Objectives Guidelines recommend the diagnosis of diabetes should be based on either plasma glucose or glycated hemoglobin (HbA 1C ) findings. However, lately studies have advocated glycated albumin (GA) as a useful alternative to HbA 1c . We conducted a systematic review and meta-analysis to determine the overall diagnostic accuracy of GA for the diagnosis of diabetes. Content We searched for articles of GA diabetes diagnostic accuracy that were published up to August 2021. Studies were selected if reported an oral glucose tolerance test as a reference test, measured GA levels by enzymatic methods, and had data necessary for 2 × 2 contingency tables. A bivariate model was used to calculate the pooled estimates. Summary This meta-analysis included nine studies, totaling 10,007 individuals. Of those, 3,106 had diabetes. The studies showed substantial heterogeneity caused by a non-threshold effect and reported different GA optimal cut-offs for diagnosing diabetes. The pooled diagnostic odds ratio (DOR) was 15.93 and the area under the curve (AUC) was 0.844, indicating a good level of overall accuracy for the diagnosis of diabetes. The effect of the GA threshold on diagnostic accuracy was reported at 15.0% and 17.1%. The optimal cut-off for diagnosing diabetes with GA was estimated as 17.1% with a pooled sensitivity of 55.1% (95% CI 36.7%–72.2%) and specificity of 94.4% (95% CI 85.3%–97.9%). Outlook GA has good diabetes diagnostic accuracy. A GA threshold of 17.1% may be considered optimal for diagnosing diabetes in previously undiagnosed individuals.

Opinion Paper

Publicly Available April 22, 2022

Ad interim recommendations for diagnosing SARS-CoV-2 infection by the IFCC SARS-CoV-2 variants working group

Giuseppe Lippi, Julien Favresse, Michael M. Gromiha, Jeffrey A. SoRelle, Mario Plebani, Brandon M. Henry

Page range: 975-981

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Abstract

This document, endorsed by the IFCC Working Group on SARS-CoV-2 Variants, aims to update previous indications for diagnosing acute SARS-CoV-2 infection, taking into consideration the evidence that has emerged after the origin and spread of new lineages and sub-lineages of the virus characterized by mutated genetics and altered biochemical, biological and clinical characteristics. These indications encompass the use of different diagnostic strategies in specific clinical settings, such as high risk of SARS-CoV-2 infection (symptomatic patients), low risk of SARS-CoV-2 infection (asymptomatic subjects) at hospital admission/contact tracing, testing in asymptomatic subjects, in epidemiologic surveys and/or population screening, along with tentative indications for identification of new lineages and/or sub-lineages of SARS-CoV-2.

Guidelines and Recommendations

Open Access May 11, 2022

Recommendations for IVDR compliant in-house software development in clinical practice: a how-to paper with three use cases

Hanneke W.M. van Deutekom, Saskia Haitjema

Page range: 982-988

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Abstract

Objectives The In Vitro Diagnostics Regulation (IVDR) will be effective in May 2022 by which in-house developed tests need to apply to the general safety and performance requirements defined in Annex I of the IVDR ruling. Yet, article 16 from Annex I about software can be hard to interpret and implement, particularly as laboratories are unfamiliar with quality standards for software development. Methods In this paper we provide recommendations on organizational structure, standards to use, and documentation, for IVDR compliant in-house software development. Results A practical insight is offered into novel standard operating procedures using three examples: an Excel file with a formula to calculate the pharmacokinetics of tacrolimus and to calculate the new dose, a rule for automated diagnosis of acute kidney injury and a bioinformatics pipeline for DNA variant calling. Conclusions We recommend multidisciplinary development teams supported by higher management, use of ISO-15189 in synergy with IEC-62304, and concise documentation that includes intended purpose, classification, requirement management, risk management, verification and validation, configuration management and references to clinical or performance evidence.

General Clinical Chemistry and Laboratory Medicine

May 9, 2022

Comparison between polynomial regression and weighted least squares regression analysis for verification of analytical measurement range

Tae-Dong Jeong, Soo-Kyung Kim, Sollip Kim, Chi-Yeon Lim, Jae-Woo Chung

Page range: 989-994

Abstract

Objectives Recently, the linearity evaluation protocol by the Clinical & Laboratory Standards Institute (CLSI) has been revised from EP6-A to EP6-ED2, with the statistical method of interpreting linearity evaluation data being changed from polynomial regression to weighted least squares linear regression (WLS). We analyzed and compared the analytical measurement range (AMR) verification results according to the present and prior linearity evaluation guidelines. Methods The verification of AMR of clinical chemistry tests was performed using five samples with two replicates in three different laboratories. After analyzing the same evaluation data in each laboratory by the polynomial regression analysis and WLS methods, results were compared to determine whether linearity was verified across the five sample concentrations. In addition, whether the 90% confidence interval of deviation from linearity by WLS was included in the allowable deviation from linearity (ADL) was compared. Results A linearity of 42.3–56.8% of the chemistry items was verified by polynomial regression analysis in three laboratories. For analysis of the same data by WLS, a linearity of 63.5–78.3% of the test items was verified where the deviation from linearity of all five samples was within the ADL criteria, and the cases where the 90% confidence interval of all deviation from linearity overlapped the ADL was 78.8–91.3%. Conclusions Interpreting AMR verification data by the WLS method according to the newly revised CLSI document EP6-ED2 could reduce laboratory workload, enabling efficient laboratory practice.

