Volume 61, Issue 5 - 60 Years of CCLM — Special Anniversary Issue

Quality in laboratory medicine is defined as “an unfinished journey”, as the more essential the laboratory information provided, the more assured its quality should be. In the past decades, the Journal Clinical Chemistry and Laboratory Medicine has provided a valuable forum for garnering new insights into the analytical and extra-analytical phases of the testing cycle, and for debating crucial aspects of quality in clinical laboratories. The impressive number of papers published in the Journal is testimony to the efforts made by laboratory professionals, national and international scientific societies and federations in the quest to continuously improve upon the pre-, intra- and post-analytical steps of the testing cycle, thus enhancing the quality of laboratory information. The paper appearing in this special issue summarizes the most important and interesting contributions published in the Journal , thus updating our knowledge on quality in laboratory medicine and offering further stimuli to identify the most valuable measures of quality in clinical laboratories.

The analytical quality of the clinical laboratory results has shown a significant improvement over the past decades, thanks to the joint efforts of different stakeholders, while the comparability among the results produced by different laboratories and methods still presents some critical issues. During these years, Clinical Chemistry and Laboratory Medicine ( CCLM ) published several papers on the harmonization issue over all steps in the Total Testing Process, training an important number of laboratory professionals in evaluating and monitoring all the criticisms inherent to the pre-analytical, as well as analytical and post analytical phases: from the consensus statement on the most informative testing in emergency setting, to the prevention and detection of hemolysis or to patients identification and tube labeling procedures, as far as to different approaches to harmonize hormones measurements or to describe new reference methods or to harmonize the laboratory report. During these years the commitment of the journal, devoted to the harmonization processes has allowed to improve the awareness on the topic and to provide specific instruments to monitor the rate of errors and to improve patients safety.

In order to guarantee patient safety, medical laboratories around the world strive to provide highest quality in the shortest amount of time. A major leap in quality improvement was achieved by aiming to avoid preanalytical errors within the total testing process. Although these errors were first described in the 1970s, it took additional years/decades for large-scale efforts, aiming to improve preanalytical quality by standardisation and/or harmonisation. Initially these initiatives were mostly on the local or national level. Aiming to fill this void, in 2011 the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) working group “Preanalytical Phase” (WG-PRE) was founded. In the 11 years of its existence this group was able to provide several recommendations on various preanalytical topics. One major achievement of the WG-PRE was the development of an European consensus guideline on venous blood collection. In recent years the definition of the preanalytical phase has been extended, including laboratory test selection, thereby opening a huge field for improvement, by implementing strategies to overcome misuse of laboratory testing, ideally with the support of artificial intelligence models. In this narrative review, we discuss important aspects and milestones in the endeavour of preanalytical process improvement, which would not have been possible without the support of the Clinical Chemistry and Laboratory Medicine ( CCLM ) journal, which was one of the first scientific journals recognising the importance of the preanalytical phase and its impact on laboratory testing quality and ultimately patient safety.

Biological variation (BV) data have many applications in laboratory medicine. However, these depend on the availability of relevant and robust BV data fit for purpose. BV data can be obtained through different study designs, both by experimental studies and studies utilizing previously analysed routine results derived from laboratory databases. The different BV applications include using BV data for setting analytical performance specifications, to calculate reference change values, to define the index of individuality and to establish personalized reference intervals. In this review, major achievements in the area of BV from last decade will be presented and discussed. These range from new models and approaches to derive BV data, the delivery of high-quality BV data by the highly powered European Biological Variation Study (EuBIVAS), the Biological Variation Data Critical Appraisal Checklist (BIVAC) and other standards for deriving and reporting BV data, the EFLM Biological Variation Database and new applications of BV data including personalized reference intervals and measurement uncertainty.

