Published since January 1, 1963

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

ISSN: 1437-4331

Editor-in-chief: Mario Plebani

Edited by: Philippe Gillery, Ronda Greaves, Karl J. Lackner, Giuseppe Lippi, Bohuslav Melichar, Deborah A. Payne, Peter Schlattmann

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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To take advantage of all the opportunities offered to members of the EFLM Academy, please access your personal area in the EFLM Academy at the link https://academy.eflm.eu/secretariat/login (if you do not remember your login details, you can use the option FORGOT PASSWORD). Click on the section “International Journals” on the left-hand side where you find CCLM as the first listed journal.

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Latest developments in the clinical laboratory sciences
Fundamental and applied approach
Novel teaching and training methods
High quality peer-review
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CCLM is the official journal of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and affiliated to the National Societies that are members of the EFLM Academy. It publishes regularly EFLM recommendations and news. CCLM is the official journal of the National Societies from Austria (ÖGLMKC); Germany (DGKL); Hungary (MLDT); Ireland (ACBI); Italy (SIBioC); Portugal (SPML); Slovenia (SZKK); and Spain (SEQC-ML) and it is affiliated to AACB (Australia).

Previous Titles

Vol. 1 - Vol. 4, 1963-1966
Zeitschrift für Klinische Chemie
Vol. 5 - Vol. 9, 1967-1971
Zeitschrift für Klinische Chemie und Klinische Biochemie
Vol. 10 - Vol. 13, 1972-1975
Zeitschrift für Klinische Chemie und Klinische Biochemie Journal of Clinical Chemistry and Clinical Biochemistry
Vol. 14 - Vol. 26, 1976-1988
Journal of Clinical Chemistry and Clinical Biochemistry Zeitschrift für Klinische Chemie und Klinische Biochemie
Vol. 27 - Vol. 28, 1989-1990
Journal of Clinical Chemistry and Clinical Biochemistry
Vol. 29 - Vol. 35, 1991-1997
European Journal of Clinical Chemistry and Clinical Biochemistry

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Volume 61 Issue 7

June 2023

Publicly Available May 30, 2023

Frontmatter

Page range: i-v

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Editorial

Publicly Available April 25, 2023

ChatGPT: Angel or Demond? Critical thinking is still needed

Mario Plebani

Page range: 1131-1132

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Mini Review

Publicly Available January 12, 2023

Diagnostic accuracy of Siemens SARS-CoV-2 Antigen (CoV2Ag) chemiluminescent immunoassay for diagnosing acute SARS-CoV-2 infection: a pooled analysis

Giuseppe Lippi, Brandon M. Henry, Mario Plebani

Page range: 1133-1139

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Abstract

Background This article provides a critical literature review and pooled analysis of diagnostic accuracy of the fully-automated Siemens SARS-CoV-2 Antigen (CoV2Ag) chemiluminescent immunoassay for diagnosis of acute SARS-CoV-2 infections. Methods An electronic search was conducted in Scopus, PubMed and medRxiv using the keywords [“Siemens AND CoV2Ag”] OR [“Siemens AND SARS-CoV-2 AND antigen”] for capturing studies that investigated the accuracy of Siemens CoV2Ag for diagnosing acute SARS-CoV-2 infection against a reference SARS-CoV-2 molecular test. The retrieved information was used for constructing a 2 × 2 table and for calculating pooled diagnostic sensitivity, specificity, Summary Receiver Operating Characteristic Curve (SROC) and Agreement. This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting checklist. Results Four studies totalling 1,310 respiratory samples (612 with high viral load) were finally included in our analysis. The cumulative area under the curve, accuracy, sensitivity, specificity, were 0.964 (95% CI, 0.957–0.971), 86.9% (95% CI, 84.9–88.7%), 0.79 (95% CI, 0.76–0.82) and 0.98 (95% CI, 0.96–0.99), respectively. The negative (NPV) and positive (PPV) predictive values were 0.77 (0.74–0.79) and 0.98 (95% CI, 0.96–99), respectively. The diagnostic sensitivity in samples with high viral load (i.e., Ct<29–30) was 0.95 (95% CI, 0.93–0.97). Conclusions The Siemens CoV2Ag fully-automated and high-throughput immunoassay approximates the minimum performance criteria for general SARS-CoV-2 antigen testing and displays excellent performance in samples with high viral load, thus representing a valuable screening solution for risk assessment in COVID-19 and for limiting viral spread.

Opinion Papers

Open Access March 7, 2023

Neurofilament light chain as neuronal injury marker – what is needed to facilitate implementation in clinical laboratory practice?

Burak Arslan, Henrik Zetterberg

Page range: 1140-1149

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Abstract

Neurobiomarkers have attracted significant attention over the last ten years. One promising biomarker is the neurofilament light chain protein (NfL). Since the introduction of ultrasensitive assays, NfL has been developed into a widely used axonal damage marker of relevance to the diagnosis, prognostication, follow-up, and treatment monitoring of a range of neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. The marker is increasingly used clinically, as well as in clinical trials. Even if we have validated precise, sensitive, and specific assays for NfL quantification in both cerebrospinal fluid and blood, there are analytical, as well as pre- and post-analytical aspects of the total NfL testing process, including biomarker interpretation, to consider. Although the biomarker is already in use in specialised clinical laboratory settings, a more general use requires some further work. In this review, we provide brief basic information and opinions on NfL as a biomarker of axonal injury in neurological diseases and pinpoint additional work needed to facilitate biomarker implementation in clinical practice.

