Spotlighting Structural Constraints on Decisions About Participation in Genomic and Precision Medicine

Public investments in genomic and precision medicine have begun to yield clinically useful interventions, most recently, for example, two new, FDA-approved gene therapies for sickle cell disease (FDA, 2023). However, there are doubts about whether everyone will derive the same benefit from translational innovations or have a fair chance at being able to access them (Dolan, Cho, and Lee 2023). Patients with low incomes and those who are members of underserved racial and ethnic groups in the U.S. are already experiencing disparities and delays in access to genetic services (McCarthy et al. 2016; Gene Hallford et al. 2020; Chapman-Davis et al. 2021; Fraiman and Wojcik 2021; Omorodion et al. 2022), which can be partly explained by inadequate preparation for genomic medicine at the health system and provider levels (National Academies of Sciences, Engineering, and and Medicine 2018). At the level of the health system, for example, genomic services delivery systems that rely on the existence of electronic health records (EHR) do not well serve individuals who receive care from multiple health systems or community-based healthcare organizations without EHRs (Williams et al. 2018). At the provider level, the primary care workforce lacks confidence in its ability to counsel patients about genetic risk and management, and fears that surfacing genetic information will result in social and insurance discrimination for its patients (Mikat-Stevens, Larson, and Tarini 2015; Hauser et al. 2018). There is also a need to implement resolutions to the workforce shortages that limit access to genetic services in areas of the country where there are few geneticists (Jenkins et al. 2021; Maiese et al. 2019; Penon-Portmann et al. 2020).

At the patient level, full access in the U.S. is further impeded by the likelihood of high out-of-pocket costs and the lack of full coverage for clinical genetic testing through public and private insurance programs or public health systems (Erwin et al. 2020; Grant et al. 2021). Lack of neighborhood resources can also negatively impact genetics clinic attendance. A retrospective cohort study by Wojcik and colleagues found that pediatric genetics patients with scheduled visits who were “no shows” at their appointment were more likely to live in a neighborhood that rated “very low” on the childhood opportunity index neighborhood, a measure that accounts for multiple dimensions of neighborhood resources, e.g., health, education, socioeconomic status (Wojcik et al. 2023). Lower zip code median income has also been associated with unscheduled and unattended appointments (Bohnhoff et al. 2019). These studies suggest economic and other resource limitations prevent the completion of genetics services, even when appointments are available.

Research with members of the public remains critical as we seek to understand and resolve the barriers to genetic testing and treatment–including low availability, access, affordability, genetics literacy, and trust in the healthcare system–that contribute to suboptimal implementation of current guidelines for genomic applications (Khoury et al. 2022). New ethical, legal, and social implications (ELSI) related to genetics and genomics translation have spurred ELSI empirical studies focused on decision-making about genome sequencing, including public support for and willingness to participate in large-scale genomics and biobanking research (e.g., Hoeyer et al. 2004; Godard, Marshall, and Laberge 2007; Kaufman et al. 2008); attitudes toward data sharing, biobank governance, and secondary research uses (e.g., Lemke et al. 2010; Lee et al. 2019; Garrison et al. 2019); perceptions of informed consent models and form preferences (e.g., Murphy et al. 2009; Beskow et al. 2010; Simon et al. 2011; Mancini et al. 2011; Master, Campo-Engelstein, and Caulfield 2015); preferences related to return of results (e.g., Haga et al. 2011; Mackley et al. 2017), and many other topics. However, in part because early adopters of genome sequencing differed substantially from the general population, fewer empirical ELSI research studies have been undertaken among individuals with low education and income and racially diverse participants (Hull and Vassy 2018). This omission could mean that important factors such as communication, trust, the role of family, and barriers to access to care, such as time constraints, finances, and study logistics, are underexplored (2018) (but see these exceptions: Isler et al. 2013; Sanderson et al. 2013; Yu et al. 2013; Joseph et al. 2017; Sedig et al. 2022; McDonald, Schwartz, and Sabatello 2022; Cakici et al. 2023).

