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Glossary
Accrual (in clinical trials)—the enrollment of qualified patients into clinical
trials.
Acute cellular rejection (ACR)—when a transplanted organ is rejected by
the immune system of the organ recipient.
Adjuvant therapy—additional cancer treatment given after the primary
treatment to lower the risk that the cancer will return. May include chemo-
therapy, radiation therapy, hormone therapy, targeted therapy, or biological
therapy.
Adnexal mass—a lump in tissue near the uterus.
Analyte—a substance that is the subject of analysis.
Analytical 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
omics, assessing a test’s ability to accurately and reliably measure the ana-
lytes of interest in the clinical laboratory, and in specimens representative
of the population of interest.
Anastrozole (Arimidex)—a drug that inhibits estrogen synthesis. This drug,
an aromatase inhibitor, may inhibit tumor growth in some breast cancers.
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Angiography—X-ray visualization of blood vessels that have been injected
with a radiographic contrast dye.
Apoptosis—a type of cell death in which a series of molecular steps in a cell
leads to its death. This is the body’s normal way of getting rid of unneeded
or abnormal cells.
Archival tissue—biological specimens collected from patients and stored for
possible future use in medical care or research.
Area under the receiver operating curve (AUC)—a measure of the ability
of a test to accurately discriminate a result indicating a particular disease
state from a result not indicating that disease state.
Aromatase inhibitor—a drug that prevents the formation of the hormone
estradiol. It is a type of hormone therapy for postmenopausal women with
estrogen receptor-positive breast cancer.
Assay—a biochemical or other measurement developed to quantify a
biomarker.
Baseline corrected—allows for the removal of background “noise” or
unnecessary peaks by running a blank set of samples that are subtracted
from the data.
Batch effects—groups of measurements with different testing results because
of variability in conditions such as testing on different days or by different
equipment operators, rather than scientific or biological differences between
samples.
Bias—the systematic but unintentional erroneous association of some char-
acteristic with a group in a way that distorts a comparison with another
group.
Bioinformatics—a field of study focused on developing fast, efficient com-
putational 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 path-
ways, networks, phenotypes, and druggable targets.
Biological plausibility—data elucidating the biological pathways underpin-
ning a causal association.
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GLOSSARY
Biological products (biologics)—a category of products regulated by the
Food and Drug Administration (FDA), 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 processes, or phar-
macologic responses to an intervention.
Biopsy—the removal of tissues or cells so they can be examined by a
pathologist.
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 partici-
pant 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.
CA-125 (also called cancer antigen 125)—a molecule that may be found
in high levels in the blood of patients with certain types of cancer, such
as ovarian cancer. CA-125 levels may be an indicator of how well cancer
treatments are working and whether a cancer will return.
Candidate omics-based test—an omics-based test in the test discovery and
development phase.
Chemotherapy—treatment with drugs that kill cancer cells.
Clinical Laboratory Improvement Amendments (CLIA)—amendments
passed by Congress in 1988 that established quality standards for all non-
research 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, reli-
ability, and timeliness of patient test results regardless of where the test is
performed.
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Clinical/biological validation—validation assessing a test’s ability to accu-
rately 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 trial—a formal study carried out according to a prospectively
defined protocol that is intended to discover or verify the safety and effec-
tiveness of procedures or interventions in humans.
Clinical utility and use stage—the last phase in the test development process
in which a validated omics-based test is assessed for use in patient manage-
ment decisions.
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 without omics testing.
Completely randomized trial design—in this report, a test result is not used
in the randomization of patients to different therapies, nor is patient accrual
stratified according to the test results.
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. This 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.
Confirmation—in this report, verifying a candidate omics-based test on an
independent sample set before the test validation phase.
Conflict of interest—a set of circumstances that creates a risk that profes-
sional 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
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GLOSSARY
planned interventions, such as baseline characteristics, prognostic factors,
or concomitant interventions.
Coronary artery disease (CAD)—damage to the heart caused by atheroscle-
rotic constriction of arteries that supply blood to the heart.
Cross-validation—a statistical method for preliminary confirmation of a
model’s performance using a single dataset, by dividing the data into mul-
tiple segments, and iteratively fitting the model to all but one segment and
then evaluating its performance on the remaining segment.
Cyclophosphamide—a synthetic, chemotherapeutic agent with antineoplastic
and immunosuppressive activities.
Diagnosis—a conclusion as to the presence of a disease.
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.
Discovery phase—the first phase in the omics-based test development pro-
cess during which candidate omics-based tests are first identified and con-
firmed on an independent set of specimens, if available.
Distant recurrence—occurs when a cancer has metastasized to another loca-
tion in the body following initial cancer treatment and remission.
Effect modifier—a measure that identifies patients who are most likely to
be sensitive or resistant to a specific treatment regimen or agent. An effect
modifier is particularly useful when that measure can be used to identify the
subgroup of patients for whom treatment will have a clinically meaningful
and favorable benefit-to-risk profile.
Endocrine therapy—treatment that aids, blocks, or removes hormones.
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.
Epigenome—the complete set of epigenetic modifications, which are heri-
table or transitory changes in phenotype or gene expression that result from
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mechanisms other than changes in the DNA sequence in a given individual,
tissue, tumor, or population.
