Objectives CD8 T-cells play an important role in interferon-gamma (IFN-γ) production as a host defense against tuberculosis (TB) infection. Therefore, QuantiFERON-TB Gold Plus (QFT-Plus) was developed by adding a TB2 tube beside the TB1 tube. This study aimed to compare and analyze the difference in IFN-γ production between the two tubes in general and specific populations. Content PubMed, Web of Science, and EBSCO were searched for studies reporting IFN-γ production levels in the TB1 and TB2 tubes. Statistical analysis was performed using RevMan 5.3. Summary A total of 17 studies met the inclusion criteria. The IFN-γ production in the TB2 tube was statistically higher than that in the TB1 tube (mean difference (MD)=0.02, 95 % confidence interval (95 % CI): 0.01–0.03). Further subgroup analysis in specific populations revealed that the MD of IFN-γ production between the TB2 and TB1 tubes was significantly higher in active TB subjects than in latent TB infection (LTBI) subjects (MD=1.13, 95 % CI: 0.49–1.77, and MD=0.30, 95 % CI: 0.00–0.60, respectively). A similar finding was found in immune-mediated inflammatory disease subjects, but not statistically significant. Interestingly, IFN-γ production capacity was lower in active TB subjects than in LTBI subjects in each of the TB1 and TB2 tubes. Outlook This study is the first to systematically compare IFN-γ production between the TB1 and TB2 tubes. The IFN-γ production was higher in the TB2 tube than in the TB1 tube, representing the host’s CD8 T-cell response magnitude to TB infection.

Publicly Available June 19, 2023

Review on adherence of the literature to official recommendations on albuminuria harmonization and standardization

Michele Mussap, Morena Sortino, Elena Monteverde, Rossella Tomaiuolo, Giuseppe Banfi, Massimo Locatelli, Anna Carobene

Page range: 2076-2083

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Abstract

Albuminuria standardization is a key issue to produce reliable and equivalent results between laboratories. We investigated whether official recommendations on albuminuria harmonization are followed in the literature. The PubMed database was searched from June 1 to September 26, 2021. The search terms included urine albumin, urine albumin-to-creatinine ratio (uACR), and albuminuria. A total of 159 articles were considered eligible; 50.9 % reported the type of urine collection. Specifically, 58.1 % collected a random spot urine specimen, 21 % collected a first morning void, and 6.2 % collected a 24-h specimen. Overall, 15 % of articles reported data on sample shipping, storage, and centrifugation and 13.3 % mentioned the preanalytical phase without any data on albuminuria. The method for albuminuria was properly described in 31.4 % of articles; of these, 54.9 % used immunological methods, and 8.9 % contained errors or missing data. Most articles (76.7 %) expressed test results as albuminuria-to-creatininuria ratio. Different decision levels were utilized in 130 articles; of these, 36 % used a decision level of ≤30 mg/g creatininuria and 23.7 % used three decision levels (≤30, 30–300, and ≥300 mg/g). The failure to follow guidelines on albuminuria harmonization was mainly found in the preanalytical phase. The poor awareness of the importance of preanalytical steps on test result may be a possible explanation.

Opinion Paper

August 4, 2023

The total testing process harmonization: the case study of SARS-CoV-2 serological tests

Alessandra Colombini, Carla Divieto, Rossella Tomaiuolo, Leonardo Mortati, Jessica Petiti, Chiara Di Resta, Giuseppe Banfi

Page range: 2084-2093

Abstract

The total testing process harmonization is central to laboratory medicine, leading to the laboratory test’s effectiveness. In this opinion paper the five phases of the TTP are analyzed, describing, and summarizing the critical issues that emerged in each phase of the TTP with the SARS-CoV-2 serological tests that have affected their effectiveness. Testing and screening the population was essential for defining seropositivity and, thus, driving public health policies in the management of the COVID-19 pandemic. However, the many differences in terminology, the unit of measurement, reference ranges and parameters for interpreting results make analytical results difficult to compare, leading to the general confusion that affects or completely precludes the comparability of data. Starting from these considerations related to SARS-CoV-2 serological tests, through interdisciplinary work, the authors have highlighted the most critical points and formulated proposals to make total testing process harmonization effective, positively impacting the diagnostic effectiveness of laboratory tests.

