Glossary

Allele—is one of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome.

Analytic validity—the accuracy of a test in detecting the specific entity that it was designed to detect. This accuracy does not imply any clinical significance, such as diagnosis.

Ancestry—is often corrected for when looking for gene–disease associations or conducting epidemiologic studies. Ancestry is important because some alleles show large differences in frequency among populations originating in different parts of the world.

Bias—the systematic but unintentional erroneous association of some characteristic with a group in a way that distorts a comparison with another group.

Bioinformatics—the branch of biology that is concerned with the acquisition, storage, display, and analysis of the information found in nucleic acid and protein sequence data.

Biologic plausibility—data elucidating the biologic pathways underpinning a causal association.

Blinding (in a controlled trial)—the process of preventing those involved in a trial from knowing the comparison group to which a particular participant belongs. The risk of bias is minimized when as few people as possible know who is receiving the experimental intervention and who the control intervention. Participants, caregivers, outcome assessors, and analysts are all candidates for being blinded. Blinding of some groups is not always possible; for example, if treatment involves active patient participation, such as attending a therapy session, a participant cannot be blinded to the type of treatment provided.

BRCA—a gene that when mutated increases a woman’s risk of developing breast cancer. Two BRCA genes have been identified: BRCA1 and BRCA2.

Causality—the causal relationship between a genetic variant and a phenotype is provisional to the conditions and the environment, such as the genetic background, in which the causal variants and the phenotype operate. The degree of probabilistic causality is determined in part by the effect sizes of the genetic variants, which typically follow a gradient ranging from minimal to large.

Chromosome—an organized package of DNA found in the nucleus of the cell. Different organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes: 22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes, X and Y. Each parent contributes one chromosome to each pair so that offspring get half their chromosomes from the mother and half from the father.

Clinical end point—a characteristic or variable that reflects how a patient feels, functions, or survives in response to an intervention.

Clinical Laboratory Improvement Amendments (CLIA)—amendments passed by Congress in 1988 that established quality standards for all nonresearch laboratory testing performed on specimens derived from humans for the purpose of providing information for the diagnosis, prevention, or treatment of disease or impairment of or assessment of health. CLIA established

quality standards for laboratories to ensure the accuracy, reliability, and timeliness of patient test results regardless of where the test is performed.

Clinical or biologic validation—validation of a test’s ability to predict accurately and reliably a clinically defined disorder or phenotype of interest.

Clinical trial—a formal study carried out according to a prospectively defined protocol that is intended to discover or verify the safety and effectiveness of procedures or interventions in humans.

Clinical utility—evidence of improved measurable clinical outcomes, and a test’s usefulness and added value to patient management and decision making compared with current management in the absence of testing.

Clinical validity—the accuracy of a test for a specific clinical purpose, such as diagnosis or prediction of risk of a disorder.

Codon—a sequence of three nucleotides that form a unit of genetic code in a DNA or an RNA molecule.

Cohort—a group of subjects who have shared a particular event during a particular time span.

Confidence interval—a measure of the uncertainty around the main finding of a statistical analysis. Estimates of unknown quantities, such as the odds ratio comparing an experimental intervention with a control, are usually presented as a point estimate and a 95% confidence interval. That means that if someone were to keep repeating a study in other samples from the same population, 95% of the confidence intervals from those studies would contain the true value of the unknown quantity. Alternatives to 95%, such as 90% and 99% confidence intervals, are sometimes used. Wider intervals indicate lower precision; narrow intervals greater precision.

Confounding—interference by a third variable that distorts the association between an independent variable and a dependent variable.

Coverage with evidence development (CED)—a Centers for Medicare & Medicaid Services (CMS) program whereby prospective data collection on a product is required for national Medicare coverage. A product that has an insufficient evidence base for CMS coverage determination could be evaluated through CED.

Diagnostic accuracy—a measure of sensitivity and specificity and a means of judging the clinical validity of a genetic test.

Diagnostic odyssey—refers to the pursuit of potentially expensive and invasive diagnostic tests in medical care.

Diagnostic test—a test used to identify or determine the presence of a disease or other condition at the time the test is performed.

DNA—the molecule that carries genetic instructions in all living things. The DNA molecule consists of two strands that wind around one another to form a shape known as a double helix. Each strand has a backbone made of alternating sugar (deoxyribose) and phosphate groups. Attached to each sugar is one of four bases—adenine (A), cytosine (C), guanine (G), and thymine (T). The two strands are held together by bonds between the bases; adenine bonds with thymine, and cytosine bonds with guanine. The sequence of the bases along the backbones serves as instructions for assembling protein and RNA molecules.

