Quality in laboratory medicine and the Journal: walking together

Introduction

Quality in laboratory medicine, a never-ending quest, has been defined as “an unfinished journey” [1]. The need to control, monitor and improve quality in clinical laboratories has grown hand in hand with the growth of technological developments as well as with the increasing value of laboratory information in the clinical decision-making process and patient management: the more essential the laboratory information provided, the more assured its quality should be [2]. One article that appeared 10 years ago in the special issue of the Journal Clinical Chemistry and Laboratory Medicine (CCLM), which celebrated its 50th anniversary, has provided the opportunity to recall and cite the relevant articles dealing with quality in clinical laboratories, and patient safety [3]. The paper highlighted, on the one hand, the impressive (about 300-fold) reduction achieved in analytical errors over the past five decades and, on the other, the growing awareness of the crucial importance of extra-analytical aspects in laboratory quality, thanks to the data collected on the vulnerability of the both pre- and post-analytical phases [4], [5], [6]. In addition, the paper recognized the impact on patient safety of laboratory errors, which give rise to diagnostic errors and increase the risk of errors that may lead to patient harm or delayed diagnosis and treatment [7]. However, the most important “take home message” was an awareness of the need to fully understand the value of the seminal “brain-to-brain” laboratory test loop concept [8, 9], and also of the fact that laboratory tests should produce “actionable results that bring a positive outcome benefit for the patient” [10]. This straightforward concepts support the value proposition for further studies of outcomes related to laboratory testing as well as the claim that the provision of a test result is of no value unless appropriately acted on [11] and, in turn, points to the need for appropriate setting and model for delivering laboratory services, while avoiding any vision of laboratory testing as a commodity performed in focused factories (silos) disconnected from diagnostic and therapeutic pathways [12]. Ten years later, on celebrating the 60th anniversary of the founding of the CCLM, it appears appropriate to ascertain whether the end-point, defined in the last sentence of the above cited article: “as quality is a never-ending journey, Clinical Chemistry and Laboratory Medicine would like to remain an important partner in this journey, assuring evidences, updates and new insights, thus stimulating laboratory professionals to improve the delivery of laboratory services to ultimately assure a safer care” [3] has really been translated in practice. Although an impressive number of articles on quality in laboratory medicine have appeared in the CCLM, and it might be a “mission impossible” to enumerate them all, the aim of this paper is to review the most interesting contributions to the improve the knowledge on the different aspects of quality.

