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Biomarkers glossary & taxonomy
Evolving Terminologies for Emerging Technologies
Comments? Questions? Revisions?
Mary Chitty MSLS
Last revised January 06, 2020

Related glossaries include  Cancer   Diagnostics overview    Drug safety   Metabolic profiling   Molecular diagnostics   Molecular Imaging  Molecular Medicine  Pharmacogenomics    SNPs & other Genetic Variations

Biomarkers & Immuno-Oncology World Congress  June 17-21, 2019 • Boston MA

accessible biomarkers: A biomarker that can be obtained in a minimally invasive manner, typically from blood, plasma, serum, saliva or urine. 

antecedent biomarkers: Most adult-onset degenerative diseases of the nervous system are likely to be a composite of related characteristics, heritable and environmental. The correlated combinations of these features constitute the trait or disease. Therefore, these types of antecedent biomarkers may or may not be directly involved in the etiology. In some instances the genetic variant is neither necessary nor sufficient to cause the disease. However, they can be powerful antecedents at any stage of the disease pathway ... By definition these antecedent biomarkers exist before the disease or the outcome occurs and are independent of other exposures. They improve the precision in the measurement of other associations, because they may be synergistic or antagonistic. Biomarkers: Potential Uses and Limitations, Richard Mayeux, NeuroRx. 2004 April; 1(2): 182–188

Biomarkers that exist before signs of a disease are present.   See also under biological markers  

biochemical biomarkers:  Biochemical biomarkers have long contributed to the assessment of risk and benefits in cancer, and routine clinical assays are available.  Richard Frank, Richard Hargreaves, . Nature Reviews Drug Discovery. 2(7): 566- 580,

biological marker (biomarker): A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations.     biomarker (medicine): Wikipedia 

biological markers:  Measurable and quantifiable biological parameters (e.g. specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health - and physiology related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. MeSH, 1989 

 1. Parameter that can be used to identify a toxic effect in an individual organism and can be used in extrapolation between species. 2. Indicator signalling an event or condition in a biological system or sample and giving a measure of exposure, effect, or susceptibility.  IUPAC Toxicology  Related/synonymous? terms: biomarkers, genetic markers, protein biomarkers, surrogate markers; Broader term: markers  Narrower term: genomic biomarkers

biological tumor markers: Cancer

biomarker: The term “biomarker”, a portmanteau of “biological marker”, refers to a broad subcategory of medical signs – that is, objective indications of medical state observed from outside the patient – which can be measured accurately and reproducibly. Medical signs stand in contrast to medical symptoms, which are limited to those indications of health or illness perceived by patients themselves. There are several more precise definitions of biomarkers in the literature, and they fortunately overlap considerably. In 1998, the National Institutes of Health Biomarkers Definitions Working Group defined a biomarker as “a characteristic that is objectively measured and evaluated as an 
indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. 
What are Biomarkers? Kyle Strimbu and Jorge A. Tavel, M.D. Curr Opin HIV AIDS. Nov 2010; 5(6): 463–466.doi:  10.1097/COH.0b013e32833ed177 

biomarker analytes: DNA, gene expression profiles, protein[s], protein expression, metabolite[s], cells or combinations of these can constitute biomarkers.

biomarker development: Pharmaceutical and biotechnology companies routinely use biomarkers to obtain quantitative metrics for drug exposure, efficacy, and safety and to inform clinical trial design with regard to patient selection, treatments, and outcomes. Biomarker science has the unique capability to catalyze precompetitive collaborations between academia, industry, regulatory agencies, and other stakeholders with the ultimate goal of accelerating the delivery of safe and effective medicines to patients, particularly in areas of high unmet need.  Gerlach, Cory V., Derzi, Mazin, Ramaiah, Shashi K, Vaidya, Vishal S. Industry Perspective on Biomarker Development and Qualification, Clinical Pharmacology & Therapeutics, 103 (1) 2018 Jan

biomarker guidelines: The National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) charged the Biomarker Task Force to develop recommendations to improve the decisions about incorporation of biomarker studies in early investigational drug trials. The Task Force members reviewed biomarker trials, the peer-reviewed literature, NCI and U.S. Food and Drug Administration (FDA) guidance documents, and conducted a survey of investigators to determine practices and challenges to executing biomarker studies in clinical trials of new drugs in early development. This document provides standard definitions and categories of biomarkers, and lists recommendations to sponsors and investigators for biomarker incorporation into such trials. Our recommendations for sponsors focus on the identification and prioritization of biomarkers and assays, the coordination of activities for the development and use of assays, and for operational activities. We also provide recommendations for investigators developing clinical trials with biomarker studies for scientific rationale, assay criteria, trial design, and analysis. Guidelines for the Development and Incorporation of Biomarker Studies in Early Clinical Trials of Novel Agents,  Dancey JE, et. al,  Clin Cancer Res. 2010 Mar 9. [Epub ahead of print]

biomarker validation: There is a lot of confusion in the world of biomarker testing when it comes to the terms “assay qualification” and “assay validation”. These two terms are not strictly defined and are even used interchangeably at times. This confusion stems from the diverse scientific backgrounds and disciplines of those of us working in the biomarker field. Scientists from a manufacturing setting, clinical setting, or research setting have a somewhat different understanding of these two terms. Conversely, there is a clear distinction between “qualification” and “validation” for those working in analytical laboratories dealing with drug manufacturing and product release. Exploratory Biomarker Testing: to Qualify or Validate the Assay? Dr. Afshin Safavi 2018   See also under valid biomarker and  validation- biomarker

biomarkers:  Biomarkers may be any parameter of a patient that can be measured, for example, mRNA expression profiles, proteins, proteomic patterns, lipids, imaging methods, or electrical signals. The best biomarkers are accurate, relatively noninvasive and easy-to-perform tests that can be done at the bedside or in the outpatient setting. These tests involve a blood or spot urine specimen, can be measured serially, and have a fast turnaround. In the past, most efforts had focused on discovering tissue and urinary biomarkers. However, there has been a recent shift to finding serum biomarkers (11), with new methods and technologies making this more practical. Stephen M. Hewitt*, James Dear and Robert A. Star, Discovery of Protein Biomarkers for Renal Diseases, J Am Soc Nephrology 15:1677-1689, 2004 

