143 Diagnostic utility of molecular and imaging biomarkers 2 Best-case and worst-case scenario Hypothetical best-case and worst-case scenarios were constructed. In the best-case scenario, the estimated pooled sensitivity, specificity, positive and negative LR would be 6.0% (95% CI: 3.9%- 9.2%), 99.8% (95% CI: 99.6%-100%), 35.69 (95% CI: 4.50-283.32) and 0.94 (95% CI: 0.92-0.97), respectively. In the worst-case scenario, the estimated pooled sensitivity, specificity, positive and negative LR would be 2.4% (95% CI: 1.0%-5.7%), 99.7% (95% CI: 97.9%-100%), 8.84 (95% CI: 0.9284.83) and 0.98 (95% CI: 0.96-1.00), respectively (Figure 4). Combined BRAF/RAS mutation analysis Among the articles selected for this review, there were 19 studies that investigated both BRAF and RAS [60, 67, 69, 75-77, 87, 88, 93, 97-100, 102, 107, 109, 114, 118, 351] (Table 20). Three of these studies investigated only BRAF and RAS mutations [77, 98, 107]. The others also investigated RET/PTC, PAX8/ PPARĪ³ and/or TRK rearrangements, or applied a commercial gene mutation panel or next generation sequencing (both discussed in a next paragraph of this Chapter). Sequential testing (RAS mutation only assessed if the specimen was negative for a BRAF mutation) was performed in two studies [77, 98]. Meta-analysis was performed to assess the diagnostic accuracy of combined BRAF and RAS mutation analysis. A total of 3,351 indeterminate thyroid nodules were included, with an average malignancy rate of 18.2% (610/3,351, range 5%-38%). A mutation was detected in 13.4% (449/3,351) of the included nodules: 130 (3.9%) BRAF mutations (114 BRAFV600E and 16 BRAFK601E) and 319 (9.5%) RAS mutations (53 HRAS, 30 KRAS, 154 NRAS and 82 unspecified RAS mutations). Mutations occurred mutually exclusive. Nodules with a nondiagnostic test result (n=79) were excluded from further analysis. Histopathology was available in 67.2% (2,199/3,272) of nodules with a conclusive test result, including 88.9% (399/449) of BRAF/RAS mutation-positive and 63.8% (1,800/2,823) of BRAF/RAS mutation-negative nodules. Of the 610 histopathologically proven malignancies, 320 (52.5%) carried a BRAF/RAS mutation: 86 of the 118 reported PTC (73%), 133 of the 260 FVPTC (51%), 26 of the 81 FTC (32%), 2 of the 17 FTC-OV (12%), 1 of 2 MTC (50%), no mPTC (0%), 6 of 9 other (67%) and 66 of the 122 unspecified thyroid carcinomas (54%) (Table 21). Between-study heterogeneity is suggested: I2 is 80.8% for sensitivity and 76.8% for specificity. Estimated pooled sensitivity, specificity, positive and negative LR are 48.0% (95% CI: 37.7%-58.5%), 94.5% (95% CI: 91.7%-96.4%), 8.69 (95% CI: 5.41-13.96), and 0.55 (95% CI: 0.45-0.68), respectively (Table 22, Figure 23). The AUC is 0.88 (95% CI: 0.85-0.90) (Figure 24). For a given prevalence of malignancy of 15%, 25% or 40%, these results correspond to an estimated PPV and NPV of 60.5% (95% CI: 48.9%-71.1%) and 91.1% (95% CI: 89.3%-92.7%), 74.3% (95% CI: 64.3%-82.3%) and 84.5% (95% CI: 81.6%-87.0%), or 85.3% (95% CI: 78.3%-90.3%) and 73.2% (95% CI: 68.9%-77.0%), respectively (Figure 25).
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