Open Access March 15, 2023

Clinical evidence requirements according to the IVDR 2017/746: practical tools and references for underpinning clinical evidence of IVD-MDs

Karine Charrière, Lionel Pazart

Page range: 1150-1157

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Abstract

In May 2022, the European Regulation 2017/746 (IVDR) came into force. It changes the approach of in vitro medical devices (IVD-MDs) for industry and institutions. It reinforces the clinical evidence requirements to improve performance, safety and transparency. Despite extended transition periods and existing guides, IVDR remains difficult to interpret and bringing devices into compliance requires efforts. The generation of clinical evidence is essential to demonstrate compliance with IVDR, and encompasses scientific validity, analytical performance and clinical performance. It is required to demonstrate, per intended use in the target population and clinical care pathway, IVD-MDs clinical performance (compared to a predefined clinical performance). Thus, there is a need for IVD-manufacturers and end-users in health care institutions, to obtain guidance on how to generate this clinical evidence. This article aims industrials and clinicians to identify key steps imposed by the IVDR for bringing IVD-MDs to the EU-market. We propose a general view of performance evaluation requirements for IVD-MDs and provide key references, including how to establish study design that will enable to document clinical performance of existing, refined or emerging medical tests. Finally, we propose a roadmap to address the relevant questions and studies in relation to the documents requested in the IVDR.

EFLM Papers

Publicly Available April 24, 2023

Potentials and pitfalls of ChatGPT and natural-language artificial intelligence models for the understanding of laboratory medicine test results. An assessment by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group on Artificial Intelligence (WG-AI)

Janne Cadamuro, Federico Cabitza, Zeljko Debeljak, Sander De Bruyne, Glynis Frans, Salomon Martin Perez, Habib Ozdemir, Alexander Tolios, Anna Carobene, Andrea Padoan

Page range: 1158-1166

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Abstract

Objectives ChatGPT, a tool based on natural language processing (NLP), is on everyone’s mind, and several potential applications in healthcare have been already proposed. However, since the ability of this tool to interpret laboratory test results has not yet been tested, the EFLM Working group on Artificial Intelligence (WG-AI) has set itself the task of closing this gap with a systematic approach. Methods WG-AI members generated 10 simulated laboratory reports of common parameters, which were then passed to ChatGPT for interpretation, according to reference intervals (RI) and units, using an optimized prompt. The results were subsequently evaluated independently by all WG-AI members with respect to relevance, correctness, helpfulness and safety. Results ChatGPT recognized all laboratory tests, it could detect if they deviated from the RI and gave a test-by-test as well as an overall interpretation. The interpretations were rather superficial, not always correct, and, only in some cases, judged coherently. The magnitude of the deviation from the RI seldom plays a role in the interpretation of laboratory tests, and artificial intelligence (AI) did not make any meaningful suggestion regarding follow-up diagnostics or further procedures in general. Conclusions ChatGPT in its current form, being not specifically trained on medical data or laboratory data in particular, may only be considered a tool capable of interpreting a laboratory report on a test-by-test basis at best, but not on the interpretation of an overall diagnostic picture. Future generations of similar AIs with medical ground truth training data might surely revolutionize current processes in healthcare, despite this implementation is not ready yet.

Publicly Available March 29, 2023

Detection of antinuclear antibodies: recommendations from EFLM, EASI and ICAP

Carolien Bonroy, Martine Vercammen, Walter Fierz, Luis E.C. Andrade, Lieve Van Hoovels, Maria Infantino, Marvin J. Fritzler, Dimitrios Bogdanos, Ana Kozmar, Benoit Nespola, Sylvia Broeders, Dina Patel, Manfred Herold, Bing Zheng, Eric Y.T. Chan, Raivo Uibo, Anna-Maija Haapala, Lucile Musset, Ulrich Sack, Gabor Nagy, Tatjana Sundic, Katarzyna Fischer, Maria-José Rego de Sousa, Maria Luisa Vargas, Catharina Eriksson, Ingmar Heijnen, Ignacio García-De La Torre, Orlando Gabriel Carballo, Minoru Satoh, Kyeong-Hee Kim, Edward K.L. Chan, Jan Damoiseaux, Marcos Lopez-Hoyos, Xavier Bossuyt, for the European Federation of Laboratory Medicine (EFLM) Working Group “Autoimmunity Testing,” the European Autoimmune Standardization Initiative (EASI) and International Consensus on Antinuclear Antibody Patterns (ICAP)

Page range: 1167-1198

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Abstract

Objectives Antinuclear antibodies (ANA) are important for the diagnosis of various autoimmune diseases. ANA are usually detected by indirect immunofluorescence assay (IFA) using HEp-2 cells (HEp-2 IFA). There are many variables influencing HEp-2 IFA results, such as subjective visual reading, serum screening dilution, substrate manufacturing, microscope components and conjugate. Newer developments on ANA testing that offer novel features adopted by some clinical laboratories include automated computer-assisted diagnosis (CAD) systems and solid phase assays (SPA). Methods A group of experts reviewed current literature and established recommendations on methodological aspects of ANA testing. This process was supported by a two round Delphi exercise. International expert groups that participated in this initiative included (i) the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group “Autoimmunity Testing”; (ii) the European Autoimmune Standardization Initiative (EASI); and (iii) the International Consensus on ANA Patterns (ICAP). Results In total, 35 recommendations/statements related to (i) ANA testing and reporting by HEp-2 IFA; (ii) HEp-2 IFA methodological aspects including substrate/conjugate selection and the application of CAD systems; (iii) quality assurance; (iv) HEp-2 IFA validation/verification approaches and (v) SPA were formulated. Globally, 95% of all submitted scores in the final Delphi round were above 6 (moderately agree, agree or strongly agree) and 85% above 7 (agree and strongly agree), indicating strong international support for the proposed recommendations. Conclusions These recommendations are an important step to achieve high quality ANA testing.