Typically, “biomarker” is defined as a laboratory measurement that reflects the activity of a disease process. There are many such markers identified for many diseases of the nervous system, for example, various magnetic resonance imaging (MRI) measures in multiple sclerosis and Alzheimer’s disease treatments, positron emission tomographic (PET) scanning of dopamine transporters in Parkinson’s disease, etc.14 In essentially all cases, these markers quantitatively correlate (either directly or inversely) with disease progression. Russell Katz, Biomarkers and Surrogate Markers: An FDA Perspective, NeuroRx 1(2): 189-195, April 2004  

The widespread use of the term "biomarker" dates back to as early as 1980.[1] The term "biological marker" was introduced in 1950s.[2][3] In 1998, the National Institutes of Health Biomarkers Definitions Working Group defined a biomarker as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention."[4][5]   Wikipedia biomarkers history

Narrower terms: genetic biomarkers, genomic biomarkers, high-impact biomarkers, protein biomarkers, proteomic biomarkers Related/synonymous? terms:  biological markers, genetic markers, surrogate markers.  Broader term: markers

Biomarkers Consortium: .The Biomarkers Consortium is a public-private biomedical research partnership managed by the Foundation for the National Institutes of Health that endeavors to discover, develop, and seek regulatory approval for biological markers (biomarkers) to support new drug development, preventive medicine, and medical diagnostics.

Despite the challenges overcome by this project, the most important lesson learned is that cross-company precompetitive collaboration is a feasible robust approach to biomarker qualification. The Biomarkers Consortium: practice and pitfalls of open-source precompetitive collaboration. Wagner JA et. al Clin Pharmacol Ther. 2010 May;87(5): 539-542.

biosignatures: Patient outcomes are too multidimensional in that a single outcome measure can miss domains of interest. It is very difficult to capture with a single measure both the benefit and the harm predicted by a surrogate endpoint. Woodcock said she foresees the future of surrogate endpoint development as featuring composite outcome measurements (i.e., biosignatures). She also envisions responder rather than population mean analyses and individualized therapy based on biomarker-derived strata. Institute of Medicine (US) Forum on Neuroscience and Nervous System Disorders. Neuroscience Biomarkers and Biosignatures: Converging Technologies, Emerging Partnerships, Workshop Summary. Washington (DC): National Academies Press (US); 2008. 1, Biomarker and Biosignature Principles. Available from:

If a biomarker is used in combination with another biomarker, the two (or more) are sometimes referred to as biosignature. Neuroscience Biomarkers and BiosignaturesConverging Technologies, Emerging Partnerships: Workshop Summary Institute of MedicineBoard on Health Sciences PolicyForum on Neuroscience and Nervous System Disorders, National Academies Press, Jan 8, 2008

bridging biomarkers:
Biomarkers of cellular injury that can link laboratory findings directly to human outcomes.  A biomarker for a given analyte or set of analytes that can be applied in both a pre- clinical and clinical setting. 

CDISC Clinical Data Interchange Standards Consortium: Regulatory

Cancer Immunotherapy and Combinations biomarkers  August 20-21, 2018  Washington, DC Program | The heterogeneity of cancer, and the complex interaction of cancer and immune cells, require sophisticated phenotypic and genotypic testing in order to answer important questions for new immuno-oncology agent discovery and clinical development. Cell-based biomarkers, biomarkers of tumor microenvironment, neoantigens, and tumor mutation burden are some of the classes of biomarkers that guide clinical development and patient care in immune-oncology

cellular biomarkers: Fundamental to many tissue- engineered devices are problems of inflammation associated with how biological cells respond to a given device when inserted into the body. ... To assure that tissue- engineered materials are free of molecular changes that could occur during the in vitro development phase, cellular biomarkers are being identified that can be used during the manufacturing process. H. Rodriguez, Cellular Biomarkers Used to Detect Damage in Tissue- Engineered Medical Products, Society for Biomaterials,  May 01, 2002, Technipubs, Recent Publications by NIST authors  
Wikipedia biomarker (cell)   

cell specific biomarkers: Using biomarkers linked to distinct, defined cell types and tissues provides a direct link to histopathology without its drawbacks, plus it provides increased sensitivity, and specificity. ...  Serum creatinine is the most widely used renal biomarker in spite of its known shortcomings. Cell-specific biomarkers are more specific and sensitive and have been known for over 40 years, but they are still underused in renal medicine and research. In particular, while many studies have shown cell-specific biomarkers to be valuable in diagnosis, there are few studies where they have been used to guide therapy or linked to quantitative changes in the kidney. Cell-specific biomarkers in renal medicine and research, Shaw M. Methods Mol Biol. 2010;641:271-302.

chemical biomarkers:  Chemical biomarkers released by the host in response to invasion and infection could provide a target for antibody arrays, mass spectrometry, and other analytical techniques to diagnose infection. In spite of these advances, general research into the biochemistry of agents and the rapid identification of pathogenicity of agents is still needed. National Security and Homeland Defense: Challenges for the Chemical Sciences in the 21st Century, National Academies Press, 2003 

clinical biomarkers:  The promise of personalized medicine has been driven by the need to accurately predict patient response to therapy while ensuring drug efficacy and safety. Reducing costs and the time required for drug development is also a driving force in the use of biomarkers. 

