Aim

The objective of the ECAT Foundation is to provide laboratories with an international proficiency testing programme which is focussed on the risk of (mainly venous) thrombosis. In this way, the accuracy of diagnosis of thrombophilia should improve, both by evaluating the performance of laboratory assays and by comparing the different metods used per assay. A prominent feature of the ECAT programme is its contribution to the development of assays, some of which are complex, or difficult to standardize.

Background

One of the activities arising from the European Concerted Action on Thrombosis (ECAT) which made its debut in 1981, is the assessment of a quality control of assays relevant to thrombophilia. It began in 1989 and was financially supported by the European Union (EU) until the end of 1993. The experience obtained was extremely useful and enabled us to continue quality assessment independent-ly of the EU. Since then the qua-lity assessment of thrombophilia has existed as an independent Foundation (ECAT Foundation). From 1989 until 1995 the circula-tion of samples and the elaboration of the results were carried out in Glasgow, UK by Drs. I. Walker and J. Conkie. In 1995 this work was transferred to the Gaubius Laboratory in Leiden, NL where P. Meijer and M. de Maat took over the work from Glasgow.

Scope

At present the ECAT Foundation comprises approximately 180 participating laboratories in 24 countries.

Scheme Design

To warrant an optimum liaison with clinical practice, we use plasma samples from normals and from patients with thrombophilia. The proficiency testing is performed 4 times a year using freezedried samples. Participants determine parameters using their routine methods. Results are prepared and sent out within 6 weeks of the dispatch of the samples. Results enable us to make a comparison between laboratories, to indicate the performance of a single laboratory, and to compare the different methods/reagents per assay.

Assays

The programme includes assays which are relevant to the risk of thrombosis. Increased risk is associated amongst other things with a genetic defect (mostly heterozygous) of blood components with an anticoagulant action such as antithrombin, Protein C, Protein S, and the Factor V Leiden mutation. The presence of Lupus Anticoagu-lants (immunoglobulins) and also of D-Dimer (a degradation product of fibrin) is associated with a predisposition to thrombotic disease. The ECAT programme includes the following assays:

Antithrombin

Protein C (activity and antigen)

Protein S (total and free antigen)

Protein S activity

Activated Protein C Resistance

Protein C Pathway

Lupus Anticoagulant

D-Dimer

At present extending the pro-gramme is being considered, with e.g. genotyping mutations of Factor V and Prothrombin, asso-ciated with thrombosis, using DNA samples.

Meetings

Participants meetings are held regularly. The aim of these meetings is to discuss results, practical aspects, the programme in the near future, contribution to the development of assays and the clinical implication of the results. The next meeting will be held in Leiden, The Netherlands, on 10 November 2000.

Research Projects

Recent research projects within the framework of the ECAT Foundation have resulted in publications on test results of Lupus Anticoagulant (1) and on the performance of semi-quantitative and quantitative D-Dimer assays (2). To gain insight into the cause of several variations the results of the ECAT scheme of the last years are being evaluated. The next edition of the book on assay procedures relevant to thrombosis appeared in 1999 (3). It gives a detailed, updated description of coagulation and fibrinolysis assays, each of which is prepared by an internationally recognized expert.

Collaboration with other Orga-nizations

To improve schemes and servi-ces the ECAT Foundation cooperates with national organizations in some countries, for instance with DEKS (Denmark) with the DGKC (Germany) and the NKK (Norway). Recently an agreement for cooperation be-tween the ECAT and NASCOLA (USA) was reached. Moreover, the ECAT cooperates with industrial firms in the development of assays, though the independence of the ECAT is strictly maintained. The ECAT Foundation is a full member of the EQALM and is prepared to follow the guidelines of ISO/IEC 43.

Information

For more information visit the website www.ecat.nl or contact the Executive Director of the ECAT Foundation, P. Meijer, P.O. Box 2215, 2301 CE Leiden, NL, phone +31 71 5181496; fax +31 71 5181330; e-mail: P.Meijer@ecat.nl

References

1. J. Arnout, P. Meijer, J. Ver-mylen. Lupus Anticoagulant testing in Europe: An analysis of results from the first European Concerted Action on Thrombo-philia (ECAT) survey using plasma spiked with monoclonal antibodies against human β2-Glycoprotein I. Thromb Haemost 1999; 81: 929-34.

