Global FT4 immunoassay standardization: an expert opinion review

Objectives Results can vary between different free thyroxine (FT4) assays; global standardization would improve comparability of results between laboratories, allowing development of common clinical decision limits in evidence-based guidelines. Content We summarize the path to standardization of FT4 assays, and challenges associated with FT4 testing in special populations, including the need for collaborative efforts toward establishing population-specific reference intervals. The International Federation of Clinical Chemistry and Laboratory Medicine Committee for Standardization of Thyroid Function Tests has undertaken FT4 immunoassay method comparison and recalibration studies and developed a reference measurement procedure that is currently being validated. Further studies are needed to establish common reference intervals/clinical decision limits. Standardization of FT4 assays will change test results substantially; therefore, a major education program will be required to ensure stakeholders are aware of the benefits of FT4 standardization, planned transition procedure, and potential clinical impact of the changes. Assay recalibration by manufacturers and approval process simplification by regulatory authorities will help minimize the clinical impact of standardization. Summary Significant progress has been made toward standardization of FT4 testing, but technical and logistical challenges remain. Outlook Collaborative efforts by manufacturers, laboratories, and clinicians are required to achieve successful global standardization of the FT4 assays.

Evaluation of 24-h urine containers for urine copper measurement by inductively coupled plasma mass spectrometry

Objective To determine the necessity for acid-washed containers for 24-h urine copper analysis. Methods Copper solutions, with concentrations relevant to clinical decision limits, were prepared by spiking both assay diluent and unknown urine samples with the copper calibrator. Samples were split between plain and acid-washed 24-h urine containers, and copper analysis was performed using inductively coupled mass spectrometry (ICP-MS). Results Measurement of copper in both spiked diluent and spiked urine samples showed minimal concentration bias between acid-washed and plain 24-h urine containers. Conclusions Acid-washed containers are not required for the measurement of copper in 24-h urine samples.

Szignifikáns inverz kapcsolat a pajzsmirigy-stimuláló hormon (TSH) és a prosztataspecifikus antigén (PSA) vérszintjei között 40–75 éves korú férfiakban

Introduction: Recent experiments and clinical studies indicate the contribution of thyroid hormones to prostate pathology. Aim: In our retrospective analyzis of university patient population, we evaluated the association between thyroid stimulatory hormone (TSH) and prostate specific antigen (PSA). Method: From the Laboratory Information System we retrieved the data of male patients between 40 and 75 years of age who had been subjected to simultaneous TSH and PSA measurements during the last 12 years (n = 7279). The association between logTSH and logPSA levels was tested with multiple regression analysis and adjusted for age. Results: Significant associations between logPSA and logTSH and age (r = 0.297 and 0.472, respectively) were detected. PSA levels were higher in patients with TSH below (n = 405) than in those with TSH within reference range (TSH 0,35–4,95 mU/ml) (n = 6698) (PSA level: 1.118 [0.639–2.338] vs. 0.920 [0.508–1.826] ng/ml, p<0.016). Based on estimates, a 10% decrease in TSH is associated with a 0.42% increase in PSA levels in our population. This corresponds to a 42% increase in PSA levels in the same patient if he would present with 0.2 mU/ml instead of 2.0 mU/ml TSH. Conclusion: The finding that hyperthyreosis might be associated with higher PSA levels indicates that PSA reference ranges would differ in hyperthyreotic and in euthyreotic patients. Probably the PSA clinical decision limits is also recommended to be modified according to the patient’s thyroid status. Orv Hetil. 2019; 160(35): 1376–1379.

A Comprehensive Statistical Framework for Determination of Commutability, Accuracy, and Agreement in Clinical DNAemia Assays

ABSTRACTDespite advances in the standardization of quantitative DNAemia tests and efforts to better understand and characterize the performance of reference materials in different assays, it remains unclear how the commutability performance of reference materials is related to intra- and interassay agreement. Building upon previous work, we describe a comprehensive framework to determine the relationship of commutability with assay accuracy and agreement. The use of this framework is illustrated using previously generated data regarding the performance of four quantitative Epstein-Bar virus (EBV) PCR assays with the WHO and ABI standards as examples. The use of these statistical tools can link the performance characteristics of one or more assays with predetermined clinical decision limits and may help improve the development, validation, and clinical utility of such DNAemia tests.

Sex-Specific Versus Overall Clinical Decision Limits for Cardiac Troponin I and T for the Diagnosis of Acute Myocardial Infarction: A Systematic Review

BACKGROUND The overall clinical decision limits of high-sensitivity cardiac troponin I (hs-cTnI; 26 ng/L) and T (hs-cTnT; 14 ng/L) may contribute to underdiagnosis of acute myocardial infarction in women. We performed a systematic review to investigate sex-specific and overall 99th percentiles of hs-cTnI and hs-cTnT derived from healthy reference populations. CONTENT We searched in PubMed and EMBASE for original studies, and by screening reference lists. Reference populations designed to establish 99th percentiles of hs-cTnI (Abbott) and/or hs-cTnT (Roche), published between January 2009 and October 2017, were included. Sex-specific and overall 99th percentile values of hs-cTnI and hs-cTnT were compared with overall clinical decision ranges (hs-cTnI, 23–30 ng/L; hs-cTnT, 13–25 ng/L). Twenty-eight studies were included in the systematic review. Of 16 hs-cTnI and 18 hs-cTnT studies, 14 (87.5%) and 11 (61.1%) studies reported lower female-specific hs-cTn cutoffs than overall clinical decision ranges, respectively. Conversely, male-specific thresholds of both hs-cTnI and hs-cTnT were in line with currently used overall thresholds, particularly hs-cTnT (90% concordance). The variation of estimated overall 99th percentiles was much higher for hs-cTnI than hs-cTnT (29.4% vs 80.0% of hs-cTnI and hs-cTnT studies reported values within the current overall clinical decision range, respectively). SUMMARY Our data show substantially lower female-specific upper reference limits of hs-cTnI and hs-cTnT than overall clinical decision limits of 26 ng/L and 14 ng/L, respectively. The statistical approach strongly affects the hs-cTnI threshold. Downward adjustment of hs-cTn thresholds in women may be warranted to reduce underdiagnosis of acute myocardial infarction in women.

Should we maintain the 95 percent reference intervals in the era of wellness testing? A concept paper

The reference interval is probably the most widely used decision-making tool in clinical practice, with a modern use aiming at identifying wellness during health check and screening. Its use as a diagnostic tool is much less recognised and may be obsolete.The present study investigates the consequences of the newpractice for the interpretation of prospective value, negative vs. positive, the probability of confirming wellness, and number of false results based on selected strategy for reference interval establishment.Calculations assumed normalised Gaussian-distributed reference intervals with analytical variation set to zero and absolute accuracy. Also assumed is the independency of tests. Probability for no values outside reference intervals in healthy subjects was calculated from the formula pUse of the 99.9 centile for health checks will increase the probability for no false from 60% to 99% for 10 tests, and from 46% to 98% for 15 tests.The probability for one false-positive result in 10 tests in a panel can be reduced from 32% to 1% if the 99.9% centile is substituted for the 95% centile. For two in 10 tests, the probability can be reduced from 8% to below 0.1%. In both cases, selection of the 99.9% centile improves the diagnostic accuracy.Reference intervals are needed as a “true” negative reference for absence of disease, and should cover the 99.9% centile of the reference distribution of an analyte to avoid false positives. For this new use, it is critical that reference persons are absolutely normal without clinical, genetic and biochemical signs of the condition being investigated. However, reference intervals cannot substitute clinical decision limits for diagnosis and medical intervention.