Publicly Available March 30, 2023

Analytical aspects of the antinuclear antibody test by HEp-2 indirect immunofluorescence: EFLM report on an international survey

Martine Vercammen, Carolien Bonroy, Sylvia Broeders, Edward K.L. Chan, Nicola Bizzaro, Dimitrios P. Bogdanos, Luis Andrade, Wim Coucke, Wilson de Melo Cruvinel, Ana Kozmar, Liisa Kuhi, Laurence Lutteri, Maria Jose Rego de Sousa, Sofie Schouwers, Lieve Van Hoovels, Xavier Bossuyt, on behalf of the EFLM Working Group on Autoimmunity Testing

Page range: 1199-1208

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Abstract

Objectives Detection of antinuclear antibodies (ANA) by indirect immunofluorescence assay using HEp-2 cells (HEp-2 IFA) is used to screen for various autoimmune diseases. HEp-2 IFA suffers from variability, which hampers harmonization. Methods A questionnaire was developed to collect information on HEp-2 IFA methodology, computer-assisted diagnosis (CAD) systems, training, inter-observer variability, quality assessment, reagent lot change control, and method verification. The questionnaire was distributed to laboratories by Sciensano (Belgium), national EASI groups (Italy, Croatia, Portugal, Estonia, Greece) and ICAP (worldwide). Answers were obtained by 414 laboratories. The results were analysed in the framework of the recent EFLM/EASI/ICAP ANA recommendations (companion paper). Results Laboratories used either HEp-2, HEp-2000, or HEp-20-10 cells and most laboratories (80%) applied the same screening dilution for children and adults. The conjugate used varied between laboratories [IgG-specific (in 57% of laboratories) vs. polyvalent]. Sixty-nine percent of CAD users reviewed the automatic nuclear pattern and 53% of CAD users did not fully exploit the fluorescence intensity for quality assurance. Internal quality control was performed by 96% of the laboratories, in 52% of the laboratories only with strongly positive samples. Interobserver variation was controlled by 79% of the laboratories. Limited lot-to-lot evaluation was performed by 68% of the laboratories. Method verification was done by 80% of the respondents. Conclusions Even though many laboratories embrace high-quality HEp-2 IFA, substantial differences in how HEp-2 IFA is performed and controlled remain. Acting according to the EFLM/EASI/ICAP ANA recommendations can improve the global performance and quality of HEp-2 IFA and nurture harmonization.

Guidelines and Recommendations

Publicly Available January 26, 2023

Variability of cardiac troponin levels in normal subjects and in patients with cardiovascular diseases: analytical considerations and clinical relevance

A consensus document by the Study Group on Cardiac Biomarkers from Italian Society of Biochemical Chemistry (SIBioC) and European Ligand Assay Society (ELAS)

Aldo Clerico, Martina Zaninotto, Alberto Aimo, Daniela M. Cardinale, Ruggero Dittadi, Maria T. Sandri, Marco Alfonso Perrone, Lucia Belloni, Antonio Fortunato, Tommaso Trenti, Mario Plebani

Page range: 1209-1229

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Abstract

In accordance with all the most recent international guidelines, the variation of circulating levels of cardiac troponins I and T, measured with high-sensitivity methods (hs-cTnI and hs-cTnT), should be used for the detection of acute myocardial injury. Recent experimental and clinical evidences have demonstrated that the evaluation of hs-cTnI and hs-cTnT variations is particularly relevant: a) for the differential diagnosis of Acute Coronary Syndromes (ACS) in patients admitted to the Emergency Department (ED); b) for the evaluation of cardiovascular risk in patients undergoing major cardiac or non-cardiac surgery, and in asymptomatic subjects of the general population aged >55 years and with co-morbidities; c) for the evaluation of cardiotoxicity caused by administration of some chemotherapy drugs in patients with malignant tumors. The aim of this document is to discuss the fundamental statistical and biological considerations on the intraindividual variability of hs-cTnI and hs-cTnT over time in the same individual. Firstly, it will be discussed in detail as the variations of circulating levels strictly depend not only on the analytical error of the method used but also on the intra-individual variability of the biomarker. Afterwards, the pathophysiological interpretation and the clinical relevance of the determination of the variability of the hs-cTnI and hs-cTnT values in patients with specific clinical conditions are discussed. Finally, the evaluation over time of the variation in circulating levels of hs-cTnI and hs-cTnT is proposed for a more accurate estimation of cardiovascular risk in asymptomatic subjects from the general population.

General Clinical Chemistry and Laboratory Medicine

Open Access January 25, 2023

Pre-analytical long-term stability of neopterin and neurofilament light in stored cerebrospinal fluid samples

Carolina Rosadas, Graham P. Taylor

Page range: 1230-1234

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Abstract

Objectives The aim of this study was to evaluate the impact of long-term sample storage on the concentrations of neopterin and neurofilament light (Nfl) in cerebrospinal fluid (CSF) samples. These are useful markers of neuroinflammation and neuronal damage and have been applied as biomarkers for several neurological diseases. However, different pre-analytical variables have potential to influence results. Methods Twenty-one CSF samples donated by patients with HTLV-1-associated myelopathy (HAM) and stored for up to 11 years at −80 °C were retested after three-years for neopterin (n=10) and Nfl (n=11) by ELISA. Results There was a strong correlation between the paired results (r>0.98, p<0.0001). Neopterin concentrations (nmol/L) ranged from 12.4 to 64 initially and from 11.5 to 64.4 when retested, with means (SD) of 30 (18.4) 1st test and 33 (19.1) 2nd test. Nfl concentrations (pg/mL) ranged from 79.9 to 3,733 initially and from 86.3 to 3,332, when retested with means (SD) of 1,138 (1,272) 1st test and 1,009 (1,114) at re-test. Conclusions Storing CSF samples at −80 °C appears not to impact the quantification of neopterin and Nfl allowing confidence in the reporting of archived samples.

