The intra-individual variation of cardiac troponin I: the effects of sex, age, climatic season, and time between samples.

OBJECTIVES: Knowing the intra-individual variation (CVi), also termed within subject biological variation, of an analyte is essential to properly interpret apparent changes in concentration. While there have been many studies assessing the CVi of cardiac troponin (cTnI), they have been limited in looking at CVi in different settings, and there is no data available on whether CVi might change in different settings. METHODS: We used our large cTnI data bank to look at the CVi of cTnI in Emergency Department (ED) patients who had an acute myocardial infarction event excluded. We looked at the effects of gender, age, climatic season, and time between samples to assess whether CVi changed. To assess the effect of age, after exclusion, we collected two samples from each subject for each study which were used to calculate the CVi between those identified groups. There were 139 males and 98 females aged <65 years and 109 males and 98 females aged ≥65 years. For gender and season, there were 122 males and 94 females in the summer period and 126 males and 102 females in the winter period. To assess long term variation there were 195 males and 153 females who had further admissions after more than 12 months. RESULTS: For the four variables listed, there were no significant differences in within individual variation (CVi), but there was a significant difference in between individual variation (CVg) for men and women with regard to age. The Index of Individuality (II) was <0.20 for all conditions studied. We noted that >90% of subjects had an reference change value (RCV) <9 ng/L. CONCLUSIONS: Because troponin concentration in patients without an identified cardiac condition change so little, delta changes are potentially of great value in assessing patients in the ED. Significant delta changes in troponin can occur without the 99th percentile being exceeded.

Reference intervals for venous blood gas measurement in adults.

OBJECTIVES: Venous blood gas (VBG) analysis is becoming a popular alternative to arterial blood gas (ABG) analysis due to reduced risk of complications at phlebotomy and ease of draw. In lack of published data, this study aimed to establish reference intervals (RI) for correct interpretation of VBG results. METHODS: One hundred and 51 adult volunteers (101 females, 50 males, 18-70 years) were enrolled after completion of a health questionnaire. Venous blood was drawn into safePICO syringes and analysed on ABL827 blood gas analyser (Radiometer Pacific Pty. Ltd.). A non-parametric approach was used to directly establish the VBG RI which was compared to a calculated VBG RI based on a meta-analysis of differences between ABG and VBG. RESULTS: After exclusions, 134 results were used to derive VBG RI: pH 7.30-7.43, partial pressure of carbon dioxide (pCO2) 38-58 mmHg, partial pressure of oxygen (pO2) 19-65 mmHg, bicarbonate (HCO3-) 22-30 mmol/L, sodium 135-143 mmol/L, potassium 3.6-4.5 mmol/L, chloride 101-110 mmol/L, ionised calcium 1.14-1.29 mmol/L, lactate 0.4-2.2 mmol/L, base excess (BE) -1.9-4.5 mmol/L, saturated oxygen (sO2) 23-93%, carboxyhaemoglobin 0.4-1.4% and methaemoglobin 0.3-0.9%. The meta-analysis revealed differences between ABG and VBG for pH, HCO3-, pCO2 and pO2 of 0.032, -1.0 mmol/L, -4.2 and 39.9 mmHg, respectively. Using this data along with established ABG RI, calculated VBG RI of pH 7.32-7.42, HCO3- 23 - 27 mmol/L, pCO2 36-49 mmHg (female), pCO2 39-52 mmHg (male) and pO2 43-68 mmHg were formulated and compared to the VBG RI of this study. CONCLUSIONS: An adult reference interval has been established to assist interpretation of VBG results.

Choice of Statistical Tools for Outlier Removal Causes Substantial Changes in Analyte Reference Intervals in Healthy Populations.

BACKGROUND: Reference intervals are an important aid in medical practice as they provide clinicians a guide as to whether a patient is healthy or diseased.Outlier results in population studies are removed by any of a variety of statistical measures. We have compared several methods of outlier removal and applied them to a large body of analytes from a large population of healthy persons. METHODS: We used the outlier exclusion criteria of Reed-Dixon and Tukey and calculated reference intervals using nonparametric and Harrell-Davis statistical methods and applied them to a total of 36 different analytes. RESULTS: Nine of 36 analytes had a greater than 20% difference in the upper reference limit, and for some the difference was 100% or more. CONCLUSIONS: For some analytes, great importance is attached to the reference interval. We have shown that different statistical methods for outlier removal can cause large changes to reported reference intervals. So that population studies can be readily compared, common statistical methods should be used for outlier removal.

