journal: Clinical Chemistry and Laboratory Medicine (CCLM)

Impact Factor: 3.7

Zeitschrift

Clinical Chemistry and Laboratory Medicine (CCLM)

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

Editor-in-Chief: Mario Plebani
Herausgegeben von: Philippe Gillery , Ronda Greaves , Karl J. Lackner , Giuseppe Lippi , Bohuslav Melichar , Peter Schlattmann und Shiyang Pan

Sprache: Englisch

Erstveröffentlichung: 1. Januar 1963

Erscheinungsweise: 12 Hefte pro Jahr

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Über diese Zeitschrift

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 international journals in the field of clinical laboratory sciences and drives progress in the field. CCLM is led by a multi-institutional editorial board. 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.
CCLM is the official journal of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM).

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

For EFLM Academy Members

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.

Ihre Vorteile

Latest developments in the clinical laboratory sciences
Fundamental and applied approach and novel teaching and training methods
Rapid online publication
High quality peer-review
No submission and publication fee
Each article easily discoverable because of Search Engine Optimization (SEO) and comprehensive abstracting and indexing services
Secure archiving by De Gruyter and the independent archiving service Portico
Authors have the option of publishing their articles under the Creative Commons Attribution (CC-BY-4.0) open access license. Open access allows authors to retain copyright and share their findings with the scientific community without restrictions. Authors who belong to an institution that has an agreement with the publisher can publish open access without paying an article processing charge (APC) or at a considerable discount

Vorherige Titel

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
Vol. 36, 1998 until now: Clinical Chemistry and Laboratory Medicine (CCLM)

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Serum neuron-specific enolase – reference interval in Danish children and the impact of preanalytical factors

3. Oktober 2025

Jacob Rudjord Therkildsen, Cindy Søndersø Knudsen, Tina Parkner

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Objectives Neuron-specific enolase (NSE) is a clinically relevant biomarker used in the assessment of neuronal damage and in the diagnosis and monitoring of certain cancers. Despite its diagnostic importance, paediatric-specific reference intervals (RIs) for NSE are currently lacking. This study aimed to establish paediatric RIs for NSE in serum and to evaluate the influence of preanalytical factors on NSE measurements. Methods Residual serum samples from routine allergy testing in 242 Danish children (aged 0.1–17.9 years) were analysed using the Roche Elecsys ® NSE assay on a Cobas platform. Both traditional non-parametric, age-partitioned RIs and continuous RIs derived via quantile regression were established. In addition, we assessed the impact of preanalytical variables, including haemolysis, and evaluated a previously proposed correction method for haemolysed samples within this cohort. Results Both the non-parametric and continuous approaches yielded consistent RIs, showing an age-dependent decline in serum NSE concentrations irrespective of sex. The traditional age-partitioned RI (95th percentile, one-sided) indicated upper limits of 36.9 μg/L and 32.0 μg/L for the age groups 0–5 and 6–17 years of age, based on samples with haemolysis <10 mg/dL haemoglobin. Conclusions This study defines age-specific paediatric RIs for serum NSE, demonstrating a physiological decline with age and highlighting higher NSE levels in healthy children compared to adults. Furthermore, within a limited range, a previously proposed simple linear correction method was validated for adjusting NSE values in mildly haemolysed samples using the newly established RIs.
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Post-analytical practices in clinical mass spectrometry laboratories: an international survey across 57 countries

2. Oktober 2025

Jenny Yeuk-ki Cheng, Brett C. McWhinney, Avis C. McWhinney, Danijela Kocic, Damien Gruson, Ronda F. Greaves, Chung Shun Ho, On behalf of the Australasian Association for Clinical Biochemistry and Laboratory Medicine (AACB), in association with the Asia-Pacific Federation for Clinical Biochemistry and Laboratory Medicine (APFCB) Paediatric Clinical Biochemistry Mass Spectrometry Harmonisation Working Group, and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Emerging Technologies Division (ETD)

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Objectives Liquid chromatography-tandem mass spectrometry (LC–MS/MS) is increasingly used in clinical laboratories due to its high analytical specificity and multiplexing capabilities. While the pre-analytical and analytical phases have seen significant advances in automation, the post-analytical phase remains a bottleneck with limited standardisation. This survey aimed to identify gaps, benchmark practices against guidelines, and inform recommendations for improving consistency and quality in post-analytical data handling. Methods A descriptive electronic survey with 53 questions was distributed via the IFCC mailing list and collaborating organisations from May to July 2024. Questions covered participant characteristics, post-analytical quality indicators (e.g., chromatograms, calibration curves, ion ratios), quality assurance, and data management. Responses were benchmarked against three LC-MS/MS guidelines. Results Of 311 initial responses, 203 valid submissions from 57 countries were analysed. Laboratories reported diverse throughput: low (<100 samples/week, n=50), medium (100–2,000 samples/week, n=125), and high (>2,000 samples/week, n=28). Key findings included inconsistent acceptance criteria (e.g., variable ion ratios and signal-to-noise thresholds), reliance on manual data transcription (38 % of laboratories), and continued use of in-house spreadsheets. Practices often deviated from guidelines, with opportunities identified for harmonisation and automation. Conclusions In collaboration with the clinical mass spectrometry community, the IFCC-ETD developed six key recommendations from this survey to address challenges and enhance consistency, quality, and efficiency in post-analytical data handling.
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Expert opinion within the context of the targeted evaluation of Regulation (EU) 2017/746 on in vitro diagnostic medical devices pursuant to Article 111 and Regulation (EU) 2024/1860

1. Oktober 2025

Michael Vogeser, Monika Brüggemann, Ulrich Sack, Christoph Weinstock, Stefan Zimmermann, Albrecht Stenzinger

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EU laws are usually evaluated after 10 years; in the case of the IVDR, the targeted evaluation was brought forward and stakeholders in laboratory diagnostics were invited to comment. The Association of the Scientific Medical Societies in Germany (AWMF; Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.), recognises a relevant need to amend the IVDR with regard to in-vitro -diagnostic medical devices that are manufactured and used in healthcare facilities but are not placed on the EU market. Inadequate overregulation is recognised and should be corrected as part of the generally required reduction of bureaucracy.
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Requiem for the Passing–Bablok nonparametric regression in assessing the agreement between two measurement methods

29. September 2025

Bruno Mario Cesana, Paolo Antonelli

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Objectives Regulatory guidelines recommend non-parametric Passing–Bablok regression for evaluating the agreement between two measurement methods in laboratory settings. However, concluding for the agreement if the 95 % CI of the slope and of the intercept include 1 and 0, respectively is incorrect since the agreement assessment must focus on a null hypothesis of not equivalence and an alternative hypothesis of equivalence. Methods We exhaustively simulated appropriate structural models with several values of slope, intercept and measurement error by keeping equal variances and means of the two methods. We calculated the slope and intercept bias of four regressions: non-parametric Passing–Bablok, Theil, Ordinary Least Squares and Deming. In addition, we calculated the percentages of the agreement according to the not shareable Passing–Bablok suggestion. Furthermore, we calculated the percentages of the 95 % CI of the slope and of the intercept included within sensible equivalence thresholds for assessing the agreement. Results Passing–Bablok procedure gives unbiased estimates, a little more and less biased than those from Deming’s regression. The percentages of rejecting the hypothesis of no-agreement, according to the wrong Passing–Bablok’s approach are correctly near to 0.05 Type I error under the agreement and also for 0.990≤slopes≤1.005. However, they are too low for slopes >1.05 and <0.950. Conclusions The Passing–Bablok 95 % CIs are too wide for being included in sensible agreement thresholds according to a population equivalence model and, finally, this approach cannot be considered under the best agreement model of the individual equivalence.
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Supporting trend detection in the cumulative display of electronic laboratory reports from multiple laboratories while preserving measurement provenance

25. September 2025

Andreas Bietenbeck, Jakob Adler, Jürgen Durner, Julian Gebauer, Sascha Lüdemann, Burkhardt Müller, Matthias Orth, Thomas Streichert, Alexander Tolios, Bernhard Wiegel, Alexander von Meyer, On behalf of the division Medical Informatics of the German Society for Clinical Chemistry and Laboratory Medicine e.V. (DGKL)

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Electronic health records will increasingly aggregate longitudinal laboratory results from multiple providers, but availability alone does not guarantee safe interpretation. We present guidance, developed by laboratory professionals with the DGKL medical informatics division, for cumulative displays that are clinically meaningful. The core principle is to group medically comparable analyses while preserving laboratory provenance so that clinicians can follow true patient trends without conflating them with laboratory-induced variation. Comparability is defined algorithmically from Logical Observation Identifiers Names and Codes (LOINC) axis: analyses estimating the same patient property (allowing serum/plasma system equivalence and mathematically convertible properties such as substance vs. mass concentration) are grouped; coding of units is harmonized via Unified Code for Units of Measure (UCUM) with consistent conversion of numeric results and corresponding reference intervals, including inequality qualifiers. Analyte-specific conversion factors should come from authoritative sources; for poorly standardized measurands (e.g., tumor markers) or when conversions are inappropriate (e.g., Lp(a)), results remain separated. Methodological distinctions that affect interpretation – such as screening vs. confirmatory drug testing and point-of-care testing – are displayed independently to signal potential analytical discontinuities. A standardized, medically meaningful default result sequence – derived from LOINC metadata and clinical nomenclatures, with alphabetic naming as a pragmatic fallback – supports cross-laboratory aggregation; rare or novel tests lacking robust standardization remain as free text. The rules-based approach updates seamlessly with LOINC releases and remains compatible with the Nomenclature for Properties and Units (NPU), facilitating cross-border exchange within the European Health Data Space. While harmonized presentation improves trend analysis, true comparability ultimately requires measurement procedures traceable to reference methods and materials.
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Moving to practice with the application of Milan model 1b-based analytical performance specifications

25. September 2025

Mauro Panteghini

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The definition of analytical performance specifications (APS) by the Milan model 1b is based on indirect approaches investigating the impact of analytical performance of the laboratory test on clinical classification and thereby on the probability of patient outcomes. As direct diagnostic outcome studies (Milan model 1a) for defining APS are now considered very difficult and costly to be performed in practice, expert groups have gathered to reach consensus on how to use available information and apply Milan model 1b to the definition of APS. They have highlighted three major aspects: a) the definition of the clinically acceptable misclassification rate(s); b) the influence of the clinical pathway and patient population and setting (disease prevalence) when diagnostic thresholds are defined, e.g., in guidelines; and c) the intended use of the test. The basic question calling for an answer is how to move forward and provide specific APS for certain measurands that are key in clinical decision making. Here, cardiac troponin testing is used as a practical example for the application of model 1b-derived APS. Proposals are made for moving to practice with the application of this model to APS definition.
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Staining and serological characteristics of the AC-30 pattern in HEp-2 IIFA: a comparative study with AC-2 pattern

25. September 2025

Chuiwen Deng, Ningxin Li, Ruxi Hu, Yina Bai, Shulan Zhang, Renfang Zhou, Yunyun Fei, Chaojun Hu

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Objectives To investigate the staining and serological characteristics of AC-30 pattern. Methods A total of 184 participants were recruited from patients who underwent routine antinuclear antibody testing between 2022 and 2023 at Peking Union Medical College Hospital. Cohort 1 (n=47) showed the AC-30 pattern on HEp-2 indirect immunofluorescence assay, and cohort 2 (n=137) showed AC-2 pattern as control. Anti-DFS70 antibody detection and DFS70 antigen adsorption assays were conducted. Pattern simulation assays were performed by combining serum samples exhibiting classic AC-2 pattern with other common HEp-2 IIFA patterns. Results Anti-DFS70 antibodies were detected in 97 % of patients in cohort one and in all patients in cohort 2. The titers of the IIFA pattern showed a weak correlation with anti-DFS70 antibody levels in cohort 1 (r=0.35, p=0.0331). In DFS70 antigen adsorption assays, a higher proportion of homogeneous nuclear staining was observed in cohort 1 (79 %) than in cohort 2 (62 %) (p=0.037). Simulated samples mixed classic AC-2 with homogeneous pattern resembled those of AC-30 pattern in both interphase and mitotic cells. Especially, the staining characteristics of AC-2 became increasingly indistinct when mixed with higher-titer homogeneous patterns. Among samples exhibiting homogeneous patterns post-DFS70 immunoadsorption, non-autoimmune conditions were more common in cohort one than cohort two. Conclusions The presence of relatively lower anti-DFS70 antibodies levels or coexisting high-titer homogeneous patterns may contribute to the development of the AC-30 pattern rather than AC-2. This finding needs to be further confirmed in larger-scale studies.
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Establishing reference intervals for high-sensitivity cardiac troponin T in neonates and infants

25. September 2025

Yue-Qi Li, Gui-Cheng Ye, Jing-Ying Yang, Gong-Jun Tan

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Objectives High-sensitivity cardiac troponin T (hs-cTnT) is used in pediatric healthcare to diagnose and assess the prognosis of various cardiac diseases, such as acute myocarditis, congenital heart disease, dilated cardiomyopathy, and heart failure. However, the standardized age-related reference intervals, 99th percentile cut-offs, and clinical guidelines are currently unavailable, especially in newborns and infants, making interpreting this biomarker challenging. Methods Residual serum samples were collected from 1,047 pediatric subjects with no cardiovascular disease, including 145 neonates and 902 infants. The concentrations of hs-cTnT were analyzed using Roche’s Elecsys Troponin T hs assay. The age-related 99th percentile cut-offs with 90 % confidence intervals (CIs) of hs-cTnT were established. Results Subjects were divided into age subgroups as follows: newborns (0–30 days, n=142), infants aged 1 month (31–60 days, n=223), 2 months (61–90 days, n=152), 3–4 months (91–150 days, n=211), 5–6 months (151–210 days, n=149), and 7 months-1 year (211–365 days, n=149). Serum hs-cTnT concentrations were highest during the first month of life and progressively declined in a year. The 99th percentile cut-offs of hs-cTnT concentration in each group were as follows: 114 (90 % CI: 114-114), 65.6 (63.7–66.1), 55.2 (54.4–55.2), 30.4 (29.1–30.9), 23.5 (22.1–23.5), 12.7 (12.4–12.7) ng/L. The 97.5th percentile cut-offs for each group were 109.4 (105.2–114), 62.5 (60.5–63.9), 52.3 (50.3–54.4), 29 (28.5–29.1), 20.5 (19.2–23.4), and 12 (12–12.1) ng/L. Conclusions This study aimed to provide reliable pediatric reference values for hs-cTnT based on a population of well-child children. These reference intervals and 99th percentile cut-offs will inform clinical decisions in the pediatric cardiology setting.
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Interference with immunofixation in a dabigatran-overdosed patient treated with idarucizumab: beware of a diagnostic pitfall

25. September 2025

Quentin Pomorski, Maxime Delrue, Ellias Bato, Mayssa Selmi, Bruno Megarbane, Georges Jourdi, Virginie Siguret

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Comparative analysis of ISO 15189:2022 with earlier versions with reference to ethics

24. September 2025

Sudip K. Datta, Nilda Fink, Estelle Bugni, Joe Wiencek, on behalf of the IFCC Task Force-Ethics

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Objectives The International Organisation for Standardisation (ISO) 15189 standard provides the requirements for quality and competence in medical laboratories. It aims to ensure that laboratories deliver accurate and reliable results for patient care. The first version of the same was published in 2003, followed by editions in 2007, 2012 and 2022. The objective of this article is to analyze the ethical commitments and requirements assumed to achieve reliable results in laboratory medicine incorporated in the ISO standard. Methods We compare the concepts and changes related to ethics introduced over time in the ISO 15189 versions. We also present, a comparative study about the evolution of ethical concepts in the clinical laboratory and how these changes have been reflected in ISO 15189 standards through 2003 to 2022. Results After a thorough comparative analysis, we observe that the ISO 15189:2022 version has strengthened the requirements for several key concepts of Ethics such as impartiality and confidentiality, and addressed the issues of laboratory users with regards to autonomy, beneficence and justice although these terminologies are not explicitly mentioned. However, several other key words and concepts have not been addressed with adequate emphasis. Conclusions We recommend that several key concepts related to ethics may need to be included in the future revisions, especially those related to new and upcoming technologies being used in laboratory diagnostics and research.
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EQALM recommendations for the analytical performance specifications for blood smear interpretation in haematology: a need for standardization

24. September 2025

Stéphanie Albarède, Erika Sárkàny, Barbara De la Salle

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Objectives The European Organization for External Quality Assurance Providers in Laboratory Medicine (EQALM) Haematology Working Group (WG) has previously provided two guidelines to support the standardization of haematology blood smear external quality assessment (EQA) (Vives CJL, Albarède S, Flandrin G, Heller S, Horvath K, Houwen B, et al. Guidelines for blood smear preparation and staining procedure for setting up an external quality assessment scheme for blood smear interpretation. Part I: control material. Clin Chem Lab Med 2004;42:922–6; Vives CJL, Van Blerk M, Albarède S, Gutierrez G, Heller S, Nordin G, et al. Guidelines for setting up an external quality assessment scheme for blood smear interpretation. Part II: survey preparation, statistical evaluation and reporting. Clin Chem Lab Med 2006;44:1039–43) but these recommendations did not include analytical performance specifications. In this paper the WG provides advice on the performance specifications for the evaluation of blood cell identification, comments on morphological characteristics and diagnostic hypothesis. Methods To develop these specifications, the WG made a survey of the practices in use by EQALM members and provided a standard set of EQA data, provided by one of the members, for performance evaluation. Results The results of this exercise show a variation in the performance assessment outcomes from one EQA provider to another, suggesting that a degree of standardisation would be of benefit to participating laboratories. Conclusions The WG has provided advice on common performance specifications, based on model 1 of the Milan Consensus (Sandberg S, Fraser CG, Horvath AR, Jansen R, Jones G, Oosterhuis W, et al. Defining analytical performance specifications: consensus statement from the 1st strategic conference of the European federation of clinical chemistry and laboratory medicine. Clin Chem Lab Med 2015;53:833–5).
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Does patient-based data monitoring allow us to reconsider the relationship between IQC and EQA?

