A model for harmonization of routine clinical chemistry results between clinical laboratories.

Clinical chemistry laboratory results from different laboratories often show large between-laboratory variation due to factors such as differences in method principles, method applications, calibration procedures or the application of different instrument factor settings within the same calibration procedure. We have examined the possible use of common calibrators to reduce this variation. Three different calibrators were compared: A, freeze-dried preparations of pooled patients' serum samples, spiked to give three concentration levels; B, freeze-dried preparations of pooled patients' serum samples selected on the basis of elevated enzyme activities at three levels; C, a single calibrator consisting of frozen pooled serum samples. These calibrators were sent to 11 participating laboratories together with 14 fresh patients' serum samples. We report the variation of the results of 21 general clinical chemistry analytes obtained in the patients' serum samples before and after recalculation on the basis of the results of the calibrators. For most analytes the use of a multiple point linear regression calibration function is able to reduce the between-laboratory variation considerably from more than 30% (enzymes) to values well within the bias limits set by European quality specifications, when the necessary conditions are met. These conditions include the commutability of the calibrator(s) with fresh patients' material. For the enzymes, calibrator material originating from selectively pooled patients' samples appeared to be necessary, whereas for the substrates selectively pooled serum calibrators spiked with exogenous supplements may be used. For harmonization to be effective in practice, calibrators need to be stable over time and to carry assigned values set by certified reference laboratories, and the quality performance of participating laboratories should be appropriately monitored.

Usefulness of EC4 essential criteria for quality systems of medical laboratories as guideline to the ISO 15189 and ISO 17025 documents. European Community Confederation of Clinical Chemistry (EC4) Working Group on Harmonisation of Quality Systems and Accreditation.

Many medical laboratories have made a start with the introduction of quality management systems. However, it is still not clear against which standards such systems should be measured. The existing ISO and CEN standards do not cover essential aspects of medical laboratories. The publication of the EC4 Essential Criteria has stimulated the development of the ISO/Draft International Standard 15189. This standard seems adequate for our type of laboratories. However, it is not easy to read. The EC4 Essential Criteria could well serve as a guide, covering additional aspects, e.g. on total quality management and budget management as required in the EFQM model, that are not (yet) included in the ISO standard. In the present article the EC4 Essential Criteria are cross-referenced with two new international ISO standards, ISO/FDIS 15189 and ISO/FDIS 17025, the latter being the successor of ISO guide 25 and EN 45000. Both new ISO documents are in compliance with the new ISO 9000:2000 standard.

Recent activities of EC4 in the harmonization of clinical chemistry in the European Union.

This article describes the recent activities of the European Communities Confederation of Clinical Chemistry (EC4). Main goal of EC4 is harmonization of clinical chemistry in the European Union and Europe. EC4's actions connected to that are training and registration of professionals, and accreditation of laboratories. The 35000 professionals practising clinical chemistry in the EU have different backgrounds (medical, pharmaceutical, science-oriented, veterinary, or microbiological). Thus, for the harmonization of training of clinical chemists, EC4 has published a European Syllabus for Postgraduate Training, and instituted a European Union Register for Clinical Chemists. The Syllabus is an indication of the level of requirements in postgraduate training. The EC4 initiative to implement the European Register for Clinical Chemists is based on the 8 years vocational training necessary to obtain sufficient knowledge in clinical chemistry according to the European Syllabus. A guide to the EC4 Register has been published; registration leads to the title European Clinical Chemist (EurClinChem). The accreditation of laboratories must be based on a total quality management system. EC4 has described guidelines (essential criteria) which it judges appropriate for establishing the quality of medical laboratory service; it does not wish to fulfil the role of an accrediting body. Moreover, a working group has been set up to seek to harmonize the work of national accrediting bodies. Therefore, it is logical that EC4 monitors the activities of the different standardizing bodies that might influence the practice of clinical chemistry in the EU. Finally, some aspects concerning the future strategy of EC4 are brought forward.

Concepts for a model of good medical laboratory services.

