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.

Public Health Relevance

In the first funding period, we discovered six QES, which are independently associated with morbidity, mortality and distinct gene variants that suggest targetable molecular pathways. This renewal builds upon our successful UML approach with integration of DL, greatly increased CT and genetic data; validates QES with histology; and translates QES to the clinic in order to facilitate testing of molecular therapies of specific QES and to redefine emphysema subtypes in clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL121270-06S2
Application #
10225220
Study Section
Biomedical Computing and Health Informatics Study Section (BCHI)
Program Officer
Postow, Lisa
Project Start
2014-08-01
Project End
2021-07-31
Budget Start
2020-08-15
Budget End
2021-07-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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