IFCC Paper

Publicly Available June 19, 2023

Quality standards and internal quality control practices in medical laboratories: an IFCC global survey of member societies

Sarah E. Wheeler, Ivan M. Blasutig, Pradeep Kumar Dabla, Jean-Marc Giannoli, Anne Vassault, Ji Lin, Kandace A. Cendejas, Armand Perret-Liaudet, Renze Bais, Annette Thomas, Egon P. Amann, Qing H. Meng

Page range: 2094-2101

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Abstract

Objectives The trueness and precision of clinical laboratory results are ensured through total quality management systems (TQM), which primarily include internal quality control (IQC) practices. However, quality practices vary globally. To understand the current global state of IQC practice and IQC management in relation to TQM the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Global Laboratory Quality (TF-GLQ) conducted a survey of IFCC member countries on IQC practices and management. Methods The survey included 16 questions regarding IQC and laboratory TQM practices and was distributed to IFCC full and affiliate member countries (n=110). A total of 46 (41.8 %) responses were received from all regions except North America. Results Of the responding countries, 78.3 % (n=36) had legislative regulations or accreditation requirements governing medical laboratory quality standards. However, implementation was not mandatory in 46.7 % (n=21) of responding countries. IQC practices varied considerably with 57.1 % (n=28) of respondents indicating that they run 2 levels of IQC, 66.7 % (n=24) indicating they run IQC every 24 h and 66.7 % (n=28) using assay manufacturer IQC material sources. Only 29.3 % (n=12) of respondents indicated that every medical laboratory in their country has written IQC policies and procedures. By contrast, 97.6 % (n=40) of responding countries indicated they take corrective action and result remediation in the event of IQC failure. Conclusions The variability in TQM and IQC practices highlights the need for more formal programs and education to standardize and improve TQM in medical laboratories.

Guidelines and Recommendations

Open Access June 14, 2023

Toolkit for emerging technologies in laboratory medicine

Ronda Greaves, Larry Kricka, Damien Gruson, Maurizio Ferrari, Helen Martin, Tze Ping Loh, Sergio Bernardini, on behalf of the IFCC Emerging Technologies Division

Page range: 2102-2114

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Abstract

An emerging technology (ET) for laboratory medicine can be defined as an analytical method (including biomarkers ) or device ( software, applications, and algorithms) that by its stage of development, translation into broad routine clinical practice, or geographical adoption and implementation has the potential to add value to clinical diagnostics. Considering the laboratory medicine-specific definition, this document examines eight key tools, encompassing clinical, analytical, operational, and financial aspects, used throughout the life cycle of ET implementation. The tools provide a systematic approach starting with identifying the unmet need or identifying opportunities for improvement (Tool 1), forecasting (Tool 2), technology readiness assessment (Tool 3), health technology assessment (Tool 4), organizational impact map (Tool 5), change management (Tool 6), total pathway to method evaluation checklist (Tool 7), and green procurement (Tool 8). Whilst there are differences in clinical priorities between different settings, the use of this set of tools will help support the overall quality and sustainability of the emerging technology implementation.

July 24, 2023

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 I: Update on laboratory tests for the study of monoclonal gammopathies

María C. Cárdenas, Ramón García-Sanz, Noemí Puig, David Pérez-Surribas, Juan Flores-Montero, María Ortiz-Espejo, Javier de la Rubia, Elena Cruz-Iglesias

Page range: 2115-2130

Abstract

Monoclonal gammopathies (MG) are characterized by the proliferation of plasma cells that produce identical abnormal immunoglobulins (intact or some of their subunits). This abnormal immunoglobulin component is called monoclonal protein (M-protein), and is considered a biomarker of proliferative activity. The identification, characterization and measurement of M-protein is essential for the management of MG. We conducted a systematic review of the different tests and measurement methods used in the clinical laboratory for the study of M-protein in serum and urine, the biochemistry and hematology tests necessary for clinical evaluation, and studies in bone marrow, peripheral blood and other tissues. This review included literature published between 2009 and 2022. The paper discusses the main methodological characteristics and limitations, as well as the purpose and clinical value of the different tests used in the diagnosis, prognosis, monitoring and assessment of treatment response in MG. Included are methods for the study of M-protein, namely electrophoresis, measurement of immunoglobulin levels, serum free light chains, immunoglobulin heavy chain/light chain pairs, and mass spectrometry, and for the bone marrow examination, morphological analysis, cytogenetics, molecular techniques, and multiparameter flow cytometry.

July 4, 2023

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 II: Methodological and clinical recommendations for the diagnosis and follow-up of monoclonal gammopathies

María C. Cárdenas, Ramón García-Sanz, Noemí Puig, David Pérez-Surribas, Juan Flores-Montero, María Ortiz-Espejo, Javier De la Rubia, Elena Cruz-Iglesias

