Marsha Michie

Not-so-incidental findings: the ACMG recommendations on the reporting of incidental findings in clinical whole genome and whole exome sequencing.

The issue of incidental findings in genomics research has been contentious, particularly in whole genome sequencing (WGS) and whole exome sequencing (WES). An incidental or secondary finding has generally been defined as ‘a finding concerning an individual research participant that has potential health or reproductive importance and is discovered in the course of conduct – but is beyond the aims of the study.’ [1]. However, as WGS and WES increasingly enter the clinical realm, these concerns are extended to individually relevant findings that are unrelated to the clinical purpose of sequencing. In May 2012, the American College of Medical Genetics and Genomics (ACMG) released a policy statement on Points to Consider in the Clinical Application of Genomic Sequencing in which they cautioned that ‘when interpreting secondary findings, or results that are generated in the course of screening asymptomatic individuals, it is critical that the standards for what is reportable be high to avoid burdening the health care system and consumers with what could be very large numbers of false positive results’ [2]. As a result, ACMG convened a working group to offer recommendations on handling incidental findings in clinical sequencing. The Working Group on Incidental Findings in Clinical Exome and Genome Sequencing of the ACMG (‘the Working Group’) published its Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing (‘the recommendations’) in March 2013 [3]. On the one hand, the recommendations take seriously the need to focus incidental findings on only those findings with clear clinical utility and actionable results. They provide a stringently curated list of specific variants that they believe rise to the level of clinical obligation to report. On the other hand, the zeal with which these variants were selected apparently encouraged the Working Group towards recommendations that depart significantly from existing practice and policy. First, they suggest that rather than reporting findings that are incidental to the purpose of the clinical sequencing as ordered, clinical sequencing laboratories have an obligation to seek out actively the variants as listed in the recommendations and include these findings in the clinical report. Second, they do not recommend considering patient preferences in reporting results. That is, all patients (or their guardians) should receive all recommended results whether they desire the information or not. This recommendation specifically includes sequencing on children. Although we support the desire of the Working Group to honor beneficence by providing patients with information that may affect their future health, we find these recommendations challenging from both an ethical and a practical perspective. Not only do they redefine incidental findings in a problematic manner, but the implication that individual autonomy should be over-ridden by physicians for the patient’s ‘own good’ is weakly supported in modern clinical ethics.

“Don't Want No Risk and Don't Want No Problems”: Public Understandings of the Risks and Benefits of Noninvasive Prenatal Testing in the United States

Background: The recent availability of new noninvasive prenatal genetic tests for fetal aneuploidy has raised questions concerning whether and how these new tests will be integrated into prenatal medical care. Among the many factors to be considered are public understandings and preferences about prenatal testing mechanisms and the prospect of fetal aneuploidy. Methods: To address these issues, we conducted a nationwide mixed-method survey of 2,960 adults in the United States to explore justifications for choices among prenatal testing mechanisms. Open responses were qualitatively coded and grouped by theme. Results: Respondents cited accuracy, followed by cost, as the most significant aspects of prenatal testing. Acceptance of testing was predicated on differing valuations of knowledge and on personal and religious beliefs. Trust in the medical establishment, attitudes toward risk, and beliefs about health and illness were also considered relevant. Conclusions: Although a significant portion of the sample population valued the additional accuracy provided by the new noninvasive tests, they nevertheless expressed concerns over high costs. Furthermore, participants continued to express reservations about the value of prenatal genetic information per se, regardless of how it was obtained.