Method evaluation is one of the critical components of the quality system that ensures the ongoing quality of a clinical laboratory. As part of implementing new methods or reviewing best practices, the peer-reviewed published literature is often searched for guidance. From the outset, Clinical Chemistry and Laboratory Medicine ( CCLM ) has a rich history of publishing methods relevant to clinical laboratory medicine. An insight into submissions, from editors’ and reviewers’ experiences, shows that authors still struggle with method evaluation, particularly the appropriate requirements for validation in clinical laboratory medicine. Here, we consider through a series of discussion points an overview of the status, challenges, and needs of method evaluation from the perspective of clinical laboratory medicine. We identify six key high-level aspects of clinical laboratory method evaluation that potentially lead to inconsistency. 1. Standardisation of terminology, 2. Selection of analytical performance specifications, 3. Experimental design of method evaluation, 4. Sample requirements of method evaluation, 5. Statistical assessment and interpretation of method evaluation data, and 6. Reporting of method evaluation data. Each of these areas requires considerable work to harmonise the practice of method evaluation in laboratory medicine, including more empirical studies to be incorporated into guidance documents that are relevant to clinical laboratories and are freely and widely available. To further close the loop, educational activities and fostering professional collaborations are essential to promote and improve the practice of method evaluation procedures.

IVD manufacturers have total responsibility in terms of the traceability of marketed in vitro diagnostic medical devices (IVD-MD). This includes the provision of a quality control (QC) material as a part of the measuring system, suitable for traceability verification and alignment surveillance by end-users in daily practice. This material [to be used for the internal QC (IQC) component I as described in this paper] should have unbiased target values and an acceptability range corresponding to analytical performance specifications (APS) for suitable (expanded) measurement uncertainty (MU) on clinical samples. On the other hand, medical laboratories (by the IQC component II as described in this paper) should improve the IQC process and its judging criteria to establish a direct link between their performance, estimated as MU of provided results, and APS defined according to recommended models to apply corrective actions if the performance is worsening with the risk to jeopardize the clinical validity of test results. The participation to external quality assessment (EQA) programs that meet specific metrological criteria is also central to the evaluation of performance of IVD-MDs and of medical laboratories in terms of harmonization and clinical suitability of their measurements. In addition to the use of commutable materials, in this type of EQA it is necessary to assign values to them with selected reference procedures and to define and apply maximum allowable APS to substantiate the suitability of laboratory measurements in the clinical setting.

Lot-to-lot verification is an integral component for monitoring the long-term stability of a measurement procedure. The practice is challenged by the resource requirements as well as uncertainty surrounding experimental design and statistical analysis that is optimal for individual laboratories, although guidance is becoming increasingly available. Collaborative verification efforts as well as application of patient-based monitoring are likely to further improve identification of any differences in performance in a relatively timely manner. Appropriate follow up actions of failed lot-to-lot verification is required and must balance potential disruptions to clinical services provided by the laboratory. Manufacturers need to increase transparency surrounding release criteria and work closer with laboratory professionals to ensure acceptable reagent lots are released to end users. A tripartite collaboration between regulatory bodies, manufacturers, and laboratory medicine professional bodies is key to developing a balanced system where regulatory, manufacturing, and clinical requirements of laboratory testing are met, to minimize differences between reagent lots and ensure patient safety. Clinical Chemistry and Laboratory Medicine has served as a fertile platform for advancing the discussion and practice of lot-to-lot verification in the past 60 years and will continue to be an advocate of this important topic for many more years to come.

This tutorial shows how to perform a meta-analysis of diagnostic test accuracy studies (DTA) based on a 2 × 2 table available for each included primary study. First, univariate methods for meta-analysis of sensitivity and specificity are presented. Then the use of univariate logistic regression models with and without random effects for e.g. sensitivity is described. Diagnostic odds ratios (DOR) are then introduced to combine sensitivity and specificity into one single measure and to assess publication bias. Finally, bivariate random effects models using the exact binomial likelihood to describe within-study variability and a normal distribution to describe between-study variability are presented as the method of choice. Based on this model summary receiver operating characteristic (sROC) curves are constructed using a regression model logit-true positive rate (TPR) over logit-false positive rate (FPR). Also it is demonstrated how to perform the necessary calculations with the freely available software R. As an example a meta-analysis of DTA studies using Procalcitonin as a diagnostic marker for sepsis is presented.

