Benjamin E. Berkman

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents

In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.

Genomics really gets personal: How exome and whole genome sequencing challenge the ethical framework of human genetics research†‡

Exome sequencing (ES) and whole genome sequencing (WGS) putatively identify all adverse functional alleles of protein‐coding genes. Accordingly, while ES/WGS are transformative new tools for gene discovery in human and medical genetics research, they also generate new manifestations of ethical issues related to the consent process, data sharing, and return of results. These manifestations have yet to be comprehensively framed, due in part to the rapidity with which new technologies for ES/WGS are being applied and because of a lack of empirical data to provide guidance. Accordingly, researchers, funding agencies, and policy makers have largely dealt with these issues intuitively. We explain how use of ES/WGS challenges: (i) models under which informed consent is typically obtained; (ii) how harms associated with data sharing are considered; and (iii) the nature of obligations surrounding unanticipated findings. We provide broad guidance about interim ways to contend with these issues and make broad recommendations for areas for novel resource and policy development.

Do Researchers Have an Obligation to Actively Look for Genetic Incidental Findings

The rapid growth of next-generation genetic sequencing has prompted debate about the responsibilities of researchers toward genetic incidental findings. Assuming there is a duty to disclose significant incidental findings, might there be an obligation for researchers to actively look for these findings? We present an ethical framework for analyzing whether there is a positive duty to look for genetic incidental findings. Using the ancillary care framework as a guide, we identify three main criteria that must be present to give rise to an obligation to look: high benefit to participants, lack of alternative access for participants, and reasonable burden on researchers. Our analysis indicates that there is no obligation to look for incidental findings today, but during the ongoing translation of genomic analysis from research to clinical care, this obligation may arise.

Disclosure of Incidental Findings From Next-Generation Sequencing in Pediatric Genomic Research

Next-generation sequencing technologies will likely be used with increasing frequency in pediatric research. One consequence will be the increased identification of individual genomic research findings that are incidental to the aims of the research. Although researchers and ethicists have raised theoretical concerns about incidental findings in the context of genetic research, next-generation sequencing will make this once largely hypothetical concern an increasing reality. Most commentators have begun to accept the notion that there is some duty to disclose individual genetic research results to research subjects; however, the scope of that duty remains unclear. These issues are especially complicated in the pediatric setting, where subjects cannot currently but typically will eventually be able to make their own medical decisions at the age of adulthood. This article discusses the management of incidental findings in the context of pediatric genomic research. We provide an overview of the current literature and propose a framework to manage incidental findings in this unique context, based on what we believe is a limited responsibility to disclose. We hope this will be a useful source of guidance for investigators, institutional review boards, and bioethicists that anticipates the complicated ethical issues raised by advances in genomic technology.

Genomic Inheritances: Disclosing Individual Research Results From Whole-Exome Sequencing to Deceased Participants’ Relatives

Whole-genome analysis and whole-exome analysis generate many more clinically actionable findings than traditional targeted genetic analysis. These findings may be relevant to research participants themselves as well as for members of their families. Though researchers performing genomic analyses are likely to find medically significant genetic variations for nearly every research participant, what they will find for any given participant is unpredictable. The ubiquity and diversity of these findings complicate questions about disclosing individual genetic test results. We outline an approach for disclosing a select range of genetic results to the relatives of research participants who have died, developed in response to relatives’ requests during a pilot study of large-scale medical genetic sequencing. We also argue that studies that disclose individual research results to participants should, at a minimum, passively disclose individual results to deceased participants’ relatives.

Incidental Medical Information in Whole-Exome Sequencing

Genomic technologies, such as whole-exome sequencing, are a powerful tool in genetic research. Such testing yields a great deal of incidental medical information, or medical information not related to the primary research target. We describe the management of incidental medical information derived from whole-exome sequencing in the research context. We performed whole-exome sequencing on a monozygotic twin pair in which only 1 child was affected with congenital anomalies and applied an institutional review board–approved algorithm to determine what genetic information would be returned. Whole-exome sequencing identified 79 525 genetic variants in the twins. Here, we focus on novel variants. After filtering artifacts and excluding known single nucleotide polymorphisms and variants not predicted to be pathogenic, the twins had 32 novel variants in 32 genes that were felt to be likely to be associated with human disease. Eighteen of these novel variants were associated with recessive disease and 18 were associated with dominantly manifesting conditions (variants in some genes were potentially associated with both recessive and dominant conditions), but only 1 variant ultimately met our institutional review board–approved criteria for return of information to the research participants.