24. September 2025

Tony Badrick, John Sioufi, Derek Holzhauser

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Currently, there is no accepted standard practice for determining the frequency of EQA challenge. The challenge frequency has evolved based on history and local requirements. However, EQA frequency should be based on identifying patient risks caused by poorly performing laboratories, methods, or processes in any phase of the total testing cycle. The role of IQC is to ensure result consistency from day to day and to halt reporting of results if there is an analytical failure. Historically, both activities have been based on synthetic control material. With the development of patient-based approaches to IQC and EQA, it is possible to continuously monitor analytical systems using the same patient parameter, usually the mean or median. These techniques can provide laboratories with additional information to reduce patient risk. There are limitations of Patient-Based Quality Assurance (PBQA), fundamentally the lack of middleware and connection of the analyzers to the EQA provider. It cannot be used to monitor the success of harmonization/standardization of assays to a reference measurement procedure. But the use of patient-based approaches offers an opportunity to reconsider how EQA can be undertaken and the relationship between IQC and EQA. If PBRTQC and PBQA could be implemented to provide daily peer group comparisons, then method-specific bias could be identified quickly by a laboratory. If this could be supplemented with a commutable, reference value assigned EQA program, then monitoring harmonization/standardization of assays to a reference measurement procedure could be achieved.
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Confirmation of the value of the labile HbA_1c/HbA_1c-ratio in the presence of a Hb J-Baltimore variant: a clinical case

23. September 2025

Erna Lenters-Westra, Ilse Schouten, Iris van Vlodrop, Emma English

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Open Access
Influence of remnant cholesterol on direct LDL and HDL cholesterol measurement accuracy

22. September 2025

Soon Sung Kwon, Hanmil Jang, John Hoon Rim, Jooyoung Cho, Jong Do Seo, Yeo-Min Yun, Yun Mi Park, Gye Cheol Kwon, Chan-Ik Cho, Sang-Guk Lee, Jong-Baeck Lim

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Objectives Identifying the potential sources of bias in the direct measurement of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) is important. In this study, we aimed to investigate the effect of remnant cholesterol on LDL-C and HDL-C levels measured using homogenous methods. Methods We obtained 41 commutable frozen serum samples and measured LDL-C and HDL-C levels. Eight measurement systems were used, and the degree of bias was obtained by comparing with the values obtained using the reference methods. Correlations among remnant cholesterol/LDL-C, remnant cholesterol/HDL-C, and bias were analyzed using Spearman’s analysis. Results In all eight systems, samples with a positive bias >4 % had lower LDL-C levels and higher remnant cholesterol levels, as measured by the reference methods, compared to those with a bias ≤4 %. A significant correlation between remnant cholesterol/LDL-C and a positive bias of LDL-C was observed in six of the eight systems evaluated. For HDL-C bias, three systems showed a positive correlation, and three systems showed a negative correlation. In some systems, LDL-C bias was higher in samples with remnant cholesterol/LDL-C ≥0.25 than in those with remnant cholesterol/LDL-C <0.25. Conclusions Remnant cholesterol has a potential effect on direct LDL-C and HDL-C measurements, which has been observed when several measurement systems are used. For these systems, manufacturers should improve the methods to reduce the interference of remnant cholesterol.
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Pitfalls of immunoassays for diagnosis of hypoglycemia of undetermined etiology

18. September 2025

Adel A.A. Ismail

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Adverse analytical finding with trimetazidine after ingesting contaminated melatonin tablets sold in pharmacies… leading to the suspension of the athlete

18. September 2025

Jean-Claude Alvarez, Pascal Kintz, Isabelle Etting

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Open Access
Comparative analysis of monocyte distribution width alterations in Escherichia coli sepsis: insights from in vivo and ex vivo models

18. September 2025

Daniela Ligi, Chiara Della Franca, Michela Pelloso, Alicia Martinez-Iribarren, Alba Leis, Erica Fabbri, Francesca Salvatori, Elena A. Sukhacheva, Giorgio Brandi, Giuditta F. Schiavano, Ferdinando Mannello

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Objectives Monocyte distribution width (MDW) is an early sepsis indicator measuring monocyte heterogeneity during massive infection. We compared MDW changes in Escherichia coli sepsis patients with the effects of living E. coli and lipopolysaccharide in an ex vivo sepsis model. We also investigated the dynamics of monocyte morpho-functional and inflammatory responses in the sepsis model. Methods Whole blood from healthy participants was in vitro stimulated with live E. coli (10 6 –10 10  CFU/mL) and LPS (0.1–10 μg/mL). Complete blood counts, including MDW, were evaluated at different time-points using DxH 690T Hematology Analyzer (Beckman Coulter). MDW values were compared with those retrospectively obtained from sepsis patients (n=23). May-Grunwald-Giemsa-stained blood smears were analyzed by digital cell morphology (CellaVision DM software). A panel of 27 inflammatory mediators was quantified in plasma (Bio-Plex 200). Results MDW values were early and significantly increased in a dose- and time-dependent manner by live E. coli and LPS treatments (p<0.01). MDW values were significantly higher in sepsis patients compared to controls and overlapped those observed in the ex vivo model. IL-1β, TNF-α, IL-8, MIP1-α, MIP-1β, Eotaxin, G-CSF, and PDGF-bb were significantly modulated after treatments. Conclusions Our findings confirm the clinical utility of MDW in sepsis diagnosis and sustain the reliability of the whole blood assay as ex vivo sepsis model. E. coli and LPS directly promote early monocyte morpho-functional modifications, mirrored by high MDW values and pro-inflammatory mediators. These results improve the knowledge on the biological basis of sepsis, providing novel evidence on the usefulness of MDW in septic conditions.
Open Access
CA-125 glycovariant assays enhance diagnostic sensitivity in the detection of epithelial ovarian cancer

18. September 2025

Stefanos Moukas, Katri Kuningas, Marjut Helle, Leena Kokko, Rainer Kimmig, Sabine Kasimir-Bauer, Paul Buderath, Kaisa Huhtinen

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Objectives Ovarian cancer is the deadliest gynaecologic malignancy. Due to the lack of reliable biomarkers for the detection of the early disease, most patients are diagnosed at an advanced stage resulting in poor survival. We therefore aimed at establishing novel CA-125 glycovariant assays to improve the diagnostic sensitivity and specificity of ovarian cancer. Methods Blood samples of 184 patients with epithelial ovarian cancers (EOC), 127 benign ovarian tumors, and 115 healthy controls were measured using GLYVAR™ Ovarian I and II assays (Uniogen) and the conventional CA-125 protein assay (CanAg CA-125 EIA, Fujirebio). Results The two glycovariant assays differentiated benign and malignant ovarian masses with 88.0 % sensitivity at 99 % specificity, whereas CA-125 showed 72.8 % sensitivity. The improved performance was most evident in patients with borderline or moderately elevated CA-125 concentration at diagnosis, which is a challenging group for differential diagnostics. The CA-125 glycovariant assays showed 2.5 times higher sensitivity (33.3 % with CA-125 vs. 83.3 % with the CA-125 glycovariants) at 94 % specificity. CA-125 glycovariants corrected 82.4 % of false positive results given by CA-125 concentrations with the commonly used cutoff 35 U/mL. Importantly, the CA-125 glycovariant assays detected 63.6 % of early-stage serous carcinomas from benign and healthy controls with very high 99 % specificity, while CA-125 had a sensitivity of only 45.5 %, representing a 40 % increase. Conclusions This is the first study describing the clinical performance of GLYVAR Ovarian I and II assays in ovarian cancer diagnostics. The results indicate that the CA-125 glycovariant assays have remarkable potential to improve ovarian cancer diagnostics.
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Not all anti-parietal cell antibody tests are equal for diagnosing pernicious anemia

5. September 2025

Valentin Lacombe, Geoffrey Urbanski

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Objectives Pernicious anemia (PA) is a common cause of vitamin B12 deficiency and requires a robust diagnosis to guide lifelong treatment. Anti-parietal cell antibodies (APCA) are frequently used as a diagnostic marker, but their poor specificity raises concerns about overdiagnosis, particularly in patients lacking the more specific but less sensitive anti-intrinsic factor antibodies (IFA). We compared the diagnostic performance of two APCA detection methods: indirect immunofluorescence (IIF) and immunodot assay. Methods We prospectively enrolled patients with B12 deficiency and APCA positivity without IFA. PA diagnosis was adjudicated by blinded expert based on histology and response to oral B12. Patients were classified as true PA (APCA-PA), false positive (APCA-FP), or undetermined. Only APCA-PA and APCA-FP cases were analyzed. Results Among 56 included patients, 19 were classified as APCA-PA and compared to 24 APCA-FP. APCA immunodot assay was positive in 19/19 APCA-PA vs. 23/24 APCA-FP (p>0.99), while APCA IIF was positive in 13/19 APCA-PA vs. 2/24 APCA-FP (p<0.001), with higher IIF titers among APCA-PA (p<0.001). Only IIF positivity was significantly associated with PA (68.4 % vs. 8.3 %, p<0.001), with 92 % specificity. This association was confirmed in multivariate analysis (OR 37.1 [95 % CI: 6.1–439.4]). APCA IIF titer was also associated with PA diagnosis (AUC 0.82 [95 % CI: 0.68–0.96]), and titer ≥1:80 further improved specificity to 96 %. Conclusions IIF is more specific than immunodot for PA diagnosis, and its result should prevail over immunodot when deciding whether to perform EGD, when EGD is not feasible, and when establishing the diagnosis if biopsies are inconclusive.
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Defining the analytical characteristics of a novel high-sensitivity point-of-care troponin I assay in its intended clinical environment

3. September 2025

James Hatherley, Sarah Davies, Suzannah Phillips, Ahmed Dakshi, Guy Miller, Lisa Bailey, Paul Collinson, Aleem Khand

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Objectives To assess the imprecision and stability of the point-of-care troponin I assay in the Emergency Department and its correlation and bias to two central laboratory troponin I assays (Siemens Atellica and Abbott Alinity). Methods Imprecision and stability testing was performed on opportunistically selected samples using whole blood in the emergency department by non-laboratory trained personnel. Assay comparisons were undertaken on samples taken from participants of the Mersey Acute Coronary syndrome Rule Out Study. Results The coefficient of variation (95 % confidence interval), at the 99th percentile for the point-of-care assay, was 8.1 % (6.1–12.1 %) but with a wide confidence interval reflective of considerable scatter at values just below the 99th percentile. The 10 % limit of quantification was 7.5 ng/L (1.7–61.8 ng/L). All samples met the ≤2 ng/L stability criteria for a duration of 4 h and under. The point-of-care assay very strongly correlated and had a negative bias with the Siemens Atellica and Abbott Alinity assays, Pearson’s R=0.99 and 0.95, mean difference −29.7 ng/L and −13.3 ng/L respectively. Conclusions The Siemens VTLi point-of-care assay fulfils high-sensitivity criteria when operated by non-laboratory trained staff using whole blood in its intended environment. Lithium heparin samples are likely stable up to 4 h. Significant bias between the point-of-care and two central laboratory assays negates the use of these assays interchangeably.
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Fecal leukocyte esterase levels predict endoscopic severity as an alternative biomarker in inflammatory bowel disease

1. September 2025

Feng-Pai Tsai, Meng-Tzu Weng, Hsin-Yun Wu, Zhi-Che Chen, Chien-Chih Tung, Chun-Ying Wang, Shu-Chen Wei

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Objectives Our previous study revealed a correlation between fecal leukocyte esterase and fecal calprotectin levels. This study assessed the predictive value of fecal leukocyte esterase compared with fecal calprotectin and C-reactive protein of inflammatory bowel disease. Methods Patients with inflammatory bowel disease who underwent ileocolonoscopy at National Taiwan University Hospital from March 2022 to March 2024 were included. Fecal leukocyte esterase and fecal calprotectin levels from stool samples collected within one month of endoscopy were analyzed. Active ulcerative colitis and Crohn’s disease were defined as Mayo endoscopic score ≥2 or simple endoscopic score for Crohn’s disease ≥7, respectively. Sensitivity, specificity, predictive values, and areas under the receiver operating characteristic curve were calculated using IBM SPSS Statistics 29. Results Of the 203 patients (100 with ulcerative colitis and 103 with Crohn’s disease), fecal leukocyte esterase levels were significantly correlated with fecal calprotectin levels (r=0.425, p<0.001) and endoscopic severity in ulcerative colitis (r=0.432, p<0.001) and Crohn’s disease (r=0.311, p=0.001). For predicting Mayo endoscopic scores ≥2 in ulcerative colitis using fecal leukocyte esterase, fecal calprotectin, and C-reactive protein, areas under the curve were 0.731, 0.785, and 0.558, respectively. For predicting simple endoscopic scores for Crohn’s disease ≥7, areas under the curve were 0.706, 0.800, and 0.770, respectively. No significant difference was observed between fecal leukocyte esterase and fecal calprotectin. Conclusions Fecal leukocyte esterase correlates with fecal calprotectin and predicts endoscopic severity in inflammatory bowel disease.
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Failure Mode and Effects Analysis (FMEA) integrating quality indicators for risk assessment of the total testing process in human papillomavirus genotyping testing: a proactive risk analysis model for molecular diagnostics

29. August 2025

Tingting Li, Yuting He, Yuanhao Chen, Shunwang Cao, Yi Wang, Chunmin Kang, Hongmei Wang, Cheng Zhang, Chang Wen, Peifeng Ke

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Objectives To develop a proactive risk assessment model for human papillomavirus (HPV) genotyping testing by integrating Failure Mode and Effects Analysis (FMEA) with quality indicators (QIs), ensuring compliance with ISO 15189:2022 and improving diagnostic accuracy. Methods A multidisciplinary team designed and performed detailed FMEA across pre-analytical, analytical, and post-analytical phases of HPV genotyping testing. To improve objectivity, we integrated Sigma metrics into the FMEA framework through a molecular diagnostics-specific model of QIs (MQI). The FMEA model systematically identified testing phases, potential failure modes, their effects, root causes, and existing controls. Risk was quantified using Severity, Occurrence (from 1-year QI data), and Detection scores (1–5 scale). Risk Priority Numbers (RPNs) were calculated (Severity × Occurrence × Detection) to prioritize failure modes, with mandatory interventions implemented for high-risk items (RPN≥40). Results Five high-risk failure modes (e.g., sample misidentification, data analysis errors) were identified and successfully mitigated to acceptable levels (RPN<40) through process optimization and standardization, achieving RPN reductions of 20–80 %. We established a molecular diagnostics-specific MQI, comprising 14 pre-analytical, 25 analytical, and three post-analytical phase QIs. QI-based risk assessment of 35 evaluable QIs for HPV genotyping testing revealed one high-risk QI (“Incorrect results due to information system failures”) and three medium-risk QIs, all of which were addressed through corrective actions. Conclusions This study developed an integrated FMEA-QI model for HPV genotyping testing, establishing both a traditional FMEA framework and a molecular diagnostics-specific MQI. The combined approach improves risk assessment objectivity and enables multidimensional analysis compared to conventional methods.
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Are vitamins A and E results truly traceable and clinically useful? A practical and critical inquiry

28. August 2025

Raúl Rigo-Bonnin, Estel Julià-Quiñones, Anna Escalante-Vilanova, Irene Aliart-Fernández

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Open Access
Quality assurance using patient split samples: recommendations for primary healthcare laboratories

26. August 2025

Anne Stavelin, Eva Rønneseth, Anne Lise Fossum, Stein Binder, Camilla Aker, Maria Kim Nguyen, Sverre Sandberg

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Objectives The increasing adoption of point-of-care testing (POCT) in primary healthcare highlights the need for robust quality assurance (QA) procedures to ensure result reliability. The patient split sample approach, i.e. comparing POCT and central laboratory results from the same patient, can be a valuable QA tool, though practical guidance for its implementation remains scarce. This study aimed to develop clear, user-friendly recommendations for non-laboratory personnel in primary healthcare laboratories on when and how to perform such comparisons and to recommend acceptable limits for the compared results. Methods In 2023, an expert group was established, composed of medical specialists in laboratory medicine, researchers, and laboratory advisors. The recommendations were formulated based on relevant literature, the professional experience of the group members, and Noklus’ educational framework for primary care laboratories. Pragmatic acceptability limits were established taking several approaches into account. The draft recommendations were audited among more than 120 Noklus employees and final consensus was reached in 2024. Results Comparing POCT results with central laboratory results is recommended when: (A) no suitable EQA program exists for a given POCT; (B) appropriate internal quality control materials are lacking or inadequate; or (C) POCT results contradict clinical expectations. Acceptable limits for the compared results were set at 15 or 20 %, depending on the measurand. Results outside these limits should be reviewed using a structured checklist. Conclusions These are the first published recommendations for using patient split samples in primary healthcare that are designed to be simple and user-friendly for non-laboratory personnel, facilitating widespread adoption.
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Biological variation of serum Golgi protein 73 concentrations

26. August 2025

Anna Stefanska, Joanna Siodmiak, Katarzyna Bergmann, Łukasz Szternel, Aleksandra Wolska, Aneta Klarkowska, Judyta Koneszko, Magdalena Krintus, Mauro Panteghini

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Age distorts the interpretation of FIB-4

26. August 2025

Arne Åsberg, Gunhild Garmo Hov, Lena Løfblad

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Objectives To determine whether the diagnostic accuracy of the liver fibrosis marker FIB-4 and the likelihood ratios (LRs) of specific FIB-4 values vary with age. Methods We used a published dataset of 540 patients diagnosed with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis. Liver biopsy showed no or early fibrosis in 391 patients, and advanced fibrosis in 149. For each group we established the relation between the mean of the natural logarithm of FIB-4 (log(FIB-4)) and age, and the standard deviation (SD) of log(FIB-4) and age. Using a parametric method, we calculated the area under the ROC curve of FIB-4 as a function of the difference in mean values of log(FIB-4) between the two groups, and the ratio of the SDs of log(FIB-4). LRs were calculated as functions of age at 35, 50 and 65 years, using a parametric method. Results The mean log(FIB-4) increased with age in both groups. The SDs of log(FIB-4) did not change with age. There was a trend towards decreasing diagnostic accuracy with age, but this finding did not reach statistical significance. The area under the ROC curve was 0.73 using a parametric method that accounted for age, and 0.79 using a traditional non-parametric method that did not account for age. The LRs of specific FIB-4 values decreased with age. Conclusions Age distorts the estimation of both diagnostic accuracy and LRs.
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An automatic chemiluminescence immunoassay for a novel biomarker NT-IGFBP-4: analytical performance and clinical relevance in heart failure

25. August 2025

Shuzheng Cao, Jing Wang, Ling Li, Yu Wu, Juan Yang, Litao Zhang, Xin Shu, Hui Wang, Yisha Jing, Yi Zhang, Zhenlu Zhang

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Objectives Insulin-like growth factor binding protein-4 (IGFBP-4) fragments are reported as emerging biomarkers for cardiovascular disease (CVD) risk assessment. To ensure data reliability and improve clinical application, the first automatic chemiluminescent immunoassay (CLIA) for NT-IGFBP-4 was developed and its distribution across CVDs was evaluated in this study. Methods Fragment-specific monoclonal antibodies were used to develop immunoassay, followed by comprehensive analytical validation, including limit of blank (LoB), limit of detection (LoD), limit of quantification (LoQ), linearity, specificity, precision, sample type compatibility, and stability. Reference intervals for NT-IGFBP-4 were established in healthy individuals, with variations analyzed based on gender, age, body mass index (BMI), and renal function. Additionally, NT-IGFBP-4 distribution was explored in CVD patients. Results The newly developed chemiluminescence assay demonstrated high specificity for NT-IGFBP-4, with excellent sensitivity (LoQ=1.0 ng/mL), broad linearity (1.0–1,000.0 ng/mL), and strong precision (CV≤3.0 %). It showed no interference from common endogenous substances, maintained compatible with various sample types, and remained stable under different storage conditions. Reference intervals showed slight variations by gender and age, with levels being independent of BMI but influenced by renal function. NT-IGFBP-4 levels were significantly elevated in CVDs, especially in heart failure, correlating with NYHA classification and LVEF (%), with higher levels indicating worse cardiac function. Conclusions The new automatic NT-IGFBP-4 (CLIA) assay offers a highly specific, sensitive and precise method for quantifying IGFBP-4 fragments. Its validated performance and disease association findings would enhance its diagnostic and prognostic potential in CVD research, particularly in heart failure.
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Toxic beauty: acute kidney injury triggered by hair-straightening treatment

22. August 2025

Oscar D. Pons-Belda, Paloma Livianos-Arias-Camison, Santiago Mariño-Lopez, Jorvi J. Aguilar-Valero, Cassandra E. Puig-Hooper

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Improvement in the turnaround time of PTH(1–84) as part of the intraoperative PTH monitoring for parathyroidectomy

22. August 2025

Beverly Buffart, Dragos Barglazan

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Rethinking the use of “one-way ANOVA” in CLSI EP15-A3 – a call for terminological precision and methodological clarity

21. August 2025

Chaochao Ma, Ling Qiu

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Open Access
Total laboratory automation: fit for its intended purposes?

