ISO 15189 is a sufficient instrument to guarantee high-quality manufacture of laboratory developed tests for in-house-use conform requirements of the European In-Vitro-Diagnostics Regulation.

The EU In-Vitro Diagnostic Device Regulation (IVDR) aims for transparent risk-and purpose-based validation of diagnostic devices, traceability of results to uniquely identified devices, and post-market surveillance. The IVDR regulates design, manufacture and putting into use of devices, but not medical services using these devices. In the absence of suitable commercial devices, the laboratory can resort to laboratory-developed tests (LDT) for in-house use. Documentary obligations (IVDR Art 5.5), the performance and safety specifications of ANNEX I, and development and manufacture under an ISO 15189-equivalent quality system apply. LDTs serve specific clinical needs, often for low volume niche applications, or correspond to the translational phase of new tests and treatments, often extremely relevant for patient care. As some commercial tests may disappear with the IVDR roll-out, many will require urgent LDT replacement. The workload will also depend on which modifications to commercial tests turns them into an LDT, and on how national legislators and competent authorities (CA) will handle new competences and responsibilities. We discuss appropriate interpretation of ISO 15189 to cover IVDR requirements. Selected cases illustrate LDT implementation covering medical needs with commensurate management of risk emanating from intended use and/or design of devices. Unintended collateral damage of the IVDR comprises loss of non-profitable niche applications, increases of costs and wasted resources, and migration of innovative research to more cost-efficient environments. Taking into account local specifics, the legislative framework should reduce the burden on and associated opportunity costs for the health care system, by making diligent use of existing frameworks.

Real-time monitoring of drug laboratory test interactions: a proof of concept.

OBJECTIVES: For the correct interpretation of test results, it is important to be aware of drug-laboratory test interactions (DLTIs). If DLTIs are not taken into account by clinicians, erroneous interpretation of test results may lead to a delayed or incorrect diagnosis, unnecessary diagnostic testing or therapy with possible harm for patients. A DLTI alert accompanying a laboratory test result could be a solution. The aim of this study was to test a multicentre proof of concept of an electronic clinical decision support system (CDSS) for real-time monitoring of DLTIs. METHODS: CDSS was implemented in three Dutch hospitals. So-called 'clinical rules' were programmed to alert medical specialists for possible DLTIs based on laboratory test results outside the reference range in combination with prescribed drugs. A selection of interactions from the DLTI database of the Dutch society of clinical chemistry and laboratory medicine were integrated in 43 clinical rules, including 24 tests and 25 drugs. During the period of one month all generated DTLI alerts were registered in the laboratory information system. RESULTS: Approximately 65 DLTI alerts per day were detected in each hospital. Most DLTI alerts were generated in patients from the internal medicine and intensive care departments. The most frequently reported DLTI alerts were potassium-proton pump inhibitors (16%), potassium-beta blockers (11%) and creatine kinase-statins (11%). CONCLUSIONS: This study shows that it is possible to alert for potential DLTIs in real-time with a CDSS. The CDSS was successfully implemented in three hospitals. Further research must reveal its usefulness in clinical practice.

Clinical usefulness of drug-laboratory test interaction alerts: a multicentre survey.

OBJECTIVES: Knowledge of possible drug-laboratory test interactions (DLTIs) is important for the interpretation of laboratory test results. Failure to recognize these interactions may lead to misinterpretation, a delayed or erroneous diagnosis, or unnecessary extra diagnostic tests or therapy, which may harm patients. The aim of this multicentre survey was to evaluate the clinical value of DLTI alerts. METHODS: A survey was designed with six predefined clinical cases selected from the clinical laboratory practice with a potential DLTI. Physicians from several departments, including internal medicine, cardiology, intensive care, surgery and geriatrics in six participating hospitals were recruited to fill in the survey. The survey addressed their knowledge of DLTIs, motivation to receive an alert and opinion on the potential influence on medical decision making. RESULTS: A total of 210 physicians completed the survey. Of these respondents 93% had a positive attitude towards receiving DLTI alerts; however, the reported value differed per case and per respondent's background. In each clinical case, medical decision making was influenced as a consequence of the reported DLTI message (ranging from 3 to 45% of respondents per case). CONCLUSIONS: In this multicentre survey, most physicians stated DLTI messages to be useful in laboratory test interpretation. Medical decision making was influenced by reporting DLTI alerts in each case. Alerts should be adjusted according to the needs and preferences of the receiving physicians.

The end of the laboratory developed test as we know it? Recommendations from a national multidisciplinary taskforce of laboratory specialists on the interpretation of the IVDR and its complications.