2. M. de Maat, P. Meijer, W. Nieuwenhuizen, F. Haverkate. Performance of semi-quantitative and quantitative D-Dimer assays in the ECAT External Quality Assessment Programme. Sem Thromb Haemost, in press.

3. Laboratory Techniques in Thrombosis, a Manual. 2nd revised edition of ECAT Assay Procedures. Eds. J. Jespersen, R. M. Bertina, F. Haverkate; Kluwer Academic Publishers, Dordrecht, Boston, London, 1999, pp. 308.

Introduction

Previously we have presented the results of a small pilot study (1) on EQA in six different Danish laboratories regarding a point mutation in coagulation factor V (1691G>A or factor V Leiden). In this small EQA we found identity in replies from the six laboratories, but a marked disagreement in genotype nomenclature was revealed. We obtained constructive ideas from the enclosed questionnaire, and found that a no-menclature specification should be itemized in the reply sheet in future EQA's. In the present EQA more laboratories were included and we were interested in certain aspects of the analysis;

1) who orders the analysis?

2) what kinds of laboratories execute the analysis and how many analyses are performed in the laboratories in question?

Materials and methods

The programme consisted of distribution of a set of nine dif-ferent samples to each laboratory for investigation of FV Leiden mutation. The laboratories received at the same time a questionnaire.

All hospital laboratories in Denmark were invited to parti-cipate in the EQA. Furthermore some laboratories from other countries usually joining DEKS´s activities participated. The num-ber of participating laboratories was thirteen (eight Danish, two Norwegian, two Finnish and one from Switzerland). Three labora-tories did not fill in the ques-tionnaire.

Results

In this EQA we found identity in replies from all of the thirteen laboratories on all of the nine samples: One homozygote, four heterozygotes and four wild-types. These optimistic findings of FV Leiden mutation analyses are not shown in a table because they are identical.

In Table 1 and 2 an extract of the responses to the questionnaire is summarised.

In Table 1 the laboratories are characterised according to type of laboratory, what kind of ward or physician that order the FV Leiden analysis and number of routine tests per year carried out in each laboratory. 70% (7/10) of the laboratories participating in the EQA were Departments of Clinical Biochemistry and 30% (3/10) were “speciality labora-tories”, ie. other laboratories than those belonging to Clinical Biochemistry departments or to departments of Clinical Genetics, these speciality laboratories are often belonging to hospital wards. The median value of number of routine tests was 250 per year (range 20-800). Hospital wards ordered the FV Leiden analysis more frequent than general practitioners (median 62.5, range 50-99 and median 19.5, range 1-50, respectively).

Table 2 shows what repertoires the laboratories utilise to diag-nose thrombophilia. Only one laboratory did not offer any clotting-based coagulation tests. Most laboratories have employed the prothrombin 2021G>A muta-tion in thrombophilia screening in addition to the standard screen-ing with antithrombin, protein C and S and FV Leiden. The tests for protein C and S and anti-thrombin are indirect genetic tests (deficiency reflecting gene-tic disorders). Only four labora-tories apply the Activated Protein C resistance functional test in addition to the FV Leiden muta-tion test, this may involve that lupus anticoagulant or anticardio-lipin antibodies are missed if no further specialised tests are used.

Discussion

It seems that hospital wards are the main purchasers of the factor V Leiden mutation analysis, which probably reflects that screening for thrombophilia is primary a specialist matter. The results from an earlier EQA (1), revealed that nomenclature appeared to be a problem as dissimilarity in genotype nomen-clature was present. In the present EQA, the nomenclature used, was still not unambiguous (data not shown). Is has to be stressed that with the increasing appearance of new mutations and single nucleotide polymor-phisms (SNP), identical terms in the reporting of test results have to be employed. This is possible by following the recommenda-tions put forward by the Nomen-clature Working Group (2).

The big challenge in the future will be implementation of EQA on large scale DNA-analysis because more SNP’s and pathogenic mutations will appear along with the uncovering of the human genome. When a disease is polygenetic, various elements of the analytical process have to be considered in an EQA, first of all test quality, good laboratory practice (3), response time and comprehensibility of the test response.

References

1. Larsen TB. EQA in clinical molecular biology: Application to a test for a point mutation in coagulation factor V (1691G to A). EQAnews 1998; 9(4): 61-63.

2. Antonarakis SE. Recommen-dations for a nomenclature sys-tem for human gene mutations. Nomenclature Working Group. Hum Mutat 1998; 11(1): 1-3.

