Accrual (in clinical trials)—the enrollment of qualified patients in clinical trials.
Adjuvant therapy—additional cancer treatment given after the primary treatment to lower the risk that the cancer will return. May include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.
Allele—any one of a series of two or more different genes that occupy the same position (locus) on a chromosome.
Allelic variant—an alteration in the normal sequence of a gene, the significance of which is often unclear until further study of the genotype and corresponding phenotype occurs in a sufficiently large population. Complete gene sequencing often identifies numerous allelic variants (sometimes hundreds) for a given gene.
Amplification—a process by which specific genetic material is increased. For some cancers, the number of copies of specific genes is higher than normal. These genes are said to be amplified.
Analyte—a substance that is the subject of analysis.
Analyte-specific reagent (ASR)—antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents, which through specific binding or chemical reaction with substances in a specimen are intended to be used in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.
Analytic validation—traditionally, assessing an assay and its measurement performance characteristics, determining the range of conditions under which the assay will give reproducible and accurate data. With respect to biomarkers, assessing a test’s ability to accurately and reliably measure the analytes of interest in the clinical laboratory, and in specimens representative of the population of interest.
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.
Archival tissue—biological specimens collected from patients and stored for possible future use in medical care or research.
Assay—a biochemical or other measurement developed to quantify a biomarker.
Bias—the systematic but unintentional erroneous association of some characteristic with a group in a way that distorts a comparison with another group.
Bioinformatics—a field of study focused on developing fast, efficient computational procedures for data reduction, data mining, and literature search techniques and developing biologically informative annotations related to DNA/RNA sequence, gene/protein expression, or the interaction of pathways, networks, phenotypes, and druggable targets.
Biological plausibility—data elucidating the biological pathways underpinning a causal association.
Biological products (biologics)—a category of products regulated by the Food and Drug Administration, including vaccines, blood, and blood components, allergenic compounds, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins.
Biomarker—a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic sequences, or pharmacologic responses to an intervention.
Biomarker test—a biochemical or other measurement developed to quantitate a biomarker. These tests can evaluate biomarkers for the detection and treatment of asymptomatic individuals (screening), establishing the presence and precise description of disease (diagnosis), estimating the risk or time to clinical outcomes (prognosis), identifying patient likelihood to benefit from certain therapies (predictive) or to experience therapy-related risks (pharmacogenomics), or treatment and posttreatment monitoring purposes (e.g., the early detection and treatment of advancing disease or complications).
Biomedical informatics—the interdisciplinary field that studies and pursues the effective uses of biomedical data, information, and knowledge for scientific inquiry, problem solving, and decision making, driven by efforts to improve human health.
Biopsy—the removal of tissues or cells so they can be examined by a pathologist.
Biorepository—a collection of biological samples, such as tissue, that can be used for research.
Biostatistics—a field of study focused on applying experimental design and data analysis to a wide range of topics in biology.
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 certain groups is not always possible; for example, if treatment involves active patient participation, such as attending a therapy session, the 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 and are known as BRCA1 and BRCA2.
Cetuximab—a monoclonal antibody drug used to treat head and neck cancers, and advanced or metastatic cancer of the colon and rectum, usually in combination with chemotherapy or irinotecan, another cancer drug.
Chemotherapy—treatment with drugs that kill cancer cells.
Circulating tumor DNA (ctDNA)—small pieces of DNA in the bloodstream that are released from dead and dying tumor cells. Potential screening biomarker for detecting somatic mutations associated with progression of cancer.
Clinical/biological validation—validation assessing a test’s ability to accurately and reliably predict the clinically defined disorder or phenotype of interest.
Clinical endpoint—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 and/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 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 decision making compared with current management absent testing.
Clinical validity—the accuracy of a test for a specific clinical purpose, such as diagnosing or predicting risk for a disorder.
Companion diagnostic—Food and Drug Administration designation for a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or
biological product. Co-development of a drug and companion diagnostic ensures faster access to promising new treatments for patients.
