United States and European Multicenter Prospective Study for the Analytical Performance and Clinical Validation of a Novel Sensitive Fully Automated Immunoassay for Calcitonin.
Interpretation of serum CT concentrations has been restricted by technical limitations in CT assays, hindering the determination of CT concentrations in physiological states (2, 9). Thus, more sensitive and reliable assays for serum CT are warranted for an accurate and timely diagnosis and differential diagnosis of MTC (6). To address these difficulties, a novel, sensitive electrochemiluminescence immunoassay (ECLIA) for serum CT was developed and prospectively validated in a large collection of patients with various benign and malignant thyroid and endocrine diseases.
Materials and Methods
In total, 1929 study participants were included. Healthy controls and patients with various thyroid and nonthyroidal diseases were recruited in 4 US centers as follows: n = 472 (24.5%) in Sarasota, FL; 272 (14.1%) in Columbus, OH; 108 (5.6%) in Rochester, MN; and 93 (4.8%) in Indianapolis, IN, and in 4 German centers as follows: n = 143 (7.4%) in Bielefeld, 101 (5.2%) in Leipzig, 23 (1.2%) in Heidelberg, and 717 (37.2%) in Mainz. CT measurements were performed in 3 US and 2 German sites (in the US, Rochester, MN; Ft. Lauderdale, FL; and St. Louis, MO; in Germany, Leipzig and Mainz). Controls had a negative personal and family history of thyroid, autoimmune, and tumor diseases; had a normal thyroid size and morphology when investigated with thyroid ultrasonography; and had thyroid-related serum hormone and antibody values within the normal range. Written informed consent was obtained from all participants, and the study was approved by all Ethical Committees and Institutional Review Boards.
Hashimoto thyroiditis is defined as a serum concentration of antithyroid peroxidase autoantibodies above the reference interval with or without increased serum concentration of antithyroglobulin autoantibodies, a hypoechoic thyroid on ultrasonography, and euthyroidism or hypothyroidism. Graves' hyperthyroidism was defined as positive anti-thyroid-stimulating hormone (TSH)-receptor autoantibodies, suppressed baseline thyroid-stimulating hormone, increased serum-free thyroid hormones fT3 and/or fT4, and enhanced vascularization of an enlarged thyroid gland on ultrasonography ("thyroid inferno"). Toxic thyroid adenoma was diagnosed via thyroid scintigraphy. Primary hyperparathyroidism was defined as increased serum parathyroid hormone concentrations, hypercalcemia, and hypophosphatemia. Secondary hyperparathyroidism was present in patients with kidney failure, increased serum creatinine and urea concentrations, normal or low serum calcium concentrations, and increased serum phosphate concentrations. Differentiated (papillary and follicular) thyroid cancer was histologically diagnosed. MTC and CCH were diagnosed both biochemically and histologically.
In total, 50 healthy volunteers underwent intravenous calcium stimulation testing at Johannes Gutenberg University (JGU). On investigation day, the volunteer fasted for at least 4 h before testing. The recommended stimulation dose of 2.5 mg pure calcium per kilogram bodyweight was administered as calcium gluconate 10% solution containing 94 g/L of calcium gluconate. As a substance with a molar mass of 448.4 g/mol, 1 mL contains 0.2 mmol calcium gluconate. As calcium has a molar mass of 40.1 g/mL, 1 mL of calcium gluconate 10% solution contains 9.1 mg calcium per milliliter. Because 2.5 mg calcium per kilogram is required, 0.3 mL of calcium gluconate 10% solution per kilogram bodyweight was administered intravenously (10 mL/min, mean variation [+ or -] 30 s). Blood samples were drawn before calcium administration (baseline value) and 1,2,3,5, and 10 min after completion of the calcium injection.