The in vitro diagnostic medical devices regulation (IVDR) will take effect in May 2022. This regulation has a large impact on both the manufacturers of in vitro diagnostic medical devices (IVD) and clinical laboratories. For clinical laboratories, the IVDR poses restrictions on the use of laboratory developed tests (LDTs). To provide a uniform interpretation of the IVDR for colleagues in clinical practice, the IVDR Task Force was created by the scientific societies of laboratory specialties in the Netherlands. A guidance document with explanations and interpretations of relevant passages of the IVDR was drafted to help laboratories prepare for the impact of this new legislation. Feedback from interested parties and stakeholders was collected and used to further improve the document. Here we would like to present our approach to our European colleagues and inform them about the impact of the IVDR and, importantly we would like to present potentially useful approaches to fulfill the requirements of the IVDR for LDTs.

The use of error and uncertainty methods in the medical laboratory.

Error methods - compared with uncertainty methods - offer simpler, more intuitive and practical procedures for calculating measurement uncertainty and conducting quality assurance in laboratory medicine. However, uncertainty methods are preferred in other fields of science as reflected by the guide to the expression of uncertainty in measurement. When laboratory results are used for supporting medical diagnoses, the total uncertainty consists only partially of analytical variation. Biological variation, pre- and postanalytical variation all need to be included. Furthermore, all components of the measuring procedure need to be taken into account. Performance specifications for diagnostic tests should include the diagnostic uncertainty of the entire testing process. Uncertainty methods may be particularly useful for this purpose but have yet to show their strength in laboratory medicine. The purpose of this paper is to elucidate the pros and cons of error and uncertainty methods as groundwork for future consensus on their use in practical performance specifications. Error and uncertainty methods are complementary when evaluating measurement data.

Impact of interactions between drugs and laboratory test results on diagnostic test interpretation - a systematic review.

Intake of drugs may influence the interpretation of laboratory test results. Knowledge and correct interpretation of possible drug-laboratory test interactions (DLTIs) is important for physicians, pharmacists and laboratory specialists. Laboratory results may be affected by analytical or physiological effects of medication. Failure to take into account the possible unintended influence of drug use on a laboratory test result may lead to incorrect diagnosis, incorrect treatment and unnecessary follow-up. The aim of this review is to give an overview of the literature investigating the clinical impact and use of DLTI decision support systems on laboratory test interpretation. Particular interactions were reported in a large number of articles, but they were fragmentarily described and some papers even reported contradictory findings. To provide an overview of information that clinicians and laboratory staff need to interpret test results, DLTI databases have been made by several groups. In a literature search, only four relevant studies have been found on DLTI decision support applications for laboratory test interpretation in clinical practice. These studies show a potential benefit of automated DLTI messages to physicians for the correct interpretation of laboratory test results. Physicians reported 30-100% usefulness of DLTI messages. In one study 74% of physicians sometimes even refrained from further additional examination. The benefit of decision support increases when a refined set of clinical rules is determined in cooperation with health care professionals. The prevalence of DLTIs is high in a broad range of combinations of laboratory tests and drugs and these frequently remain unrecognized.

Could accreditation bodies facilitate the implementation of medical guidelines in laboratories?

Several studies have shown that recommendations related to how laboratory testing should be performed and results interpreted are limited in medical guidelines and that the uptake and implementation of the recommendations that are available need improvement. The EFLM/UEMS Working Group on Guidelines conducted a survey amongst the national societies for clinical chemistry in Europe regarding development of laboratory-related guidelines. The results showed that most countries have guidelines that are specifically related to laboratory testing; however, not all countries have a formal procedure for accepting such guidelines and few countries have guideline committees. Based on this, the EFLM/UEMS Working Group on Guidelines conclude that there is still room for improvement regarding these processes in Europe and raise the question if the accreditation bodies could be a facilitator for an improvement.

A survey of patients' views from eight European countries of interpretive support from Specialists in Laboratory Medicine.