DNA sequencing—a laboratory technique used to determine the sequence of bases (A, C, G, and T) in a DNA molecule. The DNA base sequence carries the information that a cell needs to assemble protein and RNA molecules. DNA sequence information is important in investigating the functions of genes.

Exome—the portion of DNA that is transcribed into mature RNA in any type of cell in the body. Although only a small fraction of the whole genome, the exome is thought to harbor a high proportion of disease-causing mutations.

Expressivity—the range of signs and symptoms that can occur in different people with the same genetic condition.

False-negative error—an error of failing to observe a difference when there is one.

False-positive error—an error of observing a difference when there is none.

Gamete—a mature haploid male or female germ cell that is able to unite with another of the opposite sex in sexual reproduction to form a zygote.

Gene—the basic physical unit of inheritance. Genes are passed from parents to offspring and contain the information needed to specify traits. Genes are arranged, one after another, on structures called chromosomes. A chromosome contains a single, long DNA molecule, portions of which correspond to single genes. Human chromosomes have about 20,000 genes.

Gene editing—a type of genetic engineering in which DNA is inserted, deleted, or replaced in the genome of an organism by using engineered nucleases, or “molecular scissors.”

Gene panel—genetic tests that use next-generation sequencing to test multiple genes simultaneously. Also called multigene testing and multiple-gene testing.

Genetic testing—a type of medical test that identifies changes in chromosomes, genes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help to determine a person’s chance of developing or passing on a genetic disorder.

Genetic variation or variants—differences in the sequence of DNA among people.

Genetics—the study of genes, genetic variation, and heredity in organisms.

Genome—the complete sequence of DNA in a cell or organism.

Genomewide association study—a way for scientists to identify genes involved in human disease. It searches the genome for small variations, called single-nucleotide polymorphisms (SNPs, pronounced “snips”), that occur more frequently in people who have a particular disease than in people who do not. Each study can look at hundreds or thousands of SNPs at the same time. Researchers use data from this type of study to pinpoint genes that may contribute to a person’s risk of developing a given disease.

Genomics—the study of all the nucleotide sequences—including structural genes, regulatory sequences, and noncoding DNA segments—in the chromosomes of an organism or tissue sample.

Haplotype—the set of SNP alleles along a region of a chromosome. Theoretically, there could be many haplotypes in a chromosome region, but recent studies are typically finding only a few common haplotypes.

Human Genome Project—a 13-year project coordinated by the Department of Energy and the National Institutes of Health and completed in 2003. The project completed its goal of sequencing the human genome and mapping all 20,000–25,000 genes in human DNA 2 years earlier than expected owing to technologic advances.

Laboratory-developed tests (LDTs)—laboratory tests used in patient care that have been developed and are performed in a CLIA-certified clinical laboratory but have not been reviewed by the Food and Drug Administration.

Mendel’s Laws—the Law of Segregation states that every individual organism contains two alleles for each trait and that these alleles segregate (separate) during meiosis in such a way that each gamete contains only one of the alleles. An offspring thus receives a pair of alleles for a trait by inheriting homologous chromosomes from the parent organisms: one allele for each trait from each parent. The Law of Independent Assortment states that alleles for separate traits are passed independently of one another from parents to offspring. That is, the biologic selection of an allele for one trait has nothing to do with the selection of an allele for any other trait. Mendel’s Law of Dominance states that recessive alleles will always be masked by dominant alleles. Therefore, a cross between a homozygous dominant and a homozygous recessive will always express the dominant phenotype while still having a heterozygous genotype.

Mendelian disorders—disorders that result from a mutation at a single genetic locus. A locus may be present on an autosome or on a sex chromosome, and it may be manifested in a dominant or a recessive mode.

Mendelian inheritance—refers to patterns of inheritance that are characteristic of organisms that reproduce sexually. Mendelian inheritance explains the laws of inheritance that introduced the idea of dominant and recessive genes.

Mendelian traits—traits that follow Mendel’s rules of only two possible versions of a gene (one dominant, one recessive).

Meta-analysis—analysis that uses a statistical approach to combine the results of multiple studies in an effort to increase power (over individual studies), improve estimates of the size of an effect, or resolve uncertainty when reports disagree.

