Biomarker (medicine)
Encyclopedia
In medicine, a biomarker is a term often used to refer to a protein measured in blood whose concentration reflects the severity or presence of some disease state. More generally a biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism.
A biomarker can be a substance that is introduced into an organism as a means to examine organ function or other aspects of health. For example, rubidium chloride
is used as a radioactive isotope to evaluate perfusion of heart muscle.
It can also be a substance whose detection indicates a particular disease state, for example, the presence of an antibody
may indicate an infection
. More specifically, a biomarker indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment.
Biomarkers are characteristic biological properties that can be detected and measured in parts of the body like the blood or tissue. They may indicate either normal or diseased processes in the body. Biomarkers can be specific cells, molecules, or genes, gene products, enzymes, or hormones. Complex organ functions or general characteristic changes in biological structures can also serve as biomarkers. Although the term biomarker is relatively new, biomarkers have been used in pre-clinical research and clinical diagnosis for a considerable time. For example, body temperature is a well-known biomarker for fever. Blood pressure is used to determine the risk of stroke. It is also widely known that cholesterol values are a biomarker and risk indicator for coronary and vascular disease, and that C-reactive protein (CRP
) is a marker for inflammation.
A biomarker is a parameter that can be used to measure the progress of disease or the effects of treatment. The parameter can be chemical, physical or biological. In molecular terms biomarker is "the subset of markers that might be discovered using genomics, proteomics technologies or imaging technologies. Biomarkers play major roles in medicinal biology. Biomarkers help in early diagnosis, disease prevention, drug target identification, drug response etc. Several biomarkers have been identified for many diseases such as serum LDL for cholesterol, blood pressure
, P53 gene and MMPs for cancer etc. Gene based biomarker is found to be an effective and acceptable marker in the present scientific world.
In addition to long-known parameters, such as those included and objectively measured in a blood count
, there are numerous novel biomarkers used in the various medical specialties. Currently, intensive work is taking place on the discovery and development of innovative and more effective biomarkers. These "new" biomarkers have become the basis for preventive medicine, meaning medicine that recognises diseases or the risk of disease early, and takes specific countermeasures to prevent the development of disease. Biomarkers are also seen as the key to personalised medicine, treatments individually tailored to specific patients for highly efficient intervention in disease processes. Often, such biomarkers indicate changes in metabolic processes.
The "classic" biomarker in medicine is a laboratory parameter that the doctor can use to help make decisions in making a diagnosis and selecting a course of treatment. For example, the detection of certain autoantibodies
in patient blood is a reliable biomarker for autoimmune disease
, and the detection of rheumatoid factor
s has been an important diagnostic marker for rheumatoid arthritis
(RA) for over 50 years.
For the diagnosis of this autoimmune disease
the antibodies against the bodies own citrullinated proteins are of particular value. These ACPAs
, (ACPA stands for Anti-citrullinated protein/peptide antibody) can be detected in the blood before the first symptoms of RA appear. They are thus highly valuable biomarkers for the early diagnosis of this autoimmune disease. In addition, they indicate if the disease threatens to be severe with serious damage to the bones and joints, which is an important tool for the doctor when providing a diagnosis and developing a treatment plan.
There are also more and more indications that ACPAs can be very useful in monitoring the success of treatment for RA. This would make possible the accurate use of modern treatments with biologicals. Physicians hope to soon be able to individually tailor rheumatoid arthritis treatments for each patient.
According to Häupl T. et al. prediction of response to treament will become the most important aim of biomarker research in medicine. With the growing number of new biological agents, there is increasing pressure to identify molecular parameters such as ACPAs that will not only guide the therapeutic decision but also help to define the most important targets for which new biological agents should be tested in clinical studies.
An NIH study group committed to the following definition in 1998: "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention."