The introduction of cardiac troponins into clinical diagnostics has not only improved diagnostic pathways for myocardial infarction but also profoundly influenced the definition of myocardial infarction. The term troponin appeared in the literature almost 60 years ago, i.e. shortly after this journal was founded. The development of cardiac troponins from proteins involved in muscle contraction, which were in the focus of few specialized research groups from physiology and biochemistry, to one of the most frequently measured protein biomarkers in medicine is a paradigmatic success story which is also reflected in almost 300 publications on the topic in this journal. From the viewpoint of biomarker development the critical success factors were medical need, timely generation of medical evidence, and the rapid development of robust and precise laboratory assays.

New millennium diagnostic criteria for acute myocardial infarction precipitated a revolutionary shift from an approach based primarily on electrocardiography and clinical symptoms to a strategy based on biomarkers, and preferably cardiac troponins (cTn) I and T. In the last 20 years, clinical recommendations have strengthened the role of cTn and led to the development of highly sensitive (hs-cTn) assays, which are now leading players in all current clinical practice guidelines. To optimize the clinical use of these hs-cTn assays, focus on their analytical aspects has become increasingly important, emphasizing the need for the establishment of suitable analytical performance by the definition and implementation of appropriate specifications. An accurate estimate of measurement uncertainty, together with the acquisition of the highest analytical quality when very low concentrations of hs-cTn are measured, are essential requirements and should represent a practical laboratory standard in assuring optimal clinical use. Additional goals for further improving the quality of laboratory information should be the establishment of robust data concerning biological variation of cTn and the resolution of practical challenges opposed to the harmonization of cTn I results obtained by differing commercial measuring systems.

This review is an integral part of the special issue for the 60 years of the journal Clinical Chemistry and Laboratory Medicine ( CCLM ). The aim of the review is to highlight the role of the clinical laboratory since the emergence of the “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), which causes Coronavirus disease 2019 (COVID-19), with special focus on the contribution of the journal in generating knowledge in SARS-CoV-2 diagnosis. As of October 30, 2022, a total of 186 CCLM publications were dedicated to COVID-19. Of importance, major International Federation of Clinical Chemistry (IFCC) guidelines related to the diagnosis of COVID-19 were published in CCLM . Between early-2020 and late October 2022, COVID-19 publications represented around 27% of all articles in CCLM , highlighting the willingness of the editorial board to help the field in order to better describe and diagnose this new emerging disease. First launched in 1963 under the name “Zeitschrift für Klinische Chemie”, the Journal was entirely devoted to clinical chemistry in the strict sense. The various topics published in relation to COVID-19 including its diagnosis, its impact on biochemical or hematological measures, as well as biosafety measures, is the perfect example that shows that the journal has greatly diversified over time.

Objectives Procalcitonin (PCT) is a host-response biomarker that has shown clinical value for assessing the likelihood of bacterial infections and guiding antibiotic treatment. Identifying situations where PCT can improve clinical care is therefore highly important. Methods The aim of this narrative review is to discuss strategies for the usage and integration of PCT into clinical routine, based on the most recent clinical evidence. Results Although PCT should not be viewed as a traditional diagnostic marker, it can help differentiate bacterial from non-bacterial infections and inflammation states – particularly in respiratory illness. Several trials have found that PCT-guided antibiotic stewardship reduces antibiotic exposure and associated side-effects among patients with respiratory infection and sepsis. Studies have demonstrated that patient-specific decisions regarding antibiotic usage is highly complex. Factors to consider include: the clinical situation (with a focus on the pretest probability for bacterial infection), the acuity and severity of presentation, as well as PCT test results. Low PCT levels help rule out bacterial infection in patients with both low pretest probability for bacterial infection and low-risk general condition. In high-risk individuals and/or high pretest probability for infection, empiric antibiotic treatment is mandatory. Subsequent monitoring of PCT helps track the resolution of infection and guide decisions regarding early termination of antibiotic treatment. Conclusions PCT possesses high potential to improve decision-making regarding antibiotic treatment – when combined with careful patient assessment, evidence-based clinical algorithms, and continuous notification and regular feedback from all antibiotic stewardship stakeholders. Medical Journals such as Clinical Chemistry and Laboratory Medicine ( CCLM ) have played a critical role in reviewing and dissemination the high-quality evidence about assays for PCT measurement, observational research regarding association with outcomes among different populations, and interventional research proofing its effectiveness for patient care.

