Conflating race and ancestry: Tracing decision points about population descriptors over the precision medicine research life course.

Responding to calls for human genomics to shift away from the use of race, genomic investigators are coalescing around the possibility of using genetic ancestry. This shift has renewed questions about the use of social and genetic concepts of difference in precision medicine research (PMR). Drawing from qualitative data on five PMR projects, we illustrate negotiations within and between research teams as genomic investigators deliberate on the relevance of race and genetic ancestry for different analyses and contexts. We highlight how concepts of both social and genetic difference are embedded within and travel through research practices, and identify multiple points across the research life course at which conceptual slippage and conflation between race and genetic ancestry occur. We argue that moving beyond race will require PMR investigators to confront the entrenched ways in which race is built into research practices and biomedical infrastructures.

Interrogating the Value of Return of Results for Diverse Populations: Perspectives from Precision Medicine Researchers.

BACKGROUND: Over the last decade, the return of results (ROR) in precision medicine research (PMR) has become increasingly routine. Calls for individual rights to research results have extended the "duty to report" from clinically useful genetic information to traits and ancestry results. ROR has thus been reframed as inherently beneficial to research participants, without a needed focus on who benefits and how. This paper addresses this gap, particularly in the context of PMR aimed at increasing participant diversity, by providing investigator and researcher perspectives on and questions about the assumed value of ROR in PMR. METHODS: Semi-structured interviews with a purposive sample of investigators and researchers across federally funded PMR studies in three national consortia, as well as observations of study activities, focused on how PM researchers conceptualize diversity and implement inclusive practices across research stages, including navigating ROR. RESULTS: Interviewees (1) validated the value of ROR as a benefit of PMR, while others (2) questioned the benefit of clinically actionable results to individuals in the absence of sufficient resources for translating findings into health care for diverse and disadvantaged populations; (3) expressed uncertainties in applying the presumed value of ROR as a benefit for non-clinical results; and (4) and debated when the promise of the value of ROR may undermine trust in PMR, and divert efforts to return value beyond ROR. CONCLUSIONS: Conceptualizations of diversity and inclusion among PM researchers and investigators raise unique ethical questions where unexamined assumptions of the value of ROR inform study recruitment efforts to enroll minoritized and under-represented populations. A lack of consideration for resources and infrastructure necessary to translate ROR into actionable information may hinder trustworthy community-research relationships. Thus, we argue for a more intentional interrogation of ROR practices as an offer of benefit and for whom.

Rethinking Benefit and Responsibility in the Context of Diversity: Perspectives from the Front Lines of Precision Medicine Research.

INTRODUCTION: Federal agencies have instituted guidelines to prioritize the enrollment and retention of diverse participants in precision medicine research (PMR). Prior studies examining participation of minoritized communities have shown that potential benefits represent a key determinant. Human subject research guidance, however, conceptualizes potential benefits narrowly, emphasizing generalized advances in medical knowledge. Further, few studies have provided qualitative data that critically examine how the concept of "benefit" is interpreted or challenged in the context of research practice. This paper examines the experiences of PMR investigators and frontline research staff to understand how standard approaches to benefit are received, contested, and negotiated "on the ground." METHODS: Findings are drawn from a qualitative project conducted across five US-based, federally funded PMR studies. Data collection included 125 in-depth interviews with a purposive sample of investigators, research staff, community advisory board members, and NIH program officers associated with these PMR studies. RESULTS: Researchers report that the standard approach to benefit - which relies on the premise of altruism and the promise of incrementally advancing scientific knowledge - is frequently contested. Researchers experience moral distress over the unmet clinical, psychosocial, and material needs within the communities they are engaging. Many believe the broader research enterprise has a responsibility to better address these needs. CONCLUSION: Researchers frequently take issue with and sometimes negotiate what is owed to participants and to their communities in exchange for the data they provide. These experiences of moral distress and these improvisations warrant systematic redress, not by individual researchers but by the broader research ethics infrastructure.

Community Engagement in Precision Medicine Research: Organizational Practices and Their Impacts for Equity.

BACKGROUND: In the wake of mandates for biomedical research to increase participation by members of historically underrepresented populations, community engagement (CE) has emerged as a key intervention to help achieve this goal. METHODS: Using interviews, observations, and document analysis, we examine how stakeholders in precision medicine research understand and seek to put into practice ideas about who to engage, how engagement should be conducted, and what engagement is for. RESULTS: We find that ad hoc, opportunistic, and instrumental approaches to CE exacted significant consequences for the time and resources devoted to engagement and the ultimate impacts it has on research. Critical differences emerged when engagement and research decisionmaking were integrated with each other versus occurring in parallel, separate parts of the study organization, and whether community members had the ability to determine which issues would be brought to them for consideration or to revise or even veto proposals made upstream based on criteria that mattered to them. CE was understood to have a range of purposes, from instrumentally facilitating recruitment and data collection, to advancing community priorities and concerns, to furthering long-term investments in relationships with and changes in communities. These choices about who to engage, what engagement activities to support, how to solicit and integrate community input into the workflow of the study, and what CE was for were often conditioned upon preexisting perceptions and upstream decisions about study goals, competing priorities, and resource availability. CONCLUSIONS: Upstream choices about CE and constraints of time and resources cascade into tradeoffs that often culminated in "pantomime community engagement." This approach can create downstream costs when engagement is experienced as improvised and sporadic. Transformations are needed for CE to be seen as a necessary scientific investment and part of the scientific process.

