99th percentile upper reference limit of AccuTnI+3 in a Korean reference population: a multicenter study using fresh serum

Abstract We studied the analytical and clinical performance of six methods for creatine kinase (EC 2.7.3.2) isoenzyme MB (CK-MB): three immunoassays (Behring, Hybritech, and International Immunoassay Labs); one immunoinhibition assay (Roche); one immunoinhibition/column method (Du Pont); and one electrophoretic method (Beckman). Between-day precision for all kits was poor at the upper reference limit. All methods gave results linearly related to CK-MB concentration and all were free from CK-MM, CK-BB, and adenylate kinase interference. Only the Du Pont method was adversely affected by atypical isoenzymes. For diagnosis of acute myocardial infarction in a coronary care population (n = 40; prevalence = 45%), all methods were approximately 95% efficient, when appropriate reference criteria were used. Some manufacturers fail to provide data for an appropriate (acutely ill, non-infarct) reference population; decreased diagnostic specificity may result from use of reference ranges based on results for healthy subjects. Expression of CK-MB as a percent of total CK degrades efficiency unless total CK is markedly increased.

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Albumin and calcium reference interval using healthy individuals and a data-mining approach

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563220944204 ◽

2020 ◽

Vol 57 (5) ◽

pp. 373-381 ◽

Cited By ~ 2

Author(s):

N Jassam ◽

A Luvai ◽

D Narayanan ◽

D Turnock ◽

G Lee ◽

...

Keyword(s):

Metrological Traceability ◽

Reference Interval ◽

Reference Population ◽

Reference Intervals ◽

Healthy Individuals ◽

Reference Limit ◽

Common Reference ◽

Age Related ◽

Upper Reference Limit ◽

Analytical Platforms

Background Harmonization of reference intervals for analytes that have a sound calibration and metrological traceability is a widely recommended practice. The UK Pathology Harmony has recently harmonized reference intervals for calcium and albumin. In this study, we have determined the reference intervals for calcium and albumin on the UK’s most commonly used analytical platforms. Method A prospective reference population of healthy individuals was recruited according to the IFCC CRIDL criteria. A second indirect population was collected from 14 primary care setting and measured in laboratories using various analytical platforms and methods (Roche, Abbott, Beckman and Siemens analytical platforms). Results In total, 299 subjects were recruited; the central 95th centile values for calcium for three out of four analytical platforms were in a close agreement with UK Pathology Harmony reference intervals of 2.2–2.6 mmol/L. Reference intervals of BCG methods from both cohorts and irrespective of analytical platforms were higher for both lower and upper reference limits than those for BCP. In comparison, the indirect study showed an age-related variation. The younger population reference intervals varied by up to 5.7% at the lower reference limit and up to 12% at the upper reference limit compared with Pathology Harmony reference intervals, and the older population showed a variation of up to 14% at both limits. Conclusion While calcium reference intervals can be a subject for harmonization, albumin reference intervals studied showed large variation which is unsupportive of embracing a common reference interval for albumin.

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

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2016-0933 ◽

2017 ◽

Vol 55 (11) ◽

Cited By ~ 18

Author(s):

Aldo Clerico ◽

Martina Zaninotto ◽

Andrea Ripoli ◽

Silvia Masotti ◽

Concetta Prontera ◽

...

Keyword(s):

Task Force ◽

Clinical Decision ◽

Reference Population ◽

Clinical Implications ◽

Factors Affecting ◽

Reference Limit ◽

Physiological Variables ◽

Mathematical Algorithms ◽

Regulatory Bodies ◽

Upper Reference Limit

AbstractAccording 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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Multicenter Evaluation of an Automated Assay for Troponin I

Clinical Chemistry ◽

10.1093/clinchem/48.6.869 ◽

2002 ◽

Vol 48 (6) ◽

pp. 869-876 ◽

Cited By ~ 82

Author(s):

Denise Uettwiller-Geiger ◽

Alan HB Wu ◽

Fred S Apple ◽

Anthony W Jevans ◽

Per Venge ◽

...

