Description
Overview
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) hosted a two-day virtual workshop titled "Return of Individual Research Results to Participants in Observational Cohort Studies” on June 26th and 27th, 2024. Organized in collaboration with the National Human Genome Research Institute (NHGRI), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the All of Us Research Program, the workshop aimed to explore best practices for ethically returning individual research results particularly genetic and genomic findings in observational cohort studies. Addressing complex ethical, legal, logistical, and economic considerations, the workshop emphasized the need to understand stakeholders' diverse perspectives and foster collaborative discussions on precision medicine and incidental, secondary findings. Key focus areas included principles and guidance for the return of results (RoR), classification of genetic and genomic results, and ethical and clinical considerations for returning results within sociodemographic diverse communities. In addition, the workshop explored participants' perspectives, examined methods and outcomes from previous practices, and concluded with discussions on emerging technologies and other types of results, broadening the scope beyond genetics and genomics.
Key Objectives
- Explore best practices for the ethical return of genetic and genomic results to individual participants, from observational cohort studies, including types of results, methods for evaluating effectiveness, and lessons learned.
- Address the ethical and legal challenges associated with returning individual research results, and implications for families, diverse communities, and minoritized and underserved populations, while ensuring compliance with existing regulations.
- Understand participants’ perspectives and preferences on receiving research /actionable results, their perceived value and their contribution to follow-up care and outcomes.
- Assess the feasibility of returning additional types of individual results to participants, such as information on environmental exposure risks, and new technologies including digital and AI tools.
Agenda:
https://nhlbiworkshopsupport.certain.com/profile/web/index.cfm?PKwebID=0x4314e6ba - agenda
Program Book:
Video Recording
Day 1: https://nih.zoomgov.com/rec/share/DCmx5t-mm8hDFDkaz4DElopXOaj2mpoWhXKLAKJXONfdVgMYslfcbfS2qBdTcE-Q.BDQ-l79h6u0DBMpc (password: k98$y7RU)
Day 2: https://nih.zoomgov.com/rec/share/DXmZLo_WNDWe7CQ-7ZGxRmrQtv-M66KcU2c9hqT_ua5qs-xaK8rtcFPWAIOhLJs.5YLo8TrqpihonYRK (password: a#CdsE0)
Background
The return of individual research results, especially genetic and genomic findings, to participants in observational cohort studies is a complex yet essential aspect of modern research ethics. This practice involves providing participants with personalized data from their biological samples, which can significantly impact their health and well-being. Challenges include scientific and ethical dilemmas about what results to return, actionability of findings and access to follow up, legal responsibilities, logistical hurdles in ensuring accurate communication, and economic considerations related to validation and follow-up costs. A growing movement for a patient/participant-centric research approach emphasizes participants' right to access their health data and researchers' obligation to return results. Diverse stakeholder perspectives, especially those from study participants are essential to address these challenges. Initial efforts to return specific types of results, such as imaging and genetic data, have shown some benefits and been satisfactory to study participants. However, they also highlight potential challenges, with ongoing debates about which data to return, the timing, and communication methods. Despite these uncertainties, the increasing interest for returning research results among researchers and study participants continues to grow, underscoring the need for further discussions on the ethical, practical, and beneficial aspects for all stakeholders involved.
Summary
Session 1: History and Principles for Returning Incidental Individual Research Results
This session delved into the history and principles of returning incidental individual research results. It highlighted the historical context, tracing the pathway from initial objections and concerns about returning sequencing results in 2006 to the current stance that returning actionable genetic information is an ethical obligation. The discussion covered the complexities of returning primary and especially secondary findings. While primary findings are typically discovered in clinical settings with intended scope and clear protocols, secondary findings are often the results of incidental discoveries in research studies. Among the challenges associated with secondary findings are the needs for analytical validity by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, careful variant classification and proper counseling. The NHGRI Intramural's Secondary Genomics Finding Service was discussed as an example of institutionalizing the return of secondary findings.
