Raising awareness of chronic measurement error intrinsic to immunoassay measurements of small molecule analytes

in European Journal of Endocrinology
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  • 1 Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
  • 2 Pituitary Institute, Pacific Neuroscience Institute, John Wayne Cancer Institute, Santa Monica, California, USA
  • 3 Division of Endocrinology and Metabolism, National Institute of Diabetes, Digestive and Kidney Disease, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
  • 4 Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, District of Columbia, USA

Correspondence should be addressed to S J Soldin; Email: steven.soldin@nih.gov

In the recently published methodology editorial, ‘Measurement error in clinical research, yes it matters’, authors Groenwold et al. raise concerns about how measurement error and misclassification can affect the validity of biomedical studies (1). In their editorial, Groenwold et al. warn clinicians and researchers that bias due to error-prone data, for example drawing conclusions from a data set of ‘self-reported’ values as opposed to ‘true’ objectively measured values, lead to unsubstantiated claims in the literature. While it is absolutely essential to acknowledge that error can occur from many difficult-to-document variables such as BMIs or smoking habits, it is also important to point out that many of the so-called ‘objective’ laboratory measurements which are considered to be ‘true’ values are subject not only to bias, but far more importantly, to inaccuracy which is inherent in many immunoassays (thyroid hormones and cortisol are examples) and intrinsic to the method (IA) by which they are measured. Not only can these mistakenly ‘objective’ immunoassay measurements lead to unsubstantiated claims in the literature, more importantly, they frequently result in the misdiagnosis and mistreatment of patients in routine clinical practice. For example, high concentrations of cortisol binding globulin are associated with falsely low immunoassay cortisol measurements. These can lower what is a high cortisol by mass spectrometry after Synacthen stimulation (normal adrenal response) and be misinterpreted when the measured immunoassay result is falsely low suggesting adrenal insufficiency.

Over the past 30 years, our laboratory has documented significant discrepancies between the clinical presentation of patients suffering from thyroid or adrenal disorders, and the laboratory values obtained by immunoassay measurements of these analytes (2, 3, 4, 5, 6, 7, 8, 9, 10). In these cases, when liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed, the laboratory values correlated with the clinical presentations and aided in efficient diagnoses and correct treatment (11). In a recent, currently submitted for publication study, we have found that immunoassay results for small molecule hormones (thyroxine, triiodothyronine, and cortisol) are affected by both high and low concentrations of their respective binding proteins (thyroxine-binding globulin and corticosteroid-binding globulin). As binding globulin concentrations are known to vary under conditions such as pregnancy, renal diseases and the use of commonly prescribed medications such as oral contraceptives (7) and steroids, our study brings into question the accuracy of immunoassay measurements for a large population of patients (in the USA 65% of women between 15 and 49 years of age are taking oral contraceptives) (12). Moreover, some of the commonly used supplements, like biotin, interfere with immunoassays leading to false results (13).

The clinical laboratories of many institutions opt to support their endocrinology departments by providing immunoassay-testing platforms. We urge clinicians to be wary of inaccurate immunoassay values for small molecule hormones, and to advocate for LC-MS/MS testing services for the measurement of thyroid hormones and cortisol, especially when laboratory values do not match the clinical presentation of the patient.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this letter.

Funding

Relevant research on binding protein effects by the Soldin Laboratory referenced in this letter is funded by Dr Soldin’s NIH Intramural Research Award.

Author contribution statement

Anastasia Gant Kanegusuku writing-original draft preparation; writing-review and editing. Katherine Araque writing-original draft preparation; writing-review and editing. Joanna Klubo-Gwiezdzinska writing-review and editing. Steven J Soldin conceptualization; resources; writing-original draft preparation; writing-review and editing.

