Early detection of pancreatic ductal adenocarcinoma (PDAC) is an area of highest priority and an unmet need for advancing public health in the United States. Certain sub-groups of patients, such as those with germline mutations, mucinous pancreatic cysts and new-onset diabetes (NOD) are at higher than average risk for PDAC. In the immediate prior cycle, our EDRN Clinical Validation Center (CVC) at MD Anderson Cancer Center (MDACC): (a) facilitated the conduct of the first ever, multi-institutional, blinded “biomarker bakeoff” in PDAC by providing annotated biospecimens, (b) completed one of the first EDRN-defined Phase 3 biomarker studies in PDAC using pre-diagnostic samples (Fahrmann et al, Gastroenterology 2021), and (c) served as a conduit for the implementation of additional EDRN collaborative research initiatives, including a pre-diagnostic PDAC imaging consortium. Our renewal application represents a Gulf Coast-Great Lakes EDRN Clinical Validation Center (GCGLEC) in Pancreatic Cancer is comprised of UTMDACC/Lyndon B Johnson Hospital (Harris Health, TX), Henry Ford Health System (HFHS, Detroit, MI) and Ochsner Health System (OHS, New Orleans, LA) and has three major objectives: First, to implement a multi-institutional framework for collecting the highest quality biospecimens from patients with a variety of well-defined pancreatic pathologies (including early stage PDAC, pancreatic cystic lesions, and other benign pancreatic diseases, such as chronic pancreatitis, benign cysts, and endocrine tumors of low malignant potential), in order to conduct biomarker validation studies for early detection of PDAC that conform to EDRN-defined Phase 2 and Phase 3 study design. Current PDAC biomarker studies typically have sparse representation from racial and ethnic minorities, and therefore a major impetus of the GCGLEC will be to address the “disparity gap” in biomarker research by obtaining biospecimens from underrepresented minorities. Second, the GCGLEC will build upon our published Phase 3 study utilizing the “anchor panel” of CA19-9, LRG1 and TIMP-1, by conducting four additional PRoBE-compliant studies that incorporate autoantibodies, metabolites and additional protein biomarkers for improving the sensitivity of diagnosing asymptomatic PDAC without compromising the 99% or greater specificity threshold. These EDRNdefined Phase 3 studies will be conducted in pre-diagnostic cases and controls obtained from existing cohorts, including the PLCO, WHI, and the so-called “Harvard cohorts” (NHS, PHS, WHS and HPFS), as well as ongoing prospective cohorts undergoing accrual, such as the NCI-funded New Onset Hyperglcyemia and Diabetes (NOD) cohort, and the Early detection Initiation (EDI) in PDAC, a collaboration between PanCAN and the NCI. Third, the GCGLEC will serve as a “hub” for collaborative activities within and outside the EDRN, including collaborations with investigators funded by the Pancreatic Cancer Detection Consortium (PCDC), and laying the foundations for conducting an EDRN-approved multi-institutional “clinical utility” (Phase 4 study) for PDAC early detection, within a CAP/CLIA environment.