Several international standards and corresponding interpretation documents for quality management systems have been published. Although these standards are found useful to some extent, they are considered to be insufficient in several areas important for medical laboratories particularly in the pre- and post-examinational phases. The normative document for accreditation of laboratories (ISO/IEC Guide 25) is presently being revised and a document for medical laboratories (ISO/TC 212, CD 15189) is at draft stage. Both aim to include aspects of total quality management. The concept of total quality management is rather vague. Generally, its goal has been defined as "business excellence". This term, however, needs some explanation if applied to medical laboratories. Therefore, a project group of the European Confederation of Laboratory Medicine (ECLM) has developed a model for total quality management, which is based on a comprehensive management concept issued by the European Foundation for Quality Management. In the case of a medical laboratory, the term "business excellence" should be replaced by "good medical laboratory services". The proposed model could serve as a basis for future developments of total quality management standards in laboratory medicine. The goal of the "journey" should be clarified before it starts. To the best of our knowledge, this is the first attempt to develop a model of a good medical laboratory.

Additional Essential Criteria for Quality Systems of Medical Laboratories. European Community Confederation of Clinical Chemistry (EC4) Working Group on Harmonisation of Quality Systems and Accreditation.

Essential Criteria for Quality Systems of Medical Laboratories have been published recently by the European Community Confederation of Clinical Chemistry (EC4) Working Group on Harmonisation of Quality Systems and Accreditation. The Essential Criteria address the majority of critical aspects of quality management in the medical laboratory. They have been accepted by the EC4 General Assembly and are endorsed by the Forum of European Societies for Clinical Chemistry (FESCC). However, a supplement to the Essential Criteria was necessary, addressing two aspects, which are only partly covered by the Essential Criteria: the management of resources and point of care testing. Thus, the EC4 Working Group on Harmonisation of Quality Systems and Accreditation has decided to formulate Additional Essential Criteria for Quality Systems of Medical Laboratories, directed at the issues of management of resources and point of care testing. Criteria on management of resources address financial aspects, information logistics and acceptance by clients. Criteria on point of care testing address responsibilities, education of non-laboratory staff and operational aspects. The Additional Criteria are supplementary to the previously published Essential Criteria and should be read as an integral part of these.

[Laboratory testing virtually centralized to benefit both patients and drug research]. / Laboratoriumonderzoek virtueel gecentraliseerd ten behoeve van patiënt én geneesmiddelenonderzoek.

Laboratory analyses in multicentre safety studies of new drugs usually are performed in central laboratories outside the Netherlands. Patient care requires local (hospital) laboratory tests. In the so-called Virtually Centralized Laboratory the Dutch local laboratories report their results after data communication and data transformation in such a way that they seem to form one laboratory. The local analytical results are transformed by calibrating the local methods using standard preparations, thus reducing the inter laboratory variation. This concept may lead to one set of national reference values for all general clinical chemical and haematological laboratory tests.

Essential criteria for quality systems in medical laboratories.

The introduction of total quality systems in medical and clinical laboratories and accreditation of these laboratories is gaining more and more interest. In several countries laboratories have set up quality systems, and accrediation schemes are also operating. The standards of these schemes have much in common although several differences exist. There exists uncertainty in several countries on the choice of a system. Laboratory specialists are confronted with a new way of thinking concerning the management and daily practice of their laboratories. It is not clear, which standards should be used as a basis, and certainly not how to interpret such standards. Particulary in the European Union, harmonisation of criteria for quality systems is desirable. In the present paper, the document entitled "Essential Criteria for Quality Systems in Medical Laboratories" is presented. The document has been accepted in the general Assembly of the European Communities Confederation of Clinical Chemistry (EC4) and by the working group on Good Laboratory Services of the European Council on Laboratory Medicine (ECLM). The criteria in the document are focussed on the particular situation of medical laboratories, including pre- and post-analytical aspects. Reference is made, where applicable, to EN 45001, ISO 9001 and ISO guide 25 draft 3.

Quality and accreditation systems in clinical biochemistry in the European Union.

