Richard R. Sharp

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.

The Challenge of Informed Consent and Return of Results in Translational Genomics: Empirical Analysis and Recommendations

As exome and genome sequencing move into clinical application, questions surround how to elicit consent and handle potential return of individual genomic results. This study analyzes nine consent forms used in NIH-funded sequencing studies. Content analysis reveals considerable heterogeneity, including in defining results that may be returned, identifying potential benefits and risks of return, protecting privacy, addressing placement of results in the medical record, and data-sharing. In response to lack of consensus, we offer recommendations.

Why brain death is considered death and why there should be no confusion.

Neurologic determination of brain death is a complex assessment that may be misunderstood by nonspecialists and families. Recent guidelines clarify how to proceed with such an examination and are available to physicians, with the time of death in adults and children being determined by the last defining test—the apnea test. This core principle in neurology has been challenged recently in court and resulted in an unprecedented continuation of care in a 13-year-old child declared dead. This review comments on the medical, legal, and ethical quandaries introduced by this case and highlights the major elements of consensus on matters related to brain death that have been forged over 3 decades of sustained medical and societal debate. A clear appreciation by physicians and the public of the diagnostic determination of death following loss of brain function will help to prevent similar conflicts from occurring in the future.

Patients' views on incidental findings from clinical exome sequencing.

This article characterizes the opinions of patients and family members of patients undergoing clinical genomic-based testing regarding the return of incidental findings from these tests. Over sixteen months, we conducted 55 in-depth interviews with individuals to explore their preferences regarding which types of results they would like returned to them. Responses indicate a diversity of attitudes toward the return of incidental findings and a diversity of justifications for those attitudes. The majority of participants also described an imperative to include the patient in deciding which results to return rather than having universal, predetermined rules governing results disclosure. The results demonstrate the importance of a patient centered-approach to returning incidental findings.

Return of results in the genomic medicine projects of the eMERGE network

The electronic Medical Records and Genomics (eMERGE) (Phase I) network was established in 2007 to further genomic discovery using biorepositories linked to the electronic health record (EHR). In Phase II, which began in 2011, genomic discovery efforts continue and in addition the network is investigating best practices for implementing genomic medicine, in particular, the return of genomic results in the EHR for use by physicians at point-of-care. To develop strategies for addressing the challenges of implementing genomic medicine in the clinical setting, the eMERGE network is conducting studies that return clinically-relevant genomic results to research participants and their health care providers. These genomic medicine pilot studies include returning individual genetic variants associated with disease susceptibility or drug response, as well as genetic risk scores for common “complex” disorders. Additionally, as part of a network-wide pharmacogenomics-related project, targeted resequencing of 84 pharmacogenes is being performed and select genotypes of pharmacogenetic relevance are being placed in the EHR to guide individualized drug therapy. Individual sites within the eMERGE network are exploring mechanisms to address incidental findings generated by resequencing of the 84 pharmacogenes. In this paper, we describe studies being conducted within the eMERGE network to develop best practices for integrating genomic findings into the EHR, and the challenges associated with such work.

Research ethics consultation: ethical and professional practice challenges and recommendations.

The complexity of biomedical research has increased considerably in the last decade, as has the pace of translational research. This complexity has generated a number of novel ethical issues for clinical investigators, institutional review boards (IRBs), and other oversight committees. In response, many academic medical centers have created formal research ethics consultation (REC) services to help clinical investigators and IRBs navigate ethical issues in biomedical research. Key functions of a REC service include assisting with research design and implementation, providing a forum for deliberative exploration of ethical issues, and supplementing regulatory oversight. As increasing numbers of academic research institutions establish REC services, there is a pressing need for consensus about the primary aims and policies that should guide these activities. Establishing clear expectations about the aims and policies of REC services is important if REC programs are to achieve their full potential. Drawing on the experiences of a Clinical and Translational Science Award Research Ethics Consultation Working Group, this article describes three major ethical and professional practice challenges associated with the provision of REC: (1) managing multiple institutional roles and responsibilities, (2) managing sensitive information, and (3) communicating with consultation requestors about how these issues are managed. The paper also presents several practical strategies for addressing these challenges and enhancing the quality of REC services.

