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Genomic Medicine and Incidental Findings: Balancing Actionability and Patient Autonomy

      In March 2013, the American College of Medical Genetics and Genomics (ACMG) released recommendations on how to handle incidental findings (IFs) for the clinical application of whole exome or whole genome sequencing (WES/WGS).
      • Green R.C.
      • Berg J.S.
      • Grody W.W.
      • et al.
      ACMG recommendations for reporting of incidental findings in clinical exome and genomic sequencing.
      The ACMG recommended that clinical laboratories “actively search,”
      • Green R.C.
      • Berg J.S.
      • Grody W.W.
      • et al.
      ACMG recommendations for reporting of incidental findings in clinical exome and genomic sequencing.
      evaluate, and report pathogenic or likely pathogenic variants in 56 genes and report these findings to the ordering clinician, who could then “contextualize any incidental findings for the patient in light of personal and family history, physical examination, and other relevant findings.”
      • Green R.C.
      • Berg J.S.
      • Grody W.W.
      • et al.
      ACMG recommendations for reporting of incidental findings in clinical exome and genomic sequencing.
      The 2013 recommendations did not provide guidance for laboratories to offer patients of any age the ability to opt out from the reporting of IFs. The 56 genes are associated with 24 genetic cardiovascular disorders or predisposition to cancers for which confirmatory diagnostic approaches are available as well as some preventive or treatment measures that can be offered. The ACMG recommended further that those who did not agree to learn of these IFs could choose to forego the entire test. These recommendations generated much controversy, most of which focused on patients’ ability to opt out of receiving unwanted results.

      Burton H, Zimmern R. ACMG recommendations on incidental findings: a commentary. PGH Foundation website. http://www.phgfoundation.org/news/13713/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+phgfoundation_articles+%28Articles+from+the+PHG+Foundation+Newsletter%29. Published April 2, 2013. Accessed April 11, 2014.

      • Green R.C.
      • Lupski J.R.
      • Biesecker L.G.
      Reporting genomic sequencing results to ordering clinicians: incidental, but not exceptional.
      • Holtzman N.A.
      ACMG recommendations on incidental findings are flawed scientifically and ethically [letter].
      • Klitzman R.
      • Appelbaum P.S.
      • Chung W.
      Return of secondary genomic findings vs patient automony: implications for medical care.

      Maher B. Patients should learn about secondary genetic risk factors, says recommendations. Nature.com newsblog. http://blogs.nature.com/news/2013/03/patients-should-learn-about-secondary-genetic-risk-factors-say-sequencing-lab-guidelines.html. Published March 21, 2013. Accessed April 11, 2014.

      • McGuire A.L.
      • Joffe S.
      • Koenig B.A.
      • et al.
      Ethics and genomic incidental findings.
      • Ross L.F.
      • Rothstein M.A.
      • Clayton W.E.
      Mandatory extended searches in all genome sequencing: “incidental findings,” patient autonomy, and shared decision making.
      • Townsend A.
      • Adam S.
      • Birch P.H.
      • Friedman J.M.
      Paternalism and the ACMG recommendations on genomic incidental findings: patients seen but not heard [letter].
      Illustrating its commitment to participating in broad, public discussion, the ACMG Board of Directors surveyed its membership in early 2014 to ascertain how the members viewed the 2013 recommendations. In addition, the ACMG surveyed attendees of the 2014 ACMG annual meeting. The responses suggest that most members support allowing informed patients to opt out of receiving information about some or all IFs (presented at the 2014 annual ACMG business meeting). The ACMG also held open forums to discuss the recommendations, including one at each of the 2013 and 2014 annual ACMG meetings. These activities resulted in the Board revising their 2013 recommendations to allow clinical laboratories and clinicians to offer patients the ability to pursue genetic testing but opt out of receiving results covering these 56 genes.

      American College of Medical Genetics and Genomics. ACMG updates recommendation on “opt-out” for genome sequencing return of results [press release]. ACMG website. www.acmg.net. Published April 1, 2014. Accessed April 12, 2014.