In the past, biomarkers were primarily physiological indicators such as blood pressure or heart rate. More recently, biomarker is becoming a synonym for molecular biomarker, such as elevated prostate specific antigen as a molecular biomarker for prostate cancer, or using enzyme assays as liver function tests. There has recently been heightened interest in the relevance of biomarkers in oncology, including the role of KRAS in CRC and other EGFR-associated cancers. In patients whose tumors express the mutated KRAS gene, the KRAS protein, which forms part of the EGFR signaling pathway, is always ‘turned on’. This overactive EGFR signaling means that signaling continues downstream – even when the upstream signaling is blocked by an EGFR inhibitor, such as cetuximab (Erbitux) – and results in continued cancer cell growth and proliferation. Testing a tumor for its KRAS status (wild-type vs. mutant) helps to identify those patients who will benefit most from treatment with cetuximab.
Biomarkers also cover the use of molecular indicators of environmental exposure in epidemiologic studies such as human papilloma virus or certain markers of tobacco exposure such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). To date no biomarkers have been established for SCCHN.
such as survival or irreversible morbidity. If a treatment alters the biomarker, which has a direct connection to improved health, the biomarker serves as a surrogate endpoint
for evaluating clinical benefit.
Some of the main areas in which molecular biomarkers are used in the drug development process are: Early drug development studies, Safety studies, Proof of concept
studies, Molecular profiling.
Molecular biomarkers are often used in early drug development studies. For instance, they are used in phase I study for establishing doses and dosing regimen for future phase II studies. PD biomarkers are commonly observed to respond (either decrease or increase) proportionally with dose. This data, in conjunction with safety data, help determine doses for phase II studies.
In addition, Safety molecular biomarkers have been used for decades both in preclinical and clinical research
. Since these tests have become mainstream tests, they have been fully automated for both animal and human testing. Among the most common safety tests are those of liver function(e.g., transaminases, bilirubin, alkaline phosphatase
) and kidney function
(e.g., serum creatinine
, creatinine clearance, cystatin C). Others include markers of skeletal muscle
(e.g., myoglobin) or cardiac muscle
injury(e.g., CK-MB, troponin I or T), as well as bone biomarkers(e.g., bone-specific alkaline phosphatase).
A number of diseases, such as Alzheimer’s disease or rheumatoid arthritis, often begin with an early, symptom-free phase. In such symptom-free patients there may be more or less probability of actually developing symptoms. In these cases, biomarkers help to identify high-risk individuals reliably and in a timely manner so that they can either be treated before onset of the disease or as soon as possible thereafter.
In order to use a biomarker for diagnostics, the sample material must be as easy to obtain as possible. This may be a blood sample taken by a doctor, a urine or saliva sample, or a drop of blood like those diabetes patients extract from their own fingertips for regular blood-sugar monitoring.
For rapid initiation of treatment, the speed with which a result is obtained from the biomarker test is critical. A rapid test
, which delivers a result after only a few minutes, is optimal. This makes it possible for the physician to discuss with the patient how to proceed and if necessary to start treatment immediately after the test.
Naturally, the detection method for a biomarker must be accurate and as easy to carry out as possible. The results from different laboratories may not differ significantly from each other, and the biomarker must naturally have proven its effectiveness for the diagnosis, prognosis, and risk assessment of the affected diseases in independent studies.
A biomarker for clinical use needs good sensitivity
eg >=0.9, and good specificity
eg >=0.9 although they should be chosen with the population in mind so positive predictive value
and negative predictive value
are more relevant.
, bronchoalveolar lavage
, biopsy) and include nucleic acids-based biomarkers such as gene mutations or polymorphisms and quantitative gene expression
analysis, peptides, proteins, lipids metabolites, and other small molecules.
Biomarkers can also be classified based on their application such as diagnostic biomarkers (i.e., cardiac troponin for the diagnosis of myocardial infarction
), staging of disease biomarkers (i.e., brain natriuretic peptide
for congestive heart failure
), disease prognosis biomarkers (cancer biomarkers), and biomarkers for monitoring the clinical response to an intervention (HbAlc for antidiabetic treatment).