An update report on the harmonization of adult reference intervals in Australasia.

The Australasian Association of Clinical Biochemists (AACB) has over the past 5 years been actively working to achieve harmonized reference intervals (RIs) for common clinical chemistry analytes using an evidence-based checklist approach where there is sound calibration and metrological traceability. It has now recommended harmonized RIs for 18 common clinical chemistry analytes which are performed in most routine laboratories and these have been endorsed by the Royal College of Pathologists of Australasia (RCPA). In 2017 another group of analytes including urea, albumin and arterial blood gas parameters were considered and suggested harmonized RIs proposed. This report provides an update of those harmonization efforts.

Using a thyroid disease-free population to define the reference interval for TSH and free T4 on the Abbott Architect analyser.

OBJECTIVE: Thyroid disease can be subtle in its presentation, and TSH reference intervals may be artefactually increased by including persons with subclinical thyroid disease. We have therefore used a thyroid disease-free population to determine TSH and fT4 reference intervals. DESIGN: Apparently healthy subjects were assessed by health questionnaire, drug history, clinical assessment and measurement of thyroid antibodies. PATIENTS: Healthy subjects in a community setting. MEASUREMENTS: TSH, free T4, antithyroglobulin and anti-TPO were measured on the Abbott Architect analyser. Subjects with clinical abnormalities, consumption of thyroid-active medications or with thyroid antibodies above the manufacturer-quoted reference intervals were excluded. TSH and fT4 data were log-transformed, and the central 95% was used to calculate reference intervals. We assessed whether these data were normally distributed. We compared samples spanning the reference intervals for both TSH and fT4 between different assays looking at biases. RESULTS: From a population of 1,606 subjects, 140 males (18%) and 284 females (34%) were excluded. The central population 95% for TSH was 0·43-3·28 mU/l and for fT4 10·8-16·8 pmol/l. There were no age- or sex-related differences. For both analytes, the distribution was not significantly different to a Gaussian distribution (P > 0·05). For 5 commonly used assays for TSH, the maximum difference in the upper limit of the TSH reference interval was 0·48 mU/l and for fT4 the maximum difference for the upper reference limit was 4·1 pmol/l. CONCLUSIONS: A substantial proportion of apparently healthy persons have subclinical thyroid disease. These subjects must be excluded for any thyroid hormone reference interval studies.

Influence of exercise intensity and duration on functional and biochemical perturbations in the human heart.

KEY POINTS: Strenuous endurance exercise induces transient functional and biochemical cardiac perturbations that persist for 24-48 h. The magnitude and time-course of exercise-induced reductions in ventricular function and increases in cardiac injury markers are influenced by the intensity and duration of exercise. In a human experimental model, exercise-induced reductions in ventricular strain and increases in cardiac troponin are greater, and persist for longer, when exercise is performed within the heavy- compared to moderate-intensity exercise domain, despite matching for total mechanical work. The results of the present study help us better understand the dose-response relationship between endurance exercise and acute cardiac stress/injury, a finding that has implications for the prescription of day-to-day endurance exercise regimes. ABSTRACT: Strenuous endurance exercise induces transient cardiac perturbations with ambiguous health outcomes. The present study investigated the magnitude and time-course of exercise-induced functional and biochemical cardiac perturbations by manipulating the exercise intensity-duration matrix. Echocardiograph-derived left (LV) and right (RV) ventricular global longitudinal strain (GLS), and serum high-sensitivity cardiac troponin (hs-cTnI) concentration, were examined in 10 males (age: 27 ± 4 years; V̇O2, peak : 4.0 ± 0.8 l min(-1) ) before, throughout (50%, 75% and 100%), and during recovery (1, 3, 6 and 24 h) from two exercise trials. The two exercise trials consisted of 90 and 120 min of heavy- and moderate-intensity cycling, respectively, with total mechanical work matched. LVGLS decreased (P < 0.01) during the 90 min trial only, with reductions peaking at 1 h post (pre: -19.9 ± 0.6%; 1 h post: -18.5 ± 0.7%) and persisting for >24 h into recovery. RVGLS decreased (P < 0.05) during both exercise trials with reductions in the 90 min trial peaking at 1 h post (pre: -27.5 ± 0.7%; 1 h post: -25.1 ± 0.8%) and persisting for >24 h into recovery. Serum hs-cTnI increased (P < 0.01) during both exercise trials, with concentrations peaking at 3 h post but only exceeding cardio-healthy reference limits (14 ng l(-1) ) in the 90 min trial (pre: 4.2 ± 2.4 ng l(-1) ; 3 h post: 25.1 ± 7.9 ng l(-1) ). Exercise-induced reductions in ventricular strain and increases in cardiac injury markers persist for 24 h following exercise that is typical of day-to-day endurance exercise training; however, the magnitude and time-course of this response can be altered by manipulating the intensity-duration matrix.