Page range: 2131-2142

Abstract

Monoclonal gammopathies (MG) are a group of clinical entities characterized by the clonal expansion of monoclonal immunoglobulin (M-protein) secreting plasma cells (PC). This document presents the consensus recommendations of the Spanish Society of Laboratory Medicine (SEQC ML ) and the Spanish Society of Hematology and Hemotherapy (SEHH) for the study of MG. The recommendations were established based on scientific evidence and the opinion of experts in MG from the clinical laboratory and clinical hematology fields. Recommendations are proposed for the diagnosis of MG and for patient follow-up according to the type of MG and whether or not the patient is undergoing treatment, and to monitor the disease stability, response to therapy and disease progression. With respect to the diagnosis, we describe the most recent criteria and classification established by the International Myeloma Working Group (IMWG) for multiple myeloma (MM), smoldering MM, monoclonal gammopathy of undermined significance (MGUS) and other related entities. Indications are given about the analytical requirements and application of the different serum and urine laboratory tests (study, detection, identification and measurement of M-protein) and the bone marrow study. Recommendations on the clinical laboratory results report model are established to harmonize and ensure that all relevant information is available, including its content, expression, and interpretive comments.

Genetics and Molecular Diagnostics

Publicly Available June 15, 2023

The MBL2 genotype relates to COVID-19 severity and may help to select the optimal therapy

Filippo Scialò, Gustavo Cernera, Speranza Esposito, Biagio Pinchera, Ivan Gentile, Marina Di Domenico, Andrea Bianco, Lucio Pastore, Felice Amato, Giuseppe Castaldo

Page range: 2143-2149

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Abstract

Objectives Sars-CoV-2 acute infection is clinically heterogeneous, ranging from asymptomatic cases to patients with a severe, systemic clinical course. Among the involved factors age and preexisting morbidities play a major role; genetic host susceptibility contributes to modulating the clinical expression and outcome of the disease. Mannose-binding lectin is an acute-phase protein that activates the lectin-complement pathway, promotes opsonophagocytosis and modulates inflammation, and is involved in several bacterial and viral infections in humans. Understanding its role in Sars-CoV-2 infection could help select a better therapy. Methods We studied MBL2 haplotypes in 419 patients with acute COVID-19 in comparison to the general population and related the haplotypes to clinical and laboratory markers of severity. Results We recorded an enhanced frequency of MBL2 null alleles in patients with severe acute COVID-19. The homozygous null genotypes were significantly more frequent in patients with advanced WHO score 4–7 (OR of about 4) and related to more severe inflammation, neutrophilia, and lymphopenia. Conclusions Subjects with a defective MBL2 genotype (i.e., 0/0) are predisposed to a more severe acute Sars-CoV-2 infection; they may benefit from early replacement therapy with recombinant MBL. Furthermore, a subset of subjects with the A/A MBL genotype develop a relevant increase of serum MBL during the early phases of the disease and develop a more severe pulmonary disease; in these patients, the targeting of the complement may help. Therefore, COVID-19 patients should be tested at hospitalization with serum MBL analysis and MBL2 genotype, to define the optimal therapy.

General Clinical Chemistry and Laboratory Medicine

Open Access July 7, 2023

The stability of C-peptide and insulin in plasma and serum samples under different storage conditions

Delhia X. Nkuna, Siyabonga P. Khoza, Jaya A. George, Mpho R. Maphayi

Page range: 2150-2158

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Abstract

Objectives C-peptide and insulin are peptide hormones and their stability is affected by a number of pre-analytical factors. The study aimed to investigate the impact of sample type, storage temperature and time delays before centrifugation and analysis on the stability of C-peptide and insulin. Methods Ten healthy non-diabetic adults in fasting and non-fasting state were enrolled. 40 mL of blood was collected from each participant into SST and dipotassium EDTA tubes. Samples were centrifuged immediately or at timed intervals (8, 12, 48 and 72 h). After baseline measurements on the Roche Cobas e602 analyzer using electrochemiluminescence immunoassays, aliquots were stored at room temperature (RT), 2–8 and −20 °C for 4 h to 30 days. The percentage deviation (PD) from baseline was calculated and a change greater than desirable biological variation total error was considered clinically significant. Results C-peptide was more stable in separated serum than plasma (PD of −5 vs. −13 %) samples stored at 2–8 °C for 7 days and was most unstable at RT when centrifugation was delayed (PD −46 % in plasma and −74 % in serum after 48 h). Insulin was more stable in plasma than in serum under the different storage conditions with a minimum PD of −1% when stored at −20 °C for 30 days. When samples were kept unspun at RT for 72 h, PD was −23 and −80 % in plasma and serum, respectively. Conclusions C-peptide was more stable in serum provided the sample was centrifuged immediately and stored in the fridge or freezer while insulin was found to be more stable in EDTA plasma.