BACKGROUND: There is increasing interest in direct patient engagement including receiving their laboratory medicine results. We previously established an appetite for Specialists in Laboratory Medicine to support patients in understanding results. The aim of this study was to establish whether patients agreed with such an approach, determined through surveying views in eight European countries. METHODS: A standardized five-question survey was administered across eight European countries to a total of 1084 individuals attending medical outpatient clinics, with 100 patients each in Poland, Serbia, Netherlands, Turkey and Czech Republic, 101 in Estonia, 116 in Denmark and 367 in Norway. The responses across countries were compared using the chi-square test (p<0.05). RESULTS: Patients wanting their results ranged from 50% to 94% (mean 65%) of those responding positively, a mean of 72% wanted additional information with their results; direct receipt was preferred over referral to a website. Specialists in Laboratory Medicine providing such information were acceptable to a mean of 62% of those respondents wishing their results; in countries where payment was possible, there was little interest in making additional payment for such a service. CONCLUSIONS: A clear proportion of patients are interested in receiving their laboratory medicine results, the majority with explanatory notes; a role for Specialists in Laboratory Medicine is acceptable and raises the potential for direct engagement by such specialists with patients offering a new paradigm for the provision of laboratory medicine activities.

Total error vs. measurement uncertainty: revolution or evolution?

The first strategic EFLM conference "Defining analytical performance goals, 15 years after the Stockholm Conference" was held in the autumn of 2014 in Milan. It maintained the Stockholm 1999 hierarchy of performance goals but rearranged them and established five task and finish groups to work on topics related to analytical performance goals including one on the "total error" theory. Jim Westgard recently wrote a comprehensive overview of performance goals and of the total error theory critical of the results and intentions of the Milan 2014 conference. The "total error" theory originated by Jim Westgard and co-workers has a dominating influence on the theory and practice of clinical chemistry but is not accepted in other fields of metrology. The generally accepted uncertainty theory, however, suffers from complex mathematics and conceived impracticability in clinical chemistry. The pros and cons of the total error theory need to be debated, making way for methods that can incorporate all relevant causes of uncertainty when making medical diagnoses and monitoring treatment effects. This development should preferably proceed not as a revolution but as an evolution.

Why are clinical practice guidelines not followed?

Clinical practice guidelines (CPG) are written with the aim of collating the most up to date information into a single document that will aid clinicians in providing the best practice for their patients. There is evidence to suggest that those clinicians who adhere to CPG deliver better outcomes for their patients. Why, therefore, are clinicians so poor at adhering to CPG? The main barriers include awareness, familiarity and agreement with the contents. Secondly, clinicians must feel that they have the skills and are therefore able to deliver on the CPG. Clinicians also need to be able to overcome the inertia of "normal practice" and understand the need for change. Thirdly, the goals of clinicians and patients are not always the same as each other (or the guidelines). Finally, there are a multitude of external barriers including equipment, space, educational materials, time, staff, and financial resource. In view of the considerable energy that has been placed on guidelines, there has been extensive research into their uptake. Laboratory medicine specialists are not immune from these barriers. Most CPG that include laboratory tests do not have sufficient detail for laboratories to provide any added value. However, where appropriate recommendations are made, then it appears that laboratory specialist express the same difficulties in compliance as front-line clinicians.

Proposal for the modification of the conventional model for establishing performance specifications.

Appropriate quality of test results is fundamental to the work of the medical laboratory. How to define the level of quality needed is a question that has been subject to much debate. Quality specifications have been defined based on criteria derived from the clinical applicability, validity of reference limits and reference change values, state-of-the-art performance, and other criteria, depending on the clinical application or technical characteristics of the measurement. Quality specifications are often expressed as the total error allowable (TEA) - the total amount of error that is medically, administratively, or legally acceptable. Following the TEA concept, bias and imprecision are combined into one number representing the "maximum allowable" error in the result. The commonly accepted method for calculation of the allowable error based on biological variation might, however, have room for improvement. In the present paper, we discuss common theories on the determination of quality specifications. A model is presented that combines the state-of-the-art with biological variation for the calculation of performance specifications. The validity of reference limits and reference change values are central to this model. The model applies to almost any test if biological variation can be defined. A pragmatic method for the design of internal quality control is presented.

Laboratory medicine in the European Union.

The profession of laboratory medicine differs between countries within the European Union (EU) in many respects. The objective of professional organizations of the promotion of mutual recognition of specialists within the EU is closely related to the free movement of people. This policy translates to equivalence of standards and harmonization of the training curriculum. The aim of the present study is the description of the organization and practice of laboratory medicine within the countries that constitute the EU. A questionnaire covering many aspects of the profession was sent to delegates of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and Union Européenne de Médecins Spécialistes (UEMS) of the 28 EU countries. Results were sent to the delegates for confirmation. Many differences between countries were identified: predominantly medical or scientific professionals; a broad or limited professional field of interest; inclusion of patient treatment; formal or absent recognition; a regulated or absent formal training program; general or minor application of a quality system based on ISO Norms. The harmonization of the postgraduate training of both clinical chemists and of laboratory physicians has been a goal for many years. Differences in the organization of the laboratory professions still exist in the respective countries which all have a long historical development with their own rationality. It is an important challenge to harmonize our profession, and difficult choices will need to be made. Recent developments with respect to the directive on Recognition of Professional Qualifications call for new initiatives to harmonize laboratory medicine both across national borders, and across the borders of scientific and medical professions.