3. Neumaier M, Braun A, Wage-ner C. Fundamentals of quality assessment of molecular amplifi-cation methods in clinical diag-nostics. International Federation of Clinical Chemistry Scientific Division Committee on Molecular Biology Techniques. Clin Chem 1998 Jan; 44(1): 12-26.

CONSULTATIVE COMMITTEE FOR AMOUNT OF SUBSTANCE (CCQM) AND METROLOGICAL TRACEABILITY IN CHEMISTRY

René Dybkaer, Member IFCC/IUPAC C-NPU

Department of Standardization in Laboratory Medicine, H:S Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark

Tel +45 38 16 38 70, Fax +45 38 16 38 79

Under the Metre Convention of 1875, the General Conference for Weights and Measures (CGPM) maintains the International System of Units (SI). The executive arm of the CGPM is the Inter-ational Committee for Weights and Measures (CIPM) which supervises the International Bureau of Weights and Measures (BIPM) at Sèvres, France, where fundamental measurement standards and scales as well as primary reference measurement procedures are established. The technical aid to CIPM is provided by nine Consultative Committees, each studying a limited field of metrological kinds-of-quantity, such as length and time, including the relevant primary standards and primary procedures. These committees also organize highest-level key comparisons of measurements on materials distributed to the national metrological institutes [1]. The latest committee is the Consultative Committee for Amount of Substance (CCQM for Comité Consultatif pour la Quantité de Matière), established 1993. It has five working groups, namely Key comparisons, Organic analysis, Inorganic analysis, Gas analysis and Electrochemical analysis (including pH), so the field of CCQM is chemical measurement in gene-ral [2].

The data from the key comparisons, which can be looked upon as highest-level external quality assessment schemes, are entered into a BIPM database (www.bipm.fr) underpinning the degree of equivalence between the national metrology institutes that signed a Mutual Recognition Agreement (MRA) 1999-10 about calibration and measurement certificates. From this top of a calibration hierarchy – be it a calibrator or reference measurement procedure – measurement capabilities can be transferred to reference laboratories and then to routine laboratories, thus providing them with metrological traceability to the SI.

It goes without saying that traceability to a common top reference is the only way in which comparability of results over space and time is achievable for a given type of quantity. Nowadays, with cross-laboratory and trans-country service and communication, laboratory medicine cannot properly perform its role in diagnosis and therapy unless such comparability is routine. Consequently, for the EQA schemes, the values assigned to control materials have to be traceable to agreed higher metrological levels to achieve the paramount function of the schemes, namely to demonstrate trueness and interlaboratory equivalence of results among medical laboratories.

Some of the CCQM key comparisons at various stages are of direct interest to laboratory medicine, such as those concerning potassium ion in urine, calcium(II) in human liquid serum (with a link to the IMEP-17 conducted by the Institute for Reference Materials and Measurements (IRMM) in Geel), glucose in frozen serum, creatinine in lyophilized serum and pure creatinine. Furthermore, CGPM and CCQM have recently expressed a major interest in biotechnological metrology (cell lines, DNA and RNA).

The members of CCQM comprise delegates from the national metrology institutes, IRMM, the International Union of Pure and Applied Chemistry (IUPAC) and as of this year also the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC).

References

1. BIPM, The International System of Units. 7th ed., Sèvres: BIPM, 1998:152 pp.

2. CIPM, CCQM, Report of the 5th Meeting (1999-02). Sèvres: BIPM, 1999:95 pp.

EUROPEAN NETWORK ON IMPORTED INFECTIOUS DISEASE SURVEILLANCE (TropNetEurop).

T. Jelinek1, R. Behrens2, A. Björkmann3, M. Cochran4, A. Matteelli5 for TropNetEurop.

1Department of Infectious Disease and Tropical Medicine, University of Munich, Germany.

2Travel Clinic, Hospital for Tropical Diseases, London, UK.

3Department of Medicine, Unit of Infectious Diseases, Karolinska Institut, Karolinska Hospital, Stockholm, Sweden.

4Sección de Medicina Tropical, Hospital Clinic, Barcelona, Spain.

5Clinica di Malattie Infettive e Tropicali, Universitá di Brescia, Italy.

Corresponding author: Dr. Thomas Jelinek, Department of Infectious Diseases and Tropical Medicine, University of Munich, Leopoldstr. 5, 80802 Munich, Germany, Phone: +49 89 2180 3517, Fax: +49 89 33 61 12, E-mail: jelinek@lrz.uni-muenchen.de.