clinical outcomes: directly measure whether people in a trial feel or function better, or live longer. The benefit or likely benefit of a therapy, as measured by clinical outcomes (e.g., improvement in symptoms), is assessed to determine whether it outweighs any adverse effects (e.g., drug-induced liver injury). Surrogate Endpoint Resources for Drug and Biologic Development

clinical trial endpoints: A clinical trial’s endpoints measure the outcomes in the trial. When a trial evaluates the efficacy of a new medical product or a new use for an approved product, investigators may choose endpoints that directly measure the clinical outcome they want to study. Surrogate Endpoint Resources for Drug and Biologic Development

combination biomarkers: Biomarkers that are based on more than one category of analytes. (Alternatively: Integrative biomarkers, Systems biology biomarkers)  Related/narrower terms: DNA markers, genetic biomarkers, genomic biomarkers, metabolic biomarkers, metabolite biomarkers,  metabolomic biomarkers, protein biomarkers, proteomic biomarkers

diagnostic biomarkers: May span a continuum from early to more advanced disease manifestations. May be used as synonymous with disease biomarkers. See also under biological biomarkers    Narrower terms: disease onset biomarkers, monitoring biomarkers, occurrence biomarker, staging biomarkers  Related terms:  Molecular Diagnostics

digital biomarkers: consumer-generated physiological and behavioral measures collected through connected digital tools that can be used to explain, influence and/or predict health-related outcomes. Health-related outcomes can vary from explaining disease to predicting drug response to influencing fitness behaviors. In our definition of digital biomarkers, we exclude patient-reported measures (e.g., survey data), genetic information, and data collected through traditional medical devices and equipment. These data types, though still a key component of research and clinical care that may be stored digitally, are not digitally measured or truly dependent on software. Rock Heal+h, Emerging influence of digital biomarkers on healthcare   Related term: wearables

Sensors, Wearables and Digital Biomarkers in Clinical Trials Digital Endpoints and Connectivity FEBRUARY 19-20, 2019, Orlando FL  Clinical research industry is moving toward end-to-end digital clinical trials. The data collection should stay in line with this inevitable change and wearables and point-of-care sensors address this need. Furthermore, digital biomarkers translate new data sources into clinically actionable insights.

Digital Biomarkers: Biosensors, Wearables, and mHealth  June 19-20, 2019 Boston, MA  As the role of biosensors, wearables and mobile health in modern healthcare evolves, the potential of digital biomarkers to continually monitor patient health, rapidly diagnose disease, and accurately predict outcomes becomes increasingly apparent. Physiological data may now be collected via digital devices such as portables, wearables, and implantables. Mobile health, or “mHealth,” promises to transform not only the future of healthcare but also the process of clinical trials.

direct biomarkers: See under indirect biomarkers 

disease biomarkers: Biomarkers of disease: cover measurement of endogenous substances or parameters indicative of a disease process and the use of pharmacodynamic and genetic markers in evidence- based laboratory medicine and treatment (markers of efficacy). Biomarkers, Taylor & Francis, Aims & Scope 

disease markers: Nature Disease Markers archives
Narrower terms: disease risk biomarkers, disease onset biomarkers, monitoring biomarkers, occurrence biomarkers, staging biomarkers

disease onset biomarkers:  Reports onset of disease, prior to clear symptomatic evidence. Identification of such biomarkers will be quite difficult, because confirmation of disease onset will occur later, but require access to earlier samples.

disease risk biomarkers:  Typically based on DNA, in some cases disease occurrence is uncertain, in others timing of disease onset is uncertain.    Related/synonymous? term: antecedent biomarkers

DNA marker:  A cloned chromosomal locus with allelic variation that can be followed directly by a DNA- based assay such as Southern blotting or PCR. NHLBI 
Narrower terms: bridging biomarkers, efficacy biomarkers, exclusion biomarkers, inclusion biomarkers, safety biomarkers, target biomarkers, toxicity biomarkers

efficacy biomarkers: In oncology, a special class of extensively evaluated biomarkers of efficacy (surrogate endpoints) that generally correlate with desired clinical outcomes can be used as a basis for corporate decisions as well as for gaining accelerated provisional regulatory approval of a drug. E. Floyd, TM McShane, Development and Use of Biomarkers in Oncology Drug Development, Toxicol Pathol. 32 (Supplement 1) 106- 115, 2004

A biomarker that reflects beneficial effect of a given treatment. (May be simply reversal of a disease biomarker.) 

exclusion biomarkers: A biomarker that predicts that a given treatment will produce an adverse response.  Could be used to exclude patients from clinical trials.

exposure biomarkers: Biomarkers of exposure are the actual chemicals, or chemical metabolites, that can be measured in the body or after excretion from the body to determine different characteristics of an organism’s exposure. For example, a person or fish’s blood can be tested to see the levels of lead and therefore determine the exposure.  Wikipedia accessed 2018 Feb 5

genetic biomarkers: A single gene (DNA) for which a mutation, deletion, SNP or some other feature provides predictive value.

genetic markers:  A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event MeSH, 1989

Consist of specific nucleotide patterns. NHLBI 
Related term: ESTs Gene definitions UniGene (database) has marker information

Wikipedia: genetic marker 

genomic biomarkers: A measurable DNA or RNA characteristic that is an indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other inventions.    could, for example, reflect: The expression of a gene, The function of a gene, The regulation of a gene ... does not include the measurement and characterisation of proteins or low molecular weight metabolite. DNA characteristics include, but are not limited to Single Nucleotide Polymorphisms (SNPs), Variability of short sequence repeats, DNA modification, e.g. methylation, Insertions, Deletions, Copy number variation, Cytogenetic rearrangements, e.g. translations, duplications, deletions or inversions.  RNA characteristics include, but are not limited to RNA sequence, RNA expression levels, RNA processing, e.g. splicing and editing, MicroRNA levels. E15 terminology in Pharmacogenomics, ICH 2008 

Using genomic biomarkers in drug and diagnostic development and regulatory decision making is showing a lot of potential, but still requires more qualification and validation. We have identified two key application areas First, at the drug discovery stage, genomic biomarkers applied to compound profiling offer efficacy and toxicity data, allowing better decision making at earlier stages and reducing late-stage attrition. Second, in the clinical setting, genomic biomarkers have the promise in disease diagnosis/ prognosis; treatment, patient, or dose selection; and clinical safety and efficacy assessment.  A gene expression pattern (RNAs) that is able to discriminate or predict. 

