Diagnostic accuracy of Afirma gene expression classifier, Afirma gene sequencing classifier, ThyroSeq v2 and ThyroSeq v3 for indeterminate (Bethesda III and IV) thyroid nodules: a meta-analysis

Abstract

Objective: The management of thyroid nodules with indeterminate cytology (ITN) is still a challenge. To evaluate the performance of commercial molecular tests for ITN, we performed this comprehensive meta-analysis. Methods: We performed an electronic search using PubMed/Medline, Embase and the Cochrane Library. Studies assessing the diagnostic accuracy of Afirma Gene Expression Classifier (GEC), Afirma Gene Sequencing Classifier (GSC), ThyroSeq v2 (TSv2) or ThyroSeq v3 (TSv3) in patients with ITN (only Bethesda category III or IV) were selected; Statistical analyses were performed by using Stata. Results: 71 samples (GEC, n=38; GSC, n=16; TSv2, n=9; TSv3, n=8) in 53 studies, involving 6,490 fine needle aspirations (FNA) with ITN cytology with molecular diagnostics (GEC, GSC, TSv2 or TSv3) were included in the study. Meta-analysis showed the following pooled estimates: sensitivity 0.95 (95% CI, 0.94-0.97), specificity 0.35 (0.28-0.43), Positive Likelihood Ratio (LR+) 1.5 (1.3-1.6), and Negative Likelihood Ratio (LR-) 0.13 (0.09-0.19), with the best performance for TSv3 (area under the ROC curve 0.95 (0.93-0.96), followed by TSv2 (0.90 (0.87-0.92)), GSC (0.86 (0.82-0.88)) and GEC (0.82 (0.78-0.85)); with the best rule-out property for GSC (LR-, 0.07 (0.02-0.19)), followed by TSv3 (0.11 (0.05-0.24)) and GEC (0.16 (0.10-0.28); with the best rule-in for TSv2 (LR+, 2,9 (1.4-4.6)), followed by GSC (1.9 (1.6-2.4)). Meta-regression analysis revealed that study design, Bethesda category, and type of molecular test were independent factors. Conclusions: We showed that in patients with ITN, TSv3 has the best molecular diagnostic performance, followed by TSv2, GSC, and GEC. For rule-out malignancy, GSC, and for rule-in, TSV2 is superior to other tests.