Return of Research Results

There are ongoing discussions among researchers, ethicists, policymakers, and research participants about the return of individual research results (IRRs) and incidental findings (IFs) from genomic research. These issues are not new or unique to genomics, but advances in genomic technologies have brought them to the forefront. NHGRI is currently funding research to examine these questions and inform future NHGRI policy.

IRRs are the results for a specific study participant from a scientific investigation. For example, in genomics research, an IRR could be whether a research participant possesses a particular gene variant under study. IFs are a subset of IRRs-- findings that are not related to the objectives of an investigation. An example of an IF in genomics research would be finding that a study participant in an investigation of the genetics of heart disease possesses a gene variant related to Alzheimer's disease. IFs are also called secondary findings.

Anticipating an Increase

Addressing the issue of return of IRRs and IFs is relevant for a variety of fields of human health research. However, the volume of genomic data, the potential for its broad application, and advances in the interpretation of genomic data pose particular challenges in the field of genomic research. As genomic technologies have advanced and the cost of sequencing has decreased, it has become feasible to produce more genomic data in research. The greater volume of genomic data available to researchers makes the discovery of IFs more likely.

In addition, to maximize the usefulness of genomic data collected in research, this data is often made available, with appropriate protections for study participants, to the scientific community to be used in research beyond the investigation for which the data was originally collected. As the data is analyzed by different investigators for differing purposes, it is more likely that IRRs and IFs, beyond those from the original study, will be discovered.

Lastly, although much has been learned about the human genome, there remains much to be discovered. Genomic information is interpreted differently over time as more is learned. Therefore, the interpretation of a result may change in the future, and new IRRs and IFs may be discovered.

Whether, When, How to Return

Increasingly, researchers are returning IFs or IRRs from genomic research to study participants, but there is still debate about when it is appropriate to return results, what types of results should be returned, and how to return results. Many genomics researchers believe that at a minimum and after an informed consent process, incidental findings that are medically actionable (meaning that there is an associated action to reduce the risk of a disease or to treat the disease) should be returne:[1] however, determining what is actionable is also a challenge. The volume of genomic data and the potential for new findings and changing interpretations in the future makes it particularly difficult to develop recommendations and policies regarding an infrastructure and resources for returning IRRs and IFs.

Currently, the only federal law regarding return of genetic IRRs and IFs is the Clinical Laboratory Improvement Amendments of 1988 (CLIA), which sets quality standards for all laboratories performing clinical testing. CLIA prohibits the return of individual research results to research participants unless the results were obtained in a CLIA-certified laboratory. Although some scientists have obtained CLIA certification for their laboratories, most research laboratories are not CLIA-certified, and not all research laboratories have the resources to enable re-testing in a CLIA-certified laboratory. The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule also plays a currently ambiguous role regarding the return of genetic IRRs and IFs in non-CLIA certified labs. One HIPAA clause could allow research participants to obtain access to their lab test reports, even if these reports were generated in a non-CLIA lab.

The National Academies of Science, Engineering, and Medicine launched a consensus study in 2017 to evaluate the return of individual-specific research results. The committee will analyze current evidence on returning results, review the regulatory environment, and provide recommendations. Though the study is not about genomics specifically, it will grapple with many of the same questions outlined here and may help resolve regulatory uncertainty.

In the absence of laws regarding return of genetic IRRs and IFs, various groups and individuals have published recommendations and best practices. The National Heart, Lung, and Blood Institute (NHLBI) published recommendations on reporting research results to study participants in 2006 and updated them in 2010. In 2013, the Presidential Commission for the Study of Bioethical Issues released a report titled "Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts." This report recommends that all practitioners should communicate with patients, research participants and consumers about the possibility of IFs and the possible benefits and risks of pursuing IFs. Informed consent can then be obtained if the patient wishes to learn about resulting IFs, or the patient may choose to decline IF results.

In 2013, the American College of Medical Genetics (ACMG) published a list of medically actionable IFs that they recommend should be deliberately searched for and reported during clinical encounters that involve exome and genome sequencing.[2] While the recommendations do not apply to the research realm, some researchers have chosen to follow these recommendations. [3] Some researchers have proposed an expanded list of genetic variants to return.[4] Others have cautioned against the ACMG list because of concerns that only a small percentage of those that have genetic variants associated with disease will actually manifest with disease. These researchers also caution that the dearth of data on populations of non-European ancestry makes predicting risk in these populations difficult.[5] These studies and debates highlight the need for the genomic research community to continue working to understand when variants are actionable, when they should be returned, and how to return them. In 2016, the ACMG published an updated list of IFs (now called secondary findings)to return[6], but these questions remain unresolved.

NHGRI requires that the research that it funds comply with all applicable federal, state, and local laws, which includes CLIA. NHGRI has awarded grants for a variety of projects that are examining return of research results. In 2012, NHGRI organized the investigators involved in these projects into the Return of Results Consortium, and in 2013, the projects within this consortium were incorporated into the Clinical Sequencing Exploratory Research (CSER) consortium Among other aspects of clinical sequencing, the consortium investigators are researching real-life applications of returning genomic results as well as legal and ethical aspects of returning results. Members of the eMERGE Network also investigate approaches for return of genomic results, especially as it relates to incorporation into electronic health records. These grants are intended to contribute to an evidence base that may be used to inform future policy decisions. NHGRI is also participating in discussions in the field of genomics as policy makers, funders, and researchers grapple with the issue of returning genomic research results and incidental findings, and held a workshop on the topic in 2014.

[1] Jarvik GP, Amendola LM, Berg JS, Brothers K, Clayton EW, Chung W, et al. Return of genomic results to research participants: the floor, the ceiling, and the choices in between. Am J Hum Genet, 94(6):818-26. doi: 10.1016/j.ajhg.2014.04.009. 2014. [PubMed]

[2] Green RC, Berg JS, Grody WW, et al. American College of Medical Genetics and Genomics. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med, 15(7):565-574. 2013. [PubMed], [Article]

[3] Berg J.S., Amendola L.M., Eng C., Van Allen E., Gray S.W., Wagle N., Rehm H.L., DeChene E.T., Dulik M.C., Hisama F.M., Members of the CSER Actionability and Return of Results Working Group. Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium. Genet. Med, 15:860-867. 2013. [PubMed]

[4] Berg J.S., Amendola L.M., Eng C., Van Allen E., Gray S.W., Wagle N., Rehm H.L., DeChene E.T., Dulik M.C., Hisama F.M., Members of the CSER Actionability and Return of Results Working Group. Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium. Genet. Med, 15:860-867. 2013. [PubMed]

[5] Van Driest SL, Wells QS, Stallings S, et al. Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records. JAMA, 315:47. 2016. [PubMed]

[6] Kalia SS, Adelman K, Bale SJ et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med, 19:249-255. 2016. [PubMed]