Abstract
Background:
While thyroglobulin autoantibodies (TgAb) can result in false low serum thyroglobulin (Tg) immunoassay (IA) measurements, they might also be indicators of disease persistence/recurrence. Hence, accurate TgAb measurement, in addition to Tg quantification, is crucial for thyroid cancer monitoring. We compared the analytical and clinical performance of four commonly used TgAb IAs.
Methods:
We measured Tg by mass spectrometry (Tg-MS) and by four pairs of Tg and TgAb IAs (Beckman, Roche, Siemens, Thermo) in 576 samples. Limit of quantitation (LOQ) and manufacturers’ upper reference interval cut-off (URI) were used for comparisons. Clinical performance was assessed by receiving operator characteristics (ROC) curve analysis.
Results:
Quantitative and qualitative agreement between TgAb-IAs was moderate with R2 of 0.20–0.70 and κ from 0.41–0.66 using LOQ and 0.47–0.71 using URI. In samples with TgAb interference, detection rates of TgAb were similar using LOQ and URI for Beckman, Siemens, and Thermo, but much lower for the Roche TgAb-IA when the URI was used. In TgAb positive cases, the ROC areas under the curve (AUC) for the TgAb-IAs were 0.59 (Beckman), 0.62 (Siemens), 0.59 (Roche), and 0.59 (Thermo), similar to ROC AUCs achieved with Tg. Combining Tg and TgAb measurements improved the ROC AUCs compared to Tg or TgAb alone.
Conclusions:
TgAb-IAs show significant qualitative and quantitative differences. For 2 of the 4 TgAb-IAs, using the LOQ improves the detection of interfering TgAbs. All assays showed suboptimal clinical performance when used as surrogate markers of disease, with modest improvements when Tg and TgAb were combined.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Okosieme OE, Evans C, Moss L, Parkes AB, Premawardhana LD, Lazarus JH. Thyroglobulin antibodies in serum of patients with differentiated thyroid cancer: relationship between epitope specificities and thyroglobulin recovery. Clin Chem 2005;51:729–34.10.1373/clinchem.2004.044511Search in Google Scholar PubMed
2. Hoofnagle AN, Becker JO, Wener MH, Heinecke JW. Quantification of thyroglobulin, a low-abundance serum protein, by immunoaffinity peptide enrichment and tandem mass spectrometry. Clin Chem 2008;54:1796–804.10.1373/clinchem.2008.109652Search in Google Scholar PubMed PubMed Central
3. Kushnir MM, Rockwood AL, Roberts WL, Abraham D, Hoofnagle AN, Meikle AW. Measurement of thyroglobulin by liquid chromatography-tandem mass spectrometry in serum and plasma in the presence of antithyroglobulin autoantibodies. Clin Chem 2013;59:982–90.10.1373/clinchem.2012.195594Search in Google Scholar PubMed PubMed Central
4. Clarke NJ, Zhang Y, Reitz RE. A novel mass spectrometry-based assay for the accurate measurement of thyroglobulin from patient samples containing antithyroglobulin autoantibodies. J Investig Med 2012;60:1157–63.10.2310/JIM.0b013e318276deb4Search in Google Scholar PubMed
5. Spencer C, Petrovic I, Fatemi S, LoPresti J. Serum thyroglobulin (Tg) monitoring of patients with differentiated thyroid cancer using sensitive (second-generation) immunometric assays can be disrupted by false-negative and false-positive serum thyroglobulin autoantibody misclassifications. J Clin Endocrinol Metab 2014;99:4589–99.10.1210/jc.2014-1203Search in Google Scholar PubMed PubMed Central
6. Netzel BC, Grebe SK, Carranza Leon BG, Castro MR, Clark PM, Hoofnagle AN, et al. Thyroglobulin (Tg) testing revisited: Tg assays, TgAb assays, and correlation of results with clinical outcomes. J Clin Endocrinol Metab 2015;100:E1074–83.10.1210/jc.2015-1967Search in Google Scholar PubMed PubMed Central
7. Azmat U, Porter K, Senter L, Ringel MD, Nabhan F. Thyroglobulin liquid chromatography-tandem mass spectrometry has a low sensitivity for detecting structural disease in patients with antithyroglobulin antibodies. Thyroid 2016.10.1089/thy.2016.0210Search in Google Scholar PubMed PubMed Central
8. Hoofnagle AN, Roth MY. Clinical review: improving the measurement of serum thyroglobulin with mass spectrometry. J Clin Endocrinol Metab 2013;98:1343–52.10.1210/jc.2012-4172Search in Google Scholar PubMed PubMed Central
9. Spencer C, Petrovic I, Fatemi S. Current thyroglobulin autoantibody (TgAb) assays often fail to detect interfering TgAb that can result in the reporting of falsely low/undetectable serum Tg IMA values for patients with differentiated thyroid cancer. J Clin Endocrinol Metab 2011;96:1283–91.10.1210/jc.2010-2762Search in Google Scholar PubMed
10. Verburg FA, Luster M, Cupini C, Chiovato L, Duntas L, Elisei R, et al. Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement. Thyroid 2013;23:1211–25.10.1089/thy.2012.0606Search in Google Scholar PubMed