European views on patients directly obtaining their laboratory test results.

BACKGROUND: Medicine is a highly professionalized endeavour, by tradition centred on the authority of physicians. Better education and the advent of the information age cater for increased demands on society in general and on health care in particular to enable people to make informed decisions regarding themselves. Participation in medical decisions requires informed knowledge which is hard to obtain without substantial and time consuming professional help. METHODS: We performed a survey amongst the member organizations of European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) in order to investigate the recognition and preparedness of providing help to patients in interpreting their laboratory results. RESULTS: Out of 40 EFLM Member Societies, 27 sent their responses to the survey. In most cases the first line delivery of laboratory results to physicians is by computer link (63%). Patients receive their laboratory results on demand from their physician in 60% of cases. However, 34% of laboratory specialists showed a negative attitude for delivering laboratory results to patients. Yet, in 48% of countries 1-5 patients per day ask a laboratory specialist about the significance of laboratory results outside the reference range. When patients are informed about the purpose of laboratory testing, they seek information primarily from their physician, followed by the internet and the Specialist in Laboratory Medicine. CONCLUSIONS: Changing practices increasingly enabling patient access to their records are on the increase facilitated by recent innovations in information technologies. Successful transfer of some of the responsibilities of physicians, demands a mutual triangular dialogue between the patient, their physician and laboratory medicine.

Critical review of laboratory investigations in clinical practice guidelines: proposals for the description of investigation.

BACKGROUND: Correct information provided by guidelines may reduce laboratory test related errors during the pre-analytical, analytical and post-analytical phase and increase the quality of laboratory results. METHODS: Twelve clinical practice guidelines were reviewed regarding inclusion of important laboratory investigations. Based on the results and the authors' experience, two checklists were developed: one comprehensive list including topics that authors of guidelines may consider and one consisting of minimal standards that should be covered for all laboratory tests recommended in clinical practice guidelines. The number of topics addressed by the guidelines was related to involvement of laboratory medicine specialists in the guideline development process. RESULTS: The comprehensive list suggests 33 pre- analytical, 37 analytical and 10 post-analytical items. The mean percentage of topics dealt with by the guidelines was 33% (median 30%, range 17%-55%) and inclusion of a laboratory medicine specialist in the guideline committee significantly increased the number of topics addressed. Information about patient status, biological and analytical interferences and sample handling were scarce in most guidelines even if the inclusion of a laboratory medicine specialist in the development process seemingly led to increased focus on, e.g., sample type, sample handling and analytical variation. Examples underlining the importance of including laboratory items are given. CONCLUSIONS: Inclusion of laboratory medicine specialist in the guideline development process may increase the focus on important laboratory related items even if this information is usually limited. Two checklists are suggested to help guideline developers to cover all important topics related to laboratory testing.

Performance specifications for sodium should not be based on biological variation.

When increasing the quality in clinical laboratories by decreasing measurement uncertainty, reliable methods are needed not only to quantify the performance of measuring systems, but also to set goals for the performance. Sigma metrics used in medical laboratories for documenting and expressing levels of performance, are evidently totally dependent on the "total permissible error" used in the formulas. Although the conventional biological variation (BV) based model for calculation of the permissible (or allowable) total error is commonly used, it has been shown to be flawed. Alternative methods are proposed, mainly also based on the within-subject BV. Measurement uncertainty models might offer an alternative to total error models. Defining the limits for analytical quality still poses a challenge in both models. The aim of the present paper is to critically discuss current methods for establishing performance specifications by using the measurement of sodium concentrations in plasma or serum. Sodium can be measured with high accuracy but fails by far to meet conventional performance specifications based on BV. Since the use of sodium concentrations is well established for supporting clinical care, we question the concept that quality criteria for sodium and similar analytes that are under strict homeostatic control are best set by biology.

Reflective testing: adding value to laboratory testing.

