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PubMed2005

Biomarkers for systemic lupus erythematosus: a review and perspective.

PURPOSE OF REVIEW: Despite decades of extensive work in the understanding of the etiopathogenesis of systemic lupus erythematosus, few biomarkers have been validated and widely accepted for this disease. The lack of reliable, specific biomarkers not only hampers clinical management of systemic lupus erythematosus but also impedes development of new therapeutic agents. This paper reviews briefly the historical aspects of systemic lupus erythematosus biomarkers and summarizes recent studies on candidate biomarkers. RECENT FINDINGS: Recognizing the urgent need for lupus biomarkers, a Lupus Biomarker Working Group has recently been initiated to facilitate collaborative efforts aimed at identifying and validating biomarkers for systemic lupus erythematosus. Based on available data, several laboratory markers have shown promise as biomarkers for susceptibility, diagnosis, and disease activity. These include Fc receptor genes (disease susceptibility), complement C4d-bound erythrocytes (diagnosis or disease activity), CD27 plasma cells (disease activity), 'interferon signature' (disease activity), and anti-C1q antibodies (disease activity and organ involvement). SUMMARY: There is a longstanding and recently rejuvenated enthusiasm for biomarkers that precisely and specifically reflect the pathophysiologic and clinical changes in systemic lupus erythematosus. Promising candidate biomarkers have been identified but must still be validated through rigorous, large-scale multicenter studies.

Biomarkers↗

PubMedDate not supplied

Biomarker amplification by serum carrier protein binding.

Mass spectroscopic analysis of the low molecular mass (LMM) range of the serum/plasma proteome is a rapidly emerging frontier for biomarker discovery. This study examined the proportion of LMM biomarkers, which are bound to circulating carrier proteins. Mass spectroscopic analysis of human serum following molecular mass fractionation, demonstrated that the majority of LMM biomarkers exist bound to carrier proteins. Moreover, the pattern of LMM biomarkers bound specifically to albumin is distinct from those bound to non-albumin carriers. Prominent SELDI-TOF ionic species (m/z 6631.7043) identified to correlate with the presence of ovarian cancer were amplified by albumin capture. Several insights emerged: a) Accumulation of LMM biomarkers on circulating carrier proteins greatly amplifies the total serum/plasma concentration of the measurable biomarker, b) The total serum/plasma biomarker concentration is largely determined by the carrier protein clearance rate, not the unbound biomarker clearance rate itself, and c) Examination of the LMM species bound to a specific carrier protein may contain important diagnostic information. These findings shift the focus of biomarker detection to the carrier protein and its biomarker content.

Biomarkers↗

PubMed2006

Vascular biomarkers and surrogates in cardiovascular disease.

Cardiovascular biomarker research efforts have resulted in the identification of new risk factors and novel drug targets, as well as the establishment of treatment guidelines. Government agencies, academic research institutions, diagnostic industries, and pharmaceutical companies all recognize the importance of biomarkers in advancing therapies to improve public health. In drug development, biomarkers are used to evaluate early signals of efficacy and safety, to select dose, and to identify the target population. The United States Food and Drug Administration has relied on biomarkers to support clinical applications in many therapeutic fields, including cardiovascular disease. The appropriate application of cardiovascular biomarkers requires an understanding of disease natural history, the mechanism of the intervention, and the characteristics and limitations of the biomarker. Channels of communication among researcher, developer, and regulator must remain open to maximize the success of future biomarker efforts. In 2003, 2004, and 2005, an international panel of cardiovascular biomarker experts convened at the "Cardiovascular Biomarker and Surrogate Endpoints Symposia" held in Bethesda, Md, to discuss the use of biomarkers in the development of improved cardiovascular diagnostics and therapeutics. The information presented in the present report summarizes the authors' perspective distilled from these proceedings.

Atherosclerosis↗

PubMed2006

Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.

