Abstract
Background: The National Academy of Clinical Biochemistry (NACB) stresses that the reference intervals for thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) should be based on young men who lack certain risk factors and have serum TSH between 0.5 and 2.0mIU/L. However, some young men without any of the risk factors have autoantibodies, and cannot be identified by the present tools. A model for reference intervals and cut-off values should not be influenced by the prevalence of risk factors.
Methods: We developed a model of “composite logarithmic Gaussian distributions” and tested it in 1441 well-characterised subjects without clinically overt thyroid disease.
Results: TPOAb and TgAb could be measured in all individuals. The 97.5% upper limits 1) on a traditional non-parametric scale, 2) according to the NACB criteria, and 3) for our model were 284, 24 and 9.8kIU/L for TPOAb, and 84, 22 and 19kIU/L for TgAb, respectively. The decision value (defined as the concentration corresponding to 0.1% false positives) was 15kIU/L for TPOAb and 31kIU/L for TgAb. Concentrations above our reference intervals affected the corresponding distribution of TSH values. For TRAb the upper reference limits were 1) 0.75 and 2) 0.75IU/L, while our model was not applicable to TRAb because only 2–3% of the results were above the functional assay sensitivity.
Conclusions: In contrast to the NACB guidelines, our model for TPOAb and TgAb is more robust, as it is independent of the characteristics of the reference population.
Clin Chem Lab Med 2006;44:991–8.
References
1. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995; 43:55–68.10.1111/j.1365-2265.1995.tb01894.xSearch in Google Scholar
2. d'Herbomez M, Sapin R, Gasser F, Schlienger JL, Wemeau JL. Concordance of eight kits for antithyroid peroxidase autoantibodies determination. Clin Chem Lab Med 2000; 38:561–6.10.1515/CCLM.2000.082Search in Google Scholar
3. Sapin R, d'Herbomez M, Gasser F, Meyer L, Schlienger JL. Increased sensitivity of a new assay for anti-thyroglobulin antibody detection in patients with autoimmune thyroid disease. Clin Biochem 2003; 36:611–6.10.1016/S0009-9120(03)00114-0Search in Google Scholar
4. Zophel K, Saller B, Wunderlich G, Gruning T, Koch R, Wilde J, et al. Autoantibodies to thyroperoxidase (TP-OAb) in a large population of euthyroid subjects: implications for the definition of TPOAb reference intervals. Clin Lab 2003; 49:591–600.Search in Google Scholar
5. Tozzoli R, Bizzaro N, Tonutti E, Pradella M, Manoni F, Vilalta D, et al. Immunoassay of anti-thyroid autoantibodies: high analytical variability in second generation methods. Clin Chem Lab Med 2002; 40:568–73.10.1515/CCLM.2002.098Search in Google Scholar
6. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13:3–126.10.1089/105072503321086962Search in Google Scholar
7. Hoffmann RG. Statistics in the practice of medicine. J Am Med Assoc 1963; 185:864–73.10.1001/jama.1963.03060110068020Search in Google Scholar
8. Amador E, Hsi BP. Indirect methods for estimating the normal range. Am J Clin Pathol 1969; 52:538–46.10.1093/ajcp/52.5.538Search in Google Scholar
9. Bhattacharya C. A simple method of resolution of a distribution into Gaussian components. Biometrics 1967; 23:115–35.10.2307/2528285Search in Google Scholar
10. Oosterhuis WP, Modderman TA, Pronk C. Reference values: Bhattacharya or the method proposed by the IFCC? Ann Clin Biochem 1990; 27:359–65.10.1177/000456329002700413Search in Google Scholar
11. Pryce JD. Level of haemoglobin in whole blood and red blood-cells, and proposed convention for defining normality. Lancet 1960; 2:333–6.10.1016/S0140-6736(60)91480-XSearch in Google Scholar
12. Baadenhuijsen H, Smit JC. Indirect estimation of clinical chemical reference intervals from total hospital patient data: application of a modified Bhattacharya procedure. J Clin Chem Clin Biochem 1985; 23:829–39.10.1515/cclm.1985.23.12.829Search in Google Scholar PubMed
13. Elveback LR, Guillier CL, Keating FR. Health, normality, and the ghost of Gauss. J Am Med Assoc 1970; 211:69–75.10.1001/jama.1970.03170010023004Search in Google Scholar
