Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network.

The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions faced and choices made by a large multi-site clinical implementation study returning PRSs to diverse participants in handling this issue of differential performance. Our approach to managing the complexities associated with the differential performance of PRSs serves as a case study that can help future implementers of PRSs to plot an anticipatory course in response to this issue.

The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network.

PURPOSE: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants. METHODS: RoR processes were developed and approved by each eMERGE institution's internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant's disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed. RESULTS: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052). CONCLUSION: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.

Implementation of preemptive DNA sequence-based pharmacogenomics testing across a large academic medical center: The Mayo-Baylor RIGHT 10K Study.

PURPOSE: The Mayo-Baylor RIGHT 10K Study enabled preemptive, sequence-based pharmacogenomics (PGx)-driven drug prescribing practices in routine clinical care within a large cohort. We also generated the tools and resources necessary for clinical PGx implementation and identified challenges that need to be overcome. Furthermore, we measured the frequency of both common genetic variation for which clinical guidelines already exist and rare variation that could be detected by DNA sequencing, rather than genotyping. METHODS: Targeted oligonucleotide-capture sequencing of 77 pharmacogenes was performed using DNA from 10,077 consented Mayo Clinic Biobank volunteers. The resulting predicted drug response-related phenotypes for 13 genes, including CYP2D6 and HLA, affecting 21 drug-gene pairs, were deposited preemptively in the Mayo electronic health record. RESULTS: For the 13 pharmacogenes of interest, the genomes of 79% of participants carried clinically actionable variants in 3 or more genes, and DNA sequencing identified an average of 3.3 additional conservatively predicted deleterious variants that would not have been evident using genotyping. CONCLUSION: Implementation of preemptive rather than reactive and sequence-based rather than genotype-based PGx prescribing revealed nearly universal patient applicability and required integrated institution-wide resources to fully realize individualized drug therapy and to show more efficient use of health care resources.

Do research participants share genomic screening results with family members?

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network-3 (eMERGE-3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE-3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first-degree relatives. Across the sites, 279 participants completed a 1-month and/or 6-month post-results survey. By 6 months, only 34% of the 156 respondents shared their results with all first-degree relatives and 4% did not share with any. Over a third (39%) first-degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first-degree relatives compared with 11% of participants who received their results from a non-genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.

Increasing access to individualized medicine: a matched-cohort study examining Latino participant experiences of genomic screening.

PURPOSE: Multiple efforts are underway to increase the inclusion of racial minority participants in genomic research and new forms of individualized medicine. These efforts should include studies that characterize how individuals from minority communities experience genomic medicine in diverse health-care settings and how they integrate genetic knowledge into their understandings of health-care needs. METHODS: As part of a large, multisite genomic sequencing study, we surveyed individuals to assess their decision to pursue genomic risk evaluation. Participants included Latino patients recruited at Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, and non-Latino patients recruited at a large academic medical center (Mayo Clinic in Rochester, MN). Both groups agreed to receive individualized genomic risk assessments. RESULTS: Comparisons between cohorts showed that Latino respondents had lower levels of decisional conflict about pursuing genomic screening but generally scored lower on genetic knowledge. Latino respondents were also more likely to have concerns about the misuse of genomic information, despite both groups having similar views about the value of genomic risk evaluation. CONCLUSION: Our results highlight the importance of evaluating sociocultural factors that influence minority patient engagement with genomic medicine in diverse health-care settings.

Measuring Attitudes About Genomic Medicine: Validation of the Genomic Orientation Scale (GO Scale).

OBJECTIVES: Assessing public attitudes about genomic medicine is critical for anticipating patient receptivity to clinical applications of genomics. Although scholars have highlighted the importance of assessing stakeholder opinions and views regarding advances in clinical genomics, to date there has not been a robust tool for measuring these attitudes. We designed a study to evaluate the validity of an instrument we developed for measuring attitudes about genomic medicine. METHODS: We used psychometric methods to validate the Genomic Orientation Scale (GO Scale). Our goal was to create an easy-to-use tool for evaluating positive and negative attitudes about genomic medicine. RESULTS: We describe the validation testing of the GO Scale in a nationally representative sample of 1536 individuals residing in the United States. We report results from convergent and divergent validity testing and Rasch modeling analysis. The study produced a 26-item scale with 2 dimensions-optimism and pessimism. CONCLUSIONS: The GO Scale may be used to characterize attitudinal perspectives among patients, clinicians, and the public. The GO Scale may also be useful in evaluating shifts in attitude over time, for example, following educational interventions, which has not been feasible to date.

