69 Diagnostic utility of molecular and imaging biomarkers 2 generally low frequency of thyroid carcinoma in indeterminate thyroid nodules, achieving a reliable PPV – higher than 95% – can be a major challenge despite adequate test specificity. Such high demands to a ruling-in test advocate the use of a ruling-out test in populations with a limited pretest probability of malignancy. Clinical recommendation for a step-wise approach Most of the diagnostic modalities are optimized for either ruling in or ruling out malignancy. No single diagnostic addressed in the current review currently has it all: both a near-perfect sensitivity and a near-perfect specificity, and (proven) cost-effectiveness. It is extremely challenging to develop such test performance parameters in a single diagnostic. Even promising new diagnostics, such as the ThyroSeq® and ThyraMir™, require significant further optimization to get near this diagnostic utopia. With the diagnostics currently available in the clinical setting, a multimodality stepwise approach could offer a conclusive diagnosis for indeterminate thyroid nodules, sequentially combining one sensitive rule-out and one specific rule-in test. Unfortunately, thus far few studies investigated this approach [58, 108]. Combinations of (molecular) imaging and somatic genetics were especially scarce. There is currently insufficient evidence to accommodate reliable interpretation of sequentially used tests, as performance of the second test is unknown in a population preselected by the first. Besides choosing two accurate and uncorrelated tests to achieve maximum diagnostic accuracy, the sequence of testing, local availability and costs of the selected diagnostics are crucial. Costs of two or more additional tests may compromise cost-utility estimates. Available costeffectiveness studies for individual diagnostic modalities were additionally greatly susceptible to global variations in population-dependent factors such as pre-test probability of thyroid carcinoma and local test performance, and varying health care costs including the surgical reimbursement rates [53, 159, 176, 177]. Reported surgical and hospitalization costs range from $4,628 to $6,549 for hemithyroidectomy, $5,272 to $7,068 for completion thyroidectomy and $5,680 to $11,265 for initial total thyroidectomy. Secondary expenses following surgery should be considered as well, including postoperative observation, thyroid hormone replacement (approximately $150 per patient per year), treatment for hypoparathyroidism (approximately $860 per patient per year), and resolution of rare but potentially serious surgical complications [53, 158, 176, 302]. Secondary endpoints such as quality of life and survival are of minor importance to cost-effectiveness, due to the generally indolent course of differentiated thyroid cancer, adequate treatment options and overall low disease-related mortality [53, 176, 177].
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