Conflicts of interest in genetic counseling: acknowledging and accepting

Conflicts of interest (COI) in clinical practice have garnered attention in recent years, prompting a flurry of institutional and governmental policies to prevent both professional misconduct and the public perception of misconduct. Although most concerns focus on financial COI that may compromise patient care, COI in the more general sense are ubiquitous and often unavoidable. The Institute of Medicine has defined conflict of interest as “a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest.” They further clarify that conflict of interest “is not an occurrence in which primary interests are necessarily compromised. . . . A conflict of interest exists whether or not a particular individual or institution is actually influenced by the secondary interest.”1 Every one of us navigates COI in our everyday life—professional priorities often conflict with personal ones, clinicians’ with those of patients, and employees’ with those of employers. When we discuss these conflicts—if we discuss them—we frequently soften the language we use and speak of “perceived conflicts.” Although comforting, this language is misleading. It is important to recognize that COI are not simply a matter of perception. We may legitimately debate the influence COI have in particular situations, but they are an objective reality that can be defined and assessed. Recently, the objectivity of genetic counselors in some professional situations has been called into question, citing financial ties to industry.2,3 In response, the National Society of Genetic Counselors (NSGC) referenced its code of ethics, which advises members to keep in mind relationships that could undermine patient care.4 As genetic counselor Robert Resta has astutely pointed out, it is difficult for people who view themselves and their profession as being on ethically high ground to see that a conflict of interest could affect their behavior.5 Indeed, because the profession of genetic counseling is built on assisting patients in making decisions that best suit their personal needs and values, implying that genetic counselors may have conflicts of interest seems to strike at the heart of the profession’s integrity and identity. Yet, for this same reason, it is crucial that genetic counselors acknowledge that they, like all medical professionals, can and do have COI, and work to manage them. The profession of genetic counseling is relatively young; the first graduate training program was established in 1969. For the first few decades of its existence, genetic counselors were primarily employed in academic medical centers, working with physicians in the areas of reproductive genetic risk assessment and genetic testing; in pediatric clinics when families were faced with a new genetic condition in a child; and, in the late 1990s, in the setting of oncology with regard to hereditary cancer. However, in the 1990s, with new discoveries leading to new opportunities in molecular diagnostics, genetic testing began to move from academic medical centers and not-for-profit laboratories into for-profit corporate laboratories.6 This increasing commercialization expanded employment opportunities for genetic counselors, which combined with ongoing challenges in receiving insurance reimbursement for genetic counseling services,7 led to a gradual shift toward commercial laboratories as a leading employer of the United States’ more than 4,000 certified genetic counselors. With increasingly diverse employment opportunities have come questions regarding COI. COI in medicine are, of course, neither new nor exclusive to genetic counselors. The 2010 Physician Payments Sunshine Act, for example, requires that pharmaceutical companies publicly report incentive payments to physicians that may generate a COI.8 These policies have increased transparency and highlighted the challenges of COI in medicine. However, these laws do not extend to genetic counselors or to most companies that develop and sell genetic tests; the Sunshine Act focuses largely on pharmaceutical and medical device manufacturers’ relationships with physicians. For example, the Sunshine Act (had it existed at the time) would not have applied to Myriad Genetics’s training of genetic counselors in the late 1990s and early 2000s to provide direct patient counseling regarding its BRACanalysis testing for hereditary breast cancer risk and their employment of more than 20 genetic counselors to train physicians to counsel patients about the test practices, both of which raise obvious COI.9 Another concern is the practice of industry-employed genetic counselors providing direct patient care within clinics and via telehealth. This practice has caused concern because the interests of a commercial laboratory are not always in

This lifetime commitment: Public conceptions of disability and noninvasive prenatal genetic screening.

Recently, new noninvasive prenatal genetic screening technologies for Down syndrome and other genetic conditions have become commercially available. Unique characteristics of these screening tests have reignited long‐standing concerns about prenatal testing for intellectual and developmental disabilities. We conducted a web‐based survey of a sample of the US public to examine how attitudes towards disability inform views of prenatal testing in the context of these rapidly advancing prenatal genetic screening technologies. Regardless of opinion toward disability, the majority of respondents supported both the availability of screening and the decision to continue a pregnancy positive for aneuploidy. Individuals rationalized their support with various conceptions of disability; complications of the expressivist argument and other concerns from the disability literature were manifested in many responses analyzed.

Old Questions, New Paradigms: Ethical, Legal, and Social Complications of Noninvasive Prenatal Testing

Recent rapid changes in prenatal care have resulted from the discovery that cell-free fetal DNA (cffDNA) circulates in the maternal bloodstream during pregnancy (Lo et al. 1997). The discovery of cffDNA in maternal serum, combined with sequencing and bioinformatic techniques, has allowed the detection of an anomalous number of chromosomes in a developing fetus (Chiu et al. 2008; Fan et al. 2008). For the first time, clinicians can offer genetic testing in the prenatal period without using invasive procedures, such as amniocentesis, that carry a slight risk of miscarriage. Noninvasive prenatal testing (NIPT) is recognized by professional societies as a highly sensitive, non-diagnostic screening test (American College of Obstetricians and Gynecologists [ACOG] 2012; Benn et al. 2013). For some chromosomal aneuploidies, especially trisomies 13, 18, and 21, NIPT has a sensitivity and specificity in excess of 95% (Bianchi et al. 2014). Microdeletions and single-gene disorders may also be detected with NIPT through microarray, whole genome sequencing, or targeted single-nucleotide polymorphism (SNP) analysis (Fan et al. 2012; Juneau et al. 2014; Kitzman et al. 2012; Rabinowitz et al. 2014). While these techniques allow for a more detailed examination of the fetal genome, they also bring into the prenatal period many of the debates and ethical concerns previously associated with pediatric and adult sequencing (Donley, Hull, and Berkman 2012; Tabor et al. 2012). Intimately bound up with technological questions regarding NIPT are many ethical questions, and this special issue of AJOB Empirical Bioethics addresses a wide range of these issues. The articles that follow represent emerging empirical work on the ethical issues that are raised by NIPT, heightened by its rapid clinical implementation, and contextualized within the larger landscape of prenatal testing. Here, we summarize a few of these concerns and provide an overview of the articles in this issue.