An ethics framework for consolidating and prioritizing COVID-19 clinical trials.

Given the dearth of established safe and effective interventions to respond to COVID-19, there is an urgent ethical imperative to conduct meaningful clinical research. The good news is that interventions to be tested are not in short supply. Unfortunately, the human and material resources needed to conduct these trials are finite. It is essential that trials be robust and meet enrollment targets and that lower-quality studies not be permitted to displace higher-quality studies, delaying answers to critical questions. Yet, with few exceptions, existing research review bodies and processes are not designed to ensure these conditions are satisfied. To meet this challenge, we offer guidance for research institutions about how to ethically consolidate and prioritize COVID-19 clinical trials, while recognizing that consolidation and prioritization should also take place upstream (among manufacturers and funders) and at a higher level (e.g. nationally). In our proposed three-stage process, trials must first meet threshold criteria. Those that do are evaluated in a second stage to determine whether the institution has sufficient capacity to support all proposed trials. If it does not, the third stage entails evaluating studies against two additional sets of comparative prioritization criteria: those specific to the study and those that aim to advance diversification of an institution's research portfolio. To implement these criteria fairly, we propose that research institutions form COVID-19 research prioritization committees. We briefly discuss some important attributes of these committees, drawing on the authors' experiences at our respective institutions. Although we focus on clinical trials of COVID-19 therapeutics, our guidance should prove useful for other kinds of COVID-19 research, as well as non-pandemic research, which can raise similar challenges due to the scarcity of research resources.

Factors that Influence Intent to Share Genetic Information Related to Cancer Risk with Family Members.

We describe factors influencing patient decisions to share positive cancer genetic test results with family members. We focused on patients who were diagnosed with several different cancer types but did not have a family history that was suggestive of an inherited risk. Participants were recruited from Mayo Clinic and had been recently diagnosed with cancer. An 80+ gene panel was performed. Before receiving genetic test results, patients completed a 49-item survey on their intent to share their results with relatives. 1,721 (57.7%) of 2,984 individuals who elected to pursue genetic testing completed the survey. Most patients planned to share cancer-related genetic results with a spouse or partner (97.0%), at least one adult child (92.2%), at least one sibling (86.2%), and with at least one parent (70.3%). Familial support scores and familial communication scores were predictive of intent to share cancer-related genetic test results. Our data highlight differences in family communication capacity and support that are important for clinicians to consider when supporting patients who wish to share cancer-related genetic test results with family members. Our data point to several potential interventional strategies that might increase the likelihood of cancer-related genetic test results being shared with family members at risk.

Patient reactions to receiving negative genomic screening results by mail.

PURPOSE: As genomic screening is incorporated into a wider array of clinical settings, it is critical that we understand how patients may respond to a various screening results. Although multiple studies have examined how patients understand positive genomic screening results, few data exist regarding patient engagement with negative screening results. METHODS: An 82-item survey was administered to 1712 individuals who received negative genomic screening results by mail following evaluation of 109 medically actionable genes. Genetic counselors were available to assist with the interpretation of screening results. RESULTS: One thousand four hundred forty-two participants completed the survey (84.2%). The vast majority of respondents valued the information they received, with 98% of respondents reporting that negative genomic screening results were valuable and 72% indicating they would recommend genomic screening to others. Nonetheless, many respondents had questions about their genomic screening results (28%) and would have preferred to receive their screening results in person (18%). CONCLUSION: These data suggest most patients value receiving negative genomic screening results and are comfortable receiving their results by mail. Nevertheless, a significant proportion of patients also reported difficulty understanding some aspects of their results. This finding challenges the idea that communicating genomic screening results by mail alone is sufficient to meet patients' needs.

Returning genomic results in a Federally Qualified Health Center: the intersection of precision medicine and social determinants of health.

