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Inter-institutional variation in predictive value of the ThyroSeq v2 genomic classifier for cytologically indeterminate thyroid nodules

By Andrea R Marcadis, Pablo Valderrabano, Allen S Ho, Justin Tepe, Christina E Swartzwelder, Serena Byrd, Wendy L Sacks, Brian R Untch, Ashok R Shaha, Bin Xu, Oscar Lin, Ronald A Ghossein, Richard J Wong, Jennifer L Marti, Luc G.T. Morris

Posted 22 Apr 2018
bioRxiv DOI: 10.1101/306126

Background: The ThyroSeq v2 next-generation sequencing assay (ThyroSeq) estimates the probability of malignancy in indeterminate thyroid nodules (ITN). Its diagnostic accuracy in different practice settings and patient populations is not well understood. Methods: We analyzed 273 Bethesda III/IV ITN evaluated with ThyroSeq at 4 institutions: 2 comprehensive cancer centers (n=98 and 102), a multicenter healthcare system (n=60), and an academic medical center (n=13). The positive (PPV) and negative predictive values (NPV) of ThyroSeq, and distribution of final pathology were analyzed and compared to values predicted by Bayes Theorem. Results: Across 4 institutions, the PPV was 35% (22-43%), and NPV was 93% (88-100%). Predictive values correlated closely with Bayes Theorem estimates (r2=.84), although PPVs were lower than expected. RAS mutations were the most frequent molecular alteration. Among 84 RAS-mutated nodules, malignancy risk was variable (25%, range 10-37%), and distribution of benign diagnoses differed across institutions (adenoma/hyperplasia 12-85%, NIFTP 5-46%). Conclusions: In a multi-institutional analysis, ThyroSeq PPVs were variable and lower than expected. This is attributable to differences in the prevalence of malignancy, and variability in pathologist interpretations of non-invasive tumors. It is important that clinicians understand ThyroSeq performance in their practice setting when evaluating these results.

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