Table of Pharmacogenomic Biomarkers in Drug Labels, FDA, 2011  

genotypic biomarkers: The cytochrome P450 (CYP) system of drug metabolising enzymes represents the best studied set of pharmaceutically important genotypic markers. Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003 

haplotype biomarkers: Because haplotypes include the linkage of multiple SNPs, they will generally occur at lower prevalence than individual gene variants, and the more SNPs involved in a haplotype, the narrower and more Haplotypic biomarkers  precisely defined will be the patient subgroups. Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003  

"ideal" biomarker:  Vonderscher outlined the characteristics of an ideal biomarker for kidney toxicity: It should be visible early, prior to histopathological changes, and should be indicative after active damage.  It should be sensitive, but it should also correlate with the severity of damage.  It should be accessible in the peripheral tissue; in the case of the kidney, for example, it should be measurable in either the blood or the urine.  It should be analytically stable in tissue so it can be measured after some time has passed, for example, after a biopsy has been taken or a necropsy performed.  It should be translational; that is, it should bridge across species.  It should be associated with a known mechanism. Many current biomarkers are identified through statistical analysis of gene expression, as discussed in Chapter 4, but one should be able to understand the biomarker and what is really going on in a biomolecular sense when it appears.  A biomarker should be able to localize damage. For example, it should pinpoint the particular area of the kidney that has been damaged rather than just indicating kidney toxicity in general.  Given this extensive list of characteristics, a panel of biomarkers rather than any single ideal biomarker will likely be needed to characterize nephrotoxicity.  Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation.  Washington DC National Academies Press (US); 2008.

Immuno-Oncology Biomarkers 1: Quantitative Immune Profiling and Immune Monitoring August 27-28, 2018 Boston, MA Program  Advances in immuno-oncology promise to revolutionize cancer treatment. However, many patients do not respond to immunotherapy. Immune profiling promises to identify biomarkers that predict response to immunotherapy and to help monitor its progress. 

Immuno-Oncology Biomarkers 2: Predictive Biomarkers and Companion Diagnostics August 28-29, 2018 Boston, MA Program  As pharmaceutical and biotechnology companies increase their investment in immuno-oncology programs to facilitate rapid development of novel immunotherapies, there is increasing pressure to discover and validate relevant biomarkers

immunotherapy biomarkers: Immunotherapy has revolutionized cancer therapy …Checkpoint inhibitors have demonstrated unprecedented rates of durable responses in some of the most difficult-to-treat cancers; however, many treated patients do not respond, and the potential for serious side effects exists. There is a growing need to identify biomarkers that will improve the selection of patients who will best respond to therapy, further elucidate drug mechanisms of action, and help tailor therapy regimens. Biomarkers are being explored at the soluble, cellular, and genomic levels, and examples in immunotherapy include serum proteins, tumor-specific receptor expression patterns, factors in the tumor microenvironment, circulating immune and tumor cells, and host genomic factors. The search for reliable biomarkers is limited by our incomplete understanding of how immunotherapies modify the already complex immune response to cancer, as well as the contribution of immuno-editing to a dynamic and inducible tumor microenvironment and immune milieu. Biomarkers for Immunotherapy: Current Developments and Challenges. Spencer KR1, Wang J1, Silk AW1, Ganesan S1, Kaufman HL1, Mehnert JM1. Am Soc Clin Oncol Educ Book. 2016;35:e493-503. doi: 10.14694/EDBK_160766.

inclusion biomarkers: A biomarker that predicts that a given treatment will produce a positive response.  

indirect biomarkers: Biomarkers are very useful tools when the metabolic fate of the compound or the etiology of a resultant disease is completely understood. They may contribute to confusion if it is not possible to distinguish between markers of exposure and markers of disease. Such is the case for biomarkers used in the assessment of diisocyanate exposure. Biomarkers for diisocyanate exposure result from both direct and indirect effects. Molecules such as hemoglobin, albumin, tubulin, glutathione, and laminin have been implicated as having been directly modified as a result of exposure to toluene diisocyanate (TDI). In addition, indirect biomarkers have included profiles of molecules such as antibodies, cytokines, cell accumulation or proliferation, and markers of oxidative stress. WE Brown, AL Burkert, Biomarkers of toluene diisocyanate exposure Appl Occup Environ Hyg. 17(12): 840-845, Dec. 2002

kidney safety biomarkers: An illustrative and "door opening" safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the "know how" acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. Impact of biomarker development on drug safety assessment, Marrer E, Dieterle F. Toxicol Appl Pharmacol. 2010 Mar 1;243(2):167-79. Epub 2009 Dec 28.    Also known as renal safety biomarkers.

known valid biomarker:  A biomarker that is measured in an analytical test system with well established performance characteristics and for which there is widespread agreement in the medical or scientific community about the physiologic, toxicologic, pharmacologic, or clinical significance of the results. Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations. 

