Abstract Rationale Air trapping from small airway dysfunction predicts COPD outcomes, yet current inspiratory-expiratory CT metrics rely on threshold-based approaches (%voxels-856HU and -950HU) which reduce complex density distributions to binary classifications and vary with scan protocols. We developed the Densification Index (DI), a quantile-based metric that integrates densification across the entire tissue density spectrum, providing a protocol-robust assessment of gas trapping. Methods DI measures the shift in lung tissue density from inspiration to expiration across all percentiles of the HU distribution. After normalization of lung size, we rank-ordered all lung voxel densities for inspiratory and expiratory CT and computed the normalized area between inspiratory and expiratory quantile curves (Figure 1). Higher DI indicates expected densification across the tissue spectrum (healthy), while lower DI indicates impaired densification characteristic of air trapping. We computed DI in 8,563 COPDGene participants and evaluated associations with lung function (FEV₁, FEV₁/FVC), 6-minute walk distance (6MWD), quality of life (SGRQ), dyspnea (mMRC), FEV₁ decline, and all-cause mortality, adjusting for demographics, smoking, %emphysema, airway wall thickness (Pi10), and CT scanner type. Results DI values decreased progressively from non-smokers to GOLD 4 COPD (p 0.001; Figure 1). On multivariable analyses, for every 1SD decrease, DI was significantly associated with FEV₁ (adj. β = 0.16 95% CI: 0.15 to 0.18; p 0.001) and FEV₁/FVC (adj. β = 0.029, 95% CI: 0.027 to 0.03; p 0.001). With additional adjustment for baseline FEV₁, DI remained independently associated with 6MWD (β = 14.97 m, 95% CI: 11.97 to 17.97; p 0.001), SGRQ (β = -1.95, 95% CI: -2.50 to -1.40; p 0.001), and mMRC (β = -0.05, 95% CI: -0.08 to -0.02; p 0.001). DI was also associated with annualized FEV₁ decline (β = -4.04 ml/year, 95% CI: -6.03 to -2.05; p 0.001). In Cox proportional hazards analysis of DI quartiles (Low, Moderate, Severe, Very Severe), participants with severe DI impairment have higher mortality (HR = 1.22, 95% CI: 1.05-1.42; p = 0.01) and those with very severe DI impairment had substantially higher mortality (HR = 1.49, 95% CI: 1.25-1.76; p 0.001). Conclusions DI integrates densification information across the complete lung tissue density spectrum, providing a robust assessment of air trapping and predicting COPD functional decline and mortality after adjusting for structural measures of emphysema and airway wall thickness. Figure 1: (A, B) Densification Index (DI) Estimation and (C) DI across COPD Severity This abstract is funded by: This work was supported by NHLBI grants K01HL163249. U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011.
Bodduluri et al. (Fri,) studied this question.