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.

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.

Family secrets: Experiences and outcomes of participating in direct-to-consumer genetic relative-finder services.

In recent decades, genetic genealogy has become popular as a result of direct-to-consumer (DTC) genetic testing. Some DTC genetic testing companies offer genetic relative-finder (GRF) services that compare the DNA of consenting participants to identify genetic relatives among them and provide each participant a list of their relative matches. We surveyed a convenience sample of GRF service participants to understand the prevalence of discoveries and associated experiences. Almost half (46%) of the 23,196 respondents had participated in GRF services only for non-specific reasons that included interest in building family trees and general curiosity. However, most (82%) also learned the identity of at least one genetic relative. Separately, most respondents (61%) reported learning something new about themselves or their relatives, including potentially disruptive information such as that a person they believed to be their biological parent is in fact not or that they have a sibling they had not known about. Respondents generally reported that discovering this new information had a neutral or positive impact on their lives, and most had low regret regarding their decision to participate in GRF services. Yet some reported making life changes as a result of their discoveries. Compared to respondents making other types of discoveries, those who learned that they were donor conceived reported the highest decisional regret and represented the largest proportion reporting net-negative consequences for themselves. Our findings indicate that discoveries from GRF services may be common and that the consequences for individuals, while generally positive, can be far-reaching and complex.

Understanding individualised genetic interventions as research-treatment hybrids.

Until recently, medicine has had little to offer most of the millions of patients suffering from rare and ultrarare genetic conditions. But the development in 2019 of Milasen, the first genetic intervention developed for and administered to a single patient suffering from an ultrarare genetic disorder, has offered hope to patients and families. In addition, Milasen raised a series of conceptual and ethical questions about how individualised genetic interventions should be developed, assessed for safety and efficacy and financially supported. The answers to these questions depend in large part on whether individualised therapies are understood as human subjects research or clinical innovation, different domains of biomedicine that are regulated by different modes of oversight, funding and professional norms. In this article, with development and administration of the drug Milasen as our case study, we argue that at least some individualised genetic therapies are not, as some have argued, either research or treatment. Instead, they are research-treatment hybrids, a category that has both epistemological and pragmatic repercussions for funding, ethics oversight and regulation.

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.

Health equality, race and pharmacogenomics.

Pharmacogenomics is increasingly moving into mainstream clinical practice. Careful consideration must be paid to inclusion of diverse populations in research, translation and implementation, in the historical and social context of population stratification, to ensure that this leads to improvements in healthcare for all rather than increased health disparities. This review takes a broad and critical approach to the current role of diversity in pharmacogenomics and addresses potential pitfalls in order to raise awareness for prescribers. It also emphasizes evidence gaps and suggests approaches that may minimize negative consequences and promote health equality.

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.

Parental Attitudes Toward Clinical Genomic Sequencing in Children With Critical Cardiac Disease.

OBJECTIVES: Through improving diagnostics and prognostics genomic sequencing promises to significantly impact clinical decisions for children with critical cardiac disease. Little is known about how families of children with critical cardiac disease perceive the impact of genomic sequencing on clinical care choices. DESIGN: Qualitative interview study. SETTING: A high-volume, tertiary pediatric heart center. SUBJECTS: Families of children with critical cardiac disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thematic analysis of interview response content. Thirty-five families were interviewed. Three themes emerged: 1) benefits versus challenges of having genomic sequencing results, and 2) fears of clinical applications of genomic sequencing, and 3) nonclinical fears related to genomic sequencing. Participants struggled with perceived uses of genomic sequencing-derived knowledge. They described comfort in foreknowledge of their child's likely disease course but articulated significant apprehension around participating in care decisions with limited knowledge of genomic sequencing, genomic sequencing uses to inform clinical resource rationing decisions, and genomic sequencing uses by third parties impacting financial pressures families experience caring for a child with critical cardiac disease. CONCLUSIONS: Families' perceptions of genomic sequencing uses in critical cardiac disease appear to strain their overall trust in the health system. Erosion of trust is concerning because the potential of genomic sequencing in critical cardiac disease will be unrealized if families are unwilling to undergo genomic sequencing, let alone to participate in the ongoing research needed to link genomic sequencing variants to clinical outcomes. Our findings may have implications for genomic sequencing use in children with other critical, high-acuity diseases.