References

  • 1

    Groenwold RHH & Dekkers OM Measurement error in clinical research, yes is matters. European Journal of Endocrinology 2020 183 E3E5. (https://doi.org/10.1530/EJE-20-0550)

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  • 2

    Soldin OP & Soldin SJ Thyroid hormone testing by tandem mass spectrometry. Clinical Biochemistry 2011 44 8994. (https://doi.org/10.1016/j.clinbiochem.2010.07.020)

    • Search Google Scholar
    • Export Citation
  • 3

    van Deventer HE, Mendu DR, Remaley AT & Soldin SJ Inverse log-linear relationship between thyroid-stimulating hormone and free thyroxine measured by direct analog immunoassay and tandem mass spectrometry. Clinical Chemistry 2011 57 122127. (https://doi.org/10.1373/clinchem.2010.154088)

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    • Export Citation
  • 4

    Gounden V, Jonklaas J & Soldin SJ A pilot study: subclinical hypothyroidism and free thyroid hormone measurement by immunoassay and mass spectrometry. Clinica Chimica Acta: International Journal of Clinical Chemistry 2014 430 121124. (https://doi.org/10.1016/j.cca.2013.12.034)

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    • Export Citation
  • 5

    Jonklaas J, Kahric-Janicic N, Soldin OP & Soldin SJ Correlations of free thyroid hormones measured by tandem mass spectrometry and immunoassay with thyroid-stimulating hormone across 4 patient populations. Clinical Chemistry 2009 55 13801388. (https://doi.org/10.1373/clinchem.2008.118752)

    • Search Google Scholar
    • Export Citation
  • 6

    Jonklaas J, Sathasivan A, Wang H, Gu J, Burman KD & Soldin SJ Total and free thyroxine and triiodothyronine: measurement discrepancies, particularly in inpatients. Clinical Biochemistry 2014 47 12721278. (https://doi.org/10.1016/j.clinbiochem.2014.06.007)

    • Search Google Scholar
    • Export Citation
  • 7

    Masika LS, Zhao Z & Soldin SJ Is measurement of TT3 by immunoassay reliable at low concentrations? A comparison of the Roche Cobas 6000 vs. LC-MSMS. Clinical Biochemistry 2016 49 846849. (https://doi.org/10.1016/j.clinbiochem.2016.02.004)

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    • Export Citation
  • 8

    Parikh TP, Stolze B, Ozarda Y, Jonklaas J, Welsh K, Masika L, Hill M, DeCherney A & Soldin SJ Diurnal variation of steroid hormones and their reference intervals using mass spectrometric analysis. Endocrine Connections 2018 7 13541361. (https://doi.org/10.1530/EC-18-0417)

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    • Export Citation
  • 9

    Haq N, Araque KA, Gant Kanegusuku AL, Wei B & Soldin SJ Are serum cortisol measurements by immunoassays reliable? A case series. Medical Research Archives 2020 8. (https://doi.org/10.18103/mra.v8i5.2128)

    • Search Google Scholar
    • Export Citation
  • 10

    Araque KA, Klubo-Gwiezdzinska J, Nieman LK, Welsh K & Soldin SJ Assessment of thyroid function and harmonization: opinion on thyroid hormone harmonization. Therapeutic Advances in Endocrinology and Metabolism 2019 10 14. (https://doi.org/10.1177/2042018819897049)

    • Search Google Scholar
    • Export Citation
  • 11

    Welsh KJ & Soldin SJ DIAGNOSIS OF ENDOCRINE DISEASE: How reliable are free thyroid and total T3 hormone assays? European Journal of Endocrinology 2016 175 R255R263. (https://doi.org/10.1530/EJE-16-0193)

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    • Export Citation
  • 12

    Daniels K & Abma JC Current contraceptive status among women aged 15–49: United States, 2015–2017. NCHS Data Brief, 2018. (available at: https://www.cdc.gov/nchs/products/databriefs/db327.htm). Accessed on 16 July 2020.

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  • 13

    Katzman BM, Lueke AJ, Donato LJ, Jaffe AS & Baumann NA Prevalence of biotin supplement usage in outpatients and plasma biotin concentrations in patients presenting to the emergency department. Clinical Biochemistry 2018 60 1116. (https://doi.org/10.1016/j.clinbiochem.2018.07.004)

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    • Export Citation

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  • 1

    Groenwold RHH & Dekkers OM Measurement error in clinical research, yes is matters. European Journal of Endocrinology 2020 183 E3E5. (https://doi.org/10.1530/EJE-20-0550)

    • Search Google Scholar
    • Export Citation
  • 2

    Soldin OP & Soldin SJ Thyroid hormone testing by tandem mass spectrometry. Clinical Biochemistry 2011 44 8994. (https://doi.org/10.1016/j.clinbiochem.2010.07.020)

