Potential corporate uses of polygenic indexes: Starting a conversation about the associated ethics and policy issues.

Some commercial firms currently sell polygenic indexes (PGIs) to individual consumers, despite their relatively low predictive power. It might be tempting to assume that because the predictive power of many PGIs is so modest, other sorts of firms-such as those selling insurance and financial services-will not be interested in using PGIs for their own purposes. We argue to the contrary. We build this argument in two ways. First, we offer a very simple model, rooted in economic theory, of a profit-maximizing firm that can gain information about a single consumer's genome. We use the model to show that, depending on the specific economic environment, a firm would be willing to pay for statistically noisy PGIs, even if they allow for only a small reduction in uncertainty. Second, we describe two plausible scenarios in which these different kinds of firms could conceivably use PGIs to maximize profits. Finally, we briefly discuss some of the associated ethics and policy issues. They deserve more attention, which is unlikely to be given until it is first recognized that firms whose services affect a large swath of the public will indeed have incentives to use PGIs.

Is there a way to reduce the inequity in variant interpretation on the basis of ancestry?

The underrepresentation of non-European ancestry groups in current genomic databases complicates interpretation of their genetic test results, yielding a much higher prevalence of variants of uncertain significance (VUSs). Such VUS findings can frustrate the goals of genetic testing, create anxiety in patients, and lead to unnecessary medical interventions. Approaches to addressing underrepresentation of people with genetic ancestries other than European are being undertaken by broad-based recruitment efforts. However, some underrepresented groups have concerns that might preclude participation in such efforts. We describe here two initiatives aimed at meeting the needs of underrepresented ancestry groups in genomic datasets. The two communities, the Sephardi Jewish community in New York and First Peoples of Canada, have very different concerns about contributing to genomic research and datasets. Sephardi concerns focus on the possible negative effects of genetic findings on the marriage prospects of family members. Canadian Indigenous populations seek control over the research uses to which their genetic data would be put. Both cases involve targeted efforts to respond to the groups' concerns; these efforts include governance models aimed at ensuring that the data are used primarily to inform clinical test analyses and at achieving successful engagement and participation of community members. We suggest that these initiatives could provide models for other ancestral groups seeking to improve the accuracy and utility of clinical genetic testing while respecting the underlying preferences and values of community members with regard to the use of their genetic data.

Cases in Precision Medicine: Is There an Obligation to Return Reinterpreted Genetic Results to Former Patients?

Interpretation of many genetic test results can change over time as new data accumulate. Hence, physicians who order genetic tests may subsequently receive revised reports with important implications for patients' medical treatment-even for patients who are no longer in their care. Several of the ethical principles underlying medical practice suggest an obligation to reach out to former patients with this information. Discharging that obligation can be accomplished, at a minimum, by attempting to contact the former patient with their last known contact information.

The Challenge of Genetic Variants of Uncertain Clinical Significance : A Narrative Review.

Genomic tests expand diagnostic and screening opportunities but also identify genetic variants of uncertain clinical significance (VUSs). Only a minority of VUSs are likely to prove pathogenic when later reassessed, but resolution of the uncertainty is rarely timely. That uncertainty adds complexity to clinical decision making and can result in harms and costs to patients and the health care system, including the time-consuming analysis required to interpret a VUS and the potential for unnecessary treatment and adverse psychological effects. Current efforts to improve variant interpretation will help reduce the scope of the problem, but the high prevalence of rare and novel variants in the human genome points to VUSs as an ongoing challenge. Additional strategies can help mitigate the potential harms of VUSs, including testing protocols that limit identification or reporting of VUSs, subclassification of VUSs according to the likelihood of pathogenicity, routine family-based evaluation of variants, and enhanced counseling efforts. All involve tradeoffs, and the appropriate balance of measures is likely to vary for different test uses and clinical settings. Cross-specialty deliberation and public input could contribute to systematic and broadly supported policies for managing VUSs.

Is there a duty to reinterpret genetic data? The ethical dimensions.

