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Glossary Ablation—the removal of a body part or the destruction of its function, as by a surgical procedure, morbid process, or noxious substance Accelerated approval—regulatory mechanism by which new drugs meant to treat serious, life-threatening diseases or diseases for which there are no alternative treatments can be approved for marketing by the Food and Drug Administration using earlier clinical trial results than would be required for regular approvals; post-market surveillance and studies generally required ACE inhibitor—see Angiotensin-converting enzyme (ACE) inhibitor Adenomatous colon polyps—growths in the epithelial layers of the colon; can be flat, pedunculated, or sessile; result from multiple genetic mutations arising from environmental or inherited causes; can become cancerous Adhesion molecules—molecules on cell surfaces that enable cells to stick to each other or other components of the extracellular matrix Adjusted association—a measure of association between individual patients’ true endpoints and surrogate endpoints after controlling for treatment assignment; a statistical method for surrogate endpoint evaluation Age-related macular degeneration—a disease occurring when the cells making up a central area of the retina, called the macula, break down or move away from their normal positions; causes blurriness and some - times loss of the center of field of vision 

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0 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS Analytical validation—“assessing [an] assay and its measurement per- formance characteristics, determining the range of conditions under which the assay will give reproducible and accurate data” (Wagner, 2002) Angiotensin-converting enzyme (ACE) inhibitor—drug used to treat blood pressure; prevents formation of a protein that causes constriction of blood vessels, thus lowering blood pressure Angiotension receptor blocker—type of medication used to treat high blood pressure. Unlike ACE inhibitors, which prevent the formation of angiotensin II, angiotensin receptor blockers, while allowing the protein to form, prevent it from functioning. Thus, blood pressure is lowered by preventing constriction of the blood vessels. Apolipoprotein—a protein component of lipoprotein complexes Arrhythmia—loss of rhythm, denoting especially an irregularity of the heartbeat Assay—a biochemical or other measurement developed to quantitate a biomarker Atherogenic dyslipidemia—abnormal lipid levels (including abnormal cholesterol levels) having the capacity to initiate, increase, or accelerate the process of atherogenesis having the capacity to initiate, increase, or accelerate the process of atherogenesis Atherosclerosis/arteriosclerosis—condition characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries; such deposits are associated with fibrosis and calcification, and are nearly always present to some degree in middle aged and older individuals Authorized health claim—voluntary statement that characterizes the relationship between a substance and its ability to reduce the risk of disease or a health-related condition (Schneeman, 2007) that meets the significant scientific agreement (SSA) standard Autocrine signaling—hormonal signalling in which a cell produces an agent that then binds to receptors within the same cell; related to stimu- lation of T-cell growth and growth of some breast cancers Beta-carotene (β-carotene)—pigment-producing molecule in the skin of several fruits and vegetables; after ingestion, some b-carotene in blood- stream converts to two molecules of retinol (preformed vitamin A) Bias—the systematic but unintentional erroneous association of some characteristic with a group in a way that distorts a comparison with another group (IOM, 2007) Biological plausibility—data elucidating how the biological pathways leading from exposure to effect are useful Biological products (biologics)—a category of products regulated by the Food and Drug Administration, including vaccines, blood and blood

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 GLOSSARY components, allergenic compounds, somatic cells, gene therapy, tis - sues, and recombinant therapeutic proteins Biomarker—“a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a[n]. . . intervention” (Biomarkers Defini - tions Working Group, 2001). Example: cholesterol level. The committee defines “objectively” to mean “reliably and accurately” Bone mineral density (BMD)—may correlate with bone strength and a bone’s ability to bear weight; may be possible to predict fracture risk using BMD as a measure Calcium channel blocker—drug used treat heart failure caused by high blood pressure; effects the movement of calcium in the cells of the heart and blood vessels to relax blood vessels and increase the supply of blood and oxygen to the heart Calibration—the use of measurement standards and standard measure- ment protocols to ensure the precision and reproducibility of an instru- ment or other measurement method Cardiotoxic—having a deleterious effect on the action of the heart, due to poisoning of the cardiac muscle or of its conducting system Cardiovascular disease—a term encompassing diseases that affect the heart and blood vessels CD4 cell (CD4+ T-cells)—specialized cells that play a role in measuring immune response in individuals with HIV Choi criteria—a measure used to assess tumor progression in gastrointes- tinal stromal tumor (GIST); incorporate tumor size and tumor density into a metric of tumor progression; demonstrated to more accurately predict overall survival in GIST than reduction in tumor size Cholesterol—abundant steroid metabolite produced by animals and found in cell membranes and circulating in blood; excess cholesterol can lead to fatty deposits in blood vessels, a risk factor for cardiovas - cular disease Chromium picolinate—biologically active chromium salt that is used as a dietary supplement Chronic disease—a culmination of a series of pathogenic processes in response to internal or external stimuli over time that results in a clini - cal diagnosis/ailment and health outcomes Clinical endpoint—a characteristic or variable that reflects how a patient feels, functions, or survives (Biomarkers Definitions Working Group, 2001) 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 (IOM, 2007)