14. Van Peenen HJ, Lingberg DA. Limitations of laboratory quality control with reference to the “number plus” method. Am J Clin Pathol 1965; 44:322–30.10.1093/ajcp/44.3.322Search in Google Scholar PubMed
15. Cichinelli AL. The composite of two Gaussian distributions as a model for blood pressure distributions in man. Thesis. Ann Arbor, MI: University of Michigan, 1963.Search in Google Scholar
16. Jensen E, Hyltoft Petersen P, Blaabjerg O, Hansen PS, Brix TH, Hegedüs L. Establishment of a serum TSH reference interval in healthy adults. The importance of environmental factors, including thyroid antibodies. Clin Chem Lab Med 2004; 42:824–32.Search in Google Scholar
17. Hansen PS, Brix TH, Sørensen TI, Kyvik KO, Hegedüs L. Major genetic influence on the regulation of the pituitary-thyroid axis. A study of healthy Danish twins. J Clin Endocrinol Metab 2004; 89:1181–7.10.1210/jc.2003-031641Search in Google Scholar PubMed
18. Jensen E, Hyltoft Petersen P, Blaabjerg O, Hansen PS, Hegedüs L. Improved sensitivity of a TSH-receptor antibody method. Clin Chem 2005; 51:2186–7.10.1373/clinchem.2005.054676Search in Google Scholar PubMed
19. Lahti A, Hyltoft Petersen P, Boyd JC, Fraser CG, Jørgensen N. Objective criteria for partitioning Gaussian-distributed reference values into subgroups. Clin Chem 2002; 48:338–52.10.1093/clinchem/48.2.338Search in Google Scholar
20. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. J Am Med Assoc 2004; 291:228–38.10.1001/jama.291.2.228Search in Google Scholar PubMed
21. Pedersen IB, Knudsen N, Jørgensen T, Perrild H, Ovesen L, Laurberg P. Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clin Endocrinol 2003; 58:36–42.10.1046/j.1365-2265.2003.01633.xSearch in Google Scholar PubMed
22. Eskelinen S, Suominen P, Vahlberg T, Löpönen M, Isoaho R, Kivelä S-L, et al. The effect of thyroid antibody positivity on reference intervals for thyroid stimulation hormones (TSH) and free thyroxine (fT4) in an aged population. Clin Chem Lab Med 2005; 43:1380–5.10.1515/CCLM.2005.236Search in Google Scholar PubMed
23. Hoogendoorn EH, Hermus AR, de Vegt F, Ross HA, Verbeek AL, Kiemeney LA, et al. Thyreoid function and prevalence of anti-thyroperoxidase antibodies in a population with borderline sufficient iodine intake: influence of age and sex. Clin Chem 2006; 52:104–11.10.1373/clinchem.2005.055194Search in Google Scholar PubMed
24. Pedersen IB, Knudsen N, Jørgensen T, Perrild H, Ovesen L, Laurberg P. Large differences in incidences of overt hyper- and hypothyroidism associated with a small difference in iodine intake: a prospective comparative register-based population survey. J Clin Endocrinol Metab 2002; 87:4462–9.10.1210/jc.2002-020750Search in Google Scholar PubMed
25. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977; 7:481–93.10.1111/j.1365-2265.1977.tb01340.xSearch in Google Scholar PubMed
26. Hyltoft Petersen P, Blaabjerg O, Andersen M, Jorgensen LG, Schousboe K, Jensen E. Graphical interpretation of confidence curves in rankit plots. Clin Chem Lab Med 2004; 42:715–24.Search in Google Scholar
27. Bliss CI. Statistics in biology. New York: McGraw-Hill, 1967–1970.Search in Google Scholar
28. Hald A. Statistical theory with engineering applications. New York: John Wiley & Sons, 1952.Search in Google Scholar
29. Altman DG. Practical statistics for medical research. London: Chapman & Hall, 1991.10.1201/9780429258589Search in Google Scholar
30. Lund E, Blaabjerg O, Blom M, Hyltoft Petersen P, Rahbek Nørgaard J, Uldall A, et al. Reference intervals for α1-antitrypsin. Upsala J Med Sci 1994; 99:339–46.10.3109/03009739409179377Search in Google Scholar
31. Johnson AM, Hyltoft Petersen P, Whicher JT, Carlström A, MacLennan S, International Federation of Clinical Chemistry and Laboratory Medicine, Committee on Plasma Proteins. Reference intervals for serum proteins: similarities and differences between adult Caucasian and Asian Indian males in Yorkshire, UK. Clin Chem Lab Med 2004; 42:792–9.10.1515/CCLM.2004.132Search in Google Scholar PubMed
32. Lentner C, editor. Geigy Scientific Tables, vol 2, 8th ed. Basel: Ciba-Geigy, 1982.Search in Google Scholar
©2006 by Walter de Gruyter Berlin New York