Analytical validation of 39 clinical chemistry tests and 17 immunoassays on the Alinity analytical system
Ivana LapićDragana ŠeguljaKristina DukićAnamarija BogićAna Lončar VrančićSven KomljenovićTajana ŠparaklKatarina Grdiša TeodorovićVlasta Cigula KurajicaIvana LapićSaša Kralik OguićAna KozmarŽeljka VogrincDunja Rogić
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Abstract:
The aim of this study was to perform the analytical validation of Alinity c and i analyzers (Abbott Laboratories, Chicago, IL, USA) for 39 clinical chemistry tests and 17 immunoassays. Precision was evaluated at least at two concentration levels for 5 days in quintuplicate, following CLSI EP15-A3. Method comparison included parallel analysis of leftover routine samples on Alinity analyzers and the previously used Cobas c501 and e601 (Roche Diagnostics, Mannheim, Germany). Linearity was tested by preparing sequential sample dilutions with high analyte concentration, following the CLSI EP6 document. For clinical chemistry tests, within-run coefficients of variation (CV) were up to 6.0% (beta-2-microglobulin), while between-run CVs up to 5.4% (immunoglobulin M). Among immunoassays, the highest within-run CV was obtained for vitamin B12 (6.9%), while between-run for CA 19-9 (4.3%). Complete agreement with Roche analyzers was observed for 16 (41%) clinical chemistry assays and 6 (35%) immunoassays. Half of all evaluated assays did not meet the desirable biological variation criteria for bias, being especially exceeded for alpha1-antitrypsin, apolipoprotein A1, ceruloplasmin, complement C3 and C4, hemoglobin A1c, lipoprotein (a) and myoglobin, as well as some tumor markers (CA 125, CEA, fPSA, AFP, and ferritin), hormones (cortisol, DHEA-S, insulin) and vitamins (25-OHD). Linearity in the tested ranges was confirmed. Overall, this study revealed that precision criteria derived from manufacturer's claims were not satisfied for all assays while comparison study for some assays yielded differences that imply the need for additional assay evaluation prior to introduction into routine practice.Keywords:
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Coefficient of variation
The Roche Cobas c Tina-quant C-Reactive Protein (CRP) IV method has shown persistent, significant negative bias compared to other methodologies in the UK NEQAS external quality assurance (EQA) scheme. The aim of this study was to compare CRP concentrations determined by this restandardized 4th generation assay with another commercially available method to assess the extent of any bias and impact on clinical cut-offs.CRP concentrations in 38 anonymized patient serum samples were determined by a particle-enhanced immunoturbidimetric assay on the Roche Cobas c701 module and a latex assay on the Beckman Coulter AU5800 analyser over a concentration range of 1-308 mg/L.97.4% samples analysed by the Roche Tina-quant CRP IV method demonstrated a negative bias compared to the Beckman AU latex method. The mean absolute bias was -4.12 mg/L (range: -19.13-10.93 mg/L; 95% CI: -17.25-9.01 mg/L). The mean relative difference was -15.5% (range: -40-4%; 95% CI: -33.03-1.94%). This bias was seen across the range of samples assayed, including at clinically significant cut-offs of 5 mg/L (-24% bias), 20 mg/L (-5%) and 100 mg/L (-13%).The negative bias of the Roche method demonstrated in the EQA scheme appears to reflect genuine differences in patient results, rather than an EQA matrix effect, despite re-standardization of the CRP assay. This report indicates that clinical cut-offs and reference ranges may be method-dependent, which should be reflected in published guidance and interpretation provided by laboratories.
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Abstract Background High-sensitivity cardiac troponin T/I (hs-cTnT/I) assays have improved analytical sensitivity for the detection of myocardial infarction (MI). To gain clinical specificity and sensitivity, interpretation of changes in cTn concentrations over time is crucial. The 2015 ESC NSTEMI guideline defines absolute delta values as additional rule-in and rule-out criteria for MI. A critical assumption for application of this rule is that total analytical imprecision within the delta period, including inter-instrument bias, is comparable to analytical imprecision in the validation studies. Methods Data from the Dutch External Quality Assessment Scheme (EQAS) were used to calculate inter-instrument bias and estimate imprecision for the measuring range where the proposed delta values are relevant: for Roche Elecsys hs-cTnT, 5–52 and 5–12 ng/L; for Abbott Architect hs-cTnI, 2–52 and 2–5 ng/L for rule-in and rule-out, respectively. Results For Elecsys, the median inter-instrument bias is 0.3 ng/L (n = 33 laboratories), resulting in reference change values (RCVs) of 3.0 and 1.7 ng/L, respectively, for rule-in and rule-out with imprecision as claimed by the manufacturer. With RCVs smaller than the guideline’s delta thresholds, 100% of the laboratories have adequate specifications. RCVs for rule-in/rule-out increased to 4.6 ng/L/2.5 ng/L, respectively, with individual imprecisions as estimated from EQA data, resulting in 64% and 82% of laboratories with adequate specifications. For Architect, 40% of instruments (n = 10) might falsely qualify the result as clinically relevant; hence, inter-instrument bias could not be determined. Conclusions We advise laboratories that use the fast 0/1-h algorithm to introduce stringent internal quality procedures at the relevant/low concentration level, especially when multiple analyzers are randomly used.
