Nomogram integrating BRAF V600E, serum biomarkers, and ultrasound features for malignancy risk stratification in C-TIRADS category 3 and 4 thyroid nodules.

BACKGROUND: For patients with C-TIRADS 3 or 4 nodules who have undergone fine-needle aspiration cytology (FNAC), subsequent management decisions remain challenging, especially when cytological results are discordant with imaging findings or indeterminate. We built a nomogram incorporating BRAF V600E, serum biomarkers, and ultrasound features to provide an individualized risk estimate of malignancy for these nodules. METHODS: We retrospectively included 300 patients with C-TIRADS 3 or 4 nodules. All nodules were confirmed by postoperative pathology or cytology. Among these, 76 were malignant and 224 benign. After running LASSO regression with 10-fold cross-validation and applying the 1-standard error rule to select core predictors, we built the nomogram using Firth-penalized logistic regression. Internal validity was checked using bootstrap resampling with 1,000 iterations while the model's performance was evaluated using ROC curves, calibration (Hosmer-Lemeshow test, Brier score) and decision curve analysis (DCA). The additional predictive value beyond the C-TIRADS system was measured by the Net Reclassification Index (NRI) and the Integrated Discrimination Improvement (IDI). RESULTS: Five independent predictors were finally selected: BRAF V600E mutation (OR = 36.455, 95% CI: 13.381-118.094), TgAb positivity (OR = 4.808, 95% CI: 2.289-10.486), microcalcifications (OR = 4.168, 95% CI: 1.880-9.424), aspect ratio > 1 (OR = 3.027, 95% CI: 1.285-7.115), and serum VEGF (per 100 pg/mL increase, OR = 3.798, 95% CI: 1.763-8.677). Each predictor was independently associated with malignancy (all P < 0.05). The area under the curve (AUC) of our nomogram reached 0.890 (95% CI: 0.845-0.935; bootstrap-corrected: 0.886), which was significantly higher than that of C-TIRADS alone (AUC = 0.746, P < 0.001). Reclassification analysis yielded a categorical NRI of 0.436 (95% CI: 0.316-0.551, P < 0.001) and an IDI of 0.263 (95% CI: 0.182-0.341, P < 0.001). Calibration was satisfactory: the Hosmer-Lemeshow χ 2 gave 4.61 (P = 0.799), and the Brier score was 0.104. DCA demonstrated a higher net benefit across threshold probabilities ranging from 2 to 90%. CONCLUSION: The nomogram demonstrated good discriminative performance in C-TIRADS 3 or 4 nodules, supporting its utility as a post-FNAC decision aid.