      In addition, the ACMG has established a new committee that will create a mechanism for evaluating changing evidence of genetic variants for inclusion on subsequent lists of actionable variants. Although challenges remain for implementing genomic medicine, including how to effectively and efficiently discuss IF options with patients,

      Curtin C. AACR panel discusses challenges of reporting incidental findings. GenomeWeb Daily News. www.genomeweb.com/clinical-genomics/aacr-panel-discusses-challenges-reporting-incidental-findings. Published April 8, 2014. Accessed April 12, 2014.

      Anderson A. Panel debates ACMG incidental findings recommendations at annual meeting. GenomeWeb Daily News. www.genomeweb.com/sequencing/panel-debates-acmg-incidental-findings-recommendations-annual-meeting. Published March 28, 2014. Accessed April 12, 2014.

      Presidential Commission for the Study of Bioethical Issues. Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts. Washington, DC: Presidential Commission for the Study of Bioethical Issues; December 2013.

      this new position by the ACMG acknowledges the importance of tailoring the reporting of results obtained from clinical WES/WGS of each individual patient. In this article, we describe the ethical and clinical rationale for our strong agreement with this position, highlighting how the ACMG’s position more fully preserves patient decision making and autonomy in the era of next-generation sequencing (ie, massively parallel high-output sequencing of nucleic acids in which multiple DNA templates are sequenced simultaneously, enabling cost-effective analysis of large numbers of target sequences at one time).
      The initial ACMG statement has been an important first step in developing national consensus on managing clinical IFs from next-generation sequencing. It generated an intense discussion about a patient’s “right not to know” about IFs. The statement also established a starting place for considering what should be included in a list of clinically actionable genetic findings from WES/WGS. Although the discussion has been ongoing in the context of genetic and genomic research for more than a decade, with the rapid movement of next-generation sequencing into the clinical arena, initiating a broader conversation on how to handle clinical IFs is even more germane.
      When the 2013 ACMG recommendations were released, commentators

      Burton H, Zimmern R. ACMG recommendations on incidental findings: a commentary. PGH Foundation website. http://www.phgfoundation.org/news/13713/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+phgfoundation_articles+%28Articles+from+the+PHG+Foundation+Newsletter%29. Published April 2, 2013. Accessed April 11, 2014.