Conditional coverage—a policy by which insurers agree to preliminarily cover new tests with the proviso that data would be collected in conjunction with the use of the test, to assess the clinical utility and value of the test, and to create better evidence. Data collected during conditional coverage assessments are used in later decisions regarding full coverage and may be used for research purposes afterward.
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 percent confidence interval. This means that if someone were to keep repeating a study in other samples from the same population, 95 percent of the confidence intervals from those studies would contain the true value of the unknown quantity. Alternatives to 95 percent, such as 90 and 99 percent confidence intervals, are sometimes used. Wider intervals indicate lower precision; narrow intervals, greater precision.
Conflict of interest—a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest.
Confounding effects—a situation in which an intervention effect is biased because of some difference between the comparison groups apart from the planned interventions, such as baseline characteristics, prognostic factors, or concomitant interventions.
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 (see Conditional coverage). A product that has an insufficient evidence base for CMS coverage determination could be evaluated through CED.
Current Procedural Terminology (CPT®)—a listing of descriptive terms and identifying codes for reporting medical services and procedures, designed to standardize the terminology used for medical, surgical, and diagnostic services. CPT codes were first developed by the American Medical Association and are updated by the CPT Editorial Panel.
Cytotoxic therapy—any agent or process that kills cells (e.g., chemotherapy and radiotherapy).
De novo classification—a Food and Drug Administration classification of a device or diagnostic that is not equivalent to a legally marketed product.
Deletion—the loss of genetic material. Some cancers are triggered by the deletion of key genes, portions of genes, or their regulatory sequences.
Diagnosis—a conclusion as to the presence of a disease.
Diagnostic—the investigative tools and techniques used in biological studies or to identify or determine the presence of a disease or other condition. In this report, “diagnostic” is often used synonymously with “biomarker test.” These terms refer to any laboratory-based test that can be used in drug discovery and development as well as in patient care and clinical decision making.
Diagnostic test—tools and techniques used to identify or determine the presence of a disease or other condition. Any laboratory-based test that can be used in drug discovery and development as well as in patient care and clinical decision making.
Disease risk stratification—placement of an individual into a risk category based on the likelihood that a disease will develop or recur.
Distant recurrence—occurs when a cancer has metastasized to another location in the body following initial cancer treatment and remission.
DNA sequencing—a laboratory technique used to determine the exact sequence of bases (A, C, G, and T) in a DNA molecule. The DNA base sequence carries the information a cell needs to assemble protein and RNA molecules. DNA sequence information is important to investigating the functions of genes.
Enrichment trial design—the only patients entered into the clinical trial are those with positive test results at screening. These patients are randomized and/or treated.
Epidermal growth factor receptor (EGFR)—a receptor that is overproduced in several solid tumors, including breast and lung cancers. Its overproduction is linked to a poorer prognosis because it enables cell proliferation, migration, and the development of blood vessels. Several
new drugs recently approved by the Food and Drug Administration specifically target EGFR.
Epigenome—the complete set of epigenetic modifications, which are heritable or transitory changes in phenotype or gene expression that result from mechanisms other than changes in the DNA sequence in a given individual, tissue, tumor, or population.
Equipoise—that state of genuine uncertainty in the expert medical community over whether a novel treatment will be beneficial. This forms the ethical basis for assigning patients to different arms of a clinical trial.
Exome—the portion of DNA that is transcribed into mature RNA in any type of cell in the body. Though only a small fraction of the whole genome, the exome is thought to harbor a high proportion of disease-causing mutations.
False negative—the error of failing to observe a difference when in truth there is one.
False positive—the error that occurs when a difference is observed even though in truth there is none.
FDA approval—the Food and Drug Administration (FDA) can approve a device after reviewing a sponsor’s premarket approval (PMA) application that has been submitted to FDA. To acquire approval of a device through a PMA application, the applicant must provide reasonable assurance of the device’s safety and effectiveness.
FDA clearance—the Food and Drug Administration (FDA) can clear a device after reviewing a sponsor’s premarket notification, also known as a 510(k) submission (named for a section in the Food, Drug, and Cosmetic Act), that has been filed with FDA. To acquire clearance to market a device using the 510(k) pathway, the 510(k) applicant must show that the medical device is “substantially equivalent” to a device that is already legally marketed for the same use.