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Haemoglobin A
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Background: Accurate and precise tests results generated by clinical laboratories would assist correct decision making in the diagnosis and management of patients. Quality assurance, which comprises of internal quality control (IQC) and external quality assessment (EQA), is intended to ensure the reliability of the laboratory results. Objectives: To evaluate the inter-laboratory variation of haemoglobin (Hb) measurements. Design: A descriptive cross-sectional study. Subjects: EQA samples with low (A), normal (B) and high (C) Hb concentrations Setting: A total of 292 clinical laboratories selected from 21 out of 47 Kenyan Counties. Main outcome measures: Mean deviation from the expected mean of the references and coefficient of variation (CV). Results: A total of 68%, 64% and 51% of laboratories gave accurate results for the sample A, B and C respectively. Based on the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88) criteria, 61% of laboratories had acceptable performance. Interlaboratory variation of 33.3%, 25.1% and 29.4% for samples A, B and C was recorded irrespective of the analyser a laboratory used. When grouped according to the type of analyser, CV reduced to 5.1% (Haemocontrol) to 41% (Urit) for sample A, 2.2% (Celltac) to 35% (Diaspect) for sample B and 3.4% (Medonic) to 42.6% (Diaspect) for sample C. These differences were statistically significant (p <0.001) across all Hb concentrations. Conclusions: The inter-laboratory variation in Hb measurements resulted from variation in methodologies and types of analysers. Regular participation in External Quality Assessment Schemes (EQAS) is essential in order to achieve inter-laboratory comparability of Hb results.
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This brief note addresses the historical background of the invention of the enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA). These assays were developed independently and simultaneously by the research group of Peter Perlmann and Eva Engvall at Stockholm University in Sweden and by the research group of Anton Schuurs and Bauke van Weemen in The Netherlands. Today, fully automated instruments in medical laboratories around the world use the immunoassay principle with an enzyme as the reporter label for routine measurements of innumerable analytes in patient samples. The impact of EIA/ELISA is reflected in the overwhelmingly large number of times it has appeared as a keyword in the literature since the 1970s. Clinicians and their patients, medical laboratories, in vitro diagnostics manufacturers, and worldwide healthcare systems owe much to these four inventors.
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Disopyramide, an antiarrhythmic drug, was quantitated in serum by a commercially supplied enzyme immunoassay procedure. Replicate analyses of serum controls resulted in a within-assay coefficient of variation of less than or equal to 5% and a between-assay coefficient of variation of less than or equal to 7%. Regression analysis of 105 serum samples analyzed by this technique (y) and by gas chromatography (x) gave the equation y = 0.99x + 0.04 (r = 0.97). Clinical evaluation of the results indicates the enzyme immunoassay technique to be highly specific and sensitive for disopyramide. The selectivity of the assay vs other drugs has been determined.
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The Elecsys Anti-SARS-CoV-2 immunoassay (Roche Diagnostics) was developed to provide accurate, reliable detection of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated sensitivity, specificity, cross-reactivity, and agreement with a vesicular stomatitis virus-based pseudoneutralization assay for the Elecsys Anti-SARS-CoV-2 immunoassay. Sensitivity and agreement between Elecsys Anti-SARS-CoV-2 immunoassay and pseudoneutralization assay measurements were evaluated using samples from patients with PCR-confirmed SARS-CoV-2 infection, a majority of whom were hospitalized.
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The quality of the HbA1c assay is inversely proportional to the variation of the assay. Most published measures of HbA1c variation are limited by the data collection period, the statistical treatment of outliers, and even the noncommutability of the products used to generate the variation measurements. We have used an alternate approach to derive HbA1c variation, using serial patient data.HbA1c measurements of outpatient blood sample pairs drawn within 30 days of each other were made on three different immunoassay systems: the Roche INTEGRA 700, the Roche INTEGRA 400, and the Dade Dimension RxL; and two high-performance liquid chromatography assays: the Tosoh G7 and the Tosoh 2.2+. The standard deviation of duplicates was calculated for the following time intervals: 1 to 3 days, 4 to 6 days, 7 to 9 days,.., 28 to 30 days. These intra-individual variations were then plotted; extrapolation to time zero yields the long term total random error which consists of both analytic and pre-analytic error. Data collection periods were usually 2 years.At the mean HbA1cs of 7.08%, 7.14%, 7.20%, 6.96%, and 7.51% for populations tested on the Roche INTEGRA 700, Roche INTEGRA 400, Dade Dimension RxL, Tosoh 2.2+, and Tosoh G7, respectively, the total analytic imprecisions (coefficient of variation) were 2.56%, 2.29%, 2.25%, 1.66%, and 1.14%, respectively.Assessment of the HbA1c long term total imprecisions shows that while the three immunoassay systems are acceptable, the Tosoh HbA1c analyzers demonstrate superior analytic performance.
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This article reports on the performance of two "dry" chemistry devices, (Reflotron, Roche Diagnostics and Vitros, Johnson & Johnson) and compared them with classical "wet" chemistry analysers in four commercially produced quality assessment samples (Roche PNU and PPU and Seronorm Human and Human High Controls) sent repeatedly over a 12-month observation period. Eleven analytes (including five enzymes) were studied, eight of which had target values set by reference method procedures. The results showed that both devices gave comparative results for the same sample sent in different EQA-surveys. Statistically significant differences which occurred were due to the high precision of measurement with a minimal shift in the measured concentrations. They had no clinical relevance in interpretation of results. Comparisons between "dry" and "wet" chemistry results for the same analyte were almost always statistically significantly different and often large enough to influence the clinical interpretation of results. Examples here were glucose and uric acid measured with the Reflotron and compared with other Roche devices (Cobas, Hitachi). The Vitros showed deviant values for urea and creatinine, when compared with other measuring devices using liquid reagents. Differences seen were constant over time, but must be seen in context with the matrices of the samples sent. The results show the long term stability of both reagents and test kits, a necessary prerequisite for long-term controlling of precision and indirectly accuracy of patient measurements.
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