Size-dependent heterogeneity in the associations of C-TIRADS ultrasound features with malignancy in thyroid nodules.

Aim: To investigate whether the associations between Chinese Thyroid Imaging Reporting and Data System (C-TIRADS) ultrasound features and malignancy vary according to thyroid nodule size. Methods: This two-center retrospective cohort study included 3726 thyroid nodules, which were categorized according to maximum diameter as ≤1 cm or >1 cm. Extreme gradient boosting models and SHapley Additive exPlanations (SHAP) were used for exploratory visualization of the contributions of individual ultrasound features to malignancy prediction in the overall cohort and the two size subgroups. Multivariable Firth logistic regression was used to estimate the adjusted associations between the C-TIRADS features and malignancy. Single-feature interaction models were constructed to assess whether nodule size modified these associations. The discriminative performance of the original C-TIRADS model and the interaction model was compared using the area under the receiver operating characteristic curve (AUC). Center-adjusted sensitivity analyses were also performed. Results: Vertical orientation and solid composition showed greater contributions to malignancy prediction and stronger associations with malignancy in nodules ≤1 cm, whereas microcalcification and ill-defined/irregular margin or extrathyroidal extension showed stronger associations with malignancy in nodules >1 cm. Significant feature-by-size interactions were identified for vertical orientation, solid composition, microcalcification, and ill-defined/irregular margin or extrathyroidal extension, whereas no significant interactions were observed for markedly hypoechoic or comet-tail artifact. The interaction model showed a modest but statistically significant improvement in discriminative performance compared with the original C-TIRADS model (AUC 0.918 vs. 0.911, Conclusion: The associations between C-TIRADS ultrasound features and malignancy exhibit significant size-dependent heterogeneity. In nodules ≤1 cm, vertical orientation and solid composition may indicate a substantially higher likelihood of malignancy and therefore warrant particularly careful clinical evaluation, whereas microcalcification and ill-defined/irregular margin or extrathyroidal extension may be more informative for malignancy assessment in nodules >1 cm. Considering nodule size when interpreting individual C-TIRADS features may improve diagnostic discrimination.