Decision limits and the reporting of cardiac troponin: Meeting the needs of both the cardiologist and the ED physician.

Cardiac troponin is the preferred biomarker for defining the acute coronary syndrome and acute myocardial infarction. Currently, the only decision limit formally endorsed with regard to the cardiac troponins is the 99th percentile. This is a "rule-in" criterion, intended to ensure that only persons with the acute coronary syndrome are reviewed. The 99th percentile is an arbitrary cut point and there are many problems associated with its application, including defining a truly healthy population, the difficulty of standardisation of cardiac troponin assays, especially but not only cardiac troponin I, and the effects of age and sex on this parameter. The Emergency Department (ED) screens many more persons for possible acute coronary syndromes than actually have the condition and their needs are best met by a "rule-out" test that enables them to clear their busy departments of the many persons who do not actually have the condition. The needs of the ED are not optimally met using the 99th percentile. The index of individuality for the cardiac troponins is small and significant changes consistent with an acute coronary syndrome can occur without the 99th percentile being exceeded. It appears that the ED may be better served by use of delta troponin changes rather than the 99th percentile, but there are problems with this approach, particularly in persons who present late when troponin release has plateaued. In addition, there are many non-acute coronary syndrome causes for cardiac troponin release. The needs of the cardiologist and the ED physician are so different that it may be inappropriate for both groups to use the same diagnostic criteria for cardiac troponin, and it is of great importance that cardiac troponin measurement be used as only one part of the assessment of the person presenting with possible acute coronary syndrome.

Altered ventricular mechanics after 60 min of high-intensity endurance exercise: insights from exercise speckle-tracking echocardiography.

Transient reductions in myocardial strain coupled with cardiac-specific biomarker release have been reported after prolonged exercise (>180 min). However, it is unknown if 1) shorter-duration exercise (60 min) can perturb cardiac function or 2) if exercise-induced reductions in strain are masked by hemodynamic changes that are associated with passive recovery from exercise. Left ventricular (LV) and right ventricular global longitudinal strain (GLS), LV torsion, and high-sensitivity cardiac troponin T were measured in 15 competitive cyclists (age: 28 ± 3 yr, peak O2 uptake: 4.8 ± 0.6 l/min) before and after a 60-min high-intensity cycling race intervention (CRIT60). At both time points (pre- and post-CRIT60), strain and torsion were assessed at rest and during a standardized low-intensity exercise challenge (power output: 96 ± 8 W) in a semirecumbent position using echocardiography. During rest, hemodynamic conditions were different from pre- to post-CRIT60 (mean arterial pressure: 96 ± 1 vs. 86 ± 2 mmHg, P < 0.001), and there were no changes in strain or torsion. In contrast, during the standardized low-intensity exercise challenge, hemodynamic conditions were unchanged from pre- to post-CRIT60 (mean arterial pressure: 98 ± 1 vs. 97 ± 1 mmHg, not significant), but strain decreased (left ventricular GLS: -20.3 ± 0.5% vs. -18.5 ± 0.4%, P < 0.01; right ventricular GLS: -26.4 ± 1.6% vs. -22.4 ± 1.5%, P < 0.05), whereas LV torsion remained unchanged. Serum high-sensitivity cardiac troponin T increased by 345% after the CRIT60 (6.0 ± 0.6 vs. 20.7 ± 6.9 ng/l, P < 0.05). This study demonstrates that exercise-induced functional and biochemical cardiac perturbations are not confined to ultraendurance sporting events and transpire during exercise that is typical of day-to-day training undertaken by endurance athletes. The clinical significance of cumulative exposure to endurance exercise warrants further study.

Use of observed within-person variation of cardiac troponin in emergency department patients for determination of biological variation and percentage and absolute reference change values.