Estrogen receptor (ER)—a protein found in cells of reproductive tissue,
some other types of tissue, and some cancer cells. The hormone estrogen
binds to the receptor and may cause cells to grow.
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—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—FDA can clear a device after reviewing a sponsor’s premar-
ket 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.
Fluorouracil (5-FU or F5U)—an antimetabolite drug used in cancer treat-
ment. The drug may kill cancer cells by blocking DNA synthesis.
Formalin-fixed, paraffin-embedded tissue—a tissue sample that has been
preserved to enable pathological or molecular analysis.
Fully specified computational procedure— all component steps of the proce-
dure—namely, all data processing steps, normalization techniques, weights,
parameters, and other aspects of the model, as well as the precisely defined
mathematical formula or formulas used to convert the data into a predic-
tion of the phenotype of interest—are completely formulated in writing.
Genome—the complete sequence of DNA in a cell or organism.
Hazard ratio—an expression of the risk of an event in one arm of a study
as compared to the risk of the event happening in the other arm over time.
This differs from the relative risk ratio, which is a proportion of the number
of events that occur in one arm of the study as compared to the other arm.
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GLOSSARY
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 appro-
priate computing power and statistical methods.
Histopathology—examination of tissue samples in order to understand the
manifestations of disease in the organism from which the samples were
obtained.
Hormonal therapy—see Endocrine therapy.
Human epidermal growth factor receptor 2 (HER2)—a growth factor
receptor that is used as a breast cancer biomarker for prognosis and treat-
ment with the drug trastuzumab (Herceptin), which targets the protein.
In vitro device—a test that can detect disease, infection, or other health
conditions.
Institutional Review Board (IRB)—an institutional oversight body that pro-
tects 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.
Interpretation criteria—a component of the validation process that describes
the precise mathematical function and cut-off points used for interpreta-
tion of the assay results to ensure that it performs well on the assay results
yielded by the test method in the clinical laboratory.
Investigational device exemption (IDE)—an FDA 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 pre-
market notification submission.
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 FDA.
Lipidome—the complete set of lipids in a biological sample.
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Lock-down—in this report, various aspects of the test, such as the precisely
defined series of computational steps performed in processing the raw data,
the mathematical formula or formulas used to convert the data into a pre-
diction of the phenotype of interest, and the clinical assay for measuring
the selected features are recorded and no longer changed at specific points
in the development process.
Mass spectrometry—a method for separating ionized molecular particles
according to mass by applying a combination of electrical and magnetic
fields to deflect ions passing in a beam through the instrument.
Mechanism of action—the biological pathway by which a drug affects its
target in the body.
Medical device—according to FDA, 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 United States 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 dis-
ease, 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 upon 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
such as drugs and their metabolites).
Metadata—information about a dataset and how it was generated.
Methotrexate—a drug with antineoplastic and immunosuppressant activi-
ties that have the effect of inhibiting synthesis of DNA and RNA.
Microarray—a high-throughput biological assay in which different probes
are deposited on a chip surface (glass or silicon) in a miniature arrangement.
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.
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GLOSSARY
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.
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 between datasets, rather than to
the underlying biology that is shared between datasets.
Overlap (in datasets)—the use of the same samples in more than one phase
of test development.
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 an
omics-based test.
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. FDA
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.
Positive predictive value (PPV)—the probability that an individual with a
positive test result has, or will develop, the particular disease or character-
istic that the test is designed to detect. It is a measure of the ratio of true
positives to (false + true positives).
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Preanalytical variables—aspects of sample collection and handling that
need to be standardized and documented prior to test development and use.
Predictive factor—an effect modifier.
Premarket approval (PMA)—an FDA 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)—an FDA 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.)
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 set-
ting 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 speci-
mens 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.
Qualification—evidentiary process of linking a biomarker with biological
processes and clinical endpoints.
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.
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GLOSSARY
Risk stratification—the classification of patients into groups based on the
likelihood of developing or suffering effects from a disease.
Sample set—in this report, a collection of specimens or other biological
materials and the data derived from or associated with them that is used to
discover or validate an omics-based test.
Sensitivity (analytical)—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.
Serum—the fluid portion of the blood obtained after removal of fibrinogen,
other clotting factors, and cells; a clear watery fluid.
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).
Specificity (analytical)—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 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.
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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 particu-
larly 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.
Systemic therapy—treatment using substances that travel through the
bloodstream and reach and affect cells throughout the body.
Tamoxifen—a drug that interferes with activity of the hormone estrogen;
it is used to treat or reduce the risk of breast cancer.
Test validation phase—the second phase in the omics-based test develop-
ment process where the clinical test method is defined, and analytical and
clinical/biological validation are performed in a CLIA-certified laboratory.
The goal of this process is a fully defined and validated clinical test.
Training set—a group of data used to derive a computational model.
Transcriptome—the complete set of RNA transcripts from DNA in a cell.
Trastuzumab (Herceptin)—a monoclonal antibody that binds to HER2
(human epidermal growth factor receptor 2) and can kill HER2-positive
cancer cells. Used to treat breast cancer that is HER2-positive.
Undifferentiated tumor—a cancer with cells that do not have specialized
structures or functions. Undifferentiated tumor cells often grow and spread
quickly.
Utilization—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.