IMPACT: This study explores the use of measuring plasma biomarkers at exacerbation of chronic obstructive pulmonary disease (COPD), providing insight into the underlying pathogenesis of these important events. RATIONALE: The use of measuring C-reactive protein (CRP) to confirm exacerbation, or to assess exacerbation severity, in COPD is unclear. Furthermore, it is not known whether there may be more useful systemic biomarkers. OBJECTIVE: To assess the use of plasma biomarkers in confirming exacerbation and predicting exacerbation severity. METHODS: We assessed 36 biomarkers in 90 paired baseline and exacerbation plasma samples from 90 patients with COPD. The diagnosis of exacerbation fulfilled both health care use and symptom-based criteria. Biomarker concentrations were related to clinical indices of exacerbation severity. Interrelationships between biomarkers were examined to gain information on mechanisms of systemic inflammation at exacerbation of COPD. MEASUREMENTS AND MAIN RESULTS: To confirm the diagnosis of exacerbation, the most selective biomarker was CRP. However, this was neither sufficiently sensitive nor specific alone (area under the receiver operating characteristic curve [AUC], 0.73; 95% confidence interval, 0.66-0.80). The combination of CRP with any one increased major exacerbation symptom recorded by the patient on that day (dyspnea, sputum volume, or sputum purulence) significantly increased the AUC to 0.88 (95% confidence interval, 0.82-0.93; p<0.0001). There were no significant relationships between biomarker concentrations and clinical indices of exacerbation severity. Interrelationships between biomarkers suggest that the acute-phase response is related, separately, to monocytic and lymphocytic-neutrophilic pathways. CONCLUSIONS: Plasma CRP concentration, in the presence of a major exacerbation symptom, is useful in the confirmation of COPD exacerbation. Systemic biomarkers were not helpful in predicting exacerbation severity. The acute-phase response at exacerbation was most strongly related to indices of monocyte function.

Aged↗

PubMed2003

Biomarkers, validation and pharmacokinetic-pharmacodynamic modelling.

Four elements are crucial to successful pharmacokinetic-pharmacodynamic (PK/PD) modelling and simulation for efficient and effective rational drug development: (i) mechanism-based biomarker selection and correlation to clinical endpoints; (ii) quantification of drug and/or metabolites in biological fluids under good laboratory practices (GLP); (iii) GLP-like biomarker method validation and measurements and; (iv) mechanism-based PK/PD modelling and validation. Biomarkers can provide great predictive value in early drug development if they reflect the mechanism of action for the intervention even if they do not become surrogate endpoints. PK/PD modelling and simulation can play a critical role in this process. Data from genomic and proteomics differentiating healthy versus disease states lead to biomarker discovery and identification. Multiple genes control complex diseases via hosts of gene products in biometabolic pathways and cell/organ signal transduction. Pilot exploratory studies should be conducted to identify pivotal biomarkers to be used for predictive clinical assessment of disease progression and the effect of drug intervention. Most biomarkers are endogenous macromolecules, which could be measured in biological fluids. Many exist in heterogeneous forms with varying activity and immunoreactivity, posting challenges for bioanalysis. Reliable and selective assays could be validated under a GLP-like environment for quantitative methods. While the need for consistent reference standards and quality control monitoring during sample analysis for biomarker assays are similar to that of drug molecules, many biomarkers have special requirements for sample collection that demand a well coordinated team management. Bioanalytical methods should be validated to meet study objectives at various drug development stages, and possess adequate performance to quantify biochemical responses specific to the target disease progression and drug intervention. Protocol design to produce sufficient data for PK/PD modelling would be more complex than that of PK. Knowledge of mechanism from discovery and preclinical studies are helpful for planning clinical study designs in cascade, sequential, crossover or replicate mode. The appropriate combination of biomarker identification and selection, bioanalytical methods development and validation for drugs and biomarkers, and mechanism-based PK/PD models for fitting data and predicting future clinical endpoints/outcomes provide powerful insights and guidance for effective and efficient rational drug development, toward safe and efficacious medicine for individual patients.

Biomarkers↗

PubMed2003

A preliminary analysis of non-small cell lung cancer biomarkers in serum.

OBJECTIVE: To identify potential serum biomarkers that could be used to discriminate lung cancers from normal. METHODS: Proteomic spectra of twenty-eight serum samples from patients with non-small cell lung cancer and twelve from normal individuals were generated by SELDI (Surfaced Enhanced Laser Desorption/Ionization) Mass Spectrometry. Anion-exchange columns were used to fractionate the sera into 6 designated pH groups. Two different types of protein chip arrays, IMAC-Cu and WCX2, were employed. Samples were examined in PBSII Protein Chip Reader (Ciphergen Biosystem Inc) and the discriminatory profiling between cancer and normal samples was analyzed with Biomarker Pattern software. RESULTS: Five distinct potential lung cancer biomarkers with higher sensitivity and specificity were found, with four common biomarkers in both IMAC-Cu and WCX2 chip; the remaining biomarker occurred only in WCX2 chip. Two biomarkers were up-regulated while three biomarkers were down-regulated in the serum samples from patients with non-small cell lung cancer. The sensitivities provided by the individual biomarkers were 75%-96.43% and specificities were 75%-100%. CONCLUSIONS: The preliminary results suggest that serum is a capable resource for detecting specific non-small cell lung cancer biomarkers. SELDI mass spectrometry is a useful tool for the detection and identification of new potential biomarker of non-small cell lung cancer in serum.

