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IMPORTANCE Approximately 20% of thyroid nodules display indeterminate cytology. Molecular testing can refine the risk of malignancy and reduce the need for diagnostic hemithyroidectomy.OBJECTIVE To compare the diagnostic performance between an RNA test (Afirma genomic sequencing classifier) and DNA-RNA test (ThyroSeq v3 multigene genomic classifier). DESIGN, SETTING, AND PARTICIPANTSThis parallel randomized clinical trial of monthly block randomization included patients in the UCLA Health system who underwent thyroid biopsy from August 2017 to January 2020 with indeterminate cytology (Bethesda System for Reporting Thyroid Cytopathology category III or IV). INTERVENTIONS Molecular testing with the RNA test or DNA-RNA test. MAIN OUTCOMES AND MEASURES Diagnostic test performance of the RNA test compared with the DNA-RNA test. The secondary outcome was comparison of test performance with prior versions of the molecular tests. RESULTS Of 2368 patients, 397 were eligible for inclusion based on indeterminate cytology, and 346 (median [interquartile range] age, 55 [44-67] years; 266 [76.9%] women) were randomized to 1 of the 2 tests. In the total cohort assessed for eligibility, 3140 thyroid nodules were assessed, and 427 (13.6%) nodules were cytologically indeterminate. The prevalence of malignancy was 20% among indeterminate nodules. The benign call rate was 53% (95% CI, 47%-61%) for the RNA test and 61% (95% CI, 53%-68%) for the DNA-RNA test. The specificities of the RNA test and DNA-RNA test were 80% (95% CI, 72%-86%) and 85% (95% CI, 77%-91%), respectively (P = .33); the positive predictive values (PPV) of the RNA test and DNA-RNA test were 53% (95% CI, 40%-67%) and 63% (95% CI, 48%-77%), respectively (P = .33). The RNA test exhibited a higher PPV compared with the prior test version (Afirma gene expression classifier) (54% [95% CI, 40%-67%] vs 38% [95% CI, 27%-48%]; P = .01). The DNA-RNA test had no statistically significant difference in PPV compared with its prior version (ThyroSeq v2 next-generation sequencing) (63% [95% CI, 48%-77%] vs 58% [95% CI, 43%-73%]; P = .75). Diagnostic thyroidectomy was avoided in 87 (51%) patients tested with the RNA test and 83 (49%) patients tested with the DNA-RNA test. Surveillance ultrasonography was available for 90 nodules, of which 85 (94%) remained stable over a median of 12 months follow-up.CONCLUSIONS AND RELEVANCE Both the RNA test and DNA-RNA test displayed high specificity and allowed 49% of patients with indeterminate nodules to avoid diagnostic surgery. Although previous trials demonstrated that the prior version of the DNA-RNA test was more specific than the prior version of the RNA test, the current molecular test techniques have no statistically significant difference in performance.

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ThyroSeq v2 had higher specificity than Afirma GEC and allowed more patients to avoid surgery. Long-term surveillance is necessary to assess the false-negative rate of these particular molecular tests. Further studies are required for comparison with other available molecular diagnostics and for newer tests as they are developed.

Over 12% of patients receiving ipilimumab, nivolumab and/or pembrolizumab in our study sample developed an endocrine IRAE. Patients who undergo treatment with immunomodulatory therapies should be monitored for the development of endocrine IRAEs.