Another category of biomarkers includes those used in decision making in early drug development
. For instance, pharmacodynamic (PD) biomarkers are markers of a certain pharmacological response, which are of special interest in dose optimization studies.
and few recently using techniques are given below. Apart from genomics and proteomics platforms biomarker assay techniques, metabolomics, lipidomics, glycomics, and secretomics
are the most commonly used as techniques in identification of biomarkers.
2.Gene expression
3.SAGE
4.DNA Microarray
2.LS/MS
3.SELDI-TOF (or MALDI-TOF)
4.Ab Microarray
5.Tissue Microarray
of all metabolites in a biological sample. A related term, metabonomics, was introduced to refer specifically to the analysis of metabolic responses to drugs or diseases. Metabonomics become a major area of research it is the complex system
biological study,used as a to identify the biomarker for various disease. In general most of the disease case some of the metabolic pathway
had been activate or deactivated,this parameter can be used as a marker for some diseases. Serotonin production pathway activated in alcoholic drinking person it can be metabolic marker of recent alcohol consumption
.
, they have been traditionally difficult to study. However, improvements in new analytical platforms have made it possible to identify and to quantify most of lipids metabolites from a single sample. Three key platforms used for lipid profiling include mass spectrometry
, chromatography, and nuclear magnetic resonance.
Mass spectrometry was used to delineate the relative concentration and composition of high-density lipoproteins (HDL) particles from lipid extracts isolated from coronary bypass
patients and healthy volunteers. They found that HDL particles from coronary bypass patients contained significantly less sphingomyelin relative to phosphadidylcholine and higher triglycerides relative to cholesterol esters.
Lipidomic profiling was also used to study the effect of rosiglitazone, a PPARγ agonist, on lipid metabolism
on mice. Rosiglitazone was observed to alter lipid composition in different organs. It increased triglycérides accumulation in the liver; altered free fatty acids
in the heart, in the adipose tissue
, and in the heart; and reduced triglyceride levels in plasma.
Cardiac imaging is an active area of biomarker research. Coronary angiography, an invasive procedure requiring catheterization, has long been the gold standard for diagnosing arterial stenosis, but scientists and doctors hope to develop noninvasive techniques. Many believe that cardiac computed tomography
(CT) has great potential in this area, but researchers are still attempting to overcome problems related to “calcium blooming,” a phenomenon in which calcium deposits interfere with image resolution. Other intravascular imaging techniques involving magnetic resonance imaging
(MRI), optical coherence tomography
(OCT), and near infrared spectroscopy
are also being investigated.
Another new imaging biomarker involves radiolabeled fludeoxyglucose. Positron emission tomography
(PET) can be used to measure where in the body cells take up glucose. By tracking glucose, doctors can find sites of inflammation
because macrophages there take up glucose at high levels. Tumors also take up a lot of glucose, so the imaging strategy can be used to monitor them as well. Tracking radiolabeled glucose is a promising technique because it directly measures a step known to be crucial to inflammation and tumor growth.
An example from the 1980s demonstrates the pitfalls of depending too heavily on biomarkers. In the mid-1980s two new drugs, flecainide
and encainide
, were introduced to reduce ventricular arrhythmias in patients with histories of heart disease
. The drugs did indeed reduce arrhythmias. A large trial, the CAST trial, was undertaken to test the efficacy of the drugs, but the trial was stopped after a year because patients taking the drugs were found to be more than twice as likely to die as patients taking placebos. Flecainide and encainide were recalled in 1991. Their example demonstrates that improving a biomarker does not necessarily translate into increased survival.
A biomarker can be a substance that is introduced into an organism as a means to examine organ function or other aspects of health. For example, rubidium chloride
Rubidium chloride
Rubidium chloride is the alkali metal halide RbCl. This alkali halide finds diverse uses, from electrochemistry to molecular biology.-Structure:In its gas phase, RbCl is diatomic with a bond length estimated at 2.7868 Å...
is used as a radioactive isotope to evaluate perfusion of heart muscle.
