Establishing consensus-based, assay-specific 99th percentile upper reference limits to facilitate proper utilization of cardiac troponin measurements

AbstractImplementation of the 99th percentile as the upper reference limit for cardiac troponin (cTn) assays is a seemingly lucid recommendation, but, in reality, is incredibly complex. Lack of harmonization between cTn assays diminishes the ability to have a single medical decision point across manufacturer assay/instruments. Moreover, even within a single cTn assay there are several published values corresponding to the “99th percentile”. Variability in the determined value is primarily a function of population selection including: sample size, age, sex, exclusion criteria, and statistical methods. Given the complexities associated with this value, some countries have taken an expert consensus approach to endorsing harmonized, assay-specific, cTn 99th percentile values. The purpose of this manuscript is to highlight the intricacies associated with selecting a cTn 99th percentile and to review the approach that Australia used to endorse a nationwide upper reference limit for the Architect STAT hs-cTnI assay.

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High-Sensitivity Cardiac Troponin T for Risk Stratification in Patients With Embolic Stroke of Undetermined Source

Stroke ◽

10.1161/strokeaha.120.029628 ◽

2020 ◽

Vol 51 (8) ◽

pp. 2386-2394 ◽

Cited By ~ 2

Author(s):

Jan F. Scheitz ◽

Guillaume Pare ◽

Lesly A. Pearce ◽

Hardi Mundl ◽

W. Frank Peacock ◽

...

Keyword(s):

Ischemic Stroke ◽

Risk Stratification ◽

Cardiac Troponin ◽

Troponin T ◽

High Sensitivity ◽

Embolic Stroke ◽

Cardiac Troponin T ◽

Reference Limit ◽

End Point ◽

Upper Reference Limit

Background and Purpose: Optimal secondary prevention for patients with embolic stroke of undetermined source (ESUS) remains unknown. We aimed to assess whether high-sensitivity cardiac troponin T (hs-cTnT) levels are associated with major vascular events and whether hs-cTnT may identify patients who benefit from anticoagulation following ESUS. Methods: Data were obtained from the biomarker substudy of the NAVIGATE ESUS trial, a randomized controlled trial testing the efficacy of rivaroxaban versus aspirin for secondary stroke prevention in ESUS. Patients were dichotomized at the hs-cTnT upper reference limit (14 ng/L, Gen V, Roche Diagnostics). Cox proportional hazard models were computed to explore the association between hs-cTnT, the combined cardiovascular end point (recurrent stroke, myocardial infarction, systemic embolism, cardiovascular death), and recurrent ischemic stroke. Results: Among 1337 patients enrolled at 111 participating centers in 18 countries (mean age 67±9 years, 61% male), hs-cTnT was detectable in 95% and at/above the upper reference limit in 21%. During a median follow-up of 11 months, the combined cardiovascular end point occurred in 68 patients (5.0%/y, rivaroxaban 28 events, aspirin 40 events; hazard ratio, 0.67 [95% CI, 0.41–1.1]), and recurrent ischemic stroke occurred in 50 patients (4.0%/y, rivaroxaban 16 events, aspirin 34 events, hazard ratio 0.45 [95% CI, 0.25–0.81]). Annualized combined cardiovascular end point rates were 8.2% (9.5% rivaroxaban, 7.0% aspirin) for those above hs-cTnT upper reference limit and 4.8% (3.1% rivaroxaban, 6.6% aspirin) below with a significant treatment modification ( P =0.04). Annualized ischemic stroke rates were 4.7% above hs-cTnT upper reference limit and 3.9% below, with no suggestion of an interaction between hs-cTnT and treatment ( P =0.3). Conclusions: In patients with ESUS, hs-cTnT was associated with increased cardiovascular event rates. While fewer recurrent strokes occurred in patients receiving rivaroxaban, outcomes were not stratified by hs-cTn results. Our findings support using hs-cTnT for cardiovascular risk stratification but not for decision-making regarding anticoagulation therapy in patients with ESUS. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.

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The 99th percentile upper reference limit for the 5th generation cardiac troponin T assay in the United States

Clinica Chimica Acta ◽

10.1016/j.cca.2020.01.027 ◽

2020 ◽

Vol 504 ◽

pp. 172-179

Author(s):

Robert L. Fitzgerald ◽

Judd E. Hollander ◽

W. Frank Peacock ◽

Alexander T. Limkakeng ◽

Nancy Breitenbeck ◽

...

Keyword(s):

United States ◽

Cardiac Troponin ◽

Troponin T ◽

The United States ◽

Cardiac Troponin T ◽

Reference Limit ◽

Upper Reference Limit

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Emergency department triage of patients with acute chest pain: definition of cardiac troponin I decisional value to manage patients without electrocardiographic evidence of ischemia

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2004.094 ◽

2004 ◽

Vol 42 (5) ◽

Cited By ~ 1

Author(s):

Pascale Beyne ◽

Erik Bouvier ◽

Patrick Werner ◽

Pierre Bourgoin ◽

Damien Logeart ◽

...