Open Access June 14, 2023

Self-sampling of blood using a topper and pediatric tubes; a prospective feasibility study for PSA analysis using 120 prostate cancer patients

Nicas van den Brink, Rixt Even, Enver Delic, Sarah van Hellenberg Hubar-Fisher, Huub H. van Rossum

Page range: 2159-2166

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Abstract

Objectives Self-collection of blood for diagnostic purposes by blood collection assist devices (BCAD) has gained a lot of momentum. Nonetheless, there are a lack of studies demonstrating the feasibility and reliability of self-collecting capillary blood for routine (immuno)chemistry testing. In this study we describe the topper technology together with pediatric tubes to enable self-collection of blood and investigated its feasibility for PSA testing by prostate cancer patients. Methods A total of 120 prostate cancer patients for which a routine follow-up PSA test was requested, were included in this study. Patients received instruction materials and the blood-collection device consisting of a topper, pediatric tube and base-part, and performed the blood collection procedure themselves. Afterwards a questionnaire was filled-in. Finally, PSA was measured on a Roche Cobas Pro. Results The overall self-sampling success rate was 86.7 %. Furthermore, when specified per age category, a 94.7 % success rate for patients under 70 years and a 25 % success rate for patients of 80 years and older was observed. Venous and self-collected PSA were highly comparable when analyzed by Passing–Bablok regression with a slope of 0.99 and intercept of 0.00011, Spearmans correlation coefficient (0.998) and average self-collected PSA recovery of 99.8 %. Conclusions Evidence is presented that self-collected capillary blood by topper and pediatric tube from the finger is feasible, particularly for patients under 70 years. Furthermore, capillary blood self-sampling did not compromise any of the PSA test results. Future validation in a real-world setting, without supervision and including sample stability and logistics, is required.

Open Access July 4, 2023

Albumin determined by bromocresol green leads to erroneous results in routine evaluation of patients with chronic kidney disease

Marith van Schrojenstein Lantman, Anne-Els van de Logt, Elma Prudon-Rosmulder, Marloes Langelaan, Ayşe Y. Demir, Steef Kurstjens, Armando van der Horst, Aldy Kuypers, Aram Greuter, Jenny Kootstra-Ros, Eline van der Hagen, Marlies Oostendorp, Roseri de Beer, Christian Ramakers, Dirk Bakkeren, Fokke Lindeboom, Dennis van de Wijngaart, Marc Thelen, Jack Wetzels, Miranda van Berkel

Page range: 2167-2177

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Abstract

Objectives Measurement of plasma albumin is pivotal for clinical decision-making in patients with chronic kidney disease (CKD). Routinely used methods as bromocresol green (BCG) and bromocresol purple (BCP) can suffer from aselectivity, but the impact of aselectivity on the accuracy of plasma albumin results of CKD-patients is still unknown. Therefore, we evaluated the performance of BCG-, BCP- and JCTLM-endorsed immunological methods in patients with various stages of CKD. Methods We evaluated the performance of commonly used albumin methods in patients with CKD stages G1 through G5, the latter divided in two groups based on whether they received hemodialysis treatment. In total, 163 patient plasma samples were measured at 14 laboratories, on six different BCG and BCP-platforms, and four different immunological platforms. The results were compared with an ERM-DA-470k-corrected nephelometric assay. The implications on outcome is evaluated by the proportion of patient results <38 g/L for the diagnosis of protein energy wasting. Results Albumin results determined with BCP- and immunological methods showed the best agreement with the target value (92.7 and 86.2 %, respectively vs. 66.7 % for BCG, namely due to overestimation). The relative agreement of each method with the target value was platform-dependent, with larger variability in agreement between platforms noted for BCG and immunological methods (3.2–4.6 and 2.6–5.3 %) as opposed to BCP (0.7–1.5 %). The stage of CKD had similar effects on the variability in agreement for the three method-groups (0.6–1.8 % vs. 0.7–1.5 % vs. 0.4–1.6 %). The differences between methods cause discrepancies in clinical decision-making, as structurally fewer patients were diagnosed with protein energy wasting upon using BCG-based albumin results. Conclusions Our study shows that BCP is fit for the intended use to measure plasma albumin levels in CKD patients from all stages, including patients on hemodialysis. In contrast, most BCG-based platforms falsely overestimate the plasma albumin concentration.

July 19, 2023

Uncertainty in measurement and the renal tubular reabsorption of phosphate

Ian Farrance, Robert Frenkel, Kay Weng Choy

Page range: 2178-2185

Abstract

Objectives The ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate transport. TmP/GFR is most probably calculated using the formula described by Kenny and Glen or obtained from the nomogram described by Walton and Bijvoet. Even though the calculation itself is well described, no attention has been given to its measurement uncertainty (MU). The aim of this study is to provide a procedure for evaluating the MU of the Kenny and Glen formula; a procedure which is based on the Evaluation of measurement data – Guide to the expression of uncertainty in measurement (GUM). Methods TmP/GFR is a quantity value calculated from the input of measured values for serum (plasma) phosphate and creatinine, plus measured values of urine phosphate and creatinine. Given the measurement uncertainty associated with these input quantities, the GUM describes the mathematical procedures required to determine the uncertainty of the calculated TmP/GFR. From a medical laboratory perspective, these input uncertainties are the standard deviations of the respective internal quality control estimates for serum and urine phosphate, plus serum and urine creatinine. Results Based on representative measurements for the input quantities and their associated standard uncertainties, the expanded relative uncertainty for a calculated TmP/GFR is approximately 3.0–4.5 %. Conclusions With the continued relevance of the TmP/GFR procedure and the use of creatinine clearance as an estimate of GFR, the addition of an uncertainty estimate is important as an adjunct to this diagnostic procedure.