marker vaccines: Vaccines used in conjunction with diagnostic tests to differentiate vaccinated animals from carrier animals. Marker vaccines can be either a subunit or a gene- deleted vaccine. MeSH, 2001

markers: SNPs & Genetic Variations  Types of genetic maps are differentiated largely by the type of marker used. 
Narrower terms: biological markers, biomarkers, DNA markers, ESTs, genetic markers, polymorphisms; SNPs & Genetic Variations DNA fingerprints, microsatellite markers, microsatellite repeats, microsatellites,  minisatellite repeats, RFLPs, restriction enzymes, SSRs, STRs, STSs, satellites Related terms: Maps- genomic & genetic  

mechanistic markers: changes in the subcellular phenotype of the organism can lead to alterations in proteins detectable as markers. These changes, constituting mechanistic markers, are closely reflective of what is going on in the cell and how the signaling pathways are manipulated. Proteomics-based Development of Biomarkers in Cardiovascular Disease Mechanistic, Clinical, and Therapeutic Insights Manuel Mayr et al., Molecular & Cellular Proteomics 5:1853-1864, 2006.

metabolic biomarkers: At the non-clinical stage, metabolic biomarkers provide early profiles on drug efficacy, toxicity and mechanism, thus allowing more informed lead candidate selection. Many of these markers can be translated into the clinic, offering exploratory biomarkers of safety, efficacy, tolerability and pharmacodynamics. Metabolic biomarkers may also prove useful in advancing personalized medicine by allowing patient stratification and more effective clinical trial design.  Related terms: Metabolic profiling & engineering

metabolite biomarkers: Individual metabolites have already been used as disease biomarkers for years. ... Metabolomics enables the identification of biomarkers based on entire groupings of metabolites that are up- or downregulated in unison under specific conditions.  Charles W. Schmidt,  Metabolomics, What's happening downstream of DNA, Metabolite Biomarkers, Medscape, posted 6/1/2004 

A single metabolite for which presence or expression level is significant. 

metabolomic biomarkers: 
A pattern of metabolites that is able to discriminate or predict. 

miRNA biomarkers: MicroRNAs (MiRNAs) are small endogenous RNA molecules and have emerged as novel serum diagnostic biomarkers for several diseases due to their stability and detection at minute quantities  A Panel of Serum MiRNA Biomarkers for the Diagnosis of Severe to Mild Traumatic Brain Injury in Humans  Manish Bhomia  , Nagaraja S.  Balakathiresan  , Kevin K. Wang   , Linda Papa  & Radha K. Maheshwa Scientific Reports vol 6, Article number: 28148 (2016)  doi:10.1038/srep28148 

molecular markers: The three most common types of markers used today are RFLP, RAPD and isozymes.  The classes of molecular markers, Mapping plant genomes with molecular markers, Phillip McClean, 1998 

Seems also to be an umbrella term for most of the terms in this glossary. 
Wikipedia: molecular marker 

monitoring biomarkers: Reports reoccurrence or progression of disease. 

mRNA biomarkers: In medicine, mRNA transcripts are being developed as molecular biomarkers for the diagnosis and treatment of a number of diseases. These biomarkers offer early and more accurate prediction and diagnosis of disease and disease progression, and ability to identify individuals at risk. Use of microarrays also offers opportunity to identify orthogonal (uncorrelated) biomarkers not known to be linked with conventional biomarkers. mRNA transcripts as molecular biomarkers in medicine and nutrition, Roger Sundee, Journal of Nutritional Biochemistry doi:10.1016/j.jnutbio.2009.11.012  

multivariate markers: Although both univariate and multivariate analyses produced markers with high classification accuracy in the derivation sample, the multivariate marker’s diagnostic performance in the replication samples was superior. Further, supplementary analysis showed its performance to be unaffected by the loss of key regions. Multivariate and univariate neuroimaging biomarkers of Alzheimer's disease  Christian Habeck, PhD, A Norman L. Foster, MD,B Robert Perneczky, MD,C Alexander Kurz, MD,C Panagiotis Alexopoulos, MD,CD Robert A. Koeppe, PhD Alexander Drzezga, MD,F and Yaakov Stern, PhDA  Neuroimage. 2008 May 1; 40(4): 1503–1515.

We propose a general theory of phenotyping based on broadly distributed multivariate markers as the metrics of classification and standard pattern recognition algorithms as the method of class discovery.  RE Mare, Phenotyping neurons with pattern recognition of molecular mixtures Signal Processing and Its Applications, 2003. Proceedings. Seventh International Symposium 1: 689 - 692, 1 - 4 July 2003   

occurrence biomarkers:
Reports an acute disorder. 

pharmacodynamic biomarkers: Pharmacodynamic biomarkers for molecular cancer therapeutics, D. Sarker and P Workman, Advances in Cancer Research 96: 213-268, 2007  

pharmacogenomics biomarkers:
 the importance of pharmacogenomics markers has been demonstrated through the correlation of specific genetic variations in the CYP450 family. See under genomic biomarkers

pharmacological biomarkers: Measurable biological parameters that serve for drug development, safety and dosing (DRUG MONITORING).  MeSH 2008  See also Drug safety

physiological biomarkers: Various physiological responses have been measured and utilized as biomarkers.  These include studies of such basic physiological functions as respiration, changes in growth rate, feeding, excretion, etc.  Physiological responses are used to provide integrated measures of an organisms well-being, based on a range of different functional attributes. An example of one such measure is growth.  Growth is an important fitness component of individual organisms, and may have an overall impact on the success of natural populations.  It is worth noting that although changes in a single fitness component may not always have a direct influence on the overall fitness of an individual, growth tends to integrate and reflect most sublethal effects. 

PK/PD markers: Pharmacokinetic/pharmacodynamic markers

plasma biomarkers: SEE serum biomarkers

predictive biomarkers:  It is within pivotal phase III clinical trials that predictive biomarkers have the greatest potential to affect clinical practice by targeting drugs under development to relevant patient subgroups. Predictive biomarkers can be integrated into phase III clinical trials by a variety of approaches, including trial designs that uncouple the processes and actively anticipate the emergence of new biomarkers during trial execution. Parallel paths to predictive biomarkers in oncology: Uncoupling of emergent biomarker development and phase III trial execution, Sikorski R, Yao B. Sci Transl Med. 2009 Dec 9;1(10):10ps11.

