BRAFV600E-Informed TI-RADS Reclassification of Biopsy Eligibility in Thyroid Nodules: A Retrospective Oracle Decision–Simulation Study

Background/Objectives: We evaluated a hypothetical oracle strategy that assumes BRAFV600E status is known before fine-needle aspiration (FNA), although testing usually requires FNA-derived material.

Methods

This retrospective simulation included 4944 nodules from 4560 patients with linked ultrasound and molecular records following FNA evaluation. The cohort was selected for cytology and molecular testing and enriched for BRAFV600E positivity (42.4%) and TI-RADS 4C nodules (66.7%). The predefined rule combined BRAFV600E-positive upgrading with one-level downgrading of negative TI-RADS 4A/4B nodules. Outcomes were FNA-actionable classification changes and retention of originally FNA-actionable Bethesda V/VI nodules. Pre-FNA prediction was evaluated with patient-grouped cross-validation and training-fold calibration.

Results

Under the hypothetical assumption of pre-FNA knowledge of BRAFV600E status, the oracle strategy reduced FNA-actionable classifications from 3454 to 2954 (net reduction 500; 14.5%) while retaining 1843/1920 Bethesda V/VI nodules (96.0%). In the selected surgical subgroup (365/4944), malignant-nodule retention was 189/196 (96.4%; 95% CI, 92.8–98.6%), with uncertainty extending below the exploratory 95% reference. Among 97 reclassified Bethesda III/IV nodules, only 2 had surgical pathology, and 1 was malignant. Patient-grouped random forest AUC was 0.693 (95% CI, 0.678–0.707). After calibration, a training-selected high-sensitivity threshold reduced classifications by 10.6%, with Bethesda V/VI retention of 95.6% (95% CI, 94.7–96.5%).