8. August 2025

Mario Plebani

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Since the 1980s, automation has profoundly transformed clinical laboratory operations, enhancing efficiency, standardization, and throughput. This technological evolution has enabled laboratories to meet rising testing demands, address persistent workforce shortages, and control operational costs. Beyond analytical consolidation, significant progress has been made through the integration of pre-analytical and post-analytical phases, thereby improving the overall quality of the Total Testing Process (TTP). Despite the well-recognized benefits of Total Laboratory Automation (TLA) – notably improved worker safety and faster turnaround times – a number of limitations have emerged, particularly concerning operational challenges and the lack of evidence for clinical effectiveness. Future improvements should focus on the integration of pre-pre-analytical processes, miniaturization of testing platforms, consolidation of all laboratory medicine subspecialties, and enhanced data management. However, the most critical issue remains the limited evidence supporting the impact of TLA on key clinical outcomes – such as reduced length of stay in emergency departments and hospital wards, optimized diagnostic-therapeutic pathways, improved quality of care, and reduced morbidity and mortality.
Open Access
Isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedures for the quantification of total and free phenytoin in human serum and plasma

23. Juni 2025

Tobias Schierscher, Linda Salzmann, Neeraj Singh, Manuel Seitz, Janik Wild, Carina Schäfer, Friederike Bauland, Andrea Geistanger, Lorenz Risch, Christian Geletneky, Christoph Seger, Judith Taibon

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Objectives An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) was developed and validated to accurately measure serum and plasma concentrations of total and free phenytoin. Methods Quantitative nuclear magnetic resonance spectroscopy (qNMR) was used to determine the absolute content of the reference material, ensuring its traceability to SI units. The separation of phenytoin from potential unknown interferences was achieved with reversed-phase chromatography, utilizing a C8 column. A protein precipitation protocol was established for preparation of total phenytoin samples, while free phenytoin samples were prepared by membrane separation utilizing a commercially available ultrafiltration device. Assay validation and determination of measurement uncertainties was performed according to the guidelines of the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the Expression of Uncertainty in Measurement. Results These RMPs demonstrated high selectivity and specificity, with no evidence of matrix effects, allowing quantification of total and free phenytoin in ranges of 0.640–48.0 μg/mL and 0.0800–4.80 μg/mL, respectively. Intermediate precision was <3.8 %, and repeatability was 1.4–3.8 %, over all concentration levels, for both forms of phenytoin. For total phenytoin, relative mean bias ranged from −2.7–0.3 % in native serum and from 0.0–1.1 % in lithium heparin plasma. Relative mean biases for free phenytoin were 3.5–4.1 % for both native serum and ultrafiltrates. Measurement uncertainties for single measurements and target value assignment were 1.8–2.5 % and 0.9–1.7 %, respectively, for total phenytoin. For free phenytoin, these measurement uncertainties were 2.0–3.9 % and 0.9–1.4 % for single measurements and target value assignment, respectively. Conclusions We present a novel LC-MS/MS-based RMP for phenytoin in human serum and plasma that provides a traceable and reliable platform for the standardization of routine assays and evaluation of clinically relevant samples.
Open Access
An isotope dilution-liquid chromatography-tandem mass spectrometry based candidate reference measurement procedure for the simultaneous quantification of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 in human serum and plasma

20. Juni 2025

Kerstin Kandler, Neeraj Singh, Friederike Bauland, Elie Fux, Andrea Geistanger, Christian Geletneky, Judith Taibon

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Objectives An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of 25-hydroxyvitamin D2 (25OHD2) and 25-hydroxyvitamin D3 (25OHD3) in human serum and plasma is presented. Methods Quantitative Nuclear Magnetic Resonance (qNMR) spectroscopic methodology has been utilized to assign absolute content (g/g) and International System of Units (SI)-traceability to the reference materials used as primary calibrators. This RMP was developed for the simultaneous quantification of 25OHD2 and 25OHD3 in human samples, utilizing supported liquid extraction (SLE) clean-up and a two-dimensional heart-cut ID-LC-MS/MS method to minimize matrix effects and prevent the co-elution of 3-Epi-25OHD3 and 3-Epi-25OHD2. The method underwent validation in accordance with current guidelines. Selectivity was assessed using spiked samples. To evaluate potential matrix effects, a post-column infusion experiment and a comparison of standard line slopes were performed. A 5-day validation study was conducted to determine precision, accuracy and trueness of the method. Measurement uncertainty for reference value assignment was evaluated in line with the Guide to the Expression of Uncertainty in Measurement (GUM). Equivalence to Joint Committee on Traceability in Laboratory Medicine (JCTLM) listed RMPs was demonstrated through the participation in the CDC Vitamin D Standardization-Certification Program (VDSCP) as well as the RELA scheme. Results The RMP enabled the quantification of 25OHD2 and 25OHD3 within the range of 1.50 ng/mL–180 ng/mL (3.64–436 nmol/L for 25OHD2 and 3.74–449 nmol/L for 25OHD3), without interference from their respective epimer and no evidence of matrix effects. Intermediate precision was determined to be ≤4.0 % for 25OHD2 and ≤3.6 % for 25OHD3, while repeatability was ≤3.3 % for 25OHD2 and ≤2.9 % for 25OHD3 across all concentration levels. The relative mean bias for the secondary reference materials varied from −1.0 to 1.1 %, regardless of the analyte. For the spiked samples, the relative mean bias ranged from −4.2 to 1.0 % for 25OHD2 and from −3.9 to 0.9 % for 25OHD3, irrespective of all levels and matrices. Expanded measurement uncertainties (k=2) for target value assignment (n=6) were ≤3.9 % for 25OHD2 and ≤3.2 % for 25OHD3. Participation in the VDSCP and the RELA scheme showed a good agreement with results from the JCTLM listed RMPs and laboratories. Conclusions The RMP enables the accurate, precise and consistent determination of 25OHD3 and 25OHD2. The robust performance of this method supports standardization of routine assays and guarantees traceability in the measurement of individual patient samples.
Open Access
An isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of 17β-estradiol in human serum and plasma

26. Mai 2025

Myriam Ott, Tobias Santner, Neeraj Singh, Friederike Bauland, Daniel Köppl, Alexander Gaudl, Andrea Geistanger, Uta Ceglarek, Manfred Rauh, Christian Geletneky, Judith Taibon

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Objectives A new candidate isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based reference measurement procedure (RMP) has been developed for the accurate and precise quantification of 17β-estradiol (E2) in human serum and plasma covering a measurement range from 0.400 to 5,000 pg/mL (1.47–18,357 pmol/L). To address this broad range, two separate methods were created: a high sensitivity (HS) method for concentrations between 0.400 and 5.00 pg/mL (1.47–18.4 pmol/L) and a standard range (SR) method for concentrations between 5.00 and 5,000 pg/mL (18.4–18,357 pmol/L). Methods As the primary reference material, E2 (CRM 6004-a) from the National Metrology Institute of Japan was used to ensure traceability to the international system (SI). A two-dimensional heart-cut LC approach was utilized for LC-MS/MS analysis, employing a supported liquid extraction sample preparation protocol for the SR method and a liquid-liquid extraction protocol followed by derivatization for the HS method. Assay validation was conducted following current guidelines. Selectivity and specificity were assessed using spiked serum samples, while potential matrix effects were evaluated through a post-column infusion experiment and comparison of standard line slopes. Precision, accuracy, and trueness were determined using an extensive 5-day protocol. Standard measurement uncertainty was evaluated according to the Guide to the Expression of Uncertainty in Measurement (GUM), with three individual sample preparations performed on at least two different days. Equivalence with higher-order RMPs was demonstrated through participation in the CDC Steroid Hormones Standardization (HoSt) program. Results The RMP enabled the quantification of E2 within the range of 0.400–5,000 pg/mL (1.47–18,357 pmol/L), demonstrating no interference from structurally related compounds and no evidence of matrix effects. The relative mean bias of the SR method ranged from −2.4 to 1.9 % across all levels, including secondary reference materials and spiked samples, whereas the HS method exhibited a mean bias ranging from −3.0 to 2.9 %. Expanded measurement uncertainties (k=2) for target value assignment ranged from 1.7 to 4.4 % for the SR method and were found to be ≤6.1 % for the HS method. The method’s transferability was demonstrated in a comparison study at a second laboratory. Additionally, the candidate RMP exhibited excellent correlation and equivalence to JCTLM-listed RMPs through the CDC HoSt program. Conclusions In summary, the ID-LC-MS/MS-based RMP accurately quantifies E2. Its robust performance makes it suitable for standardizing routine assays and measuring individual patient samples, ensuring traceability.
Open Access
Candidate reference measurement procedure based on isotope dilution-two dimensional-liquid chromatography–tandem mass spectrometry for the quantification of androstenedione in human serum and plasma

23. Mai 2025

Myriam Ott, Friederike Bauland, Vanessa Fischer, Daniel Köppl, Alexander Gaudl, Andrea Geistanger, Uta Ceglarek, Manfred Rauh, Judith Taibon

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Objectives Androstenedione (ASD) is a biomarker used in the diagnosis of hyperandrogenism and adrenal hyperplasia. Therefore, accurate measurement of serum ASD is pivotal in clinical settings. We aimed to develop a novel highly selective reference measurement procedure (RMP) based on isotope dilution-two dimensional-liquid chromatography-tandem mass spectrometry (ID-2D-LC-MS/MS) for the quantification of ASD in human serum/plasma. Methods To achieve high selectivity and sensitivity, a two-dimensional heart-cut LC approach for LC-MS/MS and a supported liquid extraction sample preparation protocol were employed. Matrix effects were evaluated through a post-column infusion experiment and comparison of standard line slopes. Precision and accuracy were determined via a multi-day validation experiment. Reproducibility was assessed by comparing results from two independent laboratories, and measurement uncertainty (MU) was evaluated in compliance with current guidelines. Results Our novel RMP proved effective for measuring ASD concentrations ranging from 0.00800 ng/mL to 12.0 ng/mL (0.0279 nmol/L to 41.9 nmol/L) and demonstrated matrix-independence. The relative mean bias varied between 0.6 and 2.2 % across different matrices and concentration levels. Intermediate precision was observed to be between 1.2 and 1.9 %. The expanded measurement uncertainty for ASD target value assignment ranged from 1.7 to 2.5 %, irrespective of sample concentration. Equivalence to the JCTLM-listed RMP was evaluated through a method comparison study, revealing a high degree of agreement (r≥0.997). Additionally, by comparing results from two independent laboratories, the transferability and reproducibility of the RMP were confirmed. Conclusions This isotope dilution two-dimensional LC-MS/MS method can be used for the evaluation and standardization of routine assays and for measuring individual patient samples, ensuring traceability.
Open Access
Isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedures for the quantification of 24(R),25-dihydroxyvitamin D2 and 24(R),25-dihydroxyvitamin D3 in human serum and plasma

6. März 2025

Kerstin Kandler, Michael Stadlmeier, Neeraj Singh, Friederike Bauland, Andrea Geistanger, Christian Geletneky, Judith Taibon

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Objectives Isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedures (RMPs) for the quantification of 24,25(OH) 2 D2 and 24,25(OH) 2 D3 in human serum and plasma are presented. Methods Quantitative nuclear magnetic resonance (qNMR) spectroscopic methodology was utilized to assign absolute content (g/g) and SI-traceability to reference materials used as primary calibrators. For liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis a two-dimensional heart cut LC approach, in combination with a supported liquid extraction protocol, was established to mitigate matrix effects and prevent co-elution of interferences. Selectivity was determined by spiking the internal standards and similar compounds, in human serum. A post-column infusion experiment and comparison of standard line slopes was performed to evaluate matrix effects. Precision and accuracy were assessed via a multi-day validation experiment, utilizing certified secondary reference materials from the National Institute of Standards and Technology (NIST). Measurement uncertainty (MU) was evaluated per the Guide to the Expression of Uncertainty in Measurement (GUM). To demonstrate equivalence with the JCTLM-listed RMP, certified secondary reference materials were utilized. Additionally, a method comparison study was conducted with the 24,25(OH) 2 D3 method used by the CDC Vitamin D Reference Laboratory. Results The RMP allowed quantification of 24,25(OH)2D2 and 24,25(OH)2D3 within the range of 0.150–18.0 ng/mL (0.350–42.0 nmol/L 24,25(OH) 2 D2 and 0.360–43.2 nmol/L 24,25(OH) 2 D3) without interference from structurally-related compounds and no evidence of matrix effects. Intermediate precision was ≤2.3 % for 24,25(OH) 2 D2 and ≤2.9 % for 24,25(OH) 2 D3; repeatability was ≤1.4 % for 24,25(OH) 2 D2 and ≤2.1 % for 24,25(OH) 2 D3, across all concentration levels. The relative mean bias was −4.5 to 2.9 % for 24,25(OH) 2 D2, and −3.7 to 3.6 % for 24,25(OH) 2 D3. Expanded MU for reference value assignment for 24,25(OH) 2 D2 and 24,25(OH) 2 D3 for reference value assignment was ≤2.5 %, regardless of concentration level and sample type. Passing-Bablok regression revealed strong agreement between the 24,25(OH) 2 D3 results from the candidate RMPs and those provided by the CDC Vitamin D Reference Laboratory. Conclusions These RMPs permit accurate and reproducible determination of 24,25(OH) 2 D2 and 24,25(OH) 2 D3. Implementation of these methods supports routine assay standardization and patient sample measurement with confirmed traceability.
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Retraction of: External Quality Assessment Programs in the US with an emphasis on urinary sediment testing: the College of American Pathologists experience

23. Mai 2018

Eric F. Glassy, David J. Blomberg

Artikelnummer: 20180453

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External Quality Assessment Programs in the US with an emphasis on urinary sediment testing: the College of American Pathologists experience

11. August 2015

Eric F. Glassy, David J. Blomberg

Artikelnummer: 20150658

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The College of American Pathologists (CAP) has maintained the highest standards for laboratory medicine through education, evaluation, and certification. One form of External Quality Assurance – proficiency testing (PT) – is the centerpiece of that mission. Over 500 medical and scientific experts oversee CAP PT programs which include more than 600 tests performed by 22,000 laboratories in over 100 countries. It is the most comprehensive laboratory peer-review comparison program in the world. The CAP offers four urine sediment PT products tailored to the needs of different laboratories. Each includes three or four digital images, shipped twice a year. The program is overseen by the Hematology and Clinical Microscopy Resource Committee. Images are graded if there is 80% or greater consensus of either referee or participant laboratories. Failing laboratories must analyze the reasons for the failure, report the results, and initiate corrective action. Over the years, there has been a progressive decline in the number of errors, demonstrating that education and regulatory oversight are major contributors to improved PT performance and, by extension, patient care. The PT urine sediment image databank is a unique resource, representing the consensus of many laboratories. Participant and referee responses identify which morphologic variants are unambiguous and which are more difficult to classify. The PT challenges include discussions of disease pathophysiology and key morphologic features. This teaching component is what helps to set the CAP’s program apart. The discussions formed the basis for the Color Atlas of Urinary Sediment published by the CAP in 2010.
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Proadrenomedullin for prediction of early and mid-term mortality in patients hospitalized for community-acquired pneumonia

1. Januar 2000

Amaia Artaraz, Ane Uranga, Ana Jódar, Urko Aguirre, José María Quintana, Carmen Mar, Rosario Menéndez, Javier Aspa, Salvador Bello, Pedro Pablo España, Aitor Ballaz