A biomarker that is present prior to an event occurring and which predicts that outcome. 

primary biomarkers: 
 In order to search for the specific biomarkers of patients with influenza-associated encephalopathy this article analyzed all metabolites in cerebrospinal fluid (CSF) by using metabolome analysis. In all metabolites, the peaks of two molecular weights, 246.0092 and 204.0611, were significantly higher than those in other diseases including influenza without convulsion (p < .05). Kawashima H, Oguchi M, Ioi H, Amaha M, Yamanaka G, Kashiwagi Y, Takekuma K, Yamazaki Y, Hoshika A, Watanabe Y., Primary biomarkers  in cerebral spinal fluid obtained from patients with influenza-associated encephalopathy analyzed by metabolomics, Int J Neurosci 116(8): 927- 936, 2006 Aug   Related term: secondary biomarkers

probable valid biomarker:  A biomarker that is measured in an analytical test system with well established performance characteristics, and for which there is a scientific framework or body of evidence that appears to elucidate the physiologic, toxicologic, pharmacologic, or clinical significance of the test results. A probable valid biomarker may not have reached the status of a known valid marker because, for example, of anyone of the following reasons: -- the data elucidating its significance may have been generated within a single company and may not be available for public scientific scrutiny., -- The data elucidating its significance, although highly suggest, may not be co conclusive. -- Independent verification of the results may not have occurred. Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations. 

prognostic biomarkers: provide information regarding outcome irrespective of therapy. ..Candidate prognostic biomarkers for breast cancer include elevated proliferation indices such as Ki-67 and proliferating cell nuclear antigen; estrogen receptor (ER) and progesterone receptor (PR) overexpression; markers of oncogene overexpression such as c-erbB-2, transforming growth factor-α (TGF-α), and EGFr; indicators of apoptotic imbalance, including overexpression of bcl-2 and an increased bax/bcl-2 ratio; markers of disordered cell signaling such as p53 nuclear protein accumulation; alteration of differentiation signals, such as overexpression of c-myc and related proteins; loss of differentiation markers, such as TGF-β II receptor and retinoic acid receptor; and alteration of angiogenesis proteins such as vascular endothelial growth factor (VEGF) overexpression. Molecular Biomarkers for Breast Cancer Prognosis: Coexpression of c-erbB-2 and p53 Samuel W. Beenken et al, Annals of Surgery 2001 May; 233(5): 630–638.  See also under biological markers 

protein biomarkers: The challenge that the protein biomarker field is facing today is translation into clinical applications, partially due to the complexity of serum/plasma mixtures, the relative immaturity of proteomics technologies, and the high costs and low speeds of validation. Biomarkers can be protein or proteomic, but need not be.  See also genomic biomarkers, metabolic biomarkers  Broader terms: biological markers, biomarkers   Related term: biosignatures

proteomic biomarkers: A protein expression pattern that is able to discriminate or predict. 

qualitative biomarkers: those present in one patient group but not another, and are thus easily found. Clinical Proteomics: From Diagnosis to Therapy  By Jennifer E. Van Eyk, Michael J. Dunn, Wiley VCH, 2008

quantitative biomarkers: present in different patient groups, in different degrees. ... whether single proteins or groups of proteins, require the use of statistical tests to assist in their discovery. Clinical Proteomics: From Diagnosis to Therapy  By Jennifer E. Van Eyk, Michael J. Dunn, Wiley VCH, 2008

reporter biomarkers: A biomarker that is present as a result of an event occurring. 

response biomarkers:  Herein, we discuss the state of the art on treatment response assessment. While the most mature technologies for response assessment involve radiographic tests such as CT and PET, reports are emerging on biomarkers used to monitor therapeutic efficacy. Potentially, response biomarkers represent a less expensive and more convenient means of monitoring therapy, although an ideal response biomarker has not yet been described. A framework for future response biomarker discovery is described.  Response biomarkers: re-envisioning the approach to tailoring drug therapy for cancer, Shahil Amin and Oliver F.  Bathe,  BMC Cancer201616:850 Published Nov 2016     

response variability in biomarkers:  Biomarkers can be inappropriately applied or misinterpreted, because the fundamental assumptions in exposure– response relations have not been considered. Factors causing temporal and spatial variability in biomarker responses are reviewed. These include numerous geochemical and biotic variables. The variation can be minimised by appropriate study site selection, experimental replication, multivariate epidemiological approaches, normalised controls, and temporal calibration of responses; so that the regulatory use of biomarkers for biomonitoring and tracking pollution events, including chronic or multiple exposures to complex mixtures is possible. RD Handy et. al, A proposal for the use of biomarkers for the assessment of chronic pollution and in regulatory toxicology, Ecotoxicology, 12 (1-4): 331-343 Feb. 2003

risk biomarkers: Risk biomarkers [for breast cancer] are those associated with increased cancer risk and include mammographic abnormalities, proliferative breast disease with or without atypia, family clustering, and inherited germ-line abnormalities. Molecular Biomarkers for Breast Cancer Prognosis: Coexpression of c-erbB-2 and p53 Samuel W. Beenken et al, Annals of Surgery 2001 May; 233(5): 630–638. 