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 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS Clinical utility—see Utilization Computed tomography (CT)—a special radiographic technique that uses a computer to assimilate multiple x-ray images into a two-dimen- sional, cross-sectional image, which also can be reconstructed into a three-dimensional image; can reveal many soft-tissue structures not shown by conventional radiography (IOM, 2007) Congestive heart failure (CHF)—condition in which the heart is unable to maintain adequate circulation of blood in the tissues of the body or to pump out the venous blood returned to it by the venous circulation Coronary artery disease (CAD)—see Coronary heart disease Coronary heart disease (CHD)— refers to damage to the heart caused by atherosclerotic constriction of arteries supplying the heart; also known as coronary artery disease C-reactive protein (CRP)—an acute-phase, non-specific, systemic marker of inflammation; in normal individuals, CRP is a trace plasma protein, but the serum concentration of CRP can increase upward of 1,000-fold upon exposure to a strong acute stimulus, such as sepsis or acute myo- cardial infarction Cytostasis—the slowing of movement and accumulation of blood cells in the capillaries, as in a region of inflammation Cytotoxic therapy—any agent or process that kills cells (e.g., chemo- therapy and radiotherapy) Diagnosis—a conclusion as to the presence of a disease Diagnostic test—the investigative tools and techniques used in biologi- cal studies to identify or determine the presence of a disease or other condition. Any laboratory-based test that can be used in drug discov - ery and development as well as in patient care and clinical decision making (IOM, 2007) Diastolic blood pressure—blood pressure as measured during the resting phase of the heart’s rhythm Dietary guidance statement—a statement describing general dietary pat- terns, practices and recommendations that promote health; these make reference to categories of foods and not specific substances, and they do not describe relationships between a substance (specific food or food component) and a disease or health-related condition; these can be made without Food and Drug Administration review or authoriza- tion before use Disease—damage to an organ, part, structure, or system of the body such that it does not function properly (e.g., CHD), or a state of health lead - ing to such dysfunctioning (e.g., hypertension) Disease risk stratification—placement of an individual into a risk cat- egory based on the likelihood that a disease will develop or recur

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 GLOSSARY Diuretic—substance promoting loss of bodily fluids through increased production and elimination of urine Drug—materials intended for use in the diagnosis, cure, mitigation, treat- ment, or prevention of disease; materials (other than food) intended to affect the structure or any function of the body of humans or other animals Early compound screening—the process of identifying compounds with the most promise for becoming efficacious and safe therapeutics Efficacy—ability to produce a desired effect Elliptoid model—method for estimating the volume of a cancer tumor using three different, preferably orthogonal, measurements of the tumor diameter Epidemiologic studies—studies of the health of various human populations Epitope—discrete site to which an antibody binds Etiology—the science and study of the causes of disease and their mode of operation Ex vivo—experimentation or measurements done in or on tissue in an artificial environment outside the organism Familial hypercholesterolemia—metabolic disorder caused by defective or absent receptors for LDLs on cell surfaces; marked by an increase in blood plasma LDLs and by an accumulation of LDLs in the body resulting in xanthomas, atherosclerosis, and an increased risk of heart attack and coronary heart disease; inherited as an autosomal dominant trait Fit-for-purpose—being guided by the principle that an evaluation process is tailored to the degree of certainty required for the use proposed Folic acid—vitamin of the B complex that is required for normal produc- tion of red blood cells; used especially in the treatment of nutritional anemias Food—articles used for food or drink for humans or other animals, chew - ing gum, and articles used for components of any such article; inclu - sive of foods consumed as part of meals and snacks, dietary supple- ments, and components contained in them (nutrients, other bioactive substances) Friedewald formula—provides an estimate of LDL cholesterol for most fasting specimens, though its accuracy is lower at higher triglyceride concentrations. genomics—the study of all of the nucleotide sequences, including struc- tural genes, regulatory sequences, and noncoding 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

