Ethical Considerations in Precision Medicine and Genetic Testing in Internal Medicine Practice: A Position Paper From the American College of Physicians

Appendix: Background and Rationale

Position 1

Genetic testing, like any testing, should be guided by the best interests of the patient, scientific evidence, and ethical standards. The physician's ethical responsibility to practice high-value care requires consideration of the benefits and harms of any test based on the scientific evidence.

Since the mapping of the human genome in 2003, the availability of genetic testing has skyrocketed, and the cost has plummeted. The ease of accessing this new technology by both patients and physicians raises important ethical questions about whether, when, and how physicians should suggest precision medicine strategies and genetic testing to patients. As testing becomes more common, primary care physicians who engage in comprehensive risk assessments for chronic diseases and recommend tailored pharmacologic therapies will be asked to guide patients on the appropriate use of genetic testing (6).

Including the genetic basis of disease in clinical decision making has the limitations and uncertainties associated with a nascent field that is rapidly evolving and includes a wide variety of testing approaches. These range from tests for specific genetic variants with clearly defined clinical purposes, to polygenic risk scores that synthesize multiple genetic markers associated with a disease or trait to indicate risk, to exome and whole-genome sequencing tests that generate vast amounts of information of varying clinical value and are challenging to interpret. The meaning of results of tests based on sequencing technology may change over time and may introduce new uncertainties into clinical care.

Good clinical ethics depends on sound clinical evidence. As with any medical test, there is an ethical responsibility to ensure that a genetic test is clinically indicated for the patient, a judgment that involves many considerations. In addition to considering the benefits, harms, and costs, the ACP Ethics Manual provides guidance for thinking about a genetic test's characteristics and utility as ethical concerns. This entails consideration of whether the test is analytically valid (does it accurately detect the presence or absence of a genetic variant?), clinically valid (does it accurately relate the variant to the disease?), clinically useful (will the results inform the diagnosis, treatment, or prevention of a disease?), and personally useful to the patient (will the results provide important personal or familial information to inform decision making?), as well as the harms associated with the test, including potential negative consequences for the patient's life (5). Most genetic studies have been conducted in populations with European ancestry, thereby limiting direct inferences about risk to other populations. These limitations in the generalizability of our genomic evidence should be considered when discussing the risk associated with genetic variants and polygenic risk scores with patients.

The Centers for Disease Control and Prevention's Office of Public Health Genomics uses a similar framework for evaluating scientific evidence on genetic tests and guiding clinical decision making (7, 8). Testing should not be done until “potential consequences of learning genetic information are fully discussed with the patient” (5). Genetic tests can have broad implications. When testing is indicated, the following “should be made clear to patients in advance of testing” (5):

• Risks, benefits, and limitations of testing

• The possibility of uncovering information that is incidental to the reason for testing (often with uncertain disease associations or implications regarding familial relationships and identity)

• Health or other implications for family members

• Costs

• Other possible consequences (such as anxiety; discovery of unwanted information; employment discrimination; life, disability, or long-term care insurance discrimination)

For tests that involve multigene panels or exome/genome sequencing, 2 additional concerns are important. First, the test may identify genetic variants that are of uncertain clinical significance (9). Second, depending on the extent of analysis undertaken, patients may receive genetic risk information unrelated to the clinical question for which testing was initiated. Patients should be informed about potential secondary analysis and should have the option to decline it.

Achieving consensus on what genetic information is clinically actionable can be a challenge. A scenario in which a patient requests a genetic test to obtain information that may be personally meaningful but not medically actionable can pose an ethical dilemma (for example, APOE4 testing to assess risk for Alzheimer disease). In such situations, physicians should encourage patients to consider what they would do with the information; how the information may personally affect them and their biological relatives; potential adverse effects, including the consequences of associated clinical tests and procedures; and costs.

Decisions to offer genetic testing and sequencing should be guided by the best interests of the patient and the best evidence (5, 10). The physician's primary obligation is to the good of the patient. Physicians have a duty to practice evidence-based medicine and should be responsible stewards of resources while providing high-value care (5). Public health considerations are beyond the scope of this paper.

