167 Diagnostic utility of molecular and imaging biomarkers 2 7-gene GMP in Bethesda IV nodules Five studies reported results for Bethesda IV nodules, four of which used the miRInform® thyroid test [69, 75, 97, 114, 351]. A total of 795 Bethesda IV nodules were included, with a malignancy rate of 26.4% (210/795). There were 130 nodules that tested positive for a mutation (16.4%, vs 9.8% in Bethesda III nodules, p=0.01, Pearson χ2), 625 GMP negative and 40 with a nondiagnostic result. Sensitivity and specificity in individual studies ranged from 25%-67% and 86%-99%, respectively. I2 is 37.7% for sensitivity and 70.7% for specificity. The estimated pooled sensitivity, specificity, positive and negative LR are 52.6% (95% CI: 43.8%-61.2%), 96.0% (95% CI: 91.3%-98.2%), 13.1 (95% CI: 5.83-29.3) and 0.49 (95% CI: 0.41-0.60) respectively. The AUC is 0.57 (95% CI: 0.52-0.61) (Table 30, Figure 36 and Figure 37). Best-case and worst-case scenarios Due to the availability of histopathological in only 90.9%, we computed two extreme scenarios. In the best-case scenario, the GMP result was always correct in the 9.1% (151/1,664) nodules with a conclusive GMP result but no histopathological follow-up. Estimated pooled sensitivity, specificity, positive and negative LR would be 51.2% (95% CI: 42.2%-60.1%), 94.7% (95% CI: 91.5%-96.8%), 9.75 (95% CI: 5.56-17.10) and 0.52 (95% CI: 0.42-0.63), respectively. In the worst-case scenario, these performance estimates would be 30.1% (95% CI: 17.9%-46.1%), 91.2% (95% CI: 85.3%-94.9%), 3.42 (95% CI: 1.41-8.33) and 0.77 (95% CI: 0.60-0.97), respectively (Figure 4). In either scenario, the specificity of GMP testing remains high. The true test performance lies somewhere in the middle. These hypothetical results underpin the reported diagnostic accuracy of the GMP. Figure 37. SROC curve of 7-gene mutation panel analysis – Bethesda IV Summary receiver operating characteristic plot showing sensitivity versus 1-specificity of 7-gene mutation panel analysis in Bethesda IV thyroid nodules with available histopathology. 0.57 (95% CI: 0.52-0.61). AUC, area under the curve; HSROC, hierarchical summary receiver operating characteristic.
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