Appendix C

Public-Facing Background Materials: Glossary of Terms and Acronyms

Created by: Workshop planning committee and staff

Living Document: Last updated 11/28/2022

Project: National Academies for Science, Engineering, and Medicine’s Centers for Disease Control and Prevention-sponsored Workshop on Considerations for Returning Individual Genomic Results from Population-Based Surveys: Focus on the National Health and Nutrition Examination Survey

Document Purpose: Created for internal use to facilitate the work of the group (e.g., staff, sponsors, committee members, speakers, moderators, discussants) across contexts and disciplines. This is a living document that will be updated periodically as needed and requested.

National Health and Nutrition Examination Survey (NHANES)¹—A program of studies designed to assess the health and nutritional status of adults and children in the United States. The survey is unique in that it combines interviews and physical examinations.

• NHANES is a major program of the National Center for Health Statistics (NCHS).
• NCHS is part of the Centers for Disease Control and Prevention (CDC) and has the responsibility for producing vital and health statistics for the nation.

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¹ https://www.cdc.gov/nchs/nhanes/index.htm

Survey—In the NHANES context and more generally in the social science, behavioral, and population studies research space the word “surveys” is often used to refer to “the identification [of] and data collection [based on] a sample of population units [e.g., individuals, institutions].”² These are often data collection programs which include a traditional “survey” (e.g., a questionnaire that a respondent fills out) and other forms of data collection including but not limited to records linkage consent, biological data collection, environmental data collection (e.g., soil samples), and other means of data collection.

• Therefore, in the NHANES context, the term “survey” refers to the entire set of data collected, including questionnaires/forms, physical examination results, and biospecimens (including plasma, serum, urine).”

Active Survey—In the context of this workshop, “active survey” refers to data from the primary interaction with the participant but not to secondary research using the biospecimens.

Laboratory-Developed Test (LDT)—Defined by the Food and Drug Administration as an in vitro diagnostic test that is developed and used within a single testing laboratory. The FDA does not consider diagnostic devices to be LDTs if they are designed or manufactured completely, or partly, outside of the laboratory that offers and uses them. FDA has generally exercised enforcement discretion meaning that LDTs generally have not undergone FDA premarket review of analytic and clinical validity.³

Laboratory Assays—An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a target entity.

• Genotyping—Genotyping is a technology that interrogates the presence or absence of a specific subset of genetic variants in a genomic DNA sample. It identifies primarily single nucleotide variations in genetic sequence in a DNA sample.
• Sequencing—Sequencing is a technology that determines the order of nucleotides in DNA or RNA. Sequencing includes single-gene assays, gene panel tests, exome sequencing, and genome sequencing.

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² Saavedra, P. (2011). Complex sample surveys. In P. J. Lavrakas (Ed.) Encyclopedia of survey research methods. https://doi.org/10.4135/9781412963947

³ Food and Drug Administration. (2018). Laboratory developed tests. U.S. Department of Health and Human Services. https://www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed-tests (definition revised July 2023).

• • Exome sequencing—sequencing of protein-coding regions (exons) of the nuclear genomic DNA, representing about 1% of the complete DNA sequence. Exome sequencing assays can include both nuclear and mitochondrial DNA. Mutations in regulatory regions that are noncoding are typically not detected by exome sequencing.
  • Genome sequencing—sequencing of nuclear or mitochondrial genomic DNA, most often by “next-generation sequencing” (NGS). Genome sequencing is fundamentally similar to exome sequencing, or sequencing of any other subset of the genome by targeted capture techniques.
  • Transcriptome sequencing—sequencing of mRNA by NGS techniques.
  • Targeted next-generation sequencing—focuses on specific regions of interest in the genome.
• Methylation Analysis—Methylation assays assess the status of specified methylation sites, most commonly in nuclear genomic DNA through methylation chip assay technology.

Variants—variant is the currently accepted term to describe the state of a nucleotide in a DNA or RNA macromolecule that differs from the reference sequence. This term is commonly modified with terms such as “rare” or “common”, and/or “pathogenic” or “benign.” For example, if the reference sequence harbors the C (cytosine) nucleotide at a specific base position in the genome, but a tested sample harbors an A (adenosine) at that position, the A is considered a variant.

• SNPs (often pronounced “snips”)—are common single base-pair changes in DNA that occur at specific places in the genome. This term is falling out of favor, being supplanted by “common variant” as it has a number of associated connotations that are not always valid.
• Mutation—this is the former term for a rare variant, sometimes with a connotation that it is disease associated. This term is being supplanted by “rare variant” or “pathogenic variant” or sometimes both. This term is the currently correct descriptor for the process of a nucleotide being changed from one base to another—a C to A mutational event.

Annotation—annotation of a genomic DNA variant comprises a variety of analyses and predictions regarding the molecular biologic consequences of the variant.

Classification—assessment of the probability of the validity of a variant-disease association for a specific genomic variant. (e.g., using ACMG/AMP Richards et al. 2015⁴ recommendations to generate ClinVar entries.)

CLIA—Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations include federal standards applicable to all U.S. facilities or sites, that test human specimens for health assessment or to diagnose, prevent, or treat disease. The CLIA regulations specify processes for establishing performance characteristics of laboratory test, primarily analytic validity.

Primary finding—a finding in a clinical assay or test that is related to the indication for the assay or test and was purposefully sought by the analyst of the data.

Incidental finding—a finding in a clinical assay or test that is not related to the indication for the test and was not a finding that was purposefully sought by an analyst of the data.

Secondary finding—a finding in a clinical assay or test that is not related to the indication for the test but was purposefully sought in a systematic, directed analysis of the data.

Actionable finding—a finding in a clinical assay or test that has a reasonable potential to lead to a health care intervention that can reduce the morbidity or mortality of a disease.

Confirmatory testing—CLIA-compliant testing to confirm a screening test result or research finding.

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⁴ Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., Rehm, H. L., and ACMG Laboratory Quality Assurance Committee. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine, 17(5), 405–424. https://doi.org/10.1038/gim.2015.30