It can also be a substance whose detection indicates a particular disease state, for example, the presence of an antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
may indicate an infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. More specifically, a biomarker indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment.
Biomarkers are characteristic biological properties that can be detected and measured in parts of the body like the blood or tissue. They may indicate either normal or diseased processes in the body. Biomarkers can be specific cells, molecules, or genes, gene products, enzymes, or hormones. Complex organ functions or general characteristic changes in biological structures can also serve as biomarkers. Although the term biomarker is relatively new, biomarkers have been used in pre-clinical research and clinical diagnosis for a considerable time. For example, body temperature is a well-known biomarker for fever. Blood pressure is used to determine the risk of stroke. It is also widely known that cholesterol values are a biomarker and risk indicator for coronary and vascular disease, and that C-reactive protein (CRP
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
) is a marker for inflammation.
A biomarker is a parameter that can be used to measure the progress of disease or the effects of treatment. The parameter can be chemical, physical or biological. In molecular terms biomarker is "the subset of markers that might be discovered using genomics, proteomics technologies or imaging technologies. Biomarkers play major roles in medicinal biology. Biomarkers help in early diagnosis, disease prevention, drug target identification, drug response etc. Several biomarkers have been identified for many diseases such as serum LDL for cholesterol, blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
, P53 gene and MMPs for cancer etc. Gene based biomarker is found to be an effective and acceptable marker in the present scientific world.
Disease-related Biomarkers and Drug-related Biomarkers
It is necessary to distinguish between disease-related and drug-related biomarkers. Disease-related biomarkers give an indication of the probable effect of treatment on patient (risk indicator or predictive biomarkers), if a disease already exists (diagnostic biomarker), or how such a disease may develop in an individual case regardless of the type of treatment (prognostic biomarker). Predictive biomarkers help to assess the most likely response to a particular treatment type, while prognostic markers shows the progression of disease with or without treatment. In contrast, drug-related biomarkers indicate whether a drug will be effective in a specific patient and how the patient’s body will process it.In addition to long-known parameters, such as those included and objectively measured in a blood count
Blood Count
"Blood Count" is a 1967 jazz composition by Billy Strayhorn. It was originally meant for a three-piece work Strayhorn was writing for Duke Ellington and initially titled "Blue Cloud". However, Strayhorn was hospitalized in 1967 due to cancer and finished the composition while in the hospital. He...
, there are numerous novel biomarkers used in the various medical specialties. Currently, intensive work is taking place on the discovery and development of innovative and more effective biomarkers. These "new" biomarkers have become the basis for preventive medicine, meaning medicine that recognises diseases or the risk of disease early, and takes specific countermeasures to prevent the development of disease. Biomarkers are also seen as the key to personalised medicine, treatments individually tailored to specific patients for highly efficient intervention in disease processes. Often, such biomarkers indicate changes in metabolic processes.
The "classic" biomarker in medicine is a laboratory parameter that the doctor can use to help make decisions in making a diagnosis and selecting a course of treatment. For example, the detection of certain autoantibodies
Autoantibody
An autoantibody is an antibody manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body"...
in patient blood is a reliable biomarker for autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
, and the detection of rheumatoid factor
Rheumatoid factor
Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...
s has been an important diagnostic marker for rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
(RA) for over 50 years.
For the diagnosis of this autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
the antibodies against the bodies own citrullinated proteins are of particular value. These ACPAs
Anti-citrullinated protein antibody
Anti-citrullinated protein antibodies or anti-cyclic citrullinated protein antibodies are autoantibodies that are frequently detected in the blood of rheumatoid arthritis patients...
, (ACPA stands for Anti-citrullinated protein/peptide antibody) can be detected in the blood before the first symptoms of RA appear. They are thus highly valuable biomarkers for the early diagnosis of this autoimmune disease. In addition, they indicate if the disease threatens to be severe with serious damage to the bones and joints, which is an important tool for the doctor when providing a diagnosis and developing a treatment plan.