Obligations of the "Gift": Reciprocity and Responsibility in Precision Medicine.

Precision medicine relies on data and biospecimens from participants who willingly offer their personal information on the promise that this act will ultimately result in knowledge that will improve human health. Drawing on anthropological framings of the "gift," this paper contextualizes participation in precision medicine as inextricable from social relationships and their ongoing ethical obligations. Going beyond altruism, reframing biospecimen and data collection in terms of socially regulated gift-giving recovers questions of responsibility and care. As opposed to conceiving participation in terms of donations that elide clinical labor critical to precision medicine, the gift metaphor underscores ethical commitments to reciprocity and responsibility. This demands confronting inequities in precision medicine, such as systemic bias and lack of affordability and access. A focus on justice in precision medicine that recognizes the sociality of the gift is a critical frontier for bioethics.

Integrating stakeholder feedback in translational genomics research: an ethnographic analysis of a study protocol's evolution.

PURPOSE: This study describes challenges faced while incorporating sometimes conflicting stakeholder feedback into study design and development of patient-facing materials for a translational genomics study aiming to reduce health disparities among diverse populations. METHODS: We conducted an ethnographic analysis of study documents including summaries of patient advisory committee meetings and interviews, reflective field notes written by study team members, and correspondence with our institutional review board (IRB). Through this analysis, we identified cross-cutting challenges for incorporating stakeholder feedback into development of our recruitment, risk assessment, and informed consent processes and materials. RESULTS: Our analysis revealed three key challenges: (1) balancing precision and simplicity in the design of study materials, (2) providing clinical care within the research context, and (3) emphasizing potential study benefits versus risks and limitations. CONCLUSIONS: While involving patient stakeholders in study design and materials development can increase inclusivity and responsiveness to patient needs, patient feedback may conflict with that of content area experts on the research team and IRBs who are tasked with overseeing the research. Our analysis highlights the need for further empirical research about ethical challenges when incorporating patient feedback into study design, and for dialogue with genomic researchers and IRB representatives about these issues.

Anticipating uncertainty and irrevocable decisions: provider perspectives on implementing whole-genome sequencing in critically ill children with heart disease.

PURPOSE: To investigate the potential impacts of whole-genome sequencing (WGS) in the pediatric critical-care context, we examined how clinicians caring for critically ill children with congenital heart disease (CHD) anticipate and perceive the impact of WGS on their decision-making process and treatment recommendations. METHODS: We conducted semistructured in-person and telephone interviews of clinicians involved in the care of critically ill children with CHD at a high-volume pediatric heart center. We qualitatively analyzed the transcribed interviews. RESULTS: In total, 34 clinicians were interviewed. Three themes emerged: (i) uncertainty about the accuracy of WGS testing and adequacy of testing validation; (ii) the use of WGS to facilitate life-limiting decisions such as futility, rationing, and selective prenatal termination; and (iii) moral distress over using WGS with a lack of decision support. CONCLUSION: Despite uncertainty about WGS testing, the interviewed clinicians were using, and anticipated expanding the use of, WGS results to justify declarations of futility, withdrawal of care, and rationing in critically ill children with CHD. This situation is causing moral distress in providers who have to make high-stakes decisions involving WGS results, with only partial understanding of them. Decision support for clinicians, and discussion with families of the risks of using WGS for rationing or withdrawal, is needed.

A randomized study of multimedia informational aids for research on medical practices: Implications for informed consent.

