Estimation of alert and change limits and its application in the plausibility control

In the clinical laboratory, one of the most objective ways to perform the final review of patients’ measured values is the use of computerized plausibility control (i.e., set of procedures used to decide whether a patient’s measured value is valid according to established clinical and biological criteria). This study is focused on the estimation of alert and change limits to be applied to detect doubtful patients’ measured values. These limits are useful to improve the final review of patients’ measured values since these limits are produced objectively and are selected according to the clinical laboratory needs, letting the clinical laboratory professional staff to save time and effort.     

Proposed guidelines for the final review of measurement results in the clinical laboratory

The standard ISO 15189 requires a systematic review of results of clinical laboratory examinations, but it does not provide details on how to carry out such a review. In this article, the Catalan Association of Clinical Laboratory Sciences proposes a guide for this review of patients’ clinical laboratory results pertaining to rational or difference scales (‘quantitative values’). The review process is based on the so-called plausibility control, which may be defined as the set of procedures used to decide if a measurement result is valid or not according to established clinical and biological criteria, considering four variables: (1) alert limits; (2) consistency with the previous result, if any; (3) consistency with other results obtained from the same sample, if any; and (4) consistency with the diagnosis (presumed or confirmed) or, when it is not known, the origin of the request, though these last criteria are generally very weak and the derived decisions may be scantly reliable. This guide has been prepared on the behalf of the Technical Committee of the Catalan Association for Clinical Laboratory Sciences. Papers published in this section do not necessarily reflect the opinion of the Editors, the Editorial Board and the Publisher.     

Metrological reference values for estimating measurement bias in clinical laboratory sciences

Clinical laboratory quantities are measured for monitoring or diagnostic purposes. In both cases, a modification of the measurement bias can generate a false interpretation of measurement results. On the other hand, in clinical laboratory sciences, one of the most frequently used metrological reference value for calculating measurement bias is a conventional value that corresponds to the called consensus value. But this selection probably is not the best one, and some clinical and biological considerations should be made to decide the requirement for maximum permissible measurement bias and to decide the more appropriate metrological reference value. In the clinical laboratory, the medical relevance of the measurement bias of any measurement system in use depends on the measurement bias with which the biological reference values were produced. This dependence is due to the necessity that, for interpretation purposes, the current measurement bias should be the same that is included in the biological reference limits. For this reason, it is necessary to control the changes of bias during the life span of a measuring system. Several scenarios are described for the different estimations of bias.     

Towards standardization of external quality assessment schemes by using bias values based on biological variation

The precision and trueness of current instruments and methods in clinical laboratories is much better than in the past. However, the z-score and other comparison variables that are currently used in external quality assessment programs are based on relative data. Thus, they may change from program to program and also change over time within the same program and consequently may not be useful or cost-effective. We therefore devised a test-specific decision limit for accepting or rejecting test results based on a combination of the data of within- and between-subject biological variations. We then applied these limits to a group of tests performed in our laboratory and compared our results with those of external quality assessment programs. In addition, we combined external and internal quality control data on the same graph and prepared a two-dimensional graph for different levels of control sera. Inspection of all results of control sera on this new graph was more useful for decision making. We concluded that the z-score is not reliable for comparisons of test results in external quality assessment. As a substitute for this currently accepted practice, we assert that control limits based on biological variation are more reliable, and can be useful in the evaluation of both external and internal quality assessments and their combination on this new graph.     

Measurement uncertainty in microbiology

Testing laboratories wishing to comply with the requirements of ISO/IEC 17025:1999 need to estimate uncertainty of measurement for their quantitative methods. Many microbiological laboratories have had procedures available for monitoring variability in duplicate results generated by laboratory analysts for some time. These procedures, however, do not necessarily include all possible contributions to uncertainty in the calculations. Procedures for estimating microbiological method uncertainty, based on the Poisson distribution, have been published but, at times, the procedures can either underestimate uncertainty or require laboratories to undertake considerable experimental studies and more complex statistical calculations. This paper proposes procedures for estimating uncertainty of measurement in microbiology, whereby routine laboratory quality control data can be analyzed with simple statistical equations. The approaches used in these procedures are also applied to published data and examples, demonstrating that essentially equivalent results can be obtained with these procedures.     