The Elecsys[R] human CT assay is a one-step sandwich assay, based on the streptavidin-biotin-technology. One of the antibodies is biotinylated and used as capture antibody that binds to streptavidin-coated microparticles. The other antibody, covalently linked with a ruthenium complex, is used for ECLIA detection. The monoclonal detection antibody (14A2 von HyTest) recognizes the epitope FNKF (AA16-19) of the calcitonin molecule. The monoclonal capture antibody is directed against a so far unknown conformation epitope. The matrix of the calibrators consisted of commercially available horse serum (Pan Biotec GmbH). The test was applied on the automated immunoassay analyzers Cobas e411 and e601. As the used reagents had the same constituents, the 2 analyzers delivered highly comparable data. After blood withdrawal, individual samples were centrifuged within 60 min at 2000g for 10 min, and the serum was subsequently frozen at-80[degrees]C within 60-90 min. Measurement of serum CT concentration followed within 10-14 days. A direct one-to-one comparison between the Cobas analyzer and the IMMULITE 2000 or 1000 (Siemens) was performed in 350 controls and patients.
ANALYTICAL AND DIAGNOSTIC PERFORMANCE
Precision of the Elecsys hCT assay was evaluated according to the Clinical and Laboratory Standards Institute (CLSI) CLSI-EP5-A2 protocol. Three available reagent lots (MP, P02, and P03) underwent measurement by use of Cobas e 411 analyzers. Five individual sample pools (estimated concentration interval: approximately 0.7-1900 ng/L) were generated by diluting highly concentrated human samples with native human serum and plasma matrix. For the lowest concentration pool, the human serum matrix was further diluted with horse serum to reach the anticipated concentration, and 2 controls (approximately 10 and approximately 100 ng/L, respectively; PreciControl Varia) were used in randomized order of all samples on the system. Two aliquots of each sample material were used per run. Aliquots were measured on 21 days in 2 separate runs, resulting in 84 aliquots per sample. Between the 2 precision runs at each day, 10 patient samples with predefined concentration ("dummy" samples) were measured by use of the MP reagent lot only.
The statistics software program SPSS version 23 (SPSS) was used. All P values were two-sided and were considered statistically significant if <0.05. Statistical comparisons between any 2 groups of patients with respect to serum concentrations were done by the Mann--Whitney U test. Baseline demographics are expressed as median with minimum and maximum. For the estimation of reference intervals, the nonparametric percentiles were used. For all cohorts, the following descriptive parameters were determined: N, minimum, maximum, median, the 25th, 75th, and 97.5th percentiles. Sensitivity and specificity were derived by Receiver Operating Curve (ROC) analysis. Nonparametric estimates were used for the areas under the curve (AUCs) and the comparisons of AUCs. For the analysis of calcium stimulation data, the serum CT concentration was log-transformed and a linear mixed model with sex and baseline values as explanatory variables was fitted to the longitudinal data after stimulation.
The demographic data of the large volunteer collection encompassing healthy controls; patients with autoimmune thyroid diseases, benign thyroid nodules, and differentiated thyroid cancer; patients with nonthyroidal tumors; and patients with disorders of calcium homeostasis are shown in Table 1.
ANALYTICAL AND DIAGNOSTIC PERFORMANCE
The CT assay demonstrated limits of blank, detection, and quantification of 0.3, 0.5, and 1 ng/L, respectively. The highest intraassay coefficient of variation (CV; n = 21, 5 laboratories) of pooled human samples diluted with plasma matrix was 7.4% in 1 laboratory for the low concentration of 0.8 ng/L. Mean intraassay CVs for CT concentrations of 10, 50, 500, and 1900 ng/L were 1.6 (0.7)% (n = 5 laboratories). With use of the same quality control pools, interassay CVs (2 aliquots were measured on 21 days in 2 separate runs, 3 labs, and 3 lots) were determined according to CLSI-EP5: the highest CV was 7.0% at a CT concentration of 1.1 ng/L. Mean CV was 3.2 (0.8) for all aforementioned CT concentrations. Linearity was tested by CT measurements in a dilution of 1:20 from 16 sera with concentrations greater than cutoff point (median: 167.8, interval 27.1-2324.0 ng/L). Recovery was 92.1 (8.4)% (76.2-105.4%). Spiking of adrenocorticotropin hormone, prolactin, C-peptide, insulin, parathyroid hormone 1-84, calcitonin gene-related peptide, gastrin, elcatonin, catacalcin, and procalcitonin in relevant concentrations did not demonstrate any cross reactivity with serum CT concentrations. The analytical measurement interval of the CT ECLIA was 0.5-2000 ng/L in undiluted sera.