      • Holtzman N.A.
      ACMG recommendations on incidental findings are flawed scientifically and ethically [letter].
      • Ross L.F.
      • Rothstein M.A.
      • Clayton W.E.
      Mandatory extended searches in all genome sequencing: “incidental findings,” patient autonomy, and shared decision making.
      • Townsend A.
      • Adam S.
      • Birch P.H.
      • Friedman J.M.
      Paternalism and the ACMG recommendations on genomic incidental findings: patients seen but not heard [letter].
      • Wolf S.M.
      • Annas G.J.
      • Elias S.
      Patient autonomy and incidental findings in clinical genomics.
      voiced concern about the lack of provisions for patient choice in decisions about the receipt of health-related information. These concerns were consistent with our experiences at Mayo Clinic’s Individualized Medicine Clinic.
      • Lazaridis K.N.
      • McAllister T.M.
      • Babovic-Vuksanovic D.
      • et al.
      Implementing individualized medicine into the medical practice.
      In that context, we are conducting studies characterizing patients’ preferences regarding IFs. Our findings reveal that those preferences are diverse.
      • Clift K.
      • Topazian R.
      • Fiksdal A.
      • Kumbamu A.
      • McCormick J.B.
      Patients' views on incidental findings from clinical exome sequencing.
      That is, some patients do not want to know about findings that are unrelated to their primary condition, while others want to learn about all IFs, extending even to those findings that may not have apparent clinical implications. The contextual uniqueness of each patient can play a critical role in how individuals make decisions. In this sense, the initial 2013 ACMG recommendations appeared to be inconsistent with the heterogeneity and diversity of patient preferences with respect to receiving information on IFs and the importance many patients assign to individual choice.
      The revised 2014 ACMG position places greater weight on patient autonomy and shared decision making. Many clinicians encourage patients to be actively involved in health care decisions, and many patients expect to play an active part in decisions concerning their health. Indeed, although the 2013 recommendations stated that “patients have the right to decline clinical sequencing if they judge the risks of possible discovery of incidental findings to outweigh the benefits of testing,”
      • Green R.C.
      • Berg J.S.
      • Grody W.W.
      • et al.
      ACMG recommendations for reporting of incidental findings in clinical exome and genomic sequencing.
      this “all or none” approach about WES/WGS was incongruent with the spirit of individualized medicine. One can imagine that a patient may wish to undergo genomic testing for a specific indication, such as selection for an approach to cancer treatment, and yet may choose not to go forward with this approach once informed that additional unrelated information would also be disclosed.
      The 2013 recommendations raised other concerns that the most recent revision has addressed. For example, the 2013 recommendations implicitly obligated clinical laboratories to search for pathogenic or likely pathogenic variants in the 56 genes identified by the ACMG. When ordering clinicians receive the results, they must determine how best to return these findings to the patient. Although the original recommendations duly noted that the ordering clinician could decide not to return these findings to the patient, placing the clinician in a gatekeeper role, the results of clinical testing would likely be entered into the patient’s medical record, raising the potential for another clinician, unaware of the patient’s wishes, to divulge that unwanted information to the patient. In addition, some clinicians may feel a legal responsibility to share IFs with the patient, especially once reported by the laboratory, creating a potential tension between their legal and ethical duties.
      The 2014 revision also partly addresses the challenging question of what genes and diseases should be included on the list. For example, one could argue for the addition of genes such as CDH1 (associated with hereditary gastric and breast cancer) or PTCH1 (associated with Gorlin syndrome [basal cell nevus syndrome]) to the list but against TP53 (associated with Li-Fraumeni syndrome, a rare genetic condition that greatly increases the risk of several types of cancer but with limited genetic testing–related actionability for those cancers). Indeed, the original list contained 57 genes, and one (NTRK1, associated with familial medullary thyroid cancer) was removed shortly thereafter. With the inclusion of the opt-out provision, those patients who may have reservations about the implications of learning about some of the variants on the ACMG list have a way to proceed with WES/WGS. Still to be addressed is what to do for many other genes for which a limited degree of evidence exists or not as compelling data are available on their clinical importance and actionability. The pre-event probability of a given clinical outcome depends on the clinical scenario of the patient population seeking genome sequencing: currently, a substantial proportion of clinical WES is being conducted in the setting of advanced cancer with a life expectancy limited to 2 years or less. The likelihood that a pathogenic variant that has not yet manifested itself will subsequently do so in the short time remaining is likely small. For some patients as well as their families, learning about this information may create an unnecessary burden. No doubt, for others the information may be a way for the patient to pass a legacy of potentially useful information on to surviving family members. We allow patients to make decisions about other potentially lifesaving medical care, procedures, and treatments, and it seems the same choices should be provided for genetic information not sought by the patient.
      The ACMG’s initial statement and its subsequent revision have been constructive in focusing the national conversation on the ultimate goal of positively impacting patient care. In addition to prioritizing which genes may be of most benefit to patients, we believe it is feasible to allow personal choice in decisions regarding learning of IFs that exist in genomic analyses. Filters can be created and applied during bioinformatics data processing that can allow the data analysis to be conducted on the portion of the genome that the patient has chosen to learn about. These filters can be tailored to reflect patient choices. Much work is still needed on how to best elicit patient choices and how granular those choices can be in this complex arena. An unresolved dilemma is determining the best way to “bin” gene variants by disease type, actionability, or physical attribute.
      • Berg J.S.
      • Khoury M.J.
      • Evans J.P.
      Deploying whole genome sequencing in clinical practice and public health: meeting the challenge one bin at a time.
      • Berg J.S.
      • Adams N.
      • Nassar N.
      • et al.
      An informatics approach to analyzing the incidentalome.
      • Lindor N.M.
      • Johnson K.J.
      • McCormick J.B.
      • Klee E.W.
      • Ferber M.J.
      • Farrugia G.
      Preserving personal autonomy in a genomic testing era [letter].
      Binning could also decrease the amount of detailed information communicated to patients, making the situation easier and less overwhelming for them. As new methods for automated data curation develop, we need to examine in parallel the values and preferences that drive patient decision making and develop processes to facilitate meaningful conversations with patients about the types of IFs they want to be informed about. We have been piloting various mechanisms that can be used by clinicians and patients to facilitate decisions about what to learn or not learn based on one of these decision-aid tools, and we believe that methods can be refined to accomplish this.
      Much is known about how individuals respond to learning about genetic risk information, but the bulk of those data is from individuals undergoing single-gene testing.
      • Heshka J.T.
      • Palleschi C.
      • Howley H.
      • Wilson B.
      • Wells P.S.
      A systematic review of perceived risks, psychological and behavioral impacts of genetic testing.
      • Collins V.
      • Meiser B.
      • Gaff C.
      • St John D.J.
      • Halliday J.
      Screening and preventive behaviors one year after predictive genetic testing for hereditary nonpolyposis colorectal carcinoma.
      • Godino J.G.
      • van Sluijs E.M.
      • Marteau T.M.
      • Sutton S.
      • Sharp S.J.
      • Griffin S.J.
      Effect of communicating genetic and phenotypic risk for type 2 diabetes in combination with lifestyle advice on objectively measured physical activity: protocol of a randomised controlled trial.

