Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine

Mirko Peitzsch; Talia Novos; Denise Kaden; Max Kurlbaum; Antonius E. van Herwaarden; Daniel Mueller; Jo Adaway; Eric Grouzmann; Brett McWhinney; Kirsten Hoad; Gerald Woollard; Ido Kema; Christopher Boot; Martin Fassnacht; Fred Sweep; Tze P. Loh; Andrea R. Horvath; Graeme Eisenhofer

doi:10.1093/clinchem/hvab060

Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine

Mirko Peitzsch^*, Talia Novos, Denise Kaden, Max Kurlbaum, Antonius E. van Herwaarden, Daniel Mueller, Jo Adaway, Eric Grouzmann, Brett McWhinney, Kirsten Hoad, Gerald Woollard, Ido Kema, Christopher Boot, Martin Fassnacht, Fred Sweep, Tze P. Loh, Andrea R. Horvath, Graeme Eisenhofer

^*Corresponding author voor dit werk

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Background: Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results.

Methods: 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined.

Results: Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R >= 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2% (-11.6% to 16.0%) for metanephrine and 0.1% (-18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine.

Conclusions: Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.

Originele taal-2	English
Pagina's (van-tot)	1098-1112
Aantal pagina's	15
Tijdschrift	Clinical Chemistry
Volume	67
Nummer van het tijdschrift	8
DOI's	https://doi.org/10.1093/clinchem/hvab060
Status	Published - aug.-2021

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10.1093/clinchem/hvab060

Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-MethoxytyramineFinal publisher's version, 729 KBLicentie: Taverne

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Peitzsch, M., Novos, T., Kaden, D., Kurlbaum, M., van Herwaarden, A. E., Mueller, D., Adaway, J., Grouzmann, E., McWhinney, B., Hoad, K., Woollard, G., Kema, I., Boot, C., Fassnacht, M., Sweep, F., Loh, T. P., Horvath, A. R., & Eisenhofer, G. (2021). Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine. Clinical Chemistry, 67(8), 1098-1112. https://doi.org/10.1093/clinchem/hvab060

@article{db366c20195a4cb18e9f007ccb44fe54,

title = "Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine",

abstract = "Background: Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results.Methods: 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined.Results: Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R >= 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2\% (-11.6\% to 16.0\%) for metanephrine and 0.1\% (-18.0\% to 9.5\%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2\% to 64.0\%. Interrater agreement in test interpretation was >94\% for metanephrine and >84\% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine.Conclusions: Analytical methods for metanephrines are well harmonized between laboratories. However, the 16\% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.",

keywords = "harmonization, standardization, metanephrines, pheochromocytoma, paraganglioma, LC-MS, MS, TANDEM MASS-SPECTROMETRY, REFERENCE INTERVALS, LIQUID-CHROMATOGRAPHY, CLINICAL-PRACTICE, TSH IMMUNOASSAYS, PHEOCHROMOCYTOMA, DIAGNOSIS, STANDARDIZATION, PARAGANGLIOMA, INTERFERENCE",

author = "Mirko Peitzsch and Talia Novos and Denise Kaden and Max Kurlbaum and \{van Herwaarden\}, \{Antonius E.\} and Daniel Mueller and Jo Adaway and Eric Grouzmann and Brett McWhinney and Kirsten Hoad and Gerald Woollard and Ido Kema and Christopher Boot and Martin Fassnacht and Fred Sweep and Loh, \{Tze P.\} and Horvath, \{Andrea R.\} and Graeme Eisenhofer",

year = "2021",

month = aug,

doi = "10.1093/clinchem/hvab060",

language = "English",

volume = "67",

pages = "1098--1112",

journal = "Clinical Chemistry",

issn = "0009-9147",

publisher = "AMER ASSOC CLINICAL CHEMISTRY",

number = "8",

}

Peitzsch, M, Novos, T, Kaden, D, Kurlbaum, M, van Herwaarden, AE, Mueller, D, Adaway, J, Grouzmann, E, McWhinney, B, Hoad, K, Woollard, G, Kema, I, Boot, C, Fassnacht, M, Sweep, F, Loh, TP, Horvath, AR & Eisenhofer, G 2021, 'Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine', Clinical Chemistry, vol. 67, nr. 8, blz. 1098-1112. https://doi.org/10.1093/clinchem/hvab060

TY - JOUR

T1 - Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine

AU - Peitzsch, Mirko

AU - Novos, Talia

AU - Kaden, Denise

AU - Kurlbaum, Max

AU - van Herwaarden, Antonius E.

AU - Mueller, Daniel

AU - Adaway, Jo

AU - Grouzmann, Eric

AU - McWhinney, Brett

AU - Hoad, Kirsten

AU - Woollard, Gerald

AU - Kema, Ido

AU - Boot, Christopher

AU - Fassnacht, Martin

AU - Sweep, Fred

AU - Loh, Tze P.

AU - Horvath, Andrea R.

AU - Eisenhofer, Graeme

PY - 2021/8

Y1 - 2021/8

N2 - Background: Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results.Methods: 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined.Results: Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R >= 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2% (-11.6% to 16.0%) for metanephrine and 0.1% (-18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine.Conclusions: Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.

AB - Background: Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results.Methods: 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined.Results: Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R >= 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2% (-11.6% to 16.0%) for metanephrine and 0.1% (-18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine.Conclusions: Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.

KW - harmonization

KW - standardization

KW - metanephrines

KW - pheochromocytoma

KW - paraganglioma

KW - LC-MS

KW - MS

KW - TANDEM MASS-SPECTROMETRY

KW - REFERENCE INTERVALS

KW - LIQUID-CHROMATOGRAPHY

KW - CLINICAL-PRACTICE

KW - TSH IMMUNOASSAYS

KW - PHEOCHROMOCYTOMA

KW - DIAGNOSIS

KW - STANDARDIZATION

KW - PARAGANGLIOMA

KW - INTERFERENCE

U2 - 10.1093/clinchem/hvab060

DO - 10.1093/clinchem/hvab060

M3 - Article

SN - 0009-9147

VL - 67

SP - 1098

EP - 1112

JO - Clinical Chemistry

JF - Clinical Chemistry

IS - 8

ER -

Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine

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