A direct one-to-one comparison between the Cobas ECLIA analyzer (x axis) and the IMMULITE 2000 (see Fig. 1A in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/ content/vol63/issue9) or 1000 (y axis, see Fig. 1B in the online Data Supplement) was performed in different subsets of 102 and 248 controls and patients with CCH and MTC. The 2 assays revealed Passing--Bablok equations of y = 1.2x- 0.3 ng/L and y = 1.0x- 0.1 ng/L, whereas the correlation coefficient (Spearman) was r = 0.93 and r = 0.99 for Cobas analyzer and IMMULITE 2000 or 1000, respectively (P < 0.001 for both).
CT CONCENTRATIONS OF THE PATIENT COHORTS
Reference cutoff values were calculated as the 97.5 th percentile of 2 different healthy cohorts. The German cohort delivered values of 6.4 ng/L (95% CI, 5.2-9.8) and 9.5 ng/L (95% CI, 8.8-14.3) for female and males, respectively. The cutoff of the US cohort was slightly higher with values of 7.6 ng/L (6.1-12.7) and 14.3 ng/L (10.4-18.0) for females and males, respectively. The values peaked at 13 ng/L and 18 ng/L, for female and male controls, respectively (Table 2). The highest serum baseline CT values were noted in patients with untreated MTC of recent onset and in those with persistent metastatic disease. However, several samples from patients with benign thyroidal diseases and nonthyroidal conditions showed increased serum CT concentrations. Patients with renal failure (n = 8, 14%), primary hyperparathyroidism (n = 6, 10.9%), neuroendocrine tumors (n = 5, 10.2%), Graves' disease (GD; n = 5, 4.5%), and benign nodules (n = 8, 2.1%), as well as controls (n = 18, 2.3%), had serum CT concentrations above the 97.5th percentile. Compared with healthy individuals, female German patients with thyroid nodules (n = 147) demonstrated a good agreement in reference cutoff values with 6.8 ng/L (95% CI, 4.7-11.0).
To evaluate the diagnostic performance of the assay, we performed AUC analyses comparing CT results of patients with active (untreated and/or persistent) MTC and CCH with results of controls. In females, the AUC was 0.98, leading to a reference cutoff of 5.9 ng/L, whereas the AUC of males was 0.99, leading to the respective value of 10.4 ng/L (Fig. 1, A and B). Subsequently, we substituted the healthy cohort by patients with various benign disorders and compared the data with the data of those with active MTC. In females, the AUC was 0.98 with a reference cutoff value of 6 ng/L, whereas the AUC of males was 0.99 with a cutoff value of 13.3 ng/L. Diagnostic sensitivity and specificity of female and male subcohorts, respectively, were 100%/97.1% and 96.2%/96.4% for the first approach and 94.1%/ 100% and 94.4%/96.9% for the second approach (Fig. 1, C and D).
Peak serum CT concentrations were reached 2 min after calcium administration in both sexes (Table 3). Serum CT concentrations after stimulation showed a strong dependency on sex (P <0.001, see Fig. 2 in the online Data Supplement) and baseline values (P < 0.001). After removal of 1 male and 9 female probands with baseline values under the detection limit (0.5 ng/L), relative change (fold change) in serum CT concentrations with respect to baseline did not depend on baseline values and did not depend on sex any longer. Two minutes after stimulation, the concentration increased 16.1-fold, with a decay of 7.4%/min thereafter. A model-based 95% reference interval for the fold increase after 2 min amounted to [8.2, 31.6]. In absolute values, CT did not exceed 162 ng/L in males and 112 ng/L in females.
Mild-to-moderate adverse events were observed. Feelings of warmth, paresthesia, sweating, palpitations, and flush were noted within 2 min after calcium injection in 48 (96%), 22 (44%), 20 (40%), 8 (16%), and 7 (14%) volunteers, respectively, and lasted around 2 min. Late side effects, i.e., taste change, dizziness, nausea, and headaches, were observed in 15 (30%), 9 (18%), 5 (10%), and 3 (6%), respectively. These adverse events started approximately 5 min post injection and were present for 20 min maximally.