Genetic testing decisions should be driven by the ethical considerations that guide other clinical testing decisions (see the Appendix Table). Bayesian reasoning applies—the pretest likelihood of a genetic disorder may be so low, for example, that testing should not be offered. The sensitivity and specificity of the particular test need to be considered; both false-positive and false-negative genetic test results are possible. As Laine notes in discussing testing generally, “In the face of uncertainty, physicians must weigh the benefits and harms of testing and make decisions based on probabilities” (11). Tests with a high false-positive rate may cause more harm than benefit. A false-positive result is likely to be followed by unnecessary interventions, with potential for iatrogenic harm, anxiety, and cost to the patient. Clinicians' recommendations should also incorporate the standardized guidance on the clinical actionability of genetic variants developed by the National Human Genome Research Institute's ClinGen collaborative (12).

Consideration must be given to whether the results of the test will affect clinical decision making. If not, there is insufficient reason to offer the test. Laine continues: “Armed with information that a test would not alter clinical action and/or might cause harm, many patients will change their minds about wanting the test” (11). In some cases, patients may want a test to rule out the presence of a genetic variant when a condition is treatable or preventable. For example, a young adult who is negative for the BRCA1 mutation carried by a parent may find a negative test result reassuring. Clinicians can help patients think through the decision to proceed with a genetic test by balancing the tradeoffs of testing with the reassurance obtained with a negative result. Clinicians should clarify the base rate of the test, the pretest probability of the mutation in the particular patient, the potential false reassurance of a false-negative result, and whether the result is likely to change clinical decision making.

The benefits of genetic testing as part of precision medicine are greatest when it is used to answer an actionable clinical question and the genomic findings can be translated into treatment recommendations. Examples include when there is a risk for an increased predisposition to a disease that can be prevented, to guide the choice of an effective medication, to improve tumor classification to guide treatment, or to end a “diagnostic odyssey” for patients with rare disorders (13, 14). Failing to order an indicated genetic test could also substantially influence diagnosis or treatment decisions.

Position 2

Physicians should prepare to engage with patients in discussions about the opportunities and ethical challenges of genetic testing and precision medicine.

Genetic testing has to date been largely the purview of a small number of medical geneticists and genetic counselors; they will remain vital to caring for patients and guiding them on difficult decisions about whether to undergo genetic testing and what to do with the results. With the expansion of precision medicine and genetic testing, the clinical workforce will need enhanced training, guidelines, and clinical tools (15). Team-based primary care that includes input from medical geneticists and genetic counselors will be at the forefront of the ethical integration of genomics into clinical care.

As the use of genomic testing increases in clinical care, patients will turn to primary care physicians for guidance on appropriate test use, risk assessment, prevention options, and treatment decisions. Importantly, there will be some patients for whom genetic testing is clearly recommended (for example, patients with high-grade serous ovarian cancer) (16, 17). Genomic testing, however, may predict or detect susceptibility to diseases without the ability to prevent, treat, or cure them (18). Patients and clinicians will need to appreciate the nuanced distinctions between highly predictive genetic variants that indicate the presence of inherited conditions and tests that offer probabilistic information, sometimes indicating only low or moderate risk (5). Educating health care teams and creating an infrastructure for clinicians to easily access genetic counselors will be critical to the responsible integration of genomics into clinical care (19). For example, primary care physicians will benefit from training to identify inherited cardiac conditions, including arrhythmias, cardiomyopathy, and familial hypercholesterolemia. Awareness of red flags that indicate a patient may have a predisposition to an inherited cardiac condition, such as sudden unexplained death in a previously healthy young relative or a young patient with unexplained palpitations, syncope, or seizures, will help clinicians understand when to engage genetic counselors for guidance on the role of genetic testing and potential options for clinical surveillance if a patient has an inherited cardiac condition.

