Active surveillance (AS), which holds off on treatment for low-risk PCa patients until signs of progression are detected through careful monitoring, was developed as a potential solution to decrease over-treatment of low- risk cancer. For this BCC/BDL, we propose to develop multimodal biomarker panels and associated in vitro diagnostic multivariate index assays (IVDMIAs) for two specific clinical intended uses to improve the effectiveness of AS: 1) IVDMIAs using serum, urine, and biopsy tissue biomarkers to identify patients with low- risk PCa from those with aggressive disease, and/or to provide accurate clinical grading and staging to assist in AS enrollment; and 2) IVDMIAs of non-invasive (serum and urine) biomarkers to sensitively detect early signs of disease reclassification with clinically meaningful lead time for definitive treatment. To develop these biomarker panels, we propose four specific aims. Aim 1. To perform integrated proteomic and glycoproteomic characterization of multimodal clinical specimens to discover and develop biomarkers de novo as well as integrate biomarkers existing or from our current BDL/BRL for the two specific intended uses; Aim 2. To work with the BRL component of our BCC to develop high-quality assays for accurate and efficient evaluation of selected candidate biomarkers; Aim 3. (co-Aim with BRL) To develop and evaluate IVDMIAs to achieve clinically meaningful performance characteristics for the predefined clinical uses; and Aim 4. To participate in EDRN network research projects, including actively participating in and contributing to on-going and future network projects, collaborate with other BCCs and CVCs, and work with EDRN leadership, Executive Committee, and Data Management and Coordinating Center (DMCC) regarding research direction, data and results report criteria/standards, and general effort coordination. Innovations of the BDL include unique targeted AS population, state-of-the-art proteomic and glycoproteomic technologies for both biomarker discovery and pre-validation phases, immunoassays for the detection of specific modified protein forms, quantitative analysis of tissue proteins by single-cell analysis and immunohistochemistry staining as well as quantitative measurement using liquid tissue measurement. Innovative bioinformatics approaches include tools that incorporate existing clinical and biological knowledge of the disease into the quantitative analysis for discovery and IVDMIA model optimization and corroborative analysis of the PCa proteome through single-cell analysis and bulk expression data deconvolution. In summary, the proposed BCC/BDL has assembled a unique collection of well characterized multimodal biospecimen collections representative of the intended targeted populations; and proposed a clear path using state-of-the-art and innovative proteomics, glycoproteomics, statistics, and bioinformatics approaches for biomarker discovery and validation of IVDMIAs to achieve clinically mea...