BACKGROUND: Many patients presenting to the emergency department (ED) for assessment of possible acute coronary syndrome (ACS) have low cardiac troponin concentrations that change very little on repeat blood draw. It is unclear if a lack of change in cardiac troponin concentration can be used to identify acutely presenting patients at low risk of ACS. METHODS: We used the hs-cTnI assay from Abbott Diagnostics, which can detect cTnI in the blood of nearly all people. We identified a population of ED patients being assessed for ACS with repeat cTnI measurement who ultimately were proven to have no acute cardiac disease at the time of presentation. We used data from the repeat sampling to calculate total within-person CV (CV(T)) and, knowing the assay analytical CV (CV(A)), we could calculate within-person biological variation (CV(i)), reference change values (RCVs), and absolute RCV delta cTnI concentrations. RESULTS: We had data sets on 283 patients. Men and women had similar CV(i) values of approximately 14%, which was similar at all concentrations <40 ng/L. The biological variation was not dependent on the time interval between sample collections (t = 1.5-17 h). The absolute delta critical reference change value was similar no matter what the initial cTnI concentration was. More than 90% of subjects had a critical reference change value <5 ng/L, and 97% had values of <10 ng/L. CONCLUSIONS: With this hs-cTnI assay, delta cTnI seems to be a useful tool for rapidly identifying ED patients at low risk for possible ACS.

Cardiac electrical conduction, autonomic activity and biomarker release during recovery from prolonged strenuous exercise in trained male cyclists.

PURPOSE: Although markers of myocyte injury, electrolyte disturbances and an autonomic imbalance have been reported following exercise, the effect of prolonged strenuous activity on cardiac electrical conduction is not well understood. This study examined atrial and ventricular conduction dynamics during recovery from exercise. METHODS: Electrocardiographic intervals were obtained from eight highly-trained males before, during recovery (15, 30, 45 and 60 min post-exercise) and 24 h after a prolonged bout of strenuous exercise. Time-domain, frequency-domain and non-linear analyses of the RR, PR and QT intervals were analysed to investigate the effect of exercise on autonomic modulation and cardiac electrical conduction. Serum electrolyte and high-sensitivity cardiac troponin T (hs-cTnT) concentrations were measured before exercise, and after 60 min and 24 h of recovery. RESULTS: The root mean square of the successive differences of RR, PR and QT intervals was significantly reduced during recovery (p < 0.05). Normalised low- and high-frequency power of RR intervals significantly increased and decreased, respectively, during recovery. Approximate entropy of PR and QT intervals, and the QT-variability index significantly increased during recovery. All measures except mean QT interval (pre 422 ± 10 ms vs 24 h post 442 ± 11 ms, p = 0.013) returned to pre-exercise values after 24 h. Serum hs-cTnT was significantly elevated 60 min after exercise (pre 5.2 ± 0.7 ng L(-1) vs 60 min post 27.4 ± 6.2 ng L(-1), p = 0.01) and correlated with exercising heart rate (R(2) = 0.89, p < 0.001). Serum electrolyte concentrations were unchanged (p > 0.05). CONCLUSION: The results suggest suppressed parasympathetic and/or sustained sympathetic modulation of heart rate during recovery, concomitant with perturbations in atrial and ventricular conduction dynamics. Exercise-induced hs-cTnT release was heart rate dependent.

Longitudinal studies of cardiac troponin I in a large cohort of healthy children.

BACKGROUND: There is little information available on cardiac troponin concentrations in healthy young children. METHODS: Using a precommercial high-sensitivity assay from Abbott Diagnostics, we measured cardiac troponin I (cTnI) in longitudinal blood samples collected at ages 8, 10, and 12 years from a cohort of healthy, community-dwelling children. The 99th percentile values were calculated and estimates of the long-term biological variation were made. RESULTS: cTnI concentrations were above the limit of detection in 87%, 90%, and 98% of the children at ages 8, 10, and 12 years. The 99th percentiles were lower compared to a healthy adult population in both male and female children at all ages studied. At the 3 periods of study assessment, different children had cTnI concentrations above the 99th percentile. The calculated 99th percentile varied markedly depending upon whether the lowest or highest cTnI measurement for an individual child was included in the calculation. Biological variation varied markedly between 0% and 136%, the index of individuality was low at 0.36, and the reference change value was an increase of 147% or a decrease of 59%. CONCLUSIONS: In this longitudinal study of cTnI concentrations in healthy children as determined by a high-sensitivity assay, different children had concentrations of cTnI above the 99th percentile at the 3 episodes of assessment. These results suggest that in children the 99th percentile may not be a reliable index of silent cardiac disease, but rather may be indicating low-grade intercurrent illness.

Characterisation of a highly sensitive troponin I assay and its application to a cardio-healthy population.