Quantifiable, well-characterized cancer risk factors demonstrate the need for chemoprevention and define cohorts for chemopreventive intervention. For chemoprevention, the important cancer risk factors are those that can be measured quantitatively in the subject at risk. ... Generally, the risk biomarkers fit into categories based on those previously defined by Hulka: 1) carcinogen exposure, 2) carcinogen exposure/effect, 3) genetic predisposition, 4) intermediate biomarkers of cancer, and 5) previous cancers. Besides their use in characterizing cohorts for chemoprevention trials, some risk biomarkers can be modulated by chemopreventive agents. These biomarkers may be suitable surrogate endpoints for cancer incidence in chemoprevention intervention trials. Risk biomarkers and current strategies for cancer chemoprevention, Kelloff GJ et al , J Cell Biochem Suppl. 1996;25:1-14

RNA biomarkers: A huge number of human transcripts has been found that do not code for proteins, named non-protein coding RNAs. In most cases, small (miRNAs, snoRNAs) and long RNAs (antisense RNA, dsRNA, and long RNA species) have many roles, functioning as regulators of other mRNAs, at transcriptional and post-transcriptional level, and controlling protein ubiquitination and degradation. Various species of npcRNAs have been found differentially expressed in different types of cancer.  Massimo Mallardo , Palmiro Poltronieri, and Oscar Fernando D'Urso, Non-protein coding RNA biomarkers and differential expression in cancers: a review, Journal of Experimental & Clinical Cancer Research 2008, 27:19doi:10.1186/1756-9966-27-19  

safety biomarkers: Application of any new biomarker to support safety-related decisions during regulated phases of drug development requires provision of a substantial data set that critically assesses analytical and biological performance of that biomarker. Such an approach enables stakeholders from industry and regulatory bodies to objectively evaluate whether superior standards of performance have been met and whether specific claims of fit-for-purpose use are supported. Towards consensus practices to qualify safety biomarkers for use in early drug development. Sistare FD et. al, Nat Biotechnol. 2010 May;28(5):446-54. Epub 2010 May 10. 

Could be defined as the absence of any toxicity biomarkers. May not truly exist. 

secondary biomarkers: Secondary analytes are defined as analytes that, if present outside the reference range in addition to an out-of-range primary analyte, increase the risk that a specific disorder is present. A secondary analyte alone may not indicate a specific risk for the disorder in question. For simplicity, ratios of analytes are considered secondary biomarkers and are not listed. Naming and Counting Disorders (Conditions) Included in Newborn Screening Panels, Lawrence Sweetman, PhDa, David S. Millington, PhDb, Bradford L. Therrell, PhDc, W. Harry Hannon, PhDd, Bradley Popovich, PhDe, Michael S. Watson, PhDf, Marie Y. Mann, MD, MPHg, Michele A. Lloyd-Puryear, MD, PhDg and Peter C. van Dyck, MD, MPHg, PEDIATRICS Vol. 117 No. 5 May 2006, pp. S308-S314 (doi:10.1542/peds.2005-2633J)  Related terms: primary biomarkers, surrogate biomarkers, surrogate endpoints

ection biomarkers: Disease-associated analytes whose measurement is either an essential step in patient screening or the primary objective of a clinical trial. The public database contains information on most active phase III oncology clinical trials that can be examined for trends in the development of cancer therapies. But for selection biomarkers, such information is not easily accessible and so has not been examined in a comprehensive way. Here we provide a global analysis of selection biomarkers currently in use in the oncology phase III trial arena. Visualizing the Landscape of Selection Biomarkers in Current Phase III Oncology Clinical Trials, .Sikorski R, Yao B. Sci Transl Med. 2010 Jun 2;2(34):34ps27.

small molecule biomarkers: Compared to protein biomarkers, small molecule biomarkers (or metabolic biomarkers) are less species dependent. Therefore, data from animal studies with small molecule biomarkers should be translatable to the human condition. Small Molecule Biomarkers, Drumetix Laboratories, 2010 

SNP biomarkers: Genetic polymorphisms may constitute in-built determinants of individual differences in response to IFN-β. Prior attempts to identify such ‘predictors of response’ were hypothesis- driven in that they were based on preselection of candidate genes associated with Type I interferon pathways. In the present study, the authors performed the first ever nonbiased genome- wide association screen in an attempt to identify response-predictive SNPs.  Koen Vandenbroeck & Carlos Matute, Pharmacogenomics of the response to IFN-β in multiple sclerosis: ramifications from the first genome-wide screen, Pharmacogenomics, May 2008, Vol. 9, No. 5, Pages 639 - 645 (doi:10.2217/14622416.9.5.639)   Related terms: SNPs & genetic variations

staging biomarkers: Distinguishes between different stages of a chronic disorder. 

stratification biomarkers:  the use of biomarkers can help identifying patients that are more likely to respond favourably to a given therapy. Until now, biomarkers have been used in clinical practice to describe both normal and pathological conditions. Increasingly, they find application in order to stratify different patient groups in terms of clinical response, so as to develop personalised, preventive or therapeutic strategies.  Workshop "Stratification biomarkers in personalised medicine" European Commission Brussels June 10-11 2010 

surrogate biomarkers:  A “surrogate marker” can be defined as “a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy.”5 The primary difference between a biomarker and a surrogate marker is that a biomarker is a “candidate” surrogate marker, whereas a surrogate marker is a test used, and taken, as a measure of the effects of a specific treatment. Russell Katz, Biomarkers and Surrogate Markers: An FDA Perspective, NeuroRx 1(2): 189-195, April 2004 

Biomarker that reflects an indirect consequence of an event or disorder. Alternatively, secondary biomarker 

surrogate endpoint biomarkers:  tissue, cellular, or molecular alterations that occur between cancer initiation and progression. These biomarkers are used as end points in short-term chemoprevention trials. Molecular Biomarkers for Breast Cancer Prognosis: Coexpression of c-erbB-2 and p53 Samuel W. Beenken et al, Annals of Surgery 2001 May; 233(5): 630–638. 

