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Introduction

Population surveys collect information from participants by asking questions. Today, many surveys also collect biologic specimens that can be used to analyze a respondent’s DNA and other biomarkers. The National Health and Nutrition Examination Survey (NHANES) is a population survey that also administers a physical examination, collects biospecimens, and reports some test results (e.g., cholesterol levels) to the participant. While visiting communities large and small throughout the country, NHANES collects health and nutrition data from a representative sample of individuals through in-person interviews and health examinations that take place at special mobile examination centers. The examination component consists of medical, dental, and physiological examinations, as well as laboratory tests. A continuous program, the exact measures collected through NHANES vary year to year for each NHANES cycle.¹

Many of the laboratory results are shared with NHANES participants, while others are reported only if a problem is detected. Some of the collected specimens are neither analyzed nor reported, but rather are stored as part of the NHANES Biospecimen Program.² DNA specimens are one such example. Last collected in the 2011–2012 cycle, six of NHANES’s past cycles

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¹ See https://wwwn.cdc.gov/nchs/data/nhanes/survey_contents.pdf for additional information about the various measures collected by NHANES since 1999.

² The NHANES Biospecimen Program oversees the approval of proposals to use stored biospecimens; ensures appropriate long-term storage of biospecimens at the biorepositories; and arranges for transfer of biospecimens from the biorepositories to the investigators with approved proposals. For more information about the NHANES Biospecimen Program, see https://www.cdc.gov/nchs/nhanes/biospecimens/biospecimens.htm

collected DNA and genetic specimens. Those cycles included separate consents for (a) storing blood and urine for nongenetic future research (asked for all persons) and (b) storing blood for future genetic research (asked only for persons ages 20 and over). Both consents stated explicitly that the survey organization did not know what tests would be done on the specimens in the future and that participants would not be contacted with results. Consenting individuals had blood collected for DNA purification and the resulting genetic variant data that also met the quality control guidelines were deposited into the NHANES Genetic Data Repository.³ Individuals interested in accessing the genetic data must submit a proposal and have that proposal approved.

In 2014, the National Academies of Sciences, Engineering, and Medicine conducted a workshop focused on how NHANES and other population surveys should (a) implement the reporting of results from genomic research using stored specimens and (b) address informed consent for future data collection, as well as for the use of banked specimens covered by prior informed consent agreements.⁴ The workshop addressed numerous questions, such as: “Should genetic results be returned to participants?” The workshop also included presentations from five ongoing population-based survey programs that had collected or were collecting genetic specimens, in order to understand how those programs approached the issues of genomic data collection and return of results. The 2014 workshop and discussions informed the Ethics Review Board of the Centers for Disease Control and Prevention’s (CDC’s) National Center for Health Statistics (NCHS) in the development of the program’s 2019 guidelines for proposals to use banked NHANES DNA specimens for genomic research.⁵

While in the process of redesigning the NHANES program for 2025 and beyond, the CDC sponsored a workshop in 2022 to assist NHANES in thinking through the many logistic and ethical issues that must be considered when returning genomic data to study participants. A successor of sorts to the 2014 workshop that focused on issues for banked genomic specimens, the 2022 workshop was to focus on anticipated future collections of genomic data by NHANES. In particular, the 2022 workshop was to focus on the ethical considerations and current practices for returning genomic information from “active” research and population surveys. In the

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³ For additional information on the NHANES Genetic Data Repository, see https://www.cdc.gov/nchs/nhanes/biospecimens/dnaspecimens.htm

⁴ See National Research Council. (2014). Issues in returning individual results from genome research using population-based banked specimens, with a focus on the National Health and Nutrition Examination Survey: Workshop summary. The National Academies Press. https://doi.org/10.17226/18829

⁵ See Health and Nutrition Examination Survey (NHANES) DNA Specimens: Guidelines for Proposals To Use Samples and Cost Schedule, 84 F.R. 5441 (notice released February 21, 2019). https://www.federalregister.gov/d/2019-02908

context of this workshop, the term active survey was used to distinguish between data from the primary interaction with the participant versus secondary research using existing data and biospecimens (e.g., from the NHANES Biospecimens Program). The project’s full statement of task is shown below in Box 1-1. Implicit in the statement of task is the assumption that genomic data will be collected by NHANES in the future, and therefore the workshop should focus only on aspects of the process related to the return of results.

This Proceedings of a Workshop summarizes the presentations and discussions at the Workshop on Considerations for Returning Individual Genomic Results from Population-Based Surveys: Focus on the National Health and Nutrition Examination Survey, which was held virtually and live-streamed on December 2, 7, and 8, 2022. The workshop was convened by the Committee on National Statistics (CNSTAT) of the National Academies of Sciences, Engineering, and Medicine to assist NCHS in considering whether and how the CDC might best return genomic results to survey participants in both a timely and ethical manner. Funding for the workshop was provided by the CDC Office of Advanced Molecular Detection as part of the CDC Human Genomics Initiative. The workshop was developed with input from CDC’s NCHS, Office of Genomics and Precision Public Health, and Office of Science.