Responding to patients' questions will require increased knowledge and point-of-care informational tools. Additionally, physicians will need to cultivate the ability to have nuanced conversations with patients about the risks, benefits, and limitations of genetic testing. Recent evidence suggests substantial deficiencies in primary care physicians' readiness for this challenge, specifically among clinicians who are further removed from medical training (20–23). Medical schools, residency programs, and continuing medical education programs need to develop innovative and pragmatic curricula to address the current educational gap. The focus should be on applied knowledge, including what tests to order and when; why a test is or is not indicated; how to inform patients about the meaning, risks, and implications of a test; and how to disclose results to patients. This should include how to talk with patients about the “limits and the potential harms of uncertain and unwanted information while listening to patients' beliefs and preferences” (24).

Professional schools and residency programs can lay an educational foundation, although rapid changes in genomics emphasize the need for continuous learning to optimize patient outcomes (25). Physicians can access a growing number of resources, including verified peer-reviewed e-resources (26), and, whenever needed and possible, should refer to or partner with genetic counselors to provide guidance to patients (27).

Important issues that have gone unacknowledged include the potential harm to the patient and to the patient–physician relationship if laboratory results—which are often not in plain, understandable language—are shared with the patient before the physician has an opportunity to discuss them with the patient. This is similar to the concern about automatic disclosure of test results and open notes through patient portals before discussion with clinicians, and it will be magnified in implementation of the 21st Century Cures Act ban on information blocking (28). The time required for these complex encounters, which entail extensive interpretation and discussion, also poses a challenge for physicians, especially given the pressure clinicians and patients now experience in time-constrained primary care visits. This time pressure will be exacerbated if testing results in unnecessary tests, procedures, or a “cascade effect, in which ambiguous, incidental, or false positive results lead to further work-up or counseling that creates anxiety, cost, and potential harm” (29).

Position 3

Patients will need assistance from their physicians to understand the risks, benefits, and uncertainty of direct-to-consumer genetic medical testing.

Direct-to-consumer (DTC) genetic medical testing has become a reality, with risks, benefits, and uncertainty. The ability to make an autonomous choice to obtain information about one's health is a value that should be enabled by an informed understanding of the associated risks and benefits of the test (30–32). Physicians can help facilitate informed decision making by discussing risks, limitations, uncertainty, benefits, and alternatives. Patients who present to physicians with results of DTC medical testing should also be counseled on the limitations and implications of the results for themselves and their biological relatives and the potential effect of genetic information on life, long-term care, and disability insurance (33).

Some commentators believe that initial concerns about the potential for DTC testing to cause patient harm are diminished by empirical studies of consumers who reported that the results caused them to be more careful about diet and exercise and that the findings in many cases decreased anxiety (34, 35). Typically, DTC genetic medical testing focuses on tests indicating moderately or even minimally increased risk for common conditions, such as diabetes. There is also a need for broader assessment of the effect and utility of DTC testing, particularly because testing may sometimes include high-risk tests, such as testing for BRCA1/2 genetic variants that cause hereditary breast and ovarian cancer. Concerns remain about patients' understanding of results, the potential for patients to make health decisions based on incomplete information, the false security of negative findings and the effect on preventive health behaviors, the lack of data from prospective trials demonstrating improved clinical outcomes or actionable care plans, the potential for the results to influence future insurance (for example, life, disability, and long-term care insurance are not included in the Genetic Information Nondiscrimination Act [GINA]) (36) or employment status, and the privacy risks associated with DTC genetic testing (37). In addition, patients may not be aware that DTC genetic testing data can be disclosed to and used by law enforcement in certain circumstances, and DTC testing companies may not be covered by the Health Insurance Portability and Accountability Act (HIPAA) privacy law (38).

The U.S. Food and Drug Administration has expressed concerns about consumer understanding of tests, incorrect results, and their erroneous interpretation (39). There is little regulation of DTC services. Physicians can help patients clarify their motivations for pursuing testing, assess the quality of services provided, help patients understand what will happen to their data, and integrate the results into their diagnostic assessments. For example, patients should be informed that DTC testing provides genetic health risk information, that the information should not be used as a basis for major medical decisions or diagnostic purposes, and that, if indicated, these tests may need to be repeated in a clinical laboratory (40). As Gill and colleagues recently highlighted with regard to DTC BRCA mutation testing, there are problems of “over testing, misinformation and misallocation of resources” (41). These and other issues identified in this paper are serious concerns. Patients should have access to and control of their genomic information, but the information should be clinically useful. Therefore, ACP discourages the use of DTC genetic medical testing and advises that testing should be done in the context of a patient–physician relationship, with appropriate counseling.