Objective and Expert Achieve-ments

The major objective of this venture is to establish and main-tain the European Network on Imported Infectious Disease Sur-veillance (TropNetEurop), an electronic network of clinical sites related to imported infectious dis-eases. The network is designed to effectively detect emerging infections of potential regional or global impact at their point of entry into the domestic popula-tion. Sentinel Surveillance repor-ting is carried out by participating sites by use of a standardised and computerised reporting sy-stem. Immediate transmission of anonymised patient and labora-tory data to the central database assures timely detection of sentinel events. TropNetEurop can serve as convenient tool to alert Public Health authorities and trig-ger further cluster investigation. The comprehensive collection of data on notifiable and not-notifi-able infectious diseases in travel-lers make it possible to identify needs for further surveillance and investigation and provides the potential for future case-control studies by identification of speci-fic risk factors. Furthermore, advantages and hidden pitfalls of the currently used systems of notifiable diseases in Europe can be evaluated by TropNetEurop. In addition, specific research pro-jects are initiated by the network steering committee, the coordina-ting site or by participating sites themselves.

Primary objectives of TropNet-Europ are:

1) to construct and maintain a collaborative research network of clinical sites in Europe dealing with imported infectious diseas-es; and

2) to establish and maintain a clinical network for effective sentinel surveillance of imported infectious diseases in Europe.

Secondary objectives of TropNet-Europ are:

1) to create European consensus for clinical guidelines for diagnos-tic and therapeutic procedures in imported infectious diseases;

2) to identify emerging pathogens by sampling returning internatio-nal travellers, immigrants and foreign visitors;

3) to add information and accura-cy to the current, divergent Euro-pean system of disease notifica-tion;

4) to provide grounds for cluster investigation and intervention strategies by Public Health authorities; and

5) to provide the basis for perma-nent research collaboration of infectious disease centres in Europe.

Institutional Profile and Partners

The network is headed by a network of coordinators and a steering committee (five members) that have been elected for two years by all site managers. Network partners have been selected under aspects of a wide coverage in Europe with inclusion of major travel clinics as well as inpatient and outpatient sites serving international migrants, asylum seekers, professional tra-vellers and tourists. The network is defined as a constantly chang-ing and growing entity. Therefore, further collaborating sites may be included over time and some partners listed now might decide to leave the network. Several partners have a history of joint publication with each other and many have previously served as co-investigators in multicentre projects. Participants of the network have been chosen carefully from a group of clinics that have acquired ample experience in collaborating together in a wide array of scientific studies within the last years. Therefore, although the selection of collaborating partners does not provide complete coverage of all European travel clinics, TropNet-Europ has the advantage to build up on existing links and knowledge between the collaborating partners from the beginning. The network grows steadily over time. With additional reporting sites, full coverage of travel clinics can be reached. The system of partnership within the network is based on different levels of participation: a) all sites collaborate as information receiving sites (epidemiological information is distributed regularly by the co-ordinating site) with option to report single, unusual sentinel events from their clinic; b) all reporting sites collect standardised surveillance data on imported malaria, dengue and schistosomiasis; and c) all sites have the possibility to participate in one or more research projects.

Outliers in external quality assessment programs are results that do not belong to the main population of results. Outliers occur frequently in external quality assessment results and are caused by method dependent matrix effects, analytical imprecision, analytical bias or blunders. One purpose of external quality assessment programs could be described as to identify the errors among the results. An error in this context is defined as a result with an unacceptable deviation from the target concentration of the quality control material. The consensus mean of the main population of results from the appropriate method group is used as the target concentration. If a reference method value is available any difference between the consensus mean and the reference method value will then be explored afterwards according to (1). In other words, to detect errors/outliers you have to calculate the location and dispersion of the distribution of results. In order to do that accurately, you have to detect and exclude the outliers. This is in principle a circular procedure and in the following the different ways of dealing with it will be outlined.

All the following procedures should be preceded with an inspection of the results, excluding the absurd errors, e.g. use of incorrect units yielding results thou-sand times higher than expected.

A priori identification of outliers

For small numbers of results no completely consistent method exists. For the traditional method, using the mean ±3*SD (and similar methods) as the limit for exclusion of outliers, it is quite easy to construct small data sets where all the results except the last two will be excluded successively if the procedure is used recursively.