The evolving evidence base for the interpretation of variants identified in genetic and genomic testing has presented the genetics community with the challenge of variant reinterpretation. In particular, it is unclear whether an ethical duty of periodic reinterpretation should exist, who should bear that duty, and what its dimensions should be. Based on an analysis of the ethical arguments for and against a duty to reinterpret, we conclude that a duty should be recognized. Most importantly, by virtue of ordering and conducting tests likely to produce data on variants that cannot be definitively interpreted today, the health-care system incurs a duty to reinterpret when more reliable data become available. We identify four elements of the proposed ethical duty: data storage, initiation of reinterpretation, conduct of reinterpretation, and patient recontact, and we identify the parties best situated to implement each component. We also consider the reasonable extent and duration of a duty, and the role of the patient's consent in the process, although we acknowledge that some details regarding procedures and funding still need to be addressed. The likelihood of substantial patient benefit from a systematic approach to reinterpretation suggests the importance for the genetics community to reach consensus on this issue.

Choosing Flourishing: Toward a More "Binocular" Way of Thinking about Disability.

There is a long-standing debate between people who can seem to be arguing "for" and "against" disability. Those arguing for have often been disability scholars and those arguing against have often been utilitarian philosophers. At least since the mid-2000s, some on both sides have sought to move beyond that debate, but that has proved difficult. Here I seek two small steps forward. One step is critical, and is aimed at we who line up "for" disability. Specifically, I suggest that the phrase "choosing disability" is misleading in at least two ways. First, when someone argues that she should be able to gestate a child who is, e.g., deaf, she does not view deafness as a disability, but as something more like an enhancement. Second, when someone else argues that no one should selectively abort fetuses with traits like deafness, she is not arguing for choosing deafness, but against making a choice based on the presence of a disabling trait. The other step is constructive, and aimed at those lined up on both sides. I suggest that we should adopt a more "binocular" approach to thinking about disability: one which, using the social and medical "lenses" on disability, helps us see it in more depth. If we get better at having a conversation about what disability is, rather than arguing for or against it, we can get better at promoting the flourishing of people with disabilities.

Researchers' views on informed consent for return of secondary results in genomic research.

PURPOSE: Previous studies have suggested that genomic investigators generally favor offering to return at least some secondary findings to participants and believe that participants' preferences should determine the information they receive. We surveyed investigators to ascertain their views on four models of informed consent for this purpose: traditional consent, staged consent, mandatory return, and outsourced consent. METHODS: We performed an online survey of the views regarding return of secondary results held by 198 US genetic researchers drawn from our subject pool for an earlier study. Potential participants were identified through the National Institutes of Health RePORTER database and abstracts from the 2011 American Society of Human Genetics meeting. RESULTS: Under circumstances in which resource constraints are not an issue, approximately a third of respondents would endorse either staged consent or traditional consent; outsourced consent and mandatory return are favored by only a small minority. However, taking resource constraints into account, roughly half the sample would favor traditional consent, with support for staged consent dropping to 13%. CONCLUSION: Despite their liabilities, traditional approaches to consent are seen as the most viable under current circumstances. However, there is considerable interest in staged consent, assuming the infrastructure to support it can be provided.

An Introduction to Thinking about Trustworthy Research into the Genetics of Intelligence.

The advent of new technologies has rekindled some hopes that it will be possible to identify genetic variants that will help to explain why individuals are different with respect to complex traits. At least one leader in the development of "whole genome sequencing"-the Chinese company BGI-has been quite public about its commitment to using the technique to investigate the genetics of intelligence in general and high intelligence in particular. Because one needs large samples to detect the small effects associated with small genetic differences in the sequence of those base pairs, to make headway with the new sequencing technologies, one also needs to enlist much larger numbers of study participants than geneticists have enrolled before. In an effort to increase the size of a sample, one team of researchers approached the Center for Talented Youth at Johns Hopkins University. They wanted to gain access to records concerning participants in CTY's ongoing Study of Exceptional Talent, and they wanted to approach those individuals to see if they would be willing to share samples of their DNA. We agreed that CTY's dilemma about whether to give the researchers access to those records raised larger questions about the ethics of research into the genetics of intelligence, and we decided to hold a workshop at The Hastings Center that could examine those questions. Our purpose was to create what, borrowing from Sarah Richardson, we came to call a "transformative conversation" about research into the genetics of general cognitive ability-a conversation that would take a wide and long view and would involve a diverse group of stakeholders, including both people who have been highly critical of the research and people who engage in it. This collection of essays, which grew out of that workshop, is intended to provide an introduction to and exploration of this complex and important area.

