Chronic obstructive pulmonary disease (COPD) and emphysema, jointly, are the fourth leading cause of death in the US and globally. Decades of research have not found disease-modifying therapies except for a1 antitrypsin deficiency, a rare disease found by improved phenotyping, characterized by a specific emphysema subtype and caused by gene variants in SERPINA1. This renewal builds on the successful discovery of six new quantitative emphysema subtypes (QES), which were associated independently with greater symptoms, impaired function and increased mortality in addition to several genome-wide significant associations for gene variants. In the renewal, we propose to leverage over 27,000 CTs acquired over 5-7 years of follow-up from 4,500 highly phenotyped and genotyped participants to test if deep and unsupervised learning on new state-of- the-art CTs and CT angiograms will reveal additional deep-learned and molecular QES that suggest mechanistic pathways to treatment. Further, we will collect 60 explanted lungs and use state-of-the art microCT to test if QES have distinct histology and structure. Finally, we will recruit 100 patients undergoing lung cancer CT screening to test if QES will be translatable to clinical low-dose lung cancer screening CT scans acquired on contemporary scanners. Successful completion of these aims will discover new deep QES and molecular QES and validate and translate QES to further subphenotype emphysema and facilitate testing of personalize molecular therapies and, hopefully, replicate the success of therapy for a1-antitrypsin deficiency for more common emphysema subtypes.