Multivariate model—a model for measuring the effects of more than one variable at a time while analyzing a set of data, for example, looking at the effects of age, sex, and occupation on a particular outcome.

Negative predictive value (NPV)—the probability that a person who has a negative test result is truly unaffected or does not have the particular disease or characteristic that the test is designed to detect.

Next-generation sequencing—non-Sanger–based high-throughput DNA sequencing. This method enables millions or billions of DNA strands to be sequenced in parallel and yields substantially more throughput and minimizes the need for the fragment-cloning methods that are often used in Sanger sequencing of genomes.

Penetrance—the proportion of people who have a particular genetic change (such as a mutation in a specific gene) and exhibit signs and symptoms of a genetic disorder. If some people who have the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance.

Personalized medicine—an emerging practice of medicine that uses an individual person’s genetic profile to guide decisions made in regard to the prevention and diagnosis of and treatment for disease. Knowledge of a patient’s genetic profile can help doctors to select the proper medication or therapy and administer it in the proper dose or regimen. Personalized medicine is being advanced through data from the Human Genome Project.

Pharmacogenomics—a biotechnologic science that combines the techniques of medicine, pharmacology, and genomics to determine the effects of genetic differences in patients on the metabolism and hence the potential toxicity or efficacy of drugs.

Phenotype—a set of observable characteristics of a person that result from the interaction of the person’s genotype with the environment.

Polymorphism—existence of a gene in several allelic forms.

Positive predictive value—the probability that a person who has a positive test result has or will develop the particular disease or characteristic that the test is designed to detect; a measure of the ratio of true positives to false and true positives.

Precision medicine—tailoring of medical treatment to the individual characteristics of each patient to classify patients into populations that differ in their susceptibility to a particular disease or in their response to a specific treatment. Preventive or therapeutic interventions can be concentrated on those who will benefit, sparing expense to and side effects in those who will not.

Predictive factor—a measure that identifies patients who are most likely to be sensitive or resistant to a specific treatment regimen or agent. A predictive factor is particularly useful if it can be used to identify the group of patients for whom treatment will have a clinically favorable benefit-to-risk profile.

Predictive testing—a form of genetic testing also known as presymptomatic testing. Such testing is used to detect gene mutations associated with disorders that appear after birth, often later in life.

Prognosis—an assessment of the probable course of a disease.

Prognostic test—a prognostic test is used to estimate a person’s likelihood of developing a disease or experiencing a medical event.

Prospective clinical trial—a clinical trial in which patients are identified and then followed over some period.

Proteomics—the study of the structure, function, and interactions of the proteins produced by the genes of a particular cell, tissue, or organism.

Randomized controlled trials (RCTs)—a study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of the interventions is the standard of comparison or control. The control may be a standard practice, a placebo, or no intervention at all.

RNA—ribonucleic acid, a polymeric molecule that has various biologic roles in coding, decoding, regulation, and expression of genes.

RNA sequencing—an approach that uses next-generation sequencing to reveal the presence and quantity of RNA in a biologic sample at a given time.

Sensitivity (analytic)—the lowest concentration that can be distinguished from background noise. This concentration is termed an assay’s detection limit.

Sensitivity (clinical)—a measure of how often a test correctly identifies patients who have a specific diagnosis. It is calculated as the number of true-positive results divided by the number of true-positive plus false-negative results.

Single nucleotide polymorphism (SNP)—a variant DNA sequence in which the purine or pyrimidine base (e.g., cytosine) of a single nucleotide has been replaced by another such base (e.g., thymine).

Somatic mutation—an alteration in DNA that occurs after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases.

Specificity (analytic)—how well an assay detects only a specific substance and does not detect closely related substances.

Specificity (clinical)—a measure of how often a test correctly identifies the proportion of persons without a specific diagnosis. It is calculated as the number of true-negative results divided by the number of true-negative plus false-positive results.

Statistical significance—describes a result that is unlikely to have happened by chance. The usual threshold for this judgment is that the results, or more extreme results, would occur by chance with a probability of less than 0.05 if the null hypothesis is true.

Variant—Genetic variant refers to a single nucleotide polymorphism (SNP).

Whole-exome sequencing—the method of sequencing all the exons in a genome. This method allows variations in the protein-coding region of any gene to be identified. Because most known mutations that cause disease occur in exons, whole-exome sequencing is thought to be an efficient method for identifying possible disease-causing mutations.

Whole-genome sequencing—a laboratory process that determines the complete DNA sequence of an organism’s genome at a single time.