This first multicenter US and European prospective validation study has demonstrated good analytical performance and clinical utility of a novel highly sensitive CT automated immunoassay in a large study population of healthy controls, patients with various thyroidal and nonthyroidal benign and malignant disorders, as well as in patients with calcium homeostasis disorders. Compared with other commercially available CT assays (6), lower limits of detection, quantification, and lower CVs were noted, independent of the amplitude of serum CT concentrations. For the first time, reference cutoffs were derived from a large collection of healthy controls in 2 different areas, Germany and the US. Despite high variability in the respective confounders of the 2 cohorts (race, use of drugs, thyroid volume, etc.), the calculated cutoff values were comparable with an overlap in the 95% CIs of both cohorts indicating no statistical difference.
This study reveals mild to moderately increased CT concentrations in patients with various benign diseases of the thyroid and of calcium homeostasis. Thus, correct interpretation of serum CT concentrations warrants thorough clinical history and investigation. Further, this study shows that, in adults and in contrast to very young children (15, 16), serum CT concentrations should be interpreted in the setting of sex-specific reference intervals, as suggested by the American Thyroid Association guidelines (2, 9), although most centers to date have a unisex threshold for CT concentrations. Indeed because men physiologically have twice as many C cells as women (17, 18), both basal and stimulated CT secretion are sex-related (3, 4). In this context, it has been demonstrated that sex-specific CT thresholds predict occult MTC more accurately among patients with increased basal CT concentrations than unisex thresholds (4, 11).
This CT immunoassay yielded both high diagnostic sensitivity and specificity, and these diagnostic quality criteria were found to be comparable regardless of whether only healthy subjects, or a mixed-disease cohort of patients with benign diseases of the thyroid and calcium homeostasis, were used for the calculation of the cutoff value. The cutoff found in female patients with thyroid nodules was only marginally higher than the respective interval of healthy females. Nevertheless, the problem of a lower specificity for serum CT concentration in the diagnosis of MTC in subcohorts with non-C-cell diseases must be considered. The frequency of increased CT values in these cohorts was relatively low as compared with published data showing increased serum CT concentration in patients with nonhereditary CCH with Hashimoto thyroiditis, those with renal insufficiency, patients on proton pump inhibitors, smokers, and in those with neuroendocrine tumors (2, 9).
Regarding the role of both basal and stimulated CT measurements in diagnosis, the revised American Thyroid Association management guidelines for MTC offer a dual approach. Some coauthors of these guidelines feel that the sensitivity of the immunochemiluminometric assays is such that provocative testing is no longer necessary; however, others consider provocative testing to be useful in determining the timing of thyroidectomy in children who have inherited a mutated RET allele, in the evaluation of patients with persistent or recurrent MTC, and for detecting MTC in patients with nodular goiters (9).
Our results of the calcium-stimulated CT values revealed higher peak CT values in male volunteers and, in contrast to pentagastrin stimulation, markedly higher CT values (5, 6). Our stimulation data are in line with recent publications (13, 14, 19) but demonstrate a smaller interindividual variation Therefore, the previous assumption that stimulated values higher than 100 ng/L (classically obtained with the pentagastrin test) are suggestive for the presence of MTC has to be carefully reevaluated, as new cutoffs for both sexes ought to be defined on the basis of the results gained with calcium testing. Further, because the calcium stimulations on normal individuals were performed in Germany, the maximum values may be higher in the US.
In conclusion, this sensitive and validated ECLIA for automated serum CT concentration measurement in a large international clinical cohort exhibited excellent analytical performance, thereby providing an accurate and timely diagnosis of CT-related thyroid diseases.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contribution to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: Study grant to the JGU Medical Center from Roche Diagnostics, Penzberg, Germany. T. Davis, Indiana University, T.E. Davis PI, 2012-2013 and Roche, calcitonin sample collection. Expert Testimony: None declared.
Patents: None declared.
Role of Sponsor: The funding organizations played a direct role in the design of study. The funding organizations played no role in the choice of enrolled patients, review and interpretation of data, and final approval of manuscript.