There are also more and more indications that ACPAs can be very useful in monitoring the success of treatment for RA. This would make possible the accurate use of modern treatments with biologicals. Physicians hope to soon be able to individually tailor rheumatoid arthritis treatments for each patient.
According to Häupl T. et al. prediction of response to treament will become the most important aim of biomarker research in medicine. With the growing number of new biological agents, there is increasing pressure to identify molecular parameters such as ACPAs that will not only guide the therapeutic decision but also help to define the most important targets for which new biological agents should be tested in clinical studies.
An NIH study group committed to the following definition in 1998: "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention."
In the past, biomarkers were primarily physiological indicators such as blood pressure or heart rate. More recently, biomarker is becoming a synonym for molecular biomarker, such as elevated prostate specific antigen as a molecular biomarker for prostate cancer, or using enzyme assays as liver function tests. There has recently been heightened interest in the relevance of biomarkers in oncology, including the role of KRAS in CRC and other EGFR-associated cancers. In patients whose tumors express the mutated KRAS gene, the KRAS protein, which forms part of the EGFR signaling pathway, is always ‘turned on’. This overactive EGFR signaling means that signaling continues downstream – even when the upstream signaling is blocked by an EGFR inhibitor, such as cetuximab (Erbitux) – and results in continued cancer cell growth and proliferation. Testing a tumor for its KRAS status (wild-type vs. mutant) helps to identify those patients who will benefit most from treatment with cetuximab.
Biomarkers also cover the use of molecular indicators of environmental exposure in epidemiologic studies such as human papilloma virus or certain markers of tobacco exposure such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). To date no biomarkers have been established for SCCHN.
Biomarkers in Drug Development
Once a proposed biomarker has been validated, it can be used to diagnose disease risk, presence of disease in an individual, or to tailor treatments for the disease in an individual (choices of drug treatment or administration regimes). In evaluating potential drug therapies, a biomarker may be used as a surrogate for a natural endpointClinical endpoint
In a clinical research trial, a clinical endpoint generally refers to occurrence of a disease, symptom, sign or laboratory abnormality that constitutes one of the target outcomes of the trial, but may also refer to any such disease or sign that strongly motivates the withdrawal of that individual...
such as survival or irreversible morbidity. If a treatment alters the biomarker, which has a direct connection to improved health, the biomarker serves as a surrogate endpoint
Surrogate endpoint
In clinical trials, a surrogate endpoint is a measure of effect of a certain treatment that may correlate with a real clinical endpoint but doesn't necessarily have a guaranteed relationship...
for evaluating clinical benefit.
Some of the main areas in which molecular biomarkers are used in the drug development process are: Early drug development studies, Safety studies, Proof of concept
Proof of concept
A proof of concept or a proof of principle is a realization of a certain method or idea to demonstrate its feasibility, or a demonstration in principle, whose purpose is to verify that some concept or theory that has the potential of being used...
studies, Molecular profiling.
Molecular biomarkers are often used in early drug development studies. For instance, they are used in phase I study for establishing doses and dosing regimen for future phase II studies. PD biomarkers are commonly observed to respond (either decrease or increase) proportionally with dose. This data, in conjunction with safety data, help determine doses for phase II studies.
In addition, Safety molecular biomarkers have been used for decades both in preclinical and clinical research
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
. Since these tests have become mainstream tests, they have been fully automated for both animal and human testing. Among the most common safety tests are those of liver function(e.g., transaminases, bilirubin, alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
) and kidney function
Renal physiology
Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including reabsorption of glucose, amino acids, and other small molecules; regulation of sodium, potassium, and other electrolytes; regulation of fluid balance and blood pressure;...
(e.g., serum creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
, creatinine clearance, cystatin C). Others include markers of skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
(e.g., myoglobin) or cardiac muscle
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
injury(e.g., CK-MB, troponin I or T), as well as bone biomarkers(e.g., bone-specific alkaline phosphatase).