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 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS genetic fingerprint is the pattern that stems from the variable expres - sion of different genes in normal and cancer tissues (IOM, 2007) glycation—the uncontrolled, non-enzymatic reaction of sugars with pro- teins; important in the damage done to diabetics when their sugar levels rise above normal, and in damage done to critical proteins of long-lived nerve cells in aging glycosylated hemoglobin—hemoglobin to which glucose is bound; tested to monitor the long-term control of diabetes mellitus growth factor—a substance (e.g., vitamin B12 or an interleukin) that promotes cellular growth Health claim—a claim that describes the relationship between a substance (food or food component) and a disease or health-related condition; limited to claims about disease risk reduction and cannot be claims about the cure, mitigation, treatment, or prevention of disease Heart disease—see Cardiovascular disease Hemostasis regulator—biological chemical involved in the process of stopping blood flow, as from a broken blood vessel High-density lipoprotein cholesterol (HDL-C)—a lipoprotein of blood plasma that is composed of a high proportion of protein with little triglyceride and cholesterol and that is associated with decreased prob- ability of developing atherosclerosis Hill criteria—criteria used to establish cause in the case of non-infectious or chronic disease by evaluating strength, consistency, specificity, tem - porality, biological gradient, plausibility, coherence, experiment, anal - ogy; used in environmental health, toxicology, pharmacology, epide - miology, and medicine Hyperlipidemia—the presence of abnormally high amount of lipids in the circulating blood Hypertension—abnormally high arterial blood pressure that is usually indicated by an adult systolic blood pressure of 140 mm Hg or greater or a diastolic blood pressure of 90 mm Hg or greater; can result in thick- ening and inelasticity of arterial walls and damage to the heart; a risk factor for various pathological conditions or events (e.g., heart attack, heart failure, stroke, end-stage renal disease, or retinal hemorrhage) Immune response—response of an organism to a foreign substance Immunoassay—test measuring the immune response of an organism to an antigen In vitro—outside the living body and in an artificial environment In vivo—in the living body of a plant or animal Incidence—occurrence of a disease or condition Inflammatory biomarker—biological chemicals indicating tissue damage or irritation; C-reactive protein is an inflammatory biomarker

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 GLOSSARY Inflammatory response (inflammation)—a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, pain, swelling, or loss of function and that serves as a mechanism initiating the elimination of elimination of foreign sub- stances and for healing damaged tissue Insulin resistance—an organism's inability to respond to and use the insulin it produces; this condition is related to the type 2 diabetes incidence Intermediate endpoint—a biologic event or marker that is a precursor to a given health outcome (e.g., atherosclerosis for cardiovascular disease endpoints or blurred vision for macular degeneration) Intervention—any drug, device, biologic, behavioral modification, nutri- tional modification, lifestyle modification, or other treatment intended to improve health Intima-media thickness (IMT)—the thickness of the inner layers of an artery Ischemic stroke—stroke caused by thrombosis or embolism; caused by an inadequate flow of blood to heart tissue due to a constriction or block - age to blood vessels supplying it Lipoprotein—compounds containing lipid and protein; almost all lipids in plasma are lipoproteins Low-density lipoprotein cholesterol (LDL-C)—a lipoprotein of blood plasma that is composed of a moderate proportion of protein with little triglyceride and a high proportion of cholesterol and that is associated with increased probability of developing atherosclerosis Luminal structures—relating to the lumen of a blood vessel Macromolecules—large molecules, often polymeric or with colloi- dal properties; examples include many proteins, nucleic acids, and polysaccharides Magnetic resonance imaging (MRI)—method by which images are cre- ated by recording signals generated from the excitation (the gain and loss of energy) of such elements as the hydrogen of water in tissue when placed in a powerful magnetic field and pulsed with radiofre- quencies (IOM, 2007) 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 (IOM, 2007) Medical device—any instrument, apparatus, appliance, material, or other article intended to be used to affect the structure or any function of a human or animal body Mendelian randomization—the random assignment of genetic material from parents to offspring; a tool used in epidemiology to help deter-