Keyword(s):

Chest Pain ◽

Cardiac Troponin ◽

Troponin I ◽

Acute Chest Pain ◽

Final Diagnosis ◽

Cardiac Troponin I ◽

Reference Limit ◽

Coronary Syndrome ◽

Definition Of ◽

Upper Reference Limit

AbstractThe aim of this study was to define the use of a new cardiac troponin I (cTnI) assay for emergency patients with chest pain and no specific electrocardiographic changes consistent with the presence of ischemia. Patients (n=106) admitted in Emergency/Cardiology Departments for chest pain and suspicion of acute coronary syndrome (ACS) were randomized into two diagnosis groups (ACS or non-ACS) by two independent cardiologists. cTnI measurements were performed at admission, and 6 hours and 12 hours later with a new generation assay (Access AccuTnI, Beckman Coulter). Using an upper reference limit of 0.04 μg/l, 27 patients had a cTnI elevation not related to the final diagnosis of ischemia; the positive predictive value (PPV) was 67% with specificity 48%. The decisional value was re-defined and set at 0.16 μg/l, a concentration corresponding to the 99th percentile of the non-ACS patient group. Precision (coefficient of variation) was 8% at this level, PPV 97% and specificity 98%. This new decisional value is now used in our institution and could be included in standard care guidelines to improve the management of patients presenting chest pain in emergency departments.

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Improved detection of minor ischemic myocardial injury with measurement of serum cardiac troponin I

Clinical Chemistry ◽

10.1093/clinchem/43.11.2047 ◽

1997 ◽

Vol 43 (11) ◽

pp. 2047-2051 ◽

Cited By ~ 111

Author(s):

Fred S Apple ◽

Alireza Falahati ◽

Pamela R Paulsen ◽

Elizabeth A Miller ◽

Scott W Sharkey

Keyword(s):

Cardiac Troponin ◽

Myocardial Injury ◽

Troponin I ◽

Cardiac Troponin I ◽

Clinical Sensitivity ◽

Reference Limit ◽

Normal Limits ◽

Serial Serum ◽

Upper Reference Limit ◽

Serum Cardiac Troponin

Abstract This study compared the diagnostic accuracy of the measurement of serum cardiac troponin I (cTnI) with creatine kinase (CK) MB mass in patients with minor myocardial injury whose measured total CK activity did not exceed twice the upper reference limit (300 U/L for men; 200 U/L for women). Forty-eight consecutive patients presenting with chest pain and with in-hospital documentation of myocardial injury were enrolled. Electrocardiogram, echocardiogram, and serial serum CK-MB mass, cTnI, and total CK were measured over 36 h after admission. Peak total CK activity was within normal limits in 28 patients (58%). The mean (±SD) peak CK-MB mass and cTnI concentrations were: 16.4 (11.8) μg/L and 132 (13.0) μg/L; respectively. The peak biochemical marker index (defined as CK-MB or cTnI divided by its respective upper reference limit) was significantly (P <0.05) higher for cTnI than for CK-MB from 7 to 36 h. The clinical sensitivity for detection of myocardial injury for cTnI was 100% [95% confidence interval (CI): 87.2% to 100%], compared with 81.8% (CI: 67.3% to 91.8%) for CK-MB. Thus, cTnI was more sensitive than CK-MB mass for detection of myocardial injury in patients with small increases of total CK.

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Analytical evaluation of the new Beckman Coulter Access high sensitivity cardiac troponin I immunoassay

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2017-0350 ◽

2017 ◽

Vol 56 (1) ◽

Cited By ~ 15

Author(s):

Giuseppe Lippi ◽

Anna Ferrari ◽

Giorgio Gandini ◽

Matteo Gelati ◽

Claudia Lo Cascio ◽

...

Keyword(s):