Position 4

Physicians, health care systems, and others with access to patient data should safeguard the privacy, confidentiality, and security of patient information, including genomic information.

Genetic testing as a central component of precision medicine raises new challenges for privacy and the use and protection of patient information. The volume of data combined with the sensitive nature of genomic information creates a pressing need to “inform patients of genetic privacy risks and implications for themselves and family members, so that patients are able to make a well-informed decision about testing and disclosure of genetic information” (5). The American Medical Association Code of Ethics also identifies the professional duty to protect the confidentiality of patients' genetic information and to identify the circumstances under which patients are expected to notify biological relatives of the availability of information related to risk for disease (42).

Physicians should counsel patients on the implications of genetic information for family members before testing and should encourage patients to disclose genetic information to relatives who may benefit from it. In some cases, patients may not share salient genetic results with family members, and some family members may not want to receive genetic information. The familial implications of genetic information may raise the ethical question of whether physicians have a duty to warn at-risk relatives when the patient refuses to do so. Should the duty to warn at-risk relatives of a genetic susceptibility take precedence over the duty to maintain confidentiality?

Confidentiality has been a vital component of the patient–physician relationship since the time of Hippocrates. Patients trust physicians to maintain the privacy of their information, and without this trust, they would be less likely to share sensitive information. There are, however, some circumstances under which confidentiality may be breached. For example, the Tarasoff case identified an imminent threat of harm to an identifiable individual as a compelling reason to breach confidentiality in a professional relationship (43). In this case, the court reasoned that protecting an individual's safety took precedence over a mental health professional's duty of confidentiality. Is warning an at-risk family member of a genetic susceptibility without the patient's consent similar to warning a specific person of potential homicide, the facts in the Tarasoff case? Although some genetic diseases may be life-threatening and thus very serious, it would be unusual for them to pose an imminent threat. Also, unlike in the Tarasoff case, the patient is not the agent of the harm. Therefore, physicians should counsel patients on the familial implications of a genetic risk and encourage them to share that information with relatives, but the physician does not have a duty and should not disclose genetic information to relatives unless requested to do so by the patient.

Safeguarding the privacy of patients' information is a manifestation of respect for patient autonomy and control over who can access the patient's genetic information (44–46). Patients have a right to decide with whom they want to share their genetic information, and health care professionals have a corresponding obligation to respect patients' decisions. GINA protects genetic information from being used by insurers and employers (47, 48). Patients should understand the limitations of GINA, including that it does not apply to employers with fewer than 15 employees and does not apply to long-term care, life, or disability insurance.

Some forms of genetic testing, such as exome and genome sequencing, generate enough information to render a person identifiable when combined with demographic information and information from other publicly available databases (49). Using DNA from crime scenes and genealogy websites, law enforcement has identified persons responsible for various crimes (50). Patients should be informed that data protection has limits and the ability to protect privacy and confidentiality is not absolute (36, 51), and that privacy and confidentiality may be breached to prevent serious harm to others. Health care systems will need to consider new information technology strategies to ensure the security of patients' genetic and clinical information (52).

Conclusion

Precision medicine and genetic testing have the potential to advance health care by improving our understanding of diseases, early diagnosis of illness, and tailoring of therapies that could improve health outcomes. However, with this new technology comes the responsibility to carefully consider when and how to use it. Ethically implementing precision medicine requires careful attention to appropriate testing, creating systems to assist with data interpretation, and protecting data privacy and security. Physicians will need to improve their own genetic literacy through an ongoing, lifelong learning approach so that they can engage patients in informed conversations about the appropriateness, risks, and benefits of precision medicine and genetic testing.