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.

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.

Individualized interventions for rare genetic conditions and the research-treatment spectrum: Stakeholder perspectives.

PURPOSE: Advances in the study of ultrarare genetic conditions are leading to the development of targeted interventions developed for single or very small numbers of patients. Owing to the experimental but also highly individualized nature of these interventions, they are difficult to classify cleanly as either research or clinical care. Our goal was to understand how parents, institutional review board members, and clinical geneticists familiar with individualized genetic interventions conceptualize these activities and their implications for the relationship between research and clinical care. METHODS: We conducted qualitative, semi-structured interviews with 28 parents, institutional review board members, and clinical geneticists and derived themes from those interviews through content analysis. RESULTS: Individuals described individualized interventions as blurring the lines between research and clinical care and focused on hopes for therapeutic benefit and expectations for generalizability of knowledge and benefit to future patients. CONCLUSION: Individualized interventions aimed at one or few patients reveal the limitations of a binary framing of research and clinical care. As a hybrid set of activities, individualized interventions suggest the need for flexibility and new frameworks that acknowledge these activities across the spectrum of research and clinical care.

Trustworthiness matters: Building equitable and ethical science.

Trustworthy science requires research practices that center issues of ethics, equity, and inclusion. We announce the Leadership in the Equitable and Ethical Design (LEED) of Science, Technology, Mathematics, and Medicine (STEM) initiative to create best practices for integrating ethical expertise and fostering equitable collaboration.

Promoting equity, inclusion, and efficiency: A team science approach to the development of authorship guidelines for a multi-disciplinary research team.

Large research teams and consortia present challenges for authorship. The number of disciplines involved in the research can further complicate approaches to manuscript development and leadership. The CHARM team, representing a multi-disciplinary, multi-institutional genomics implementation study, participated in facilitated discussions inspired by team science methodologies. The discussions were centered on team members' past experiences with authorship and perspectives on authorship in a large research team context. Team members identified challenges and opportunities that were used to create guidelines and administrative tools to support manuscript development. The guidelines were organized by the three values of equity, inclusion, and efficiency and included eight principles. A visual dashboard was created to allow all team members to see who was leading or involved in each paper. Additional tools to promote equity, inclusion, and efficiency included providing standardized project management for each manuscript and making "concept sheets" for each manuscript accessible to all team members. The process used in CHARM can be used by other large research teams and consortia to equitably distribute lead authorship opportunities, foster coauthor inclusion, and efficiently work with large authorship groups.

Targeting Representation: Interpreting Calls for Diversity in Precision Medicine Research.

Scientists have identified a "diversity gap" in genetic samples and health data, which have been drawn predominantly from individuals of European ancestry, as posing an existential threat to the promise of precision medicine. Inadequate inclusion as articulated by scientists, policymakers, and ethicists has prompted large-scale initiatives aimed at recruiting populations historically underrepresented in biomedical research. Despite explicit calls to increase diversity, the meaning of diversity - which dimensions matter for what outcomes and why - remain strikingly imprecise. Drawing on our document review and qualitative data from observations and interviews of funders and research teams involved in five precision medicine research (PMR) projects, we note that calls for increasing diversity often focus on "representation" as the goal of recruitment. The language of representation is used flexibly to refer to two objectives: achieving sufficient genetic variation across populations and including historically disenfranchised groups in research. We argue that these dual understandings of representation are more than rhetorical slippage, but rather allow for the contemporary collection of samples and data from marginalized populations to stand in as correcting historical exclusion of social groups towards addressing health inequity. We trace the unresolved historical debates over how and to what extent researchers should procure diversity in PMR and how they contributed to ongoing uncertainty about what axes of diversity matter and why. We argue that ambiguity in the meaning of representation at the outset of a study contributes to a lack of clear conceptualization of diversity downstream throughout subsequent phases of the study.

Three decades of ethical, legal, and social implications research: Looking back to chart a path forward.