Key ethical issues and considerations emphasized by all speakers in the session included the Obligation to Return Results- the ethical responsibility to return actionable significant genetic findings to participants together with the concept of Beneficence and Non-Maleficence – the principal of avoiding harm. Speakers in this session regarded the use of the American College of Medical Genetics and Genomics (ACMG) list as a starting point for actionable findings. Although this list may evolve over time, it includes gene-disease pairs where medical recommendations are expected to improve health outcomes. Additional ethical principles such as reciprocity and transparency were highlighted, focusing on participants’ rights and desire to know along with appreciation and building trust. The session also tackled challenges of returning results due to informed consent including “opt out” options, psychological impacts, financial costs. It was suggested that policies should prioritize minimizing harm by considering weak refusers who might make a mistake.
Session 2: Categories of Individual Genomic and Genetic Results and Analytical Validation
This session focused on categorizing and validating genomic and genetic results, highlighting the diversity of findings that can arise from genetic testing. It began with an overview of various genetic variations, including single nucleotide variants, indels, structural variants, and somatic mutations. It continued with the distinction of monogenic results versus Variants of Uncertain Significance (VUS) and the utility of risk prediction tools such Polygenic Risk Score (PRS), each presenting their own unique challenges. Speakers emphasized that the complexity of returning results necessitates analytical validation and compliance with federal and state regulations, such as FDA LDT (Laboratory developed tests) approval, College of American Pathologist (CAP) and CLIA standards, as well as HIPAA (Health Insurance Portability and Accountability Act) regulations. While the utility of PRS in existing risk prediction models depends on the quality of genotyping and imputation, it is also important to address biases by using diverse ancestral samples in validation studies to ensure accuracy and equity in genetic healthcare. While the implications of returning PRS results may be simpler than monogenic mutations, there is still a need for clear communication and transparency regarding PRS limitations and uncertainties. The session also covered the implications of somatic mutations and the dynamic nature of clonal hematopoiesis, stressing the need for ongoing monitoring and flexibility in research protocols to adapt to emerging therapies. A discussion on the complexity of VUS results emphasized that not all VUS are made equal and that lack of sufficient evidence at the time of testing does not preclude future re-interpretation of pathogenic variants, especially for understudied populations. The questions on whether, how, and who is trained to communicate results, particularly uncertain risk as well as the implications for family members and cascade testing were also discussed. Overall, the session thoroughly examined the scientific, regulatory, and ethical dimensions involved in returning different genomic and genetic results, underscoring the importance of robust validation, compliance with existing regulations, and equitable practices.
Session 3: The Practice of Returning Genomic Results and Lessons Learned
Insights from a variety of studies and programs were shared in this session, focusing on the practicalities and lessons learned in returning genomic results to participants. It began with a detailed discussion of the Finnish GeneRISK study of the utility of PRS for cardiovascular diseases. This study illustrated the benefits of the integration of genetic data with national health registries and highlighted the predictive value of PRS, especially for early-onset diseases. The session also covered the eMERGE (Electronic Medical Records and Genomics ) Network's efforts to return genome-informed risk assessments (GIRA) for common conditions such as heart disease and diabetes, obesity, breast cancer, asthma, which combine genetic, clinical, and family history data to create comprehensive risk profiles for participants. The Jackson Heart Study's approach highlighted the importance of community-partnered and informed strategies for enhanced genetic health literacy, trust, engagement in research, and for achieving a high level of interest in returning individual genetic results to study participants. An important ethical lesson was shared from the COPDgene (Chronic Obstructive Pulmonary Disease Gene) study, originally aimed at identifying genetic determinants of Chronic Obstructive Pulmonary Disease but incidentally investigators found potential hepatitis C virus infection in more than 2% of study participants. The study convened a multi-disciplinary committee with a representation of investigators, bioethicists, and study participants who unanimously supported the return of these incidental results. While the majority of identified participants were already clinically diagnosed, the actions taken by the study contributed to enhanced participants’ satisfaction and trust. The AoU (All of Us) Research Program, uniquely exempt from CLIA validation returns genetic ancestry, traits, ACMG designated actionable genes and pharmacogenetic results, shared experience providing participants with the opportunity to opt-in and receive their genetic information along with genetic counseling. With community partners, the program built tools to ensure participants' understanding of consent, developed culturally appropriate educational resources, and strategies for participants to access healthcare. The session concluded with reflections on the need for ongoing adaptation of protocols/policy to improve RoR, ensuring that participants receive meaningful, actionable information that enhances their health outcomes.
