This Notice of Funding Opportunity (NOFO) will support, through the cooperative agreement mechanism, investigator-initiated observational studies or biomarker validation studies that require prospective collection of data/biospecimens or continued analysis of data/biospecimens. This NOFO will promote advanced analytic and/or clinical validation of strong candidate biomarkers and endpoints for diagnostic or prognostic utility to demonstrate that biomarker or endpoint change is reliably correlated with pathophysiology, clinical outcome, therapeutic target engagement or treatment response. It is assumed that a candidate biomarker has been identified and assay technology or method of detection has been developed. Specifically, it is expected that the initial discovery of the biomarker or assay will have been performed on a pre-existing set of human biospecimens with the same disease or condition as that in the proposed validation application. This biomarker validation NOFO will support analytic validation studies that establish the accuracy, precision, sensitivity, specificity, reportable range of test results for the test system, reference intervals (normal values) with controls and calibrators; establish the desired magnitude and reliability of the association between the biomarker or endpoint and disease pathophysiology, clinical outcome, target engagement or treatment response; and demonstrate test reproducibility and harmonization of assays or equipment across testing sites. This NOFO will also support clinical validation studies that validate the proposed biomarkers in a new, independent cohort to estimate the prevalence of the marker within patients for the intended clinical use; establish that the biomarker or endpoint acceptably identifies, measures, or predicts response for the disease or condition of interest; and establish an appropriate cut-off or threshold for a biomarker assay for the intended clinical context.