On the occasion of the 60th anniversary of Clinical Chemistry and Laboratory Medicine ( CCLM ) we present a review of recent developments in the discipline of laboratory hematology as these are reflected by papers published in CCLM in the period 2012–2022. Since data on CCLM publications from 1963 to 2012 are also available, we were able to make a comparison between the two periods. This interestingly revealed that the share of laboratory hematology papers has steadily increased and reached now 16% of all papers published in CCLM . It also became evident that blood coagulation and fibrinolysis, erythrocytes, platelets and instrument and method evaluation constituted the ‘hottest’ topics with regard to number of publications. Some traditional, characteristic CCLM categories like reference intervals, standardization and harmonization, were more stable and probably will remain so in the future. With the advent of important newer topics, like new coagulation assays and drugs and cell population data generated by hematology analyzers, laboratory hematology is anticipated to remain a significant discipline in CCLM publications.

D-dimer is a fibrin degradation product encompassing multiple cross-linked D domains and/or E domains present in the original fibrinogen molecule, whose generation is only theoretically possible when hemostasis and fibrinolysis pathways are concomitantly activated. D-dimer measurement has now become a pillar in the diagnosis/exclusion and prognostication of venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC), when incorporated into validated clinical algorithms and especially using age-adjusted diagnostic thresholds. Although emerging evidence is also supporting its use for predicting the duration of anticoagulant therapy in certain categories of patients, the spectrum of clinical applications is constantly expanding beyond traditional thrombotic pathologies to the diagnosis of acute aortic dissection, acute intestinal ischemia and cerebral venous thrombosis among others, embracing also clinical management of coronavirus disease 2019 (COVID-19). Recent findings attest that D-dimer elevations are commonplace in patients with severe acute respiratory syndrome (SARS-CoV-2) infection (especially in those with thrombosis), its value predicts the clinical severity (up to death) of COVID-19 and remains more frequently increased in COVID-19 patients with post-discharge clinical sequelae. Further, D-dimer-based anticoagulant escalation may be associated with a lower risk of death in patients with severe SARS-CoV-2 infection and, finally, D-dimer elevation post-COVID-19 vaccination mirrors an increased risk of developing vaccine-induced thrombocytopenia and thrombosis (VITT).

The platelet function analyser (PFA) is a prevalent platelet function screening instrument, and comes in two models–the original PFA-100 and the contemporary PFA-200. The instruments have ‘identical’ output, being a ‘closure time’ (CT). Moreover, normal reference ranges provided by the manufacturer, for the specific test cartridges, are the same for both models. There are three different types of test cartridge: collagen/epinephrine (C/Epi), collagen/adenosine diphosphate (C/ADP), and “Innovance PFA P2Y” (only available in certain geographical locations). The PFA-100 was released in the mid 1990s, and so is approaching 50 years of age. The PFA-200, released in some locations in the mid 2010s, is destined to eventually replace the PFA-100, but is not yet available in the USA. The test system is highly sensitive to von Willebrand disease (VWD; C/Epi and C/ADP) and to aspirin therapy (C/Epi only), but only has moderate sensitivity to defects in platelet function and/or deficiencies in platelet number. Accordingly, recommendations for use for screening platelet function vary according to user experience. Some workers have alternatively used the PFA to assess thrombosis risk or pre-operative bleeding risk. In this review, we provide an overview of the history of PFA, and summarise its current clinical utility.

