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Artificial intelligence in CT for quantifying lung changes in the era of CFTR modulators. RATIONALE: Chest computed tomography (CT) remains the imaging standard for demonstrating cystic fibrosis airway structural disease in vivo. However, visual scorings as an outcome measure are time-consuming, require training, and lack high reproducibility. OBJECTIVE: To validate a fully automated artificial intelligence-driven scoring of cystic fibrosis lung disease severity. METHODS: Data were retrospectively collected in three cystic fibrosis reference centers, between 2008 and 2020, in 184 patients 4 to 54-years-old. An algorithm using three two-dimensional convolutional neural networks was trained with 78 patients' CTs (23 530 CT slices) for the semantic labeling of bronchiectasis, peribronchial thickening, bronchial mucus, bronchiolar mucus, and collapse/consolidation. 36 patients' CTs (11 435 CT slices) were used for testing versus ground-truth labels. The method's clinical validity was assessed in an independent group of 70 patients with or without lumacaftor/ivacaftor treatment (n=10 and 60, respectively) with repeat examinations. Similarity and reproducibility were assessed using Dice coefficient, correlations using Spearman test, and paired comparisons using Wilcoxon rank test. MEASUREMENT AND MAIN RESULTS: The overall pixelwise similarity of artificial intelligence-driven versus ground-truth labels was good (Dice coefficient=0.71). All artificial intelligence-driven volumetric quantifications had moderate to very good correlations to a visual imaging scoring (p<0.001) and fair to good correlations to FEV1% at pulmonary function test (p<0.001). Significant decreases in peribronchial thickening (p=0.005), bronchial mucus (p=0.005), bronchiolar mucus (p=0.007) volumes were measured in patients with lumacaftor/ivacaftor. Conversely, bronchiectasis (p=0.002) and peribronchial thickening (p=0.008) volumes increased in patients without lumacaftor/ivacaftor. The reproducibility was almost perfect (Dice>0.99). CONCLUSION: Artificial intelligence allows a fully automated volumetric quantification of cystic fibrosis-related modifications over an entire lung. The novel scoring system could provide a robust disease outcome in the era of effective CFTR modulator therapy.