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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 US medical center (2012-2016). All indeterminate nodules underwent reflexive molecular testing with the 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. 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 = .04). The positive predictive value (PPV) of GEC remained consistent across ultrasound categories (ATA high suspicion, 64% vs all other ATA categories, 48%; P = .39). The ATA high-suspicion category had higher specificity than a suspicious GEC result (93% vs 51%; P < .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.

Original publication




Journal article


J Endocr Soc

Publication Date





molecular testing, ACR TI-RADS, ATA, nodule, thyroid, ultrasound