June 22, 2023

Urine transfer devices may impact urinary particle results: a pre-analytical study

Nathan Debunne, Joris Delanghe, Leen Raman, Matthijs Oyaert

Page range: 2186-2194

Abstract

Objectives Well-standardized procedures in the pre-analytical phase of urine diagnostics is of utmost importance to obtain reliable results. We investigated the effect of different urine collection methods and the associated urine transfer tubes on urine test strip and particle results. Methods In total, 146 selected urine samples were subdivided into three different collection containers and subsequently transferred into its accompanying transfer tube (BD, Greiner, Sarstedt vacuum and Sarstedt aspiration). As reference, the original urine sample was directly measured on the analyser. Both chemical test strip analysis (Sysmex UC-3500) and fluorescence flow cytometry particle analysis (Sysmex UF-5000) were performed on all samples. Results No statistically significant differences in test strip results were found between the studied transfer methods. On the contrary, transfer of urine samples to the secondary tubes affected their particle counts. Clinically significant reductions in counts of renal tubular epithelial cells and hyaline casts were observed using the BD and Greiner transfer tubes and in counts of pathological casts using the BD, Greiner and Sarstedt vacuum tubes. Conclusions The results of this study indicate that the use of urine transfer tubes may impact counts of fragile urine particles. Clinical laboratories need to be aware about the variation that urine collection methods can induce on urine particle counts.

Open Access July 24, 2023

Analytical and clinical validation of a blood progranulin ELISA in frontotemporal dementias

Francisco Meda, Joel Simrén, Barbara Borroni, Valentina Cantoni, Silvana Archetti, Giorgio Biasiotto, Ulf Andreasson, Kaj Blennow, Hlin Kvartsberg, Henrik Zetterberg

Page range: 2195-2204

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Abstract

Objectives Heterozygous mutations in the granulin ( GRN ) gene may result in haploinsufficiency of progranulin (PGRN), which might lead to frontotemporal dementia (FTD). In this study, we aimed to perform analytical and clinical validation of a commercial progranulin kit for clinical use. Methods Analytical validation parameters including assay precision, selectivity, measurement range, dilution linearity, interferences and sample stability were tested according to previously described procedures. For clinical validation, PGRN levels were measured in plasma from 32 cognitively healthy individuals, 52 confirmed GRN mutation carriers, 25 C9orf72 mutation carriers and 216 patients with different neurodegenerative diseases of which 70 were confirmed as non-mutation carriers. Results Among the analytical validation parameters, assay precision and repeatability were very stable (coefficients of variation <7 %). Spike recovery was 96 %, the measurement range was 6.25–400 μg/L and dilution linearity ranged from 1:50–1:200. Hemolysis did not interfere with progranulin levels, and these were resistant to freeze/thaw cycles and storage at different temperatures. For the clinical validation, the assay was capable of distinguishing GRN mutation carriers from controls and non- GRN mutation carriers with very good sensitivity and specificity at a cut-off of 57 μg/L (97 %, 100 %, respectively). Conclusions In this study, we demonstrate robust analytical and diagnostic performance of this commercial progranulin kit for implementation in clinical laboratory practice. This easy-to-use test allows identification of potential GRN mutation carriers, which may guide further evaluation of the patient. This assay might also be used to evaluate the effect of novel PGRN-targeting drugs and therapies.

June 28, 2023

Early changes in S100B maternal blood levels can predict fetal intrauterine growth restriction

Laura Abella, Ebe D’Adamo, Mariachiara Strozzi, Valentina Botondi, Ernesto Abella, Maurizio Cassinari, Laura Mazzucco, Antonio Maconi, Michela Testa, Cristian Zanelli, Roberta Patacchiola, Michela Librandi, Jacopo Osmelli, Maura Carabotta, Francesco Chiarelli, Diego Gazzolo