Fluorescence in situ hybridization (FISH)—a method for detecting the presence of DNA sequences through the use of fluorescent probes.
Formalin-fixed, paraffin-embedded (FFPE) tissue—a tissue sample that has been preserved to enable pathological or molecular analysis.
Genome—the complete sequence of DNA in a cell or organism.
Genomics—the study of all of the nucleotide sequences, including structural genes, regulatory sequences, and non-coding DNA segments, in the chromosomes of an organism or tissue sample. One example of the application of genomics in oncology is the use of microarray or other techniques to uncover the genetic “fingerprint” of a tissue sample. This genetic fingerprint is the pattern that stems from the variable expression of different genes in normal and cancer tissues.
Genotype—the genetic makeup of an organism or cell.
Germline mutation—a gene change in a body’s reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring. Germline mutations are passed on from parents to offspring. Also called hereditary mutation.
Health Insurance Portability and Accountability Act (HIPAA)—an Act passed in 1996 that includes privacy and security regulations regarding disclosure and use of medical information.
Herceptin—see human epidermal growth factor receptor 2.
High-dimensional data—large datasets characterized by the presence of many more variables than observations, such as datasets that result from measurements of hundreds to thousands of molecules in a relatively small number of biological samples. The analysis of such datasets requires appropriate computing power and statistical methods.
High-throughput technology—any approach using robotics, automated machines, and computers to process many samples at once.
Histopathology—examination of tissue samples in order to understand the manifestations of disease in the organism from which the samples were obtained.
Human epidermal growth factor receptor 2 (HER2)—a growth factor receptor that is used as a breast cancer biomarker for prognosis and treatment with the drug trastuzumab (Herceptin), which targets the protein.
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 genome and map-
ping all 20,000-25,000 genes in human DNA 2 years earlier than anticipated, due to technological advances.
Imatinib—a small-molecule compound originally developed for treating chronic myelogenous leukemia and gastrointestinal stromal tumors, imatinib (STI571, Gleevec) is a selective tyrosine kinase inhibitor that binds to the ATP-binding pocket and blocks the tyrosine kinase activities of Abl, c-kit, and PDGFR.
Immunohistochemistry—the process of detecting antigens (e.g., proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues.
Immunotherapy—the treatment of disease by inducing, enhancing, or suppressing an immune response.
In vitro device—a test that can detect disease, infection, or other health conditions.
Institutional Review Board (IRB)—an institutional oversight body that protects human safety, privacy, and autonomy and ensures informed consent.
Intended use—a statement describing a device’s intended application, taking into account whether such use could harm the patient or consumer. The product manufacturer’s intended use should be clearly marked on printed and graphic materials for proposed labels and promotional claims.
Investigational device exemption (IDE)—a Food and Drug Administration designation that allows an investigational device to be used in a clinical study to collect safety and effectiveness data supporting a premarket approval application or a premarket notification submission.
Laboratory-developed tests (LDTs)—laboratory tests used in patient care that have been developed and are performed in a Clinical Laboratory Improvements Amendments–certified clinical laboratory, but have not been reviewed by the Food and Drug Administration.
Lipidome—the complete set of lipids in a biological sample.
Loss of heterozygosity—loss of one allele at a specific position on a chromosome.
Mechanism of action—the biological pathway by which a drug affects its target in the body.
Medical device—according to the Food and Drug Administration, an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory that is recognized in the official National Formulary, or the US Pharmacopoeia, or any supplement to them; or, is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or, is intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent on being metabolized for the achievement of any of its primary intended purposes.
Metabolome—the complete set of small-molecule metabolites found with a biological sample (including metabolic intermediates in carbohydrate, lipid, amino acid, nucleic acid, and other biochemical pathways, along with hormones and other signaling molecules, as well as exogenous substances, e.g., drugs and their metabolites).
Metabolomics—the systematic study of the unique chemical fingerprints that specific cellular processes leave behind, that is, small-molecule metabolites.