Adult↗

PubMed2003

A parametric empirical Bayes method for cancer screening using longitudinal observations of a biomarker.

A revolution in molecular technology is leading to the discovery of many biomarkers of disease. Monitoring these biomarkers in a population may lead to earlier disease detection, and may prevent death from diseases like cancer that are more curable if found early. For markers whose concentration is associated with disease progression the earliest detection is achieved by monitoring the marker with an algorithm able to detect very small changes. One strategy is to monitor the biomarkers using a longitudinal algorithm that incorporates a subject's screening history into screening decisions. Longitudinal algorithms that have been proposed thus far rely on modeling the behavior of a biomarker from the moment of disease onset until its clinical presentation. Because the data needed to observe the early pre-clinical behavior of the biomarker may take years to accumulate, those algorithms are not appropriate for timely development using new biomarker discoveries. This manuscript presents a computationally simple longitudinal screening algorithm that can be implemented with data that is obtainable in a short period of time. For biomarkers meeting only a few modest assumptions our algorithm uniformly improves the sensitivity compared with simpler screening algorithms but maintains the same specificity. It is unclear what performance advantage more complex methods may have compared with our method, especially when there is doubt about the correct model for describing the behavior of the biomarker early in the disease process. Our method was specifically developed for use in screening for cancer with a new biomarker, but it is appropriate whenever the pre-clinical behavior of the disease and/or biomarker is uncertain.

Algorithms↗

PubMed2006

Imaging biomarkers as surrogate endpoints for drug development.

The employment of biomarkers (including imaging biomarkers, especially PET) in drug development has gained increasing attention during recent years. This has been partly stimulated by the hope that the integration of biomarkers into drug development programmes may be a means to increase the efficiency and effectiveness of the drug development process by early identification of promising drug candidates--thereby counteracting the rising costs of drug development. More importantly, however, the interest in biomarkers for drug development is the logical consequence of recent advances in biosciences and medicine which are leading to target-specific treatments in the framework of "personalized medicine". A considerable proportion of target-specific drugs will show effects in subgroups of patients only. Biomarkers are a means to identify potential responders, or patient subgroups at risk for specific side-effects. Biomarkers are used in early drug development in the context of translational medicine to gain information about the drug's potential in different patient groups and disease states. The information obtained at this stage is mainly important for designing subsequent clinical trials and to identify promising drug candidates. Biomarkers in later phases of clinical development may--if properly validated--serve as surrogate endpoints for clinical outcomes. Regulatory agencies in the EU and the USA have facilitated the use of biomarkers early in the development process. The validation of biomarkers as surrogate endpoints is part of FDA's "critical path initiative".

Biomarkers↗

PubMed2006

Fit-for-purpose method development and validation for successful biomarker measurement.

Despite major advances in modern drug discovery and development, the number of new drug approvals has not kept pace with the increased cost of their development. Increasingly, innovative uses of biomarkers are employed in an attempt to speed new drugs to market. Still, widespread adoption of biomarkers is impeded by limited experience interpreting biomarker data and an unclear regulatory climate. Key differences preclude the direct application of existing validation paradigms for drug analysis to biomarker research. Following the AAPS 2003 Biomarker Workshop (J. W. Lee, R. S. Weiner, J. M. Sailstad, et al. Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development. A conference report. Pharm Res 22:499-511, 2005), these and other critical issues were addressed. A practical, iterative, "fit-for-purpose" approach to biomarker method development and validation is proposed, keeping in mind the intended use of the data and the attendant regulatory requirements associated with that use. Sample analysis within this context of fit-for-purpose method development and validation are well suited for successful biomarker implementation, allowing increased use of biomarkers in drug development.

Biomarkers↗

PubMed2006

Carboxyhemoglobin and thiocyanate as biomarkers of exposure to carbon monoxide and hydrogen cyanide in tobacco smoke.