Biomarker requirements
For chronic diseases, whose treatment may require patients to take medications for years, accurate diagnosis is particularly important, especially when strong side effects are expected from the treatment. In these cases, biomarkers are becoming more and more important, because they can confirm a difficult diagnosis or even make it possible in the first place.A number of diseases, such as Alzheimer’s disease or rheumatoid arthritis, often begin with an early, symptom-free phase. In such symptom-free patients there may be more or less probability of actually developing symptoms. In these cases, biomarkers help to identify high-risk individuals reliably and in a timely manner so that they can either be treated before onset of the disease or as soon as possible thereafter.
In order to use a biomarker for diagnostics, the sample material must be as easy to obtain as possible. This may be a blood sample taken by a doctor, a urine or saliva sample, or a drop of blood like those diabetes patients extract from their own fingertips for regular blood-sugar monitoring.
For rapid initiation of treatment, the speed with which a result is obtained from the biomarker test is critical. A rapid test
Point-of-care testing
Point-of-care testing is defined as medical testing at or near the site of patient care. The driving notion behind POCT is to bring the test conveniently and immediately to the patient. This increases the likelihood that the patient, physician, and care team will receive the results quicker,...
, which delivers a result after only a few minutes, is optimal. This makes it possible for the physician to discuss with the patient how to proceed and if necessary to start treatment immediately after the test.
Naturally, the detection method for a biomarker must be accurate and as easy to carry out as possible. The results from different laboratories may not differ significantly from each other, and the biomarker must naturally have proven its effectiveness for the diagnosis, prognosis, and risk assessment of the affected diseases in independent studies.
A biomarker for clinical use needs good sensitivity
Sensitivity
Stimulus|Sensitivity may refer to:* Sensitivity , the ability to react to a stimulus* Sensitivity , the strength of physical or emotional reaction in people* Sensitivity , variations in process dynamics and control systems...
eg >=0.9, and good specificity
Specificity
Specificity may refer to:* Being specific * Specificity , the proportion of negatives in a binary classification test which are correctly identified...
eg >=0.9 although they should be chosen with the population in mind so positive predictive value
Positive predictive value
In statistics and diagnostic testing, the positive predictive value, or precision rate is the proportion of subjects with positive test results who are correctly diagnosed. It is a critical measure of the performance of a diagnostic method, as it reflects the probability that a positive test...
and negative predictive value
Negative predictive value
In statistics and diagnostic testing, the negative predictive value is a summary statistic used to describe the performance of a diagnostic testing procedure. It is defined as the proportion of subjects with a negative test result who are correctly diagnosed. A high NPV means that when the test...
are more relevant.
Biomarker classification and application
Biomarkers can be classified based on different parameters. They can be classified based on their characteristics such as imaging biomarkers (CT, PET, MRI) or molecular biomarkers. Molecular biomarkers can be used to refer to nonimaging biomarkers that have biophysical properties, which allow their measurements in biological samples (e.g., plasma, serum, cerebrospinal fluidCerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
, bronchoalveolar lavage
Bronchoalveolar lavage
Bronchoalveolar lavage is a medical procedure in which a bronchoscope is passed through the mouth or nose into the lungs and fluid is squirted into a small part of the lung and then recollected for examination. BAL is typically performed to diagnose lung disease...
, biopsy) and include nucleic acids-based biomarkers such as gene mutations or polymorphisms and quantitative gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
analysis, peptides, proteins, lipids metabolites, and other small molecules.
Biomarkers can also be classified based on their application such as diagnostic biomarkers (i.e., cardiac troponin for the diagnosis of myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
), staging of disease biomarkers (i.e., brain natriuretic peptide
Brain natriuretic peptide
Brain natriuretic peptide , now known as B-type natriuretic peptide or GC-B, is a 32 amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells...
for congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
), disease prognosis biomarkers (cancer biomarkers), and biomarkers for monitoring the clinical response to an intervention (HbAlc for antidiabetic treatment).
