41 Diagnostic utility of molecular and imaging biomarkers 2 Studies of cost-effectiveness yielded variable results, but most concluded that GEC testing would not be cost-effective over conventional surgical management or other diagnostic modalities in various clinical settings [53, 159, 175-178]. The first of these studies proclaimed cost-effectiveness of the GEC even prior to publication of the first validation study by Alexander et al., and has been criticized for several important methodological caveats. This study professedly overestimated test specificity at 75%, overestimated the rate of permanent complications from thyroid surgery, and did not consider the regularly reported GEC test failures [54-56, 168, 175, 176, 179]. A recent study determined population-dependent thresholds for feasible cost-effectiveness by comparing GEC performance to conventional surgical management in a local Bethesda III/IV population. GEC-guided management was not cost-effective, adding $1,197 to the $11,119 expenses for conventional treatment while hardly improving QALYs. Sensitivity analysis showed that the GEC would only become cost-effective if its specificity exceeds 71%, if it costs less than $2,640, or if the population malignancy rate decreases from the actual 24% to below 9.2%. This price threshold for cost-effectiveness decreases as the malignancy rate increases, as low as $2,023 per test at 35% cancer prevalence [175]. Furthermore, existing inter-institutional differences in test performance have consequences for local applicability and effectiveness [165, 172]. Marti et al. compared GEC performance in distinct populations of two large hospitals. The reproducibility of the tests’ sensitivity and specificity was good, but utility strongly depended on the local prevalence of malignancy: as the population malignancy rate increased, a rarer negative GEC became less reliable to rule out malignancy. Oppositely, at low malignancy rates a negative GEC merely confirmed that the probability of cancer was low. In neither situation, the GEC changed the management strategy. GEC testing was most useful if the malignancy rate ranged between 15% and 21%, comparable to the prevalence reported by Alexander et al. [164, 172]. Finally, the degree of missing histology is a major limitation to the performed studies. None of the studies following the key publication by Alexander et al. had complete histopathologic follow-up; histopathological confirmation ranged between 35% and 82% of specimens [164]. Missing histology mainly comprised GEC negative nodules, likely resulting in overestimated sensitivity (i.e. missing some malignancies in the many unoperated GEC-negative nodules) and underestimated specificity (i.e. relatively more GEC-positive nodules with benign histology (false-positives) were operated on than GECnegative nodules with benign histology (true-negatives)). The trend that studies with higher surgical rates for GEC-negative nodules showed more moderate results supports these hypotheses [164, 168, 180]. A recent meta-analysis by Santhanam et al. included seven studies and reported 96% pooled sensitivity and 31% pooled specificity for the GEC in Bethesda III, IV and V thyroid nodules with histopathological follow-up [181]. The authors expected that more than 90% of patients with a negative test would be treated conservatively [181]. However, in individual studies up to 25% of patients pursued surgery or conservative treatment despite GEC-based recommendation to do the opposite [165, 168]. This observation is crucial to cost-utility analyses. In addition, expensive ruleout tests such as the Afirma® GEC should not be performed in case surgery is considered for other reasons, such as cosmetic or mechanical complaints.
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