Study Identifies Effectiveness of RNA, DNA-RNA Tests for Diagnosis of Indeterminate Thyroid Nodules


“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,” wrote Masha J. Livhits, MD, and colleagues.

A comparison of the diagnostic performance between the Afirma genomic sequencing classifier RNA test and the ThyroSeq v3 multigene genomic classifier DNA-RNA test revealed no statistically significant differences in sensitivity and specificity for diagnosis of malignancy in cytologically indeterminate thyroid nodules.

Additionally, this study allowed almost half of the patients with indeterminate thyroid nodules to avoid diagnostic surgery on the basis of a benign molecular test result.

“In light of these findings, the choice of molecular test may hinge on factors other than diagnostic performance, such as cost, processing time, sample inadequacy rate, and information regarding specific mutations that may guide future treatment,” the study authors led by Masha J. Livhits, MD, wrote in the conclusion of the study, which was published in JAMA Oncology in December 2020.

In this parallel, randomized clinical trial (NCT02681328) of monthly block randomization, patients in the UCLA Health system who underwent thyroid biopsy with indeterminate cytology were evaluated.

The primary end point was diagnostic test performance of the RNA test compared with the DNA-RNA test. Among the secondary end points was a comparison of test performance with previous versions of each type of molecular test.

Among a total of 2368 patients, 397 were deemed eligible for inclusion based on indeterminate cytology and 346 were randomized to 1 of the 2 tests. Of the overall cohort assessed for eligibility, 3140 thyroid nodules were assessed, 427 (13.6%) of which were cytologically indeterminate. Moreover, malignancy was identified in 20% of indeterminate nodules.

The benign call rate was found to be 53% (95% CI, 47%-61%) with RNA testing and 61% (95% CI, 53%-68%) with DNA-RNA testing. The corresponding rates of sensitivity for the tests were 100.0% (95% CI, 88.8%-100.0%) and 96.9% (95% CI, 83.8%-99.9%). The specificity of the RNA test was 79.6% (95% CI, 71.7%-86.1%) versus 84.8% (95% CI, 77.0%-90.7%) with the DNA-RNA test (P = .33). Further, the positive predictive values (PPV) of the RNA test and DNA-RNA test were 54% (95% CI, 40%-67%) and 63% (95% CI, 48%-77%), respectively (P = .33).

“Both the RNA test and DNA-RNA test [used in this study] are the most highly validated current molecular tests for the diagnosis of indeterminate thyroid nodules,” the authors noted.

When the compared with the PPV of a previous version of the test (38%; 95% CI, 27%-48%), the RNA test exhibited a statistically significant improvement (P = .01). However, compared with its prior version (58%; 95% CI, 43%-73%), the DNA-RNA test had no statistically significant difference in PPV (P = .75).

Importantly, diagnostic thyroidectomy was avoided in a total of 87 patients (51%) screened with the RNA test and in 83 (49%) screened with the DNA-RNA test. Additionally, surveillance ultrasonography was available for 90 nodules, of which 85 (94%) remained stable over a median of 12 months follow-up.

The authors noted that this study is not without limitations, the most notable being that it was restricted by nonoperative management for most indeterminate nodules with benign molecular test results. However, previous validation studies support the high sensitivity observed herein, based upon high sensitivity (91% for RNA testing vs 94% for DNA-RNA testing) and very low false-negative rates (2% for RNA testing vs 3% for DNA-RNA testing) reported for operative management of all indeterminate nodules.


Livhits MJ, Zhu CY, Kuo EJ, et al. Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules. Published online December 10, 2020. JAMA Oncology. doi: 10.1001/jamaoncol.2020.5935

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