Another category of biomarkers includes those used in decision making in early drug development
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
. For instance, pharmacodynamic (PD) biomarkers are markers of a certain pharmacological response, which are of special interest in dose optimization studies.
Types
Biomarkers validated by genetic and molecular biology methods can be classified into three types.- Type 0 - Natural history markers
- Type 1 - Drug activity markers
- Type 2 - Surrogate markers
Discovery of molecular biomarker
Molecular biomarkers have been defined as biomarkers that can be discovered using basic and acceptable platforms such as genomics and proteomics.Many genomic and proteomics techniques are available for biomarker discoveryBiomarker discovery
Biomarker discovery is the process by which biomarkers are discovered. It is a medical term.Many commonly used blood tests in medicine are biomarkers. The way that these tests have been found can be seen as biomarker discovery. However, their identification has mostly been a one-at-a time approach...
and few recently using techniques are given below. Apart from genomics and proteomics platforms biomarker assay techniques, metabolomics, lipidomics, glycomics, and secretomics
Secretomics
Secretomics is a subset of proteomics in which all of the secreted proteins of a cell, tissue, or organism are analyzed. Secreted proteins are involved in a variety of physiological processes, including cell signaling and matrix remodeling, but are also integral to invasion and metastasis of...
are the most commonly used as techniques in identification of biomarkers.
Genomic Approach
1.Northern blotNorthern blot
The northern blot is a technique used in molecular biology research to study gene expression by detection of RNA in a sample. With northern blotting it is possible to observe cellular control over structure and function by determining the particular gene expression levels during differentiation,...
2.Gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
3.SAGE
Serial Analysis of Gene Expression
Serial analysis of gene expression is a technique used by molecular biologists to produce a snapshot of the messenger RNA population in a sample of interest in the form of small tags that correspond to fragments of those transcripts. The original technique was developed by Dr. Victor Velculescu...
4.DNA Microarray
DNA microarray
A DNA microarray is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome...
Proteomic Approach
1.2D-PAGE2.LS/MS
3.SELDI-TOF (or MALDI-TOF)
4.Ab Microarray
5.Tissue Microarray
Tissue microarray
Tissue microarrays consist of paraffin blocks in which up to 1000 separate tissue cores are assembled in array fashion to allow multiplex histological analysis.-History:...
Metabolomics Approach
The term metabolomics has been recently introduced to address the global analysisDifferential geometry and topology
Differential geometry is a mathematical discipline that uses the techniques of differential and integral calculus, as well as linear and multilinear algebra, to study problems in geometry. The theory of plane and space curves and of surfaces in the three-dimensional Euclidean space formed the basis...
of all metabolites in a biological sample. A related term, metabonomics, was introduced to refer specifically to the analysis of metabolic responses to drugs or diseases. Metabonomics become a major area of research it is the complex system
Complex system
A complex system is a system composed of interconnected parts that as a whole exhibit one or more properties not obvious from the properties of the individual parts....
biological study,used as a to identify the biomarker for various disease. In general most of the disease case some of the metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
had been activate or deactivated,this parameter can be used as a marker for some diseases. Serotonin production pathway activated in alcoholic drinking person it can be metabolic marker of recent alcohol consumption
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
.
Lipidomics Approach
Lipidomics refers to the analysis of lipids. Since lipids have unique physical propertiesPhysical property
A physical property is any property that is measurable whose value describes a physical system's state. The changes in the physical properties of a system can be used to describe its transformations ....
, they have been traditionally difficult to study. However, improvements in new analytical platforms have made it possible to identify and to quantify most of lipids metabolites from a single sample. Three key platforms used for lipid profiling include mass spectrometry
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
, chromatography, and nuclear magnetic resonance.