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 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS mine whether a health outcome is caused by genetic or environmental factors or to elucidate gene–gene or gene–environment interactions Metabolomics—the systematic study of the unique chemical fingerprints that specific cellular processes leave behind, that is, small-molecule metabolites (IOM, 2007) Microarray—a high-throughput biological assay in which different probes are deposited on a chip surface (glass or silicon) in a miniature arrange- ment; DNA microarrays most commonly used (IOM, 2007) Myocardial infarction—an acute episode of heart disease marked by the death or damage of heart muscle due to insufficient blood supply to the heart muscle, usually as a result of a coronary thrombosis or a coronary occlusion and that is characterized especially by chest pain Myxoid degeneration—a degenerative process in which the connective tissues are replaced by a gelatinous or mucoid substance Neural tube effects—a group of birth defects that involve the central ner- vous system; result from failure of the neural tube to properly form Normal sinus rhythm—normal heart rhythm Null hypothesis—the hypothesis that an intervention has no effect (i.e., that there is no true difference in outcomes between a treatment group and a control group); typically, if statistical tests indicate that the P- value is at or above the specified a-level (e.g., 0.01 or 0.05), then any observed treatment effect is not statistically significant, and the null hypothesis cannot be rejected Nutrient content claim—statements about the level of a nutrient or dietary substance in the product, using terms such as free, high, and low, or they compare the level of a nutrient in a food to that of another food, using terms such as more, reduced, and lite Opportunity cost—for any decision, the loss of the benefits of the next best alternative decision Oxidation—chemical reaction between a substance and oxygen. Fire and rust are examples of oxidative processes. P-value—a measure of the probability that a subsequent measurement’s magnitude would be equal or greater to the measured magnitude if the null hypothesis is true—in other words, if there is no true difference between the control and experimental groups Paracrine signal—referring to the release of locally acting substances from endocrine cells Paraneoplastic—caused by or resulting from the presence of cancer in the body, but not the physical presence of cancerous tissue in the part or organ affected Pathogenesis—the mode of origin or development of any disease or morbid process

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 GLOSSARY Pathophysiology—processes leading to the incidence or progression of disease or other health-related condition; alteration in function as dis - tinguished from structural defects Patient selection—in clinical trials, patient selection (inclusion/exclusion) by disease subset or probability of response/adverse events Peripheral vascular disease—a type of cardiovascular disease caused by atherosclerosis of the arteries to the limbs, reducing the blood supply and therefore depriving the limb muscles of oxygen Pharmacodynamic assay—a test used to determine a drug’s activity; can be used to select dose quantities and schedule Pharmacologic response—the effect of a drug on an organism in relation to the concentration of the drug Phase I trial—clinical trial in a small number of patients in which the toxicity and dosing of an intervention are assessed (IOM, 2007) Phase II trial—clinical trial in which the safety and preliminary efficacy of an intervention are assessed in patients (IOM, 2007) Phase III 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 (IOM, 2007) Phospholipid—any of numerous lipids in which phosphoric acid as well as a fatty acid is esterified to glycerol and which are found in all living cells and in the bilayers of cell membranes Phytosterol—cholesterol-like compounds found in vegetable oils, nuts, and legumes; may reduce serum cholesterol Plaque—a well-demarcated yellow area or swelling on the surface of the artery; produced by intimal lipid deposit Plasma—the fluid portion of the circulating blood Pleiotropic effects—having multiple phenotypic expressions; for exam- ple, the non-lipid effects of statins, including the anti-inflammatory and antithrombotic properties that contribute to an improvement in vascular function Polymorphism—occurrence in the same population of two or more geno- types of such proportion that the most rare cannot be maintained by recurrent mutation alone; heritable variations in low-density lipo - proteins; variant lipoproteins exhibit different antigenic and chemical properties compared with normal lipoproteins Positive harm—something that is intended to do good is not only ineffec- tive, but causes definite harm as an unintended side effect Positive predictive value—the probability that an individual with a posi- tive test has, or will develop, a particular disease, or characteristic, that the test is designed to detect; a measure of the ratio of true positives to (false + true positives) (IOM, 2007)

