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

Large-scale sequencing tests, including whole-exome and whole-genome sequencing (WES/WGS), are rapidly moving into clinical use.1 Sequencing is already being used clinically to identify therapeutic opportunities for cancer patients who have run out of conventional treatment options, to help diagnose children with puzzling neurodevelopmental conditions, and to clarify appropriate drug choices and dosing in individuals. To evaluate and support clinical applications of these technologies, the National Human Genome Research Institute (NHGRI) and National Cancer Institute (NCI) have funded studies on clinical and research sequencing under the Clinical Sequencing Exploratory Research (CSER) program as well as studies on return of results (RoR). Most of these studies use sequencing in real-world clinical settings and collect data on both the application of sequencing and the impact of receiving genomic findings on study participants. They are occurring in the context of controversy over how to obtain consent for exome and genome sequencing,2 whether to return results, and the role of patient/ participant preferences — controversy fueled by publication of the American College of Medical Genetics and Genomics (ACMG) recommendations for clinical sequencing in 20123 and management of incidental findings in 2013,4 with ensuing commentaries.5 Indeed, debate over the ACMG recommendations on incidental findings prompted a recent amendment of those recommendations.6 To identify approaches used at leading U.S. institutions engaged in translating sequencing from research to clinical care, we analyzed the consent forms used in six CSER studies (funded as of early 2012), and three R01 studies in the RoR (now CSER-ELSI) Consortium. All were written before the release of the 2013 ACMG recommendations on incidental findings,7 although some involve investigators who participated in that writing group. While prior work has analyzed consent forms in genome sequencing,8 these nine studies aim specifically to develop best practices for clinical use.9 By analyzing their consent forms, we sought to shed light on current approaches to consent for research on returning genomic results, broadly defined here to include both diagnostic and incidental findings from sequencing.10 In particular, we aimed to assess the degree to which broad areas of agreement were evident. The nine studies are among the first NIH-funded studies to consider the many practical issues associated with clinical applications of WES/WGS. Each made relatively independent decisions about how to explain sequencing, its limitations, and potential findings. Our analysis addresses four key questions: (1) What results do these studies plan to return to participants? (2) How are participant preferences taken into account in determining whether to return results? (3) What potential benefits and risks are identified? and (4) How are privacy, placement of results into the medical record, risk of re-identification, and data-sharing addressed?