Diagnostic Value of Molecular Testing in Sonographically Suspicious Thyroid Nodules

Abstract

Objective Molecular testing can refine the diagnosis for the 20% of thyroid fine needle aspiration biopsies that have indeterminate cytology. We assessed the diagnostic accuracy of molecular testing based on ultrasound risk classification. Methods This retrospective cohort study analyzed all thyroid nodules with indeterminate cytology at an academic U.S. medical center (2012-2016). All indeterminate nodules underwent reflexive molecular testing with Afirma Gene Expression Classifier (GEC). Radiologists performed blinded reviews to categorize each nodule according to the American Thyroid Association (ATA) ultrasound classification and the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS). GEC results and diagnostic performance were compared across ultrasound risk categories. Results Of 297 nodules, histopathology confirmed malignancy in 65 (22%). Nodules by ATA classification were 8% high suspicion, 44% intermediate, and 48% low/very low suspicion. A suspicious GEC result was more likely in ATA high suspicion nodules (81%) than in nodules of all other ATA categories (57%; P = 0.04). The positive predictive value (PPV) of GEC remained consistent across ultrasound categories (ATA high suspicion, 64% vs. all other ATA categories, 48%; P = 0.39). The ATA high suspicion category had higher specificity than a suspicious GEC result (93% vs 51%; P < 0.01). A suspicious GEC result did not increase specificity for the ATA high suspicion category. Conclusion The PPV of molecular testing remained consistent across ultrasound risk categories. However, a suspicious GEC result was very likely in ATA high suspicion nodules and did not improve specificity in this sonographic category.

Thyroseq v3, Afirma GSC, and microRNA Panels Versus Previous Molecular Tests in the Preoperative Diagnosis of Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis

“…Regarding molecular panels, 25 studies evaluated the diagnostic performance of the Afirma GEC ( 8 , 16 , 17 , 40 , 47 – 54 , 56 – 58 , 61 , 63 , 64 , 66 – 70 , 72 , 76 , 77 ), and four articles reported the Afirma GSC ( 16 , 17 , 57 , 70 ). Thyroseq versions 2 and 3 were found in nine ( 11 , 15 , 58 , 59 , 61 , 62 , 71 , 73 , 75 ) and four papers ( 14 , 55 , 59 , 65 ), respectively, while ThyraMIR/ThyGenX ( 23 , 67 , 68 ) and ResettaGX Reveal ( 61 , 67 , 68 ) were explored in three studies, respectively.…”

“…The panels with the fewest assessments were ThyraMIR/ThyGeNEXT and miRInform ( 23 , 74 ). The majority of the studies (n = 32) evaluate a single molecular panel, of which 18 articles reported Afirma GEC alone ( 8 , 40 , 47 – 54 , 56 , 63 , 64 , 66 , 69 , 72 , 76 , 77 ), nine papers assessed second or third version of Thyroseq NGS ( 11 , 14 , 15 , 55 , 62 , 65 , 71 , 73 , 75 ) and lastly, ThyraMIR/ThyGeNEXT, ThyraMIR/ThyGenX, miRInform and RosettaGX Reveal were each approached in a study ( 21 , 23 , 60 , 74 ). Among the nine studies that measured up more that two molecular panels, four paper compared Afirma GEC and GSC ( 16 , 17 , 57 , 70 ), two manuscripts reported a comparison between Afirma GEC and Thyroseq v2 ( 58 , 61 ), two papers investigated the diagnostic performance of Afirma GEC, RosettaGX and Interpace MPT ( 67 , 68 ) and Jug et al.…”

“…A total of 25 studies involving 4,538 cytologically ITNs of the 4,424 participants evaluated the Afirma GEC performance ( 8 , 17 , 40 , 47 – 54 , 56 – 58 , 61 , 63 , 64 , 66 – 70 , 72 , 76 , 77 ). The recruitment period ranged from May 2009 until June 2018.…”

“…We determined a high risk of bias for the “Patient selection” domain in the pooled studies due to lack of consecutive or random enrollment or inappropriate exclusion in several articles ( 8 , 11 , 14 , 16 , 17 , 21 , 49 – 52 , 60 , 62 – 65 , 67 – 69 , 71 , 73 , 76 , 77 ). Almost all records scored an unclear risk of bias for the “Index test” domain as they did not report whether the molecular panel was interpreted without knowledge of the histopathological diagnosis ( 17 , 20 , 30 , 32 , 35 , 38 , 41 – 44 , 46 – 50 , 53 – 57 , 59 – 61 , 103 ).…”

“…However, to better understand the overall detection efficacy, we have further performed a sensitivity analysis series. Excluding those studies ( 8 , 48 , 67 , 76 ) pinpointed by the bivariate box plot (see Supplementary Figure 12 ) as outliers we retrieved a SE of 0.97 (95% CI: 0.94 to 0.98), SP of 0.17 (95% CI: 0.14 to 0.20) and an AUC of 0.47 (95% CI: 0.42 to 0.51), as presented in Supplementary Figures 13, 14 .…”