Open Access February 24, 2023

Development of a candidate reference measurement procedure by ID-LC-MS/MS for total tau protein measurement in cerebrospinal fluid (CSF)

Chiara Giangrande, Hélène Vaneeckhoutte, Amandine Boeuf, Béatrice Lalere, Christophe Hirtz, Sylvain Lehmann, Milena Quaglia, Vincent Delatour

Page range: 1235-1244

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Abstract

Objectives In clinical pratice, tau protein measurement generally relies on immunoassays (IAs), whose major drawback is the lack of results comparability due to differences in selectivity and/or calibration. This underlines the importance of establishing a traceability chain for total tau (t-tau) measurements. The objective of this work is to develop a higher order candidate reference measurement procedure (RMP) for the absolute quantification of t-tau in cerebrospinal fluid (CSF). Methods To calibrate the candidate RMP and establish metrological traceability to the SI units, a primary calibrator consisting in a highly purified recombinant protein was sourced. Its purity was evaluated by liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) and the protein mass fraction in solution was certified by amino acid analysis (AAA). An isotopically-labelled homologue was obtained to develop a candidate RMP by isotope dilution mass spectrometry (IDMS) for t-tau absolute quantification in CSF. Calibration blends and quality control (QC) materials were gravimetrically prepared and subjected to the same preparation workflow as CSF samples, followed by LC-HRMS analysis in Parallel Reaction Monitoring (PRM) mode. Results A primary calibrator has been developed and an IDMS candidate RMP has been validated for CSF t-tau. The candidate RMP was used to certify t-tau concentration in three pools of CSF (low, medium, high). Conclusions The candidate RMP will pave the road towards global standardization of CSF t-tau measurements. Together with commutable Certified Reference Materials (CRMs), it will allow evaluating and improving the accuracy and comparability of results provided by IAs.

Open Access January 31, 2023

Assessing the commutability of candidate reference materials for the harmonization of neurofilament light measurements in blood

Ulf Andreasson, Johan Gobom, Vincent Delatour, Guy Auclair, Yoav Noam, Stephen Lee, Jason Wen, Andreas Jeromin, Burak Arslan, Aleksandra Maceski, Eline Willemse, Henrik Zetterberg, Jens Kuhle, Kaj Blennow

Page range: 1245-1254

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Abstract

Objectives Neurofilament light chain (NfL) concentration in blood is a biomarker of neuro-axonal injury in the nervous system and there now exist several assays with high enough sensitivity to measure NfL in serum and plasma. There is a need for harmonization with the goal of creating a certified reference material (CRM) for NfL and an early step in such an effort is to determine the best matrix for the CRM. This is done in a commutability study and here the results of the first one for NfL in blood is presented. Methods Forty paired individual serum and plasma samples were analyzed for NfL on four different analytical platforms. Neat and differently spiked serum and plasma were evaluated for their suitability as a CRM using the difference in bias approach. Results The correlation between the different platforms with regards to measured NfL concentrations were very high (Spearman’s ρ≥0.96). Samples spiked with cerebrospinal fluid (CSF) showed higher commutability compared to samples spiked with recombinant human NfL protein and serum seems to be a better choice than plasma as the matrix for a CRM. Conclusions The results from this first commutability study on NfL in serum/plasma showed that it is feasible to create a CRM for NfL in blood and that spiking should be done using CSF rather than with recombinant human NfL protein.

Open Access February 8, 2023

Surface plasmon resonance assays for the therapeutic drug monitoring of infliximab indicate clinical relevance of anti-infliximab antibody binding properties

Melina K. Grasmeier, Susanne Weber, Matthias Treiber, Markus A. Thaler, Peter B. Luppa

Page range: 1255-1265

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Abstract

Objectives The therapeutic antibody infliximab (IFX) has improved the life quality of numerous autoinflammatory disease patients. However, IFX can trigger the generation of anti-drug antibodies (ADA), whose optimal evaluation and management are currently subject of controversial discussions. We present two novel surface plasmon resonance (SPR) biosensor assays for therapeutic drug monitoring of IFX and characterization of ADA and investigated the diagnostic value of ADA binding properties. Methods IFX and ADA were quantified via developed SPR biosensor assays (IFXmon and ADAmon, respectively) and diagnostics-approved ELISA in sera from inflammatory bowel disease patients. Pre-analytic ADA enrichment with magnetic beads enabled analytical drug tolerance of the ADAmon assay. The dissociation ratio (DissR) as an index for ADA:IFX binding stability was calculated from the SPR sensorgrams of ADA quantification runs. Results IFX levels determined by IFXmon assay and ELISA showed high agreement, whereas ADA quantification concordance between ADAmon assay and ELISA was poor. In patients, DissR was predominantly constant over time and differed significantly between therapy outcomes. A DissR cut-off of 1.524 indicated undetectable IFX levels with 71.4% sensitivity and 88.9% specificity. Additionally, the SPR reference surface was exploited as serum-individual negative control to check result plausibility within multi-sample run sequences. Conclusions Overall, both SPR biosensor assays exhibited reliable quantitative performance with accuracies superior to their ELISA counterparts and precision inferior to ELISA only for ADAmon. DissR presented itself as promising ADA binding parameter and could contribute to both earlier and more tailored therapeutic decisions.

Open Access February 13, 2023

An antibody-free LC-MS/MS method for the quantification of sex hormone binding globulin in human serum and plasma

Bas Sleumer, Jordan Zwerwer, Martijn van Faassen, Michel J. Vos, Rainer Bischoff, Ido P. Kema, Nico C. van de Merbel

Page range: 1266-1274

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Abstract

Objectives Sex hormone binding globulin (SHBG) is a hormone binding protein which plays an important role in regulating the transport and availability of biologically active androgens and estradiol to target cells and used to calculate free testosterone concentrations. Methods A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed, featuring an albumin removal step followed by a tryptic digestion. After a reduction step with dithiothreitol and alkylation with iodoacetamide three signature peptides were used for the quantification of SHBG. Results The method enables the quantification of serum and plasma SHBG over the clinically relevant range of 200–20,000 ng/mL and was validated according to the most recent guidelines. The LC-MS/MS method correlates well with the Abbott Alinity immunoassay (R 2 >0.95), but the LC-MS/MS results are on average 16–17% lower than the immunoassay results, which is consistent for all three signature peptides. Conclusions The LC-MS/MS method which includes an albumin depletion step allows quantification of SHBG in serum and plasma without an immunocapture step at clinically relevant SHBG levels, thus contributing to better lab-to-lab consistency of results.