Cardiac Troponin ◽

Troponin I ◽

Limit Of Detection ◽

High Sensitivity ◽

Cardiac Troponin I ◽

Analytical Performance ◽

The Novel ◽

Reference Limit ◽

Automated Immunoassay ◽

Upper Reference Limit

AbstractBackground:This study was aimed to evaluate the analytical performance of the novel chemiluminescent and fully-automated Beckman Coulter Access hsTnI high-sensitivity immunoassay for measurement of cardiac troponin I (cTnI).Methods:The study, using lithium heparin samples, included assessment of limit of blank (LOB), limit of detection (LOD), functional sensitivity, linearity, imprecision (within run, between-run and total), calculation of 99th percentile upper reference limit (URL) in 175 healthy blood donors (mean age, 36±12 years; 47% women) and comparison with two other commercial cTnI immunoassays.Results:The LOB, LOD and functional sensitivity of Access hsTnI were 0.14, 0.34 and 1.35 ng/L, respectively. The within-run, between-run and total imprecision was 2.2%–2.9%, 4.6%–5.4%, and 5.4%–6.1%, respectively. The linearity was excellent in the range of cTnI values between 0.95 and 4195 ng/L (r=1.00). The 99th percentile URL was 15.8 ng/L. Measurable cTnI values were found in 173/175 healthy subjects (98.9%). Good agreement of cTnI values was found with AccuTnI+3 (r=0.97; mean bias, −9.3%), whereas less satisfactory agreement was found with Siemens Dimension Vista cTnI (r=0.95; mean bias, −55%).Conclusions:The results of our evaluation of the Beckman Coulter Access hsTnI indicate that the analytical performance of this fully-automated immunoassay is excellent.

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Temporal Evolution of Serum Concentrations of High‐Sensitivity Cardiac Troponin During 1 Year After Acute Coronary Syndrome Admission

Journal of the American Heart Association ◽

10.1161/jaha.120.017393 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Victor J. van den Berg ◽

Rohit M. Oemrawsingh ◽

Victor A. W. M. Umans ◽

Isabella Kardys ◽

Folkert W. Asselbergs ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Cardiac Troponin ◽

Troponin I ◽

Temporal Evolution ◽

High Sensitivity ◽

Interindividual Variation ◽

Mixed Effect ◽

Reference Limit ◽

Coronary Syndrome ◽

Upper Reference Limit

Background Detailed insights in temporal evolution of high‐sensitivity cardiac troponin following acute coronary syndrome (ACS) are currently missing. We aimed to describe and compare the post‐ACS kinetics of high‐sensitivity cardiac troponin I (hs‐cTnI) and high‐sensitivity cardiac troponin T (hs‐cTnT), and to determine their intra‐ and interindividual variation in clinically stable patients. Methods and Results We determined hs‐cTnI (Abbott) and hs‐cTnT (Roche) in 1507 repeated blood samples, derived from 191 patients with ACS (median, 8/patient) who remained free from adverse cardiac events during 1‐year follow‐up. Post‐ACS kinetics were studied by linear mixed‐effect models. Using the samples collected in the 6‐ to 12‐month post‐ACS time frame, patients were then considered to have chronic coronary syndrome. We determined (differences between) the average hs‐cTnI and average hs‐cTnT concentration, and the intra‐ and interindividual variation for both biomarkers. Compared with hs‐cTnT, hs‐cTnI peaked higher (median 3506 ng/L versus 494 ng/L; P <0.001) and was quicker below the biomarker‐specific upper reference limit (16 versus 19 days; P <0.001). In the post–6‐month samples, hs‐cTnI and hs‐cTnT showed modest correlation ( r spearman =0.60), whereas the average hs‐cTnT concentration was 5 times more likely to be above the upper reference limit than hs‐cTnI. The intraindividual variations of hs‐cTnI and hs‐cTnT were 14.0% and 18.1%, while the interindividual variations were 94.1% and 75.9%. Conclusions Hs‐cTnI peaked higher after ACS and was quicker below the upper reference limit. In the post–6‐month samples, hs‐cTnI and hs‐cTnT were clearly not interchangeable, and average hs‐cTnT concentrations were much more often above the upper reference limit than hs‐cTnI. For both markers, the within‐patient variation fell largely below beween‐patient variation. Registration URL: https://www.trialregister.nl ; unique identifiers: NTR1698 and NTR1106.

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Sex-Specific 99th Percentile Upper Reference Limits for High Sensitivity Cardiac Troponin Assays Derived Using a Universal Sample Bank

Clinical Chemistry ◽

10.1093/clinchem/hvz029 ◽

2020 ◽

Vol 66 (3) ◽

pp. 434-444 ◽

Cited By ~ 12

Author(s):

Fred S Apple ◽

Alan H B Wu ◽

Yader Sandoval ◽

Anne Sexter ◽

Sara A Love ◽

...

