Los bisfosfonatos, más allá de la RAE / Bisphosphonates, beyond the Royal Spanish Academy

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Guidelines to Subcontracting Clinical Laboratory Examinations a Proposal of the Catalan Association for Clinical Laboratory Sciences.

Clinical laboratories, acting as subcontractors, do not always supply information on the quality of their examination procedures and results. Thus, its selection by a contracting organization is often based only in economical criteria. This article gives some guidelines to subcontractors on how to describe its quality characteristics in order to be appropriately contracted.

Variability of the biological variation.

A great diversity among within-subject and between-subject biological variation data is shown from previously published works. Consequently, most of the proposed applications of biological variation to set metrological goals or requirements should be revisited.

Certification of the mass concentration of creatine kinase isoenzyme 2 (CK-MB) in the reference material BCR 608.

We describe the certification of a mass concentration value in the already prepared creatine kinase-2 reference material (BCR 608). Creatine kinase-2 was purified from human heart. The purified enzyme was diluted in order to measure its protein concentration by the Doetsch method. A protein concentration value of 124.30+/-13.17 mg/l was assigned to the stock solution of purified creatine kinase-2. This stock solution was diluted in 25 mmol/l piperazine-N,N'-bis[2-ethanesulfonic acid] (PIPES) pH 7.2, containing 2 mmol/l ADP, 5 mmol/l 2-mercaptoethanol, 154 mmol/l sodium chloride and 50 g/l human albumin to obtain a stable liquid standard of known creatine kinase-2 mass concentration (80.36 microg/l). This standard was then used to recalculate the creatine kinase-2 mass concentration measured in the BCR 608 material by immunoassay. The mass concentration of creatine kinase-2 in samples of reconstituted BCR 608 was certified to be 93.30+/-9.65 microg/l.

Multicentric reference values for some quantities measured with Tina-Quant reagents systems and RD/Hitachi analysers.

Ten clinical laboratories in different regions of Spain have shared the search for reference individuals and the production of reference values for quantities concerning ferritin, transferrin, rheumatoid factors, C-reactive protein and antistreptolysin O, using Tina-Quant reagents systems and RD/Hitachi analysers. All the logistic work has been done in co-operation with the supplier of the reagents and analysers (Roche Diagnostics España, S.L., Barcelona). The reference limits produced in the virtual laboratory are derived from the blend of reference values obtained by each laboratory. The multicentric reference limits were estimated according to the recommendations of the International Federation of Clinical Chemistry. The work done is a model of co-operation between the in vitro diagnostic industry and clinical laboratories for the production of reference values.

Regional reference values for some quantities measured with the ADVIA Centaur analyser. A model of co-operation between the in vitro diagnostic industry and clinical laboratories.

This work is a model of co-operation between the in vitro diagnostic industry and clinical laboratories for the production of reference values. Thirteen clinical laboratories having an ADVIA Centaur analyser and representing the majority of the geographical regions of Spain have shared the search for reference individuals and the production of reference values for thyrotropin, free thyroxine, free triiodothyronine, cobalamine and folate concentrations in serum. All the logistic work has been done in co-operation with the Spanish supplier of the ADVIA Centaur analyser. The reference limits produced in the virtual laboratory are derived from the blend of reference values obtained by each laboratory. The multicentre reference limits were estimated according to the recommendations of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC).

Multicentric reference values for some quantities measured with the Elecsys 2010 analyser.

Several clinical laboratories in different regions of Spain have shared the search for reference individuals and the production of reference values for quantities concerning thyrotropin, non-protein bound thyroxine, triiodothyronine, cobalamines and folates, using an Elecsys 2010 analyser. All the logistic work has been done in co-operation with the supplier of the analyser (Roche Diagnostics España, S.L., Barcelona). The reference limits produced in the virtual laboratory are in fact derived from the blend of reference values obtained by each laboratory. The multicentric reference limits were estimated according to the recommendations of the International Federation of Clinical Chemistry. The work done represents a model of co-operation between the in vitro diagnostic industry and clinical laboratories for the production of reference values.

Need for revisiting the concept of reference values.

The reference values concept has been adopted by health care professionals, including clinical chemists, laboratory scientists, and clinicians and simultaneously by all the official organizations in charge of the establishment of legislation. But the estimation of reference limits, and the evaluation of biological variability need to be improved at the level of the procedures, which are currently too long and too expensive and not feasible easily for all laboratories. The procedures for obtaining reference values, if we follow the original documents, are complex, and that is the main reason that clinical chemists or diagnostic kit manufacturers have not used them systematically. There is clearly a need that scientific societies and international organizations propose practical recommendations: 1) Recommendations to describe methods linked to systematic error. * How to transfer reference limits from one laboratory to another laboratory using different methods? * Should we determine reference limits for each method? * How can we differentiate bias due to the populations from these due to the method? Clear collaborations with manufacturers involved in kits and diagnostic systems are needed. 2) Practical recommendations linked to the reference population. * How to select a homogeneous population? (Careful recommendations on the choice between healthy individuals, blood donors and individuals hospitalised for other diseases should be given.) * How to estimate ethnic differences? * How to define the exclusion and inclusion criteria according to quantity? * How to deal with the question of reference limits for unstable periods, aging or old people particularly, when the difference between aging and disease is very difficult to define? 3) Practical recommendations on the statistical methods to be used. * How to make a good choice of the interquartile interval? Should we use and present only the centiles 2.5 or 97.5, or on the contrary should we give other centiles in addition, for example 5, 10, 75, 80, 85, 90? 4) Practical recommendations linked to the use of the concept of the reference values. * How to make this concept more concrete and to have official definitions which are better understandable and not only abstract? * How to demonstrate the value of using simultaneously reference limits and decision limits, and what does each of these limits bring to results interpretation? * How to improve the presentation of the results? How to give more information on biological variability in the laboratory data, taking into account the scientific validity of their determination? Should we use new information techniques and new communication systems for reaching these objectives? The responses to all these questions could only be provided if there is a concerted effort at the international level. Practical recommendations should be given, which would be very useful for a better understanding and use of reference values by laboratory scientists and clinicians.

Indirect reference limits estimated from patients' results by three mathematical procedures.

Presently, only a few clinical laboratories produce their own reference values, while the great majority use reference intervals reported in the literature. An alternative to this unsatisfactory situation is to estimate indirect reference limits by means of mathematical/statistical procedures from patients' results obtained routinely in the laboratory. The procedures of Bhattacharya (A simple method of resolution of a distribution into Gaussian components. Biometrics 1967;23:115-135) Martin et al. (Reference values based on populations accessible to hospitals. In: Gräsbeck R, Alström T, editors. Reference Values in Laboratory Medicine. Chischester: Wiley, 1981:233-262) and Kairisto et al. (Generation of reference values for cardiac enzymes from hospital admission laboratory data. Eur J Clin Chem Clin Biochem 1994;32:789-796) were applied to 14 biochemical quantities. In order to verify these procedures, the indirect reference limits obtained from patients' results were validated by statistical comparison with reference limits estimated from a reference sample according to recommendations of the International Federation of Clinical Chemistry (IFCC). Calculated indirect reference limits for most quantities studied were reliable, but indirect reference limits for bilirubins and potassium ion substance concentrations, alanine aminotransferase, and aspartate aminotransferase catalytic concentrations in serum were not suitable. We conclude that indirect reference limits can be obtained from patients' results by all procedures studied when skewness and kurtosis of mixed distribution are not too large, but other factors also seem to have an influence on the reliability of these procedures.