Page range: 2205-2211

Abstract

Objectives Intrauterine growth restriction (IUGR) represents one of the main causes of perinatal mortality and morbidity. Nowadays, IUGR early diagnosis is mandatory in order to limit the occurrence of multiorgan failure, especially the brain. Therefore, we investigated whether longitudinal S100B assessment in maternal blood could be a trustable predictor of IUGR. Methods We conducted a prospective study in 480 pregnancies (IUGR: n=40; small for gestational age, SGA: n=40; controls: n=400) in whom S100B was measured at three predetermined monitoring time-points (T1: 8–18 GA; T2: 19–23 GA; T3: 24–28 GA). Results Lower S100B in IUGR fetuses than SGA and controls (p<0.05, for all) at T1–T3. Receiver operating characteristic curve showed that S100B at T1 was the best predictor of IUGR (sensitivity: 100 %; specificity: 81.4 %) than T2, T3. Conclusions The early lower S100B concentration in pregnant women lately complicated by IUGR support the notion that non-invasive early IUGR diagnosis and monitoring is becoming feasible. Results open the way to further studies aimed at diagnosing and monitoring fetal/maternal diseases at earliest time.

Reference Values and Biological Variations

Open Access June 28, 2023

Interpreting two TSH results from the same patient

Arne Åsberg, Gustav Mikkelsen

Page range: 2212-2215

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Abstract

Objectives When the patient’s mean (setpoint) concentration of an analyte is unknown and the physician tries to judge the clinical condition from the analyte concentration in two separate specimens taken a time apart, we believe that the two values should be judged against a bivariate reference interval derived from clinically healthy and stable individuals, rather than using univariate reference limits and comparing the difference between the values against reference change values (RCVs). In this work we compared the two models, using s-TSH as an example. Methods We simulated two s-TSH measurement values for 100,000 euthyreot subjects, and plotted the second value against the first, along with a markup of the central 50, 60, 70, 80, 90, and 95 % of the bivariate distribution, in addition to the 2.5 and 97.5 percentile univariate reference limits and the 2.5 and 97.5 percentile RCVs. We also estimated the diagnostic accuracy of the combination of the 2.5 and 97.5 univariate percentile reference limits and the 2.5 and 97.5 percentile RCVs against the central 95 % of the bivariate distribution. Results Graphically, the combination of the 2.5 and 97.5 univariate reference limits and the 2.5 and 97.5 percentile RCVs did not accurately delineate the central 95 % of the bivariate distribution. Numerically, the sensitivity and specificity of the combination were 80.2 and 92.2 %, respectively. Conclusions The concentrations of s-TSH measured in two samples taken at separate times from a clinically healthy and stable individual cannot be accurately interpreted using the combination of univariate reference limits and RCVs.

Cancer Diagnostics

July 3, 2023

Integrated plasma and exosome long noncoding RNA profiling is promising for diagnosing non-small cell lung cancer

Na Wang, Cong Yao, Changliang Luo, Shaoping Liu, Long Wu, Weidong Hu, Qian Zhang, Yuan Rong, Chunhui Yuan, Fubing Wang

Page range: 2216-2228

Abstract

Objectives Non-small cell lung cancer (NSCLC) accounts for more than 80 % of all lung cancers, and its 5-year survival rate can be greatly improved by early diagnosis. However, early diagnosis remains elusive because of the lack of effective biomarkers. In this study, we aimed to develop an effective diagnostic model for NSCLC based on a combination of circulating biomarkers. Methods Tissue-deregulated long noncoding RNAs (lncRNAs) in NSCLC were identified in datasets retrieved from the Gene Expression Omnibus (GEO, n=727) and The Cancer Genome Atlas (TCGA, n=1,135) databases, and their differential expression was verified in paired local plasma and exosome samples from NSCLC patients. Subsequently, LASSO regression was used to screen for biomarkers in a large clinical population, and a logistic regression model was used to establish a multi-marker diagnostic model. The area under the receiver operating characteristic (ROC) curve (AUC), calibration plots, decision curve analysis (DCA), clinical impact curves, and integrated discrimination improvement (IDI) were used to evaluate the efficiency of the diagnostic model. Results Three lncRNAs-PGM5-AS1, SFTA1P, and CTA-384D8.35 were consistently expressed in online tissue datasets, plasma, and exosomes from local patients. LASSO regression identified nine variables (Plasma CTA-384D8.35, Plasma PGM5-AS1, Exosome CTA-384D8.35, Exosome PGM5-AS1, Exosome SFTA1P, Log10CEA, Log10CA125, SCC, and NSE) in clinical samples that were eventually included in the multi-marker diagnostic model. Logistic regression analysis revealed that Plasma CTA-384D8.35, exosome SFTA1P, Log10CEA, Exosome CTA-384D8.35, SCC, and NSE were independent risk factors for NSCLC (p<0.01), and their results were visualized using a nomogram to obtain personalized prediction outcomes. The constructed diagnostic model demonstrated good NSCLC prediction ability in both the training and validation sets (AUC=0.97). Conclusions In summary, the constructed circulating lncRNA-based diagnostic model has good NSCLC prediction ability in clinical samples and provides a potential diagnostic tool for NSCLC.

