Indirect reference intervals for thyroid function tests: refineR, RefLim and effects of pathological test results

Finn Erik Aas; Alexander Bauer Westbye; Magnus A R Husøy; Oskar E Kelp; Svetlana N Zykova; Per M Thorsby

doi:10.1016/j.clinbiochem.2026.111101

Indirect reference intervals for thyroid function tests: refineR, RefLim and effects of pathological test results

Clin Biochem. 2026 Mar:142:111101. doi: 10.1016/j.clinbiochem.2026.111101. Epub 2026 Feb 15.

Authors

Finn Erik Aas¹, Alexander Bauer Westbye², Magnus A R Husøy³, Oskar E Kelp², Svetlana N Zykova², Per M Thorsby⁴

Affiliations

¹ Hormone Laboratory, Dept. Medical Biochemistry, Oslo University Hospital, Aker, PO Box 4959 Nydalen, 0424 Oslo, Norway; Endocrinology and Metabolism Research Group, Oslo University Hospital, Aker, PO Box 4959 Nydalen, 0424 Oslo, Norway. Electronic address: fieaas@ous-hf.no.
² Hormone Laboratory, Dept. Medical Biochemistry, Oslo University Hospital, Aker, PO Box 4959 Nydalen, 0424 Oslo, Norway; Endocrinology and Metabolism Research Group, Oslo University Hospital, Aker, PO Box 4959 Nydalen, 0424 Oslo, Norway.
³ Laboratory of Medical Biochemistry, Innlandet Hospital Trust, 2609 Lillehammer, Norway.
⁴ Hormone Laboratory, Dept. Medical Biochemistry, Oslo University Hospital, Aker, PO Box 4959 Nydalen, 0424 Oslo, Norway; Endocrinology and Metabolism Research Group, Oslo University Hospital, Aker, PO Box 4959 Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, PO Box 1171 - Blindern, 0318 Oslo, Norway.

PMID: 41702486
DOI: 10.1016/j.clinbiochem.2026.111101

Abstract

Background: Biochemical tests with reference intervals (RIs) are extensively used in medicine. RIs should reflect the population tested, and indirect methods for RI construction are increasingly used. Thyroid function tests (TFTs) are used to diagnose and monitor thyroid disorders, that are especially common among women. We report investigations into factors that influence indirect TFT RIs using real world data.

Methods: Indirect RIs were calculated (refineR and RefLim) for two laboratories with very different proportions of pathological results for thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3), all measured on Abbott Alinity i. For one laboratory total thyroxine (TT4) and total triiodothyronine (TT3) were also investigated. Effects of pathological results on indirect RIs were investigated and indirect RIs were compared to direct RIs from Abbott and from a reference population (HUNT4).

Results: Some TFT RIs differed markedly between the two laboratories, but removal of suspected pathological results reduced the discrepancy. Choice of algorithm for indirect RIs influenced the RIs, and indirect RIs were wider than the direct RIs from HUNT4. Most of our calculated RIs - from indirect (real world data) or direct (HUNT4) methods - were markedly narrower than Abbott-provided RIs, particularly for FT4 and FT3.

Conclusions: Indirect RIs for TFT are easily calculated but are affected by several factors that laboratories should be aware of. Manufacturer-provided RIs can differ markedly from in-house RIs.

Keywords: HUNT4; Indirect reference interval; Thyroid; refineR.

MeSH terms

Adult
Algorithms
Female
Humans
Male
Middle Aged
Reference Values
Thyroid Diseases* / blood
Thyroid Diseases* / diagnosis
Thyroid Function Tests* / methods
Thyroid Function Tests* / standards
Thyroid Gland
Thyrotropin / blood
Thyroxine* / blood
Triiodothyronine* / blood

Substances

Triiodothyronine
Thyroxine
Thyrotropin