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Objectives Our study sought to determine the usefulness of biomarkers of systemic inflammation (C-reactive protein (CRP), procalcitonin (PCT) and proadrenomedullin (proADM)) on hospital admission, as compared to the CURB65 score, for predicting 30- and 90-day mortality in patients hospitalized for community acquired pneumonia (CAP). Methods Observational, prospective study of adults admitted for CAP in four Spanish teaching hospitals. Disease severity was determined within the first 24 h of diagnosis, using the CURB65 score. CRP, PCT and proADM levels were assessed from samples obtained in the Emergency Department (ED). We compared the capacity of the different biomarkers and the CURB65 score to predict pneumonia-related 30- and 90-day mortality. Results A total of 956 patients hospitalized with CAP were included, 462 in the internal and 494 in the external sample. Of the biomarkers, proADM showed the greatest AUC for predicting 30- and 90-day mortality (0.80 and 0.76 respectively). Mortality at 30 and 90 days increased as proADM levels rose. When proADM was used as a continuous variable, CURB65 showed a similar predictive capacity (AUC 0.80) to both crude and age-adjusted proADM (AUC 0.80 and 0.83 respectively) for 30-day mortality. The same was also true for 90-day mortality. However, proADM used as a categorical variable had a greater predictive capacity for 90-day mortality than the CURB65 score (<0.001). Conclusions Amongst patients admitted for CAP, the use of proADM obtained in the ED may be useful for identifying patients at greatest risk of mortality, with a similar predictive capacity to the CURB65 score.
Open Access
Counting cells is not enough: toward a global vision for quality and training in hematology

1. Januar 2000

Michela Pelloso, Mario Plebani

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Flow cytometry, cytology and histology in the diagnosis of ocular hematologic neoplasms: a 15-year monocentric experience with a focus on ocular lymphomas

1. Januar 2000

Alessandra Falda, Veronica Davanzo, Dario Marino, Carolina Molin, Paola Fogar, Jasmine Turkman, Jenny Zuin, Silvia Finotto, Marco Pizzi, Giulia Midena, Federica Vianello, Angelo Paolo Dei Tos, Martina Montagnana, Raffaele Parrozzani, Daniela Basso

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Objectives Ocular lymphomas are rare diseases that occur in ocular adnexa or specific intraocular regions. Although histology remains the gold standard, cytology and flow cytometry (FCM) are fundamental, mainly when a biopsy sampling is technically demanding. This study evaluated the effectiveness of FCM in diagnosing ocular diseases, especially hematologic malignancies, and compared its performance with the other techniques. Methods In this monocentric study we collected patient characteristics from 165 patients referred to Padua University Hospital. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV), accuracy and concordance rate were evaluated for cytologic, FCM, and/or histologic analyses performed. Results Patients were classified as having hematologic neoplasms (n=86), non-hematologic neoplasms (n=33) or non-neoplastic diseases (n=46). Hematologic neoplasms comprised 74 cases with ocular adnexal hematologic lesions and 12 cases with intraocular lymphomas and leukemias. FCM analysis of ocular specimens allowed valuable results in 71/86 hematologic cases, failure being mainly due to absence of cellularity (8/15). Histology showed 100 % PPV for both hematologic and non-hematologic neoplasms; FCM reached 97 and 66 %, and cytology 80 and 91 %, respectively. Concordance between FCM and cytology was lower (κ<0.61) than with histology (κ=0.677). FCM phenotype matched ocular lymphoma histotype in 95.8 % of cases. The lymphocytic infiltrate by FCM was 39.5 % in non-neoplastic, 64 % in non-hematologic and 89.5 % in hematologic diseases with B lymphocyte prevalence of 31.3 %, 21.0 % and 93.3 %, respectively. Clonality analysis remains essential regardless of these values. Conclusions FCM provides rapid results, studies numerous markers simultaneously, and analyzes ocular aspirates from minimally invasive samples. For this reason, it is desirable to permanently integrate this technique into the diagnostic process of ocular disorders, particularly when hematologic malignancies are suspected, as part of an integrated multidisciplinary pathway.
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Beyond cut-offs: optimizing presepsin for neonatal late-onset sepsis

1. Januar 2000

Cinzia Auriti, Domenico Umberto De Rose, Lucilla Ravà, Fiammetta Piersigilli, Maria Paola Ronchetti

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Open Access
Cross reactivity of endogenous and exogenous 25-hydroxyvitamin D₂ in commercial vitamin D assays; an evaluation using the Dutch external quality assessment scheme

1. Januar 2000

Erika Huijser, Judith A.P. Bons, Annemieke C. Heijboer

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Open Access
An isotope dilution-liquid-chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of total and free valproic acid in human serum and plasma

1. Januar 2000

Tobias Schierscher, Linda Salzmann, Neeraj Singh, Sandra Fleischer, Carina Schäfer, Julia Hoop, Friederike Bauland, Andrea Geistanger, Lorenz Risch, Christoph Seger, Judith Taibon

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Objectives An isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (cRMP) was developed and validated to measure serum and plasma concentrations of the total and free form of valproic acid. Methods Quantitative nuclear magnetic resonance spectroscopic methodology was used to determine the absolute content (g/g) of the reference material, ensuring traceability to SI units. Separation of valproic acid from potential unknown interferences was achieved with reversed-phase chromatography. A protein precipitation protocol was established for sample preparation for total valproic acid, while the free form was separated by ultrafiltration. Assay validations and measurement uncertainties were aligned with guidelines from the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the Expression of Uncertainty in Measurement. Results The cRMPs were highly selective and specific with no evidence of matrix effects, allowing quantifying total and free valproic acid in a range of 2.40–145 μg/mL and 1.60–42.0 μg/mL, respectively. Intermediate precision was <4.0 % and repeatability CV ranged from 0.9 to 3.5% for all concentrations of free and total valproic acid. The relative mean bias ranged from −0.4 to 4.1 % for native serum and from −0.3 to 3.5 % for Li-heparin plasma levels for total valproic acid. Free valproic acid showed mean biases between −2.9 and 4.0 % for native serum and ultrafiltrates. Measurement uncertainties for single measurements and target value assignment ranged from 1.7 to 3.4 % and 0.9–1.3 %, respectively, for total valproic acid. Free valproic acid ranged from 2.0 to 4.1 % and from 0.8 to 1.5 % for single measurements and target value assignment, respectively. Conclusions We present novel ID-LC-MS/MS-based cRMPs for total and free valproic acid in human serum and plasma which provides a traceable and reliable platform for the standardization of routine assays and evaluation of clinically relevant samples.
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Biological variation of serum transthyretin concentrations

1. Januar 2000

Anna Stefanska, Joanna Siodmiak, Łukasz Szternel, Katarzyna Bergmann, Aleksandra Wolska, Aneta Klarkowska, Judyta Ostrowska, Magdalena Krintus, Mauro Panteghini

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Open Access
An isotope dilution-liquid-chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of mycophenolic acid in human serum and plasma

1. Januar 2000

Tobias Schierscher, Linda Salzmann, Neeraj Singh, Carina Schäfer, Luc Sungauer, Friederike Bauland, Andrea Geistanger, Lorenz Risch, Christian Geletneky, Christoph Seger, Judith Taibon

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Objectives A candidate reference measurement procedure (RMP) based on isotope dilution (ID) liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated to accurately measure serum and plasma concentrations of mycophenolic acid (MPA). Methods Quantitative nuclear magnetic resonance (qNMR) spectroscopy was utilized for determining the absolute content of the reference material, guaranteeing its traceability to SI units. Separation of MPA from potential interferences, whether known or unknown, was accomplished by using a C18 column. For sample preparation, a protocol for protein precipitation followed by a high dilution step was established. Assay validation and measurement uncertainty determination were conducted following the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the Expression of Uncertainty in Measurement guidelines. Results The RMP demonstrated high selectivity and specificity without any indication of a matrix effect, enabling the quantification of MPA in the range between 0.240 and 18.0 mg/L. The intermediate precision and repeatability (n=60, measurements) were found to be <3.7 % and <3.0 %, respectively, across all concentration levels and independent from the matrix. The relative mean bias ranged from −1.9 to 2.1 % for serum and from −0.5 to 1.8 % for Li-heparin plasma levels. The measurement uncertainties for single measurements and target value assignment were found to be <6.4 % and <3.0 % (k=2), respectively. Conclusions We are pleased to present a new LC-MS/MS-based candidate RMP for MPA in human serum and plasma which offers a traceable and reliable platform for the standardization of routine assays and evaluation of clinically relevant samples.
Open Access
Creatinine measurement from finger stick dried blood spots with a routine chemistry analyzer for estimation of GFR

1. Januar 2000

J. Corné van Dam, Leosa R. Soels, Lotte Hofstee, Aster L. van der Werff, Ivar de Wilde, Timothy S.Q. Visser, Wessel Warners, Tim van Slooten, Michael Y. Schakelaar, Wouter M. Tiel Groenestege

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Objectives Measuring creatinine levels is essential for assessing kidney function. However, traditional venous sampling poses challenges in terms of sample collection, storage, and transportation. Recently, dried blood spot (DBS) analysis has emerged as a potential alternative for measuring creatinine levels, although its clinical application remains limited. Creatinine measurements from DBS could facilitate chronic kidney disease screening, medication management, and at-home patient monitoring. Methods Precision and hematocrit effect were assessed according to Clinical and Laboratory Standards Institute protocols to validate creatinine measurements in DBS. Subsequently, the protocol was applied in a method comparison involving 115 patients. Lastly, robustness was assessed by investigating creatinine stability over time and the influence of spotting effects. Results Creatinine measurements in DBS resulted in low bias and correcting for hematocrit further improved accuracy. A comparison of creatinine and estimated glomerular filtration rate (eGFR) between venous plasma and finger stick DBS showed an R 2 of 0.97 and 0.86, respectively. Moreover, sensitivity and specificity for detecting decreased eGFR (<60 mL/min/1.73 m 2 ) were 91 and 96 %, respectively. Creatinine remained stable in DBS for up to a month at −20 °C and 4 °C, up to six days at 20 °C, and one day at 37 °C. Finally, spotting effects such as double spotting had negligible effects. Conclusions In conclusion, creatinine from DBS can be analyzed using an automated high-throughput chemistry analyzer, enabling accurate eGFR classification. This method may support blood sampling at home for screening programs, patient follow-up, and medication management.
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Saliva sampling matters for salivary diagnostics of viral infections

1. Januar 2000

Chuixi Kong, Hongxu Chen, Yingye Weng, Xu Zhang, Enzhu Xia, Jiaqi Mao, Chenhao Yao, Xuhua Li, Xubo Qian, Zhigang Jin

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Saliva, a non-invasive biofluid with a variety of biomolecules, has been increasingly recognized as a reliable specimen in the diagnostics of viral infections. Compared to the standard specimens represented by blood and nasopharyngeal swab, saliva is advantageous in non-invasive, simple collection, convenient storage and compatibility with self-testing and large-scale screening. Saliva is an all-round specimen for viral detection as the shedding of viral nucleic acid fragments, antigens and the secretion of virus-specific antibodies are present in saliva. Accordingly, saliva has been widely used to detect a variety of viruses, including saliva-borne, air-borne and blood-borne transmitted viruses. However, challenges also arise as diverse methods during collection, storage and processing of the saliva could lead to discordant results among different studies. It is now aware that the methodology of saliva sampling is critical to the detection of viral biomarkers in the accuracy, repeatability and consistence with the data retrieved from the standard specimens. Therefore, establishing a standardized procedure for saliva sampling is crucial. Here we focus on a dozen factors that may affect the results of salivary diagnostic of viral infections and suggest a set of standardized procedures for saliva sampling, aiming to minimize result variation and benefit the application of saliva in salivary diagnostics of viral infections.
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Clinical validation of a DBS-based LC-MS/MS method for 25-hydroxyvitamin D: from lab sampling to home sampling

1. Januar 2000

Liesl Heughebaert, Rosalie Ghesquière, Christophe P. Stove

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Objectives As (a lack of) vitamin D has been linked to a wide variety of chronic diseases, there is growing interest in generating robust epidemiological data. Consequently, the need for large-scale biological sample collection has increased. In this context, dried blood spot (DBS) microsampling offers a minimally invasive alternative to venous sampling. However, to allow interpretation of DBS-based 25-hydroxyvitamin D (25-(OH)D) results, the set-up of a clinical validation study is essential to assess the agreement with the reference matrix, plasma. Methods Venous plasma and whole blood, venous DBS (vDBS) and capillary DBS (cDBS) were collected from 44 healthy volunteers to evaluate the agreement between the different sample types for 25-(OH)D quantification. To transform cDBS-based results to plasma concentrations, a hematocrit (Hct)-dependent conversion factor was applied and evaluated using four different Hct determination approaches. All samples were analysed using previously described validated LC-MS/MS methods. Results No clinically relevant methodological (vDBS vs. whole blood) or sampling-site related (cDBS vs. vDBS) issues were observed. Following Hct-dependent conversion, good agreement between the cDBS-derived and actually measured plasma results was obtained, as 90 % of the results lay within 20 % of the plasma result, independent of the Hct approach used. Additionally, weighted Cohen’s kappa values of 0.83–0.85 were obtained across the different Hct approaches, indicating substantial to almost perfect agreement in vitamin D status classification. Conclusions Following Hct-dependent conversion, cDBS can be used as a reliable and practical alternative matrix to plasma for large-scale monitoring of vitamin D status in epidemiological and public health contexts.
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Performance evaluation of quantitative hemoglobin A₂ and fetal hemoglobin testing using commercially lyophilized vs. in-house whole blood controls in Chinese clinical laboratories: a 12-year analysis of National External Quality Assessment Data

1. Januar 2000

Yating Ma, Zhongli Du, Juan Tang, Chengshan Xu, Gaofeng Hu, Yukun Han, Chenbin Li, Jie Ma

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Objectives To analyze the performance of laboratories in the China National External Quality Assessment Scheme (China NEQAS) for HbA 2 and HbF testing, and to propose strategies for quality improvement. Methods Data were obtained from China NEQAS from 2013 to 2024 using both commercially lyophilized controls and in-house whole blood controls. The distributions of methods and instruments were analyzed. Inter-laboratory coefficient variations (CVs) and target values were compared between two types of controls and between method-instrument platforms over 12 years. Results The in-house controls remained homogeneous and stable for almost one month at 2–8 °C and for one year at −80 °C. Capillary electrophoresis (CE) became the dominant method, adopted by 84.3 % of labs in 2024. For HbA 2 , two EQA controls had comparable concentration ranges and inter-laboratory CVs. HbF in-house controls covered broader pathological concentrations than commercial ones. CE demonstrated lower inter-laboratory CVs for both analytes: HbA 2 was 2.1 ± 1.8 % vs. 5.5 ± 4.8 % (high-performance liquid chromatography, HPLC) and 6.5 ± 4.1 % (agarose gel electrophoresis, AGE), while HbF was 3.2 ± 1.9 % vs. 5.0 ± 1.6 % (HPLC) and 8.6 ± 6.8 % (AGE). Significant discrepancies in maximum-to-minimum mean concentrations were observed among different method-instrument platforms when testing the same controls (up to 10 % for HbF). Conclusions In-house controls demonstrate homogeneity, stability and intrinsic commutability, and have an expanded concentration range, can serve as a reliable alternative to commercial controls for EQA. High-precision techniques such as CE should be favoured. Furthermore, the development of reference methods and commutable reference materials is essential for standardization.
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Critical appraisal of presepsin for diagnosing late-onset sepsis in critically ill neonates

1. Januar 2000

XiaoMei Wang, SongQian Yang

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Methodological evaluation and clinical interpretation of hs-cTnI and hs-cTnT variations: a reappraisal

1. Januar 2000

Aldo Clerico, Martina Zaninotto, Mario Plebani

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Recent debates have focused on the impact of analytical imprecision in high-sensitivity cardiac troponin (hs-cTnI and hs-cTnT) assays on the diagnosis of non-ST-elevation myocardial infarction (NSTEMI), based on the absolute delta thresholds for the rapid rule-in/rule-out algorithms in emergency department (ED) according to the 2020 ESC guidelines. Consensus guidelines by the AACC/IFCC and the Fourth Universal Definition of Myocardial Infarction emphasize precision at the 99th percentile upper reference limit and the clinical significance of biomarker changes. Evidence from the Italian Study Group on Cardiac Biomarkers demonstrates that hs-cTn assays generally achieve ≤10 % CV at concentrations relevant to diagnostic thresholds, and recommends a Reference Change Value (RCV) >30 % to define clinically meaningful variation. Conversely, van Schrojenstein Lantman et al. aimed to define the assay performance specifications (APS) required to reliably detect the recommended absolute delta thresholds and the consequences of failure to meet these APS. The aim of this opinion paper is to highlight the methodological and conceptual differences between these two approaches. More specifically, while APS are influenced by both assay characteristics and clinical context, the RCV approach is based on the intra-individual biological variation that remains consistently low (individual index ≈0.3), supporting the interpretation of circulating troponins as markers of physiological cardiomyocyte turnover. Ultimately, diagnosis of acute myocardial infarction requires integration of biomarker changes with clinical evidence of ischemia, ECG, and imaging findings. Emerging artificial intelligence–based models that combine hs-cTn with clinical variables further improve diagnostic accuracy, underscoring the importance of contextual interpretation and paving the way toward personalized medicine in the management of suspected NSTE-ACS.
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Early autoimmune signature in a young woman: palmar erythema, capillaroscopic abnormalities, and triple autoantibody positivity including anti-nucleosome

1. Januar 2000

Angelo Nigro

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Öffentlich zugänglich
The role of AI in pre-analytical phase – use cases

1. Januar 2000

Hikmet Can Çubukçu

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The pre-analytical phase of laboratory testing, encompassing processes from test ordering to sample analysis, represents the most error-prone component of laboratory medicine, accounting for 68–98 % of laboratory mistakes. These errors compromise patient safety, increase healthcare costs, and disrupt operational efficiency. Artificial intelligence (AI) and machine learning (ML) technologies have emerged as promising solutions to address these challenges across multiple pre-analytical applications. This narrative review examines current AI research applications and commercial implementations across seven key pre-analytical domains: clot detection, wrong blood in tube (WBIT) error detection, sample dilution management, chemical manipulation detection in urine samples, serum quality assessment based on hemolysis/icterus/lipemia (HIL), test utilization optimization, and automated tube handling. Research studies demonstrate impressive performance, with neural networks achieving accuracies exceeding 95 % for clot detection, XGBoost models reaching 98 % accuracy for WBIT detection, and deep learning systems attaining AUCs above 0.94 for test recommendation systems. However, a significant translation gap persists between research prototypes and commercial deployment. Academic models excel at pattern recognition using curated datasets but face limitations including single-center validation, retrospective designs, and integration challenges. Commercial solutions prioritize deterministic controls, barcoding, and sensor-based approaches that ensure reliability and scalability, with limited explicit AI implementation. Successful clinical laboratory translation requires multicenter prospective validation, robust laboratory information system integration, regulatory compliance frameworks, and evaluation metrics focused on operational outcomes rather than solely statistical performance. As infrastructure and standards mature, strategic AI adoption in pre-analytical tasks offers measurable improvements in safety, efficiency, and cost-effectiveness.
Open Access
Mass spectrometry based precision diagnostics: on the cusp of selective testing