May 2, 2022

Transport stability profiling – a proposed generic protocol

Lars Willems, Michael Paal, Michael Vogeser

Page range: 995-1002

Abstract

Objectives Diagnostic samples are exposed to a spectrum of variables during transport to laboratories; therefore, the evaluation of a rather comprehensive stability profile of measurands is warranted. While appropriate testing standards have been established for pharmaceuticals and reagents, this is not the case for diagnostic samples. The aim of our work was to develop and evaluate a protocol applicable to diagnostic samples. Methods An isochronous approach with representation of temperature and exposure duration in a two-dimensional matrix was established. The deviations of the measurement results from the baseline associated with the exposure are evaluated with respect to the measurement uncertainty of the analytical measurement procedure applied. Variables of the experiment are documented in a standardized matrix. As a proof-of-concept, we profiled the stability patterns of a number of measurands at four temperature levels over up to 72 h in primary serum sample tubes. Results The protocol proved to be workable and allowed the description of a comprehensive stability profile of a considerable number of compounds based on 21 small-volume primary samples collected from each volunteer and exposed according to this protocol. Conclusions A straightforward and feasible isochronous protocol can be used to investigate in detail the effects of different pre-processing conditions on the stability of measurands in primary samples during transport to diagnostic laboratories. This is of significance as pre-analytical logistics become increasingly important with the centralization of analytical services.

April 26, 2022

Impact of ultra-low temperature long-term storage on the preanalytical variability of twenty-one common biochemical analytes

Estibaliz Alegre, Nerea Varo, Pilar Fernández-Calle, Sofía Calleja, Álvaro González

Page range: 1003-1010

Abstract

Objectives Retrospective studies frequently assume analytes long-term stability at ultra-low temperatures. However, these storage conditions, common among biobanks and research, may increase the preanalytical variability, adding a potential uncertainty to the measurements. This study is aimed to evaluate long-term storage stability of different analytes at <−70 °C and to assess its impact on the reference change value formula. Methods Twenty-one analytes commonly measured in clinical laboratories were quantified in 60 serum samples. Samples were immediately aliquoted and frozen at <−70 °C, and reanalyzed after 11 ± 3.9 years of storage. A change in concentration after storage was considered relevant if the percent deviation from the baseline measurement was significant and higher than the analytical performance specifications. Results Preanalytical variability (CV P ) due to storage, determined by the percentage deviation, showed a noticeable dispersion. Changes were relevant for alanine aminotransferase, creatinine, glucose, magnesium, potassium, sodium, total bilirubin and urate. No significant differences were found in aspartate aminotransferase, calcium, carcinoembryonic antigen, cholesterol, C-reactive protein, direct bilirubin, free thryroxine, gamma-glutamyltransferase, lactate dehydrogenase, prostate-specific antigen, triglycerides, thyrotropin, and urea. As nonnegligible, CV P must remain included in reference change value formula, which was modified to consider whether one or two samples were frozen. Conclusions After long-term storage at ultra-low temperatures, there was a significant variation in some analytes that should be considered. We propose that reference change value formula should include the CV P when analyzing samples stored in these conditions.

April 18, 2022

Development of a liquid chromatography mass spectrometry method for the determination of vitamin K1, menaquinone-4, menaquinone-7 and vitamin K1-2,3 epoxide in serum of individuals without vitamin K supplements

Andreas Meinitzer, Dietmar Enko, Sieglinde Zelzer, Florian Prüller, Nerea Alonso, Eva Fritz-Petrin, Markus Herrmann

Page range: 1011-1019

Abstract

Objectives Vitamin K and metabolites have a beneficial role in blood coagulation, bone metabolism and growth. However, the determination of vitamin K concentrations in the blood in patients consuming a diet with naturally occurring vitamin K is currently challenging. We aim to develop a cost-effective and rapid method to measure vitamin K metabolites with potential application for clinics and research. Methods We developed a simple liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the determination of vitamin K1, menaquinone-4 (MK-4), menaquinone-7 (MK-7) and vitamin K1-2,3 epoxide in human serum and validated the method in a study cohort of 162 patients tested for carbohydrate malabsorption and in 20 patients with oral phenprocoumon intake. Results The overall precision (CVs) ranged between 4.8 and 17.7% in the specified working range (0.06–9.0 nmol/L for all analytes except for MK-7 with 0.04–6.16 nmol/L). In the malabsorption cohort samples, measured values were obtained for all different vitamin K metabolites except for vitamin K1-2,3 epoxide. This metabolite could be detected only in patients with phenprocoumon intake. The good performance of the method is especially achieved by the interaction of three factors: the use of lipase in the sample preparation, the use of an atypical fluorinated reversed phase column, and a logarithmic methanol gradient. Conclusions The described method is able to determine the concentration of four vitamin K metabolites in a time-efficient, simple and cost-effective manner. It can be suitable for both routine clinics and research.