      Scuffham TM, Macmillan JC. Huntington disease: who seeks presymptomatic genetic testing, why and what are the outcomes [published online ahead of print January 8, 2014]? J Genet Couns. http://dx.doi.org/10.1007/s10897-013-9678-z.

      • Lynch H.T.
      • Snyder C.
      • Lynch J.F.
      • et al.
      Patient responses to the disclosure of BRCA mutation tests in hereditary breast-ovarian cancer families.
      These experiences with single-gene testing may not be a fair comparison to WES/WGS testing. With the former, a person knows what is being tested and has sought the test to determine his or her risk for carrying genetic variants causing the disease. In contrast, WES/WGS is not selective, and the results may reveal much more information than originally desired or anticipated. The landscape has changed appreciably, and it is no longer clear what it means to be well prepared to get results from clinical WES/WGS. These issues require additional study in well-designed clinical trials to understand more about the risks and benefits of receiving information on IFs. This is especially true for the release of IFs to children and their parents.
      The vibrant discussions that have ensued since the release of the 2013 ACMG recommendations are encouraging, including those that the ACMG itself has hosted. It is important that these ongoing updates of the recommendations continue and that the discussions have input from all stakeholders including, but not limited to, patient advocacy groups, regulatory agencies, geneticists and genetic counselors, oncologists, hematologists, pediatricians and pediatric subspecialists, bioethicists, sequencing experts, and industry partners. The recent revisions to the ACMG’s recommendations place greater weight on the diversity of patient interests and the importance of individual autonomy. As many have acknowledged, we need to develop new ways to assist patients in making informed choices that best fit their individual needs and better understand how individual patients perceive actionability. We believe an individualized, patient-centered approach to WES/WGS is necessary and attainable to realize the full potential of sequencing techniques to improve medical care.

      References

        • Green R.C.
        • Berg J.S.
        • Grody W.W.
        • et al.
        ACMG recommendations for reporting of incidental findings in clinical exome and genomic sequencing.
        Genet Med. 2013; 15: 565-574
      1. Burton H, Zimmern R. ACMG recommendations on incidental findings: a commentary. PGH Foundation website. http://www.phgfoundation.org/news/13713/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+phgfoundation_articles+%28Articles+from+the+PHG+Foundation+Newsletter%29. Published April 2, 2013. Accessed April 11, 2014.

        • Green R.C.
        • Lupski J.R.
        • Biesecker L.G.
        Reporting genomic sequencing results to ordering clinicians: incidental, but not exceptional.
        JAMA. 2013; 310: 365-366
        • Holtzman N.A.
        ACMG recommendations on incidental findings are flawed scientifically and ethically [letter].
        Genet Med. 2013; 15: 750-751
        • Klitzman R.
        • Appelbaum P.S.
        • Chung W.
        Return of secondary genomic findings vs patient automony: implications for medical care.
        JAMA. 2013; 310: 369-370
      2. Maher B. Patients should learn about secondary genetic risk factors, says recommendations. Nature.com newsblog. http://blogs.nature.com/news/2013/03/patients-should-learn-about-secondary-genetic-risk-factors-say-sequencing-lab-guidelines.html. Published March 21, 2013. Accessed April 11, 2014.