Keyword(s):

Statistical Method ◽

Cardiac Troponin ◽

Hemoglobin A1c ◽

Limit Of Detection ◽

High Sensitivity ◽

Clinical Implications ◽

Robust Methods ◽

Exclusion Criteria ◽

Reference Limits ◽

Before And After

Abstract Background How to select healthy reference subjects in deriving 99th percentiles for cardiac troponin assays still needs to be clarified. To assist with global implementation of high sensitivity (hs)-cardiac troponin (cTn) I and hs-cTnT assays in clinical practice, we determined overall and sex-specific 99th percentiles in 9 hs-cTnI and 3 hs-cTnT assays using a universal sample bank (USB). Methods The Universal Sample Bank (USB) comprised healthy subjects, 426 men and 417 women, screened using a health questionnaire. Hemoglobin A1c (>URL 6.5%), NT-proBNP (>URL 125 ng/L) and eGFR (<60 mL/min), were used as surrogate biomarker exclusion criteria along with statin use. 99th percentiles were determined by nonparametric, Harrell--Davis bootstrap, and robust methods. Results Subjects were ages 19 to 91 years, Caucasian 58%, African American 27%, Pacific Islander/Asian 11%, other 4%, Hispanic 8%, and non-Hispanic 92%. The overall and sex-specific 99th percentiles for all assays, before and after exclusions (n = 694), were influenced by the statistical method used, with substantial differences noted between and within both hs-cTnI and hs-cTnT assays. Men had higher 99th percentiles (ng/L) than women. The Roche cTnT and Beckman and Abbott cTnI assays (after exclusions) did not measure cTn values at ≥ the limit of detection in ≥50% women. Conclusions Our findings have important clinical implications in that sex-specific 99th percentiles varied according to the statistical method and hs-cTn assay used, not all assays provided a high enough percentage of measurable concentrations in women to qualify as a hs-assay, and the surrogate exclusion criteria used to define normality tended to lower the 99th percentiles.

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Preoperative cardiac troponin below the 99th-percentile upper reference limit and 30-day mortality after noncardiac surgery

Scientific Reports ◽

10.1038/s41598-020-72853-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jungchan Park ◽

Cheol Won Hyeon ◽

Seung-Hwa Lee ◽

Sangmin Maria Lee ◽

Junghyun Yeo ◽

...

Keyword(s):

Cardiac Troponin ◽

Primary Outcome ◽

Multivariate Analyses ◽

Limit Of Detection ◽

High Sensitivity ◽

Noncardiac Surgery ◽

Surgical Patients ◽

Reference Limit ◽

Risk Of Mortality ◽

Upper Reference Limit

Abstract Preoperative high-sensitivity cardiac troponin (hs-cTn) above the 99th-percentile upper reference limit (URL) is associated with mortality after noncardiac surgery. This study aimed to evaluate whether preoperative hs-cTn concentrations above the lowest limit of detection (LOD) but below the 99th-percentile URL can predict mortality after noncardiac surgery.From January 2010 to April 2019, a total of 12,415 noncardiac surgical patients with preoperative hs-cTn I below the 99th-percentile URL were enrolled. The patients were divided into two groups according to preoperative hs-cTn I concentration: (1) [hs-cTn] below the LOD (6 ng/L), and (2) mildly elevated [hs-cTn] but below the 99th-percentile URL (40 ng/L). The primary outcome was 30-day mortality. Of the 12,415 patients enrolled, 7958 (64.1%) were in the LOD group whereas 4457 (35.9%) were in the mild elevation group. The incidence of 30-day mortality was significantly greater in the mild elevation group (2.1% vs. 4.0% hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.39–2.16; p < 0.001) in the multivariate analyses. The propensity score matched analyses also produced a similar result (2.6% vs. 4.2% HR 1.61; 95% CI 1.26–2.07; p < 0.001). The threshold at which the risk of mortality increased corresponded to a preoperative hs-cTn I ≥ 12 ng/L. Patients with preoperative hs-cTn I above the LOD and below the 99th-percentile URL had greater 30-day mortality after noncardiac surgery.

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Use of small-sample-based reference limits on a group basis

Clinical Chemistry ◽

10.1093/clinchem/40.9.1698 ◽

1994 ◽

Vol 40 (9) ◽

pp. 1698-1702 ◽

Cited By ~ 5

Author(s):

E A van der Meulen ◽

P J Boogaard ◽

N J van Sittert

Keyword(s):

Sample Size ◽

Reference Sample ◽

Nonparametric Test ◽

Small Sample ◽

Reference Limit ◽

Health Assessments ◽

Group Basis ◽

Test Of Significance ◽

Upper Reference Limit ◽

Limit Estimate

Abstract The evaluation of a biochemical or hematological quantity measured in a study group of employees during occupational health assessments involves a comparison with a reference sample group. Part of this evaluation consists of checking whether the percentage of values larger than a predetermined upper reference limit is significantly larger than the percentage normally expected (2.5%, if the 97.5 percentile is used as the upper reference limit). The reference limit, however, is estimated from a random reference sample, the size of which, for many reasons, may be relatively small; as a consequence, the reference limit estimate will be imprecise. In situations in which the reference sample size is smaller than or not much larger than the study sample size, this imprecision results in the usual binomial test of significance being highly inappropriate. We provide an exact nonparametric test valid for all reference sample sizes.

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