In ELSI research, the diversity of methodology offers opportunities for leveraging empirical, normative, and conceptual research to provide guidance and policy interventions (Parker et al. 2019). Empirical research is especially important when guiding principles do not map onto the evolving realities on the ground. As one example, a facet of the long-standing normative recommendation identifying a researchers’ “duty to return’’ clinically actionable genomic results (Fernandez, Kodish, and Weijer 2003; Ravitsky and Wilfond 2006), that is beginning to be examined empirically is whether those results are properly considered a benefit of research participation. Though perhaps technically actionable, they are unlikely to be viewed as such by medically underserved individuals, those underrepresented in genomic datasets (on which determinations of clinical utility depend), and those without resources to enact prevention or afford follow up care (Neuhaus and Crane 2021, Stewart et al. 2020, Sabatello et al. 2020, Hiratsuka et al. 2020). Similarly, the long-standing recommendation that research participants should not receive a financial benefit in exchange for their research participation because it would be coercive (Truog, Kesselheim, and Joffe 2012) has also begun to be challenged (Savulescu 2001; Roberts, Pereira, and McGuire 2017; Wendler 2020; Tsosie et al. 2021). At issue in this case is both the growing recognition that accepting the extreme financial asymmetries in the genomics research enterprise–which disproportionately benefit commercial entities who utilize patient data to create their products–is morally inadequate, and the possibility that the translation of genomics research will fail without the research enrollment and clinical data of ancestrally diverse individuals (Jabloner and Walker 2023). Empirical research with individuals underrepresented in genomics research aimed at understanding which inducements to research are “undue” (Macklin 1981; Lee 2019) and which are reasonable and compatible with informed consent (Emanuel 2004; Largent et al. 2012) has the potential to bring welcome clarity to our normative confusion on this issue and present alternatives to de facto, low-value offers.

This special issue of AJOB Empirical Bioethics includes four primary research papers, which were initially presented at the 5^th ELSI Congress: Innovating for a Just and Equitable Future held June 1–3, 2022, a biennial conference supported by the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) and organized by the ELSI Congress 2022 Organizing Committee.¹ The organizing committee selected advancing equity and justice in the context of ELSI research as the meeting theme. After the congress, the Center for ELSI Resources and Analysis (CERA), an NHGRI-funded organization managed by teams at Stanford and Columbia Universities that is focused on enhancing the production, sharing, and use of ELSI research and building the ELSI community, issued a separate call for papers devoted to the congress theme for this issue and invited all conference presenters to submit a proposal for an article based on their congress presentation. Four proposals were selected by the journal for inclusion (Coulombe and Laberge 2024; Oladayo et al. 2024, Thomas et al. 2024; McMahon et al. 2023). To contextualize these four papers, CERA added a report of results from its empirical study of the results dissemination goals and practices of ELSI researchers (2024, this issue) and an invited editorial by Rajagopalan, Cakici, and Bloss that envisions a future in which empirical ELSI research is deployed early and continuously in the translation pipeline to align the goals of publicly funded science with local, public interests (2024, this issue).