A robust method that has been in use in some of Labqualitys programs for method groups with less than 7 results depends on the existence of a quality goal for imprecision, an allowable error, here expressed as a coefficient of variation (CV). The group median is calculated and if there are results deviating more than 3 times the allowable CV*median they are excluded. The procedure should not be repeated recursively after exclusion of results since the procedure will not converge in all cases.

When no independent information on the mean and standard deviation is available, the extreme deviations can be tested following the procedure originally described by Dixon (2,3). Test quotients of the difference between the extreme and next to extreme result divided by the range of all the results are compared to tabulated critical values. For samples with more than 3 results, quotients of the form (x_n-x_(n-i))/(x_n-x_j) are used with small values of i and j, where the results, x, are ordered with x_n the largest result and x₁ the smallest for testing high extreme results. For testing low extreme results, x_n is taken as the smallest result and x₁ the largest. Critical values for the quotients are tabulated in (2,3). The critical values assume a normal distribution of the results. Alternatively, the extreme studentized (“transformed to a Student distribution”) deviates can be tested (Grubb's test) (4-6) where the normalised deviation from the mean, (x_n – μ)/SD, is compared to critical values. The mean, μ, and standard deviation, SD, are calculated from the sample of results. This test is equivalent to testing the ratio of variances with and without the potential outlier (4,5). For more than 25 results, the test for the extreme studentized deviate should be used. For these tests, critical values assuming normal distributions of the results are tabulated in (3).

Calculation of means and SDs using robust methods

The procedures described above aim to identify outliers, exclude these results and then calculate reliable consensus means and standard deviations (SDs). Subsequently, errors or outliers are then identified using these means and SDs. It would be more straightforward to calculate reliable means and SDs directly, using robust methods not biased by extreme results, i.e. using the median as a robust estimate of the mean. An iterative procedure is recommended and described in detail in (1), where the extreme values are trimmed in a series of iterations until stable estimates are achieved. The initial value for the mean, x*, are set at the median of x_iand for the SD, s*, equal to 1.483 times the median of the numerical values of (x_i-x*), where x_iare the individual results. In each iteration values deviating more than 1.5 times s* from x* are set at x* + 1.5 times s* for positive deviations and x* - 1.5 times s* for negative deviations. In each iteration new values for x* and s* are calculated as the mean and 1.134 times the SD of the trimmed results. The trimming is continued until the values of the mean and SD become stable. The estimates are then used in the identification of errors and outliers.

Example

The 18 results shown in figure 2 sorted in increasing order are from a program for external quality assessment of methylmalonic acid in plasma. As judged by a visual inspection, the highest result of 0.17 µmol/l could be an outlier and the remainder seems to be close to a normal distribution. 0.17 µmol/l has a deviation close to 3 SDs from the mean value and would be judged a borderline outlier following the traditional 3 SD criterion. Dixon’s test proves the result to be an outlier with more than 99% probability and Grubb’s test with more than 95%. The preliminary calculations for Tukey’s test yields hinges of 0.097 and 0.115 µmol/l, a midspread of 0.0185 µmol/l, hence the lower and upper outer fence will be 0.041 and 0.171 µmol/l, respectively. According to Tukey’s test, 0.17 µmol/l is not an outlier. The robust calculation returns stable values to four digits for the mean and SD after 2 iterations of 0.104 and 0.0123 µmol/l and assuming a normal distribution, 0.17 µmol/l is an outlier with more than 99% probability. The calculated robust estimates of the mean and SD are the same as those calculated for the remaining 17 results to 3 decimals.

Dixon’s and Grubb’s tests are more sensitive than Tukey’s test for this example. This is often seen when comparing parametric and non-parametric tests. Since most samples of results within a method group in external quality assessment are normally distributed, a consistent approach will be to use Dixon’s test for small method groups (e.g. less than 12 results) and the robust calculation of the mean and SD for larger samples. Following the re-commendations of (1), deviations from target or reference method values could then be discussed on the basis of consensus means and appropriate quality goals.

3. Lentner C, Ed. Geigy Scientific Tables, Volume 2. Statistical Methods (Section 17, p. 206-7). Eighth edition, 1982 CIBA-GEIGY Limited, Basle, Switzerland.

5. Dixon WJ. Ratios involving extreme values. Ann Math Statist 1950; 21: 488-506.

6. Motulsky D. Grubbs’ test for detecting outliers. www.graphpad.com/articles/grubbs.htm

7. Libeer JCPM. External quality assessment in clinical laboratories. (Chapter IV, Section 4 p. 207-20). 1993. Universitaire Instelling Antwerpen, Belgium.