1. Januar 2000

Michelle P. van der Helm, L. Renee Ruhaak, Christa M. Cobbaert

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New technologies and advances in human biology are paving the way for better patient management and outcomes in laboratory medicine. Precision diagnostics, as an essential component of P5 medicine, implies a shift towards selective testing of defined measurands, enabling a higher understanding of interindividual diversity and (patho-)biology at the molecular level. Precision diagnostics can potentially overcome some of the current inadequacies in diagnostic care pathways, caused by suboptimal tests leading to misclassifications and avoidable patient harm. Additionally, molecular methods have the potential to be standardizable upfront, allowing embedding of the metrological traceability concept. Over the last decade, especially mass spectrometry (MS) is gaining momentum and proving its potential as a selective measurement method for immunoassay replacement, add-on test and/or reference measurement procedure (RMP). In this context, the current place of MS in laboratory medicine is discussed, followed by cases from laboratory developed tests (LDTs), commercially available tests, highlighting also future MS applications. It is time for a wake-up call to promote a selective testing approach that accurately resembles individual biology, principally to be used when molecular definition is clinically relevant for classification ability and patient benefit. We provide a compilation for the laboratory specialist when to opt for molecularly defined tests. Ideally, the evolution to precision diagnostics is part of a changing healthcare landscape, where molecular fingerprints and patient diversity are inclusive. This will enable early detection of preclinical symptoms and start a shift from curative to preventive and personalized care.
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Reimagining External Quality Assessment for precision medicine: a perspective from biochemistry laboratories

1. Januar 2000

Stanford Chigaro, Maria Mvere

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External Quality Assessment (EQA) is central to quality assurance in laboratory medicine, providing independent measures of tests trueness, and inter-laboratory comparability. Traditional EQA schemes, designed around stable and well-characterised measurands, have been successful in routine analytes such as electrolytes and liver enzymes. However, the rise of precision medicine presents new challenges that extend beyond the scope of traditional EQA models. Advances in genomics, proteomics and metabolomics require quality systems capable of evaluating complex and context-specific biomarkers which may lack reference materials or established targets values. This creates a paradox: while EQA depends on standardisation, precision medicine is individualised. To remain relevant, EQA must evolve from static, one-size-fits-all models into adaptive, technology-driven, and clinically contextualised systems. In our view, the evolution of EQA must be immediate and decisive. Adaptive program design, cloud-based digital integration, AI-assisted analytics, and hybrid models provide a roadmap towards more flexible and clinically relevant systems. Together, these approaches offer a template for ensuring that EQA continues to safeguard quality while supporting innovation in personalised diagnostics.
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Thresholds adjustments and impact on clinical performance of three FIT assays in a colorectal cancer screening program

1. Januar 2000

Jean Dubé, Rosalie Plantefève, Maude Bonin, Luc Galarneau, Jean-Denis Rousseau, François Corbin, Charles Ménard, Artuela Çaku

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Objectives Fecal immunochemical tests (FITs) from various manufacturers yield different results, leading to variable positivity rates and clinical performance. These differences can influence the healthcare costs of a colorectal cancer screening program (CRC-SP), specifically when switching among FIT manufacturers. The analytical and clinical performance of three FITs was investigated to determine adjusted thresholds using positivity rate harmonization. Methods A cohort of 6,600 participants from the Quebec CRC-SP received collection kits from three different manufacturers to sample the same fresh stool. Participants with positive results were referred for a colonoscopy which was considered positive if advanced neoplasia (AN) was detected. Positivity rates were determined for each FIT at an unadjusted threshold. Adjusted thresholds were determined using a positivity rate harmonization strategy. Clinical performance was then evaluated for each supplier at unadjusted and adjusted thresholds. Results Among 5,513 participants who fulfilled the inclusion criteria, 327 underwent colonoscopy. The FIT positivity rates at unadjusted thresholds differed between manufacturers. The adjusted thresholds determined to yield the same positivity rate were different for each FIT. A total of 69 participants were diagnosed with AN. Significant differences in concordance, discordance, sensitivity, and specificity were observed when using the unadjusted threshold. After applying adjusted thresholds, differences in clinical performance between manufacturers were no longer statistically significant. Conclusions Threshold adjustment using a positivity rate harmonization strategy render differences in clinical performance statistically nonsignificant and leads to a stable colonoscopy rate between manufacturers. CRC screening programs should determine adjusted thresholds when changing FIT suppliers or when using multiple assays.
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Value is equal to outcome/costs: how to apply to laboratory medicine

1. Januar 2000

Rossella Tomaiuolo, Giuseppe Banfi

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The concept of value, defined as health outcomes achieved per monetary unit spent, has profoundly reshaped modern healthcare delivery. While Value-Based Healthcare models have permeated many clinical disciplines, laboratory medicine has been slow to integrate this paradigm shift. In this opinion paper, we argue for a strategic repositioning of clinical laboratories as core enablers of value in healthcare systems. Laboratory diagnostics, long considered ancillary, should be reframed as pivotal tools that support outcome-based, cost-effective decision-making. We explore how laboratory parameters contribute to clinical value through predictive accuracy, diagnostic specificity, and operational appropriateness – factors that directly influence patient outcomes and resource allocation. Examples such as vitamin D testing, albumin as a biomarker of biological age, and NT-proBNP in heart failure demonstrate the potential and pitfalls of volume-driven laboratory utilization. Beyond technical excellence, we emphasize the importance of interpretive collaboration, health literacy, and ethical stewardship of diagnostic resources. Structural challenges, including commoditization, delocalization via point-of-care testing, and the limited use of patient-reported outcomes in laboratory settings, are critically examined. Finally, we highlight emerging policy frameworks across Europe that align reimbursement models with measurable outcomes, advocating for the integration of laboratories in clinical governance and value-based procurement. In this renewed perspective, laboratories are not merely data providers but agents of personalized, sustainable, and patient-centered care.
Open Access
An isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of cortisone in human serum and plasma

1. Januar 2000

Myriam Ott, Neeraj Singh, Marie Kubicova, Friederike Bauland, Daniel Köppl, Alexander Gaudl, Andrea Geistanger, Uta Ceglarek, Manfred Rauh, Christian Geletneky, Judith Taibon

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Objectives Cortisone is an inert precursor/metabolite of the potent steroid hormone cortisol. Measurement of serum cortisone levels and the cortisol-cortisone ratio can be useful for the diagnosis of dysfunction in the regulation of cortisol levels (i.e., severe and subtle apparent mineralocorticoid excess, low-renin primary aldosteronism). Therefore, an isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedure (RMP) to quantify cortisone in human serum/plasma was developed and validated. Methods Quantitative nuclear magnetic resonance (qNMR) was utilized to assign absolute content (g/g) and SI-traceability to reference materials used as primary calibrators. A supported liquid extraction sample preparation protocol as well as a two-dimensional heart-cut LC approach for LC-MS/MS analysis were employed to mitigate matrix effects and prevent co-elution of interferences. Selectivity was determined by analyzing a matrix sample containing the analyte, the internal standard and six potential interferents. A post-column infusion experiment and a comparison of standard line slopes were performed to evaluate matrix effects. An extensive protocol over five days was applied to determine precision, accuracy and trueness. Measurement uncertainty (MU) was evaluated in compliance with current guidelines. Results This RMP is suitable for analyzing cortisone within the 0.0800–120 ng/mL (0.222–333 nmol/L) range, demonstrating selectivity, sensitivity and matrix independence. Intermediate precision was ≤3.4 %, repeatability was ≤2.9 % across all concentration levels and relative mean bias ranged from −3.7 to 2.8 % across all tested matrices and concentrations. Expanded MU (k=2) for target value assignment (n=6) ranged from 2.1 to 5.5 %, irrespective of concentration or sample type. Conclusions This RMP allows for accurate and reproducible determination of cortisone in human serum and plasma. Implementation of this method supports routine assay standardization and patient sample measurement with confirmed traceability.
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Analysis of total cholesterol results measured in the initial period of the Croatian screening program for familial hypercholesterolemia: a pilot study

1. Januar 2000

Gordana Juričić, Antonija Perović, Jasminka Matica, Kornelija Perković-Radojković, Vesna Horvat, Dario Mandić, Tamara Devčić-Ljubić, Zdravka Doljanin, Irena Užović, Katarina Jedrejčić, Sonja Podolar, Nena Peran, Željka Severinac, Ines Kelava, Ivanka Maldini, Marijan Oršulić, Krešimir Kuleš

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Objectives In 2023, Croatia implemented a screening program for familial hypercholesterolemia (FH) targeting children entering the first grade of primary school. The program is based on total cholesterol (TC) concentration measurements. This pilot study aimed to assess and compare TC results obtained using different analytical platforms during the program’s initial phase (2023–2024). Methods Retrospective data from laboratories across Croatia were analyzed. Results covered the following analyzers: Beckman Coulter AU (BC), Abbott Alinity/Architect c (AA), Roche Cobas c (RC) and Siemens Atellica CH (SA). Statistical analyses included Kruskal–Wallis and chi-square tests using the program’s cut-off values. Bland–Altman and Passing-Bablok analyses were used to assess differences in a direct comparison study of 40 samples. To reduce variability, TC values were also expressed as multiples of the median (MoM), calculated separately for each platform. Results The study included 17,694 children. Median TC values (IQR) differed significantly across platforms: BC (4.3 [3.8–4.7] mmol/L), AA (4.1 [3.7–4.5]), RC (4.1 [3.7–4.5]), and SA (4.0 [3.6–4.4]); p<0.001. BC and SA results differed significantly from all other platforms, while no significant difference was found between RC and AA. The distribution of TC results also varied significantly (p<0.001). In the comparison study, all platforms showed statistically significant differences (p<0.001). In contrast, MoM values showed no statistically significant differences between analyzers (p=0.106) or in distribution when applying various MoM-based cut-offs. Conclusions Although variations in TC measurements across platforms are small, they are statistically significant and affect FH classification. MoM normalization may support harmonization in future screening protocols.
Open Access
Ionized calcium in serum exposed to air

1. Januar 2000

Robin Mirdell, Ganan Solika

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Spun citrate samples as a suitable alternative for platelet measurement. Is recollection necessary? A preliminary study

1. Januar 2000

Ana Nikler, Brankica Šimac, Vanja Radišić Biljak

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ADORE: the performance characteristics of five automated platforms in the analysis of urinary dysmorphic erythrocytes and pathological casts

1. Januar 2000

Jolien J. Luimstra, Xue D. Manz, Rüya G. Koçer, Hilde H.F. Remmelts, Dorien M. Rotteveel, Ayşe Y. Demir

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Objectives Automated urine particle analyzers are increasingly employed in clinical laboratories to standardize urinalysis. These systems can reduce workload, turnaround time and the inter-observer variation. This study aimed to assess the performance of five automated urine particle analyzers in detecting and categorizing dysmorphic erythrocytes (isomorphic-, dysmorphic erythrocytes, acanthocytes) and pathological casts, in particular erythrocyte casts, for screening of glomerular vs. non-glomerular hematuria, compared to manual phase-contrast microscopy, as the reference method. Methods The analytical performance of five automated urine particle analyzers, Atellica UAS 800, FUS-3000Plus, iQ200, SediMAX conTRUST Pro, and UF-4000, for measuring and categorizing erythrocytes and pathological casts was evaluated. Urine samples spiked with erythrocytes were used to assess precision and performance characteristics, while 68 urine samples from patients with glomerular hematuria were analyzed for concordance. Results Automated analyzers demonstrated acceptable precision at middle and high erythrocyte concentrations. At low levels, the iQ200 performed relatively well and the SediMAX met the manufacturer’s precision criteria. Manual on-screen review was required for 90 % of samples analyzed to achieve acceptable results for dysmorphic erythrocytes and cast detection. None of the analyzers exhibited strong agreement with manual microscopy for identifying isomorphic-, dysmorphic erythrocytes or acanthocytes (concordance <0.80), whereas the FUS-3000 and UF-4000 had relatively higher sensitivities for pathological cast detection (58.6 and 69.6 %, respectively). Conclusions Current automated urine particle analyzers are limited in accurately identifying dysmorphic erythrocytes and pathological casts, necessitating manual microscopy for reliable assessment. While automation offers potential for standardization and efficiency, significant technological advancements are required to improve diagnostic accuracy, reliability, and clinical applicability.
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Hemolysis index. Can we uncritically trust manufacturer declarations?

1. Januar 2000

Alen Vrtaric, Marijana Miler, Nora Nikolac Gabaj, Ivana Celap, Valentina Vidranski, Marina Bocan, Petra Filipi, Marija Kocijancic

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Objectives Hemolysis is a common preanalytical interference in clinical biochemistry, affecting up to 3.3 % of routine samples and contributing to approximately 60 % of rejected specimens. It results from the release of intracellular constituents, such as hemoglobin and potassium, into the plasma due to cell membrane disruption. This interference is often evaluated through hemolysis index (HI) thresholds defined by in vitro diagnostic (IVD) analyzers, but these thresholds may not align with clinical needs or biological variation. Methods A descriptive study was conducted from February to April 2025, comparing the hemolysis interference data of 72 clinical chemistry analytes across five major manufacturers: Abbott, Beckman Coulter, BioSystems, Roche, and Siemens. Manufacturer package inserts were reviewed and compared to the CLSI C56-A guideline for hemolysis interference testing. Results The compliance of manufacturers with the CLSI guideline varied significantly. Siemens had the highest compliance, reporting hemolysis interference at two analyte levels in 46/71 of cases, while BioSystems did not report analyte concentrations for any tested parameters. Criteria for significant interference was often missing, and in many cases, manufacturers used arbitrary thresholds, such as 10 % bias. Additionally, acceptance criteria and reported bias values were inconsistent across manufacturers, with only Abbott and Siemens providing detailed bias data. Conclusions Manufacturer instructions often lack completeness and consistency, making it crucial for clinical laboratories to independently validate hemolysis thresholds. A harmonized approach, incorporating manufacturer data, research, and local validation, is essential to improve laboratory quality, minimize misinterpretations, and ensure compliance with regulatory standards.
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ReferenceRangeR: a novel tool designed to facilitate reference interval estimation and verification

1. Januar 2000

Gunnar Brandhorst, Maike Voß, Werner Wosniok, Farhad Arzideh, Rainer Haeckel, Daniel Rosenkranz, Thomas Streichert, Astrid Petersmann

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Objectives Reference intervals (RIs) are essential for interpreting laboratory test results. It is recommended that each medical laboratory establishes and reviews its own RIs. The use of direct methods is often unfeasible for most laboratories, while indirect methods are a more viable alternative. However, these methods require not only medical, but also statistical and technical expertise, thereby limiting accessibility for many laboratories. To address this challenge, a web-based application was developed to facilitate the estimation and verification of RIs using real-world laboratory data. Methods The application was developed using R Studio and the Shiny web framework. The tool supports five indirect methods for reference interval estimation: refineR, TMC, TML, kosmic and reflimR. Furthermore, a Docker container was designed to enable a secure local deployment. Results Up to 200,000 laboratory test results can be included via a straightforward copy-and-paste input. The tool provides recommendations for sex-based stratification by performing statistical analysis. In addition, a drift-detection algorithm was developed to analyze whether age-based stratification is necessary. The results of RI estimation are displayed and visualized alongside the underlying data distribution. Existing RIs can be verified by comparing them against calculated intervals. Conclusions ReferenceRangeR is a user-friendly tool for estimating and verifying RIs using real-world laboratory data, eliminating the need for statistical or technological expertise, thereby supporting laboratory professionals in meeting the current regulatory standards.
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Innovative closed tube protocol reveals a super critical early preanalytical phase of whole blood glucose stability in routine matrices

1. Januar 2000

Guillaume Grzych, Arnaud Pinsart, Inès Defauwes, Manon Campas, Elodie Grifnée, Pascal de Tullio, Etienne Cavalier

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Performance of GFAP and UCH-L1 compared to S100B in detecting intracranial injury: influence of age, hemolysis, neurodegenerative diseases, and extracranial fractures in a prospective cohort of over 1,000 patients

1. Januar 2000

Antoine Puravet, Vincent Sapin, Jean-Baptiste Bouillon-Minois, Bruno Pereira, Julie Durif, Benjamin Bouthors, Farès Moustafa, Jeannot Schmidt, Damien Bouvier, Charlotte Oris

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Objectives To compare the diagnostic performances of GFAP and UCH-L1 with S100B in detecting intracranial injury, while investigating the impact of confounding factors. Methods In a large prospective cohort of 1,010 patients with mild traumatic brain injury, we first evaluated the clinical performances of S100B and the GFAP/UCH-L1 combination. To explore the impact of pre-analytical interferences on GFAP and UCH-L1 levels, HIL indices (hemolysis, icterus, lipemia) were measured using the Atellica ® analyzer, and spiking experiments were performed with increasing concentrations of hemolysate, bilirubin, and Intralipid ® . We then assessed the influence of four confounders on biomarker specificity: age over 80 years, hemolysis, neurodegenerative diseases, and extracranial fractures. Finally, we evaluated the ability of the biomarkers to predict clinical outcomes at one month. Results S100B and the GFAP/UCH-L1 combination showed sensitivities of 96 and 100 %, and specificities of 25 and 27 %, respectively. False positives were significantly associated with age >80 and extracranial fractures for S100B; with age >80 and neurodegenerative diseases for GFAP; and with age >80, hemolysis, and extracranial fractures for UCH-L1. UCH-L1 levels were markedly increased by hemolysis, starting at 400 mg/L of hemoglobin. Age was the only confounding factor to significantly affect specificity. Using age-adjusted thresholds in patients over 80 increased specificity to 30 % for S100B and 33 % for GFAP/UCH-L1. Overall, the biomarkers exhibited limited predictive value and performed poorly for one-month clinical outcomes. Conclusions S100B and the GFAP/UCH-L1 combination demonstrated very high sensitivities, close to 100 %, with specificities of approximately 30 % for the diagnosis of intracranial lesions. Age-adjusted thresholds improve specificity in older patients, supporting their clinical implementation. This study also provides the first evidence that hemolysis significantly elevates UCH-L1 concentrations from 400 mg/L of hemoglobin.
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Impact of renal and hepatic function on dihydropyrimidine dehydrogenase phenotype assessed by enzyme activity in peripheral blood mononuclear cells and uracilemia

