The influence of analytical bias on diagnostic misclassifications.

Quality specifications for analytical imprecision and bias based on the state of the art; 'biology' and 'analysis of clinical situations' have been proposed by several scientists. Most interesting is the assessment of 'diagnostic misclassifications' based on direct evaluation of the consequences of analytical bias on the percentage of false positives and false negatives from a clinical decision situation, or based on the percentage of healthy individuals outside each reference limit when common reference intervals are used. With use of graphical or computer simulations assuming increasing (positive or negative) analytical bias, the expected percentage of misclassifications can be estimated- and, for the error for which the outcome (the fraction of misclassifications) is considered unacceptable, the maximum allowable analytical bias can be defined. An overview is given of previous proposals for specification of allowable analytical bias, and new examples are presented: (i) for S-transferrin. an analytical bias of +10% will increase the percentage of healthy individuals with measured concentration values above the upper reference limit from 2.5 to 10% (ii) the percentage of healthy men with concentration values for S-cholesterol above 6.2 mmol/l (240 mg/dl) will vary between 25 and 85% for analytical bias from - 1.0 to +1.0 mmol/l (+/- 16%): (iii) for glycated haemoglobin, two examples are given which illustrate the effect of analytical bias on the risk of retinopathy and so-called 'microalbuminuria' for measured values identical to the target 7.5% and 10.1% glycated haemoglobin, respectively. It is concluded that analytical bias may have significant impact on diagnostic performance, better standardization is needed, and quality specifications for allowable analytical bias should be based on medical usefulness criteria or, if such data are not available, on biological criteria.

Analytical quality goals and assessment to ensure transferability of laboratory results.

About 3 years ago NORDKEM started a project entitled 'Medical Need for Quality Specifications in Clinical Laboratories'. This communication describes the general approach of this project and a subproject oriented towards problems of transferability of clinical laboratory data. Attempts are made to estimate clinical goals for analytical measurements--either used alone or in combinations with other measurements or observations--in defined clinical situations. Various methodologies are used for the assessment of the clinical goals, starting, e.g., from clinical situations or biological reference data. The analytical quality specifications are expressed as total allowable errors. It is necessary to complement specifications of 'clinical goals' with data describing characteristics of the measurement procedure, preanalytical errors and internal and external quality assurance procedures in order to establish the laboratory quality specification guaranteed by the laboratory. Problems of transferability of clinical laboratory results occur both within a laboratory/hospital and between laboratories/hospitals/health care units, problems that sometimes make communication of laboratory results difficult or even meaningless. In order to study the transferability of clinical laboratory data within a health care region, so called 'transformation functions' could be used to characterize each laboratory in a strict quality assessment/proficiency testing procedure on the basis of analytical quality specifications. Under certain conditions, e.g. for analytical procedures with high specificity and documented stable analytical performance, numerical correction of analytical bias could be performed to decrease interlaboratory variation to a level specified by medical needs.

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.

A quality manual for the clinical laboratory including the elements of a quality system. Proposed guidelines.

Development of quality manuals is a means for the promotion of quality in clinical laboratories by describing the total quality system. It also provides opportunity of checking whether the quality system is implemented in reality and demonstrates to the hospital administration and the clinicians that the laboratory is committed to quality. The intention of these guidelines is to describe the elements of the quality system for a large clinical laboratory, and to present such a system in the form of a quality manual. The proposed guidelines comply, where relevant, with ISO/IEC guide 25 'General requirements for the technical competence of testing laboratories' and EN 45001 'General criteria for the operation of testing laboratories'. The document may be used as an aid for laboratories wishing to be accredited according to EN 45001, or intending to apply for formal certification of their quality systems, according to ISO 9001 'Quality systems--Model for quality assurance in design/development, production, installation, and servicing' utilizing ISO 9004 'Quality management and quality system elements--guidelines; Part 2 Guidelines for service'. However, information about the minimum requirements for official recognition should be obtained from the particular accreditation or certification body concerned.

Reduced oxygen affinity contributes to improved oxygen releasing capacity during erythropoietin treatment of renal anaemia.

In addition to haemoglobin concentration, haemoglobin oxygen affinity plays a major role in the oxygen releasing capacity of the blood. In this study we have measured oxygen affinity as P50 and calculated the oxygen releasing capacity of blood from 10 haemodialysis patients treated with erythropoietin (rHuEpo). The patients were examined with different assays before start of treatment, after 11 weeks, and after 27 weeks. During the first phase of treatment the oxygen releasing capacity improved because of an increase in the haemoglobin concentration and P50. During the second phase there was a further significant increase in haemoglobin concentration, but due to a decrease in the P50 value the oxygen releasing capacity remained unchanged. Despite an unchanged oxygen releasing capacity and total blood volume, the antihypertensive treatment had to be increased during that phase of treatment. An increase in whole-blood viscosity may explain the increased need of antihypertensive drugs. The increase in P50 during the first phase of rHuEpo treatment can probably be explained by decreased mean age of the erythrocyte population and implies that the beneficial effect is greater than could be concluded from the increase in haemoglobin concentration.