The determination of biomarkers in human body fluids is a useful tool, which allows the quantitative assessment of the exposure to chemicals or complex mixtures of chemicals and of early biological effects as a result of the exposure. Biomarkers require validation before their successful application in human studies. This review describes some general purposes of human biomonitoring and biomarkers including the requirements for validation. Risk assessment and harm reduction of smoking and tobacco products, respectively, is a very suitable field for the application of biomarkers. A brief historical review shows that the application of biomarkers of exposure and effect in human smoking goes back more than 150 years. Two 'classical' biomarkers of exposure to tobacco, namely carboxyhemoglobin (COHb and its equivalent carbon monoxide in exhalate, COex) and thiocyanate (SCN) in body fluids are discussed in terms of sources of exposure, metabolism, disposition kinetics and influencing host factors. Data on COHb/COex and SCN in nonsmokers and smokers as well as the power to discriminate between smokers and nonsmokers are presented. Both biomarkers are significantly correlated with the daily cigarette consumption. Smoking machine-derived yields of the precursors carbon monoxide and hydrogen cyanide were not correlated with COHb/COex and SCN, respectively. It is concluded that, while COHb/COex is a useful biomarker for assessing the smoke inhalation, preferably in controlled studies, the application of SCN in body fluids as a biomarker for smoking is limited, mainly due to the abundance of other sources for SCN.

Biomarkers↗

PubMed2000

The use of biomarkers to assess the impact of pollution in coastal environments of the Iberian Peninsula: a practical approach.

Within the frame of the 2nd Iberian Congress of Environmental Contamination and Toxicology (University of the Basque Country, Leioa, June 1998) a workshop was held about the use of biomarkers in marine pollution monitoring. Among others, the following biomarkers received special attention: metallothionein induction, acetylcholinesterase inhibition, cytochrome P450 system induction, imposex, lysosomal enlargement and lysosomal membrane destabilisation, and peroxisome proliferation. These biomarkers can be used to evaluate exposure to and effect of different contaminants (metals, organic xenobiotics and organometallic compounds) and they can be measured using different methodological approaches (biochemistry, cytochemistry, immunochemical methods based on the use of biotechnology). Before the application of a set of biomarkers in pollution monitoring programmes, well-defined protocols of Quality Assurance have to be established to allow adequate comparison of results. It is also necessary to include analysis of standard reference materials and to obtain detailed knowledge of basal values and seasonal variations of the biomarkers in various species, as well as to integrate the information obtained with the different biomarkers. Marine bivalve molluscs such as mussels are appropriate sentinel species for most of the biomarkers proposed except for the induction of the cytochrome P450 system, which should be measured in fish, and the degree of imposex, which is a biomarker of exposure to TBT specifically measured in certain gastropod molluscs. As a result of the workshop, a battery of biomarkers of contaminant exposure and effects are proposed that could be incorporated into programmes monitoring the quality of the coastal environment in the Iberian Peninsula. These measures would be undertaken in conjunction with chemical measures of contaminant burdens in selected sentinel species.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

Biomarker responses in human populations: towards a worldwide map.

The discipline of epidemiology studies the determinants of diseases in human populations, identifies causes, determines outcomes and develops prevention strategies. Traditional epidemiology is most useful for studies of acute, relatively common diseases with short incubation periods but less so for studies of chronic low incidence diseases with long incubation periods. Molecular epidemiology, which employs biological responses or biomarkers as surrogates of exposures or effects, can help with the latter. For this reason, there is a great interest in developing and validating biomarkers. DNA damage underlies an important group of chronic diseases with long incubation periods, i.e., cancer. Biomarkers may measure the exposures that induce the DNA damage, the damage itself, or individual susceptibility to damage. Before they can be used for human population research, however, these measures must be validated. Biomarker validation critically depends on field studies. This is accomplished through transitional epidemiological studies that 'bridge the gap' between laboratory and field. Transitional epidemiological studies are of three varieties: (i) Developmental, (ii) Characterization, and (iii) Applied. Biomarkers are the dependent variables in transitional studies. An international network of laboratories for human population monitoring requires yet another dimension for validation, i.e., the comparability of results among laboratories must be determined. This will be achieved by sample sharing projects, with workshops to compare results. Only then can results in one population be compared with results in another. Interlaboratory standardization of assays for biomarkers validated by transitional studies will have far-reaching benefits. It will allow development of worldwide databases of background values for the various biomarkers-or biomarker maps. This, in turn, will facilitate problem identification and eventually constitute the baselines for area-specific population monitoring. Biomarker databases so developed can be compared with worldwide databases for cancer and heritable diseases, validating the former as statistical surrogates of the latter.

