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 chemotherapy, 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 analytes 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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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. 327

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328 EVOLUTION OF TRANSLATIONAL OMICS 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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329 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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330 EVOLUTION OF TRANSLATIONAL OMICS 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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331 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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332 EVOLUTION OF TRANSLATIONAL OMICS 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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333 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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334 EVOLUTION OF TRANSLATIONAL OMICS 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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335 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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336 EVOLUTION OF TRANSLATIONAL OMICS 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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337 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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338 EVOLUTION OF TRANSLATIONAL OMICS 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.