The Coming Explosion in Genetic Testing — Is There a Duty to Recontact? — NEJM

Perspective

The Coming Explosion in Genetic Testing — Is There a Duty to Recontact?

Reed E. Pyeritz, M.D., Ph.D.

N Engl J Med 2011; 365:1367-1369October 13, 2011

Article

References

The question of whether a duty exists to recontact patients about new genetic information has been debated for several decades without consensus, but the emergence of new technologies compels us to reconsider this complex matter. Ordering a “genetic test,” such as a chromosome analysis or a search for a mutation, is different from ordering a complete blood count. Before obtaining a specimen, counseling of the patient is required in order to discuss confidentiality, potential anxiety, stigma or discrimination, the interpretation and implications of possible results, and relevant follow-up options. Ideally, both pre- and post-test counseling would be conducted by genetic counselors, but there aren't enough such professionals to meet the current demands.

Uncertainty in the results of many genetic tests, such as gene sequencing and cytogenomic arrays, presents a conundrum. A result may be abnormal and clearly pathologic, reflecting a disease that is present, a disease that will appear later, or a susceptibility to a common disease. Conversely, depending on the thoroughness of the analysis, a “negative” result may not mean that the patient doesn't have a mutation. Perhaps the most confounding outcomes are “variants of unknown significance” — the primary findings in 5 to 30% of all gene-sequencing results. The complexities inherent in genetic testing will expand markedly as whole-genome sequencing becomes more widespread.1 The thousands of whole-genome analyses performed to date have all revealed clear mutations in several genes and many variants of unknown significance.2 The clinical implications of much genetic variation will eventually become clearer, but today uncertainty is the rule. Emphasizing this point, and the need for rigorous pre- and post-test counseling, does not, in my view, constitute genetic exceptionalism. These are facts of life.

Determining whether, when, and how to recontact patients when the interpretation of their genetic test changes involves ethical, legal, and practical considerations. Ten salient issues should stimulate and inform the debate (see tableConsiderations Regarding Recontacting Patients with New Information on Past Genetic Tests.). Most require further investigation.

First, improved understanding of genetic variation will eliminate clinical uncertainties. Individual practitioners can research periodically what has been learned about each patient, but tracking every patient with one variant of unknown significance, let alone many such variants, requires vast amounts of time. If recontacting is considered the standard of care, bioinformatics systems that flag patients with updated interpretations will be essential. Though primary care providers are best positioned to recontact patients, they are currently unlikely to have advanced information technology.

Second, in any whole-genome sequencing, many pathologic alterations will be found that have no direct relevance for the clinical indication that prompted the test but are potentially relevant to the patient.3 An “incidentaloma” discovered on a clinical CT scan would probably be pursued through counseling and further evaluation, but the sheer number of potentially adverse findings in a whole-genome analysis will overwhelm any clinician.

Third, it's unclear whose responsibility it is to recontact a patient.4 At $1,000, whole-genome sequencing is considerably less expensive than an analysis of one or two genes. Some conditions can be caused by a mutation in one of a dozen genes, so whole-genome sequencing will soon be the most cost-effective procedure. Whoever orders such an analysis, whether specialist or primary care provider, may have little expertise in deciphering or counseling about the “incidentalomes” and variants of unknown significance mentioned in the report. The burden of further interpretation may revert to the primary care physician, who may not have ordered the test and may have to rely on the consultant's report rather than the complete details of the data. One option would be for the laboratory to report only information relevant to the reason the test was ordered. Alternatively, the decision about how much information should be included in the report could be left to the patient. Most might choose the entire genome analysis, unless a price differential deters them.

Fourth, a genome sequence incorporated into a patient's health record is a double-edged sword. Anyone with access to the record can obtain the data. But does any physician who encounters the patient and uses the record thereby become responsible for informing the patient about new genetic interpretations? Entering in the record only genomic information that is currently actionable might reduce liability when information emerges about other sequences, but it might also preclude action on a genetic variation when its meaning becomes clear. Fifth, expectations of patients who might be recontacted have been studied in several settings. Most indicated that they wanted to be updated, though the cost of updating them was not addressed. Some chose, for various reasons, to avoid learning about new information. Sixth, a change in the interpretation of a genetic test result might have implications for people other than the patient. If a variant of unknown significance later turns out to be pathologic, the patient's relatives would have a new testing option. Similarly, an incidental finding on whole-genome sequencing could be important to family members. Determining who, if anyone, is responsible for informing at-risk relatives involves clinical, ethical, and legal questions. Seventh, our ability to interpret genetic laboratory tests needs to move beyond the simple delineation of genomic sequences. The effects of most genetic alterations depend on numerous factors, including genetic and epigenetic interactions, the microbiome, the environment, chance, and personal behavior. We are in the very early stages of integrating genetics into our understanding of systems biology for application to immediate and future health issues. Eighth, all these issues are magnified by direct-to-consumer (DTC) genetic testing. Anyone can submit a sputum sample to a commercial enterprise and receive information about the risks for a growing number of common diseases. Despite the disclaimer that DTC testing companies don't provide medical advice, most consumers pursue genotyping to improve their health. Two problems with DTC testing have been widely discussed: the relative risk that any allele conveys for a specific disease is modest; and the clinical utility of the information is virtually unknown. However, consumers bring results of DTC genotyping to their physicians. If these results are entered in the medical record, as some consumers desire, is the physician obligated to update the patient as new markers and clinical utility are defined? Ninth, an agreement to recontact might result in maintaining a physician–patient relationship that would otherwise be terminated. Even absent a formal agreement, entering into the record a new interpretation of a genetic test that a consultant ordered in the past may legally reestablish the relationship, and failure to recontact the patient could be viewed as abandonment. Finally, strategies for educating clinicians and consumers about the uncertainties of genetic testing are just being formulated. Medical schools, residency programs, professional societies, and patient organizations all have important roles to play.

Until substantial progress is made in addressing these issues, health care professionals who order or receive the reports of genetic tests must consider whether they have a duty to recontact patients. The American College of Medical Genetics distinguishes medical geneticists serving as one-time consultants from those with an ongoing relationship with a patient and states that in the former case, the burden rests with the primary care physician.5 However, a survey of medical geneticists a decade ago found opinion divided about a responsibility to recontact patients. The conclusion then was that establishing a duty to recontact was ethically desirable but logistically impractical. This tension persists today.

Clinicians could decide arbitrarily whether to update patients or involve them in the decision. Until capabilities improve, clinicians should accept with caution an explicit duty to recontact — and should discuss their position when they counsel patients about genetic testing. The one-time consultant might explicitly terminate the physician–patient relationship after review of the initial test results. A discussion during a consultation can identify patients who don't want to be updated, and those who do can be informed about available resources.

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Source Information

From the Center for the Integration of Genetic Healthcare Technologies, Leonard Davis Institute for Health Economics, Center for Bioethics, and Departments of Medicine and Genetics, University of Pennsylvania, Philadelphia.

The Coming Explosion in Genetic Testing — Is There a Duty to Recontact? — NEJM