Mass spectrometry was used to delineate the relative concentration and composition of high-density lipoproteins (HDL) particles from lipid extracts isolated from coronary bypass
Coronary artery bypass surgery
Coronary artery bypass surgery, also coronary artery bypass graft surgery, and colloquially heart bypass or bypass surgery is a surgical procedure performed to relieve angina and reduce the risk of death from coronary artery disease...
patients and healthy volunteers. They found that HDL particles from coronary bypass patients contained significantly less sphingomyelin relative to phosphadidylcholine and higher triglycerides relative to cholesterol esters.
Lipidomic profiling was also used to study the effect of rosiglitazone, a PPARγ agonist, on lipid metabolism
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
on mice. Rosiglitazone was observed to alter lipid composition in different organs. It increased triglycérides accumulation in the liver; altered free fatty acids
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
in the heart, in the adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
, and in the heart; and reduced triglyceride levels in plasma.
Imaging biomarkers
Many new biomarkers are being developed that involve imaging technology. Imaging biomarkers have many advantages. They are usually noninvasive, and they produce intuitive, multidimensional results. Yielding both qualitative and quantitative data, they are usually relatively comfortable for patients. When combined with other sources of information, they can be very useful to clinicians seeking to make a diagnosis.Cardiac imaging is an active area of biomarker research. Coronary angiography, an invasive procedure requiring catheterization, has long been the gold standard for diagnosing arterial stenosis, but scientists and doctors hope to develop noninvasive techniques. Many believe that cardiac computed tomography
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(CT) has great potential in this area, but researchers are still attempting to overcome problems related to “calcium blooming,” a phenomenon in which calcium deposits interfere with image resolution. Other intravascular imaging techniques involving magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI), optical coherence tomography
Optical coherence tomography
Optical coherence tomography is an optical signal acquisition and processing method. It captures micrometer-resolution, three-dimensional images from within optical scattering media . Optical coherence tomography is an interferometric technique, typically employing near-infrared light...
(OCT), and near infrared spectroscopy
Near infrared spectroscopy
Near-infrared spectroscopy is a spectroscopic method that uses the near-infrared region of the electromagnetic spectrum...
are also being investigated.
Another new imaging biomarker involves radiolabeled fludeoxyglucose. Positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET) can be used to measure where in the body cells take up glucose. By tracking glucose, doctors can find sites of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
because macrophages there take up glucose at high levels. Tumors also take up a lot of glucose, so the imaging strategy can be used to monitor them as well. Tracking radiolabeled glucose is a promising technique because it directly measures a step known to be crucial to inflammation and tumor growth.
Potential disadvantages
Not all biomarkers should be used as surrogate endpoints to assess clinical outcomes. Biomarkers can be difficult to validate and require different levels of validation depending on their intended use. If a biomarker is to be used to measure the success of a therapeutic intervention, the biomarker should reflect a direct effect of that intervention.An example from the 1980s demonstrates the pitfalls of depending too heavily on biomarkers. In the mid-1980s two new drugs, flecainide
Flecainide
Flecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias . It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation , paroxysmal supraventricular tachycardia Flecainide acetate is a class Ic antiarrhythmic agent used to...
and encainide
Encainide
Encainide is a class Ic antiarrhythmic agent. It is no longer used because its frequent proarrhythmic side effects....
, were introduced to reduce ventricular arrhythmias in patients with histories of heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
. The drugs did indeed reduce arrhythmias. A large trial, the CAST trial, was undertaken to test the efficacy of the drugs, but the trial was stopped after a year because patients taking the drugs were found to be more than twice as likely to die as patients taking placebos. Flecainide and encainide were recalled in 1991. Their example demonstrates that improving a biomarker does not necessarily translate into increased survival.
External links
- The latest news about oncology biomarkers
- Biomarkers Study goes on: An article
- Biomarkers Schizophrenia proteomics: biomarkers on the path to laboratory medicine?
- Environmental Biomarkers Initiative at Pacific Northwest National Laboratory
- Biomarkers in Medicine journal
- Center for Integration of Medicine and Innovative Technology
- Dmarker -- A Bio-Marker Inference System for Human Diseases
- BIO-NMD: Research into biomarkers for neuromuscular disease