Clinical consequences of a miscalibrated digoxin immunoassay

A routine audit revealed that the analytical method used to measure digoxin concentrations by our statewide pathology provider in 2009 was underestimating digoxin concentrations by 10%. The assay was recalibrated by the manufacturer in 2010, but clinical outcomes of the underestimation were never measured. This is a pilot study to describe the prescribing behavior around out-of-range digoxin concentrations and to assess whether miscalibrated digoxin immunoassays contribute to clinically relevant effects, as measured by inappropriate alterations in digoxin doses.About 30,000 digoxin concentrations across the State Hospital system were obtained in 2 periods before and after recalibration of the digoxin assay. Digoxin concentration means were calculated and compared and were statistically significantly different. Subsequently, a single-centered retrospective review of 50 randomly chosen charts was undertaken to study the clinical implications of the underestimated concentrations.Mean digoxin concentrations for 2009 and 2011 were significantly different by 8.8% (confidence interval, 7.0%-10.6%). After recalculating the 2009 concentrations to their "corrected" values, there was a 16% increase in the number of concentrations within the range when compared with the 2011 concentrations (41.48% versus 48.04%). However, overall, this did not cause unnecessary dose changes in patients who were "borderline" or outside the therapeutic range when compared with controls (P = 0.10). The majority of decisions were based on the clinical impression rather than concentration alone (85.1% versus 14.9%), even when the concentration was outside the "therapeutic range."Although recalculating digoxin concentrations measured during 2009 to their corrected values produced a significant change in concentration and values inside and outside the range, this does not seem to have had an influence on patient treatment. Rather, clinicians tended to use the clinical impression to dose digoxin

A critical evaluation of the Beckman Coulter Access hsTnI: analytical performance, reference interval and concordance

We investigated the analytical performance, outlier rate, carryover and reference interval of the Beckman Coulter Access hsTnI in detail and compared it with historical and other commercial assays.We compared the imprecision, detection capability, analytical sensitivity, outlier rate and carryover against two previous Access AccuTnI assay versions. We established the reference interval with stored samples from a previous study and compared the concordances and variances with the Access AccuTnI+3 as well as with two commercial assays.The Access hsTnI had excellent analytical sensitivity with the calibration slope 5.6 times steeper than the Access AccuTnI+3. The detection capability was markedly improved with the SD of the blank 0.18-0.20 ng/L, LoB 0.29-0.33 ng/L and LoD 0.58-0.69 ng/L. All the reference interval samples had a result above the LoB value. At a mean concentration of 2.83 ng/L the SD was 0.28 ng/L (CV 9.8%). Carryover (0.005%) and outlier (0.046%) rates were similar to the Access AccuTnI+3. The combined male and female 99th percentile reference interval was 18.2 ng/L (90% CI 13.2-21.1 ng/L). Concordance amongst the assays was poor with only 16.7%, 19.6% and 15.2% of samples identified by all 4 assays as above the 99th, 97.5th and 95th percentiles. Analytical imprecision was a minor contributor to the observed variances between assays.The Beckman Coulter Access hsTnI assay has excellent analytical sensitivity and precision characteristics close to zero. This allows cTnI measurement in all healthy individuals and the capability to identify numerically small differences between serial samples as statistically significant. Concordance in healthy individuals remains poor amongst assays

an international multi center serum protein electrophoresis accuracy and m protein isotyping study part i factors impacting limit of quantitation of serum protein electrophoresis

AbstractBackgroundSerum protein electrophoresis (SPEP) is used to quantify the serum monoclonal component or M-protein, for diagnosis and monitoring of monoclonal gammopathies. Significant imprecision and inaccuracy pose challenges in reporting small M-proteins. Using therapeutic monoclonal antibody-spiked sera and a pooled beta-migrating M-protein, we aimed to assess SPEP limitations and variability across 16 laboratories in three continents.MethodsSera with normal, hypo- or hypergammaglobulinemia were spiked with daratumumab, Dara (cathodal migrating), or elotuzumab, Elo (central-gamma migrating), with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Provided with total protein (reverse biuret, Siemens), laboratories blindly analyzed samples according to their SPEP and immunofixation (IFE) or immunosubtraction (ISUB) standard operating procedures. Sixteen laboratories reported the perpendicular drop (PD) method of gating the M-protein, while 10 used tangent skimming (TS). A mean percent recovery range of 80%–120% was set as acceptable. The inter-laboratory %CV was calculated.ResultsGamma globulin background, migration pattern and concentration all affect the precision and accuracy of quantifying M-proteins by SPEP. As the background increases, imprecision increases and accuracy decreases leading to overestimation of M-protein quantitation especially evident in hypergamma samples, and more prominent with PD. Cathodal migrating M-proteins were associated with less imprecision and higher accuracy compared to central-gamma migrating M-proteins, which is attributed to the increased gamma background contribution in M-proteins migrating in the middle of the gamma fraction. There is greater imprecision and loss of accuracy at lower M-protein concentrations.ConclusionsThis study suggests that quantifying exceedingly low concentrations of M-proteins, although possible, may not yield adequate accuracy and precision between laboratories

Highly sensitive troponin assays - a two-edged sword?

The advent of cardiac troponin (cTn) assays has redefined acute myocardial infarction (AMI) and revolutionised the care of patients with suspected AMI presenting to emergency departments (EDs). So central has cTn measurement become to the diagnosis of AMI that, since 2000, the formal criteria start with detection of rise and/or fall in serum troponin levels (with at least one value above the 99th percentile of the value distribution of a reference population for an assay with optimal precision at this level, defined as a coefficient of variation ≤ 10%), to which clinical evidence of myocardial ischaemia is added in regard to symptoms, electrocardiogram (ECG) changes or findings on cardiac imaging. This revised definition of AMI, with cTn assays using 99th percentile cut‐off values, has altered the epidemiology of the disease. Data from Western Australia suggest that in the two decades before the advent of cTn testing in 1998, age‐specific hospitalisation rates for AMI had decreased by an average of 30%, but this downward trend was abolished between 1998 and 2004

Proposed addendum to 2012 recommendations for standardised reporting of protein electrophoresis in Australia and New Zealand

It is apparent that there is a need for greater harmonisation of the reporting and quantification of paraproteins on protein electrophoresis with the introduction of the electronic health record and recent survey findings indicating ongoing areas of heterogeneity on serum protein electrophoresis. The proposed addendum aims to update the 2012 recommendations for standardised reporting of protein electrophoresis in Australia and New Zealand. The sections which need to be updated include those on the quantification of gamma- and non-gamma-migrating paraproteins; interpretive commenting in specimens with a paraprotein and/or small abnormal bands; the utility of serum free light chains compared with Bence Jones protein measurement; and a new table with interpretive commenting for serum free light chains. It is expected that such standardised reporting will reduce both variation between laboratories and the risk of misinterpretation of results