Open Access July 13, 2023

Diagnostic accuracy of extended HPV DNA genotyping and its application for risk-based cervical cancer screening strategy

Hongyu Xie, Xuan Rao, Junyan Li, Lifang Yao, Ying Ji, Juan Zhang, Hui Wang, Xinyu Wang, Xiao Li

Page range: 2229-2236

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Abstract

Objectives To evaluate the consistency of 14 high-risk HPVs (hr-HPVs) detection between extended HPV DNA genotyping and a well-validated partial HPV genotyping kit, and to explore the diagnostic accuracy of risk stratification strategy based on extended HPV genotyping for cervical cancer (CC) screening. Methods Baseline data from a clinical trial of recombinant HPV 9-valent vaccine in China was analyzed. All enrolled women aged 20–45 years received cervical cytology, HPV detection by extended and partial HPV genotyping kits. Those who met the indications would further receive colposcopy. The primary endpoints were cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+). Results A total of 8,000 women were enrolled between April 2020 and July 2020 and 83/33 cases were diagnosed as CIN2+/CIN3+. The overall agreement between the extended and partial HPV genotyping was 92.66 %. And the agreement further increased with the progression of lesions, which lead to similarly high sensitivity and negative predictive value of these kits. A stratified triage strategy of CC screening was constructed based on the immediate CIN2+/CIN3+ risk of specific HPV. Compared with the conventional HPV primary CC screening strategy, the risk-based strategy had higher specificity for CIN (CIN2+: 94.84 vs. 92.46 %, CIN3+: 96.05 vs. 91.92 %), and needed fewer colposcopies for detecting one cervical disease. Conclusions Extended HPV genotyping had good agreement with a well-validated partial HPV genotyping CC primary screening kit in hr-HPV detection. Extended HPV genotyping could facilitate risk-based stratified management strategy and improve the diagnostic accuracy of primary CC screening.

Infectious Diseases

Publicly Available June 29, 2023

Performance evaluation of SARS-CoV-2 antigen detection in the post-pandemic era: multi-laboratory assessment

Yuqing Chen, Lei Feng, Yanxi Han, Zihong Zhao, Zhenli Diao, Tao Huang, Yu Ma, Wanyu Feng, Jing Li, Ziqiang Li, Cong Liu, Lu Chang, Jinming Li, Rui Zhang

Page range: 2237-2247

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Abstract

Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen detection is an indispensable tool for epidemic surveillance in the post-pandemic era. Faced with irregular performance, a comprehensive external quality assessment (EQA) scheme was conducted by the National Center for Clinical Laboratories (NCCL) to evaluate the analytical performance and status of SARS-CoV-2 antigen tests. Methods The EQA panel included ten lyophilized samples containing serial 5-fold dilutions of inactivated SARS-CoV-2-positive supernatants of the Omicron BA.1 and BA.5 strains and negative samples, which were classified into “validating” samples and “educational” samples. Data were analyzed according to qualitative results for each sample. Results A total of 339 laboratories in China participated in this EQA scheme, and 378 effective results were collected. All validating samples were correctly reported by 90.56 % (307/339) of the participants and 90.21 % (341/378) of the datasets. The positive percent agreement (PPA) was >99 % for samples with concentrations of 2 × 10 7 copies/mL but was 92.20 % (697/756) for 4 × 10 6 copies/mL and 25.26 % (382/1,512) for 8 × 10 5 copies/mL samples. Colloidal gold was the most frequently used (84.66 %, 320/378) but showed the lowest PPAs (57.11 %, 1,462/2,560) for positive samples compared with fluorescence immunochromatography (90 %, 36/40) and latex chromatography (79.01 %, 335/424). Among 11 assays used in more than 10 clinical laboratories, ACON showed a higher sensitivity than other assays. Conclusions The EQA study can help to validate whether it’s necessary to update antigen detection assays for manufacturers and provide participants with information about the performance of assays to take the first step toward routine post-market surveillance.