Metadata—information about a dataset and how it was generated.
Microarray—a high-throughput biological assay in which different probes are deposited on a chip surface (glass or silicon) in a miniature arrangement.
Molecularly targeted therapy—in contrast with cytotoxic therapy, molecularly targeted therapies exploit known “driver” biomarkers as therapeutic targets in diseases such as oncology. Determining the driver status of a biomarker is known as target validation.
Multivariate model—measuring the impact of more than one variable at a time while analyzing a set of data, for example, looking at the impact of age, sex, and occupation on a particular outcome.
Negative predictive value (NPV)—the probability that an individual with a negative test result is truly unaffected and/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. These technologies enable millions or billions of DNA strands to be sequenced in parallel, yielding substantially more throughput and minimizing the need for the fragment-cloning methods that are often used in Sanger sequencing of genomes.
Off-label use—using a drug that either has not been approved by the Food and Drug Administration or has not been approved for the purpose for which it is being used.
Omics—scientific disciplines comprising study of related sets of biological molecules. Examples of omics disciplines include genomics, transcriptomics, proteomics, metabolomics, and epigenomics.
Omics-based test—an assay composed of or derived from many molecular measurements and interpreted by a fully specified computational model to produce a clinically actionable result.
Overfitting—occurs when the model-fitting process unintentionally exploits characteristics of the data that are due to noise, experimental artifacts, or other chance effects that are not shared among datasets, rather than to the underlying biology that is shared among datasets.
Pathway biomarker—a biomarker that can be detected in one or several key steps along a biochemical pathway that may be perturbed in cancer cells. Because of their broad applicability, pathway biomarkers may be useful in assessing the effectiveness of multiple drugs in different types of cancers.
Patient management—decisions about the care and treatment of individual patients, based on information about their disease status and history.
Performance characteristics—the sensitivity, accuracy, and specificity of a biomarker-based test.
Pharmacodynamics—the study of the biochemical and physiological effects of drugs, the mechanisms of drug action, and the relationship between drug concentration and effect. Pharmacodynamics is the study of what a drug does to the body, as opposed to pharmacokinetics, which is the study of what a body does to a drug.
Pharmacogenomics—a biotechnological 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.
Pharmacokinetics—the study of the time course of substances, such as drugs, in an organism. Pharmacokinetics is used to determine how long a drug remains in the body.
Phase I clinical trial—clinical trial in a small number of patients in which the toxicity and dosing of an intervention are assessed.
Phase II clinical trial—clinical trial in which the safety and preliminary efficacy of an intervention are assessed in patients.
Phase III clinical trial—large-scale clinical trial in which the safety and efficacy of an intervention are assessed in a large number of patients. The Food and Drug Administration generally requires new drugs to be tested in Phase III trials before they can be put on the market.
Phenotype—the physical traits of an individual.
Polymerase chain reaction (PCR)—a technique for duplicating genetic sequences in vitro by as many as a billion times. This technique enables the detection of relatively scarce genetic material.
Polymorphism—existence of a gene in several allelic forms.
Positive predictive value (PPV)—the probability that an individual with a positive test result has, or will develop, the particular disease or characteristic that the test is designed to detect. It is a measure of the ratio of true positives to (false + true positives).
Positron emission tomography (PET)—a highly sensitive technique that uses radioactive probes to image in vivo tumors, receptors, enzymes, DNA replication, gene expression, antibodies, hormones, drugs, and other compounds and processes.
Precision medicine—tailoring of medical treatment to the individual characteristics of each patient to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Preventative or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not.
Predictive factor—a measure that identifies patients most likely to be sensitive or resistant to a specific treatment regimen or agent. [A predictive factor] is particularly useful when that measure can be used to identify the subgroup of patients for whom treatment will have a clinically meaningfully favorable benefit-to-risk profile.
Premarket approval (PMA)—a Food and Drug Administration approval for a new test or device that enables it to be marketed for clinical use. To receive this approval, the manufacturer of the product must submit the clinical data showing the product is safe and effective for its intended use.