Genomic Medicine and Incidental Findings: Balancing Actionability and Patient Autonomy

M.J.B., ter for Mayo .S.P.). I n March 2013, the American College of Medical Genetics and Genomics (ACMG) released recommendations on how to handle incidental findings (IFs) for the clinical application of whole exome or whole genome sequencing (WES/WGS). The ACMG recommended that clinical laboratories “actively search,” evaluate, and report pathogenic or likely pathogenic variants in 56 genes and report these findings to the ordering clinician,who could then “contextualize any incidental findings for the patient in light of personal and family history, physical examination, and other relevant findings.” The 2013 recommendations did not provide guidance for laboratories to offer patients of any age the ability to opt out from the reporting of IFs. The 56 genes are associated with 24 genetic cardiovascular disorders or predisposition to cancers for which confirmatory diagnostic approaches are available as well as some preventive or treatment measures that can be offered. The ACMG recommended further that those who did not agree to learn of these IFs could choose to forego the entire test. These recommendations generated much controversy, most of which focused on patients’ ability to opt out of receiving unwanted results. Illustrating its commitment to participating in broad, public discussion, the ACMGBoard of Directors surveyed its membership in early 2014 to ascertain how the members viewed the 2013 recommendations. In addition, the ACMG surveyed attendees of the 2014 ACMG annual meeting. The responses suggest that most members support allowing informed patients to opt out of receiving information about some or all IFs (presented at the 2014 annual ACMG business meeting). The ACMG also held open forums to discuss the recommendations, including one at each of the 2013 and

Practical Guidance for Charting Ethics Consultations

It is generally accepted that appropriate documentation of activities and recommendations of ethics consultants in patients’ medical records is critical. Despite this acceptance, the bioethics literature is largely devoid of guidance on key elements of an ethics chart note, the degree of specificity that it should contain, and its stylistic tenor. We aim to provide guidance for a variety of persons engaged in clinical ethics consultation: new and seasoned ethics committee members who are new to ethics consultation, students and trainees in clinical ethics, and those who have significant experience with ethics consultation so that they can reflect on their practice. Toward the goal of promoting quality charting practices in ethics consultations, we propose recommendations on a broad array of questions concerning clinical ethics consultation chart notes, including whether and when to write a chart note, and practical considerations for the tenor, purpose, and content of a chart note. Our broader aim is to promote discussion about good charting practices in clinical ethics, with the hope of contributing to clear standards of excellence in clinical ethics consultation.

Building a Central Repository for Research Ethics Consultation Data: A Proposal for a Standard Data Collection Tool.

Clinical research ethics consultation services have been established across academic health centers over the past decade. This paper presents the results of collaboration within the CTSA consortium to develop a standard approach to the collection of research ethics consultation information to serve as a foundation for quality improvement, education, and research efforts. This approach includes categorizing and documenting descriptive information about the requestor, research project, the ethical question, the consult process, and describing the basic structure for a consult note. This paper also explores challenges in determining how to share some of this information between collaborating institutions related to concerns about confidentially, data quality, and informatics. While there is much still to be learned to improve the process of clinical research ethics consultation, these tools can advance these efforts, which, in turn, can facilitate the ethical conduct of research.

Next-generation disadvantages: identifying potential barriers to integrating genomics into underserved medical settings

Numerous voices within the genetics community believe that translational genomic research and new forms of personalized medicine must include populations of all social, economic and racial backgrounds [1,2]. To increase the likelihood that new genomic tools are available to all who may benefit from their application, we must identify and then work to eliminate potential barriers that would limit access to emerging genomic technologies or reduce their clinical impact or personal utility. One such barrier is that the high cost of genomic applications, such as whole-genome or -exome sequencing, may put these technologies out of reach for many patients. Smart and colleagues, along with other investigators and policy-makers, suggest that it is not yet clear if medically underserved communities will ever benefit from personalized genomic medicine (PGM) if costs or insurance plans are barriers [3]. Even if a larger number of insurance companies begin covering genomic services, uninsured or underinsured families would likely have limited access to these technologies. Currently, some limited types of genetic tests, when indicated clinically, are available to patients on Medicaid [4]. However, as genomic sequencing becomes more integrated into standard care, replacing traditional single gene or multiplex genetic tests, it is unknown whether public or private insurers will continue to cover these services. Even if these programs cover genomic services, this will not address the millions of Americans living within the insurance gap, who are not eligible for public support, but do not have adequate private insurance. Moreover, the implications of the Affordable Care Act for the translation of PGM to clinical settings are not yet known.