Abstract Consistent with the overall mission of NINDS for the PAR-21-056 Announcement, Analytical Validation of a Candidate Biomarker for Neurological Disease, we have assembled a team of investigators from the International Initiative on Traumatic Brain Injury Research (IntBIR) to conduct analytical validation of 7 emerging TBI biomarkers: UCH-L1, GFAP, NfL, Tau, brain derived (BD) Tau, pTau-181 and pTau-231. The absolute values reported for any particular analyte, measured on different platforms, often differ substantially, making it difficult to interpret findings across studies and limiting their eventual clinical adoption. To achieve clinical acceptance, assessment of pre-analytical variables, namely how small variations of sample collection protocols and analytical methods influence the results, is essential for establishing standard operating procedures. Universal cut-offs and population-based reference intervals (RI) also will assist in interpretation of biomarker results. Such efforts in the pre-competitive space will substantially ease the transition from research-use-only into clinical practice. This will be the first study to investigate the role of neurotrauma biomarkers as monitoring biomarkers of the temporal evolution of TBI in two common clinical Contexts of Use (COU). We will assay existing blood samples collected in > 80 hospitals worldwide as part of the USA TRACK-TBI study, the European CENTER-TBI study, and the Canadian CanTBI study, for the 7 biomarkers selected for this project. The first COU focuses on patients evaluated in the ED and discharged to their home. We will investigate the risk stratification/prognostic value of these TBI biomarkers to detect or predict the occurrence of persistent post-concussion syndrome. The second COU focuses on patients admitted to the intensive care unit with severe TBI. We will investigate the relationship and effect size of secondary biomarker elevations with TBI complications such as intracranial hypertension, as a neuromonitoring role. These pre-competitive space studies are important for the development of these biomarkers in the TBI arena, as well as the near future use and adoption in the acute clinical setting.