Keyword(s):

Detection Limit ◽

Troponin I ◽

Reference Population ◽

Reference Limit ◽

Automated Assay ◽

Heparin Plasma ◽

Edta Plasma ◽

Upper Reference Limit ◽

Matched Samples ◽

Assay Interference

Abstract Background: Cardiac troponin I (cTnI) is a powerful tool to aid in the diagnosis of myocardial infarction and cardiac muscle damage. We describe an assay that overcomes problems of early assays that were often affected by cTnI degradation, assay interference, poor sensitivity, and imprecision. Methods: The analytical performance of the Access® AccuTnITM assay (Beckman Coulter) was evaluated at five institutions. Controls, zero calibrator, and diluted patient samples were used to determine precision, detection limit, functional sensitivity, and linearity. The 97.5 and 99 percentiles of a reference population were determined. Common interferents and heterophilic patient samples were tested. Equimolarity was determined by assaying samples with various ratios of free and complexed cTnI. Matched samples drawn into serum, EDTA, lithium heparin, and sodium heparin sample tubes were compared. Results: Total imprecision (CVs) was 4.0–8.8% between 0.40 and 31 μg/L cTnI. The detection limit was <0.01 μg/L. The 97.5 percentile upper reference limit (URL) was 0.03 μg/L (CV = 20%), and the 99 percentile URL was 0.04 μg/L (CV = 14%). Total CVs of 10% and 20% were seen at and above 0.06 and 0.03 μg/L, respectively. The assay was linear to >60 μg/L and not affected by common assay interferents. An equimolar response was observed with free, complexed, phosphorylated, and dephosphorylated forms of cTnI. Results were 4% lower in serum and 14% lower in EDTA plasma than in lithium heparin plasma (P <0.01), independent of cTnI concentration. Conclusion: AccuTnI is a sensitive and precise assay for the measurement of cTnI.

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Where does subclinical hypothyroidism start?

Nuklearmedizin ◽

10.1055/s-0038-1623926 ◽

2005 ◽

Vol 44 (02) ◽

pp. 56-61 ◽

Cited By ~ 14

Author(s):

G. Wunderlich ◽

Th. Grüning ◽

R. Koch ◽

H. Döge ◽

J. Kotzerke ◽

...

Keyword(s):

Reference Range ◽

Clinical Biochemistry ◽

Reference Group ◽

Reference Population ◽

Total Study Population ◽

Autoimmune Thyroid ◽

Reference Limit ◽

Study Population ◽

Definition Of ◽

Upper Reference Limit

SummaryThe upper limit of the TSH reference range is currently under discussion. In its recent guidelines, the National Academy of Clinical Biochemistry (NACB) recommended the use of ~2.5 mIU/L, rather than ~4 mIU/L, due to the fact that reference populations, on which the definition of the reference range is based, contain persons undergoing an initial phase of autoimmune thyroid disease. This will skew the upper reference limit of TSH. Ultrasonography, in addition to measurement of thyroid autoantibodies, should be used to exclude these persons. Objective: The present study investigates whether the NACB recommendation also applies for a region of mild iodine deficiency. Methods: According to NACB criteria, a reference population (713 persons) was defined out of a total study population of 1442. The TSH reference range was calculated in this reference group and in further subgroups by percentiles. The results were compared with the total study population and the NACB recommendation. All assays used were provided by BRAHMS Diagnostica AG, Hennigsdorf, Germany. Results: As expected, all median TSH values, excluding the median of the group with a hypoechogenic thyroid were close to 1.2 mIU/L. The 97.5th percentile in the reference population was 3.35 mIU/L. However, there was no difference compared to the total study population. Conclusion: The upper reference limit for TSH based on a reference population according to NACB criteria came down to 3.35 mIU/L, but not to ~2.5 mIU/L. Interestingly, there is no difference compared to the total study population.

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Increased canine pancreatic lipase immunoreactivity (cPLI) and 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6′-methylresorufin) ester (DGGR) lipase in dogs with evidence of portal hypertension and normal pancreatic histology: a pilot study

Journal of Veterinary Diagnostic Investigation ◽

10.1177/10406387211003987 ◽

2021 ◽

pp. 104063872110039

Author(s):

Gonçalo Serrano ◽

Dominique Paepe ◽

Tim Williams ◽

Penny Watson

Keyword(s):

Portal Hypertension ◽

Liver Disease ◽

Pilot Study ◽

Pancreatic Lipase ◽

Glutaric Acid ◽

Inclusion Criteria ◽

Reference Limit ◽

Clinical Presentations ◽

Upper Reference Limit

The clinical presentations of both liver disease and pancreatitis are nonspecific and overlapping, which may cause difficulty in diagnosis. In our retrospective pilot study, we assessed whether dogs with evidence of portal hypertension and absence of pancreatitis on pancreatic histology have increases in canine pancreatic lipase immunoreactivity (cPLI) and 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6′-methylresorufin) ester (DGGR) lipase. We included dogs that had been presented between 2008 and 2019 if they had normal pancreatic histology, histologically confirmed hepatopathy, and if canine pancreas-specific lipase (Spec cPL; Idexx) or DGGR lipase had been measured. Only dogs with portal hypertension were included. Six dogs fulfilled the inclusion criteria. Four of 6 and 2 of 6 dogs had Spec cPL and DGGR lipase exceeding the upper reference limit, respectively. From the 4 dogs with increased Spec cPL, 2 had concentrations of 200–400 µg/L and 2 had concentrations ≥ 400 µg/L. Our results suggest that canine portal hypertension might lead to increased Spec cPL and DGGR lipase values in the absence of pancreatitis on histology. Until more evidence in a larger number of dogs with portal hypertension is available, both tests should be interpreted cautiously in the presence of portal hypertension.