8. Strike PW. Statistical methods in laboratory medicine. (Chapter 2, Section 10.2, p. 34-6). 1991. Butterworth-Heinemann Ltd. Oxford.

QUALITY IN THE SPOTLIGHT. MEETING ON QUALITY IN MEDICAL LABORATORIES IN ANTWERP ON OCTOBER 19^th AND 20^th 2000

Dr. Henk M.J. Goldschmidt. Dept. of CKCHL, St. Elisabeth Hospital, Tilburg, The Netherlands. Tel: +31 13 5392693, Fax: +31 13 5352390,

Dr. Jean Claude Libeer. Institute of Public Health Louis Pasteur, Brussels, Belgium. Tel: +32 2 642 55 27, Fax: +32 2 642 56 45,

For the sixth consecutive year this international meeting will be held at the Elzenveld Conference Center in Antwerp. This years conference is sub-titled "EFQM model in medical laboratories" and is arranged in cooperation with the European Foundation for Quality Management in Brussels. The two-day conference will focus on the laboratory environment, its suppliers, its customers and how these should interact as defined in the EFQM quality system. The quest for the best: but how to define and afford the best? In Stockholm in April 1999, quality specifications were given for various phases of the laboratory work: are they in use? The chain model industry-transport-laboratory-physician-patient needs to be re-explored. Starting from a general point of view we will discuss and evaluate if and how the EFQM (European Foundation for Quality Management) model is applicable to medical laboratories. This important, general model is designed to support total quality management in any branch. Then the nine EFQM model parameters will be evaluated towards their practicability in medical laboratories. The EFQM model in medical laboratories is based upon five enablers: leadership, people management, policy & strategy, resources, processes and four result oriented issues: people satisfaction, customer satisfaction, impact on society, business results. Through this evaluation the entire spectrum of quality issues in medical laboratories will be overseen again. But also the very practical EFQM RADAR scoring card to provide a quick scan of the quality of your particular laboratory will be outlined. What is the relation between the EFQM model and the chain model that was advocated for many years at the Antwerp quality meetings? Again speakers of the highest level will lecture, instruct and discuss the relevant quality issues in medical laboratories. Look in the various issues of The Journal of Accreditation and Quality Assurance (e.g. 4/3 '99 and 4/9-10 '99) for the proceedings of the past years. The Westgard quality award (previous awardees Dr. René Dybkaer and Dr. Adam Uldall) will be given again to an outstanding scientist in the field of TQM in medical laboratories by Prof. Westgard himself. A group of over 20 well known experts in the field will present and elaborate recent developments in the quality thinking in medical laboratories.

Peter K. Mogensen. Novo Nordisk A/S, 6E.2.14, Novo Allé, DK-2880 Bagsvaerd, Denmark. E-mail: pkm@novo.dk

Dr. Michael Noble (clinical microbiology). Clinical Microbiology Proficiency Testing, University of British Columbia, Room 328A, Heather Pavilion C, Floor 27, Heather Street, Vancouver, BC V5Z, Canada. E-mail: mnoble@ interchange.ubc.ca

Dr. Joergen Kurtzhals (clinical parasitology). Dept. Clin. Microbiol., Statens Serum Institute, Artillerivej 5, DK-2300 Copenhagen S, Denmark. E-mail: jku@ssi.dk

Dr. Igor Bondarenko (clinical virology). Russian Research Institut for Metrology, 19 Moskovsky Pr., St. Petersburg, 198005 Russia. E-mail: bigor@mail.lanck.net

Dr. Nils Joergensen (clinical biochemistry). Dept. Clin. Biochem. Soenderborg Hospital, DK-6400 Soenderborg, Denmark. E-mail: nils.borg@po.ia.dk

Dr. Jan Moeller (clinical biochemistry). Dept. Clin. Biochem. Skejby Sygehus, Aarhus University Hospital, Brendstrupgaardsvej, DK-8200 Aarhus, Denmark. E-mail: jan@kba.sks.au.dk

Dr. Vives Corrons (haematology). Haematology Lab. Dept., Escala 1 B – Planta 3, Hospital Clinic 1 Provincial, C/ Villaroel 170, ES-08036 Barcelona, Spain. E-mail: jlvives@medicina.ub.es