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Objective: To construct a predictive model to discriminate adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) from invasive adenocarcinoma (IAC) appearing as pure ground-glass nodules (pGGNs) using computed tomography (CT) histogram analysis combined with morphological characteristics and to evaluate its diagnostic performance.Materials and Methods: Two hundred eighty-nine patients with surgically resected solitary pGGN and pathologically diagnosed with AIS, MIA, or IAC in our institution from January 2014 to May 2018 were enrolled in our study. Two hundred twenty-six pGGNs (79 AIS, 84 MIA, and 63 IAC) were randomly selected and assigned to a model-development cohort, and the remaining 63 pGGNs (11 AIS, 29 MIA and 23 IAC) were assigned to a validation cohort. The morphological characteristics were established as model A and histogram parameters as model B. The diagnostic performances of model A, model B, and model A + B were evaluated and compared via receiver operating curve (ROC) analysis and logistic regression analysis.Results: Entropy (odd ratio [OR] = 23.25, 95%CI: 6.83-79.15, p < 0.001), microvascular sign (OR = 8.62, 95%CI: 3.72-19.98, p < 0.001) and the maximum diameter (OR = 4.37, 95%CI: 2.44-7.84, p < 0.001) were identified as independent predictors in the IAC group. The area under the ROC (Az value), accuracy, sensitivity and specificity of model A + B were 0.896, 88.1%, 79.4% and 91.4%, respectively, exhibiting a significantly higher Az value than either model A or model B alone (0.785 vs 0.896, p < 0.001; 0.849 vs 0.896, p = 0.029). Model A + B also conveyed a good diagnostic performance in the validation cohort, with an Az value of 0.851.Conclusion: Histogram analysis combined with morphological characteristics exhibit a superior diagnostic performance in discriminating AIS-MIA from IAC appearing as pGGNs. [ABSTRACT FROM AUTHOR]