PURPOSE: This report describes the return of sequencing results to low-income Latino participants recruited through a Federally Qualified Health Center (FQHC). We describe challenges in returning research results secondary to social determinants of health and present lessons learned to guide future genomic medicine implementation studies in low-resource settings. METHODS: Five hundred Latino adults (76% women) consented to research sequencing for a predetermined panel of actionable genes. Providers and staff from the FQHC were engaged to align processes with the practice and a community advisory board grounded the project in the local community. RESULTS: A pathogenic/likely pathogenic variant was present in 10 participants (2%). Challenges in return of results included the time lag (582 ± 53 days) between enrollment and returning actionable results, difficulty reaching participants, missed appointments, low health literacy, lack of health insurance, and reconciling results with limited information on family history. Return of one actionable result was deferred due to acute emotional distress secondary to recent traumatic life events. CONCLUSION: The social determinants of health influence the implementation of genomic medicine in low-income populations in low-resource settings. Considering nonbiological factors that contribute to disparities will be necessary to better appreciate how genomic medicine may fit within the context of health equity.

Participant choices for return of genomic results in the eMERGE Network.

PURPOSE: Secondary findings are typically offered in an all or none fashion when sequencing is used for clinical purposes. This study aims to describe the process of offering categorical and granular choices for results in a large research consortium. METHODS: Within the third phase of the electronic MEdical Records and GEnomics (eMERGE) Network, several sites implemented studies that allowed participants to choose the type of results they wanted to receive from a multigene sequencing panel. Sites were surveyed to capture the details of the implementation protocols and results of these choices. RESULTS: Across the ten eMERGE sites, 4664 participants including adolescents and adults were offered some type of choice. Categories of choices offered and methods for selecting categories varied. Most participants (94.5%) chose to learn all genetic results, while 5.5% chose subsets of results. Several sites allowed participants to change their choices at various time points, and 0.5% of participants made changes. CONCLUSION: Offering choices that include learning some results is important and should be a dynamic process to allow for changes in scientific knowledge, participant age group, and individual preference.

Ethical priority of the most actionable system of biomolecules: the metabolome.

The metabolome is a system of small biomolecules (metabolites) and a direct result of human bioculture. Consequently, metabolomics is well poised to impact anthropological and biomedical research for the foreseeable future. Overall, we provide a perspective on the ethical, legal, and social implications (ELSI) of metabolomics, which we argue are often more alarming than those of genomics. Given the current mechanisms to fund research, ELSI beyond human DNA is stifled and in need of considerable attention.

Should pretest genetic counselling be required for patients pursuing genomic sequencing? Results from a survey of participants in a large genomic implementation study.

PURPOSE: We assessed the decision-making of individuals pursuing genomic sequencing without a requirement for pretest genetic counselling. We sought to describe the extent to which individuals who decline genetic counselling reported decisional conflict or struggled to make a decision to pursue genomic testing. METHODS: We administered a 100-item survey to 3037 individuals who consented to the Return of Actionable Variants Empirical study, a genomic medicine implementation study supported by the National Institutes of Health (USA) eMERGE consortium. The primary outcomes of interest were self-reported decisional conflict about the decision to participate in the study and time required to reach a decision. RESULTS: We received 2895 completed surveys (response rate=95.3%), and of these respondents 97.8% completed the decisional conflict scale in its entirety. A majority of individuals (63%) had minimal or no decisional conflict about the pursuit of genomic sequencing and were able to reach a decision quickly (78%). Multivariable logistic regression analyses identified several characteristics associated with decisional conflict, including lower education, lower health literacy, lower self-efficacy in coping, lack of prior experience with genetic testing, not discussing study participation with a family member or friend, and being male. CONCLUSION: As genomic sequencing is used more widely, genetic counselling resources may not be sufficient to meet demand. Our results challenge the notion that all individuals need genetic counselling in order to make an informed decision about genomic sequencing.

Assessing optimism and pessimism about genomic medicine: Development of a genomic orientation scale.