Since its discovery in the late 1960s, HbA 1c has proven to be a major biomarker of diabetes mellitus survey and diagnosis. Other biomarkers have also been described using classical laboratory methods or more innovative, non-invasive ones. All biomarkers of diabetes, including the historical glucose assay, have well-controlled strengths and limitations, determining their indications in clinical use. They all request high quality preanalytical and analytical methodologies, necessitating a strict evaluation of their performances by external quality control assessment trials. Specific requirements are needed for point-of-care testing technologies. This general overview, which describes how old and new tools of diabetes mellitus biological survey have evolved over the last decade, has been built through the prism of papers published in Clinical Chemistry and Laboratory Medicine during this period.

Mass spectrometry (MS) has been a gold standard in the clinical laboratory for decades. Although historically refined to limited areas of study such as neonatal screening and steroid analysis, technological advancements in the field have resulted in MS becoming more powerful, versatile, and user-friendly than ever before. As such, the potential for the technique in clinical chemistry has exploded. The past two decades have seen advancements in biomarker detection for disease diagnostics, new methods for protein measurement, improved methodologies for reliable therapeutic drug monitoring, and novel technologies for automation and high throughput. Throughout this time, Clinical Chemistry and Laboratory Medicine has embraced the rapidly developing field of mass spectrometry, endeavoring to highlight the latest techniques and applications that have the potential to revolutionize clinical testing. This mini review will highlight a selection of these critical contributions to the field.

One hundred years ago, the role of vitamin D for bone mineralization and the prevention of rickets was discovered. Vitamin D comprises a group of over 50 metabolites with multiple functions that go far beyond calcium homeostasis and bone mineralization. Approximately 50 years ago, first methods for the measurement of 25-hydroxyvitamin D (25(OH)D) in human blood were developed. Over the years, different analytical principals were employed including competitive protein binding assays, high-performance liquid chromatography, various immunoassay and mass spectrometric formats. Until the recent standardization of serum 25(OH)D measurement, agreement between methods was unsatisfactory. Since then, comparability has improved, but substantial variability between methods remains. With the advent of liquid chromatography tandem mass spectrometry (LC-MS/MS), the accurate determination of 25(OH)D and other metabolites, such as 24,25(OH)2D, becomes increasingly accessible for clinical laboratories. Easy access to 25(OH)D testing has triggered extensive clinical research showing that large parts of the population are vitamin D deficient. The variable response of vitamin D deficient individuals to supplementation indicates that assessing patients’ vitamin D stores by measuring 25(OH)D provides limited insight into the metabolic situation. Meanwhile, first evidence has emerged suggesting that the simultaneous measurement of 25(OH)D, 24,25(OH)2D and other metabolites allows a dynamic evaluation of patients’ vitamin D status on metabolic principals. This may help to identify patients with functional vitamin D deficiency from those without. It can be expected that research into the assessment vitamin D status will continue for another 50 years and that this will help rationalizing our approach in clinical practice.

Tumor markers are a heterogeneous group of substances released by cancer cells into bloodstream, but also expressed by healthy tissues. Thus, very small concentrations can be present in plasma and serum from healthy subjects. Cancer patients tend to show increased levels correlating with tumor bulk, but false positive results could be present in patients with benign conditions. The correct interpretation of TM results could be challenging and many factors should be considered, from pre-analytical conditions to patient concomitant diseases. In this line, the Clinical Chemistry and Laboratory Medicine journal has made important contributions though several publications promoting the adequate use of TM and therefore improving patient safety. TM measurement offers valuable information for cancer patient management in different clinical contexts, such as helping diagnosis, estimating prognosis, facilitating early detection of relapse and monitoring therapy response. Our review analyzes the clinical usefulness of tumor markers applied in most frequent epithelial tumors, based on recent evidence and guidelines.