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Neuroblastoma—When are Urinary Catecholamines and Their Metabolites ‘Normal’?

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328802500604 ◽

1988 ◽

Vol 25 (6) ◽

pp. 620-626 ◽

Cited By ~ 5

Author(s):

D J Worthington ◽

E M Hammond ◽

B B Eldeeb ◽

A Green ◽

G M Addison ◽

...

Keyword(s):

Urinary Excretion ◽

The Other ◽

Published Data ◽

Single Test ◽

Creatinine Concentration ◽

Urinary Catecholamines ◽

Clinical Sensitivity ◽

Reference Limit ◽

Upper Reference Limit ◽

The Individual

The overproduction of catecholamines and their metabolites is a well recognised feature of neuroblastoma. Published data are scarce for their urinary excretion in children with neuroblastoma and in ill children in whom this diagnosis may be considered. We have determined a graphical upper reference limit for total catecholamines, total metadrenalines and HMMA in urine, expressed as a ratio to the creatinine concentration, for a group of 174 children with neuroblastoma and 704 hospitalised children with other disorders. This graph has been determined by examining the overlap region between the results for the two groups of children and avoids the irregularities caused by statistical outliers. The sensitivity and specificity of the individual tests indicate that total catecholamines is marginally the best single test to perform when trying to diagnose neuroblastoma, with the best clinical sensitivity being achieved by examining both total catecholamines and HMMA. Only two of the 174 children with neuroblastoma would not have been detected using these two tests. Total metadrenalines did not appear to add any further information and could be dropped from the repertoire in favour of the other two measurements.

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Cardiac Troponin T Concentrations, Reversible Myocardial Ischemia, and Indices of Left Ventricular Remodeling in Patients with Suspected Stable Angina Pectoris: a DOPPLER-CIP Substudy

Clinical Chemistry ◽

10.1373/clinchem.2018.288894 ◽

2018 ◽

Vol 64 (9) ◽

pp. 1370-1379 ◽

Cited By ~ 7

Author(s):

Peder L Myhre ◽

Torbjørn Omland ◽

Sebastian I Sarvari ◽

Heikki Ukkonen ◽

Frank Rademakers ◽

...

Keyword(s):

Myocardial Ischemia ◽

Wall Motion ◽

Troponin T ◽

Left Ventricular ◽

Reference Limit ◽

Lv Mass ◽

Lv Remodeling ◽

Perfusion Defects ◽

Stable Cad ◽

Upper Reference Limit

Abstract BACKGROUND Cardiac troponin T concentrations measured with high-sensitivity assays (hs-cTnT) provide important prognostic information for patients with stable coronary artery disease (CAD). However, whether hs-cTnT concentrations mainly reflect left ventricular (LV) remodeling or recurrent myocardial ischemia in this population is not known. METHODS We measured hs-cTnT concentrations in 619 subjects with suspected stable CAD in a prospectively designed multicenter study. We identified associations with indices of LV remodeling, as assessed by cardiac MRI and echocardiography, and evidence of myocardial ischemia diagnosed by single positron emission computed tomography. RESULTS Median hs-cTnT concentration was 7.8 ng/L (interquartile range, 4.8–11.6 ng/L), and 111 patients (18%) had hs-cTnT concentrations above the upper reference limit (>14 ng/L). Patients with hs-cTnT >14 ng/L had increased LV mass (144 ± 40 g vs 116 ± 34 g; P < 0.001) and volume (179 ± 80 mL vs 158 ± 44 mL; P = 0.006), lower LV ejection fraction (LVEF) (59 ± 14 vs 62 ± 11; P = 0.006) and global longitudinal strain (14.1 ± 3.4% vs 16.9 ± 3.2%; P < 0.001), and more reversible perfusion defects (P = 0.001) and reversible wall motion abnormalities (P = 0.008). Age (P = 0.009), estimated glomerular filtration rate (P = 0.01), LV mass (P = 0.003), LVEF (P = 0.03), and evidence of reversible myocardial ischemia (P = 0.004 for perfusion defects and P = 0.02 for LV wall motion) were all associated with increasing hs-cTnT concentrations in multivariate analysis. We found analogous results when using the revised US upper reference limit of 19 ng/L. CONCLUSIONS hs-cTnT concentrations reflect both LV mass and reversible myocardial ischemia in patients with suspected stable CAD.