Expanding Use of cfDNA Screening in Pregnancy: Current and Emerging Ethical, Legal, and Social Issues

Purpose of ReviewIn 2011, screening platforms became available in the US that detect and analyze fragments of cell-free placental DNA (cfDNA) in maternal blood serum. Marketed as noninvasive prenatal tests (NIPT), cfDNA screening is more accurate than previously available serum screening tests for certain aneuploidies. The combination of a noninvasive procedure, high specificity and sensitivity, and lower false positive rates for some aneuploidies (most notably Down’s syndrome) has led to broad clinician and patient adoption. New ethical, legal, and social issues arise from the increased use and expanded implementation of cfDNA in pregnancy.Recent FindingsRecently, several professional associations have amended their guidelines on cfDNA, removing language recommending its use in only “high-risk” pregnancies in favor of making cfDNA screening an available option for women with “low-risk” pregnancies as well. At the same time, commercial cfDNA screening laboratories continue to expand the range of available test panels. As a result, the future of prenatal screening will likely include a broader range of genetic tests in a wider range of patients.SummaryThis article addresses the ethical, legal, and social issues related to the shift in guidance and expanded use of cfDNA in pregnant women, including concerns regarding routinized testing, an unmet and increasing demand for genetic counseling services, social and economic disparities in access, impact on groups living with disabling conditions, and provider liability.

Offering Prenatal Screening in the Age of Genomic Medicine: A Practical Guide

AIMS In September, 2015, Mayo Clinic convened a panel of national thought leaders on prenatal screening, medical genetics, and obstetrics and gynecology practice. RESULTS During the 2-day symposium, participants discussed the implications of the shift toward broader prenatal screening using cell-free placental DNA in maternal serum (cfDNA screening). Key topics included challenges around the pace of change in the prenatal screening market, uncertainty around reimbursement, meeting the need for patient counseling, and potential challenges in interpreting and returning cfDNA screening results. INNOVATION Here, we describe the challenges discussed and offer clinical recommendations for practices who are working to meet them. CONCLUSION As the spread of prenatal genetic screening continues, providers will increasingly need to update their practice to accommodate new screening modalities.

Impact of the increased adoption of prenatal cfDNA screening on non-profit patient advocacy organizations in the United States.

The ‘Stakeholder Perspectives on Noninvasive Prenatal Genetic Screening’ Symposium was held in conjunction with the 2015 annual meeting of the International Society for Prenatal Diagnosis. During the day‐long meeting, a panel of patient advocacy group (PAG) representatives discussed concerns and challenges raised by prenatal cell‐free DNA (cfDNA) screening, which has resulted in larger demands upon PAGs from concerned patients receiving prenatal cfDNA screening results. Prominent concerns included confusion about the accuracy of cfDNA screening and a lack of patient education resources about genetic conditions included in cfDNA screens. Some of the challenges faced by PAGs included funding limitations, lack of consistently implemented standards of care and oversight, diverse perspectives among PAGs and questions about neutrality, and lack of access to training and genetic counselors. PAG representatives also put forward suggestions for addressing these challenges, including improving educational and PAG funding and increasing collaboration between PAGs and the medical community.