Lung cancer currently represents a leading cause of cancer death. Substantial progress achieved in the medical therapy of lung cancer during the last decade has been associated with the advent of targeted therapy, including immunotherapy. The targeted therapy has gradually shifted from drugs suppressing general mechanisms of tumor growth and progression to agents aiming at transforming mechanisms like driver mutations in a particular tumor. Knowledge of the molecular characteristics of a tumor has become an essential component of the more targeted therapeutic approach. There are specific challenges for biomarker determination in lung cancer, in particular a commonly limited size of tumor sample. Liquid biopsy is therefore of particular importance in the management of lung cancer. Laboratory medicine is an indispensable part of multidisciplinary management of lung cancer. Clinical Chemistry and Laboratory Medicine ( CCLM ) has played and will continue playing a major role in updating and spreading the knowledge in the field.

Identifying the cause of pleural effusion is challenging for pulmonologists. Imaging, biopsy, microbiology and biochemical analyses are routinely used for diagnosing pleural effusion. Among these diagnostic tools, biochemical analyses are promising because they have the advantages of low cost, minimal invasiveness, observer independence and short turn-around time. Here, we reviewed the past, present and future of pleural fluid biochemical analysis. We reviewed the history of Light’s criteria and its modifications and the current status of biomarkers for heart failure, malignant pleural effusion, tuberculosis pleural effusion and parapneumonic pleural effusion. In addition, we anticipate the future of pleural fluid biochemical analysis, including the utility of machine learning, molecular diagnosis and high-throughput technologies. Clinical Chemistry and Laboratory Medicine ( CCLM ) should address the topic of pleural fluid biochemical analysis in the future to promote specific knowledge in the laboratory professional community.

Over the past three decades, laboratory medicine has significantly evolved thanks to technological advances made possible by new materials and evidence. Clinicians’ ongoing requests for powerful, rapid, and minimally invasive tests has led manufacturers to develop rapid, accurate, and sensitive tests that can increase diagnostic accuracy and improve follow-up, bringing laboratory medicine ever closer to personalized medicine. The aim of this study was to critically review the main problems of the current Tg and CT biomarkers for the diagnosis/monitoring of DTC and MTC, respectively, and to identify the advantages and challenges of using the new laboratory biomarkers in the clinical management of patients with differentiated and medullary thyroid cancer. Insufficient harmonization of Tg and CT assays and lack of interchangeability of laboratory results and cutoff values pose challenges for comparability and standardization of procedures and methods. New diagnostic and monitoring approaches such as PCT or the Tg doubling time have proven to be effective. Close collaboration between clinicians and laboratory specialists remains essential to translate the advantages and limitations of current assays into appropriate clinical interpretation criteria. Over the years, the journal Clinical Chemistry and Laboratory Medicine ( CCLM ) has taken many steps to develop advanced research and technology in the diagnosis and monitoring of tumor cancer and to help clinicians translate it into clinical practice.

Parathyroid hormone (PTH) determination is of paramount importance for the exploration of diseases related with calcium metabolism and for the follow-up of patients suffering from bone and mineral disorders associated with chronic kidney diseases (CKD-MBD). Unfortunately, the biologically active form of PTH, i.e. 1–84 PTH, circulates in the blood stream with many fragments and post-translationally modified forms, which decreases the specificity of immunoassays. The assays used to measure PTH, either from 2nd or 3rd generation, are not standardised, which may lead to interpretation errors and clinical consequences. Reference ranges for PTH have neither been always correctly established and the stability of the peptide is also a matter of concern. Fortunately, these last years, newer techniques using mass spectrometry (either high resolution or triple quadripole) coupled with liquid chromatography have been developed, which will help to standardise the different assays. Indeed, PTH assays standardisation is one of the task of the IFCC Committee for Bone Metabolism. Such standardisation will allow a better consistency in the interpretation of the results and will promote studies aiming at the establishment of correct reference ranges.