Biomarkers↗

PubMed2005

Alkoxyresorufin-O-deethylase activities and polychlorinated biphenyl patterns in shrews as biomarkers in environmental risk assessments: sensitivity and specificity.

Alkoxyresorufin-O-deethylase (AROD) biomarkers are useful indicators of the exposure of organisms to dioxin-like compounds. In the current study, an in vivo validation of the use of such biomarkers in shrews was conducted. Furthermore, the use of changes in polychlorinated biphenyl (PCB) patterns as an animal-friendly alternative to AROD biomarkers was evaluated. Two experiments and a field study were conducted in which dose-response relations were established between levels of sigma-PCBs in shrews on one hand and their AROD activities and changes in PCB patterns on the other. We demonstrate that the changes in PCB patterns are as sensitive as the classic AROD biomarkers. The experiments also showed a substrate-specific induction of AROD biomarkers and a related PCB congener-specific metabolism. This implies that congener-specific analysis of PCBs can reveal activities of specific AROD biomarkers. Gender-specific induction of AROD activities in shrews was shown in the field study, whereas the relationship between exposure and changes in PCB patterns did not differ between genders. It is concluded that (i) AROD biomarkers are useful biomarkers to assess exposure of shrews to specific organochlorines and that (ii) changes in PCB patterns can be used as an animal-friendly alternative to these AROD biomarkers.

Animals↗

PubMedDate not supplied

A proposal for the use of biomarkers for the assessment of chronic pollution and in regulatory toxicology.

Despite a wealth of information on biomarkers, they are not routinely used for regulatory purposes, even though the potential benefits of biomarkers to rationalise complex exposure-response relationships are clear. 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. We propose and define the characteristics of biomarkers of chronic exposure or effect, which must measure changes in pollution/effect against long-term changes in other general stresses (disease, nutrition, environmental quality), relate to cumulative injury, and remain responsive over months or years. Neuroendocrine, immunological, and histological biomarkers are suggested for chronic pollution. We propose a regulatory framework for biomarkers based on a weight of evidence approach that can integrate biomarkers in risk assessment and long-term monitoring programmes.

Animals↗

PubMed2001

Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: a meta-analysis.

STUDY OBJECTIVE: We sought to evaluate quantitatively the evidence on the diagnostic performance of presentation and serial biochemical markers for emergency department diagnosis of acute cardiac ischemia (ACI), including acute myocardial infarction (AMI) and unstable angina. METHODS: We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998. We examined the diagnostic performance of creatine kinase, creatine kinase-MB, myoglobin, and troponin I and T testing. Diagnostic performance was assessed by using estimates of test sensitivity and specificity and was summarized by summary receiver-operating characteristic curves. RESULTS: Only 4 studies were found that evaluated all patients with ACI; 73 were found that focused only on a diagnosis of AMI. To diagnose ACI, presentation biomarker tests had sensitivities of 16% to 19% and specificities of 96% to 100%; serial biomarker tests had sensitivities of 31% to 45% and specificities of 95% to 98%. Considering only the diagnosis of AMI, presentation biomarker tests had summary sensitivities of 37% to 49% and summary specificities of 87% to 97%; serial biomarker tests had summary sensitivities of 79% to 93% and summary specificities of 85% to 96%. Variation of test sensitivity was best explained by test timing. Longer symptom duration or time between serial tests yielded higher sensitivity. CONCLUSION: The limited evidence available to evaluate the diagnostic accuracy of biomarkers for ACI suggests that biomarkers have very low sensitivity to diagnose ACI. Thus, biomarkers alone will greatly underdiagnose ACI and will be inadequate to make triage decisions. For AMI diagnosis alone, multiple testing of individual biomarkers over time substantially improves sensitivity, while retaining high specificity, at the expense of additional time. Further high-quality studies are needed on the clinical effect of using biomarkers for patients with ACI in the ED and on optimal timing of serial testing and in combination with other tests.

Acute Disease↗

PubMed1999

Biomarkers of exposure, sensitivity and disease.