Session 4: Responsibility and Value of Returning Individual Results
This session examined the empirical data and ethical responsibilities associated with the return of individual research results. The session began with underscoring the significant increase in the number of people who have been sequenced globally and the resulting implications for returning potentially life-saving information. The session also highlighted the need for standardized approaches and discussed the complexities of managing these returns across different populations. Speakers shared different models of returning results from various members of a care teams such as genetic counselors, primary care clinicians, pharmacists, and study coordinators. Discussions underscored the importance of tailoring disclosure methods to the type of result and the participant's context, advocating for a nuanced approach that emphasizes sensitivity, and compassion while minimizing patient distress. Speakers introduced the concept of tailoring RoR based on type of result into high-touch (a one-on-one counseling session either in-person or a virtual session for pathogenic or likely pathogenic actionable variations) vs. low-touch (email, participant portal or other digital tools for ancestry or negative screening) approaches. The session highlighted the critical need for striving for equitable outcomes through engagement of practices that are culturally sensitive when disclosing information to study participants with various levels of access to care and health literacy. Case studies from Federally-Qualified Health Centers, PopSeq and BabySeq Studies, Geisinger’s MyCode Community Health Initiative, and GUARDD (Genetic testing to understand and address renal disease disparities) demonstrated how integrating genomic research into routine care can address health disparities, with a particular focus on community engagement and provider education. The session concluded by reflecting on the operational challenge of providing financial assistance and follow-up care and the needs to strengthen the collaborations among researchers, community members and organizations such as Community Advisory Board, patients and clinical experts so that approaches meet the needs of diverse participants and busy clinicians.
Session 5: New Technologies and Other Types of Results
The final session delved into the implications of new technologies for returning research results, expanding the discussion beyond traditional genomic findings. The session began with an overview of cell-free DNA (cfDNA) tests, including their use in non-invasive prenatal testing and multi-cancer early detection, emphasizing the benefits and challenges of these methods, such as handling false positives and ensuring accurate interpretation. The growing integration of genetic test results into electronic health records (EHRs) was discussed, highlighting the potential for improving accessibility and clinical utility, while also noting current limitations in data standardization and the need for structured, machine-readable formats. RoR from wearable devices illustrated the ethical obligation to provide participants with actionable health information, the benefits of increased self-awareness, and the challenges of ensuring data accuracy and managing the associated costs. Environmental health studies were also addressed, showcasing the importance of reporting back findings to communities, particularly those impacted by environmental contaminants, and the need for culturally appropriate communication strategies. The session emphasized the importance of developing robust frameworks for returning diverse types of results, balancing the benefits and risks, and ensuring equity in access to health information.
Patients and Study Participant Perspectives
The workshop featured study participants and representatives, who provided invaluable insights into the real-world impact of returning individual research results. Their narratives highlighted the emotional journey and varied responses to receiving genetic information, often marked by anxiety, confusion, or fear, especially when results indicated a predisposition to serious conditions. These stories emphasized the critical role of receiving information from genetic counselors, clinicians or trained lay persons in understanding their results, alleviating concerns, and making informed and shared decisions about their health and that of their families. Clear, accessible information was a recurrent theme, with patients and study participants expressing a preference for plain language explanations, visual aids, and practical guidance on the next steps, alongside access to follow-up support from knowledgeable professionals. Disparities in access to genetic services and the impact of socioeconomic factors were also highlighted, with patients from underserved communities sharing challenges related to accessing care, building trust, understanding complex information, and managing the financial implications of further testing or treatment. The psychological and familial impacts of receiving genetic results were explored, underscoring the responsibility of sharing significant health information with family members and the potential for genetic information to alter family dynamics. Overall, study participant and patients’ perspectives strongly emphasized the necessity of patient/participant-centered practices prioritizing clear communication, equitable access, and comprehensive support, ensuring that the RoR is a beneficial and empowering process for all participants.
Conclusion
The workshop provided a comprehensive overview of the historical context, ethical principles, and practical challenges associated with returning individual research results. Highlighting the diverse perspectives of researchers, clinicians, genetic counselors, patients, and study participants underscored the value of clear communication, equitable practices, and robust validation processes. The integration of new technologies and methods into the return of results further emphasized the evolving landscape of genomic research. Addressing these challenges and seizing the opportunities to enhance the practice of returning research results could improve the rigor and participant-centeredness of genomics research.