Pre-pre- and pre-analytical phase

An exploration of the initial steps of the total testing process (TTP) has revealed that the pre-pre- and pre-analytical phases are more vulnerable to errors than other steps, accounting for about 70% of all errors in laboratory medicine [13]. This evidence, confirmed in several other articles, prompted a series of initiatives and studies aiming to reduce the risk of errors and improve upon quality. The European Federation for Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for Preanalytical Phase (WG-PRE) continues to be active in this field, contributing to many seminal publications in the Journal. The paper published in 2015 considered the management of test requesting, the implementation of the European Union (EU) Directive on needlestick injury prevention, the harmonization of fasting requirements for blood sampling, the influence of physical activity and medical contrast media on in vitro diagnostic testing, updates about preanalytical quality indicators, the feasibility of an External Quality Assessment Scheme (EQAS) for the preanalytical phase, and specific notions concerning evidence-based quality management of the preanalytical phase [14]. In 2017, the EFLM WG-PRE published another paper on how innovation and technologies may contribute to improving the quality of pre-analytical steps of TTP [15] and, in 2019, another article collected data on sample stability, preanalytical challenges in hematology testing, feces analysis, bio-banking, liquid profiling, mass spectrometry, next generation sequencing, and laboratory automation. In addition, the paper highlighted the importance of recognizing and measuring the exact sampling time, of technology aids in managing inappropriate utilization of laboratory resources, and the management of hemolyzed samples and preanalytical quality indicators [16]. In 2021, the Journal published a consensus document that reviewed pre-analytical requirements contained in ISO 15189:2012 and provided guidance for laboratories on how to meet these requirements [17]. More recently, a study by the EFLM WG-PRE provided valuable information on developments achieved in the pre-analytical phase, including the endorsement of a dedicated checklist aimed at preventing preanalytical diagnostic errors in clinical trials (PREDICT) [18]. This checklist targets specific preanalytical aspects, those more vulnerable to human errors, thus encompassing test selection, patient preparation, along with blood samples collection, handling, preparation, transportation, storage and retrieval before testing. In addition, the paper stressed the need for multidisciplinary convergences, thus paving the way for a new frontier: integrated diagnostics [19]. Other important articles deal with recommendations for venous blood sample collection [20, 21], order of blood draw [22], and the management of hemolyzed samples [23], [24], [25]. Various studies have been published on stability and storage conditions for many measurands including commonly requested clinical biochemistry tests [26], new biomarkers for neurological diseases [27], circulating free DNA [28] and microRNA (miRNA) [29], as well as measurands in cerebrospinal fluid [30] and fecal biomarkers [31]. However, although various studies and databases assessing the stability of analytes in different settings already existed, guidance on how to perform and report stability studies was lacking until the publication of the paper on a recommended guideline and checklist for reporting stability studies [32]. This checklist is of great value in harmonizing and improving the quality of further studies aiming to evaluate the stability of measurands of clinical interest. An issue of fundamental importance for quality and patient safety in the pre-analytical phase regards patient and sample identification, and the paper by Van Dongen-Lases and colleagues represented a step forward in the worldwide harmonization of patient identification and tube labeling procedures designed to reduce the risk of preanalytical errors and enhance patient safety [33]. Improvement in the pre-analytical phase concerns not only traditional centralized laboratory testing but also point-of-care testing (POCT), as highlighted in the study by Van Hoof et al. [34]. Further papers provided new information and evidence on pneumatic transportation systems (PTSs), widely used in hospitals for rapid blood sample transportation. Indeed, PTS may affect sample integrity, particularly when different carriers are used, and acceleration profiles are to be verified and validated [35, 36].

Finally, CCLM has published some updated papers on quality indicators in the pre-analytical phase as a follow-up after consensus was gained on the list of harmonized QIs developed [37, 38]. This was a reasonable premise for the further step: achievable and realistic performance targets in pre-analytical quality based on the knowledge of the state-of-the-art [39]. The identification and establishment of performance targets in the pre-analytical phase was a fundamental step in making further efforts to improve quality and reduce the risk of errors in the initial steps of the TTP. The lesson learned after establishing and setting valuable performance specifications in the analytical phase has now been applied to all other extra-analytical phases, thus enhancing quality and patient safety in the laboratory testing.