July 3, 2023

Serum sPD-L1 levels are elevated in patients with viral diseases, bacterial sepsis or in patients with impaired renal function compared to healthy blood donors

Lorin Loacker, Alexander Egger, Vilmos Fux, Rosa Bellmann-Weiler, Günter Weiss, Andrea Griesmacher, Gregor Hoermann, Franz Ratzinger, Helmuth Haslacher, Hubert Schrezenmeier, Markus Anliker

Page range: 2248-2255

Abstract

Objectives Immune checkpoints play an important role in maintaining the balance of the immune system and in the development of autoimmune diseases. A central checkpoint molecule is the programmed cell death protein 1 (PD-1, CD279) which is typically located on the surface of T cells. Its primary ligand PD-L1 is expressed on antigen presenting cells and on cancer cells. Several variants of PD-L1 exist, among these soluble molecules (sPD-L1) present in serum at low concentrations. sPD-L1 was found elevated in cancer and several other diseases. sPD-L1 in infectious diseases has received relatively little attention so far and is therefore subject of this study. Methods sPD-L1 serum levels were determined in 170 patients with viral infections (influenza, varicella, measles, Dengue fever, SARS-CoV2) or bacterial sepsis by ELISA and compared to the levels obtained in 11 healthy controls. Results Patients with viral infections and bacterial sepsis generally show significantly higher sPD-L1 serum levels compared to healthy donors, except for varicella samples where results do not reach significance. sPD-L1 is increased in patients with impaired renal function compared to those with normal renal function, and sPD-L1 correlates significantly with serum creatinine. Among sepsis patients with normal renal function, sPD-L1 serum levels are significantly higher in Gram-negative sepsis compared to Gram-positive sepsis. In addition, in sepsis patients with impaired renal function, sPD-L1 correlates positively with ferritin and negatively with transferrin. Conclusions sPD-L1 serum levels are significantly elevated in patients with sepsis, influenza, mesasles, Dengue fever or SARS-CoV2. Highest levels are detectable in patients with measles and Dengue fever. Also impaired renal function causes an increase in levels of sPD-L1. As a consequence, renal function has to be taken into account in the interpretation of sPD-L1 levels in patients.

Letters to the Editor

Publicly Available June 29, 2023

Results of the first survey of the EFLM Task Force Preparation of Labs for Emergencies (TF-PLE)

Giuseppe Lippi, Janne Cadamuro, Elisa Danese, Emmanuel J. Favaloro, Julien Favresse, Brandon M. Henry, Snežana Jovičić, Tomris Ozben, Mario Plebani, Jecko Thachil

Page range: e235-e238

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June 21, 2023

Thrombocytopenia and hyperinflammation are induced by extracellular histones circulating in blood

Rosaria Vincenza Giglio, Daniela Ligi, Chiara Della Franca, Bruna Lo Sasso, Julia Zulema Rivas, Luisa Agnello, Ferdinando Mannello, Marcello Ciaccio

Page range: e239-e243

June 21, 2023

Bilirubin color interference on prothrombin time and activated partial thromboplastin time tests assessed in patients with liver disease

Erica Scalambrino, Elena M. Faioni, Marigrazia Clerici, Ilaria Avarello, Marco Capecchi, Samantha Pasca, Armando Tripodi

Page range: e244-e247

June 15, 2023

Laboratory response to paradigm change in hemophilia treatment

How to monitor patients simultaneously treated with emicizumab and Factor VIII concentrate?

Marjan Shafaati Lambert, Maria Bruzelius, Nida Mahmoud Hourani Soutari, Susanna Ranta, Jovan P. Antovic

Page range: e248-e250

June 12, 2023

MALDI-ISD mass spectrometry analysis as a simple and reliable tool to detect post-translational modifications of hemoglobin variants: the case of Hb Raleigh

Selene De Benedittis, Patrizia Spadafora, Marco Gaspari, Gabriele Qualtieri, Olivier Gallo, Gemma Di Palma, Francesca Cavalcanti, Luigi Citrigno, Antonio Qualtieri

Page range: e251-e254

June 9, 2023

Method validation for a greener approach to the quantification of 25-hydroxy vitamin D3 in patient serum using supported liquid extraction and liquid chromatography-tandem mass spectrometry

Gavin Turrell, Thilini Thrimawithana, Catherine Itsiopoulos, Ronda F. Greaves, Rosita Zakaria

Page range: e255-e258

June 14, 2023

Interest of minigene splicing reporter assay in familial hypobetalipoproteinemia genetic diagnosis: the example of the missense mutation APOB c.1468C>T

Zoé Henry, Alexandre Janin, Séverine Nony, Oriane Marmontel, Bertrand Cariou, Marie Marrec, Cyrielle Caussy, Sybil Charrière, Philippe Moulin, Jennifer Rieusset, Frédéric Perros, Mathilde Di Filippo

Page range: e259-e262

June 19, 2023

Laboratory medicine unveiling an unusual cause of D-lactic acidosis as the trigger of decompensation of a rare inborn error of metabolism

Charles R. Lefèvre, Elise Sacaze, Léna Damaj, Paul Rollier, Marie Lenski, Camille Le Stradic, Claude Bendavid, Pascal Reynier, Xavier Dieu, Delphine Prunier, Caroline Moreau, Chadi Homedan

Page range: e263-e267

About this journal

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

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Topics

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

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

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