Key Opportunities and Themes
- Explore institutional-level solutions for returning results aiming for clear policies including high-touch and low-touch paths for returning both planned and unexpected results, emphasizing transparency, reciprocity, equity, and beneficence.
- Research and improve current methods for opting out, ensuring those who are interested in obtaining their results can access them without complex consent processes, and develop educational resources to aid informed decisions.
- Develop robust classification and counseling processes for variants of uncertain significance (VUS) to improve equitable communication and help participants understand their results and follow-up care.
- Continue to evaluate the clinical utility of polygenic risk scores (PRS) alongside traditional risk factors to improve the precision of disease risk assessments, and to improve the accuracy of PRS through inclusive research across diverse populations.
- Use multiple modalities (e.g., visual aids, detailed reports) to enhance genetic literacy and continuously refine communication strategies based on participant feedback.
- Use a team approach involving genetic counselors, primary care clinicians, and support staff to tailor result disclosures based on patient preferences and result types. Advance genomics literacy for clinicians and study participants.
- Engage community stakeholders early and throughout the research process to incorporate diverse perspectives and ensure better outcomes, using community or multi-stakeholder advisory boards, and iterative feedback processes.
- Integrate genomic research into routine care of underserved and low-income populations, including at federally qualified health centers, to address health disparities, focusing on community engagement and education.
- Integrate genetic test results into electronic health records (EHRs) in structured, machine-readable formats.
- Leverage wearable devices to provide actionable health information, balancing data accuracy with meaningful reports.
- Stay abreast of evolving data and its clinical implications through continuous research and updates, integrating new findings like clonal hematopoiesis (CHIP) into risk assessments and treatment protocols, and expanding the use of cfDNA, and environmental health results tests.
Participants
Workshop Co-Chairs
- Carol R. Horowitz, MD, MPH
- Iftikhar J. Kullo, MD
NHLBI Leadership
- David Goff, MD, PhD, FACP, FAHA
NHLBI Co-Chairs
- Ronit Yarden, PhD, MHSA
- Ye Yan, PhD
- Yuling Hong, MD, MSc, PhD
Additional members of the Organizing Committee
Julie Mikulla, MBA, MSc, RN, PMP, NHLBI
Cashell Jaquish, PhD, NHLBI
Melissa Garcia, MPH, NHLBI
Sharon Smith, PhD, NHLBI
Charlene Schramm, PhD, NHLBI
Weiniu Gan, PhD, NHLBI
Jane Ye, PhD, NHLBI
Pankaj Qasba, PhD, NHLBI
Afshin Parsa, MD, MPH NIDDK
Robb Rowley, MD, NHGRI
Mollie Minear, PhD, NICHD
Anastasia Wise, PhD, OD, NIH
Speakers and Moderators
- Lisa Bastarache, MS
- Benjamin Berkman, JD, MPH
- Alexander Bick, MD, PhD
- Leslie Biesecker, MD
- Kyle Brothers, MD, PhD
- April Carson, PhD, MSPH
- Beth Cooney, BA
- Keith Diaz, PhD
- Malia Fullerton, DPhil
- Richard A. Gibbs, PhD
- Crystal Gonzalez, MSW
- Robert Green, MD, MPH
- Heather Hampel, MS, CGC
- Candace Hanley, MPH
- Jodi D. Hoffman, MD, FACMG
- Carol R. Horowitz, MD, MPH
- Jodell Linder Jackson, PhD
- Gail Jarvik, MD, PhD
- Elizabeth Karlson, MD, MS
- Sadiya Sana Khan, MD, MS
- Iftikhar J. Kullo, MD
- Barry Make, MD
- Yoshira Ornelas Van Horne, PhD
- Samuli Ripatti, PhD
- Marylyn Ritchie, PhD, FACMI
- Mimsie Robinson, MA, PhD
- Juliann Savatt, MS, CGC
- Gabriel Shaibi, PhD
- Stephen Sodeke, PhD
- Alexandra Walsh, MA
- Anastasia Wise, PhD
Disclaimer: The findings, knowledge gaps, and opportunities described here represent a summary of individual opinions and ideas expressed during the workshop. The summary does not represent a consensus opinion or directive made to or by NHLBI or NIH.