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Within-run precision and outlier detection for the Abbott ARCHITECT cardiac troponin I assay Peter A Kavsak, Lorna Clark, Sara Lancaster and Andrew C Don-Wauchope Ann Clin Biochem 2014 51: 512 originally published online 13 May 2014 DOI: 10.1177/0004563214534400 The online version of this article can be found at: http://acb.sagepub.com/content/51/4/512

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Letter Annals of Clinical Biochemistry 2014, Vol. 51(4) 512–514 acb.sagepub.com

Within-run precision and outlier detection for the Abbott ARCHITECT cardiac troponin I assay Sawyer et al.1 assessed the rate of cardiac troponin I (cTnI) outliers on the Abbott ARCHITECT analyzers. Importantly, they focused on the critical region where the difference between the results of duplicate measurements exceeded the allowable difference, with one of the two measurements above the 99th percentile cutoff (50.04 mg/L) and termed this a ‘critical outlier’.1 Their findings are noteworthy in that the critical outliers appear to be false positives with the root cause unknown but unlikely to be related to an analyzer malfunction. Our laboratory, since November 2012, has used the Abbott ARCHITECT cTnI assay for routine clinical care. In addition to regular commercial quality control (QC) material, we monitor performance using a low cTnI concentration patient-pool QC material (approximately 0.03 mg/L).2,3 Recently, our laboratory switched to the 500-test reagent pack from the 100-test reagent pack and through monitoring with the lowpool QC material identified possible positive cTnI outliers at this critical region. After assurances from the manufacturer that the analyzer was functioning appropriately, we set up a series of experiments utilizing a pool of patient samples with ‘normal’ cTnI concentrations to explore the extent of positive outliers and to assess if it was related to a specific analyzer or cTnI reagent lot. Briefly, for experiment 1 we obtained ethylenediaminetetraacetic acid plasma from patient samples that had a reported concentration of 0.02 mg/L, pooled the material, and aliquoted in 10 individual cups to be analysed on an 8200 (Site 1) and 16200 (Site 2) analyzer after 60 min of instrument inactivity with the same 500-test reagent lot (Lot#17117UN13). The imprecision was doubled on the 8200 as compared with the 16200 analyzer (CV ¼ 26.6% vs. 13.0%; Table 1, experiment 1), with the contributing factor being the first elevated result. Of note, assessing higher concentration patient pools at Site 1 (midpool mean (n/CV) ¼ 0.521 mg/L (n ¼ 9/2.2%), highpool mean (n/CV) ¼ 5.542 mg/L (n ¼ 10/2.6%)) using

the same 500-test reagent lot, there was no evidence of an elevated first result effect (i.e. highest concentration obtained after first result). To assess if this first result outlier at the low/normal concentration was due to the specific 500-test reagent lot stored at Site 1, experiment 2 was performed using a 100-test reagent lot (Lot#95509UN13) and a 500-test reagent (Lot#17117UN13) obtained from Site 2. Three rounds of testing were performed with both lots of cTnI reagent with at least 20 min of inactivity before each round of testing (Table 1, experiment 2). These data demonstrate that the first elevated result was apparent only with the 500- and not the 100-test reagent lot at Site 1. Experiment 3 was performed on two additional 500-test reagent lots (Lot#89576UN13 and 23070UN13) versus the 100test reagent lot, and the first elevated result effect was also evident with the different 500-test reagent lots. Sawyer et al. did not indicate whether a 500- or 100test reagent lot was used during their study, nor were they able to identify if the critical outlier was with the first result after a period of inactivity. Our experiments suggest that contributing factors to variability include a period of inactivity on the analyzer (i.e. in running mode with no samples being processed) and the reagent pack size. During our investigation, at no time did we observe differences 50.03 mg/L with the normal pool that may have been misinterpreted clinically as a significant change.4 We were able to uncover this positive first result outlier only with a normal cTnI patient-pool, thus reaffirming the importance of monitoring cTnI assays with appropriate QC material below the 99th percentile, regardless of using a high-sensitivity or sensitive assay.3,5 Finally, our findings indicate a renewed importance of performing within-run precision testing when evaluating cTnI reagent lots. Acknowledgements Abbott Diagnostics for technical support and evaluation/ scout kits.

