Biomarkers validation process

The following section discusses the three main steps of the biomarker validation process, or the fife cycle of a biomarker (1) its identification and development, (2) its validation using epidemiological methods, and (3) its application in etiological or clinical studies. 

To date, the frame in the discovery phase, within the global biomarker finding process, is the common aspect of all metabolomic works linked to AD. Thus, most of metabolomic studies have been focused in the search of new biomarker candidates in the apparition and development of AD with high impact on novel hypotheses generation. Currently, there is a growing need to reliably validate those findings by increasing the cohort of clinical patients, to measure and validate the potential of the revealed biomarkers. 

Validation of a biomarker begins with the description of the pathogenesis of a disease and culminates when it is determined that the biomarker is applicable to clinical trials. This validation process follows a stepwise process depending on the stage of drug development. 

FIGURE 6.1 Conceptual diagram of fit for purpose biomarkers method validation. The method validation processes include four activity circles prevalidation (preanalytical consid eration and method development), exploratory method validation, in study method validation and advanced method validation. The processes are continuous and iterative, dictated by the purpose of the biomarker application. The solid arrows depict the normal flow of biomarker development (prevalidation), method validation (exploratory or advanced), and application (in study method validation). The process could include moving the chosen biomarkers from exploratory mechanistic pilot studies to advanced validation and confirmatory studies, or from exploratory validation to advanced validation after changes in critical business decision. The broken arrows represent scenarios where validation data do not satisfy study requirements, necessitating assay refinement or modification. 

Notes The use of confounding or clinically similar conditions to test biomarkers in the primary validation and validation process is vital to determining which prospective biomarkers are directly related to the disease or whether they are markers of other factors (age, sex, diet, etc.). With many disease states, there are... 

Kohler, K., Seitz, H., 2012. Validation processes of protein biomarkers in serum- a cross platform comparison. Sensors (Basel) 12, 12710—12728. 

Compared to efficacy, safety is typically more multifactorial, as it is dependent on homeostasis of virtually all cellular processes. A wider number and diversity of potential molecular and cellular effects of compound interactions may affect safety than may affect efficacy or bioavailability. Accordingly, cytotoxicity assessment is less specific, more multi parametric and extrapolatable with less certainty, unless there are specific safety signals indicated by the chemical structure or by its precedents. Extrapolation of safety biomarker data needs a greater foundation of mechanistic understanding of both in vitro and in vivo pathogenesis of toxicities, as well as rigorous, empirical validation of models. 

A variety of methods for validation of environmental standards can be used. The choice of the best method depends both on the standard and on the aspect that is to be validated. For example, mesocosm studies or other semiheld studies may be useful for validation purposes. The use of biomarkers may also help to generate confidence in a standard. Preferably, the standard itself should be validated, but often validation for methods is lacking. In these cases, one can decide to validate the separate building blocks of the standard-setting process. 

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