BACKGROUND: Abbott Diagnostics have developed a new highly sensitive troponin I (hs-TnI) assay. We have assessed its analytical characteristics and applied the assay to a population of apparently cardio-healthy persons. METHODS: We assessed imprecision, bias compared to the previous generation assay, matrix effects, and interferences and applied the assay to an apparently healthy population, deriving the 99th percentile limit of the distribution of values in reference populations for men and women separately. RESULTS: The dynamic range of the assay was ranged from 0.5-50,000 ng/L (pg/mL). The 10% CV was at a concentration of 3.9 ng/L, and the 20% CV was at a concentration of 1.8 ng/L. The new and current version of the TnI assay were highly correlated [slope: 0.98 (95%CI:0.88-1.07), y-intercept:1.20 (95%CI:-2.35-4.75) r²=0.99]. The 99th percentile limit of the distribution of values in a reference population was different for males and females: for males 14.0 ng/L and for females 11.1 ng/L and at these concentrations the assay CV was 5.0%. TnI was detectable in nearly all patient samples from the healthy reference population (98.6%). CONCLUSIONS: This new hs-TnI assay is able to measure to an order of magnitude lower than the current generation TnI assay from the same manufacturer. With TnI being detectable in nearly all apparently healthy subject samples this suggests that TnI presence does not always indicate cardiomyocyte necrosis.

Gamma-Glutamyl Transferase (GGT) Is the Leading External Quality Assurance Predictor of ISO15189 Compliance for Pathology Laboratories.

Pathology results are central to modern medical practice, informing diagnosis and patient management. To ensure high standards from pathology laboratories, regulators require compliance with international and local standards. In Australia, the monitoring and regulation of medical laboratories are achieved by conformance to ISO15189-National Pathology Accreditation Advisory Council standards, as assessed by the National Association of Testing Authorities (NATA), and an external quality assurance (EQA) assessment via the Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP). While effective individually, integration of data collected by NATA and EQA testing promises advantages for the early detection of technical or management problems in the laboratory, and enhanced ongoing quality assessment. Random forest (RF) machine learning (ML) previously identified gamma-glutamyl transferase (GGT) as a leading predictor of NATA compliance condition reporting. In addition to further RF investigations, this study also deployed single decision trees and support vector machines (SVM) models that included creatinine, electrolytes and liver function test (LFT) EQA results. Across all analyses, GGT was consistently the top-ranked predictor variable, validating previous observations from Australian laboratories. SVM revealed broad patterns of predictive EQA marker interactions with NATA outcomes, and the distribution of GGT relative deviation suggested patterns by which to identify other strong EQA predictors of NATA outcomes. An integrated model of pathology quality assessment was successfully developed, via the prediction of NATA outcomes by EQA results. GGT consistently ranked as the best predictor variable, identified by combining recursive partitioning and SVM ML strategies.

Age-related differences in hs-cTnI concentration in healthy adults.

BACKGROUND: Because the 99th percentile is of such importance in defining myocardial injury and myocardial infarction, it is important to know whether there are real age-related differences in troponin 99th percentiles. METHODS: We went to our database from the Canberra Heart Study where 1062 apparently healthy subjects were extensively screened for occult cardiac disease, and looking at persons aged <65 years and >65 years, for men and women separately, we compared a variety of cutpoints from the 99th percentile down to the 50th percentile. RESULTS: With our rigorous criteria for defining cardiac health, we excluded 67.2% of males aged >65 years and 53.8% of women aged 65 years and older. Even with these rigorous exclusions we found that at every cutpoint examined between the 99th percentile and the 50th percentile, persons aged <65 years had lower troponin I concentrations that persons aged 65 years and older. Similarly, at every cutpoint examined, women had lower troponin I concentrations than did men. For the 4 separate groups examined (men and women, age < 65 years and 65 years and older) after the exclusions of persons with subclinical cardiac disease, the distributions were not significantly different to a Gaussian distribution. CONCLUSIONS: With the rigorous exclusions of persons with subclinical cardiac disease, and the fact that our populations have a Gaussian distribution, our data suggests that age-related hs-cTnI concentrations are real. This has important implications particularly when assessing older persons in the Emergency Department.

The importance of low level QC for high sensitivity troponin assays.