    • Search Google Scholar
    • Export Citation
  • 3

    van Deventer HE, Mendu DR, Remaley AT & Soldin SJ Inverse log-linear relationship between thyroid-stimulating hormone and free thyroxine measured by direct analog immunoassay and tandem mass spectrometry. Clinical Chemistry 2011 57 122127. (https://doi.org/10.1373/clinchem.2010.154088)

    • Search Google Scholar
    • Export Citation
  • 4

    Gounden V, Jonklaas J & Soldin SJ A pilot study: subclinical hypothyroidism and free thyroid hormone measurement by immunoassay and mass spectrometry. Clinica Chimica Acta: International Journal of Clinical Chemistry 2014 430 121124. (https://doi.org/10.1016/j.cca.2013.12.034)

    • Search Google Scholar
    • Export Citation
  • 5

    Jonklaas J, Kahric-Janicic N, Soldin OP & Soldin SJ Correlations of free thyroid hormones measured by tandem mass spectrometry and immunoassay with thyroid-stimulating hormone across 4 patient populations. Clinical Chemistry 2009 55 13801388. (https://doi.org/10.1373/clinchem.2008.118752)

    • Search Google Scholar
    • Export Citation
  • 6

    Jonklaas J, Sathasivan A, Wang H, Gu J, Burman KD & Soldin SJ Total and free thyroxine and triiodothyronine: measurement discrepancies, particularly in inpatients. Clinical Biochemistry 2014 47 12721278. (https://doi.org/10.1016/j.clinbiochem.2014.06.007)

    • Search Google Scholar
    • Export Citation
  • 7

    Masika LS, Zhao Z & Soldin SJ Is measurement of TT3 by immunoassay reliable at low concentrations? A comparison of the Roche Cobas 6000 vs. LC-MSMS. Clinical Biochemistry 2016 49 846849. (https://doi.org/10.1016/j.clinbiochem.2016.02.004)

    • Search Google Scholar
    • Export Citation
  • 8

    Parikh TP, Stolze B, Ozarda Y, Jonklaas J, Welsh K, Masika L, Hill M, DeCherney A & Soldin SJ Diurnal variation of steroid hormones and their reference intervals using mass spectrometric analysis. Endocrine Connections 2018 7 13541361. (https://doi.org/10.1530/EC-18-0417)

    • Search Google Scholar
    • Export Citation
  • 9

    Haq N, Araque KA, Gant Kanegusuku AL, Wei B & Soldin SJ Are serum cortisol measurements by immunoassays reliable? A case series. Medical Research Archives 2020 8. (https://doi.org/10.18103/mra.v8i5.2128)

    • Search Google Scholar
    • Export Citation
  • 10

    Araque KA, Klubo-Gwiezdzinska J, Nieman LK, Welsh K & Soldin SJ Assessment of thyroid function and harmonization: opinion on thyroid hormone harmonization. Therapeutic Advances in Endocrinology and Metabolism 2019 10 14. (https://doi.org/10.1177/2042018819897049)

    • Search Google Scholar
    • Export Citation
  • 11

    Welsh KJ & Soldin SJ DIAGNOSIS OF ENDOCRINE DISEASE: How reliable are free thyroid and total T3 hormone assays? European Journal of Endocrinology 2016 175 R255R263. (https://doi.org/10.1530/EJE-16-0193)

    • Search Google Scholar
    • Export Citation
  • 12

    Daniels K & Abma JC Current contraceptive status among women aged 15–49: United States, 2015–2017. NCHS Data Brief, 2018. (available at: https://www.cdc.gov/nchs/products/databriefs/db327.htm). Accessed on 16 July 2020.

    • Search Google Scholar
    • Export Citation
  • 13

    Katzman BM, Lueke AJ, Donato LJ, Jaffe AS & Baumann NA Prevalence of biotin supplement usage in outpatients and plasma biotin concentrations in patients presenting to the emergency department. Clinical Biochemistry 2018 60 1116. (https://doi.org/10.1016/j.clinbiochem.2018.07.004)

    • Search Google Scholar
    • Export Citation