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Clin Chem. 2009 Nov;55(11):2019-25. doi: 10.1373/clinchem.2009.124560. Epub 2009 Aug 27.

Composite reference interval for thyroid-stimulating hormone and free thyroxine, comparison with common cutoff values, and reconsideration of subclinical thyroid disease.

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Department of Chemical Endocrinology and Department of Endocrinology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.



Examination of the 2-dimensional probability distribution of thyroid-stimulating hormone (TSH) and free thyroxine (FT(4)) shows that the widths of the TSH and FT(4) reference intervals derived from this bivariate distribution are mutually interdependent, an aspect commonly ignored when interpreting thyroid testing results with separate reference intervals for TSH and FT(4). We desired to establish and critically evaluate a composite reference interval for TSH and FT(4) to allow bivariate classification of biochemical thyroid conditions.


FT(4) and TSH results of 871 healthy individuals [361 women and 510 men, 18-40 years old, without history of thyroid-related disease or medication, negative for anti-thyroid peroxidase (anti-TPO) antibody] were transformed to standard normal variables by logarithmic transformation with correction for skewness and subsequent normalization. We established a 95% reference interval of the distance of each FT(4)/TSH pair of values to the center of the 2-dimensional probability distribution.


The bivariate 95% reference interval is enclosed by a circular profile with radius 2.45 SD. By contrast, conventional reference intervals comprise a square with the boundaries of -1.96 and +1.96 SD for both FT(4) and TSH that enclose only 90% of all data. Compared with the +/-1.96 SD square, the bivariate reference interval classified 4% fewer of 3651 healthy individuals older than 40 years as subclinically hyperthyroid and 14% fewer of 712 anti-TPO-positive healthy individuals as subclinically hypothyroid.


Conventional application of separate cutoff values for FT(4) and TSH leads to overestimation of the incidence of subclinical thyroid disease. Application of a composite overall reference interval is recommended.

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