Premarket notification or 510(k)—a Food and Drug Administration review process that enables a new test or device to be marketed for clinical use. This review process requires manufacturers to submit data showing the accuracy and precision of their product and, in some cases, its analytical sensitivity and specificity. Manufacturers also have to provide documentation supporting the claim that their product is substantially equivalent to one already on the market. This review does not typically consider the clinical safety and effectiveness of the product. (See also FDA clearance.)
Proficiency testing—laboratories performing non-waived tests must enroll laboratory personnel in tests specific to the subspecialty relevant to the tests they will evaluate. The Clinical Laboratory Improvement Amendments requires proficiency testing of personnel at least once every 2 years.
Prognosis—an assessment of the probable course of a disease given the risk factors present in an individual; this assessment may affect treatment decisions.
Prognostic factor—a measure correlated with a clinical outcome in the setting of natural history or a standard-of-care regimen; it is a variable used to estimate the risk of or time to clinical outcomes.
Prospective clinical trial—a clinical trial in which patients are identified and then followed forward in time.
Prospective–retrospective clinical study—an analysis using archived specimens from previously conducted prospective clinical trials that addressed the intended clinical use of the test.
Proteome—the complete set of proteins expressed by a cell, tissue, or organism.
Proteomics—the study of the structure, function, and interactions of the proteins produced by the genes of a particular cell, tissue, or organism. The application of proteomics in oncology may involve mass spectroscopy, two-dimensional polyacrylamide gel electrophoresis, protein chips, and other techniques to uncover the protein “fingerprint” of a tissue sample. This protein fingerprint is the pattern that stems from the various amounts and types of all the proteins in the sample.
PSA test—a blood test that detects prostate-specific antigen. The PSA test was approved by the Food and Drug Administration in 1985 for prostate cancer recurrence, and has also been widely used as a screening test for prostate cancer. Due to concerns of overdiagnosis and overtreatment, its value as a screening test is being examined.
Qualification—evidentiary process of linking a biomarker with biological processes and clinical endpoints.
Quality-adjusted life-year (QALY) index—an index that combines measures of quality of life with length of life.
Randomized block trial design—a test result needs to be available at the time of screening patients for accrual, and the result is used to stratify the randomization of patients to different therapies.
Risk stratification—the classification of patients into groups based on the likelihood of developing or suffering effects from a disease.
Sample bias—see Bias.
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 with 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.
Standard of care—in medicine, treatment that experts agree is appropriate, accepted, and widely used. Also called best practice and standard therapy.
Standard operating procedures (SOPs)—instructions detailing steps and activities of a process or procedure.
Statistical and bioinformatics validation—verifying that the omics-based test can perform its intended task. Ideally, this involves ensuring that the test can accurately predict the clinical outcome of interest in an independent set of samples that were not used in developing the test. Such validation is particularly important because omics-based tests typically involve computational models whose parameters can be “overfit” in any single dataset, leading to an overly optimistic sense of the test’s accuracy.
Statistical significance—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 was true. Statistical tests produce a p-value used to assess this.
Surrogate endpoint—a biomarker that is intended to substitute for a clinical endpoint in a therapeutic clinical trial and is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.
Systemic therapy—treatment using substances that travel through the bloodstream and reach and affect cells throughout the body.
Target validation—demonstration that a potential drug target plays a key role in the disease process.
Transcriptome—the complete set of RNA transcripts from DNA in a cell. Trastuzumab—see human epidermal growth factor receptor 2 (HER2).
Tumor marker—substances that are produced by cancer or by other cells of the body in response to cancer or certain benign (noncancerous) conditions. Most tumor markers are proteins. However, more recently, patterns of gene expression and changes to DNA have also begun to be used as tumor markers.
Usage—contextual analysis based on the specific use proposed and the applicability of available evidence to this use. This includes a determination of whether the validation and qualification conducted provide sufficient support for the use proposed.
Validation—the process of assessing the assay or measurement performance characteristics.
Whole genome sequencing—a laboratory process that determines the complete DNA sequence of an organism’s genome at a single time.