Validated biomarker

Kelsey K Harvard School of Public Health, Boston, MA Identify and validate biomarkers of lead poisoning National Institute of Environmental Health Sciences... 

Biological, individual, and variations between individuals (such as gender, age, and nutrition) affect peptidomes and require careful consideration in order to find valid biomarkers. A few, equally important factors for successful proteomic biomarker research are high sample quality, high sensitivity, and reproducibility that depend on proper selection of the high quality samples. 

Continued researeh into the development of sensitive and specific biomarkers of exposure and effect for 3,3 -dichlorobenzidine, and the validation of these biomarkers in occupationally exposed individuals would be valuable. Since at this point there are no validated biomarkers of exposure and effect in adults, it makes sense to focus efforts on occupationally exposed adults rather than children who are unlikely to be exposed. There are no data on interactions of 3,3 -dichlorobenzidine with other chemicals in children or adults. There are no pediatric-specific methods to reduce peak absorption for 3,3 -dichlorobenzidine... 

New biomarkers will be useful in hepatotoxicity risk assessment if the data quality and validity can be established. The FDA defines a valid biomarker as one that can be measured in an analytical test system with well-established performance characteristics and has an established scientific framework or body of evidence that elucidates the significance of the test results [160]. Although there is no formerly agreed upon path, biomarker validation should include appropriate end-points for study (i.e., toxicology, histopathology, bioanalytical chemistry, etc.) and dose- and time-dependent measurements. An assessment of species, sex and strain susceptibility is also important to evaluate across species differences. More specific considerations for validation of gene and protein expression technologies are reviewed by Corvi et al. and Rifai et al. [144, 147]. 

Improve animal toxicology study designs to incorporate use of validated biomarkers to characterize biomarker-response relationships that can be used to interpret human biomonitoring data. 

Although there is no doubt that TAC is a good measure of total content of antioxidants in food and beverages, it cannot say anything about the bioavailability of these compounds. More important from a clinical point of view is the question of whether TAC can be a valid biomarker of the antioxidant status of the body. 

There is a continuing need for validated biomarkers of exposure that provide information on the frequency, duration, and intensity of an exposure, as well as a better understanding of distribution, metabolism, and excretion within the individual. Likewise, continued development of analytical methods (e.g. Monte Carlo) that provide a broad characterization of exposure and dose-response relationships should be encouraged. 

Data destined for pharmacokinetic analysis consist of one or more drug concentration vs. time observations, while pharmacodynamic data consist of specific concentration levels corresponding to a specific therapeutic effect or its validated biomarker. One distinguishes two types of data ... 

A variety of biomarkers have been shown to be valuable individually for one or several toxicant or disease situations. Few of these biomarkers have been systematically evaluated for the plethora of situations that might provoke false positive responses. Acceleration of the current pace of biomarker evaluation and qualification demands (a) the availability of panels of biomarker-assays that can be comparatively evaluated on well-defined common sample sets, (b) fit-for-purpose performance evaluation in controlled animal studies with carefully benchmarked histological endpoints and samples from well-defined focused clinical trial cohorts, and (c) ready availability of banked blood and urine sample archives from clinical trial populations with carefully documented morbidities such as the Framingham Heart Study,45 or the Drug-Induced Liver Injury Network (DILIN) prospective study,46 to name a few. Availability of such panels of validated biomarker assays and well-documented preclinical and clinical samples, as well as increased cooperation between animal model researchers and clinical researchers will enable individual biomarkers to be qualified for sensitivity of specifically defined adverse events, qualified for appropriate specificity using samples of defined benign events, and collected into panels that yield complementary information about the health and safety of animals and patients. 

Validated biomarkers in combination with clinical end point... 

At present there is an urge to validate biomarkers that can be introduced into clinics, even through the efforts in biomarker identification (50-52). Over... 

Many, if not all, of these procedures have evolved over many years and with continuous feedback within the scientific communities around the world. Much of this has been conducted within an organization called the Clinical Laboratory Standards Institute (CLSI) formerly known as the National Committee for Clinical Laboratory Standards (NCCLS). Many guidance documents are available from this organization s Web site (see below) that explain how some of the assay performance characteristics are established for the purposes of diagnostics. A number of these experiments are very similar to, or indeed the same as, experiments we conduct in validating biomarker assays for use in drug development and are listed in Table 7.1. 

Table 2.5 fists enzymes and transporters that have not reached the known valid or probable valid biomarker status, and are considered exploratory biomarkers. For some genes (e.g., CYP3A4), the correlation between certain genotypes and enzyme or transporter activities was observed in vitro only. For others (e.g., ABCBl), contradictory data have been published for different drags and the correlation between SNP... 

Determination of Different Genotype Croups based on Known Valid and Probable Valid Biomarkers... 

Table 2.4 DNA-based biom arkers of enzyme activities consid ered as valid biomarkers. ...

---