11. Algeciras-Schimnich A, Lasho MA, Ness KM, Cheryk LA, Grebe SK. The Roche Elecsys and Siemens-Centaur thyroglobulin autoantibody assays show comparable clinical performance to the recently unavailable Beckman-Coulter access thyroglobulin autoantibody assay in identifying samples with potentially false-low thyroglobulin measurements due to thyroglobulin autoantibody interference. Thyroid 2011;21:813–4.10.1089/thy.2011.0158Search in Google Scholar PubMed PubMed Central
12. Feldt-Rasmussen U, Verburg FA, Luster M, Cupini C, Chiovato L, Duntas L, et al. Thyroglobulin autoantibodies as surrogate biomarkers in the management of patients with differentiated thyroid carcinoma. Curr Med Chem 2014;21:3687–92.10.2174/0929867321666140826120844Search in Google Scholar PubMed
13. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The american thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1–133.10.1089/thy.2015.0020Search in Google Scholar PubMed PubMed Central
14. McHugh ML. Interrater reliability: the kappa statistic. Biochem Med 2012;22:276–82.10.11613/BM.2012.031Search in Google Scholar
15. Latrofa F, Ricci D, Sisti E, Piaggi P, Nencetti C, Marino M, et al. Significance of low levels of thyroglobulin autoantibodies associated with undetectable thyroglobulin after thyroidectomy for differentiated thyroid carcinoma. Thyroid 2016;26:798–806.10.1089/thy.2015.0621Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Tumor microenvironment and systemic disease: a dual target in medical oncology (also in the case of biomarkers)
- Reviews
- Sample types applied for molecular diagnosis of therapeutic management of advanced non-small cell lung cancer in the precision medicine
- The impact of pneumatic tube system on routine laboratory parameters: a systematic review and meta-analysis
- Opinion Paper
- How to reduce scientific irreproducibility: the 5-year reflection
- EFLM Paper
- Strategies to define performance specifications in laboratory medicine: 3 years on from the Milan Strategic Conference
- General Clinical Chemistry and Laboratory Medicine
- Intensive educational efforts combined with external quality assessment improve the preanalytical phase in general practitioner offices and nursing homes
- Separate patient serum sodium medians from males and females provide independent information on analytical bias
- Are admission procalcitonin levels universal mortality predictors across different medical emergency patient populations? Results from the multi-national, prospective, observational TRIAGE study
- Biochemical testing in a laboratory tent and semi-intensive care of Ebola patients on-site in a remote part of Guinea: a paradigm shift based on a bleach-sensitive point-of-care device
- Efficient reporting of the estimated glomerular filtration rate without height in pediatric patients with cancer
- Evaluation of thyroid test utilization through analysis of population-level data
- Relation of serum γ-glutamyl transferase activity with copper in an adult population
- Impact of a single oral dose of 100,000 IU vitamin D3 on profiles of serum 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 in adults with vitamin D insufficiency
- Automated antinuclear immunofluorescence antibody analysis is a reliable approach in routine clinical laboratories
- Infrared analyzers for breast milk analysis: fat levels can influence the accuracy of protein measurements
- Hematology and Coagulation
- A new approach to define acceptance limits for hematology in external quality assessment schemes
- The effects of transport by car on coagulation tests
- Combined measurement of factor XIII and D-dimer is helpful for differential diagnosis in patients with suspected pulmonary embolism
- Reference Values and Biological Variations
- Influence of age, gender and body mass index on late-night salivary cortisol in healthy adults
- Cancer Diagnostics
- Assessment of real-time PCR method for detection of EGFR mutation using both supernatant and cell pellet of malignant pleural effusion samples from non-small-cell lung cancer patients
- Detection of EGFR mutations in patients with non-small cell lung cancer by high resolution melting. Comparison with other methods
- Predicting outcomes of EGFR-targeted therapy in non-small cell lung cancer patients using pleural effusions samples and peptide nucleic acid probe assay
- Analytical and clinical performance of thyroglobulin autoantibody assays in thyroid cancer follow-up
- Thyroglobulin autoantibodies before radioiodine ablation predict differentiated thyroid cancer outcome
- Cardiovascular Diseases
- Real life dabigatran and metabolite concentrations, focused on inter-patient variability and assay differences in patients with atrial fibrillation
- Infectious Diseases
- HIV avidity index performance using a modified fourth-generation immunoassay to detect recent HIV infections
- Letters to the Editor
- Effect of age on serum prostate-specific antigen in women