Open Access May 5, 2022

TSH-receptor autoantibodies in patients with chronic thyroiditis and hypothyroidism

Mariella Giannone, Miriam Dalla Costa, Chiara Sabbadin, Silvia Garelli, Monica Salvà, Stefano Masiero, Mario Plebani, Diego Faggian, Nicoletta Gallo, Fabio Presotto, Loris Bertazza, Davide Nacamulli, Simona Censi, Caterina Mian, Corrado Betterle

Page range: 1020-1030

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Abstract

Objectives The reported prevalence of TSH-receptor (TSHR) autoantibodies (TRAb) in patients with chronic thyroiditis (CT) range from 0 to 48%. The objective was to study the prevalence of TRAb in patients with CT and hypothyroidism and to correlate it with gender, age, thyroid dimensions, TSH levels, and autoimmune diseases. Methods The study comprised 245 patients with CT and hypothyroidism (median age 42 years, 193 females, 52 males) and 123 Italian healthy subjects matched for sex and age as controls. TRAb were tested with ELISA using a >2.5 IU/L cut off for positivity. TSHR blocking (TBAb) and TSHR stimulating autoantibodies (TSAb) were measured in 12 TRAb-positive patients using bioassays with Chinese hamster ovary (CHO) cells expressing wild-type or R255D-mutated TSHR. Results TRAb positivity was found in 32/245 (13.1%) patients and significantly correlated (p<0.05) with TSH levels. TRAb positivity was significantly higher in males vs. females (p=0.034), in females 16–45 years of age vs. >45 years of age (p<0.05) and in patients with reduced vs. normal/increased thyroid dimensions (p<0.05). Linear regression analysis showed a correlation between TRAb concentrations with age (p<0.05) and TRAb concentrations with TSH (p<0.01). In bioassay with TSHR-R255D all 12 patients tested were TBAb-positive while 33% were also TSAb-positive suggesting the presence of a mixture of TRAbs with different biological activities in some patients. Conclusions TRAb have been found in patients with CT and hypothyroidism. A mixture of TBAb and TSAb was found in some patients and this may contribute to the pathogenesis of thyroid dysfunction during the course of the disease.

April 25, 2022

Evaluation of the AFIAS-1 thyroid-stimulating hormone point of care test and comparison with laboratory-based devices

Sascha Dierks, Reiner Andag, Friederike Gauss, Kathrin Budde, Paul Francke, Manuela Peschka, Andreas Fischer, Julie Schanz, Astrid Petersmann

Page range: 1031-1038

Abstract

Objectives Thyroid-stimulating hormone (TSH) is the routine primary screening test to assess thyroid function and rapid measurement of TSH levels is highly desirable especially in emergency situations. In the present study, we compared the analytical performance of a commercially available point-of-care test (AFIAS-1) and five laboratory-based systems. Methods Left over material of 60 patient plasma samples was collected from patient care and used in the respective assay. For statistical analysis of the produced data Bland-Altman and Passing-Bablok regression analysis were applied. Results Good correlation (r=0.982 or higher) was found between all devices. Slopes from regression analysis ranged from 0.972 (95% CI: 0.927–1.013) to 1.276 (95% CI: 1.210–1.315). Among the compared devices, imprecision was high in terms of coefficient of variation (CV=10.3%) for low TSH concentrations and lower (CV=7.3%) for high TSH concentrations. Independent of the method used, we demonstrated a poor standardization of TSH assays, which might impact clinical diagnosis e.g. of hyperthyreosis. Conclusions This study shows that the point-of-care (POC) test AFIAS-1 can serve as an alternative to laboratory-based assays. In addition the data imply that better standardization of TSH measurements is needed.

May 11, 2022

Lack of analytical interference of dydrogesterone in progesterone immunoassays

Tanja K. Eggersmann, Albert Wolthuis, Peter H. van Amsterdam, Georg Griesinger

Page range: 1039-1045

Abstract

Objectives Progesterone, a sex steroid, is measured in serum by immunoassay in a variety of clinical contexts. One potential limitation of steroid hormone immunoassays is interference caused by compounds with structural similarity to the target steroid of the assay. Dydrogesterone (DYD), an orally active stereoisomer of progesterone, is used for various indications in women’s health. Herein, we report a systematic in vitro investigation of potential interference of DYD and its active metabolite 20α-dihydrodydrogesterone (DHD) in seven widely used, commercially available progesterone assays. Methods Routine human plasma samples were anonymized and pooled to create three graded concentration levels of progesterone (P4 high, P4 medium, P4 low). Each pooled P4 plasma sample (6–7 mL) was spiked at high, medium, and “none” concentration with DYD/DHD and was divided into 0.5 mL aliquots. The blinded aliquots were analyzed by seven different laboratories with their routine progesterone assay (six different immunoassays and one liquid chromatography–tandem mass spectrometry assay, respectively) within the Dutch working group on endocrine laboratory diagnostics of the Dutch Foundation for Quality Assessments in Medical Laboratories. Results The sample recovery rate (P4 result obtained for sample spiked with DYD/DHD, divided by the result obtained for the corresponding sample with no DYD/DHD × 100) was within a ±10% window for the medium and high P4 concentrations, but more variable for the low P4 samples. The latter is, however, attributable to high inter- and intra-method variability at low P4 concentrations. Conclusions This study does not indicate any relevant interference of DYD/DHD within routinely used progesterone assays.