Analytical phase

In 2014, the EFLM organized a Strategic Conference in Milan on ‘Defining analytical performance goals 15 years after the Stockholm Conference on Quality Specifications in Laboratory Medicine’, proposing a simplified hierarchy with three models for defining analytical performance specifications (APS) [40]. However, the term “simplified hierarchy”, sounds inappropriate as, in fact, the revised hierarchy allows clinical laboratories to focus on the three valuable models to establish APS: Model 1, based on the effect of analytical performance on clinical outcomes; Model 2, based on components of biological variation of the measurand; and Model 3, based on the state-of-the-art. In addition, clinical laboratories were encouraged to identify laboratory investigations in which the links between the test, clinical decision-making and clinical outcomes are straightforward and robust. However, in most laboratory investigations for which population-based or subject-specific biological variation data can be established, Model 2 is much more suitable. CCLM has recently dedicated a special issue on biological variation and its adoption to establish APS [41]. After the Milan Conference, the EFLM set up five Task Finish Groups (TFGs) to address the most debatable issues, reported in a seminal paper published in the Journal [42]. If the model based on biological variation seems to be more appropriate and feasible for most measurands, that based on outcome studies may allow a more satisfactory definition of the relationship between the analytical performance of tests and health outcomes, and can be used to set analytical performance criteria aiming to improve the clinical reliability and cost-effectiveness of laboratory tests [43]. More recently, Panteghini and colleagues published a stimulating article on APS for measuring uncertainty in common biochemical measurands according to the above cited Milan models [44], and on the importance of measurement uncertainty (MU) as a key quality indicator for defining both the performance of an IVD measuring system and the laboratory itself [45]. Further contributions on MU have been made by Plebani and coauthors [46] and by other Authors, who have discussed the comparison between the benefits of the MU approach with respect to total error (TE) in the assessment of laboratory performance [47], [48], [49]. A series of papers have updated the knowledge of laboratory professionals concerning the main tools used in clinical laboratories for monitoring and improving analytical quality: internal quality control (IQC) and external quality assessment (EQA). Programs should be redesigned to permit IVD traceability surveillance in addition to the traditional measurement of random errors [50, 51]. Moreover, some papers have highlighted the importance of real-time patient-based quality control and its integration with traditional IQC [52], [53], [54]. EQA is crucial for ensuring acceptable analytical quality in medical laboratories, and CCLM has published numerous papers dealing with this issue and with improvement in adopting valuable APS [55], the harmonization of currently available programs [56, 57], the increasing importance of EQA programs in the accreditation of medical laboratories according to ISO 15189 [58], and the role of commutable materials for assuring clinical traceability of laboratory results [59]. Importantly, EQA programs consider not only clinical biochemistry measurands but all other laboratory tests, including coagulation [60], hematology [61] circulating tumor DNA (ctDNA) and other molecular tests [62]. Further contributions regard lot-to-lot variation, “a neglected issue” [63] until the recent publications of seminal papers which not only make an in-depth evaluation of challenges in, and risks to, the reliability of results, but also propose potential solutions [64], including an approach for determining acceptable between reagent lot variation. This valuable risk-based solution obviates the clinical impact of between-reagent lot variation [65]. Another important contribution made by Vogeser and Seger highlights the evidence that, although routine internal and external quality control measurements interpreted by statistical methods are mandatory in identification of random analytical variation and systematic calibration bias over time, no individual sample can be considered “under individual quality control”, as interferences associated with an individual diagnostic sample can compromise analytical results [66]. The concept of “irregular analytical errors” is founded on evidence that “analytical quality is an unfinished journey” [1] and, even more interesting, has promoted studies for identification of irregular analytical errors related to immunoassay methods that cannot be detected using traditional laboratory quality control procedures [67] and for management of this problem to minimize risk to patient safety [68, 69].

Post-analytical phase

The ISO15189 standard for medical laboratory quality [70] defines the post-analytical phase as the processes following the examination that includes a review of results. The following processes include retention and storage of clinical material as well as disposal of samples (and waste). In terms of quality of pathology reports, however, the post-analytical phase includes the formatting, releasing, reporting and retention of examination results for future access. In a study by Sikaris, an evaluation was made of the most important aspects of post-analytical quality, including reference intervals, clinical decision limits, critically abnormal results, and identifying the need to establish appropriate performance specifications [71]. Sciacovelli and coauthors conducted a study following the above described study design, based on the voluntary participation of clinical laboratories in the project on QIs of the Working Group “Laboratory Errors and Patient Safety” (WG-LEPS) of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) [37, 38]. Based on the data collected, the authors identified provisional performance specifications in the post-analytical phase [72]. In a further contribution, Thue and Sandberg used data from a post-analytical EQA program to identify appropriate APS [73]. Interpretative comments made to enable improvement in the interpretation of laboratory results were the basis of a study made by Vasikaran and coauthors, which provides valuable information and suggestions for assuring quality provision of interpretative comments [74]. More recently, the Journal has published an article by Cadamuro et al., written on behalf of the EFLM Working Group for Postanalytical Phase (WG-POST), dealing with laboratory report and innovative formats that should allow better interpretation by physicians and patients [75].