The European Community Confederation of Clinical Chemistry (EC4) formed in Nice in April 1993 has established a working group on laboratory accreditation. The aim of the group is to explore the possibilities for harmonisation of accreditation and quality systems in clinical laboratories in the European Community (EC). It is felt essential that professions should play a key role in the process, and that the principle of subsidiarity should be observed in relation to implementation and organisation in individual member states. The first task has been to collect information concerning such systems. In September 1993 a questionnaire was distributed to the twelve IFCC related societies for clinical chemistry in the EC. By December 1994 eleven societies had responded. The questionnaire related to the existence or planned introduction of quality and accreditation systems, the basis of the standards used and requirements for analytical aspects and qualifications of staff as well as professional aspects. Questions also addressed the way in which inspection were organised, the selection and training of inspectors, the organisation of systems and what interest there was in harmonisation. The results of this study are presented in this paper.

A case of hyperalphalipoproteinemia associated with albumin complexing.

We present a 3 year follow up of a new type of hyperalphalipoproteinemia with stable high density lipoprotein (HDL) concentrations around 6.0 mmol/l in a female with persistently elevated erythrocyte sedimentation rate (ESR). By density gradient ultracentrifugation, next to the intensively colored HDL2-fraction, an additional band between HDL3 and the serum proteins was seen consistently. The patient's plasma contained an unique complex of albumin with apoprotein A-I. Her IgM was 3- to 4-fold elevated was not complexed to HDL. Familial forms of hyperalphalipoproteinemia could be excluded. As a presumed reason for the existence of the HDL-albumin complex we found that the patient's post-heparin plasma lipoprotein lipase activity was over 2-fold increased, while that of hepatic lipase was over 2-fold decreased: no common cause for the existence of the albumin complex and the increased concentration of IgM was found.

Between-country comparability of clinical chemistry results: an international quality assessment survey of 17 analytes in six European countries through existing national schemes.

Two lyophilized control sera were distributed through seven national external quality assessment schemes in six European countries--Belgium, Switzerland, France, The Netherlands, Sweden and the United Kingdom--participated in the study. The results for 17 routine analytes were obtained from almost 5000 laboratories for the two sera. The organizers of the schemes were asked to process the results according to a common outlier removal procedure, and submit method-related data if available. The two sera were also distributed through the external/internal scheme of The Netherlands, and the within-laboratory standard deviations calculated in this scheme have been used in a scaling procedure for the external mean values and between-laboratory standard deviations of the participating countries. The results show remarkable agreement in the national mean values for practically all analytes, but considerable differences in the between-laboratory variation. Data from comparable method groups was obtained for 12 analytes from Belgium, France, The Netherlands and the UK. Though revealing some specific differences between methods and countries, the method-related data are generally in agreement with the all-method data. In this study reference method values were only available for cholesterol. The high degree of agreement found suggests, however, that mutual recognition of all-method mean values in national schemes could be acceptable, especially for analytes for which reliable reference methods are not available. The major element of variation is between-laboratory rather than between-country.

Combi scheme: new combined internal/external quality-assessment scheme in The Netherlands.

The Dutch Foundation for Quality Assessment in Clinical Chemistry (SKZL) is the professional organization that conducts external quality-assessment schemes in The Netherlands. However, such schemes in fact assess the performance of the internal quality-control systems of the participating laboratories. In this paper we describe a new concept, relating the data for internal control materials with those for external samples and thereby leading to a combined external/internal scheme (Combi). The statistical principles underlying the Combi scheme are discussed and examples of the graphical presentation of the results are shown. Because the laboratory data are transmitted over the public telephone system to the computers of the SKZL, we also describe the principles of the data communication. At two-month intervals a statistical presentation is sent to all participants. The central database is updated daily with the received results, making possible an on-line consultation regarding the statistics of the accumulated findings of the control materials in use.

Minimizing interlaboratory variation in routine assays of serum cholesterol through the use of serum calibrators.

A cholesterol standardization program was developed in The Netherlands for clinical laboratories that use their analytical results as indicators of cardiovascular risk. Participants with sufficient precision but inaccurate results are encouraged to use serum-based calibrators as a means to decrease bias. A regional pilot survey and thereafter a national one were carried out in 31 and 138 laboratories, respectively, to investigate whether use of the serum-calibration procedure could improve routinely performed cholesterol measurements. To participants in our national quality-control surveys were mailed three calibrators (pooled human serum) and five human-serum controls, for analysis of cholesterol on four different days. Reference method values had been assigned to the calibrators by the Netherlands Reference Laboratory, applying the U.S. Centers for Disease Control modification of the Abell-Kendall procedure. Using the calibration curves based on results for the serum calibrators decreased the between-laboratory variation (SD) by at least 50%, with improved accuracy for non-enzymatic methods. The initial within-laboratory precision was generally good, and improvements in it were small. To our knowledge, standardization results involving so many routine hospital laboratory procedures have not been previously reported.