February 2, 2023

Accurate stratification between VEXAS syndrome and differential diagnoses by deep learning analysis of peripheral blood smears

Floris Chabrun, Valentin Lacombe, Xavier Dieu, Franck Geneviève, Geoffrey Urbanski

Page range: 1275-1279

Abstract

Objectives VEXAS syndrome is a newly described autoinflammatory disease associated with UBA1 somatic mutations and vacuolization of myeloid precursors. This disease possesses an increasingly broad spectrum, leading to an increase in the number of suspected cases. Its diagnosis via bone-marrow aspiration and UBA1 -gene sequencing is time-consuming and expensive. This study aimed at analyzing peripheral leukocytes using deep learning approaches to predict VEXAS syndrome in comparison to differential diagnoses. Methods We compared leukocyte images from blood smears of three groups: participants with VEXAS syndrome (identified UBA1 mutation) (VEXAS); participants with features strongly suggestive of VEXAS syndrome but without UBA1 mutation (UBA1-WT); participants with a myelodysplastic syndrome and without clinical suspicion of VEXAS syndrome (MDS). To compare images of circulating leukocytes, we applied a two-step procedure. First, we used self-supervised contrastive learning to train convolutional neural networks to translate leukocyte images into lower-dimensional encodings. Then, we employed support vector machine to predict patients’ condition based on those leukocyte encodings. Results The VEXAS, UBA1-WT, and MDS groups included 3, 3, and 6 patients respectively. Analysis of 33,757 images of neutrophils and monocytes enabled us to distinguish VEXAS patients from both UBA1-WT and MDS patients, with mean ROC-AUCs ranging from 0.87 to 0.95. Conclusions Image analysis of blood smears via deep learning accurately distinguished neutrophils and monocytes drawn from patients with VEXAS syndrome from those of patients with similar clinical and/or biological features but without UBA1 mutation. Our findings offer a promising pathway to better screening for this disease.

Open Access April 12, 2023

Establishing quality indicators for point of care glucose testing: recommendations from the Canadian Society for Clinical Chemists Point of Care Testing and Quality Indicators Special Interest Groups

Julie L.V. Shaw, Saranya Arnoldo, Lori Beach, Ihssan Bouhtiauy, Davor Brinc, Miranda Brun, Christine Collier, Elie Kostantin, Angela W.S. Fung, Anna K. Füzéry, Yun Huang, Sukhbir Kaur, Michael Knauer, Lyne Labrecque, Felix Leung, Jennifer L. Shea, Vinita Thakur, Laurel Thorlacius, Allison A. Venner, Paul M. Yip, Vincent De Guire

Page range: 1280-1287

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Abstract

Objectives Monitoring quality indicators (QIs) is an important part of laboratory quality assurance (QA). Here, the Canadian Society of Clinical Chemists (CSCC) Point of Care Testing (POCT) and QI Special Interest Groups describe a process for establishing and monitoring QIs for POCT glucose testing. Methods Key, error prone steps in the POCT glucose testing process were collaboratively mapped out, followed by risk assessment for each step. Steps with the highest risk and ability to detect a non-conformance were chosen for follow-up. These were positive patient identification (PPID) and repeat of critically high glucose measurements. Participating sites were asked to submit aggregate data for these indicators from their site(s) for a one-month period. The PPID QI was also included as part of a national QI monitoring program for which fifty-seven sites submitted data. Results The percentage of POCT glucose tests performed without valid PPID ranged from 0–87%. Sites without Admission-Discharge-Transfer (ADT) connectivity to POCT meters were among those with the highest percentage of POCT glucose tests performed without valid PPID. The percentage repeated critically high glucose measurements ranged from 0–50%, indicating low compliance with this recommendation. A high rate of discordance was also noted when critically high POCT glucose measurements were repeated, demonstrating the importance of repeat testing prior to insulin administration. Conclusions Here, a process for establishing these QIs is described, with preliminary data for two QIs chosen from this process. The findings demonstrate the importance of QIs for identification and comparative performance monitoring of non-conformances to improve POCT quality.

April 6, 2023

Clinical implication by differential analytical performances of serum free light chain quantitation analysis using fully automated analyzers

Shin Young Yun, John Hoon Rim, Hak Park, Hyein Kang, Sang-Guk Lee, Jong-Baeck Lim

Page range: 1288-1299

Abstract

Objectives Free light chain (FLC) is used for the diagnosis and prediction with regard to the progression risk of plasma cell disorders and Freelite reagent using the SPAplus analyzer (The Binding Site) has been one of the widely used option. However, N Latex FLC reagent with the Atellica CH 930 analyzer (Siemens Healthineers) has shown the advantages of automation and high throughput. We aimed to evaluated clinical implication by differential analytical performances of two assays. Methods A total of 322 serum samples were collected from 193 patients requested for FLC analysis including 131 multiple myeloma patients. The precision, linearity, dilution recovery of N Latex FLC assay was evaluated. We compared the two assays and analyzed the monomer-dimer pattern for discrepant results. Results The precision, linearity, and dilution recovery performance was appropriate for the routine use in clinical laboratories. Despite the good correlation within normal range, proportional bias up-to 170% was observed in samples with high concentrations especially for lambda. The higher value samples with N Latex FLC assay contained more monomer forms than controls. All opposite changes of FLC burden by the N Latex FLC assay proved to present concordant dynamic changes when assessed by serum protein electrophoresis. Conclusions Clinical laboratories should be aware of the inter-assay variability of FLC quantitative measurements using different platforms, especially for high concentrations of both kappa and lambda measurements, possibly due to monomer/dimer ratio diversity. Clinical interpretations for multiple myeloma disease status might not be dramatically affected only when the same assay is utilized during follow-up periods.