surrogate endpoint marker:  The rare biomarker that can substitute (or be a surrogate) for a clinical end point, such as survival, stroke, fracture, or cancer recurrence.  Stephen M. Hewitt*, James Dear and Robert A. Star, Discovery of Protein Biomarkers for Renal Diseases, J Am Soc Nephrology 15:1677-1689, 2004 

surrogate endpoints:  are used instead of clinical outcomes in some clinical trials. Surrogate endpoints are used when the clinical outcomes might take a very long time to study, or in cases where the clinical benefit of improving the surrogate endpoint, such as controlling blood pressure, is well understood. Clinical trials are needed to show that surrogate endpoints can be relied upon to predict, or correlate with, clinical benefit. Surrogate endpoints that have undergone this testing are called validated surrogate endpoints and these are accepted by the FDA as evidence of benefit. Between 2010 and 2012, the FDA approved 45 percent of new drugs on the basis of a surrogate endpoint. .Surrogate Endpoint Resources for Drug and Biologic Development

Outcome measures that are not of direct practical importance but are believed to reflect outcomes that are important; for example, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart attacks. Surrogate endpoints are often physiological or biochemical markers that can be relatively quickly and easily measured, and that are taken as being predictive of important clinical outcomes. They are often used when observation of clinical outcomes requires long follow-up.  Cochran Collaborative Glossary .  Also called: Intermediary outcomes, Surrogate outcomes  Related terms: biomarkers, surrogate markers.  

surrogate markers: can be defined as “ …a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy.” The primary difference between a biomarker and a surrogate marker is that a biomarker is a “candidate” surrogate marker, whereas a surrogate marker is a test used, and taken, as a measure of the effects of a specific treatment. 5. Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 282: 790–795, 1999  Russell Katz, Biomarkers and Surrogate Markers: An FDA Perspective, NeuroRx. 2004 Apr; 1(2): 189–195. doi:  10.1602/neurorx.1.2.189  PMCID: PMC534924  PMID:15717019  Related terms: biomarkers, surrogate endpoints  

susceptibility biomarkers:: Include genetic factors which alter susceptibility to drugs and other chemicals. Biomarkers, Taylor & Francis, Aims & Scope  

target biomarkers: A biomarker that reflects the presence of a specific molecular drug target.   Related term: gene target: Drug Targets

therapeutic markers: become evident as the treatment of a chronic disease progresses in the patient. These markers are influenced by many factors, including individual nature of the disease, drug treatment, patient activities, etc. Proteomics-based Development of Biomarkers in Cardiovascular Disease Mechanistic, Clinical, and Therapeutic Insights Manuel Mayr et al., Molecular & Cellular Proteomics 5:1853-1864, 2006.

translational biomarkersThe pharmaceutical industry must find ways to improve the unacceptably high attrition rate during drug development. Clearly, pharma has moved away from treat-and-see testing of new drugs in patients, with a strong current focus on generating translational biomarkers early in the research process to enable more predictive evaluation of drug action in clinical trials. Underlying such a translational medicine approach is the intensive search for and use of high-quality biomarkers indicative of successful drug target engagement, pharmacological effects, efficacy or safety. From biomarker strategies to biomarker activities and back, van Gool AJ, Henry B, Sprengers ED.,  Drug Discov Today. 2010 Feb;15(3-4):121-6. Epub 2009 Nov 18.

tumor markers: Cancer  Related term: biological tumor markers

type 0 biomarkers: Markers of the natural history of a disease and correlate longitudinally with known clinical indices, such as symptoms over the full range of disease states.... Type 0 markers can be characterized in phase 0 clinical studies, in which a reliable assay is used in a well defined patient population for a specified period of time. Ideally, a linear (positive or negative) relationship is established with the 'gold standard' clinical assessor.  Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003    Related term: Regulatory phase zero 

type I biomarkers: Capture the effects of an intervention in accordance with the mechanism of action of a drug , even though the mechanism may not be associated with clinical outcome. ...A priori validation of Type I biomarkers is impossible for truly novel targets without an effective positive control treatment. By definition, the more innovative the target, the less validated will be the associated biomarkers.  Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580,

type II biomarkers: Are considered surrogate endpoints because a change in that marker predicts clinical benefit. ... Type II biomarkers (or surrogate end-points) must be relevant both to the mechanism of action of the drug and to the pathophysiology of the disease. Changes in the biomarker should reflect treatment benefit and therefore effective therapy is necessary for this validation. Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, J

valid biomarker: A  biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic, or clinical significance of test results. The classification of biomarkers is context specific. Likewise, validation of a biomarker is context-specific and the criteria for validation will vary with the intended use of the biomarker.  The clinical utility (e.g. predict toxicity, effectiveness or dosing) and use of epidemiology/ population data (e.g. strength of genotype- phenotype associations) are examples of approaches that can be used to determine the specific context the necessary criteria for validation.  Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA,  March 2005  Non-binding recommendations.    Narrower terms: known valid biomarker, probable valid biomarker  See also genomic biomarkers

validation - biomarkers:  Cancer Cancer biomarker validation distinguishes between analytical validation and clinical validation. 

Biomarker Resources
BEST Biomarkers, Endpoints and other tools Resources, NCBI Bookshelf 
Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework, Clinical Pharmacology and Therapeutics 69: 89- 95, 2001
Considerations in the evaluation of surrogate endpoints in clinical trials: Summary of a National Institutes of Health workshop, Controlled Clinical Trials 22¨485-502, 2001 
Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003
FDA, E15 definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories April 2008
IUPAC International Union of Pure and Applied Chemistry, GLOSSARY FOR CHEMISTS OF TERMS USED IN TOXICOLOGY Clinical Chemistry Division, Commission on Toxicology, Pure and Appl. Chem., 65 ( 9):  2003- 2122, 1993. 1200+ definitions.  

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IUPAC definitions are reprinted with the permission of the International Union of Pure and Applied Chemistry.

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