Causal inference analysis of the radiologic progression in the chronic obstructive pulmonary disease

There is limited evidence regarding the causal inference of emphysema and functional small airway disease in the subsequent progression of chronic obstructive pulmonary disease (COPD). Patients consisting of two independent cohorts diagnosed with COPD and underwent two serial chest CT scans were included. Total percent emphysema (PRM^Emph) and fSAD (PRM^fSAD) was quantified via PRM. To investigate the progression of emphysema, we divided COPD patients with PRM^Emph < 10% into low and high PRM^fSADgroup, matched with similar baseline characteristics, and conducted nonparametric hypothesis tests based on randomization inference using Wilcoxon signed rank test and Huber's M statistics. In patients with baseline PRMEmph < 10%, there were 26 and 16 patients in the low PRM^fSA group and 52 and 64 patients in the high PRM^fSA in the derivation and validation cohorts, respectively. In the both low and high PRM^fSAD groups, there were 0.11 and 1.43 percentage point increases (Huber's M statistic p = 0.016) and 0.58 and 2.09 percentage point increases (p = 0.038) in the proportion of emphysema in the derivation and validation cohorts, respectively. On the contrary, among patients with baseline PRM^fSAD < 20%, there was no significant differences in the interval changes of PRM^fSAD between the low and high PRM^Emph groups in both cohorts. In COPD patients with low emphysema, group with baseline high PRM^fSAD showed greater change of PRM^Emph than those with low PRM^fSAD in both the derivation and validation cohorts. Imaging-based longitudinal quantitative analysis may provide important evidence that small airway disease precedes emphysema in CT-based early COPD patients.