 1/2 is not the ONLY example of a relatively common genetic variant with real predictive utility. The list assembled by ACMG is going to get added to – and perhaps subtracted from – over time. But there are a limited number of circumstances where the risk of harm is so great and so well substantiated that in the event of a bad outcome, our justification after the fact for not identifying and disclosing those results would ring hollow in our own ears.
2. Setting a standard that relies on pre-test counseling is unrealistic as the use of genome-based testing expands beyond the genetics clinic.
The best thing about the ACMG recommendations is that they are what I like to call reality-based. First, genetic testing is increasingly used in all sorts of subspecialties (cardiology, pediatrics, audiology, oncology, etc). We can’t dictate to them how to do pre-test counseling, and even if we could, they are not necessarily prepared to explain genetic concepts. We imagine a world where sequence-based testing is a first-line alternative in all sorts of medical situations, from emergencies to routine medicine. If you assume that an expert and careful process of informed consent does not occur, as it absolutely will not in many circumstances, then you need to establish what happens by default, when the clinician does not have any information on patient preferences. This set of recommendations doesn’t close the book on that process, but it does provide a really well thought out starting place. It gives you a baseline: if nothing else don’t miss these. That’s tremendously valuable.
Additionally, standards that rely on pre-test counseling may sound ideal, but often prescribe procedures for the informed consent that are problematic in their own right. Informed consent is not a junk drawer where you cram everything that does not fit somewhere else. Beyond a certain point, pre-test counseling becomes a process of wearing down rather than educating a patient – in writing or in person, the moral equivalent of ten pages of fine print is a bludgeon and not a tool.
3. Inconsistent reporting from laboratories is dangerous.
No question but that the thrust of the ACMG recommendations is to suggest that this is information that should be delivered to the patients and their families. But in fact, the guidelines don’t dictate what a clinician should tell a patient; they spell out what a lab should give to a clinician. They set standards for what a lab should be obligated to look for and report in all uses of exome and genome sequencing. And even if you take issue with the list, there is still a benefit to establishing uniformity. Currently, the labs that do commercial exome sequencing vary widely in reporting procedures – some give back a great range of results, others only those relevant to the diagnostic question, and others provide a choice. For the clinician, this means that advising a patient for what to expect from testing must be tailored to each lab’s protocol. And it leaves a lot of room for confusion. For instance, a physician accustomed to getting incidental information on – say cardiomyopathies – might see the absence of that information as a clean bill of health, when it might merely represent the typical practice of a certain lab.
Clinicians, the ACMG report acknowledges, will put the results in context for patients and families. Therefore, the recommendations as written provide more room for clinical judgment than the headline suggest. It is at the clinical level that family history, medical history and immediate context are integrated into how, what and when information is given out. Patient preferences can be taken into account, as can the priorities of a patient or a family in times of stress.
Furthermore, since most incidental findings (including carrier status, pharmacogenetic information, etc) are not included in this list, there is a lot of room for a clinician who design a process based largely on patient preferences. The recommended list is a floor and not a ceiling; it begins but does not end the dialogue between the provider and the patient.
In reviewing the current debate over the return of incidental findings, the ACMG report categorizes the two sides thusly: there are genetic libertarians and the genetic empiricists. Libertarians wish to give individuals unfettered access to their genomic information – all the hits, Google-style – and trust the algorithmic magic of search engines and accumulated wiki-wisdom to bring test-takers closer to the truth than physicians can by doling out information according to their own judgment (in support of which, the libertarians are likely to cite the lack of genetics expertise among physicians, and you can’t argue with that). Empiricists – and I am a little less certain about how well that word applies – are more concerned with the dangers of over-sharing, and they typically point to the potentially misleading nature of results with a small or unsubstantiated effect size and the loss of autonomy that occurs when information is thrust unrequested upon patients or given out to parents and caretakers on behalf of minors. The good news for ACMG is that their recommendations have come under attack from both sides, so they can reasonably assume that they are doing something right.
This libertarian-empiricist divide can reflect many prisms: age; personal experience; East Coast establishment values versus a West Coast ethos of let-the–information-run-free. In any event, it is the more protective point of view that emphasizes the value of genetics expertise and counseling, and the genetic counseling community tends to identify strongly with norms that stress caution in terms of what, when and how information is shared with patients. But we should be carefully not to become reflexively protective of our own practices so that we cannot reexamine them to reflect changes in what we know, or the best interests of our patients and their families.