1. Januar 2000

Sara Contu, Manon Launay, Hélène Bouges Le Royer, Laurence Simon, Audrey Mignot, Eva Seutin, Renaud Schiappa, Philippe Follana, Anne Creisson, Ludovic Evesque, Marie-Christine Etienne-Grimaldi

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Objectives To investigate the relationship between uracilemia (U) and dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMC) and whether they are influenced by renal or hepatic impairment. Methods This retrospective study included 176 cancer patients with pre-treatment U (UPLC-MSMS assay) and PBMC-DPD (radioenzymatic assay) analyzed the same day (routine phenotyping). Blood renal (creatinine, BUN) and hepatic (ALT, AST, GGT, ALP, albumin, bilirubin) work-up was performed within 15 days before or up to 4 days after DPD phenotyping. Biochemical markers were categorized according to CTCAEv5.0 grade (G). Glomerular filtration rate (eGFR) was estimated (CKD-EPI and EKFC). Non-parametric statistical tests were used. Results Prevalence of partial deficiency was 3.4 % based on PBMC-DPD (i.e. ≤100 pmol/min/mg) and 6.3 % based on U (i.e. ≥16 μg/L). No complete deficiency was observed. Fifteen patients out of 176 (8.5 %) exhibited discordant DPD status between PBMC activity and U. The correlation between PBMC-DPD and U was significant but weak (r= −0.309, p<0.001). PBMC-DPD (mean 246, median 235, range 62–926 pmol/min/mg prot) was not influenced by renal or hepatic impairment. U (mean 9.6, median 8.5, range 1.7–57.8 μg/L) was significantly higher in patients with elevated BUN (normal vs. >1-UNL, p=0.009), GGT (G0 vs. G1 vs. G2 vs. G3, p<0.001), AST (G0 vs. G≥1, p=0.015), or with hypoalbuminemia (G0 vs. G ≥ 1, p=0.045). Categorized creatinine or eGFR did not influence U. Conclusions It remains unclear whether renal and/or hepatic impairment acts as a confounding factor affecting the accuracy of uracilemia testing, or whether truly impacts DPD activity, suggesting caution in U interpretation.
Open Access
Estimated waste generation from 1 million basic metabolic panels: a multisite U.S. study

1. Januar 2000

Seema Khattri Bhandari, Kwaku Twum, Erving T. Laryea, Yaqing Du, Raeshun T. Glover, Rachel G. Brackbill, William Butler, Khushbu Patel, Christopher W. Farnsworth, Christina C. Pierre, Steven W. Cotten, Joesph R. Wiencek

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Objectives Clinical laboratory operations consume large amounts of electricity and water and generate considerable quantities of solid waste. In this study, we quantified and compared the estimated solid waste produced from performing one million basic metabolic panels (BMPs) across five major high-throughput chemistry analyzer systems commonly used in the United States. Additionally, we estimated the carbon emissions associated with the electricity and water usage of each analyzer to better understand their environmental impact. Methods Five academic medical centers each using a different clinical chemistry analyzer system, collected their respective annual vendor purchase data (January 2022–December 2022). Consumables including reagent cartridges, packaging boxes, inserts associated with reagents, calibrators, and QC materials were categorized and weighed separately. Solid waste estimates for one million BMPs were calculated based on institutional testing volumes. Water and electricity usage for the analyzer systems was obtained and estimated CO 2 emissions (CO 2 e) were determined using standard emission factors and calculators. Results The study found that performing one million BMPs on wet chemistry analyzer platforms, Abbott, Beckman, Roche and Siemens generated 995 kg, 1,274 kg, 579 kg and 489 kg of solid waste respectively while the dry chemistry Ortho system produced 160,593 kg. The majority of waste across all platforms was plastic. Annualized CO 2 e from electricity and water use totaled to 69,665 kg CO 2 e. Conclusions Analysis of BMPs generates substantial amounts of solid waste and CO 2 e across major diagnostic platforms. These findings emphasize the urgent need for sustainability strategies in diagnostic laboratories to address their environmental footprint.
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Hierarchy of reference interval models: advancing laboratory data interpretation

1. Januar 2000

Thomas Streichert, Mustafa Özçürümez, Jasmin Weninger, Ali Canbay, Abdurrahman Coskun

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Accurate interpretation of laboratory data is a critical step in clinical decision-making. This requires the availability of reliable reference data for comparison. Reference data can be derived from various sources, including hospital or laboratory databases, groups of reference individuals, or an individual’s own data, and can be estimated using different statistical approaches. In addition to the possible lack of standardization of measurement methods this diversity results in the availability of multiple reference intervals for a given measurand. However, selecting the most appropriate reference data is challenging and requires a systematic approach to identify the best available option for each measurand. In this opinion paper, we aim to develop a systematic approach for constructing a hierarchical structure encompassing all known reference interval (RI) models, to discuss the advantages and disadvantages of each, and to provide a framework for selecting the most appropriate RI for routine clinical practice. To illustrate the model visually, we constructed a hierarchical pyramid with the less reliable reference intervals positioned at the base, gradually increasing in reliability toward the top. Based on the data sources and the statistical approaches used to estimate RIs, we conclude that, at least from a theoretical perspective, the currently widespread model – discrete population-based RIs derived from hospital or laboratory data – occupies the lowest level, that is, it represents the ground of the hierarchical pyramid, whereas multivariate continuous personalized RIs reside at the top.
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A robust ddPCR assay for the absolute quantification of miR-192-5p in hepatocellular carcinoma liquid biopsies

1. Januar 2000

Xinmiao Liu, Yefan Zhang, Narisu Narisu, Fan Wu, Ke Zhang, Yulin Sun, Hongjun Gao

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Objectives MicroRNA-192-5p, a liver-enriched miRNA downregulated in hepatocellular carcinoma (HCC), is a promising biomarker, but its clinical use is limited by technical challenges in detecting low-abundance plasma miRNAs. This study innovatively uses droplet digital PCR (ddPCR) with locked nucleic acid (LNA)-modified probes to develop an ultrasensitive and standardized method for miRNA quantification in liquid biopsies. Methods Following Minimum Information for Publication of Quantitative Real-Time PCR Experiments guidelines, seven primer-probe combinations were screened by qPCR, and one with the lowest Ct variability (Ct <35) was selected. LNA-modified Probe P-2 was designed to enhance target hybridization. Reaction conditions were optimized to 1 μM primers, 300 nM probes, and 55 cycles. Analytical validation included trueness, precision, sensitivity, linear range, and interference testing. Plasma from 87 HCC patients and 57 controls was analyzed, and a logistic model combining miR-192-5p, AFP, and AFU was evaluated. Results The LNA probe improved positive droplet counts by 32 %. The dPCR showed excellent precision (intra-batch CV 2.31–21.63 %, inter-batch 17.54 %) and trueness (R=0.92 vs. RT-qPCR). Sensitivity thresholds were LoB=1.75, LoD=3.33, LoQ=13.45 copies/μL, with linear range 13.45–129,693 copies/μL (R 2 =0.9965). It tolerated low hemoglobin and triglycerides but was affected by bilirubin. HCC patients had lower miR-192-5p (444.2 vs. 753.5 copies/μL, p<0.001), with AUC=0.70. The multi-marker model had AUC=0.88. Conclusions This LNA-optimized ddPCR assay resolves miRNA liquid biopsy barriers. The combinatorial model outperforms single biomarkers, offering a clinical tool for the precise quantification of HCC-specific miRNAs. Standardized workflows ensure reproducibility, and multicenter studies are needed for validation.
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Spot urine is a suitable matrix for measurement of copeptin

1. Januar 2000

Julie Sherfan, Sonya Franke, Myron Lee, David R. Sullivan

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Objectives To validate urine as a suitable matrix for copeptin measurements, derive a urinary copeptin/creatinine ratio in an apparently healthy sample of the population, and assess pre-analytical conditions such as collection type and storage temperatures that affect stability and recovery. Methods Matrix effect was determined by spiking the manufacturer’s calibrator F simultaneously into pooled serum and aliquots of spot urine sample donated by a single volunteer. Stability was assessed without preservatives as well as 0.0032× g of thymol or 1 mL of 5 M hydrochloric acid. The urinary copeptin-to-creatinine ratio reference limit was derived from random spot urines collected from 120 apparently healthy volunteers who met the selection criteria. Results Our in-house derived urinary copeptin-to-creatinine ratio was<2.5 pmol/mmol creatinine, and there was a statistically significant difference in urinary copeptin concentration between males and females, but this was eliminated when corrected for urine creatinine. 24-h and spot urine with and without preservatives were stable for 7 days at 4–8 °C, 23–25 °C, and −20 °C. Limits of blank, limits of detection, and limit of quantitation were 1.1 pmol/L, and 1.81 pmol/L, respectively. Conclusions Urine matrix does not distort the kinetics of the BRAHMS Thermo Fisher Copeptin assay and therefore could be measured with high accuracy. The clinical utility of urinary copeptin is still unknown, however, there is growing interest in this area in patient with autosomal polycystic kidney disease.
Open Access
VeRUS: verification of reference intervals based on the uncertainty of sampling

1. Januar 2000

Matthias Beck, Florian Dufey, Tatjana Ammer, André Schützenmeister, Jakob Zierk, Christopher M. Rank, Manfred Rauh

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Objectives Laboratories are required to routinely verify reported reference intervals (RIs), but common verification methods like the CLSI-EP28-A3c binomial test are often impractical due to sample collection requirements. Indirect verification methods like equivalence limits (ELs) use routine data from patient care but lack systematic evaluation. This study aimed to develop and evaluate a novel indirect verification method: verification of reference intervals based on the uncertainty of sampling (VeRUS). Methods VeRUS compares the to-be-verified candidate RI to an RI estimated from local routine data. Acceptable differences are based on the sampling uncertainty intrinsic to the nonparametric method for establishing RIs with n=120 samples. The three verification methods were systematically compared with simulated test sets resembling 10 differently distributed biomarkers and a wide range of plausible candidate RIs. Results The binomial test is inherently unable to reject too wide RIs; e.g. the 99.8 %-interval, for which ELs and VeRUS showed high rejection rates (mean 89.2 %, SD 31.5 % and mean 95.8 %, SD 2.3 %, respectively). Moreover, the binomial test incorrectly accepts 29.3 % of “too narrow” 80%-intervals, whereas the false acceptance rates of ELs and VeRUS were lower (mean 21.7 %, SD 40.9 % and mean 7.2 %, SD 4.7 %, respectively). Overall, both indirect verification methods demonstrated increased statistical power, while ELs were least consistent among different biomarker distributions. Conclusions Its robust performance without the need for sample collection makes VeRUS an attractive tool for RI verification. By enabling routine verification of previously practically unverifiable RIs (e.g., in pediatrics), VeRUS may enhance clinical decision-making and improve patient care.
Open Access
Tafasitamab interference in immunofixation electrophoresis

1. Januar 2000

Rebecca S. Treger, Susan L. Fink

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Open Access
Predictive genomic medicine enlarges the spectrum of predisposing mutations for head and neck cancers via a panel of 56 genes selected for human neoplasia in Southern Italy: a pilot study

1. Januar 2000

Federica Di Maggio, Giulia Togo, Ettore Pavone, Alessandra Calabrese, Petra Claudia Camilla D’Orsi, Maria Luisa Marciano, Giovanni Marino, Franco Ionna, Francesco Salvatore, Marcella Nunziato

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Objectives Oral squamous cell carcinoma (OSCC) is the most prevalent form of squamous cell carcinomas of the head and neck (SCCHN), accounting for over 90 % of all oral cavity malignancies (approximately 275,000 new cases are worldwide diagnosed annually). Early-stage oral squamous cell carcinoma (T1 and T2) has a 5-year survival rate of up to 80 %. Survival rates decrease to 20–30 % at later stages (T3-T4). Each year, there are between 275,000 and 300,000 new cases of OSCC, and over 150,000 deaths worldwide. OSCC are usually non-hereditary tumors, although familial epidemiology has been recently reported. Methods From 2022 to 2024, we enrolled 56 patients from the complex structure of maxillofacial surgery and ORL, National Cancer Institute – IRCCS – Fondazione G. Pascale. The individuals enrolled underwent molecular testing via a multigene panel of 56 genes related to cancer predisposition customized in our laboratory. The panel included BRCA1 and BRCA2 . Results We identified a total of 7 pathogenic mutations annotated in clinical databases as ClinVar, in BRCA2 (two different variants), BRCA1 , MUTYH , BRIP1 , FANCM and FANCC genes (approximately 12.5 % of our patients). The results show a frequent predisposition to head and neck tumors similar to or even greater than that observed in other types of neoplasia, such as breast and ovarian cancers or colon cancer), with a predisposition of approximately 10 %. Conclusions Our results confirm that, similarly to other more studied tumors, predictive genomic medicine can play a crucial role in the early identification of germline mutations in head and neck cancers. This approach should be considered for the early detection of OSCC particularly for individuals at increased risk, e.g., those with a family history of the disease, who may also be candidates for targeted molecular therapies based on their genetic profile.
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57^th National Congress of the Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC – Laboratory Medicine)

1. Januar 2000

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Prognostic utility of serial procalcitonin measurements in ICU sepsis: a laboratory-led modelling approach in a resource-limited setting procalcitonin modelling for sepsis mortality in a low-resource ICU

1. Januar 2000

Aaqilah Fataar, Annalise E. Zemlin, Elsie C. Kruger

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Objectives Procalcitonin (PCT) is increasingly used to support sepsis diagnosis, but its role in predicting outcomes remains uncertain, particularly in low-resource settings. We evaluated whether single and serial PCT measurements were associated with 28-day mortality in critically ill adults with suspected sepsis. Methods We conducted a retrospective study of adult intensive care unit (ICU) patients with suspected sepsis and at least one PCT measurement at a tertiary hospital in South Africa (August 2022-July 2023). Baseline PCT was analysed using multivariable logistic regression. Among patients with ≥2 PCT values, we examined the association between PCT slope (from patient-level linear regression) and mortality. Latent class mixed models (LCMM) were used to identify PCT trajectory subgroups. Results Of 371 patients, 119 (32 %) died within 28 days. Higher baseline log-PCT was independently associated with increased mortality (adjusted odds ratio [aOR] 1.58; 95 % CI 1.01–2.50). A rising PCT slope trended toward higher mortality (aOR 3.56 per unit/day; p=0.06). LCMM identified three trajectory classes with distinct mortality risks (class 2: aOR 4.53; class 3: aOR 4.35, vs. reference). These models were based entirely on laboratory data and did not assess clinical scoring systems. Conclusions Both baseline and serial PCT measurements predicted mortality in ICU patients with suspected sepsis. Modelling approaches based on routine laboratory data may offer scalable tools for early risk stratification in resource-limited settings.
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Comparison of the cardiac troponin I-cardiac troponin T-troponin C complex and cardiac troponin I and T in distinguishing myocardial infarction using a single sample at presentation

1. Januar 2000

Ling Li, Yuqing Liu, Yu Wu, Juan Yang, Litao Zhang, Xin Shu, Hui Wang, Yisha Jing, Tongxin Ni, Liyao Gou, Yi Zhang, Zhenlu Zhang

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Objectives The potential relationship between cardiac troponin (cTn) composition and etiologies of myocardial injury may provide diagnostic insights for myocardial infarction (MI). We compared the performance of novel ternary cTnI–cTnT–TnC complex (ITC) assays with high-sensitivity (hs)-cTnI and hs-cTnT in differentiating MI patients at presentation. Methods Plasma samples from 1,210 patients with suspected MI were collected. Major cTn forms were quantified using long-cTnT ITC complex, hs-total ITC complex, hs-cTnI and hs-cTnT assay. We compared the assay performance based on the 99th percentile upper reference limits (URLs), evaluated their area under the receiver operating characteristic curve (AUC), and assessed their ability to differentiate MI using established cut-off values. Results A total of 138 (11.4 %) patients were diagnosed with MI. 86 % patients had long-cTnT ITC complex concentration below the 99th percentile URLs (sensitivity: 0.818, specificity: 0.943, NPV: 0.975, PPV: 0.649). AUC was 0.959 for long-cTnT ITC complex, comparable to hs-cTnI (0.953) and superior to hs-total ITC complex (0.889) and hs-cTnT (0.927). Using established cut-off values, the long-cTnT ITC complex assay classified 10 % of patients as rule-in and 52 % as rule-out (sensitivity: 0.993, NPV: 0.998, specificity: 0.972, PPV: 0.760), which was comparable to hs-cTnI and better than hs-total ITC complex and hs-cTnT. In early-presenting patients, the long-cTnT ITC complex demonstrated enhanced discrimination and improved diagnostic performance. Conclusions The long-cTnT ITC complex assay demonstrated performance comparable to hs-cTnI and superior to hs-total ITC complex and hs-cTnT in distinguishing MI using a single sample at presentation. These findings suggest its potential utility in improving risk stratification and triage strategies, particularly among early-presenting patients.
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Towards harmonization of autoantibody detection in relation to paraneoplastic neurological syndromes (PNS): a European Survey on laboratory practices

1. Januar 2000

Matthijs Oyaert, Marco Schreurs, David Goncalves, Dina Patel, Ravishankar Sargur, Carol Stanley, Monica Probst, Marie-Agnès Durey, Jan Damoiseaux, Carolien Bonroy

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Objectives Detection of paraneoplastic anti-neuronal antibodies (PNS autoantibodies) aids in diagnosing the particular syndrome and guides the search for an underlying tumor. To identify opportunities for harmonization that could enhance diagnostic value, we assessed variability in autoimmune serological testing for PNS across laboratories. Methods The European Autoimmunity Standardisation Initiative (EASI) developed a questionnaire addressing testing methods, digital tools, interpretation, clinical context, and quality assurance. This was distributed through two external quality assessment (EQA) providers (UK NEQAS and IfQ Lübeck) to clinical labs routinely performing PNS autoantibody assays. Results Among 139 responding laboratories, 78 % perform both cerebellum indirect immunofluorescence (IIF) and line/dot blot assays on serum and cerebrospinal fluid (76 %). Alignment on sample dilution (61 %) and conjugate type (70 %) is variable. Differences in antigen composition and reporting strategies contribute to variability in line/dot blot testing. Digitization is widespread for line/dot blot data (87 %) but limited for cerebellum IIF (31 %). About 53 % use testing algorithms that vary by sample type and requested antibodies. Internal quality control is performed by 89 % (IIF) and 48 % (line/dot blot), mainly using commercial controls. Nearly half (43 %) participate in multiple EQA programs; 46 % (IIF) and 42 % (line/dot blot) have ISO15189 certification, with 20 % planning certification. Positivity rates are low (<6 % in 73 % of labs), indicating low pre-test probability. While only 46 % restrict testing by discipline, most labs access clinical context (84 %) and interact with clinicians (63 %). Conclusions Considerable variability exists in PNS autoantibody assay execution, reporting, and quality control. Introducing lab-specific recommendations may harmonize practices and improve diagnostic quality.
Open Access
Dental amalgams and blood mercury concentrations in American adults