April 4, 2023

Simultaneous analysis of antihyperglycemic small molecule drugs and peptide drugs by means of dual liquid chromatography high-resolution mass spectrometry

Aline C. Vollmer, Lea Wagmann, Armin A. Weber, Markus R. Meyer

Page range: 1300-1308

Abstract

Objectives The study aimed to evaluate dual liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS) for the simultaneous analysis of small and large molecule drugs by development and application of a validated bioanalytical method. Methods The oral antihyperglycemic drugs (OAD) dapagliflozin, empagliflozin, glibenclamide, glimepiride, metformin, pioglitazone, repaglinide, saxagliptin, sitagliptin, and vildagliptin, as well as the antihyperglycemic peptides exenatide, human insulin, insulin aspart, insulin degludec, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, and semaglutide were included in the analytical procedure. Analytes were extracted using a combination of protein precipitation and solid-phase extraction. Two identical reversed-phase columns were used for separation followed by Orbitrap high-resolution mass spectrometry. The whole procedure was validated according to international recommendations. Results Different MS parameters had to be used for the two analyte groups, but dual LC separation allowed elution of all analytes within 12 min using the same column type. The analytical procedure was accurate and precise for most of the compounds except for exenatide, semaglutide, and insulin glargine, which were included qualitatively in the method. Analysis of proof-of-concept samples revealed OAD concentrations mostly within their therapeutic range, insulins could be detected in five cases but at concentrations below the lower limit of quantification except for one case. Conclusions Dual LC in combination with HRMS was shown to be a suitable platform to analyze small and large molecules in parallel and the current method allowed the determination of a total of 19 antihyperglycemic drugs in blood plasma within 12 min.

Reference Values and Biological Variations

January 27, 2023

Reference intervals for thyroid biomarkers to enhance the assessment of thyroid status in childhood and adolescence

Simona Ferraro, Ester Luconi, Valeria Calcaterra, Erika Cordaro, Alice Bianchi, Cristina Cereda, Gianvincenzo Zuccotti, Peter Kavsak, Mario Plebani, Elia Mario Biganzoli, Giuseppe Marano, Patrizia Boracchi

Page range: 1309-1318

Abstract

Objectives The determination of assay-dependent upper and lower reference limits (URL, LRL) of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) during childhood and adolescence, is challenging. Methods Thyroid hormones were measured via the Abbott Alinity system in 502 euthyroid children partitioned in the following age groups: ≤2, 2.1–10, and 10.1–18 years. The 97.5th and 2.5th percentiles (URL and LRL) were derived according to CLSI EP28- A3c guidelines. Quantile regression models were used to assess: (a) 90% confidence intervals of the URL and LRL, (b) the effect of age on URL and LRL within each age class and on overall age range, (c) the difference between the URLs and LRLs estimated for each age partition with an estimate of the confidence interval divided by the reference interval being derived (CI/RI). Results The CI/RI for the LRLs are smaller as compared to the URLs, except for FT4 for the 2.1–10 years age group. Considering the CI/RI and the overlap between CIs across the three age groups, one single LRL might be considered for TSH, FT3 and FT4 between 0 and 18 years. However, for the URL, there was a noticeable decrease in the URL over the 3 age groups for all three biomarkers, with there being no overlap in CIs for the URL between the ≤2 vs. the 10.1–19 years age groups. Conclusions A common LRL for TSH, FT4 and FT3 for patients aged ≤18 years may be utilized when these biomarkers are measured with the Alinity system. For the URLs the use of age-specific URLs for these biomarkers is recommended.

April 12, 2023

Biological variation of CA 15-3, CA 125 and HE 4 on lithium heparinate plasma in apparently healthy Caucasian volunteers

Louise Guillaume, Virginie Chapelle, Matthieu Deltombe, Arnaud Nevraumont, Antoine Mairesse, Diane Maisin, Damien Gruson

Page range: 1319-1326

Abstract

Objectives Tumor markers are well-known for being important tools in the support of diagnosis, monitoring of treatment efficacy and follow-up of cancers. CA 125, CA 15-3 and HE 4 have demonstrated potential efficacy in other clinical indications. The main objective was to evaluate the biological variation of these glycoproteins using two different immunoassays in an apparently healthy Caucasian population. Methods Nineteen healthy volunteers including 11 women and 8 men were sampled weekly for 5 consecutive weeks. Samples were analyzed in duplicate on Lumipulse ® G600II (Fujirebio) and on the Cobas e602 (Roche Diagnostics) analyzers. After assessment of normality, exclusion of outliers and analysis of homogeneity of variance, analytical variation (CV A ), within-subject biological variation (CV I ) and between-subject biological variation (CV G ) were determined using a nested ANOVA. Results CV A , CV I and CV G were determined on both analyzers and both genders. For CA 125, the CV A ranges from 1.0 to 3.4%, the CV I from 5.7 to 13.8% and the CV G from 32.2 to 42.9%. For CA 15-3, the CV A is between 1.1 and 3.4%, the CV I between 3.9 and 6.5% and the CV G between 43.7 and 196.9%. Lastly, HE 4 has CV A values between 1.4 and 2.4%, CV I between 5.1 and 10.5% and CV G between 7.1 and 12.6%. Conclusions Our study provided updated data on the biological variation of CA 125, HE 4 and CA 15-3. These data allow to improve the clinical interpretation and thus the management of the patient.