The “Right Not to Know” in the Genomic Era: Time to Break From Tradition?

The target article by Clayton and colleagues (2014) helpfully lays out the differences between two recent sets of genetic testing guidelines, referred to as the “AAP/ACMG” (American Academy of Pediatrics [AAP] and American College of Medical Genetics and Genomics [ACMG] 2013; Ross et al. 2013) and “ACMG ES/GS” (exome sequencing/genome sequencing) (Green et al. 2013; Incidental findings 2013) statements. These statements differ markedly in their respective positions on the testing of children for adult-onset disorders that cannot be treated during childhood. While AAP/ACMG generally discourages such testing, ACMG ES/GS requires analysis of some gene variants that could predict adult-onset disorders in children. This difference reflects a dramatic shift in the priority granted to a person’s “right not to know” genetic information. ACMG ES/GS explicitly acknowledges that its support for generating genetic results for adult-onset conditions in children is a departure from previous recommendations. Its authors argue that the interests of other parties, including the child’s parents, must be taken into account: “To mask or withhold the incidental finding is to state that the child’s right not-to-know supersedes the parent’s opportunity to discover a life-threatening risk factor” (Green et al. 2013, 572; Incidental findings 2013). This stance has been met with significant criticism; some argue that the ACMG ES/GS recommendations contradict ethical clinical practice by failing to preserve a child’s future choice about genetic results (Allyse and Michie 2013; Wolf, Annas, and Elias 2013), and others argue that these recommendations are also problematic from the parents’ perspective, impinging on their right to refuse information and even lifesaving treatments based on that information (Burke et al. 2013). Are these critiques valid, or is the “right not to know” an anachronistic concept in the genomic era? The current formulation of a right not to know emerged in relation to the ability to test for a small number of devastating genetic conditions with distinctive features. The introduction of large-scale sequencing in the clinical setting prompts us to consider the extent to which the right not to know paradigm still holds true, given the dramatically expanded scope and diversity of information that is likely to be generated.

The Ethics of Allocating Uterine Transplants

In September 2014, a healthy male child was born in Sweden following a successful uterine transplantation (UTx). The event brought hope to many women without functional uteruses around the world. Having a child with a transplanted uterus is now possible, and as knowledge of the procedure proliferates and interest in UTx grows, it is important to begin thinking about how a scarce supply of uteruses will be allocated. This article represents a first discussion of the range of factors that must be considered in answering the allocation question. The primary issues addressed are (1) the motivation to seek treatment, (2) allocation by age, (3) child-rearing capacity, and (4) the amount of infertility treatment required. A set of eligibility and ranking criteria are presented. These criteria are not exhaustive but are intended to spark discussion about how uteruses can be allocated in a just manner.