BACKGROUND: With the advent of the new high-sensitivity troponin assays, it is becoming critical to measure troponin accurately to low concentrations. To ensure assay performance is acceptable, appropriate QC must be run. METHODS: In addition to the routine use of commercial QC material, we prepared pools of human QC material with low troponin concentrations close to the limit of quantitation, and ran these regularly on our laboratory analysers. RESULTS: Over 3 years we found no drift or shift in our hs-cTnI assay. We found that only the very low concentration human QC material gave warning of precision problems with the hs-cTnI assay. At the time of the documented poor assay precision, the higher concentration QC material indicated satisfactory performance. CONCLUSIONS: Choice of QC material with an appropriate concentration is important for any assay. For hs-cTn assays, it is of particular importance to use control material with a concentration near to the limit of quantitation.

Missed detection of significant positive and negative shifts in gentamicin assay: implications for routine laboratory quality practices.

INTRODUCTION: A product recall was issued for the Roche/Hitachi Cobas Gentamicin II assays on 25th May 2016 in Australia, after a 15 - 20% positive analytical shift was discovered. Laboratories were advised to employ the Thermo Fisher Gentamicin assay as an alternative. Following the reintroduction of the revised assay on 12th September 2016, a second reagent recall was made on 20th March 2017 after the discovery of a 20% negative analytical shift due to erroneous instrument adjustment factor. MATERIALS AND METHODS: The practices of an index laboratory were examined to determine how the analytical shifts evaded detection by routine internal quality control (IQC) and external quality assurance (EQA) systems. The ability of the patient result-based approaches, including moving average (MovAvg) and moving sum of outliers (MovSO) approaches in detecting these shifts were examined. RESULTS: Internal quality control data of the index laboratory were acceptable prior to the product recall. The practice of adjusting IQC target following a change in assay method resulted in the missed negative shift when the revised Roche assay was reintroduced. While the EQA data of the Roche subgroup showed clear negative bias relative to other laboratory methods, the results were considered as possible 'matrix effect'. The MovAvg method detected the positive shift before the product recall. The MovSO did not detect the negative shift in the index laboratory but did so in another laboratory 5 days before the second product recall. CONCLUSIONS: There are gaps in current laboratory quality practices that leave room for analytical errors to evade detection.

Newer cardiac troponin I assays have similar performance to troponin T in patients with end-stage renal disease.

BACKGROUND: Troponin T is present in the blood of a majority of patients with endstage renal disease (ESRD) undergoing regular dialysis and presence of troponin T is a predictor of adverse outcome in these patients. With several new formulations of troponin I assays available, this study was performed to see whether these newer assays were able to detect troponin I in these patients more effectively than the older assays. METHODS: One hundred and forty-three patients undergoing regular haemodialysis or peritoneal dialysis had plasma collected and troponin T and troponin I measured by a variety of assays. RESULTS: The newer troponin I assays (Abbott Architect, Bayer Centaur and Beckman Accu-TnI) were able to detect troponin I (>75% of samples) as effectively as the Roche assay was able to detect troponin T, while other troponin I assays had a much lower rate of detection of troponin - DPC Immulite 2000 16% and Abbott AxSYM 35%. However, the troponin T assay had more samples detected at concentrations corresponding to an assay CV of 10% (59% of samples) than did the newer troponin I assays (highest on the Bayer Centaur at 37%). CONCLUSIONS: Newer assays demonstrate that troponin I is present in a similar number of samples as is troponin T, in the blood of patients with dialysis-dependent renal failure, and these newer troponin I assays identify patients at risk of experiencing a cardiac event.

Statistical considerations for determining high-sensitivity cardiac troponin reference intervals.

The troponin 99th percentile is used as the laboratory decision point in the diagnosis of acute myocardial infarction. A recent publication has shown that the statistical treatment for outlier removal may dramatically change the calculated troponin 99th percentile. We have used our large database from the previously reported Canberra Heart Study to independently assess the effect of various methods for removing outliers on the calculated 99th percentile. We have performed the same exercise using the troponin 97.5th percentile as an exercise to assess how outlier removal may affect calculated upper reference intervals for any analyte which uses this boundary. For healthy males aged <75years the hs-cTnI troponin 99th percentile varied by a factor>3× depending upon the outlier removal method chosen and for the 97.5th percentile the variation was >50%. For women the variation in the hs-cTnI 99th percentile varied by a factor of nearly 2×. Qualitatively similar results were obtained forhs-cTnT. This is not simply a problem for troponin reference intervals. All analyte reference intervals have the potential to be significantly affected by the method chosen for outlier removal. To ensure that studies can be meaningfully compared, guidance on procedures for removing outliers needs to be standardized as a matter of urgency.