        • McGuire A.L.
        • Joffe S.
        • Koenig B.A.
        • et al.
        Ethics and genomic incidental findings.
        Science. 2013; 340: 1047-1048
        • Ross L.F.
        • Rothstein M.A.
        • Clayton W.E.
        Mandatory extended searches in all genome sequencing: “incidental findings,” patient autonomy, and shared decision making.
        JAMA. 2013; 310: 367-368
        • Townsend A.
        • Adam S.
        • Birch P.H.
        • Friedman J.M.
        Paternalism and the ACMG recommendations on genomic incidental findings: patients seen but not heard [letter].
        Genet Med. 2013; 15: 751-752
      3. American College of Medical Genetics and Genomics. ACMG updates recommendation on “opt-out” for genome sequencing return of results [press release]. ACMG website. www.acmg.net. Published April 1, 2014. Accessed April 12, 2014.

      4. Curtin C. AACR panel discusses challenges of reporting incidental findings. GenomeWeb Daily News. www.genomeweb.com/clinical-genomics/aacr-panel-discusses-challenges-reporting-incidental-findings. Published April 8, 2014. Accessed April 12, 2014.

      5. Anderson A. Panel debates ACMG incidental findings recommendations at annual meeting. GenomeWeb Daily News. www.genomeweb.com/sequencing/panel-debates-acmg-incidental-findings-recommendations-annual-meeting. Published March 28, 2014. Accessed April 12, 2014.

      6. Presidential Commission for the Study of Bioethical Issues. Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts. Washington, DC: Presidential Commission for the Study of Bioethical Issues; December 2013.

        • Wolf S.M.
        • Annas G.J.
        • Elias S.
        Patient autonomy and incidental findings in clinical genomics.
        Science. 2013; 340: 1049-1050
        • Lazaridis K.N.
        • McAllister T.M.
        • Babovic-Vuksanovic D.
        • et al.
        Implementing individualized medicine into the medical practice.
        Am J Med Genet C Semin Med Genet. 2014; 166: 15-23
        • Clift K.
        • Topazian R.
        • Fiksdal A.
        • Kumbamu A.
        • McCormick J.B.
        Patients' views on incidental findings from clinical exome sequencing.
        Annual ACMG meeting March. 2014; (Accessed May 7, 2014)
        • Berg J.S.
        • Khoury M.J.
        • Evans J.P.
        Deploying whole genome sequencing in clinical practice and public health: meeting the challenge one bin at a time.
        Genet Med. 2011; 13: 499-504
        • Berg J.S.
        • Adams N.
        • Nassar N.
        • et al.
        An informatics approach to analyzing the incidentalome.
        Genet Med. 2013; 15: 36-44
        • Lindor N.M.
        • Johnson K.J.
        • McCormick J.B.
        • Klee E.W.
        • Ferber M.J.
        • Farrugia G.
        Preserving personal autonomy in a genomic testing era [letter].
        Genet Med. 2013; 15: 408-409
        • Heshka J.T.
        • Palleschi C.
        • Howley H.
        • Wilson B.
        • Wells P.S.
        A systematic review of perceived risks, psychological and behavioral impacts of genetic testing.
        Genet Med. 2008; 10: 19-32
        • Collins V.
        • Meiser B.
        • Gaff C.
        • St John D.J.
        • Halliday J.
        Screening and preventive behaviors one year after predictive genetic testing for hereditary nonpolyposis colorectal carcinoma.
        Cancer. 2005; 104: 273-281
        • Godino J.G.
        • van Sluijs E.M.
        • Marteau T.M.
        • Sutton S.
        • Sharp S.J.
        • Griffin S.J.
        Effect of communicating genetic and phenotypic risk for type 2 diabetes in combination with lifestyle advice on objectively measured physical activity: protocol of a randomised controlled trial.
        BMC Public Health. 2012; 12: 444
      7. Scuffham TM, Macmillan JC. Huntington disease: who seeks presymptomatic genetic testing, why and what are the outcomes [published online ahead of print January 8, 2014]? J Genet Couns. http://dx.doi.org/10.1007/s10897-013-9678-z.

        • Lynch H.T.
        • Snyder C.
        • Lynch J.F.
        • et al.
        Patient responses to the disclosure of BRCA mutation tests in hereditary breast-ovarian cancer families.
        Cancer Genet Cytogenet. 2006; 165: 91-97