Acknowledgments: The authors are grateful to N. Matheis, M. Kanitz, E. Kolbe, Ch. Fottner, P. von der Saal, N. Schomacher, M. Engler (JGU Thyroid Lab, Mainz, Germany), RE Ostlund (Core Laboratory for Clinical Studies, Washington University, St. Louis, MO), and M. Petruso (Nationwide Laboratory Services, Fort Lauderdale, FL) for data collection; to K. Fell (Leipzig University, Germany) for excellent laboratory work; and to K. Brown and R Kolm (both, Roche Diagnostics) for editorial support and study management.
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George J. Kahaly,  * Alicia Algeciras-Schimnich,  Thomas E. Davis,  Tanja Diana,  Joachim Feldkamp,  Stefan Karger,  Jochem Konig,  Mark A. Lupo,  Friedhelm Raue,  Matthew D. Ringel,  Jennifer A. Sipos,  and Juergen Kratzsch 
 Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes-Gutenberg University Medical Center, Mainz, Germany;  Mayo Clinic, Rochester, MN;  Indiana University School of Medicine, Indianapolis, IN;  City Hospital, Bielefeld, Germany;  Clinic for Endocrinology and Nephrology, Leipzig University, Germany;  Institute of Medical Biostatistics, Epidemiology and Informatics, JGU Medical Center, Mainz, Germany;  Thyroid & Endocrine Center of Florida, Sarasota, FL;  Endocrine Practice, Heidel berg, Germany;  The Ohio State University College of Medicine and Arthur G. James
Comprehensive Cancer Center, Columbus, OH; 10 Institute for Clinical Chemistry,
Leipzig University, Germany.
* Address correspondence to this author at: Johannes Gutenberg University Medical Center, Langenbeckstreet 1, Mainz 55101, Germany. Fax +49-6131-17-3460; e- mail email@example.com.
Received December 9,2016; accepted May 10,2017.
Previously published online at DOI: 10.1373/clinchem.2016.270009
 Nonstandard abbreviations: CT, calcitonin; ECLIA, electrochemiluminescence immunoassay; MTC, medullary thyroid carcinoma; CCH, C-cell hyperplasia; GD, Graves' disease; AUC, area under the curve.
Caption: Fig. 1. ROC curves in the various collectives: ROC curve for the determination of diagnostic sensitivity and specificity in the measurement of CT from healthy females (n = 398) vs female patients with active (untreated and/or persistent) MTC and CCH (n = 32); AUC = 0.98 (95% CI, 0.96-0.99); P < 0.0001; Youden index J: 0.93 (A). ROC curve for the determination of diagnostic sensitivity and specificity in the measurement of CT from healthy males (n = 385) vs male patients with active MTC and CCH (n = 34); AUC = 0.99 (95% CI, 0.98-0.99); P < 0.0001; Youden index J: 0.94 (B). ROC curve for the determination of diagnostic sensitivity and specificity in the measurement of CT from females with thyroid nodules, primary hyperparathyroidism, toxic adenoma, GD, Hashimoto thyroiditis, and renal failure with secondary hyperparathyroidism (n = 644) vs female patients with active MTC or CCH (n = 32); AUC = 0.98 (95% CI, 0.96-0.99); P < 0.0001; Youden index J: 0.94 (C). ROC curve for the determination of diagnostic sensitivity and specificity in the measurement of CT from males with thyroid nodules, hyperparathyroidism, toxic adenoma, GD, HT, and renal failure with secondary hyperparathyroidism (n = 177) vs male patients with active MTC or CCH (n = 34); AUC = 0.99 (95% CI, 0.96-0.99); P <0.0001; Youden index J: 0.99 (D).