What Does the Duty to Warn Require

We all have a duty to warn others when we can easily provide information to protect them from significant harm. In the medical context, a duty to warn patients and research subjects who are at risk of a disease is widely recognized. More recently, a similar duty to warn relatives of patients or research subjects has been discussed in the literature (Offit et al. 2004). Several prominent organizations have provided guidance on the disclosure of genetic information to family members in the clinical context (American Society of Clinical Oncology 2003; American Society of Human Genetics [ASHG] 1998; Green et al. 2013; Institute of Medicine 1994; President’s Commission 1998). These groups agree that health care professionals have an obligation to inform patients about the potential for genetic risks to relatives (ASHG 1998). McGuire and colleagues have proposed that this duty expands to include individuals participating in research when the relevant information or tests have been validated (McGuire, Caulfield, and Cho 2008). Most commentators and organizations argue that this duty has to be balanced against the obligation to maintain the confidentiality of genetic information and to respect the desires of those who wish not to know certain information. In the case presented, there is a strong ethical justification to inform subjects’ relatives about the mutation and the availability of genetic testing and counseling. The research team is in the unique position of having information that is clinically actionable and could prevent serious harm in some people with the genetic mutations. There are several interventions, including treatment with preventive antibiotics, vaccination, and bone-marrow transplant, that could prevent or possibly cure disease. Without knowledge of this syndrome, therapeutic interventions may be delayed, overlooked, or mismanaged. For example, prior to discovery of the mutation in question, a patient could receive a bone-marrow transplant from a sibling who unknowingly carried the same mutation. This could contribute to a patient’s subsequent relapse and death after transplant. For this reason, it is critically important to screen related donors for the relevant mutations. Additionally, this genetic information can be relevant when making reproductive decisions. In many respects, therefore, failure to disclose this information could lead to significant harm. Although there is a strong justification for disclosing this information, how the information should be disclosed is not straightforward. First, it is important to consider the value of respecting the confidentiality of subjects who may not want their health information disclosed to family members. Some of the subjects who were involved in the study are now deceased. With respect to deceased subjects, in the absence of a prospective conversation about disclosure after death, the researchers would not know whether the deceased subjects had preferences to keep their information confidential that would be violated by contacting their relatives. Even if deceased subjects had previously expressed a desire to maintain confidentiality, however, it is difficult to see how they would be harmed by disclosure after their death, and these desires likely would be outweighed by the potential to prevent serious harm to their relatives (Chan et al. 2012). With regard to living subjects, family-mediated contact may be the best approach. Ideally, the subject would share information with the research team about family members who may be at risk and would facilitate contact with those family members. Family members may sometimes neglect to, or choose not to, disclose health information within their family (Gaff et al. 2007), however, which raises the question of what the research team should do if some living subjects do not wish to reveal their health information. In some cases, parents may decide that they would not like to have their children tested for the genetic mutation. Acknowledging that parents are given considerable discretion over medical decision making for their children and that the syndrome may not affect some individuals until they are adults, the wishes of a parent with regard to genetic testing generally should be respected if the child is a minor. Nevertheless, given that there are medical interventions that can help prevent or cure disease, it would be reasonable for researchers to urge reluctant parents to have their children tested for the mutation. For parents who continue to decline testing for their children, it will be important to try to foster an ongoing conversation with the point of contact so that even if the information is not shared with an at-risk individual immediately, there is still some possibility of sharing the information at a later date. When a subject does not want the team to contact relatives who are adults, however, the team should weigh the ethical duty to warn against the duty to maintain confidentiality in each case, and there will likely be cases in which the duty to warn trumps confidentiality. The American Society of Human Genetics permits unauthorized disclosure when: attempts to encourage disclosure on the part of the patient have failed; the harm is highly likely to occur and is serious, imminent, and foreseeable; the at-risk relative(s) is identifiable; and the disease is preventable, treatable, or medically accepted standards indicate that early monitoring will reduce the genetic risk. (ASHG 1998, 474) These conditions appear to be met in this case, given the potential for serious harm, the options for treatment and prevention, and the fact that early monitoring and intervention could reduce the risks of serious complications in the future. Thus, unauthorized disclosure may be permissible if attempts to encourage disclosure fail, but should be considered an option of last resort. Finally, the approach to disclosure should not merely be a way to increase recruitment for the research, and would ideally include genetic counseling to convey the information appropriately. For this reason, it is important to explain to individuals how they can obtain testing and treatment even if they decline study participation, and to provide genetic counseling to all individuals about the test and their results.

Parental Consent for the Use of Residual Newborn Screening Bloodspots Respecting Individual Liberty vs Ensuring Public Health

renewing federal funding for the state-run newborn screening programs 1 that have proven to be extraordinarily effective at saving children from lifelong disability. 2 The bill included a last-minute amendment, however, that has generated immense concern among state newborn screening program officials and biomedical researchers. The amendment, which remains in effect until an updated Common Rule is released, stipulates that research on deidentified newborn dried bloodspots must be classified as research involving human subjects, thus requiring explicit parental informed consent. Public health officials’ major concern is that requiring explicit consent from parents may reduce the number of samples available for research and could even negatively affect newborn screening participation overall. 3 This shift represents a significant departure from long-standing practice; dried bloodspots research has traditionally been outside of the human subjects research regulations. The Common Rule currently defines human subjects research as activities in which either the research investigator obtains samples through direct interaction with living individuals or the samples are linked to individually identifiable private information. Dried bloodspots are deidentified before use by researchers, which is why research on dried bloodspots was interpreted not to be human subjects research until this new law. In this Viewpoint, we explore the implications of the law’s approach, highlighting the effects of requiring explicit informed consent for dried bloodspots research.