PURPOSE: This review is to evaluate the use of biomarkers as an indication of past exposure to radiation or other environmental insults, individual sensitivity and risk for the development of late occurring disease. OVERVIEW: Biomarkers can be subdivided depending on their applications. Markers of exposure and dose can be used to reconstruct and predict past accidental or occupational exposures when limited or no physical measurements were available. Markers of risk or susceptibility can help identify sensitivity individuals that are at increased risk for development of spontaneous disease and may help predict the increased risk in sensitive individuals associated with environmental or therapeutic radiation exposures. Markers of disease represent the initial cellular or molecular changes that occur during disease development. Each of these types of biomarkers serves a unique purpose. OUTLINE: This paper concentrates on biomarkers of dose and exposure and provides a brief review of biomarkers of sensitivity and disease. The review of biomarkers of dose and exposure will demonstrate the usefulness of biomarkers in evaluation of physical factors associated with radiation exposure, such as LET, doserate and dose distribution. It will also evaluate the use of biomarkers to establish relationships that exist between exposure parameters such as energy deposition, environmental concentration of radioactive materials, alpha traversals and dose. In addition, the importance of biological factors on the magnitude of the biomarker response will be reviewed. Some of the factors evaluated will be the influence of species, tissue, cell types and genetic background. The review will demonstrate that markers of sensitivity and disease often have little usefulness in dose-reconstruction and, by the same token, many markers of dose or exposure may not be applicable for prediction of sensitivity or risk.

Animals↗

PubMed2005

Air samples versus biomarkers for epidemiology.

BACKGROUND: It has been speculated on theoretical grounds that biomarkers are superior surrogates for chemical exposures to air samples in epidemiology studies. METHODS AND RESULTS: Biomarkers were classified according to their position in the exposure-disease continuum-that is, parent compound, reactive intermediate, stable metabolite, macromolecular adduct, or measure of cellular damage. Because airborne exposures and these different biomarkers are time series that vary within and between persons in a population, they are all prone to measurement error effects when used as surrogates for true chemical exposures. It was shown that the attenuation bias in the estimated slope characterising a log exposure-log disease relation should decrease as the within- to between-person variance ratio of a given set of air or biomarker measurements decreases. To gauge the magnitudes of these variance ratios, a database of 12,077 repeated observations was constructed from 127 datasets, including air and biological measurements from either occupational or environmental settings. The within- and between-person variance components (in log scale, after controlling for fixed effects of time) and the corresponding variance ratios for each set of air and biomarker measurements were estimated. It was shown that estimated variance ratios of biomarkers decreased in the order short term (residence time < or =2 days) > intermediate term (2 days < residence time < or =2 months) > long term biomarkers (residence time >2 months). Overall, biomarkers had smaller variance ratios than air measurements, particularly in environmental settings. This suggests that a typical biomarker would provide a less biasing surrogate for exposure than would a typical air measurement. CONCLUSION: Epidemiologists are encouraged to consider the magnitudes of variance ratios, along with other factors related to practicality and cost, in choosing among candidate surrogate measures of exposure.

Air Pollutants↗

PubMed2002

Delivery of high-quality biomarker assays.

Biomarker measurements now support key decisions throughout the drug development process, from lead optimization to regulatory approvals. They are essential for documenting exposure-response relationships, specificity and potency toward the molecular target, untoward effects, and therapeutic applications. In a broader sense, biomarkers constitute the basis of clinical pathology and laboratory medicine. The utility of biomarkers is limited by their specificity and sensitivity toward the drug or disease process and by their overall variability. Understanding and controlling sources of variability is not only imperative for delivering high-quality assay results, but ultimately for controlling the size and expense of research studies. Variability in biomarker measurements is affected by: biological and environmental factors (e.g., gender, age, posture, diet and biorhythms), sample collection factors (e.g., preservatives, transport and storage conditions, and collection technique), and analytical factors (e.g., purity of reference material, pipetting precision, and antibody specificity). The quality standards for biomarker assays used in support of nonclinical safety studies fall under GLP (FDA) regulations, whereas, those assays used to support human diagnostics and healthcare are established by CLIA (CMS) regulations and accrediting organizations such as the College of American Pathologists. While most research applications of biomarkers are not regulated, biomarker laboratories in all settings are adopting similar laboratory practices in order to deliver high-quality data. Because of the escalation in demand for biomarker measurements, the highly-parallel (multi-plexed) assay platforms that have fueled the rise of genomics will likely evolve into the analytical engines that drive the biomarker laboratories of tomorrow.

Biomarkers↗