Cancer Diagnostics

January 27, 2023

Individual risk prediction of high grade prostate cancer based on the combination between total prostate-specific antigen (PSA) and free to total PSA ratio

Simona Ferraro, Davide Biganzoli, Roberta Simona Rossi, Franco Palmisano, Marco Bussetti, Enrica Verzotti, Andrea Gregori, Filippo Bianchi, Marco Maggioni, Ferruccio Ceriotti, Cristina Cereda, Gianvincenzo Zuccotti, Peter Kavsak, Mario Plebani, Giuseppe Marano, Elia Mario Biganzoli

Page range: 1327-1334

Abstract

Objectives Clinical practice guidelines endorse the stratification of prostate cancer (PCa) risk according to individual total prostate-specific antigen (tPSA) values and age to enhance the individual risk-benefit ratio. We defined two nomograms to predict the individual risk of high and low grade PCa by combining the assay of tPSA and %free/tPSA (%f/tPSA) in patients with a pre-biopsy tPSA between 2 and 10 μg/L. Methods The study cohort consisted of 662 patients that had fPSA, tPSA, and a biopsy performed (41.3% with a final diagnosis of PCa). Logistic regression including age, tPSA and %f/tPSA was used to model the probability of having high or low grade cancer by defining 3 outcome levels: no PCa, low grade (International Society of Urological Pathology grade, ISUP<3) and high grade PCa (ISUP≥3). Results The nomogram identifying patients with: (a) high vs. those with low grade PCa and without the disease showed a good discriminating capability (∼80%), but the calibration showed a risk of underestimation for predictive probabilities >30% (a considerable critical threshold of risk), (b) ISUP<3 vs. those without the disease showed a discriminating capability of 63% and overestimates predictive probabilities >50%. In ISUP 5 a possible loss of PSA immunoreactivity has been observed. Conclusions The estimated risk of high or low grade PCa by the nomograms may be of aid in the decision-making process, in particular in the case of critical comorbidities and when the digital rectal examinations are inconclusive. The improved characterization of the risk of ISUP≥3 might enhance the use for magnetic resonance imaging in this setting.

Cardiovascular Diseases

January 26, 2023

Using logistic regression models to investigate the effects of high-sensitivity cardiac troponin T confounders on ruling in acute myocardial infarction

Li Liu, Xueya Cai, Tanzy Love, Matthew Corsetti, Andrew M. Mathias, Andrew Worster, Jinhui Ma, Peter A. Kavsak

Page range: 1335-1342

Abstract

Objectives Confounding factors, including sex, age, and renal dysfunction, affect high-sensitivity cardiac troponin T (hs-cTnT) concentrations and the acute myocardial infarction (AMI) diagnosis. This study assessed the effects of these confounders through logistic regression models and evaluated the diagnostic performance of an optimized, integrated prediction model. Methods This retrospective study included a primary derivation cohort of 18,022 emergency department (ED) patients at a US medical center and a validation cohort of 890 ED patients at a Canadian medical center. Hs-cTnT was measured with 0/3 h sampling. The primary outcome was index AMI diagnosis. Logistic regression models were optimized to predict AMI using delta hs-cTnT and its confounders as covariates. The diagnostic performance of model cutoffs was compared to that of the hs-cTnT delta thresholds. Serial logistic regressions were carried out to evaluate the relationship between covariates. Results The area under the curve of the best-fitted model was 0.95. The model achieved a 90.0% diagnostic accuracy in the validation cohort. The optimal model cutoff yielded comparable performance (90.5% accuracy) to the optimal sex-specific delta thresholds (90.3% accuracy), with 95.8% agreement between the two diagnostic methods. Serial logistic regressions revealed that delta hs-cTnT played a more predominant role in AMI prediction than its confounders, among which sex is more predictive of AMI (total effect coefficient 1.04) than age (total effect coefficient 0.05) and eGFR (total effect coefficient −0.008). Conclusions The integrated prediction model incorporating confounding factors does not outperform hs-cTnT delta thresholds. Sex-specific hs-cTnT delta thresholds remain to provide the highest diagnostic accuracy.

Infectious Diseases

February 2, 2023

Assessment of humoral and cellular immunity after bivalent BNT162b2 vaccination and potential association with reactogenicity

Gian Luca Salvagno, Laura Pighi, Brandon M. Henry, Myriam Valentini, Beatrice Tonin, Damiano Bragantini, Gianluca Gianfilippi, Simone De Nitto, Mario Plebani, Giuseppe Lippi

Page range: 1343-1348

Abstract

Objectives This study investigated the feasibility and clinical value of using a novel, automated and high-throughput SARS-CoV-2 Interferon Gamma Release Assay (IGRA), combined with total anti-SARS-CoV-2 antibodies assessment, for evaluating the immune response after bivalent BNT162b2 vaccination. Methods A cohort of healthcare workers, who already underwent primary vaccination and boosting with monovalent BNT162b2 vaccine, received a booster dose of the new BNT162b2 bivalent formulation. Blood samples were taken immediately before vaccination (T0) and 1 month afterwards (T1). Humoral and cellular immunity were assayed with Roche Elecsys Anti-SARS-CoV-2 and Roche Elecsys IGRA SARS-CoV-2, respectively. Results The study population consisted of 51 subjects (median age: 43 years; 51% females). Total anti-SARS-CoV-2 antibodies and IGRA SARS-CoV-2 values increased at T1 from 9,050 to 25,000 BAU/mL (p<0.001), and from 0.44 to 0.78 IU/mL (p=0.385), accounting for median increase of 2.0 and 1.6 folds, respectively. Increased T1 values of total anti-SARS-CoV-2 antibodies and IGRA SARS-CoV-2 were recorded in 100% and 68.6% subjects, respectively. In those with baseline values below the median, post-vaccine levels displayed larger increases of 3.3 and 5.1 folds for anti-SARS-CoV-2 total antibodies and IGRA SARS-CoV-2, respectively. The variation of total anti-SARS-CoV-2 antibodies was inversely associated with their T0 values (r=−0.97; p<0.001), whilst that of IGRA SARS-CoV-2 was inversely associated with its T0 value (r=−0.58; p<0.001). No other signifcant associations were found with demographical or clinical variables, including side effects. Conclusions The bivalent BNT162b2 vaccine booster enhances humoral and cellular immunity against SARS-CoV-2, especially in recipients with lower baseline biological protection.