Informed consent for return of incidental findings in genomic research.

PURPOSE: Researchers face the dilemma of how to obtain consent for return of incidental findings from genomic research. We surveyed and interviewed investigators and study participants, with the goal of providing suggestions for how to shape the consent process. METHODS: We performed an online survey of 254 US genetic researchers identified through the NIH RePORTER database, abstracts from the 2011 American Society of Human Genetics meeting, and qualitative semi-structured interviews with 28 genomic researchers and 20 research participants. RESULTS: Most researchers and participants endorsed disclosure of a wide range of information about return of incidental findings, including risks, benefits, impact on family members, data security, and procedures, for return of results in the event of death or incapacity and for recontact. However, most researchers were willing to devote 30 min or less to this process and expressed concerns that disclosed information would overwhelm participants, a concern shared by many participants themselves. CONCLUSION: There is a disjunction between the views of investigators and participants about the amount of information that should be disclosed and the practical realities of the research setting, including the time available for consent discussions. This strongly suggests the need for innovative approaches to the informed consent process.

Neuroimaging: beginning to appreciate its complexities.

For over a century, scientists have sought to see through the protective shield of the human skull and into the living brain. Today, an array of technologies allows researchers and clinicians to create astonishingly detailed images of our brain's structure as well as colorful depictions of the electrical and physiological changes that occur within it when we see, hear, think and feel. These technologies-and the images they generate-are an increasingly important tool in medicine and science. Given the role that neuroimaging technologies now play in biomedical research, both neuroscientists and nonexperts should aim to be as clear as possible about how neuroimages are made and what they can-and cannot-tell us. Add to this that neuroimages have begun to be used in courtrooms at both the determination of guilt and sentencing stages, that they are being employed by marketers to refine advertisements and develop new products, that they are being sold to consumers for the diagnosis of mental disorders and for the detection of lies, and that they are being employed in arguments about the nature (or absence) of powerful concepts like free will and personhood, and the need for citizens to have a basic understanding of how this technology works and what it can and cannot tell us becomes even more pressing.

Models of consent to return of incidental findings in genomic research.

Genomic research-including whole genome sequencing and whole exome sequencing-has a growing presence in contemporary biomedical investigation. The capacity of sequencing techniques to generate results that go beyond the primary aims of the research-historically referred to as "incidental findings"-has generated considerable discussion as to how this information should be handled-that is, whether incidental results should be returned, and if so, which ones.Federal regulations governing most human subjects research in the United States require the disclosure of "the procedures to be followed" in the research as part of the informed consent process. It seems reasonable to assume-and indeed, many commentators have concluded-that genomic investigators will be expected to inform participants about, among other procedures, the prospect that incidental findings will become available and the mechanisms for dealing with them. Investigators, most of whom will not have dealt with these issues before, will face considerable challenges in framing meaningful disclosures for research participants.To help in this task, we undertook to identify the elements that should be included in the informed consent process related to incidental findings. We did this by surveying a large number of genomic researchers (n = 241) and by conducting in-depth interviews with a smaller number of researchers (n = 28) and genomic research participants (n = 20). Based on these findings, it seems clear to us that routine approaches to informed consent are not likely to be effective in genomic research in which the prospect of incidental findings exists. Ensuring that participants' decisions are informed and meaningful will require innovative approaches to dealing with the consent issue. We have identified four prototypical models of a consent process for return of incidental findings.

Researchers' views on return of incidental genomic research results: qualitative and quantitative findings.

PURPOSE: Comprehensive genomic analysis including exome and genome sequencing is increasingly being utilized in research studies, leading to the generation of incidental genetic findings. It is unclear how researchers plan to deal with incidental genetic findings. METHODS: We conducted a survey of the practices and attitudes of 234 members of the US genetic research community and performed qualitative semistructured interviews with 28 genomic researchers to understand their views and experiences with incidental genetic research findings. RESULTS: We found that 12% of the researchers had returned incidental genetic findings, and an additional 28% planned to do so. A large majority of researchers (95%) believe that incidental findings for highly penetrant disorders with immediate medical implications should be offered to research participants. However, there was no consensus on returning incidental results for other conditions varying in penetrance and medical actionability. Researchers raised concerns that the return of incidental findings would impose significant burdens on research and could potentially have deleterious effects on research participants if not performed well. Researchers identified assistance needed to enable effective, accurate return of incidental findings. CONCLUSION: The majority of the researchers believe that research participants should have the option to receive at least some incidental genetic research results.