Efforts to characterize stakeholder attitudes about the implementation of genomic medicine would benefit from a validated instrument for measuring public views of the potential benefits and harms of genomic technologies, which would facilitate comparison across populations and clinical settings. We sought to develop a scale to evaluate attitudes about the future of genomic medicine. We developed a 21-item scale that examined the likelihood of various outcomes of genomic medicine. The scale was administered to participants in a genomic sequencing study. Exploratory factor analysis was conducted and bivariate correlations were calculated. The genomic orientation (GO) scale was completed by 2895 participants. A two-factor structure was identified, corresponding to an optimism subscale (16 items, α = 0.89) and a pessimism subscale (5 items, α = 0.63). Genomic optimism was positively associated with a perceived value of genetic test results, higher health literacy, and decreased decisional conflict about participation in a genomic research study. Genomic pessimism was associated with concerns about genetic testing, lower health literacy, and increased decisional conflict about the decision to participate in the study. The GO scale is a promising tool for measuring both positive and negative views regarding the future of genomic medicine and deserves further validation.

Where Will We Draw the Line? Public Opinions of Human Gene Editing.

The application of gene editing technologies to prevent or mitigate genetic disease in humans is considered one of its most promising applications. However, as the technology advances, it is imperative to understand the views of the broader public on how it should be used. We conducted focus groups to understand public views on the ethical permissibility and governance of gene editing technologies in humans. A total of 50 urban and semirural residents in the upper Midwest took part in six focus groups. Participants expressed multiple concerns about nonmedical uses of gene editing and its potential for unknown harms to human health, and were divided as to whether the individual patient or "medical experts" should be charged with overseeing the scope of its application. As potential stakeholders, the perspectives from the general public are critical to assess as genome editing technologies advance toward the clinic.

Marketing the Research Missions of Academic Medical Centers: Why Messages Blurring Lines Between Clinical Care and Research Are Bad for both Business and Ethics.

Academic Medical Centers (AMCs) offer patient care and perform research. Increasingly, AMCs advertise to the public in order to garner income that can support these dual missions. In what follows, we raise concerns about the ways that advertising blurs important distinctions between them. Such blurring is detrimental to AMC efforts to fulfill critically important ethical responsibilities pertaining both to science communication and clinical research, because marketing campaigns can employ hype that weakens research integrity and contributes to therapeutic misconception and misestimation, undermining the informed consent process that is essential to the ethical conduct of research. We offer ethical analysis of common advertising practices that justify these concerns. We also suggest the need for a deliberative body convened by the Association of American Medical Colleges and others to develop a set of voluntary guidelines that AMCs can use to avoid in the future, the problems found in many current AMC advertising practices.

African American Living Donors' Attitudes About APOL1 Genetic Testing: A Mixed Methods Study.

RATIONALE & OBJECTIVE: African American live kidney donors ("donors") have a greater risk for kidney failure than European American donors. Apolipoprotein L1 gene (APOL1) variants in African Americans may be associated with this disparity. STUDY DESIGN: Cross-sectional mixed-methods design. SETTING & PARTICIPANTS: African American donors at 1 transplantation center. ANALYTICAL APPROACH: Semistructured interviews assessed attitudes about APOL1 genetic testing, willingness to undergo APOL1 testing, hypothetical decisions about donating with 2 APOL1 variants, and demographics. Surveys assessed perceptions of ethnic identity and genetics knowledge. Interview transcriptions were analyzed using thematic analysis. Survey data were analyzed using descriptive statistics. RESULTS: 23 donors participated in semistructured interviews. Most (96%) reported that transplantation centers should routinely offer APOL1 genetic testing to all African American potential donors. Most (87%) would have been willing to undergo APOL1 testing before donating. Although study participants noted that APOL1 testing may deter African American potential donors from donating, most (61%) would have donated even if they had 2 high-risk APOL1 variants. Several themes emerged. Study participants believed that APOL1 testing was beneficial for providing information to help donors make informed donation decisions. Participants expressed concern about APOL1 variants placing donors at harm for kidney failure, and therefore valued taking preventive health measures. Participants believed that potential donors would experience psychological distress from learning that they have 2 gene variants and could harm their recipients. Participants were apprehensive about insurance coverage and costs of APOL1 testing and feared that APOL1 genetic test results could discriminate against African Americans. LIMITATIONS: Findings may not be generalizable to African American potential donors. CONCLUSIONS: Findings suggest that African American donors support APOL1 genetic testing yet fear that APOL1 variants and genetic testing could adversely affect donors' health and ethnic identity. Transplantation centers using APOL1 genetic testing should address African American donors' concerns about APOL1 genetic testing to optimize future donors' informed consent practices.

Return of genomic results to research participants: the floor, the ceiling, and the choices in between.

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.