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Objective We describe a stratified sampling design that combines electronic health records (EHRs) and United States Census (USC) data to construct the sampling frame and an algorithm to enrich the sample with individuals belonging to rarer strata. Materials and Methods This design was developed for a multi-site survey that sought to examine patient concerns about and barriers to participating in research studies, especially among under-studied populations (eg, minorities, low educational attainment). We defined sampling strata by cross-tabulating several socio-demographic variables obtained from EHR and augmented with census-block-level USC data. We oversampled rarer and historically underrepresented subpopulations. Results The sampling strategy, which included USC-supplemented EHR data, led to a far more diverse sample than would have been expected under random sampling (eg, 3-, 8-, 7-, and 12-fold increase in African Americans, Asians, Hispanics and those with less than a high school degree, respectively). We observed that our EHR data tended to misclassify minority races more often than majority races, and that non-majority races, Latino ethnicity, younger adult age, lower education, and urban/suburban living were each associated with lower response rates to the mailed surveys. Discussion We observed substantial enrichment from rarer subpopulations. The magnitude of the enrichment depends on the accuracy of the variables that define the sampling strata and the overall response rate. Conclusion EHR and USC data may be used to define sampling strata that in turn may be used to enrich the final study sample. This design may be of particular interest for studies of rarer and understudied populations.

In the decade since the Human Genome Project was completed, the knowledge and technologies that this project enabled have led to a remarkable evolution in the way biorepositories are designed and operate. Early biobanks were often designed to facilitate the study of a single condition, while biobanks established in the last decade have more frequently been created with a broader research mission in mind.1 Accompanying this transition have come other changes in biobank practices, including the generation and storage of genome-scale sequencing data, frequent sharing of biosamples and data, pooling of resources among sample collections, and increased interest in returning genetic research results to sample donors. As biorepository practices have become more complex, the task of developing appropriate informed consent practices has become more challenging. There are at least three reasons for this. First, the regulations that govern research with human subjects in the U.S., known collectively as the Common Rule, were written at a time when many of the recent innovations in biobank practices were not anticipated. Second, Institutional Review Boards (IRBs) are tasked with evaluating whether research studies meet both federal regulations and local standards for acceptable research, yet IRB members are often unfamiliar with the complexities of biobanks. Third, it can be quite challenging to explain these practices in informed consent documents in a way that is easy for potential research participants to read and understand. Because of these challenges, several groups have developed practical guidance on informed consent. For example, the website of the National Human Genome Research Institute (NHGRI), Genome.gov, provides model informed consent language developed for genomic research studies, including biobanks.2 The NHGRI website also hosts a white paper developed by our group, the Electronic Medical Records and Genomics (eMERGE) Network.3 This document provides model language for informed consent documents that investigators may adapt for their own biorepository projects. One limitation of these resources, however, is their focus on adult research participants. There are currently no similar resources that address the unique issues that arise for biorepositories that aim to collect samples from pediatric participants. This is an important gap in the literature, since the challenges associated with biobanking are magnified in the setting of pediatric research. The ability of children to engage in informed decision-making varies according to their developmental level, so parental permission is usually required for pediatric research participation. However, a parent’s permission for a child to participate in research is quite different from an adult’s consent for his or her own research participation. A parent’s decision must account for the best interests of the child, while at the same time balancing the future autonomy of the child and the needs of the family. To be sure, there is a robust literature on these unique issues that arise in pediatric research,4,5 including a number of helpful papers that address pediatric biorepositories specifically.6,7 However, it can be difficult for investigators and IRB members to distill these empirical and analytical resources into concrete practices related to the informed consent process. This document is designed to address that need. Writing on behalf of the Consent, Education, Regulation, and Consultation (CERC) workgroup of the eMERGE Network, we provide pediatric-focused guidance for investigators and IRB members working in the U.S regulatory context on pediatric informed consent practices for biorepositories.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

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 inclusion of genomic data in the electronic health record raises important ethical, legal, and social issues. In this article, we highlight these challenges and discuss potential solutions. We provide a brief background on the current state of electronic health records in the context of genomic medicine, discuss the importance of equitable access to genome-enabled electronic health records, and consider the potential use of electronic health records for improving genomic literacy in patients and providers. We highlight the importance of privacy, access, and security, and of determining which genomic information is included in the electronic health record. Finally, we discuss the challenges of reporting incidental findings, storing and reinterpreting genomic data, and nondocumentation and duty to warn family members at potential genetic risk.