April 27, 2022

A comprehensive comparison between ISAC and ALEX² multiplex test systems

Anouk C.M. Platteel, Pieter van der Pol, Jean-Luc Murk, Ingrid Verbrugge-Bakker, Marian Hack-Steemers, Theo H.W.M. Roovers, Michiel Heron

Page range: 1046-1052

Abstract

Objectives Diagnosis of type I hypersensitivity is based on anamnesis, provocation as well as blood- and skin testing. Multiplex specific IgE (sIgE) testing enables determination of sIgE antibodies against multiple recombinant or purified natural allergen components. The aim of this study was to evaluate the performance of the novel ALEX 2® (Allergy Explorer, ALEX 2 test introduced on the market November 2019) multiplex platform and to compare it with the ImmunoCAP ISAC ® test system. Methods Serum samples of 49 patients, routinely determined with ISAC, were selected based on positive results covering in total most of the 112 ISAC components. Cohen’s kappa, negative percent agreement (NPA), and positive percent agreement (PPA) of ALEX 2 data compared to ISAC data (as a non-reference standard) were computed for those allergen components present on both platforms (n=103). Furthermore, in some samples sIgE results against allergen extracts and/or -components tested with either ImmunoCAP ® (ThermoFisher) or IMMULITE ® (Siemens) were available and compared to ALEX 2 results. Results The overall agreement between ISAC and ALEX 2 common allergen components was 94%. NPA and PPA were respectively 95 and 90%. Kappa values differed for specific allergen groups and varied between 0.60 and 0.92 showing moderate to almost perfect agreement. Of the qualitative discrepancies between ALEX 2 and ISAC, 59% were related to weak positive results i.e. results under 1 kUA/L or 1 ISU, respectively. Conclusions The method comparison between ISAC and ALEX 2 multiplex tests showed a high concordance for those allergen components present on both platforms.

Open Access April 15, 2022

Detection of subarachnoid haemorrhage with spectrophotometry of cerebrospinal fluid – a comparison of two methods

Marcus Clarin, Annika Petersson, Henrik Zetterberg, Kim Ekblom

Page range: 1053-1057

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Abstract

Objectives Spectrophotometric absorption curve analysis of cerebrospinal fluid (CSF) for oxyhaemoglobin and bilirubin is necessary to accurately diagnose subarachnoid haemorrhage (SAH) in patients with typical symptoms but with negative findings on X-ray examinations. In this study, we evaluated the performance of two methods for interpreting absorption curves; one method from the United Kingdom National External Quality Assessment Service (UK-NEQAS) and the other from the national quality assurance programme in Sweden (Equalis). Methods Consecutive absorbance curves (n=336) were interpreted with two different methods, and their performance was compared to the diagnosis as stated in the patient records. Results The UK-NEQAS method displayed equal sensitivity to the Equalis method, but the specificity of the UK-NEQAS method was significantly higher than the Equalis method resulting in fewer false positive results. For UK-NEQAS, a positive predictive value (PPV) of 84.6% and a negative predictive value (NPV) of 99.7% were observed, whereas the Equalis method had a PPV of 27.5% and an NPV of 99.7%. Conclusions The semi-automated method based on the guidelines from UK-NEQAS provides an efficient and correct interpretation of absorbance curves with short turn-around times. We propose using this method for the routine interpretation of CSF spectrophotometric curves.

April 12, 2022

Importance of cerebrospinal fluid storage conditions for the Alzheimer’s disease diagnostics on an automated platform

Rosa Ferrer, Nuole Zhu, Javier Arranz, Inmaculada Porcel, Shaimaa El Bounasri, Oriol Sánchez, Soraya Torres, Josep Julve, Alberto Lleó, Francisco Blanco-Vaca, Daniel Alcolea, Mireia Tondo

Page range: 1058-1063

Abstract

Objectives Alzheimer’s disease (AD) is considered the most common cause of dementia in older people. Cerebrospinal fluid (CSF) Aβ1-42, Aβ1-40, total Tau (t-Tau), and phospho Tau (p-Tau) are important biomarkers for the diagnosis, however, they are highly dependent on the pre-analytical conditions. Our aim was to investigate the potential influence of different storage conditions on the simultaneous quantification of these biomarkers in a fully-automated platform to accommodate easier pre-analytical conditions for laboratories. Methods CSF samples were obtained from 11 consecutive patients. Aβ1-42, Aβ1-40, p-Tau, and t-Tau were quantified using the LUMIPULSE G600II automated platform. Results Temperature and storage days significantly influenced Aβ1-42 and Aβ1-40 with concentrations decreasing with days spent at 4 °C. The use of the Aβ1-42/Aβ1-40 ratio could partly compensate it. P-Tau and t-Tau were not affected by any of the tested storage conditions. For conditions involving storage at 4 °C, a correction factor of 1.081 can be applied. Diagnostic agreement was almost perfect in all conditions. Conclusions Cutoffs calculated in samples stored at −80 °C can be safely used in samples stored at −20 °C for 15–16 days or up to two days at RT and subsequent freezing at −80 °C. For samples stored at 4 °C, cutoffs would require applying a correction factor, allowing to work with the certainty of reaching the same clinical diagnosis.