Towards a new paradigm of quality in laboratory medicine

The body of evidence collected in the last few decades demonstrates that the extra-analytical phases of the TTP are more error-prone than the analytical phase. However, the paradigm has been questioned because analytical quality is unsatisfactory when evaluated on the sigma scale, which is one of the best available approaches for providing objective estimates and metrics in several industries [76]. Furthermore, current data on analytical errors derive from the more frequently requested and simpler measurands, using automated and standardized methods. Therefore, despite the impressive reduction achieved in analytical errors, further improvements are needed, although it is important to bear in mind that real improvement in the quality of laboratory medicine would hinge upon an enhanced awareness of TTP as a set of interrelated and interacting activities that transform biologic patient samples into valuable laboratory results and information, that ultimately assures the most appropriate possible clinical and economical outcomes. This concept has been described in a paper published in the Journal in 2016, which describes the “five rights” rules to be observed in order to assure accurate and reliable laboratory information [77]. As the brain-to-brain loop was conceived as a continuum, only “good samples” can assure good assays, and compliance with the five rights in the pre-pre and pre-analytical phase is crucial to achieving accurate analytical results. In fact, without the integrity of biological samples, even the most sophisticated and metrologically traceable methods cannot guarantee an accurate and reliable analytical result. But this is not enough: analytical results should be converted into useful laboratory information, and therefore a further “five rights” should be observed in both the post- and post-post-analytical phases to assure effective and actionable laboratory data. This new paradigm offers an opportunity to move towards an effective model of value-based laboratory medicine [78], restoring the mission of clinical laboratories to provide timely and accurate information for promoting maintenance of wellness, predict susceptibility to disease, assure prevention, make an early diagnosis, ensure valuable prognostication and administer personalized treatment [79].

Quality measurement: which and how?

The measurement, core to the practice of medicine, drives much of the day-to-day decision making [80], and laboratory information plays an increasingly dominant role in modern medicine. In view of the evidence that added value underpins the ultimate quality of laboratory testing, the changing face of quality is shifting from analytical results to a global view of the TTP, including the acknowledgment and effective utilization of laboratory information. This, in turn, calls for the revision of measurements in laboratory medicine. As shown in Figure 1, there are at least three categories of measures to be used in clinical laboratories. The first, which is traditional, is the measurement of analytical quality, the second is the use of quality indicators in the TTP, and the third is the outcomes-based approach.

Figure 1:

Measures in clinical laboratory.

Measurement of analytical quality is a cornerstone of medical laboratory efforts to control and improve upon daily practices, and clinical laboratories use these measures for: a) internal monitoring/improvement of laboratory results; b) inter-laboratory benchmarking; c) complying with regulatory (regional, national and/or international) requirements. These measures, currently based on the hierarchy of APS, provide information on accuracy and measurement uncertainty, thanks to the data collected in IQC and EQA programs. However, they cannot measure quality in the extra-analytical phases, and efforts have been made to develop a list of harmonized quality indicators for evaluating and improving the quality of TTP [37, 38]. The internal dimension of quality in laboratory medicine is monitored using the abovementioned indicators of analytical and extra-analytical quality, which have dramatically improved quality in the last few decades. Further efforts must be made to improve both IQC and EQA programs, particularly in the metrological traceability era, as they are formidable tools for assuring accurate and reliable laboratory results. However, the value proposition in laboratory medicine calls for additional measures, pertaining to the outcome-based approach rather than to the quality of processes and procedures. Only outcome measures may provide information on the value of laboratory testing in patient management and clinical pathways, and further efforts and researches should be promoted in this field. The adoption of more valuable measures of quality will also transform the role of laboratory professionals who, rather than being faceless executors, will become process owners and, ultimately, as shown in Figure 2, members of diagnostic teams.

Figure 2:

Role of laboratory professionals according to different quality measures (“you are and will be what you measure”).

Conclusions

As quality in laboratory medicine is a moving target, CCLM was, is, and always will be, a strategic partner for providing laboratory professionals and other stakeholders with the opportunity to publish papers dealing with new insights on quality in clinical laboratories, and will be a platform for debating all issues related to this key topic.