115 Diagnostic utility of molecular and imaging biomarkers 2 BRAF mutation analysis in Bethesda IV nodules We extracted results for BRAF mutation analysis in 1,418 nodules with cytology corresponding to the Bethesda IV category from 20 of the included studies [67, 69, 75, 79, 88, 90, 92, 95, 97, 98, 101, 103, 104, 111-118, 351]. In contrast to the Bethesda III group, scarcely 2.2% (31/1,418) of documented Bethesda IV nodules tested positive for BRAF mutation, all of which had histopathological followup. In total, surgery was performed in 94.2% (1,294/1,373) of Bethesda IV nodules with a conclusive result of the mutation analysis. The prevalence of malignancy was 26.0% (368/1,418), among which 61 (17%) PTC, 214 (58.2%) FVPTC, 44 (12%) FTC and 21 (5.7%) FTC-OV. The BRAF mutation-positive malignancies were 43% (13/30) PTC and 40% (12/30) FVPTC and 17% unspecified (5/30). I2 is 74.8% for sensitivity and 0.0% for specificity. The estimated pooled sensitivity, specificity, positive LR, negative LR and AUC are 6.8% (95% CI: 3.0%-14.8%), 100% (95% CI: 97.8%-100%), 139.96 (95% CI: 2.30-8,518.26), 0.93 (95% CI: 0.88-0.99) and 0.96 (95% CI: 0.93-0.97), respectively (Table 7, Figure 10 and Figure 11). Even though specificity is high, testing for the BRAF mutation in Bethesda IV nodules does not seem useful due to the low frequency of this oncogenic mutation in the group of prevalently follicular type thyroid tumours. Figure 9. SROC curve of BRAF mutation analysis – Bethesda III nodules Summary receiver operating characteristic plot showing sensitivity versus 1-specificity of BRAF mutation analysis in Bethesda III thyroid nodules with available histopathology. AUC = 0.92 (95% CI: 0.89-0.94). AUC, area under the curve; HSROC, hierarchical summary receiver operating characteristic.
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