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 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS 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 (IOM, 2007) Postmarket studies—may be mandated by the Food and Drug Admin- istration for already approved drugs or devices to review potential risks Precision—a measure of random error; inversely related to random error; confidence intervals are computed to demonstrate the precision of rela- tive risk estimates Predictive value—the ability to predict the change in the outcome of a disease given a particular intervention using a specified patient measurement Prentice criteria—stringent requirements to be met before a biomarker can definitively substitute for a clinical endpoint for a given use; briefly, the criteria state that a biomarker must perfectly correlate with the clinical outcome it is meant to replace and capture the entire effect of the intervention used to bring about the effect on the clinical outcome Prevalence (disease)—the number of existing cases of a disease in a given population at a specific time Prevention—the use of medical and public health tools to prevent dis- ease, injury, or other events injurious to health Prognosis—an assessment of the probable course of a disease given the risk factors present in an individual; this assessment may affect treat- ment decisions Prognostic value—the ability to predict disease outcome or course using a specified patient measurement Protease—biological chemical that reacts with proteins, degrading them chemically and making them non-functional 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 spec- troscopy, 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 (IOM, 2007) Qualification—evidentiary process of linking a biomarker with biological processes and clinical endpoints Qualified health claim—voluntary statement that characterizes the rela- tionship between a substance and its ability to reduce the risk of dis- ease or a health-related condition (Schneeman, 2007) that does not meet the significant scientific agreement (SSA) standard

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 GLOSSARY Randomized controlled trial (RCT)—a study in which the participants are assigned by chance to separate groups that compare different treat- ments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best Relative effect—the effect of a treatment on the distribution of true end- points versus surrogate endpoints; component of a statistical method for surrogate endpoint evaluation Relative risk—the ratio of the risk of disease in exposed individuals to the risk of disease in non-exposed individuals Risk–benefit analysis—the comparison of the risk of a situation to its benefits Risk biomarker—biomarker that indicates a component of an individu- al’s level of risk for developing a disease or level of risk for developing complications of a disease Risk stratification—the classification of patients into groups based on the likelihood of developing or suffering effects from a disease Safety biomarker—a biomarker that can be used to identify patients at high risk for serious side effects, to monitor early signs of toxicity, or to predict the likelihood for severe toxicity Sample bias—see Bias Saturated fat— fat having no double bonds; chemically the most stable type of fat; solid at room temperature; come chiefly from animal food products; tend to raise the level of cholesterol in the blood Screening—the use of risk factor analysis and biomarker assays to detect early-stage disease in the asymptomatic population Sensitivity (analytical)—the lowest concentration that can be distin- guished from background noise; this concentration is termed an assay’s detection limit (IOM, 2007) 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 (IOM, 2007). Sepsis—the presence of various pathogenic organisms, or their toxins, in the blood or tissues Serum—the fluid portion of the blood obtained after removal of fibrino- gen, other clottting factors, and cells; a clear watery fluid, especially that moistening surface of serous membranes Significant scientific agreement (SSA)—judgment that qualified experts would likely agree that the scientific evidence supports the substance– disease relationship that is the subject of a proposed health claim