May 5, 2022

Estimating urine albumin to creatinine ratio from protein to creatinine ratio using same day measurement: validation of equations

Guillaume Résimont, Laura Vranken, Hans Pottel, François Jouret, Jean-Marie Krzesinski, Etienne Cavalier, Pierre Delanaye

Page range: 1064-1072

Abstract

Objectives Severity of chronic kidney disease is defined by glomerular filtration rate (GFR) and albuminuria (ACR) by the KDIGO and are related to cardiovascular outcomes and end-stage-kidney-failure. However, proteinuria (PCR) is more often available than ACR in records. Recently, equations were developed to estimate ACR from PCR. We investigated their performances in our population. Methods In the academic medical hospital of Liège, we retrospectively analysed same day measurement of ACR and PCR and staged them according to the KDIGO A1-A2-A3 categories. Analyser Roche Cobas (R) gathered 2,633 urinalysis (May 2018-May 2019) and analyser Abbott Alinity (A) 2,386 urinalysis (May 2019-March 2020). We compared the KDIGO staging of mACR and eACR obtained from Weaver’s and Sumida’s equations. Results Median age was 63 [52;71]/64 [53;72] years old, 43/42% were female; 78/74% had diabetes; proportion of mACR-A1 was 65.6%/64.2%, A2 was 25.5%/25.5% and A3 was 8.8%/10.3% (Method R/A, respectively). Both equations gave similar distribution of KDIGO staging of eACR. Overall agreements were higher than 88% regardless of the analyser or of the equation. Performances in between equations were equivalent according to the multi-level AUC (multinomial logistic regression model). Conclusions Good concordance was observed between mACR and eACR regardless of the equation or of the analyser. No patient with an A3-measured ACR was estimated within the KDIGO A1 category. Though ACR should be measured when clinically needed, it may be reasonably estimated from the PCR through these equations, for epidemiologic retrospective studies or research purposes.

May 11, 2022

An automated, rapid fluorescent immunoassay to quantify serum soluble programmed death-1 (PD-1) protein using testing-on-a-probe biosensors

Jun Zhang, Lin Chen, Qin Xu, Yue Tao, Jie Pan, Jianmin Guo, Jing Su, Hui Xie, Yuxin Chen

Page range: 1073-1080

Abstract

Objectives Soluble programmed death-1 (sPD-1) plays an essential role in the pathogenesis and progression of various diseases, including chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). Currently, there is no Food and Drug Administration–approved sPD-1 immunoassay available for routine clinical testing. Most sPD-1 detections employed enzyme-linked immunosorbent assay (ELISA) method for research purpose, which is complicated by intensive manual operation and cannot achieve automatic detection. Therefore, we aimed to develop an automated, rapid immunoassay for sPD-1 measurement based on testing-on-a-probe (TOP) biosensors and evaluate its performance in patients with hepatic diseases. Methods We developed an automatic fluorescent immunoassay using TOP biosensors using a pair of mouse anti-PD-1 monoclonal antibodies (mAbs), which were evaluated by biolayer interferometry. The sensitivity, linearity, and repeatability of the novel immunoassay were analyzed, and its compatibility with an established ELISA kit was evaluated. Further, we quantified sPD-1 level in healthy individuals as well as patients with CHB, hepatic cirrhosis, and HCC. Results The TOP assay to quantify sPD-1 was developed and performed on an automatic fluorescent analyzer within 20 min, which showed good precision with coefficients of variation less than 10% and good linearity ranging from 2 to 3,000 pg/mL. The results tested by our TOP assay correlated well with the established ELISA assay (r=0.92, p<0.0001). Using our TOP assay, sPD-1 was significantly elevated in patients with chronic hepatitis, hepatic cirrhosis and hepatocarcinoma if compared to healthy control, respectively (p<0.0001). Conclusions An automated, rapid fluorescent immunoassay to quantify serological sPD-1 protein using TOP biosensors was developed and showed acceptable analytical performance including precision, linearity, and good correlation with the established ELISA assay, with the great potential in clinical practice.

Hematology and Coagulation

Open Access May 11, 2022

The VES-Matic 5 system: performance of a novel instrument for measuring erythrocyte sedimentation rate

