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Prediabetes is a recognized entity but has been incompletely characterized in a contemporary context. We sought to characterize participants with prediabetes with extensive multi-dimensional clinical and laboratory data and to identify predictors of progression to diabetes. The Project Baseline Health Study (PBHS) is a multi-site prospective U.S. cohort study of 2502 adults with deep clinical phenotyping at enrollment. At enrollment and follow-up, participants were classified by diabetes status (diabetes [DM], prediabetes [preDM], or no diabetes [noDM]) based on glucose, A1c, medications, and self-reported medical history. Principal component analysis (PCA) was performed on 1clinical, survey, and lab variables to create orthogonal factors composed of correlated variables, which were compared between groups using linear models. Logistic regression was used to identify factors associated with progression from preDM to DM. At enrollment, 16participants had noDM; 544 had preDM; and 352 had DM. Over up to 4 years of follow-up, 52 participants with preDM developed DM. PCA identified 33 factors composed of clusters of clinical variables; 24 factors differed significantly by diabetes status: 6 factors significantly differed between noDM and both preDM and DM after adjustment for multiple comparisons, including factors with variables of glucose measures, anthropometry and physical function (q= 1.3 × 10−21) , red blood cell indices (q= 8.3 × 10−10) , lung function (q= 2.0 × 10−6) , cardiac function (q= 0.001) , and risk of chronic disease. Five factors were significantly associated with progression to DM, including factors of anthropometry and physical function [OR (95% CI) 0.6 (0.5,0.9) ], hematologic measures, and cardiac function. Conclusions: PBHS participants with preDM demonstrated pathophysiologic changes in cardiac, pulmonary, and hematology measures and declines in physical function that precede DM and could be markers of higher risk of progression to DM and complications. Disclosure R.Chatterjee montgomery: Research Support; Bristol-Myers Squibb Company, Epigenomics AG. L.C.Kwee: None. N.Pagidipati: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, ESPERION Therapeutics, Inc., Consultant; Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eggland's Best, Eli Lilly and Company, Novartis AG, Novo Nordisk, Sanofi, Verily Life Sciences. A.F.Hernandez: Consultant; Merck & Co., Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH. F.Rodriguez: Advisory Panel; Amgen Inc., Consultant; HealthPals, Novartis Pharmaceuticals Corporation, Novo Nordisk, Stock/Shareholder; Carta Healthcare, Inc. K.W.Mahaffey: Consultant; Novo Nordisk. L.Palaniappan: Consultant; Amgen Inc. S.H.Shah: Research Support; Verily Life Sciences. Funding The Baseline Health Study and this analysis were funded by Verily Life Sciences, San Francisco, California.