Medical need for quality specifications--a NORDKEM project for selecting the appropriate quality in clinical laboratories.

The Nordic Clinical Chemistry Project (NORDKEM) has during its existence run several projects dealing with analytical quality requirements and the specifications of such requirements. The latest project-"Medical Need for Quality Specifications in Laboratory Medicine"-started three years ago and is now to be reported. The project consists of three main subprojects and a large number of associated projects. The main subprojects deal with: *External quality assurance for proteins (Per Hyltoft Petersen et al.) *Transferability of clinical laboratory data (Torgny Groth & C-H de Verdier) *Terminology (René Dybkaer) "Clinical goals" are assessed using different kinds of procedures. Comparison with the characteristics of "the analytical procedures" and "the quality assurance programs" gives the Management of the clinical laboratory a background for determining the "analytical quality specifications" of the laboratory. Procedures for setting up clinical goals and analytical quality specifications are given and they are further exemplified in the associated projects. Clinical goals and the analytical quality specifications are expressed and calculated in similar ways as total allowable error (TEa), as a coefficient of variation or an absolute error within defined concentration intervals.

Transferability of clinical laboratory data within a health care region.

Analytical data for S-Creatinine and S-Urate are presented from seventeen laboratories in the Swedish Uppsala-Orebro regional quality assessment program. The bias and imprecision as well as the instability of the measurement procedures in the participating laboratories were estimated over three 14-week periods. Bias was estimated by a linear least squares fit of the difference between measured and assigned values vs. assigned values, and expressed in absolute and relative terms. Instability of the measurement procedures was estimated by comparing slope and intercept of regression lines of measured vs. assigned values from three fourteen week periods. According to our experiences we recommend regression analysis to describe the performance of the analytical methods of a laboratory over time. The results show that most laboratories fell within the limits of +/- 15% bias for S-Creatinine above 100 mumol l-1 and +/- 17% for S-Urate at concentrations above 250 mumol l-1. Various steps to reduce the inter-laboratory variability are suggested, including numerical correction of individual laboratory results using correction functions. In a few laboratories, instability was too high to allow for numerical corrections of analytical results.

The use of knowledge-based information systems for interpreting specialized clinical chemistry analyses--experience from erythrocyte enzymes and metabolites.

A knowledge-based information system has been constructed to facilitate and standardize the interpretation of data obtained from specialized analyses in clinical chemistry. For illustration the system was applied to metabolic studies of erythrocytes from patients in whom hereditary disorders are suspected to explain the presence of a haemolytic anaemia or a polycythaemia. The study includes assay of the catalytic activity of 10 different enzymes and the concentration of some key metabolites. The knowledge-based system is an excellent tool for documentation, updating and transfer of knowledge of the interpretative process. This will reduce the risk of changes in this process being made without sound motivation and documentation. Furthermore, the statistical and graphic features of the system provide data for long-term quality assessment and insights into reference sample groups which are used to update decision levels.

Lack of success with a combination of alanine and phosphoenolpyruvate as an additive for liquid storage of red cells at 4 degrees C.

Red cells were stored at 4 degrees C in a storage solution containing alanine or alanine plus phosphoenolpyruvate (PEP). The intention was to investigate whether alanine and PEP might act synergistically to maintain a normal level of both red cell ATP and 2.3 diphosphoglycerate (2.3 DPG) under normal liquid storage conditions. Storage in the presence of alanine kept the red cell concentration of 2.3 DPG higher than the reference solution for an extended period of time, provided the initial pH was about 7.0 (37 degrees C). When the pH of the storage solution containing alanine plus PEP was lowered to facilitate the transport of PEP into the red cells, the concentration of 2.3 DPG was lowered to a rate equal to that in the reference solution. The level of ATP was also about the same as in the reference solution. The majority of the added PEP was continuously converted to 2 phosphoglycerate and 3 phosphoglycerate in the extracellular fluid. A small amount of unconverted PEP penetrated the red cell membrane when the pH went below 6.5; this occurred after 3 weeks of storage. The intracellularly located PEP, however, was not metabolized to 2.3 DPG to any significant extent within the first 6 weeks of storage. These findings indicate that PEP is not suitable as an additive for liquid storage of red cells at 4 degrees C. The combination of alanine and PEP that theoretically could be a suitable additive for liquid storage of red cells was not satisfactory in practice.

A combined data- and knowledge base system for the interpretation of metabolic investigations of erythrocytes from hemolytic and polycythemic patients.

A knowledge based-information system has been constructed to facilitate and standardize the interpretation of data obtained from specialized analyses in laboratory medicine. For illustration the system was applied to metabolic studies of erythrocytes from patients in whom hereditary disorders are suspected to explain the presence of a hemolytic anemia or polycythemia. The study includes assay of the catalytic activity of ten different enzymes and the concentration of some key metabolites. The knowledge based system is an excellent tool for documentation, updating and transfer of knowledge about the interpretative process. This will reduce the risk that changes in this process are made without sound motivation and documentation. Furthermore, the statistical and graphic features of the system provide data for long-term quality assessment and insights into reference sample groups which are used to update decision limits. A few cases are used to illustrate the advantages of the system.