Elisa Piva, Alice Stoppa, Michela Pelloso, Mario Plebani

Page range: 1081-1090

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Abstract

Objectives The VES-Matic 5 is an automated analyzer that assesses erythrocyte sedimentation rate based on a modified Westergren sedimentation technique. Instrument performance was established by addressing the recommendations of the International Council for Standardization in Haematology. Methods Comparison against the reference Westergren method was performed for all samples, and further for the low, middle, and upper third of the analytical range. Intra-run precision, inter‐run precision, and interference studies were further assessed. This study included the evaluation of reference ranges. Results The comparison of methods by Passing–Bablok analysis has shown a good agreement without systematic or proportional differences. The regression equation was y =−0.646 + 0.979x. The mean bias of −0.542 was obtained by Bland–Altman analysis and the upper limit of 8.03 with the lower limit of −9.11 can be considered clinically acceptable. Intra-run and inter-run precision were good for each parameter and interference studies did not show any significant bias with exception of anemia samples, which showed a proportional difference when comparing high erythrocyte sedimentation rate values. Using the local adult reference population, we verified the reference ranges in comparison to those available in the literature, and according to the Clinical Laboratory Standards Institute (CLSI) EP28-A3C document. We determined the upper limit partitioned by gender and the following age groups: from 18 to 50, from 50 to 70, and over 70. Conclusions The VES-Matic 5 analyzer presented good comparability with the reference method. As there are commercial quality control and suitable external quality assessment (EQA) material and programs, the VES-Matic 5 can be employed appropriately for routine purposes.

Cancer Diagnostics

Open Access April 28, 2022

Is thyroglobulin a reliable biomarker of differentiated thyroid cancer in patients treated by lobectomy? A systematic review and meta-analysis

Luca Giovanella, Luca Ceriani, Maria Luisa Garo

Page range: 1091-1100

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Abstract

Objectives The prognostic role of thyroglobulin in predicting recurrence in differentiated thyroid cancer (DTC) patients treated by lobectomy is controversial. This systematic review with meta-analysis aimed to update the current evidence deepening the reliability of circulating thyroglobulin in assessing the early response and in predictive recurrence. Methods The methodology was registered in the PROSPERO database under the protocol number CRD42021288189. A systematic search was carried out on PubMed, Embase, Web of Science, and Scopus from September to November 2021 without time and language restrictions. The literature search strategy was based on the following keywords: Thyroglobulin AND (Lobectomy OR Hemithyroidectomy). Results After screening 273 articles, seven studies were included in the systematic review, and only six of them were included in the meta-analysis for a total of 2,455 patients. Circulating thyroglobulin was found non-reliable in assessing early response and predicting recurrence in patients with hemithyroidectomy, especially those with a low initial ATA classification. Conclusions Our study does not support serum thyroglobulin levels for monitoring patients with low-risk DTC treated with lobectomy, and weak evidence supports its role for intermediate- or high-risk patients. Studies with longer follow-up, different study designs, and stringent inclusion/exclusion criteria are needed to evaluate the role of thyroglobulin in recurrence prediction.

Cardiovascular Diseases

April 28, 2022

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

Gus Koerbin, Julia M. Potter, Marcela Pinto do Nascimento, Louise Cullen, Samuel L. Scanlan, Catherine Woods, Peter E. Hickman

Page range: 1101-1109

Abstract

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.

Infectious Diseases

Open Access April 27, 2022

A cohort analysis of SARS-CoV-2 anti-spike protein receptor binding domain (RBD) IgG levels and neutralizing antibodies in fully vaccinated healthcare workers

Andrea Padoan, Chiara Cosma, Foscarina della Rocca, Francesco Barbaro, Claudia Santarossa, Luigi Dall’Olmo, Luisa Galla, Annamaria Cattelan, Vito Cianci, Daniela Basso, Mario Plebani

Page range: 1110-1115

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Abstract

Objectives The waning of humoral immunity after COVID-19 vaccine booster (third dose) has not yet been fully evaluated. This study updates data on anti-SARS-CoV-2 spike protein receptor binding domain (S-RBD) binding antibodies (bAb) and neutralizing antibodies (NAb) levels in individuals with homologous vaccination 3–4 months after receiving the booster dose. Methods Fifty-five healthcare workers (HCW) from Padova University-Hospital were asked to collect serum samples for determining antibodies (Ab) at 12 (t 12 ) and 28 (t 28 ) days, at 6 months (t 6m ) after their first Comirnaty/BNT162b2 inoculation, and 3–4 months after receiving the 3rd homologous booster dose. HCW were monitored weekly for SARS-CoV-2 infection. Ab titers were measured by two chemiluminescent immunoassays, one targeting the S-RBD immunoglobulin G (IgG), and one surrogate viral neutralization test (sVNT), measuring NAb. Results Twenty of the HCW had natural COVID-19 infection (COVID+) at different times, before either the first or the second vaccination. Median S-RBD IgG and NAb levels and their interquartile ranges 3–4 months after the 3rd dose were 1,076 (529–3,409) kBAU/L and 15.8 (11.3–38.3) mg/L, respectively, for COVID−, and 1,373 (700–1,373) kBAU/L and 21 (12.8–53.9) mg/L, respectively, for COVID+. At multivariate regression analyses, with age and gender included as covariates, S-RBD IgG bAb and sVNT NAb levels were closely associated with the time interval between serological determination and the 3rd vaccine dose (log 10 β coeff =−0.013, p=0.012 and log 10 β coeff =−0.010, p=0.025) for COVID+, whereas no such association was found in COVID− individuals. Conclusions The third booster dose increases anti-SARS-CoV-2 Ab levels, elevated levels persisting for up to 3–4 months. Waning of Ab levels appears to be less pronounced for COVID+ individuals.