The workshop was structured to bring together medical practitioners, scientists, and researchers from multiple disciplines and countries to share their research and insights on factors that NHANES would need to consider should a genetic component be added to the data collection protocol. With input from key staff at the CDC, the planning committee developed a workshop agenda and within a very short time frame was able to solicit useful, high-quality presentations regarding a hypothetical, nonspecified genetic test or tests. The discussions provided information and real-world examples that highlighted key components most relevant to NHANES. A constraint of this workshop is that despite several inquiries from the planning committee, the workshop sponsors could not share information about the genomic-related scientific proposals that NHANES had under consideration at the time. Rather, NHANES asked the planning committee to focus on the ethical and operational considerations on the return of results aspect of an unspecified genetic test and to cover the range of options for genetic testing (and related considerations for the return of results). The project’s full statement of task is in Box 1-1.

The mission of CNSTAT is to provide advice to the federal government and the nation grounded in current scientific knowledge and practice that will lead to improved statistical methods and information upon which to base public policy. CNSTAT seeks to advance the quality of statistical information, contribute to the statistical policies and coordinating activities of the federal government, and help provide a forward-looking vision for the federal statistical system and national statistics more broadly in service of the public good.

ROLE OF THE PLANNING COMMITTEE

This proceedings has been prepared by the workshop rapporteur as a factual summary of what occurred at the workshop. The planning

committee’s role was limited to planning and convening the workshop. The views contained in the proceedings are those of individual workshop participants and do not necessarily represent the views of all workshop participants, the planning committee, or the National Academies of Sciences, Engineering, and Medicine.

ORGANIZATION OF THE PROCEEDINGS

This document describes the workshop presentations and discussions that followed each topic.⁶ The chapters are organized around the workshop sessions, which included an overview of NHANES’s current structure and the current genetic landscape, key considerations and operational processes currently being used when returning clinically actionable genetic results, regulatory roles and issues, and informed consent. The final session of the workshop focused on lessons from other research studies that have considered returning genetic results to participants and a panel discussion in which the planning committee chair and members highlighted and discussed what they saw as key themes and messages from across the workshop to help NCHS as it moves forward. The workshop agenda is provided in Appendix A. Biographical sketches of the steering committee members and workshop presenters are included in Appendix B.

Note that the presentations and discussions often use technical terminology and alphanumeric codes when referring to specific genes, methods, and regulatory or legal matters. This proceedings makes every effort to define and explain terms, acronyms, and codes that may be unfamiliar to readers across different disciplines in the text or footnotes. In addition, the planning committee created a glossary of terms and a primer on NHANES and made these materials available to the speakers and the public in advance of the workshop. Copies of the background materials provided to the speakers in advance and to attendees via the website are provided in Appendix C (glossary of terms) and Appendix D (primer on NHANES).^7,8

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⁶ Presenters’ slides and videos of the entire workshop are available at https://www.nationalacademies.org/our-work/workshop-on-considerations-for-returning-individual-genomic-results-from-population-based-surveys-focus-on-the-national-health-and-nutrition-examination-survey

⁷ All materials included in the appendixes were bundled into a PDF as a single “Agenda Packet” and posted to the workshop website in advance of the workshop; they can be accessed here: https://www.nationalacademies.org/documents/embed/link/LF2255DA3DD1C41C0A42D-3BEF0989ACAECE3053A6A9B/file/DCA44248ED0D1144EC2B56610BCF1A2B7537A5D0F5EF?noSaveAs=1

⁸ Readers who encounter an unfamiliar term that is not defined in the text may consider consulting one or more of the following websites: https://www.cdc.gov/genomics/about/glossary.htm; https://www.genome.gov/genetics-glossary; https://www.cancer.gov/publications/dictionaries

OPENING REMARKS TO THE WORKSHOP

Brian Moyer, director of NCHS, explained that because NCHS is in the process of redesigning the NHANES program for 2025 and beyond, the agency has an opportunity to rethink the NHANES data collection processes around genomics. Moyer noted that adding DNA specimen collection and genetics testing as part of NHANES active survey data collection is one possibility under consideration. However, Moyer explained that such a move would prompt questions about how best to protect the survey participants, and NCHS was looking forward to receiving guidance about how it can best conduct and return genomic results to its survey participants in a manner that is both timely and ethical.

Jeffrey R. Botkin, chair of the 2022 workshop planning committee and emeritus professor of pediatrics, human genetics, and internal medicine at the University of Utah, introduced the workshop by sharing his perspective as a person with some background in public health. He stated that NHANES has “been quite significant for understanding the health of the American population” and offered that this is an exciting opportunity to consider what the role of genetics might be going forward with this important survey. Botkin went on to share that the planning committee had worked together to define the workshop topics and identify the speakers with knowledge and experience who can give a broader perspective on the complicated issues at play, with a particular emphasis on the return of genetic results. In his final remarks, Botkin shared that the workshop is explicitly focused on adults, explaining that while children participate in NHANES, they add an additional layer of complexity when it comes to genetics. Botkin concluded by summarizing the workshop agenda for the day and introducing the first session.