BACKGROUND/AIMS: Participant understanding is a key element of informed consent for enrollment in research. However, participants often do not understand the nature, risks, benefits, or design of the studies in which they take part. Research on medical practices, which studies standard interventions rather than new treatments, has the potential to be especially confusing to participants because it is embedded within usual clinical care. Our objective in this randomized study was to compare the ability of a range of multimedia informational aids to improve participant understanding in the context of research on medical practices. METHODS: We administered a web-based survey to members of a proprietary online panel sample selected to match national US demographics. Respondents were randomized to one of five arms: four content-equivalent informational aids (animated videos, slideshows with voice-over, comics, and text) and one no-intervention control. We measured knowledge of research on medical practices using a summary knowledge score from 10 questions based on the content of the informational aids. We used analysis of variance and paired t-tests to compare knowledge scores between arms. RESULTS: There were 1500 completed surveys (300 in each arm). Mean knowledge scores were highest for the slideshows with voice-over (65.7%), followed by the animated videos (62.7%), comics (60.7%), text (57.2%), and control (50.3%). Differences between arms were statistically significant except between the slideshows with voice-over and animated videos and between the animated videos and comics. Informational aids that included an audio component (animated videos and slideshows with voice-over) had higher knowledge scores than those without an audio component (64.2% vs 59.0%, p < .0001). There was no difference between informational aids with a character-driven story component (animated videos and comics) and those without. CONCLUSION: Our results show that simple multimedia aids that use a dual-channel approach, such as voice-over with visual reinforcement, can improve participant knowledge more effectively than text alone. However, the relatively low knowledge scores suggest that targeted informational aids may be needed to teach some particularly challenging concepts. Nonetheless, our results demonstrate the potential to improve informed consent for research on medical practices using multimedia aids that include simplified language and visual metaphors.

Reflections on the cost of "low-cost" whole genome sequencing: framing the health policy debate.

The cost of whole genome sequencing is dropping rapidly. There has been a great deal of enthusiasm about the potential for this technological advance to transform clinical care. Given the interest and significant investment in genomics, this seems an ideal time to consider what the evidence tells us about potential benefits and harms, particularly in the context of health care policy. The scale and pace of adoption of this powerful new technology should be driven by clinical need, clinical evidence, and a commitment to put patients at the centre of health care policy.

A comparison of institutional review board professionals' and patients' views on consent for research on medical practices.

BACKGROUND/AIMS: In the context of research on medical practices, which includes comparative effectiveness research and pragmatic clinical trials, empirical studies have begun to raise questions about the extent to which institutional review boards' interpretations and applications of research regulations align with patients' values. To better understand the similarities and differences between these stakeholder groups, we compare and contrast two surveys: one of institutional review board professionals and one of patients, which examine views on consent for research on medical practices. METHODS: We conducted online surveys of two target populations between July 2014 and March 2015. We surveyed 601 human subjects research professionals out of 1500 randomly selected from the Public Responsibility in Medicine and Research membership list (40.1% response rate), limiting analysis to 537 respondents who reported having had institutional review board experience. We also surveyed 120 adult patients out of 225 approached at subspecialty clinics in Spokane, Washington (53.3% response rate). Our survey questions probed attitudes about consent in the context of research on medical practices using medical record review and randomization. The patient survey included three embedded animated videos to explain these concepts. RESULTS: A majority of institutional review board professionals distinguished between consent preferences for medical record review and randomization, ranked clinicians as the least preferred person to obtain participant consent (54.6%), and viewed written or verbal permission as the minimum acceptable consent approach for research on medical practices using randomization (87.3%). In contrast, most patients had similar consent preferences for research on medical practices using randomization and medical record review, most preferred to have consent conversations with their doctors rather than with researchers for studies using randomization (72.6%) and medical record review (67.0%), and only a few preferred to see research involving randomization (16.8%) or medical record review (13.8%) not take place if obtaining written or verbal permission would make the research too difficult to conduct. Limitations of our post hoc analysis include differences in framing, structure, and language between the two surveys and possible response bias. CONCLUSION: Our findings highlight a need to identify appropriate ways to integrate patient preferences into prevailing regulatory interpretations as institutional review boards increasingly apply research regulations in the context of research on medical practices. Dialogue between institutional review boards and research participants will be an important part of this process and should inform future regulatory guidance.