Publicly Available April 28, 2022

Patients with severe COVID-19 do not have elevated autoantibodies against common diagnostic autoantigens

Antigona Ulndreaj, Mingyue Wang, Salvia Misaghian, Louis Paone, George B. Sigal, Martin Stengelin, Christopher Campbell, Logan R. Van Nynatten, Antoninus Soosaipillai, Atefeh Ghorbani, Anu Mathew, Douglas D. Fraser, Eleftherios P. Diamandis, Ioannis Prassas

Page range: 1116-1123

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Abstract

Objectives Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19) presents occasionally with an aberrant autoinflammatory response, including the presence of elevated circulating autoantibodies in some individuals. Whether the development of autoantibodies against self-antigens affects COVID-19 outcomes remains unclear. To better understand the prognostic role of autoantibodies in COVID-19, we quantified autoantibodies against 23 markers that are used for diagnosis of autoimmune disease. To this end, we used serum samples from patients with severe [intensive care unit (ICU)] and moderate (ward) COVID-19, across two to six consecutive time points, and compared autoantibody levels to uninfected healthy and ICU controls. Methods Acute and post-acute serum (from 1 to 26 ICU days) was collected from 18 ICU COVID-19-positive patients at three to six time points; 18 ICU COVID-19-negative patients (sampled on ICU day 1 and 3); 21 ward COVID-19-positive patients (sampled on hospital day 1 and 3); and from 59 healthy uninfected controls deriving from two cohorts. Levels of IgG autoantibodies against 23 autoantigens, commonly used for autoimmune disease diagnosis, were measured in serum samples using MSD ® U-PLEX electrochemiluminescence technology (MSD division Meso Scale Discovery ® ), and results were compared between groups. Results There were no significant elevations of autoantibodies for any of the markers tested in patients with severe COVID-19. Conclusions Sample collections at longer time points should be considered in future studies, for assessing the possible development of autoantibody responses following infection with SARS-CoV-2.

May 2, 2022

Cerebrospinal fluid markers of inflammation and brain injury in Lyme neuroborreliosis – a prospective follow-up study

Ivar Tjernberg, Paula Gyllemark, Henrik Zetterberg, Kaj Blennow, Jan Ernerudh, Pia Forsberg, Johanna Sjöwall, Anna J. Henningsson

Page range: 1124-1132

Abstract

Objectives The purpose of this study was to evaluate levels and kinetics of cerebrospinal fluid (CSF) markers of inflammation and brain injury in patients with Lyme neuroborreliosis (LNB). Methods Adult patients with clinically suspected LNB were enrolled, in a prospective clinical study in the South East of Sweden. Patients were classified according to the European Federation of Neurological Societies’ guidelines. Definite cases of LNB were re-examined one month later including a repeat CSF investigation. Routine laboratory parameters were investigated along with CSF levels of neurodegenerative markers glial fibrillary acidic protein (GFAp), total tau (t-tau) and neurofilament light protein (NFL), as well as neuroinflammatory markers soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL-40 and CXCL13. Non-LNB served as controls. An additional comparison group consisted of spinal anesthesia subjects (SAS) without known central nervous system conditions. Results CSF levels of sTREM2 and CXCL13 were elevated in definite LNB patients at diagnosis compared with non-LNB patients (p<0.001) and SAS (p≤0.01). In addition, CSF levels of sTREM2, YKL-40 and CXCL13 rapidly declined in at follow-up after antibiotic treatment. In contrast, CSF levels of GFAp and t-tau did not differ across LNB groups, and did not change after treatment. Conclusions Although in a limited number of LNB patients, the results indicate a predominance of microglial and neuroinflammatory involvement rather than parenchymal CNS injury in CSF at diagnosis of LNB with a prompt decline after antibiotic treatment. The findings provide pathogenetic insights and may be of value in differential diagnosis of CSF findings.

Letters to the Editors

Publicly Available April 20, 2022

Misleading nomenclature of units of WHO materials used for standardization of SARS COv-2 serology

Young Bae Lee Hansen, Koh Furuta, Sridevi Devaraj, Fatma Meric Yilmaz, Gunnar Nordin

Page range: e151-e152

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Publicly Available April 25, 2022

Assessment of the humoral response in Omicron breakthrough cases in healthcare workers who received the BNT162b2 booster

Julien Favresse, Jean-Michel Dogné, Jonathan Douxfils

Page range: e153-e156

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Publicly Available May 2, 2022

COVID-19 related mortality and religious denomination vs. genetics

Joris R. Delanghe, Marijn M. Speeckaert, Marc L. De Buyzere

Page range: e157-e158

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April 11, 2022

Unexpectedly low tacrolimus concentrations attributed to inappropriately labeled water container from the instrument manufacturer

Erik Ames, Raffick A.R. Bowen

Page range: e159-e160

April 15, 2022

Effects of different pepsinogen cut offs in the screening of apparently healthy people

Shui Fu, Qi-Lei Hu, Liang Zhang, Zuo-Jie Li

Page range: e161-e164

April 28, 2022

Low levels of G17 and Barrett esophagus: a clinical relationship

Francesco Di Mario, Lorella Franzoni, Marilisa Franceschi, Kryssia Isabel Rodriguez-Castro, Michele Russo, Pellegrino Crafa