Open Access February 10, 2023

Three rounds of a national external quality assessment reveal a link between disharmonic anti-SARS-CoV-2 antibody quantifications and the infection stage

Christoph Buchta, David Springer, Jovana Jovanovic, Christian Borsodi, Lisa Weidner, Nazanin Sareban, Ulla Radler, Mathias M. Müller, Andrea Griesmacher, Elisabeth Puchhammer-Stöckl, Thomas Wagner, Christof Jungbauer, Karin Stiasny, Lukas Weseslindtner

Page range: 1349-1358

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Abstract

Objectives The WHO’s standardized measuring unit, “binding antibody units per milliliter (BAU/mL),” should allow the harmonization of quantitative results by different commercial Anti-SARS-CoV-2 immunoassays. However, multiple studies demonstrate inter-assay discrepancies. The antigenic changes of the Omicron variant affect the performance of Spike-specific immunoassays. This study evaluated the variation of quantitative Anti-SARS-CoV-2-Spike antibody measurements among 46, 50, and 44 laboratories in three rounds of a national external quality assessment (EQA) prior to and after the emergence of the Omicron variant in a diagnostic near-to-real-life setting. Methods We analyzed results reported by the EQA participant laboratories from single and sequential samples from SARS-CoV-2 convalescent, acutely infected, and vaccinated individuals, including samples obtained after primary and breakthrough infections with the Omicron variant. Results The three immunoassays most commonly used by the participants displayed a low intra-assay and inter-laboratory variation with excellent reproducibility using identical samples sent to the participants in duplicates. In contrast, the inter-assay variation was very high with all samples. Notably, the ratios of BAU/mL levels quantified by different immunoassays were not equal among all samples but differed between vaccination, past, and acute infection, including primary infection with the Omicron variant. The antibody kinetics measured in vaccinated individuals strongly depended on the applied immunoassay. Conclusions Measured BAU/mL levels are only inter-changeable among different laboratories when the same assay was used for their assessment. Highly variable ratios of BAU/mL quantifications among different immunoassays and infection stages argue against the usage of universal inter-assay conversion factors.

Corrigendum

Publicly Available April 21, 2023

Where is laboratory medicine headed in the next decade? Partnership model for efficient integration and adoption of artificial intelligence into medical laboratories

Anna Carobene, Federico Cabitza, Sergio Bernardini, Raj Gopalan, Jochen K. Lennerz, Clare Weir, Janne Cadamuro

Page range: 1359-1359

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Letters to the Editor

Publicly Available February 17, 2023

Please do not call it Theranos

Eleftherios P. Diamandis

Page range: e103-e104

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January 17, 2023

Lot-to-lot bias for high-sensitivity cardiac troponin I concentrations ≥1000 ng/L

Peter A. Kavsak

Page range: e105-e107

January 16, 2023

Lot-to-lot reagent changes and commutability of quality testing materials for total bile acid measurements

Corey Markus, Suzette Coat, Hanns-Ulrich Marschall, Susan Matthews, Tze Ping Loh, Wayne Rankin, William M. Hague

Page range: e108-e111

January 16, 2023

On the importance of sampling interval in studies of biological variation in thyroid function

Stig Andersen, Johannes Riis, Jesper S. Karmisholt, Stine L. Andersen

Page range: e112-e114

January 24, 2023

Stability of plasma renin concentration based on plasma freezing time, as an adjunct to the stability data reported in the paper by Hepburn and others

Charlotte Oris, Damien Bouvier, Bruno Pereira, Adèle Saintonge, Anaïs Coelho, Vincent Sapin

Page range: e115-e117

January 31, 2023

Falsely low beta-hCG results in pregnant woman on Siemens Atellica: don’t forget the “hook effect”

Adrien Nizet, Philippe Jeanmart, Lucas Dewalque, Quentin Bodson

Page range: e118-e120

January 13, 2023

Proenkephalin A 119–159 (penKid) – a novel biomarker and its quantification on the Nexus IB10 POC system for assessing kidney function

Jared Cobb, Karolina Szczesna, Axel Schulze, Huy Ngo, McKenna Doyle, Tyler Do, Minh Vu, John Nguyen, Julia Löffler, Maryna Borshchivska, Deborah Bergmann, Elizabeth Shin, Tobias Hartmann, Damien Gruson

Page range: e121-e125

January 27, 2023

Investigating the polyuria-polydipsia syndrome: the “PP” Shiny app

Kay Weng Choy, Evangelia Georgiadis

Page range: e126-e127

Open Access January 27, 2023

Evaluation of a novel, stand-alone system to measure interleukin-6

Sascha Dierks, Mechthild Wiederhold, Julie Schanz, Andreas Fischer, Moritz Schnelle

Page range: e128-e130

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January 16, 2023

Spurious low WBC count in the WNR channel of Sysmex XN-9000 hematology analyzer in a case with leukocyte aggregation

Qingkai Dai, Luyun Peng, Rui Shi

Page range: e131-e133

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Editor-in-Chief
Mario Plebani, Padova, Italy

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Bohuslav Melichar, Olomouc, Czech Republic
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Vincent Delatour, Paris, France
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Johannes J.M.L. Hoffmann, Nuenen, Netherlands
Evgenija Homšak, Lenart, Slovenia
Zhi-De Hu, Hohhot, P.R. China
Berend Isermann, Leipzig, Germany
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Online ISSN: 1437-4331
Print ISSN: 1434-6621
Type: Journal
Language: English
Publisher: De Gruyter
First published: January 1, 1963
Publication Frequency: 12 Issues per Year
Audience: basic scientists, translational researchers, clinical researchers, industry scientists and professionals in the field of laboratory medicine