Variance reduction in analytical processes in the clinical laboratory by digital filtering.

A model is postulated describing the fluctuations in analytical chemical processes in the clinical laboratory. In this model the process variations are described by a non-stationary stochastic process with a significant time-varying mean value. Experiments short-term variance within a run and a long-term variance between runs determined by the time-varying mean value. For four different analytical systems used for determining six serum analytes between-run variance was demonstrated to be significantly greater than within-run variance. Based on the model a digital filtering procedure is presented which in each run estimates the process mean and subsequently corrects serum samples for its deviation. Thus significant variance reductions are obtained. The filtering procedure was tested for the determination in inorganic phosphate with a continuous-flow system in an experimental environment.

Comparison of routine analytical methods in the Netherlands for seven serum constituents using pattern recognition.

Routine analytical methods for seven serum analytes (calcium, chloride, cholesterol, glucose, inorganic phosphate, urate, and urea) are assessed using data from the Netherlands coupled external/internal quality control program. From the results of a trial each method can be described by four features: measures of bias, between-day precision, tendency to give erroneous results, interlaboratory variance. These four features of each trial determine a vectorpoint in the four-dimensional space for a particular method. From 12 trials a maximum of 12 vectorpoints per analytical method was obtained. Pattern recognition techniques allowed the detection of clusters of vectorpoints. Analytical methods having vectorpoints classified in different clusters perform differently. The mean feature values of the vectorpoints forming a cluster determine the quality of that cluster. A weighting procedure reveals the importance of the respective features for discriminating the clusters. For all of the seven analytes, clusters of vectorpoints were found. Different features appeared to contain discriminatory power for different analytes. For six analytes (calcium, chloride, cholesterol, glucose, inorganic phosphate, and urea) an analytical method was found to classify predominantly in the qualitative best cluster. One analytical method for the determination of chloride and one for glucose, inorganic phosphate, and urea did not cluster at all.

Standards versus standardised methods in enzyme assay.

In a trial of the Netherlands coupled external/internal quality control program a control serum and an enzyme standard were analysed over a period of eight weeks, five times each week. Five enzymes were determined: alkaline phosphatase, creatine kinase, lactate dehydrogenase, alanine aminotransferase, and gamma-glutamyltransferase. The measured values in the serum were converted to the standards. Those laboratories using the recommended methods also submitted their non-transformed serum values. The following standardisation techniques have been compared: (a) no standardisation of methodology but use of enzyme standards; (b) standardisation of methodology; (c) standardisation of methodology combined with use of an enzyme standard. Results were submitted to analysis of variance. Standardisation of methodology did not yield smaller interlaboratory variation than the standardisation with enzyme standards. In this trial a combination of both standardisation techniques yielded generally better results. Results for gamma-glutamyltransferase indicate that standardisation of substrate may be necessary apart from the use of an enzyme standard. The preparation of stable enzyme standards is stressed.

Intra-individual variation of serum cholesterol, triglycerides and high density lipoprotein cholesterol in normal humans.

The intra-individual variation in the concentrations of serum cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-chol) was determined in 53 healthy subjects, without extreme standardization of test subjects and sampling conditions. Within 1 year, the intra-individual variation of the subjects ranged from 3.9 to 10.9% for cholesterol; from 12.9 to 40.8% for triglycerides, and from 3.6 to 12.4% for HDL-chol. More than 60% of the average total intra-individual variation was caused by biological fluctuations and the remainder was the result of analytical variation. Thus, a single measurement of these serum constituents in an individual can be misleading or meaningless, unless the value is considerably outside the normal range. No significant diurnal variation was found in the concentrations of serum cholesterol and HDL-chol. The maximal post-prandial increase of the serum triglycerides was twice as great in the men than in the women. Finally, significant trends in the fluctuations of serum lipids and HDL-chol during 1 year were not found.