Declaration of conflicting interests PK has received grant support and/or honorarium for work related to cardiac biomarkers from Abbott

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Letter

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Table 1. Within-run precision using ‘normal’ cTnI patient-pools to identify a specific lot and instrument outlier effect. Experiment 1 at Sites 1 and 2 500-test pack Lot#17117UN13 Low patient pool (mg/L)

Site 1 8200 500-test pack

Site 2 16200 500-test pack

Cup1 Cup2 Cup3 Cup4 Cup5 Cup6 Cup7 Cup8 Cup9 Cup10 Mean CV

0.021 0.011 0.010 0.011 0.012 0.012 0.011 0.010 0.012 0.011 0.012 26.6%

0.016 0.018 0.016 0.018 0.017 0.016 0.013 0.015 0.014 0.012 0.016 13.0%

Experiment 2 at Site 1 only Low patient pool (mg/L) 100-test pack Lot#95509UN13

Cup1 Cup2 Cup3 Cup4 Cup5 Cup6 Cup7 Cup8 Cup9 Cup10 Mean CV

500-test pack Lot#17117UN13

100-test pack Loaded at 12:10

100-test pack Loaded at 12:36

100-test pack Loaded at 13:03

500-test pack from Site 2 Loaded at 14:16

500-test pack from Site 2 Loaded at 14:44

500-test pack from Site 2 Loaded at 15:20

0.024 0.024 0.022 0.026 0.021 0.024 0.026 0.026 0.023 0.026 0.024 7.5%

0.024 0.025 0.026 0.026 0.024 0.024 0.023 0.024 0.023 0.031 0.025 9.4%

0.028 0.030 0.026 0.023 0.025 0.024 0.025 0.028 0.028 0.023 0.026 9.2%

0.030 0.013 0.015 0.017 0.015 0.016 0.015 0.016 0.014 0.015 0.017 29.1%

0.029 0.015 0.013 0.015 0.019 0.013 0.012 0.013 0.014 0.014 0.016 32.2%

0.024 0.014 0.013 0.013 0.018 0.018 0.012 0.016 0.015 0.014 0.016 22.7%

Experiment 3 at Site 1 only Pack size/Lot#

500-test/89576UN13 100-test/95553UN13 500-test/23070UN13 100-test/95553UN13

Low patient pool (mg/L) Cup1 Cup2 Cup3 Cup4 Cup5 Mean CV

0.039 0.028 0.024 0.023 0.023 0.027 24.8%

0.028 0.026 0.023 0.040 0.027 0.029 22.7%

0.023 0.018 0.015 0.015 0.018 0.018 18.4%

Shaded concentration is the highest concentration observed during run.

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0.022 0.023 0.025 0.018 0.021 0.022 11.9%

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Annals of Clinical Biochemistry 51(4)

Laboratories, Beckman Coulter, Randox Laboratories, Roche Diagnostics.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical approval Not applicable.

3. Kavsak PA. Quality control material testing and the importance of ‘‘treating it like a patient’s sample’’. Clin Biochem 2014; 47: 147–149. 4. Kavsak PA, Worster A, You JJ, et al. Ninety-minute vs 3h performance of high-sensitivity cardiac troponin assays for predicting hospitalization for acute coronary syndrome. Clin Chem 2013; 59: 1407–1410. 5. Kavsak PA, Hill SA, McQueen MJ, et al. Implications of adjustment of high-sensitivity cardiac troponin T assay. Clin Chem 2013; 59: 574–576.

Peter A Kavsak1,2, Lorna Clark2, Sara Lancaster2 and Andrew C Don-Wauchope1,2 1 Department of Pathology and Molecular Medicine, McMaster University, Canada 2 Juravinski Hospital and Cancer Centre, Hamilton, Canada

Guarantor PK.

Contributorship PK, LC, SL designed the experiments. LC and SL oversaw the analyses of samples. PK and AD analysed the results and drafted the manuscript.

Corresponding author: Pete Kavsak, Juravinski Hospital and Cancer Centre, 711 Concession Street, Hamilton, ON Canada L8V 1C3. Email: [email protected]

References 1. Sawyer N, Blennerhassett J, Lambert R, et al. Outliers affecting cardiac troponin I measurement: comparison of a new high sensitivity assay with a contemporary assay on the Abbott ARCHITECT analyser. Ann Clin Biochem Epub ahead of print 23 September 2013. 2. Kavsak PA, Shortt C, Pond G, et al. High-sensitivity cardiac troponin I for predicting death in a female emergency department population. Clin Chem 2014; 60: 271–273.

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Within-run precision and outlier detection for the Abbott ARCHITECT cardiac troponin I assay.

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