1. Januar 2000

David A. Geier

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Objectives Dental amalgam (50 % mercury (Hg) by weight) is a commonly used material to restore a tooth damaged by decay. In recent years, amalgam safety has become a matter of ongoing controversy. This hypothesis-testing epidemiological study evaluated the relationship between blood Hg concentrations and amalgams in American adults. Methods Examination of the 2015–2016 National Health and Nutrition Examination Survey (NHANES) was undertaken using SAS, version 9.4 (Cary, NC, USA), survey regression statistical modeling (with adjustments for covariates). A total of 180,811,187 weighted-Americans (n=1,377) between the ages of 18–70 years-old, with known: dental filing surface status; urinary Hg concentrations; total and blood Hg species (inorganic and methyl-Hg) concentrations; bodyweight; and urine flow rates were examined. Results Significant increases were found in the blood concentrations of total and inorganic Hg, when comparing adults exposed to amalgams as compared to adults not exposed to amalgams. Amalgam surfaces significantly correlated with blood inorganic Hg concentrations, and estimated daily Hg vapor doses from amalgams significantly correlated with blood total and inorganic Hg concentrations. This study supports the importance of blood as an important transport avenue for Hg, which is dose-dependently released by amalgams, to accumulate in tissues and cells throughout the body. Conclusions Persons with amalgams, desiring to lower their blood Hg concentrations, should consult with a dentist trained and certified in safe amalgam removal. Also, pharmaceutical treatments to reduce/render non-toxic the blood Hg concentrations from amalgams should be considered. Efforts should be made to reduce/eliminate the continued use of amalgams.
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Small-scale external quality assessment of methylated SHOX2 and RASSF1A detection in China: findings from 2023–2024

1. Januar 2000

Chengxiang Chu, Xiaoyu Fan, Chunli Shi, Ran Zhao, Yingwei Chen, Xiaobo Hu, Xueliang Wang

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Objectives DNA methylation in short homeobox gene 2 ( SHOX2 ) and RAS association domain family protein 1 ( RASSF1A ) shows significant auxiliary diagnostic value for early-stage lung cancer. However, the detection accuracy is frequently compromised because of the complexity of the analytical procedures. This pilot external quality assessment (EQA) study evaluated the performance of methylated SHOX2 ( mSHOX2 ) and methylated RASSF1A ( mRASSF1A ) detection across clinical laboratories in China. Methods A sample panel was prepared containing two mSHOX2 -positive samples, one mRASSF1A -positive sample, one mSHOX2 and mRASSF1A double-positive sample, and one negative sample. The panel was randomly coded and distributed to clinical laboratories for mSHOX2 and mRASSF1A detection in 2023 and 2024. The returned results were compared and scored to evaluate laboratory performance. Results The sample panel demonstrated sufficient stability and applicability. Results were collected from 21 laboratories in 2023 and 29 laboratories in 2024. Approximately 90.5 % (19/21) and 75.9 % (22/29) laboratories achieved correct results in 2023 and 2024, respectively. Out of the 105 results in 2023 and 145 results in 2024, 1 false negative and 3 false positives were observed in 2023 and 6 false negatives and 12 false positives in 2024. Conclusions This two-round EQA study in China emphasizes the need for improvement in the performance of mSHOX2 and mRASSF1A methylation detection. These results underscore the critical role of EQA schemes in monitoring and improving the detection quality in clinical laboratories. To address the challenges in mSHOX2 and mRASSF1A detection, targeted recommendations are proposed to enhance detection accuracy and reliability.
Open Access
Short- and medium-term pre-analytical stability of human serum insulin-like growth factor-1

1. Januar 2000

Jaco C. Louw, Jaya A. George, Siyabonga P. Khoza, Sean Currin

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Objectives Insulin-like growth factor-1 (IGF-1) is a peptide hormone currently lacking data surrounding its pre-analytical stability. This study aimed to investigate the impact of delaying centrifugation and analysis at different storage temperatures on the in vitro stability of IGF-1. Methods The study followed the Checklist for Reporting Stability Studies (CRESS). Ten healthy, adult participants were recruited to donate 40 mL of blood each. Blood was collected into serum separator tubes. Samples were aliquoted and split into two main categories i.e., immediate centrifugation (timepoint zero) and delayed centrifugation (by 8 and 24 h). These categories were further subdivided into different storage temperatures i.e., −20 °C, 4 °C, 20–25 °C and 30 °C. All measurements were conducted in duplicate on a DiaSorin LIAISON ® XL (Via Crescentino snc, Saluggia, Italy). Analysis occurred immediately after centrifugation (timepoint zero), after 8, 24, 48, 72, 168 and 672 h in the respective categories. The percentage deviation (PD) from baseline was calculated and a maximum permissible difference of ≥10.7 % (based on biological variation) was considered significant. Results In our study, IGF-1 was stable for at least 72 h regardless of delay in centrifugation or storage temperature. Samples that were refrigerated were stable until 168 h (PD≤5.5 %) regardless of a delay in centrifugation. Samples that were frozen at −20 °C were stable up to 672 h (PD −1.5 %). Conclusions IGF-1 is stable up to 72 h after sampling regardless of delay in centrifugation or storage temperature. Stability may be lengthened to 7 days by refrigerating at 4 °C.
Open Access
An isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of cortisol in human urine

1. Januar 2000

Myriam Ott, Friederike Bauland, Daniel Köppl, Alice Ayik, Andrea Geistanger, Manfred Rauh, Judith Taibon

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Objectives Precise and accurate determination of urinary cortisol is important for diagnosis and monitoring of cortisol excess and deficiency. To achieve this, a selective and specific, isotope-dilution two-dimensional heart-cut liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method was developed. Methods A novel, two-dimensional heart-cut LC-MS/MS method was developed using a Waters Acquity BEH C18 column and a Raptor Biphenyl column, with water (A1) and with 0.2 mM ammonium fluoride in water (A2) and methanol (B1+B2) as mobile phases. This approach was complemented by a supported liquid extraction (SLE) sample preparation protocol. Matrix effects were assessed through post-column infusion experiments and comparisons of standard line slopes across matrices. A multi-day validation study evaluated accuracy and precision of the candidate reference measurement procedure (RMP) and measurement uncertainty (MU) was estimated in compliance with current guidelines. Reproducibility was assessed by performing a method comparison study between two independent laboratories. Results In the first LC column dimension, cortisol and prednisolone were separated from cortisone, prednisone, and 20-beta-dihydrocortisone. Baseline separation of cortisol from prednisolone was achieved in the second dimension. No interfering signals were detected at the retention time for quantifier and internal standard transitions in any urine samples analysed. No significant matrix effect, ion suppression, or enhancement was observed. Linearity was successfully demonstrated (r≥0.999); residuals were randomly distributed in a quadratic model via linear regression with an 1/x weighting. The lower limit of the measuring interval was determined at 2.00 ng/mL (5.52 nmol/L), displaying a relative deviation of −0.1 %, a coefficient of variation (CV) of 2.9 %, and recoveries of 96–103 %. Intermediate precision ranged from 1.9–3.2 % and repeatability CV from 1.6–2.7 %. Relative mean bias ranged from −3.5–1.2 %, indicating method accuracy was unaffected by matrix variance. Measurement uncertainties (k=1) for cortisol were ≤3.4 % across different concentrations and sample types. The expanded uncertainty at a 95 % confidence level (k=2) was ≤6.8 %. An increased number of measurements (n=6) for target value assignment reduced the uncertainty to 0.8–1.3 % (k=1), yielding an expanded uncertainty (k=2) of 1.7–2.5 %. Conclusions The validation results confirm the robustness, accuracy, and reliability of this RMP for determination of cortisol in human urine within a working range of 2.00–220 ng/mL (5.52–552 nmol/L).
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Familial erythrocytosis and phenotypic heterogeneity associated with different defects in alpha globin genes: a significant new case of Hb Wroclaw (α88(F9) Ala>Glu; HBA1: c.266C>A)

1. Januar 2000

Valentina Carrai, Cristina Giubbilei, Tiziana Biagioli, Massimo Maffei, Massimo Mogni, Sabrina Davì, Marialaura Galli, Sauro Maoggi, Domenico Coviello, Giovanni Ivaldi

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Reviewer Acknowledgment

1. Januar 2000

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Capillary blood in core laboratories: current and future challenges

1. Januar 2000

Álvaro González, Sara Deza, Julia Maroto-García, Nerea Varo

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Capillary blood sampling is gaining recognition as a patient-centered alternative to traditional venipuncture. Its main advantages are that it is less invasive, reduces patient discomfort, and potentially can be performed without the direct supervision of a healthcare professional. These features could facilitate access to healthcare, particularly for patients with limited access to clinical facilities or those requiring frequent testing, thereby supporting telemedicine, and improving participation in screening programs and clinical trials. However, its integration into routine clinical practice requires the development of standardized traceable processes and user-friendly collection kits that preserve sample quality and have preanalytical error rates comparable to those of venipuncture. Compliance with ISO 15189 and integration into existing laboratory workflows are essential. Moreover, device affordability and compatibility with analyzers will determine accessibility and scalability. Addressing logistical, regulatory, and technical challenges is key to fully realizing its potential as a patient-centric solution in modern healthcare, where the robustness of analytical data derived from capillary blood could be comparable to that obtained from venous blood. In this review, we analyze the potential role of capillary blood in routine clinical practice, highlighting its benefits and challenges and determining the conditions necessary for its successful implementation.
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Recommendations for the study of monoclonal gammopathies in the clinical laboratory. A consensus of the Spanish society of laboratory medicine and the Spanish society of hematology and hemotherapy. Part III: clinical and analytical recommendations for the study of monoclonal gammopathies by MALDI-TOF mass spectrometry

1. Januar 2000

Cristina Agulló, Noemí Puig, Nerea Varo, María Ángeles Iglesias, Carmen Mugueta, Rosa Pello, Bruno Paiva, Joaquín Martínez-López, Sergio Castro, María Cruz Cárdenas, Ramón García-Sanz, David Pérez-Surribas, Juan Flores-Montero, María Ortiz-Espejo, Javier de la Rubia, Elena Cruz-Iglesias, Adrián Fontán, María Isidoro-García, Jesús San-Miguel, María Victoria Mateos

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Monoclonal gammopathies (MGs) represent a diverse group of plasma cell disorders that range from asymptomatic premalignant conditions to aggressive malignancies such as multiple myeloma (MM). Mass spectrometry (MS) based serum analysis offers a non-invasive, highly sensitive alternative to conventional techniques for identifying and quantifying M-proteins. It enables more precise assessment of treatment response and residual disease, particularly in patients with suspected complete response (CR), those not eligible for bone marrow procedures, or those treated with monoclonal antibodies that may interfere with standard assays. This guideline document, endorsed by the Spanish Society of Laboratory Medicine (SEMEDLAB) and the Spanish Society of Hematology (SEHH), provides comprehensive recommendations for the clinical and analytical application of MS in the detection and monitoring of M-proteins in patients with MGs. The document outlines optimal use of MS at diagnosis, during follow-up, and in reporting practices, with a focus on standardized implementation, interpretative criteria, and clinical decision-making support.
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Pro-gastrin releasing peptide as a tumor marker of medullary thyroid carcinoma: a comparative bivariate meta-analysis

1. Januar 2000

Petra Petranović Ovčariček, Federica D’Aurizio, Alfredo Campennì, Frederik Anton Verburg, Luca Giovanella

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Objectives Calcitonin (CT) is the established biomarker for medullary thyroid carcinoma (MTC), but its measurement is hampered by analytical limitations. Procalcitonin (PCT) and pro-gastrin-releasing peptide (ProGRP) have been proposed as alternative or complementary markers, yet the diagnostic value of ProGRP remains uncertain. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of ProGRP for MTC and compare its performance with CT. Methods This study followed PRISMA-DTA and SEDATE guidelines. PubMed, Embase, Cochrane Library, and Open Grey were searched through June 2025 without language or date restrictions. Eligible studies assessed serum ProGRP for diagnosis or follow-up of MTC and reported or allowed reconstruction of 2 × 2 contingency data. Two reviewers independently screened, extracted data, and assessed study quality using QUADAS-2. A Bayesian bivariate random-effects meta-analysis estimated pooled sensitivity, specificity, likelihood ratios, and diagnostic odds ratios. Comparative analyses were performed for ProGRP studies also reporting CT. Results Eight studies (n=4,080) were included; four reported both ProGRP and CT (n=1,064). ProGRP showed pooled sensitivity of 74 % and specificity of 95 % (AUC 0.82), while CT achieved 94 % sensitivity and 91 % specificity (AUC 0.89). Subgroup analyses confirmed consistent ProGRP performance across diagnostic and follow-up settings. No publication bias was observed. Conclusions ProGRP demonstrates high specificity but lower sensitivity than CT for MTC diagnosis and surveillance. Although not a replacement for CT, ProGRP may serve as a valuable complementary biomarker, particularly in inconclusive cases. Harmonization of assays and prospective validation are required to define universal thresholds and integrate ProGRP into multimarker diagnostic algorithms.
Open Access
Potential savings of two practical interventions on vitamin D ordering practices at a large academic medical center

1. Januar 2000

Stephanie A. Hart, Jeremy T. Brown, Joesph R. Wiencek

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Development and validation of a machine learning model for accurate detection of wrong blood in tube errors in hospitalized patients

1. Januar 2000

Jordi Tortosa-Carreres, Ana Vañó-Bellver, Andreu Martínez-Cerezuela, Óscar Fuster-Lluch, Lucía García-Ruiz, Elena Rodríguez-Romero, Antonio Sierra-Rivera, Ana Comes-Raga, Carlos Cátedra, Virginia Tadeo-Garisto, Alexandra Igumnova-Dubovikova, Rafael Gisbert-Criado, Laura Sahuquillo-Frias, Begoña Laiz-Marro

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Objectives To develop and validate a machine-learning model based on routinely available biochemical and hematological parameters for detecting wrong blood in tube (WBIT) errors in hospitalized patients. Methods A retrospective multicenter study including one internal cohort (IC) and two external validation cohorts (EVC, EVC2). The IC was balanced (50 % correct, 50 % WBIT; 25 % real, 25 % simulated), while EVC (n=800) and EVC2 (n=460) represented more realistic scenarios (95 % correct, 5 % WBIT; equally distributed between real and simulated). Parameters present in ≥ 95 % of requests were selected, and their normalized variation from the immediately preceding result was calculated. The IC was divided into a training set (IC-TS, n=324) and an internal validation set (IC-VS, n=108). Feature selection was refined with Elastic Net before training an XGBoost model. Performance was assessed in IC-VS, EVC, and EVC2. For benchmarking, the model’s discriminative ability was also compared with a multivariate Mahalanobis-based approach and with univariate delta checks within IC-TS/IC-VS. Results Sixteen of 25 candidate variables were retained. The model achieved ROC-AUC values of 0.98–0.99 and PR-AUC values of 0.93–0.99 across all validation cohorts. Recalibration improved positive predictive value and net benefit by reducing false positives, with a slight decrease in sensitivity, although all values remained ≥90 %. Specificities ranged from 98 to 99 %. The model consistently outperformed both the multivariate Mahalanobis approach and univariate delta checks within the internal cohort. Conclusions This machine-learning model, leveraging widely available routine laboratory parameters, shows strong potential for integration into clinical workflows, enhancing WBIT detection and improving patient safety.
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Keeping pace with patient safety by developing and qualifying higher-order reference measurement procedures for laboratory measurement standardization

1. Januar 2000

Mauro Panteghini, Robert Wielgosz

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Open Access
Automated reticulocyte counting: advances, standardization challenges, and clinical accessibility

1. Januar 2000

Hongyin Zhou, Yaxin Huang, Ruijian Zhuang, Shunyan Xiong, Jiaming Zou, Tianji Li, Yonggang Hu

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With the advent of flow cytometry and dedicated fluorescent dyes in the 1980s, automated reticulocyte enumeration has effectively superseded conventional manual microscopy, dramatically boosting throughput and precision while, through metrics including the immature reticulocyte fraction (IRF) and reticulocyte production index (RPI), delivering previously unattainable diagnostic resolution for anemia phenotyping, longitudinal tracking of marrow erythropoiesis, and evaluation of functional iron deficiency. Yet appreciable heterogeneity in analytical principles, reagent chemistry, and calibration frameworks persists across platforms, constraining result comparability and uniform interpretation across systems. The International Council for Standardization in Haematology (ICSH) is advancing commutable reference materials built on stable cell lines or synthetic microspheres, together with globally harmonized reference intervals, to achieve interoperable performance among instruments. Concurrently, the capital expense and servicing requirements of high-end fully automated analyzers continue to be a major impediment to clinical access to automated reticulocyte testing. This narrative review focuses on the “standardization and clinical accessibility of automated reticulocyte counting,” systematically elaborating the core technical principles and characteristics of mainstream instruments, analyzing advances and challenges in standardization, and envisioning its application prospects in global clinical practice.
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Pleural effusion with a thyroid signature: diagnostic utility of pleural fluid thyroglobulin

1. Januar 2000

Luca Giovanella, Jessica Barizzi, Petra Petranović Ovčariček, Federica D’Aurizio, Luca Mazzucchelli

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Comparison of seven different enzymatic methods for serum glycated albumin in pregnant women: a multicenter study

1. Januar 2000

Dandan Sun, Zheng Cao, Mingyuan Jiao, Xiuzhi Guo, Ran Gao, Chaochao Ma, Ying Zhu, Lian Hou, Ying Meng, Meng Wang, Songlin Yu, Yicong Yin, Ling Qiu

