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Background: Disease accumulates in the small airways without being detected by conventional measurements. Objectives: To quantify small airway disease using a novel computed tomography (CT) inspiratory-to-expiratory approach called the disease probability measure (DPM) and to investigate the association with pulmonary function measurements. Methods: Participants from the population-based CanCOLD study were evaluated using full-inspiration/full-expiration CT and pulmonary function measurements. Full-inspiration and full-expiration CT images were registered, and each voxel was classified as emphysema, gas trapping (GasTrap) related to functional small airway disease, or normal using two classification approaches: parametric response map (PRM) and DPM (VIDA Diagnostics, Inc., Coralville, IA, USA). Results: The participants included never-smokers (n = 135), at risk (n = 97), Global Initiative for Chronic Obstructive Lung Disease I (GOLD I) (n = 140), and GOLD II chronic obstructive pulmonary disease (n = 96). PRMGasTrap and DPMGasTrap measurements were significantly elevated in GOLD II compared to never-smokers (p < 0.01) and at risk (p < 0.01), and for GOLD I compared to at risk (p < 0.05). Gas trapping measurements were significantly elevated in GOLD II compared to GOLD I (p < 0.0001) using the DPM classification only. Overall, DPM classified significantly more voxels as gas trapping than PRM (p < 0.0001); a spatial comparison revealed that the expiratory CT Hounsfield units (HU) for voxels classified as DPMGasTrap but PRMNormal (PRMNormal- DPMGasTrap = -785 ± 72 HU) were significantly reduced compared to voxels classified normal by both approaches (PRMNormal-DPMNormal = -722 ± 89 HU; p < 0.0001). DPM and PRMGasTrap measurements showed similar, significantly associations with forced expiratory volume in 1 s (FEV1) (p < 0.01), FEV1/forced vital capacity (p < 0.0001), residual volume/total lung capacity (p < 0.0001), bronchodilator response (p < 0.0001), and dyspnea (p < 0.05). Conclusion: CT inspiratory-to-expiratory gas trapping measurements are significantly associated with pulmonary function and symptoms. There are quantitative and spatial differences between PRM and DPM classification that need pathological investigation.