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0 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS Specificity (analytical)—how well an assay detects only a specific sub- stance and does not detect closely related substances (IOM, 2007) Specificity (clinical)—a measure of how often a test correctly identifies the proportion of persons without a specific diagnosis; calculated as the number of true-negative results divided by the number of true- negative plus false-positive results (IOM, 2007) Statin—any of a group of drugs (as lovastatin and simvastatin) that inhibit the synthesis of cholesterol and promote the production of LDL-binding receptors in the liver, resulting in a decrease in the level of LDL and a modest increase in the level of HDL circulating in blood plasma Structure–function claim—statements describing the role of a nutrient or dietary ingredient intended to affect normal structure or function in humans; may characterize the means by which a nutrient or dietary ingredient acts to maintain such structure or function; may describe general well-being from consumption of a nutrient or dietary ingredi - ent; manufacturer is responsible for ensuring the accuracy and truth - fulness of the statement; FDA does not review these claims prior to manufacturer use Substance—a specific food (tomato) or component of food (lycopene), whether in conventional food or dietary supplement form Supplement—a product taken by mouth that contains a dietary ingredi- ent intended to supplement the diet; dietary ingredients may include: vitamins, minerals, herbs or other botanicals, amino acids, and sub - stances such as enzymes, organ tissues, glandulars, and metabolites; may be found in forms such as tablets, capsules, softgels, gelcaps, liquids, or powders Surrogate endpoint—a biomarker that is intended to substitute for a clini- cal endpoint. A surrogate endpoint is expected to predict clinical ben - efit (or harm or lack of benefit or harm) based on epidemiologic, thera- peutic, pathophysiologic, or other scientific evidence (IOM, 2007) Surrogate threshold effect—the minimum treatment effect on the sur- rogate endpoint necessary to predict a non-zero effect on the true end- point; provides information relevant to the practical use of a surrogate endpoint and can be interpreted from a clinical point of view Surveillance—population-level monitoring for early detection and treat- ment of advancing disease or complications Systolic blood pressure—the highest blood pressure that occurs during a beat of the heart, just after the left ventricle has contracted Target validation—demonstration that a potential drug target plays a key role in the disease process Therapeutic intervention—actions taken (through administration of a drug or other means) to treat a disease or other health-related condition

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 GLOSSARY Therapy monitoring—the process of determining whether a therapy is having the intended effect on a disease and whether adverse effects arise Total cholesterol—total amount of cholesterol (both LDL and HDL) in the blood Toxicology—the science of understanding the effects of chemicals on humans and other organisms Triglyceride—any of a group of lipids that are esters formed from one molecule of glycerol and three molecules of one or more fatty acids, are widespread in adipose tissue, and commonly circulate in the blood in the form of lipoproteins Troponin—protein of muscle that together with tropomyosin forms a regulatory protein complex controlling the interaction of actin and myosin and that when combined with calcium ions permits muscular contraction (e.g., of the heart) True endpoint—the endpoint for which a surrogate endpoint is sought Tumor response rates—in its most primitive form: tumor shrinkage; defined by a change in tumor bulk; commonly used for making deci - sions regarding approval of anticancer drugs in the 1970s Tumor size—inconsistently defined biomarker often used for determining efficacy of cancer therapeutics Type 2 diabetes—diabetes mellitus of a common form that develops especially in adults and most often in obese individuals and that is characterized by hyperglycemia resulting from impaired insulin utili- zation coupled with the body’s inability to compensate with increased insulin production ultracentrifuge—a high-speed centrifuge by means of which large mol- ecules (proteins, nucleic acids) are caused to sediment at practicable rates; used for determination of molecular weights utilization—contextual analysis based on the specific use proposed and the applicability of available evidence to this use. This includes a deter- mination of whether the validation and qualification conducted pro - vide sufficient support for the use proposed Validation—see Analytical validation Vasodilator—an agent that causes dilation of the blood vessels Ventricular tachycardia—relatively rapid heart action (whether physio- logical or pathological) that is associated with the generation of electri - cal impulses within the ventricles and is characterized by an electrocar- diogram having a broad QRS complex. A QRS complex is a measurable characteristic of an electrocardiogram Viral fitness—refers to the relative replication competence of a virus (e.g., HIV) under defined circumstances; generally assessed in tissue culture systems; its relevance to the clinical situation may be difficult to fully establish

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 EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS REFERENCES Biomarkers Definitions Working Group. 2001. Biomarkers and surrogate endpoints: Pre - ferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 69(3):89–95. IOM (Institute of Medicine). 2007. Cancer biomarkers: The promises and challenges of improving detection and treatment. Washington, DC: The National Academies Press. Schneeman, B. 2007. FDA's review of scientific evidence for health claims. Journal of Nutri- tion 137(2):493–494. Wagner, J. A. 2002. Overview of biomarkers and surrogate endpoints in drug development. Disease Markers 18(2):41–46.