- Falsely elevated thyroid-stimulating hormone value due to anti-ruthenium antibodies in a patient with primary hypothyroidism: a case report
- High titers of anti-infliximab antibody do not interfere with Abbott immunoassays
- Extraordinarily elevated serum CA19-9 in a patient with posterior mediastinum cyst: a case report
- Low levels of 25-OH vitamin D in women with endometriosis and associated pelvic pain
- Evaluation of serum cortisol biological variation in the evening withdrawal
- Distinction between urine crystals by automated urine analyzer SediMAX conTRUST is specific but lacks sensitivity
- Impact of heat-inactivation on anti-Toxoplasma IgM antibody levels
Articles in the same Issue
- Frontmatter
- Editorial
- Tumor microenvironment and systemic disease: a dual target in medical oncology (also in the case of biomarkers)
- Reviews
- Sample types applied for molecular diagnosis of therapeutic management of advanced non-small cell lung cancer in the precision medicine
- The impact of pneumatic tube system on routine laboratory parameters: a systematic review and meta-analysis
- Opinion Paper
- How to reduce scientific irreproducibility: the 5-year reflection
- EFLM Paper
- Strategies to define performance specifications in laboratory medicine: 3 years on from the Milan Strategic Conference
- General Clinical Chemistry and Laboratory Medicine
- Intensive educational efforts combined with external quality assessment improve the preanalytical phase in general practitioner offices and nursing homes
- Separate patient serum sodium medians from males and females provide independent information on analytical bias
- Are admission procalcitonin levels universal mortality predictors across different medical emergency patient populations? Results from the multi-national, prospective, observational TRIAGE study
- Biochemical testing in a laboratory tent and semi-intensive care of Ebola patients on-site in a remote part of Guinea: a paradigm shift based on a bleach-sensitive point-of-care device
- Efficient reporting of the estimated glomerular filtration rate without height in pediatric patients with cancer
- Evaluation of thyroid test utilization through analysis of population-level data
- Relation of serum γ-glutamyl transferase activity with copper in an adult population
- Impact of a single oral dose of 100,000 IU vitamin D3 on profiles of serum 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 in adults with vitamin D insufficiency
- Automated antinuclear immunofluorescence antibody analysis is a reliable approach in routine clinical laboratories
- Infrared analyzers for breast milk analysis: fat levels can influence the accuracy of protein measurements
- Hematology and Coagulation
- A new approach to define acceptance limits for hematology in external quality assessment schemes
- The effects of transport by car on coagulation tests
- Combined measurement of factor XIII and D-dimer is helpful for differential diagnosis in patients with suspected pulmonary embolism
- Reference Values and Biological Variations
- Influence of age, gender and body mass index on late-night salivary cortisol in healthy adults
- Cancer Diagnostics
- Assessment of real-time PCR method for detection of EGFR mutation using both supernatant and cell pellet of malignant pleural effusion samples from non-small-cell lung cancer patients
- Detection of EGFR mutations in patients with non-small cell lung cancer by high resolution melting. Comparison with other methods
- Predicting outcomes of EGFR-targeted therapy in non-small cell lung cancer patients using pleural effusions samples and peptide nucleic acid probe assay
- Analytical and clinical performance of thyroglobulin autoantibody assays in thyroid cancer follow-up
- Thyroglobulin autoantibodies before radioiodine ablation predict differentiated thyroid cancer outcome
- Cardiovascular Diseases
- Real life dabigatran and metabolite concentrations, focused on inter-patient variability and assay differences in patients with atrial fibrillation
- Infectious Diseases
- HIV avidity index performance using a modified fourth-generation immunoassay to detect recent HIV infections
- Letters to the Editor
- Effect of age on serum prostate-specific antigen in women
- Falsely elevated thyroid-stimulating hormone value due to anti-ruthenium antibodies in a patient with primary hypothyroidism: a case report
- High titers of anti-infliximab antibody do not interfere with Abbott immunoassays
- Extraordinarily elevated serum CA19-9 in a patient with posterior mediastinum cyst: a case report
- Low levels of 25-OH vitamin D in women with endometriosis and associated pelvic pain
- Evaluation of serum cortisol biological variation in the evening withdrawal
- Distinction between urine crystals by automated urine analyzer SediMAX conTRUST is specific but lacks sensitivity
- Impact of heat-inactivation on anti-Toxoplasma IgM antibody levels