Conflicts of interest in genetic counseling: persistent underlying questions

To the Editor: We appreciate Iacoboni and colleagues’1 letter as a welcome continuation of the conversation that we hoped to promote. Iacoboni et al. also mention the work of the Task Force on conflicts of interest (COI), recently commissioned by the National Society of Genetic Counselors; these resources, made available after our commentary was submitted, are another welcome addition to this much-needed conversation. Iacoboni et al., who are all employed by Invitae Corporation, describe their laboratory’s efforts to mitigate COI among their genetic counselors (GCs)—including multiple points of disclosure and a noncommissioned salary structure—which we wholeheartedly applaud. In our view, it is unfortunate that, in the absence of industry regulation or accountability on this issue, patients cannot be assured that all laboratories make similar efforts. It is worthwhile to reiterate that we do not believe that laboratory-employed GCs are unable to provide quality patient care. As we emphasized in our commentary, “We recognize that genetic counselors employed by laboratories are likely no less focused on providing the best, professionally responsive care than any other genetic counselor.”2 This observation, however, does not negate the simple fact of COI for GCs who are simultaneously beholden to the National Society of Genetic Counselors’ Code of Ethics, which calls for GCs to enable patient decision making with balanced information about options and alternatives, and to a commercial employer whose existence depends on maintaining or increasing test sales. As the Institute of Medicine defines it, the concept of COI pertains to the situation (i.e., working for a corporate entity while simultaneously providing care), not to the actions taken. COI do not necessarily mean that a clinician does or will compromise his or her duties to patients, and are certainly not prima facie evidence of unethical behavior. COI are an important professional issue for the entire genetic counseling profession, and our discussion of the topic is in no way a personal attack on the competence or capabilities of GCs working in commercial laboratories. We also agree that further empirical research on this issue and its real and potential consequences is important, and appreciate Iacoboni and colleagues’ recent work in beginning to fill this evidence gap. However, the most important question, from our perspective, is not whether laboratoryemployed GCs provide quality patient care. We believe a larger issue at stake is the usage of laboratoryemployed GCs within the marketing plans of commercial genetic testing laboratories, whose undisputed primary interest is to increase genetic test sales. The availability of posttest genetic interpretation by a certified GC is undoubtedly a plus for laboratories seeking to expand their clinician networks and market share. And commercial laboratories have consistently pushed to market their tests beyond current professional recommendations. In only one recent example, the chief executive officer of Counsyl characterized the company’s goals as “making expanded carrier screening as routine as taking folic acid, noninvasive prenatal screening as routine as an ultrasound, and hereditary cancer screening as well-known as a pap smear.”3 The conflicts that arise from these GC-laboratory relationships are likely to become even more complex as laboratories expand their test offerings to include bigger panels, and even wholeexome sequencing aimed at the healthy population, in order to maximize testing volume. Finally, as Iacoboni et al. point out, we are in a time of provider scarcity; however, the model of laboratory-employed GCs providing patient-facing services does not solve this problem. On the contrary, the shortage of providers qualified to provide clinical genetic counseling is being created in part by commercial testing laboratories, who are generating new markets through programs that promote expansive genetic testing to people who do not have a medical or family history indication for testing. One such example is Invitae’s new “proactive” Genetic Health Screen.4 While we are glad to see that consultation with a GC is available for these patients, this model shifts resources away from those who have identified indications for services within health care institutions. The innovative delivery models mentioned by Iacoboni et al., including telehealth, are equally effective when used by nonlaboratory-employed GCs, who may deliver care through provider or insurance networks or through contractual arrangements with clinician groups. As we noted in our original commentary, genetic counseling is a young profession—and one in which patients, who may have only a single encounter on which to judge, can easily lose trust. Disclosure and mitigation of COI can help maintain public trust and institutional trustworthiness, if implemented transparently with accountability. The potential policy solutions we suggested did include possible limits on patientfacing genetic counseling by laboratory-employed GCs, but more importantly they focused on a publicly accessible database of COI disclosures and a broad slate of mitigation strategies for both laboratories and health-care institutions. We still believe that genetic counseling, as a profession, needs to continue this difficult but important conversation, and to work toward cooperative and responsible solutions.

Findings of Nonparentage: A Case for Autonomy

We read with interest Palmor and Fiester’s recent article arguing for a blanket ban on reporting incidental findings of nonparentage (IFNP) when conducting pediatric genetic testing.1 The decision whether to disclose IFNP creates disruptions in clinical care, they argue, because it “undermines consistency, transparency, and uniformity across the institution or practice” (p. 184) and places the “moral burden” of these decisions on health care providers, where they do not belong (p. 187). This argument is reminiscent of the 2013 recommendations by the American College of Medical Genetics (ACMG), which recommended uniformly returning 57 actionable genetic findings from whole genome … E-mail: marsha.michie{at}ucsf.edu