Table 1. Demographic data. N (female/male) Age (years) Healthy controls 783 (398/385) 27.0 (20-79) Post-thyroidectomy 126 (97/29) 56.0 (24-90) Benign nodules 375 (298/77) 50.0 (21-99) Toxic adenoma 36 (27/9) 63.0 (29-84) GD 111 (85/26) 47.0 (21-84) HT 187 (161/26) 45.0 (21-74) Hyperparathyroidism 55 (43/12) 61.0 (31-87) Renal failure 57 (30/27) 70.0 (32-85) NET 49 (25/24) 56.0 (24-84) DTC 72 (47/25) 57.0 (27-81) CCH 4(1/3) 53.5 (29-68) MTC (cured) 12 (8/4) 53.0 (35-80) MTC (untreated/persistent) 62(31/31) 55.0 (30-79) Total 1929 (1251/678) 41.0 (20-99) Age values are stated as median values and minimum-maximum. N, number; HT, Hashimoto thyroiditis; NET, neuroendocrine tumor; DTC, differentiated Thyroid cancer. Table 2. Serum CT concentration (ng/L) in all cohorts. Cohort P25 Median P75 Max Controls Female <0.5 0.8 1.8 12.7 Male 1.6 3 5.0 18 Post-thyroidectomy Female <0.5 <0.5 <0.5 2.6 Male <0.5 <0.5 <0.5 0.9 Benign nodules Female <0.5 <0.5 1.4 10.1 Male 1.5 2.6 5.7 21.1 Toxic adenoma Female <0.5 0.7 1.9 8.1 Male 1.2 1.6 5.5 8.0 GD Female <0.5 <0.5 1.7 13.5 Male 1 3 4.5 19.9 HT Female <0.5 <0.5 0.9 10.1 Male 1.8 2.7 5.5 8.7 Hyperparathyroidism Female <0.5 0.8 1.9 11.7 Male 1.1 5.7 13 26.3 Renal failure Female <0.5 1 2 10.4 Male 1.7 4.9 7.7 27.4 NET Female <0.5 <0.5 1.2 869.3 Male 0.7 4.5 7.9 28.6 DTC Female <0.5 <0.5 <0.5 4.7 Male <0.5 <0.5 <0.5 15.2 CCH Female 14.3 14.3 14.3 14.3 Male 14.2 16.6 NA 21.3 MTC (cured) Female <0.5 <0.5 1 1.8 Male <0.5 0.6 5.6 7.2 MTC (untreated/persistent) Female 96.8 218 2227 334 600 Male 284.3 1936 10 950 146800 Total Female <0.5 <0.5 1.5 334 600 Male 1.3 2.9 5.7 146800 Cohort N > P97.5 % Controls Female 9 2.3 Male 9 2.3 Post-thyroidectomy Female 0 0 Male 0 0 Benign nodules Female 5 1.7 Male 3 3.9 Toxic adenoma Female 1 3.7 Male 0 0 GD Female 4 4.7 Male 1 3.8 HT Female 2 1.2 Male 0 0 Hyperparathyroidism Female 2 4.7 Male 4 33.3 Renal failure Female 3 10 Male 5 18.5 NET Female 3 12 Male 2 8.3 DTC Female 0 0 Male 1 4 CCH Female 1 100 Male 3 100 MTC (cured) Female 0 0 Male 0 0 MTC (untreated/persistent) Female 31 100 Male 30 96.8 Total Female 61 4.9 Male 58 8.6 Max, Maximum; P25, P75, and P97.5,25th, 75th and 97.5th percentile; HT, Hashimoto thyroiditis; NET, Neuroendocrine tumor; DTC, Differentiated thyroid cancer. Table 3. Calcium-stimulated serum CT values in healthy volunteers (n = 50). Female Male (N = 25) (N = 25) Age, years Median 24 25 Interval 20-49 21-39 Body mass index, kg/[m.sup.2] Median 21.4 23.6 Interval 18.4-39.1 18.2-29.8 CT, ng/L, at baseline Median 0.9 2.9 Interval <0.5-5.9 <0.5-8.3 CT, ng/L, 1 min after intravenous calcium administration Median 11.7 43.7 Interval 1.4-104.7 8.6-145.2 CT, ng/L, 2 min Median 15.8 43.9 Interval 1.5-111.8 9.1-161.7 CT, ng/L, 3 min Median 15.6 41.8 Interval 1.6-103.1 7.7-144.1 CT, ng/L, 5 min Median 13.2 33.6 Interval 1.6-80.2 6.3-129.8 CT, ng/L, 10 min Median 9.1 25.5 Interval 1.1-50.8 5.8-102 CT, ng/L, total Median 15.8 46.8 Interval 1.6-111.8 9.1-161.7
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|Title Annotation:||Endocrinology and Metabolism|
|Author:||Kahaly, George J.; Algeciras-Schimnich, Alicia; Davis, Thomas E.; Diana, Tanja; Feldkamp, Joachim; K|
|Date:||Sep 1, 2017|
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