Reflective testing is a procedure in which the laboratory specialist adds additional tests and/or comments to an original request, after inspection (reflection) of the results. It can be considered as an extension of the authorization process where laboratory tests are inspected before reporting to the physician. The laboratory specialist will inevitably find inconclusive results, and additional testing can contribute to make the appropriate diagnosis. Several studies have been published on the effects of reflective testing. Some studies focus on the opinion of the general practitioners or other clinicians, whereas other studies were intended to determine the patient's perspective. Overall, reflective testing was judged as a useful way to improve the process of diagnosing (and treating) patients. There is to date scarce high quality scientific evidence of the effectiveness of this procedure in terms of patient management. A randomized clinical trial investigating this aspect is however ongoing. Cost effectiveness of reflective testing still needs to be determined in the future. In conclusion, reflective testing can be seen as a new dimension in the service of the clinical chemistry laboratory to primary health care. Additional research is needed to deliver the scientific proof of the effectiveness of reflective testing for patient management.

How do laboratory specialists advise clinicians concerning the use and interpretation of renal tests?

BACKGROUND: The aim of this study was to elucidate how laboratory specialists advise clinicians concerning renal parameters and to compare their advice with guideline recommendations. METHODS: A questionnaire was distributed to laboratory specialists in Norway and The Netherlands together with two case histories from a primary health-care setting and one from a hospital setting, simulating questions from clinicians. The investigations that laboratory specialists suggested were compared to a test panel that was predefined based on clinical practice guideline recommendations (the 'recommended test panel'). The critical differences between two test results (creatinine, estimated glomerular filtration rate [eGFR] and albumin/creatinine ratio [ACR]) and the anticipated precision of the MDRD equation were evaluated. RESULTS: Fifty-two of the 100 laboratory specialists responded, and most of these were regularly contacted by clinicians to discuss laboratory results. Less than 30% would suggest using the recommended test panel to evaluate renal function in the two primary-care patients. For creatinine and eGFR, median changes stated to signal improvement or deterioration in renal function (creatinine: -14% and +14%, respectively; eGFR: +18% and -13%, respectively) were similar to what could be calculated using information on analytical and within-subject variation from the literature. There were variable critical differences for the ACR results (median values of -50% for improvement and +67% for deterioration). Only 23% of the participants would recommend a gold standard clearance examination for a patient who was to undergo nephrotoxic chemotherapy. CONCLUSION: Questions from GPs about renal parameters are answered differently by laboratory specialists, and adherences to guideline recommendations are low on some issues.

Measurement uncertainty for practical use.

Uncertainty is an inseparable part of all kinds of measurements performed in clinical laboratories. Accreditation standards including the ISO/IEC 17025:2017 and ISO 15189:2012 require that laboratories have routines for calculating the measurement uncertainty of reported results. Various guidelines such as CLSI EP29, Nordest 537, and ISO 20914:2019 have proposed methods for this purpose. However, due to the conceived complexity of the proposed calculation methods, these guidelines have not been generally and effectively applied in clinical laboratories. High workload and measurand heterogeneity favor a pragmatic utilitarian approach. The purpose of this paper is to describe such an approach, including its advantages and disadvantages. Measurement uncertainty should include the most influential factors affecting patients' test results. Since patients' samples for the same measurand can be analyzed in one laboratory or several laboratories using different measuring systems, the measurement uncertainty should be calculated using results obtained from analyzing the same internal quality control material if commutable or patients pooled/split samples.

Awareness of drug laboratory test interactions is important for prevention of unnecessary additional diagnostics: An example.

BACKGROUND: Elevated levels of Chromogranin A (CgA) may be indicative of a neuroendocrine tumour (NET), but increased levels are also observed after intake of proton pump inhibitors (PPIs). The incidence of diagnostic confusion because of this drug-laboratory test interaction (DLTI) was examined. METHODS: Medical records of 238 patients with elevated CgA concentrations were obtained from three hospitals. The following data were extracted: PPI prescription at the time of CgA measurement, medical decision making based on elevated CgA concentrations, final diagnosis, comorbidity and other prescribed drugs. RESULTS: From 238 patients with elevated CgA concentrations, 132 used PPIs. Of these patients, 57 patients did not have a NET. In 9 of these 57 patients (16%), diagnostic work up revealed no medical cause of an elevated CgA concentration. Somatostatin receptor imaging was ordered in 4 out of 9 cases, with no abnormalities observed. In 6 out of 9 cases, CgA measurement was repeated after PPI discontinuation resulting in normalisation of CgA concentrations. CONCLUSION: In this retrospective patient record study we observed that part of the elevated CgA concentrations in patients could be caused by the usage of PPIs causing unnecessary diagnostic work-up for the exclusion of a NET. These observations illustrate the need for better DLTI awareness.