More than thirty years ago in the United States, the National Center for Human Genome Research (NCHGR) at the National Institutes of Health (NIH) and its partner in the Human Genome Project (HGP), the Department of Energy (DOE), called for proposals from social scientists, ethicists, lawyers, and others to explore the ethical, legal, and social implications (ELSI) of mapping and sequencing the human genome. Today, nearly twenty years after the completion of the HGP, the ELSI Research Program of the National Human Genome Research Institute (NHGRI) continues this support. It has fostered the growth of ELSI research into a global field of study, uniquely positioned at the nexus of many academic disciplines and in proximity to basic and applied scientific research. We examine the formation of the first ELSI program and consider whether science policy in the public interest can exist within the confines of a set-aside from the NHGRI budget.

A scoping review of ethics considerations in clinical natural language processing.

Objectives: To review through an ethics lens the state of research in clinical natural language processing (NLP) for the study of bias and fairness, and to identify gaps in research. Methods: We queried PubMed and Google Scholar for articles published between 2015 and 2021 concerning clinical NLP, bias, and fairness. We analyzed articles using a framework that combines the machine learning (ML) development process (ie, design, data, algorithm, and critique) and bioethical concepts of beneficence, nonmaleficence, autonomy, justice, as well as explicability. Our approach further differentiated between biases of clinical text (eg, systemic or personal biases in clinical documentation towards patients) and biases in NLP applications. Results: Out of 1162 articles screened, 22 met criteria for full text review. We categorized articles based on the design (N = 2), data (N = 12), algorithm (N = 14), and critique (N = 17) phases of the ML development process. Discussion: Clinical NLP can be used to study bias in applications reliant on clinical text data as well as explore biases in the healthcare setting. We identify 3 areas of active research that require unique ethical considerations about the potential for clinical NLP to address and/or perpetuate bias: (1) selecting metrics that interrogate bias in models; (2) opportunities and risks of identifying sensitive patient attributes; and (3) best practices in reconciling individual autonomy, leveraging patient data, and inferring and manipulating sensitive information of subgroups. Finally, we address the limitations of current ethical frameworks to fully address concerns of justice. Clinical NLP is a rapidly advancing field, and assessing current approaches against ethical considerations can help the discipline use clinical NLP to explore both healthcare biases and equitable NLP applications.

Challenges and potential solutions to health disparities in genomic medicine.

Significant disparities in the clinical usefulness of genomic information across diverse groups are due to underrepresentation in genetic databases and inequitable access to genetic services. Remedying disparities is immediately needed to ensure that genomic medicine is more equitable but will take a long-term commitment and active engagement of diverse communities.

Strategies of inclusion: The tradeoffs of pursuing "baked in" diversity through place-based recruitment.

US funding agencies have begun to institutionalize expectations that biomedical studies achieve defined thresholds for diversity among research participants, including in precision medicine research (PMR). In this paper, we examine how practices of recruitment have unfolded in the wake of these diversity mandates. We find that a very common approach to seeking diverse participants leverages understandings of spatial, geographic, and site diversity as proxies and access points for participant diversity. That is, PMR investigators recruit from a diverse sampling of geographic areas, neighborhoods, sites, and institutional settings as both opportunistic but also meaningful ways to "bake in" participant diversity. In this way, logics of geographic and institutional diversity shift the question from who to recruit, to where. However, despite seeing geographic and site diversity as social and scientific 'goods' in the abstract and as key to getting diverse participants, PMR teams told us that working with diverse sites was often difficult in practice due to constraints in funding, time, and personnel, and inadequate research infrastructures and capacity. Thus, the ways in which these geographic and institutional diversity strategies were implemented resulted ultimately in limiting the meaningful inclusion of populations and organizations that had not previously participated in biomedical research and reproduced the inclusion of institutions that are already represented. These prevailing assumptions about and practices of "baked-in" diversity in fact exacerbate and produce other forms of inequity, in research capacity and research representation. These findings underscore how structural inequities in research resources must be addressed for diversity to be achieved in both research sites and research participants.

Beyond inclusion: Enacting team equity in precision medicine research.

PURPOSE: To identify meanings of and challenges to enacting equitable diversification of genomics research, and specifically precision medicine research (PMR), teams. METHODS: We conducted in-depth interviews with 102 individuals involved in three U.S.-based precision medicine research consortia and conducted over 400 observation hours of their working group meetings, consortium-wide meetings, and conference presentations. We also reviewed published reports on genomic workforce diversity (WFD), particularly those relevant to the PMR community. RESULTS: Our study finds that many PMR teams encounter challenges as they strive to achieve equitable diversification on scientific teams. Interviewees articulated that underrepresented team members were often hired to increase the study's capacity to recruit diverse research participants, but are limited to on-the-ground staff positions with little influence over study design. We find existing hierarchies and power structures in the academic research ecosystem compound challenges for equitable diversification. CONCLUSION: Our results suggest that meaningful diversification of PMR teams will only be possible when team equity is prioritized as a core value in academic research communities.