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Objective: We examine pathways of airway alteration due to wall thinning, narrowing, and obliteration in chronic obstructive pulmonary disease (COPD) using CT-derived airway metrics., Methods: Ex-smokers (N = 649; age mean ± std: 69 ± 6 years; 52% male) from the COPDGene Iowa cohort (September 2013-July 2017) were studied. Total airway count (TAC), peripheral TAC beyond 7th generation (TACp), and airway wall thickness (WT) were computed from chest CT scans using previously validated automated methods. Causal relationships among demographic, smoking, spirometry, COPD severity, airway counts, WT, and scanner variables were analysed using causal inference techniques including direct acyclic graphs to assess multi-pathway alterations of airways in COPD., Results: TAC, TACp, and WT were significantly lower (P < .0001) in mild, moderate, and severe COPD compared to the preserved lung function group. TAC (TACp) losses attributed to narrowing and obliteration of small airways were 4.59%, 13.29%, and 32.58% (4.64%, 17.82%, and 45.51%) in mild, moderate, and severe COPD, while the losses attributed to wall thinning were 8.24%, 17.01%, and 22.95% (12.79%, 25.66%, and 33.95%) in respective groups., Conclusions: Different pathways of airway alteration in COPD are observed using CT-derived automated airway metrics. Wall thinning is a dominant contributor to both TAC and TACp loss in mild and moderate COPD while narrowing and obliteration of small airways is dominant in severe COPD., Advances in Knowledge: This automated CT-based study shows that wall thinning dominates airway alteration in mild and moderate COPD while narrowing and obliteration of small airways leads the alteration process in severe COPD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)