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Abstract 14870: Clinical Significance of Troponin Elevation in a Contemporary Hospitalized Population: Endotypes, Morbidity and In-hospital Mortality

Circulation ◽

10.1161/circ.142.suppl_3.14870 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Michael Briscoe ◽

Robert A Sykes ◽

Thomas Krysztofiak ◽

Kenneth Mangion ◽

Oliver H Peck ◽

...

Keyword(s):

Clinical Significance ◽

Myocardial Injury ◽

Troponin I ◽

Coronary Revascularization ◽

High Sensitivity ◽

Hospitalized Patients ◽

Troponin Elevation ◽

Reference Limit ◽

Upper Reference Limit

Introduction: Unplanned hospitalizations are commonly associated with a circulating troponin concentration >99 th percentile upper reference limit (URL). In order to better understand the clinical significance of troponin elevation, we evaluated outcomes in hospitalized patients according to cardiac endotype. Methods: We prospectively screened consecutive hospitalized patients with elevated high-sensitivity troponin-I (hs-TnI) concentrations (Abbott ARCHITECT troponin-I assay; sex-specific URL, 99 th centile: male: >34ng/L; female: >16ng/L) within a regional cardiac care network (population 650,000). A cardiology clinical team adjudicated individual patient records and assigned endotypes by consensus agreement according to the Fourth Universal Definition of Myocardial Infarction (MI). Endotypes were sub-classified into etiological category by inciting event(s). Characteristics and comorbidity were compared and outcomes recorded on virtual follow-up until June 2 nd 2020. Results: A total of 390 consecutive patients with ≥1 hs-TnI value >URL between March 1-April 15, 2020, were evaluated; 44 patients were excluded ( Duplicates: 2; Missing data: 41; Research patient: 1 ). Of 346 who qualified for inclusion, an index diagnosis of Type 1 MI (T1MI), T2MI and myocardial injury were assigned in 115 (33.2%), 79 (22.8%) and 152 (43.9%) patients, respectively. Compared with T1MI, patients with T2MI and myocardial injury had lower peak hs-TnI values (median [IQR]: 86 [250-697] vs 5020 [853-7774]ng/L; p< 0.01), lower estimated 10-year survival (40.2% vs 53.4%; p=0.002), less frequently underwent coronary revascularization (1.4% vs 45.2%; p<0.0005) and had longer inpatient stay (13.0 vs 6.1 days). Inpatient and overall mortality rates from admission to follow-up (median [range]: 71 [0-151] days) were higher among patients with T2MI and myocardial injury (19.9% vs 7.8%; p=0.004; and 26.0% vs 11.3%; Log rank (Mantel-Cox) X 2 = 1.927; p=0.003) independent of similar cardiovascular risk profiles. Conclusions: Despite lower peak circulating troponin concentrations, patients with T2MI and myocardial injury had higher inpatient mortality, lower estimated 10-year survival and longer in-hospital stay compared to those with T1MI.

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High-sensitivity troponin assays: analytical and clinical aspects

Diagnostyka Laboratoryjna ◽

10.5604/01.3001.0008.2546 ◽

2016 ◽

Vol 51 (4) ◽

pp. 315-320

Author(s):

Magdalena Krintus

Keyword(s):

Myocardial Infarction ◽

Clinical Symptoms ◽

High Sensitivity ◽

Reference Population ◽

Clinical Aspects ◽

Analytical Sensitivity ◽

Reference Limit ◽

Highly Sensitive ◽

Time Required ◽

Highly Sensitive Troponin

Cardiac troponins are considered the most sensitive and specific biomarkers for the diagnosis of acute coronary syndromes (ACS). According to the Third Universal Definition of Acute Myocardial Infarction, the diagnosis requires a rise / or fall of troponin concentration with at least one value exceeding the 99th percentile upper reference limit (URL) in a reference population with the coexistence of clinical symptoms of ischemia. The introduction of highly sensitive assays has resulted in lower detection limits for the concentration of troponin, allowing for early diagnosis of, as well as the detection of quantifiable concentrations of this biomarker in healthy subjects. According to current guidelines, the use of high-sensitivity tests can shorten the time required to make clinical decisions from the current 3-6 hours to 1-2 hours. The use of highly sensitive troponin assays also carries other potential benefits associated with their predictive value, as well as challenges that include reduced specificity for myocardial infarction, lack of standardization or the presence of biological variability. Given the increasing availability of new, highly sensitive troponin assays we should be aware that their increased analytical sensitivity and precision is accompanied by accurate clinical assessment of the patient, and takes into account other non-cardiac causes of their increased concentrations.

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