The four research papers highlight the ways that context and diverse lived experiences influence and potentially constrain decisions about participation in genomic and precision medicine. For example, the systematic review by Laberge and Coulombe identifies 13 factors beyond the quality of a person’s understanding of a genetic test and their personal values or beliefs that can influence their genetic testing decision. Intended to inform their work on a new measurement tool designed to assess the quality of informed consent for clinical genetic testing, the study demonstrates the salience of third-party involvement in the testing decision, affective state when the test is offered, time constraints, and cost, among other contextual factors (Coulombe and Laberge 2024). Similarly, the phenomenology-informed qualitative study by Thomas and colleagues illustrates that Black women–a group that some researchers have treated as homogenous–have varied perceptions of noninvasive prenatal genetic screening, even when they have experienced apparent commonalities across their lived experiences such as anti-Black racism, gender-based oppression, and shared health status (Thomas et al. 2024). This finding invites deeper study of Black women’s decision-making about genetic technologies aimed at facilitating their unconstrained reproductive choices. Both the preferences of parents of children with orofacial clefts and their physicians related to the return of secondary genetic findings in Africa are explored in the survey study by Oladayo and colleagues. Consistent with the literature, most patients in the study wanted to receive all information from genetic testing, including all secondary findings. Most health care providers surveyed agreed that patients should have a say in the decision to return secondary findings, but also reported that a lack of resources for patients was a barrier to incorporating genetics into their clinical practice (Oladayo et al. 2024). This points to a need for further study aimed at determining the extent to which resource constraints influence the ROR practices of physicians. The ethnographic study of five NIH-funded, precision medicine projects by McMahon and colleagues highlights decisional conflict among investigators and research staff as return of results becomes increasingly normalized as a benefit of research participation under the largely untested assumption that research participants derive value when they receive this information. Specific concerns include whether genetic results should be the primary benefit to diverse and disadvantaged participants, the absence of informational resources to help with interpretation and healthcare infrastructure that would make the possession of results meaningful, and damage to public trust in research, should participants be oversold on their value as a recruitment strategy (McMahon et al. 2023).

These contributions highlight gaps in our knowledge about the broadening set of genomic medicine users, including how they interact with, and what they would need to overcome access barriers at the health system and provider level. More empirical ELSI research, like the work in this issue, that tests theoretical considerations against empirically derived information from practice–especially that which is aimed at refining the normative recommendations that shape our interactions with new genomics research participants and patients–is important. We hope the ELSI research community will collaborate and take up the call.

Deanne Dunbar Dolan
Center for ELSI Resources and Analysis (CERA), Stanford University School of Medicine, Stanford, California, USA[email protected] Mildred K. Cho
Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, California, USA Sandra Soo-Jin Lee
Division of Ethics, Department of Medical Humanities & Ethics, Columbia University, New York, New York, USA

Acknowledgements

This special issue would not be possible without the support of the National Human Genome Research Institute and its support of the biennial ELSI Congress (Grant number U13HG010830) and the Center for ELSI Resources and Analysis (Grant number U24HG010733). We are grateful to Editor-in-Chief, Holly Tabor, Executive Managing Editor Bela Fishbeyn, and the publishers of the AJOB Empirical Bioethics, Tiana Y. Sepahpour, Rachel H. Lee, and several anonymous reviewers for the opportunity to present this research to the community. We hope the conclusions presented in this issue will stimulate both scholarship and action.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Human Genome Research Institute under grant numbers U13HG010830 and U24HG010733.

Notes

1 The ELSI Congress was co-directed by Sandra Soo-Jin Lee and Mildred Cho, who convened an organizing committee that included Dounya Alami-Nassif (Columbia University), Paul Appelbaum (Columbia University), Jessica Blanchard (University of Oklahoma), Joy Boyer (NHGRI), Larry Brody (NHGRI), Shawneequa Callier (George Washington University), Mildred Cho (Stanford University), Deanne Dunbar Dolan (Stanford University), Gail Henderson (University of North Carolina), Steven Joffe (University of Pennsylvania), Angelica Johnson (Columbia University), Dave Kaufman (NHGRI), Gabriel Lázaro-Muñoz (Harvard Medical School), Sandra Soo-Jin Lee (Columbia University), Nicole Lockhart (NHGRI), Caroline Moore (Stanford University), Osagie Obasogie (UC Berkeley), Lisa Parker (University of Pittsburgh), Kayte Spector-Bagdady (University of Michigan), Rene Sterling (NHGRI), James Tabery (University of Utah), Wendy Uhlmann (University of Michigan), Emily Van Poetsch (Stanford University), Joe Vitti (Broad/Harvard/MIT), Alexis Walker (Columbia University), Joon-Ho Yu (University of Washington), and Rachel Yarmolinsky (Columbia University).