On good and bad forms of medicalization.

The ongoing 'enhancement' debate pits critics of new self-shaping technologies against enthusiasts. One important thread of that debate concerns medicalization, the process whereby 'non-medical' problems become framed as 'medical' problems. In this paper I consider the charge of medicalization, which critics often level at new forms of technological self-shaping, and explain how that charge can illuminate--and obfuscate. Then, more briefly, I examine the charge of pharmacological Calvinism, which enthusiasts, in their support of technological self-shaping, often level at critics. And I suggest how that charge, too, can illuminate and obfuscate. Exploring the broad charge of medicalization and the narrower counter charge of pharmacological Calvinism leads me to conclude that, as satisfying as it can be to level one of those charges at our intellectual opponents, and as tempting as it is to lie down and rest with our favorite insight, we need to gather the energy to have a conversation about the difference between good and bad forms of medicalization. Specifically, I suggest that if we consider the 'medicalization of love,' we can see why critics of and enthusiasts about technological self-shaping should want (and in some cases have already begun) to distinguish between good and bad forms of such medicalization.

Wrestling with Public Input on an Ethical Analysis of Scientific Research.

Bioethicists frequently call for empirical researchers to engage participants and community members in their research, but don't themselves typically engage community members in their normative research. In this article, we describe an effort to include members of the public in normative discussions about the risks, potential benefits, and ethical responsibilities of social and behavioral genomics (SBG) research. We reflect on what might-and might not- be gained from engaging the public in normative scholarship and on lessons learned about public perspectives on the risks and potential benefits of SBG research and the responsible conduct and communication of such research. We also provide procedural lessons for others in bioethics who are interested in engaging members of the public in their research.

Wrestling with Social and Behavioral Genomics: Risks, Potential Benefits, and Ethical Responsibility.

In this consensus report by a diverse group of academics who conduct and/or are concerned about social and behavioral genomics (SBG) research, the authors recount the often-ugly history of scientific attempts to understand the genetic contributions to human behaviors and social outcomes. They then describe what the current science-including genomewide association studies and polygenic indexes-can and cannot tell us, as well as its risks and potential benefits. They conclude with a discussion of responsible behavior in the context of SBG research. SBG research that compares individuals within a group according to a "sensitive" phenotype requires extra attention to responsible conduct and to responsible communication about the research and its findings. SBG research (1) on sensitive phenotypes that (2) compares two or more groups defined by (a) race, (b) ethnicity, or (c) genetic ancestry (where genetic ancestry could easily be misunderstood as race or ethnicity) requires a compelling justification to be conducted, funded, or published. All authors agree that this justification at least requires a convincing argument that a study's design could yield scientifically valid results; some authors would additionally require the study to have a socially favorable risk-benefit profile.

Recommendations for Responsible Development and Application of Neurotechnologies.

Advancements in novel neurotechnologies, such as brain computer interfaces (BCI) and neuromodulatory devices such as deep brain stimulators (DBS), will have profound implications for society and human rights. While these technologies are improving the diagnosis and treatment of mental and neurological diseases, they can also alter individual agency and estrange those using neurotechnologies from their sense of self, challenging basic notions of what it means to be human. As an international coalition of interdisciplinary scholars and practitioners, we examine these challenges and make recommendations to mitigate negative consequences that could arise from the unregulated development or application of novel neurotechnologies. We explore potential ethical challenges in four key areas: identity and agency, privacy, bias, and enhancement. To address them, we propose (1) democratic and inclusive summits to establish globally-coordinated ethical and societal guidelines for neurotechnology development and application, (2) new measures, including "Neurorights," for data privacy, security, and consent to empower neurotechnology users' control over their data, (3) new methods of identifying and preventing bias, and (4) the adoption of public guidelines for safe and equitable distribution of neurotechnological devices.