Defining normality in a European multinational cohort: Critical factors influencing the 99th percentile upper reference limit for high sensitivity cardiac troponin I

Krintus, Magdalena; Koziński, Marek; Boudry, Pascal; Lackner, Karl J.; Lefèvre, Guillaume; Lennartz, Lieselotte; Lotz, Johannes; Manysiak, Sławomir; Shih, Jessie; Skadberg, Øyvind; Chargui, Ahmed Taoufik; Sypniewska, Grażyna

doi:10.1016/j.ijcard.2015.03.282

Cited by 46 publications

(26 citation statements)

References 36 publications

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“…The proportion with detectable troponin I concentrations ranged between 43.1% and 79.1%, depending on the LoD that is employed (troponin I has an LoD range of 1.1–1.9 ng/L). Previous studies applied a fixed LoD of 1.9 ng/L and reported a range of detectable troponin I concentrations between 64% and 81% 6 16. Percentages of measurable troponin levels stratified by sex are shown in online supplementary table S1.…”

Section: Resultsmentioning

confidence: 99%

“…Second, intrinsic assay differences may play a role, in particular the frequency and distribution of extreme values, where differences across assays can profoundly impact the robustness of the 99th percentile estimation. Third, and of high clinical importance, sex and age differences across reference cohorts may have contributed to substantial heterogeneity 6 11–18…”

Section: Introductionmentioning

confidence: 99%

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Direct comparison of clinical decision limits for cardiac troponin T and I

Kimenai

Henry

Kallen

et al. 2016

Heart

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Direct comparison reveals numerically similar thresholds for hs-cTnT and hs-cTnI assays. This finding is in line with recently reported underdiagnosis of AMI with the current decision limit of 26 ng/L for hs-cTnI, especially among women. Downwards adjustment of the hs-cTnI threshold, differentiated for sex, would equalise clinical decision limits for both assays, and may prevent further underdiagnosis of AMI.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Direct comparison of clinical decision limits for cardiac troponin T and I

Kimenai

Henry

Kallen

et al. 2016

Heart

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“…No studies found significant gender-related differences in cTnI values of pediatric age subjects (Table 2 and Figure 2) [15,33,34,50]. On the other hand, adult males usually present cTnI values that are, on average, twofold higher than those in women; in this age group, the calculated 99th URL values are strongly gender-dependent [14,29,49].…”

Section: Gendermentioning

confidence: 95%

“…A more satisfactory definition of differences in cTnI circulating levels according to gender and age is now available thanks to the highly sensitive method using the ARCHITECT platform, able to measure biomarker values above the LoD value in the majority of healthy subjects from the day of birth to senescence [14,15,33,34,[49][50][51]. No studies found significant gender-related differences in cTnI values of pediatric age subjects (Table 2 and Figure 2) [15,33,34,50].…”

Section: Gendermentioning

confidence: 99%

“…Nor is adequate attention paid to the approach for selecting a "normal" reference population and the criteria to use for calculating the 99th URL value for cTn assays. Indeed, recent studies have demonstrated the importance of the statistical manipulation of data in determining the 99th URL values, in particular regarding the use of more robust statistical methods [26,27,49]. Moreover, some authors suggest the clinical relevance of determining 99th URL values using the popular cTnI and cTnT immunoassays on the same very large reference population in order to better evaluate and accurately compare the differences among methods [9].…”

Section: Future Perspectivesmentioning

confidence: 99%

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The 99th percentile of reference population for cTnI and cTnT assay: methodology, pathophysiology and clinical implications

Clerico

Zaninotto

Ripoli

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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According to recent international guidelines, including the 2012 Third Universal Definiton of Myocardial Infarction by the Joint ESC/ACCF/AHA/WHF Task Force, an increase in cardiac troponin (cTn) levels over the 99th percentile upper reference limit (99th URL) should be considered clinically relevant, this cut-off being measured with an imprecision ≤10 CV%. In theory 99th URL values strongly depend not only on demographic and physiological variables (i.e. criteria for considering the reference population "healthy"), but also on the analytical performance of cTn methods and mathematical algorithms used for the calculation. The aim of the present article was therefore to review the methodological and pathophysiological factors affecting the evaluation and calculation of the 99th URL for cTn assay. The critical analysis made showed that no uniform procedure is followed, and nor have experts or regulatory bodies provided uniform guidelines for researchers or cTn assays manufacturers as an aid in "their quest to define normality". In particular, little attention has been paid to the way in which a healthy reference population is to be selected, or the criteria for calculating the 99th URL value for cTn assays, thus highlighting the need for international recommendations not only for demographic and physiological variables criteria for defining a healthy reference population, but also for calculating mathematical algorithms for establishing/ calculating clinical decision values. An expert consensus group, comprising laboratory and clinical scientists, biomedical statisticians, industrial and regulatory representatives, should be responsible for drawing up these guidelines.

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Determination of high‐sensitivity cardiac troponin T upper reference limits under the improved selection criteria in a Chinese population

Zhang

Han

Zhao

et al. 2019

Clinical Laboratory Analysis

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Background:There is no common consensus on how to define the reference population for determination of high-sensitivity cardiac troponin (hs-cTn) upper reference limit (URL). This study aimed to establish 99th percentile URLs of hs-cTnT under both 2018 AACC/IFCC criteria and improved selection criteria for further judging whether two URLs are different. Methods:Applying the stratified cluster sampling protocol, this study took 1848 apparently healthy subjects in communities of Shenyang China as the screening objects.We first followed 2018 AACC/IFCC criteria using surrogate biomarker for diabetes, myocardial dysfunction, renal dysfunction, and electrocardiogram. Then, we followed improved selection criteria to exclude hypertension, overweight and obesity, and dyslipidemia by physical examination and laboratory screening. Accordingly, 99th percentile URLs of hs-cTnT were established. Results: If the 2018 AACC/IFCC criteria were applied, 99th percentile URLs (90% confidence interval) of hs-cTnT male, female, and total were 19 (17-20) ng/L, 16 (15-17) ng/L, and 18 (16-19) ng/L, respectively. If added a single supplementary selection criteria, 99th percentile URLs of hs-cTnT total reduced to 16 ng/L, 17 ng/L, and 16 ng/L, respectively. If the improved selection criteria were applied, 99th percentile URLs (90% confidence interval) of hs-cTnT male, female, and total were 18 (14-24) ng/L, 13 (11-16) ng/L, and 16 (13-17) ng/L, respectively. The 99th percentile URLs of hs-cTnT male were higher than those of female in every age group. Conclusions: Improved selection criteria through questionnaire survey, physical examination, and laboratory screening to further exclude hypertension, overweight and obesity, and dyslipidemia can avoid overestimation of the 99th percentile URL of hs-cTnT. K E Y W O R D S 99th percentile, high-sensitivity cardiac troponin T, reference population, selection criteria This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Defining normality in a European multinational cohort: Critical factors influencing the 99th percentile upper reference limit for high sensitivity cardiac troponin I

Cited by 46 publications

References 36 publications

Direct comparison of clinical decision limits for cardiac troponin T and I

Direct comparison of clinical decision limits for cardiac troponin T and I

The 99th percentile of reference population for cTnI and cTnT assay: methodology, pathophysiology and clinical implications

Determination of high‐sensitivity cardiac troponin T upper reference limits under the improved selection criteria in a Chinese population

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