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Objectives To evaluate the consistency of seven enzymatic glycated albumin (GA) assays in pregnant women based on a multicenter study. Methods Samples were collected from pregnant women at three different gestational stages: 4–13 weeks (n=150), 24–28 weeks (n=300, including 150 GDM subjects), and 29–40 weeks (n=300, including 150 GDM subjects), across three hospitals between July 2022 and December 2023 in China. These samples were analyzed using seven enzymatic GA methods (Lucica, Norudia, BSBE, Maccura, Meikang, Reebio, and Zybio assays). Spearman correlation analysis, Passing–Bablok regression, and Bland–Altman plots were used to evaluate the consistency between the Lucica used in our laboratory and the other selected assays. The effects of albumin concentration and gestational stage on the consistency of GA were evaluated through stratified analyses. Results The correlation coefficients between Lucica and the other six assays for GA% measurement ranged from 0.741 to 0.906 (p<0.0001), with the mean relative biases ranging from −15.5 to +6.7 %. In trimester-stratified analysis, the highest correlation coefficient was observed in the first trimester for all assays except Maccura, and the bias increased with advancing gestational age for all assays except BSBE. In albumin-stratified analysis (30–45 g/L), the correlation increased with increasing albumin concentration for all assays, while the bias decreased except for BSBE and Maccura assays. Conclusions Poor analytical consistency was observed in enzymatic GA assays for pregnant women, with discrepancies varying across gestational stages and albumin concentrations. Reference intervals for pregnant women should be established based on trimester-stratified and manufacturer-specific criteria.
Open Access
Towards a global framework of entrustable professional activities for undergraduate clinical laboratory interns: a competency-based approach

1. Januar 2000

Xiaohui Zhang, Ziyue Qin, Mengxiao Xie, Yuan Mu, Ye Jiang, Hongmei Ding, Ying Chen, Chunlei Zuo, Jing Wei, Ting Wang

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Objectives The aim of this study is to develop a core competency-based EPAs framework for undergraduate interns in the clinical laboratory. Methods The EPAs framework was developed in three stages: formation of a research team, drafting of an initial EPAs framework, and reviewing EPAs framework. This study employed a literature review and a modified Delphi method to construct EPAs. Furthermore, a preliminary validation of established EPAs framework was conducted among 23 interns and their supervisors. Results A framework encompassing 10 EPAs was developed, including: occupational exposure and protection, collection of various types of clinical specimens, reception and preprocessing of various types of clinical specimens, basic manual operations for laboratory tests, basic instrument operations for laboratory tests, judgment on the releasability of test reports, notification of critical values, laboratory quality control, interpretation of test reports, communication with clinicians and patients. Experts in the two rounds of Delphi showed high enthusiasm, authority, coordination, and concentration. Scores for each EPA indicator’s importance, familiarity, observability, universality, and accuracy were all exceeded 3.5 points, with a coefficient of variation below 0.25. Furthermore, expected confidence levels for each indicator were established at four key internship milestones. In pilot study, significant discrepancy were found between self- and director-assessments across most EPAs (p<0.05), with interns consistently rating themselves higher, particularly in complex tasks. Conclusions With its robust validity and systematic structure, this EPAs framework provides a scalable model for assessing clinical laboratory interns. It effectively enhances internship competency and promotes global standardization in clinical laboratory education.
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Use of indirect methods and machine learning algorithms for the estimation of reference intervals, taking cortisol measurements as an example

1. Januar 2000

Fatma Demet Arslan, Georg Hoffmann

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Objectives This study aims to determine reliable reference intervals (RIs) for total cortisol (TC) in adults considering the effects of both age and blood collection time, using indirect methods and machine learning approaches. Methods Serum TC results from blood samples collected between 08:00 and 10:00 am at the first outpatient visit were included in the study. Serum TC were measured using a Roche Elecsys Cortisol II kit. Estimated RIs by indirect methods with the support of R packages (refineR and reflimR) for the implementation of machine learning algorithms (mclust and rpart) were compared with the manufacturer’s reference interval (RI) (48–195 μg/L). Results Estimated RIs by refineR and reflimR (57–256 μg/L and 62–271 μg/L, respectively) were wider than the manufacturer’s RI. When reflimR was applied to Box-Cox-transformed data with the lambda value of 0.284 suggested by refineR, an RI of 57–251 μg/L was obtained, which was like that obtained with refineR. An even better match with the manufacturer’s RI was achieved using Gaussian mixture modelling with the mclust, which suggested one out of four clusters with an RI of 55.8–187 μg/L. Clustering the data with rpart suggested stratification into two age groups (≤35 and >35 years) and three blood collection periods (08:00–08:45, 08:45–09:35, and 09:35–10:00). The TC levels demonstrated the highest concentrations in the early morning (8:00–08:45) and in young adults (18–35 years). Conclusions This study highlights the necessity of considering both age and blood collection time in clinical interpretation and demonstrates the effectiveness of indirect methods and machine learning approaches in the verification of RIs for hormones with known heterogeneity.
Open Access
An isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of cortisol in human serum and plasma

1. Januar 2000

Myriam Ott, Neeraj Singh, Friederike Bauland, Daniel Köppl, Kerstin Kandler, Alexander Gaudl, Andrea Geistanger, Uta Ceglarek, Manfred Rauh, Christian Geletneky, Judith Taibon

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Objectives Accurate measurement of serum cortisol is crucial for the diagnosis and management of adrenal disorders. Thus, we have developed a novel isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedure (RMP) to quantify cortisol in human serum/plasma, offering higher sensitivity and reliability compared to existing RMPs. Methods Quantitative Nuclear Magnetic Resonance spectroscopic (qNMR) methodology has been utilized to assign the absolute content (g/g) and SI-traceability to the reference materials. A novel two-dimensional heart-cut liquid chromatography (LC) approach was implemented for the LC-MS/MS, combined with a supported liquid extraction (SLE) sample preparation protocol. A multi-day validation experiment assessed precision and accuracy. Reproducibility was assessed by comparing procedure results between two independent laboratories, and measurement uncertainty (MU) was evaluated in compliance with current guidelines. Results The established RMP exhibited high sensitivity, with a quantification range of 0.800–600 ng/mL (2.21–1,655 nmol/L), exceeding the ranges of existing JCTLM-listed RMPs. Intermediate precision was ≤2.6 %, and repeatability ranged from 0.9 to 1.9 % across all concentration levels. The relative mean bias ranged from −1.3 to 1.4 % for all matrices and concentration levels. Measurement uncertainties (MU) for cortisol in single measurements were ≤2.8 % regardless of the concentration level and sample type. Using the certified International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference panel, the equivalence between the candidate RMP and the Joint Committee on Traceability in Laboratory Medicine (JCTLM) listed RMPs (NRMeth 57 and NRMeth 8) was assessed, revealing excellent agreement. Conclusions This RMP allows for highly sensitive and reproducible determination of cortisol. The performance of the RMP facilitates the standardization of routine assays and ensures traceability in the measurement of individual patient samples.
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EFLM checklist for the assessment of AI/ML studies in laboratory medicine: enhancing general medical AI frameworks for laboratory-specific applications

1. Januar 2000

Anna Carobene, Janne Cadamuro, Glynis Frans, Hanoch Goldshmidt, Zeljiko Debeljak, Sander De Bruyne, William van Doorn, Johannes Elias, Habib Özdemir, Salomon Martin Perez, Helena Lame, Alexander Tolios, Federico Cabitza, Andrea Padoan, On behalf of the European Federation of Clinical Chemistry and Laboratory Medicine Committee on Digitalisation and Artificial Intelligence

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The integration of artificial intelligence (AI) and machine learning (ML) into laboratory medicine shows promise for advancing diagnostic, prognostic, and decision-support tools; however, routine clinical implementation remains limited and heterogeneous. Laboratory data presents unique methodological and semantic complexities – method dependency, analyte-specific variation, and contextual sensitivity-not adequately addressed by general-purpose AI reporting guidelines. To bridge this gap, the EFLM Committee on Digitalisation and Artificial Intelligence (C-AI) proposes an expanded checklist to support assessment of requirements and recommendations for the development of AI/ML models based on laboratory data. Building upon the widely adopted ChAMAI checklist (Checklist for assessment of medical AI), our proposal introduces six additional items, each grounded in the CRoss Industry Standard Process for Data Mining (CRISP-DM) framework and tailored to the specificities of laboratory workflows. These extensions address: (1) explicit documentation of laboratory data characteristics; (2) consideration of biological and analytical variability; (3) the role of metadata and peridata in contextualizing results; (4) analyte harmonization and standardization practices; (5) rigorous external validation with attention to dataset similarity; and (6) the implementation of FAIR data principles for transparency and reproducibility. Together, these recommendations aim to foster robust, interpretable, and generalizable AI systems that are fit for deployment in clinical laboratory settings. By incorporating these laboratory-aware considerations into model development pipelines, researchers and practitioners can enhance both the scientific rigor and practical applicability of AI tools. We advocate for the adoption of this extended checklist by developers, reviewers, and regulators to promote trustworthy and reproducible AI in laboratory medicine.
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Point of care testing of biochemical markers for monitoring astronauts during long duration missions in deep space

1. Januar 2000

Simona Ferraro, Sohini Sengupta, Julie Shaw, Anilkumar Dave, Maurizio Cheli, Rafael Colon, Gianvincenzo Zuccotti, Christopher E. Mason, Santica Marcovina

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Background Investigations into human performance and health status during long-duration spaceflights are ongoing aboard the International Space Station (ISS) and are critical for planning missions beyond Low Earth Orbit (LEO). This review evaluates the current evidence on point-of-care-testing (POCT) in space, discussing requirements for POCT to support astronaut health during extended deep space missions and the potential for technology transfer to terrestrial healthcare. Contents Microgravity disrupts biochemical and hormonal regulation, leading to reversible homeostatic dysregulation across multiple organ systems in astronauts during spaceflight in LEO. Missions beyond LEO may significantly increase risks of morbidity and mortality in particular for cardiovascular disease. The ability to assess key organ functions by expanding the range of detectable biomarkers on POCTs is crucial for ongoing health monitoring, urgent clinical decisions, and future mission planning. The recent implementation of high-sensitivity cardiac troponin I on POCT will be essential for early identifying myocardial injury and facilitating telemedicine support. Furthermore, the development and use of reference change values (RCV) in space environment, derived from biomarkers measured longitudinally in real-time onboard, will be crucial to differentiate clinically relevant changes in biomarkers levels from alterations induced by microgravity. This approach may overcome the use of traditional cut-off values which are assessed and generally applied under stable terrestrial conditions. Summary Clinical laboratory capabilities on the ISS are currently minimal. As missions lengthen, and extend beyond LEO, enhanced POCT is needed. Limited data on POCT performance in space highlight the importance of laboratory professionals’ involvement to ensure high-quality testing and accurate interpretation.
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Multi-cancer early detection revisited: insights and lessons from the PATHFINDER 2 study

1. Januar 2000

Giuseppe Lippi, Mario Plebani, Eric Topol

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Measuring neurofilament light in human plasma and cerebrospinal fluid: a comparison of five analytical immunoassays

1. Januar 2000

Udit Sheth, Rebecca Harrison, Kyle Ferber, Erin G. Rosenbaugh, Amanda Bevis, Rohini Khillan, Michael Benatar, Nicole L. Bjorklund, Elena Di Daniel, Glenn A. Harris, Olga I. Kahn, Yongge Liu, Henrik Zetterberg, Laura L. Mitic, Danielle Graham, Tania F. Gendron

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Objectives Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays. Methods To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS. Results Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL. Conclusions Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, usability, footprint, and intended use, should be considered.
Open Access
Impact of pneumatic tube system transport and blood collection tubes on cell-free DNA analysis of plasma samples

1. Januar 2000

Luisa Matos do Canto, Cecilie Mondrup Jacobsen, Peter H. Nissen, Johanne Andersen Højbjerg, Jonna Skov Madsen, Torben Frøstrup Hansen, Rikke Fredslund Andersen

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Objectives Transporting blood samples with pneumatic tube systems (PTSs) is routine in many hospitals. The influence of PTS transport on cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analyses has not been comprehensively tested. Methods Paired blood samples from non-patient donors and cancer patients were transported manually or by PTS at two Danish hospitals using different PTS. A g-logger evaluated the forces applied to samples in each transport method. The concentration of short and long cfDNA fragments and ctDNA markers was analyzed using droplet digital PCR (ddPCR) and compared according to transportation. Different blood collection tubes (BCTs) were also investigated. Results All transportation methods subject samples to significantly different forces. The cfDNA concentration was slightly higher in samples transported with the Sumetzberger PTS than manually. There were no differences in cfDNA, whether using EDTA or Roche BCTs transported using Tempus600 or manually. Colorectal cancer patient samples showed insignificant changes in ratio of fragment lengths when transported by PTS compared to manual transport. In metastatic cancer patients, only a minor change in long/short fragment ratio was observed in PTS-transported samples. No discrepancy in ctDNA concentration/fraction was observed in cancer patient samples. Higher yields of cfDNA were obtained from EDTA samples, but no other differences were observed among the tested BCTs. Conclusions Although PTS transport introduced minor variations in cfDNA concentrations, these did not impact ctDNA interpretation. However, as PTSs vary in design, their pre-analytical effects should be carefully assessed, particularly as ctDNA analysis becomes more widely implemented in clinical practice.
Open Access
Optimization and comparison of genomic DNA extraction from whole blood collected in PAXgene blood RNA tube using automated platforms

1. Januar 2000

Jianlan You, Tomoe Shiomi, Paul Zappile, Luis Chiriboga, Sandra Mendoza, Andre L. Moreira

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Objectives With the development of genomic technologies, the isolation of genomic DNA (gDNA) from clinical samples has become more important for both clinical diagnostics and research studies. Blood samples collected in PAXgene Blood RNA Tubes, which are typically used for RNA extraction, can be used for gDNA extraction, particularly in clinical studies when only such blood samples are available. Methods We optimized the pre-treatment of blood samples collected in PAXgene Blood RNA Tubes. For the first time, three magnetic bead-based automated platforms (QIAsymphony SP, Maxwell RSC and KingFisher Apex) were compared for gDNA extraction from these blood samples. Additionally, the effects of storage at 4 °C or freeze-thaw cycles of the blood samples on gDNA yield were investigated. High-throughput extraction in 96-well format was evaluated. Results Systematic optimization of blood sample pre-treatment shows that prolonged incubation at room temperature and/or increased centrifugation speed and time improved gDNA yield from blood samples collected in PAXgene Blood RNA Tubes. QIAsymphony SP (4.27 ± 2.19 µg) and Maxwell RSC (4.82 ± 2.96 µg) produced significantly higher gDNA yields than KingFisher Apex (1.09 ± 0.61 µg). Higher gDNA yields were obtained with shorter storage time at 4 °C or fewer freeze-thaw cycles of the blood samples. In the 96-well format extraction, gDNA yields ranged from 0.24 to 13.46 µg. Conclusions Not all magnetic bead-based automated platforms are suitable for gDNA extraction from blood samples collected in PAXgene Blood RNA Tubes. Systematic pre-treatments optimization provides guidance for routine and high-throughput workflows, and storage conditions and freeze-thaw cycles offer practical reference for biobanking.
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ROTEM-guided diagnostic pathway in a centralized Laboratory Medicine setting: an organizational report

1. Januar 2000

Monica Bovara, Margherita Scapaticci, Mario Sebastiani, Sebastiano Nigro, Marina Bioli, Maria Beatrice Rondinelli, Rita Mancini, Andrea Bartolini

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Open Access
Comparative analysis of plasma p-tau217 immunoassays: challenges for standardization and harmonization

1. Januar 2000

Burak Arslan, Johan Gobom, Ulf Andreasson, Fernando Gonzalez-Ortiz, Nicholas J. Ashton, Henrik Zetterberg, Hlin Kvartsberg

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Open Access
An isotope dilution-liquid chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of mycophenolic acid glucuronide in human serum and plasma

1. Januar 2000

Tobias Schierscher, Janik Wild, Neeraj Singh, Martina Bachmann, Julia Hoop, Friederike Bauland, Andrea Geistanger, Lorenz Risch, Christoph Seger, Judith Taibon

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Objectives A candidate reference measurement procedure (RMP) based on isotope dilution (ID) liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated to accurately measure serum and plasma concentrations of mycophenolic acid glucuronide (MPAG). Methods Quantitative nuclear magnetic resonance (qNMR) spectroscopy was utilized for determining the absolute content (mass fraction; g/g) of the reference material, thereby, establishing the traceability to SI units. Separation of MPAG from potential interferences, whether known or unknown, was accomplished by using a Phenomenex Luna C18(2) column. For sample preparation, a protocol based on protein precipitation followed by a high-dilution step was established. A multi-day validation experiment evaluated precision and accuracy. Reproducibility was determined by comparing the results of the procedure between two independent laboratories. Measurement uncertainty (MU) was assessed in accordance with current guidelines. Results The RMP demonstrated high selectivity and specificity enabling the quantification of MPAG in the range between 0.750 and 600 μg/mL. The intermediate precision and repeatability (n=60, measurements) were found to be in the range from 0.9 to 3.7 % for serum samples and from 1.2 to 4.6 % for plasma samples. The repeatability was less than 3.5 % for serum samples and less than 4.0 % for plasma samples. The relative mean bias ranged from −0.9 to 3.2 % for serum samples and from −0.3 to 2.9 % for plasma samples. The expanded measurement uncertainties (k=2) for single measurements ranged between 2.4 and 7.7 % and were further reduced performing a target value assignment (n=6) resulting in expanded measurement uncertainties between 1.8 and 3.3 % (k=2), respectively. Conclusions We herein present a new LC-MS/MS-based candidate RMP for MPAG in human serum and plasma which offers a traceable and reliable platform for the standardization of routine assays and evaluation of clinically relevant samples.

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Journal Impact Factor	3.7	2024, Journal Citation Reports (Clarivate, 2025)
5-year Journal Impact Factor	3.8	2024, Journal Citation Reports (Clarivate, 2025)
Journal Citation Indicator	1.53	2024, Journal Citation Reports (Clarivate, 2025)
CiteScore	6.9	2024, Scopus (Elsevier B.V., 2025)
SCImago Journal Rank	0.952	2024, SJR (Scimago Lab, 2025; Data Source: Scopus)
Source Normalized Impact per Paper	1.306	2024, CWTS Journal Indicators (CWTS B.V., 2025; Data Source: Scopus)

Clinical Chemistry and Laboratory Medicine (CCLM)

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