Page range: e165-e167

Open Access May 5, 2022

(In)direct chloride ISE measurements, room for improvement

Jenny E. Kootstra-Ros, Eline A.E. van der Hagen, Marith van Schrojenstein Lantman, Marc Thelen, Miranda van Berkel, On Behalf of the SKML General Clinical Chemistry Group

Page range: e168-e171

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April 27, 2022

New concept of interactive academic poster used in medical scientific congress presented in the EuroMedLab 2021 Munich Session

Guillaume Grzych, Fanny Lemonnier, Jean David Pekar, Manon Deschildt, Joan Bitan

Page range: e172-e174

About this journal

Objective
Clinical Chemistry and Laboratory Medicine (CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. It is focused on basic and applied research and cutting-edge clinical laboratory medicine. CCLM is one of the leading journals in the field, with an impact factor over 8. All contributions submitted for publication in CCLM are single-blind peer reviewed by at least two experts in the field. CCLM is led by a multi-institutional editorial board. It is issued monthly, both in print and electronically. Letters to the Editor and Congress Abstracts are published online only.

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Topics

clinical biochemistry
clinical genomics and molecular biology
clinical haematology and coagulation
clinical immunology and autoimmunity
clinical microbiology
drug monitoring and analysis
evaluation of diagnostic biomarkers
disease-oriented topics (cardiovascular disease, cancer diagnostics, diabetes)
new reagents, instrumentation and technologies
new methodologies
reference materials and methods
reference values and decision limits
quality and safety in laboratory medicine
translational laboratory medicine
clinical metrology

Article formats
Research Articles, Reviews, Mini Reviews and Opinion Papers on all aspects of clinical chemistry and laboratory medicine, Guidelines and Recommendations, Point/Counterpoint Articles, Letters to the Editor, Editorials

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Volume 60 Issue 7

Issue of Clinical Chemistry and Laboratory Medicine (CCLM)

Frontmatter

The never-ending quest for antibody assays standardization and appropriate measurement units

Glycated albumin in diabetes mellitus: a meta-analysis of diagnostic test accuracy

Abstract

Ad interim recommendations for diagnosing SARS-CoV-2 infection by the IFCC SARS-CoV-2 variants working group

Abstract

Recommendations for IVDR compliant in-house software development in clinical practice: a how-to paper with three use cases

Abstract

Comparison between polynomial regression and weighted least squares regression analysis for verification of analytical measurement range

Abstract

Transport stability profiling – a proposed generic protocol

Abstract

Impact of ultra-low temperature long-term storage on the preanalytical variability of twenty-one common biochemical analytes

Abstract

Development of a liquid chromatography mass spectrometry method for the determination of vitamin K1, menaquinone-4, menaquinone-7 and vitamin K1-2,3 epoxide in serum of individuals without vitamin K supplements

Abstract

TSH-receptor autoantibodies in patients with chronic thyroiditis and hypothyroidism

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Evaluation of the AFIAS-1 thyroid-stimulating hormone point of care test and comparison with laboratory-based devices

Abstract

Lack of analytical interference of dydrogesterone in progesterone immunoassays

Abstract

A comprehensive comparison between ISAC and ALEX2 multiplex test systems

Abstract

Detection of subarachnoid haemorrhage with spectrophotometry of cerebrospinal fluid – a comparison of two methods

Abstract

Importance of cerebrospinal fluid storage conditions for the Alzheimer’s disease diagnostics on an automated platform

Abstract

Estimating urine albumin to creatinine ratio from protein to creatinine ratio using same day measurement: validation of equations

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An automated, rapid fluorescent immunoassay to quantify serum soluble programmed death-1 (PD-1) protein using testing-on-a-probe biosensors

Abstract

The VES-Matic 5 system: performance of a novel instrument for measuring erythrocyte sedimentation rate

Abstract

Is thyroglobulin a reliable biomarker of differentiated thyroid cancer in patients treated by lobectomy? A systematic review and meta-analysis

Abstract

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

Abstract

A cohort analysis of SARS-CoV-2 anti-spike protein receptor binding domain (RBD) IgG levels and neutralizing antibodies in fully vaccinated healthcare workers

Abstract

Patients with severe COVID-19 do not have elevated autoantibodies against common diagnostic autoantigens

Abstract

Cerebrospinal fluid markers of inflammation and brain injury in Lyme neuroborreliosis – a prospective follow-up study

Abstract

Misleading nomenclature of units of WHO materials used for standardization of SARS COv-2 serology

Assessment of the humoral response in Omicron breakthrough cases in healthcare workers who received the BNT162b2 booster

COVID-19 related mortality and religious denomination vs. genetics

Unexpectedly low tacrolimus concentrations attributed to inappropriately labeled water container from the instrument manufacturer

Effects of different pepsinogen cut offs in the screening of apparently healthy people

Low levels of G17 and Barrett esophagus: a clinical relationship

(In)direct chloride ISE measurements, room for improvement

New concept of interactive academic poster used in medical scientific congress presented in the EuroMedLab 2021 Munich Session

A comprehensive comparison between ISAC and ALEX² multiplex test systems