Toward standardization of quality assessment in laboratory medicine by using the same matrix samples for both internal and external quality assessments

The main purpose of quality assurance procedures in clinical laboratories is to ensure that test results are appropriate to maintain excellence in the diagnosis, monitoring, and treatment of disease. However, in current practice, no standardized procedure or frequency for the evaluation of methods exists, particularly in external quality assessment. Furthermore, different quality control materials are typically used for internal and external quality assessment. To overcome these discrepancies, we used samples with the same matrix for both internal and external quality assessments of a group test performed in our laboratory. We then calculated total error using real bias (target value obtained by reference method) and the imprecision of each test and compared our results with the total error allowable, derived from biological variation data. We suggest that the strategy of using the same matrix samples for both internal and external quality assessment is cost-effective, can be readily used by staff, and will facilitate the standardization of quality control in clinical laboratories.     

A Microtiter Plate Assay for Sulfonamides

Abstract

Sulfamethoxazole, sulfisoxazole, and sulfadiazine are sulfonamides used in the treatment of several infectious diseases. Several studies have demonstrated that the amino substituent plays an important role in both the toxicity and the therapeutic effect of these drugs. In view of these findings, a rapid and convenient method of analysis would be useful for monitoring selected patients receiving these drugs. With the increasing use of microtiter plate methodology in the clinical laboratory, an assay based upon the Bratton-Marshall reaction with the amino substituent was adapted to the microtiter plate format. The results indicate that the microtiter plate assay for sulfonamides retains the sensitivity and linearity necessary for analysis of sulfonamides in biological fluids at clinically relevant concentrations. The assay is simple, rapid, convenient, and suitable for monitoring procedures where only the measurement of the active drug concentration is required.     

Solid/liquid separation of flocculated suspensions

Solid-liquid separation operations leading to the concentration and isolation of fine particles dispersed in liquids are important in the chemical and mineral processing industries. In spite of this, the procedures available for the prediction of equipment performance remain crude. Almost all major mineral and chemical processing companies now have a clear priority in R&D budgets to develop new approaches to waste minimization; a major part of the problem faced by these industries relates to the effect of management of waste slurries. The processes that manage final waste slurries are often classical “end-of-pipe” solutions. One of the key aims of the present broad program is to understand how to manipulate the structure of slurries within the process so that finally it is possible to engineer clear liquor and simultaneously manageable or tractable waste solids. The best way to process such wastes relies on understanding how to control the compressibility and viscosity of these materials.A generalized approach to understanding and prediction of solid-liquid separation methods based on the measurement of fundamental material properties is reviewed here. This is of value in designing more efficient methods and ultimately to optimizing the performance of solid-liquid separation methods and the selection of flocculants for any given slurry. The model identifies two key parameters, the compressional yield stress Py(φ) and the hindered settling factor r(φ) and laboratory test procedures for the direct measurement of both have been developed. The application of this model to a variety of thickening and filtration processes is demonstrated and a direct relationship between the model parameters and the conventional cake resistance as utilised by current filtration engineers is provided.     

ISO 17025: practical benefits of implementing a quality system

As a laboratory certified to ISO 9001:2000 and accredited to ISO 17025, rtech laboratories has incorporated an overall system for technical and quality management, which results in benefits observed in daily laboratory practices. Technical requirements were updated to include the addition of formal personnel training plans and detailed records, method development and validation procedures, measurement of method uncertainty, and a defined equipment calibration and maintenance program. In addition, a stronger definition of the sample preparation process was documented to maintain consistency in sampling, and a more rigorous quality control monitoring program was implemented for chemistry and microbiology. Management quality improvements focused on document control to maintain consistent analytical processes, improved monitoring of supplier performance, a contract review process for documenting customer requirements, and a system for handling customer comments and complaints, with continuous improvement through corrective and preventive action procedures and audits. Quarterly management review of corrective actions, nonconforming testing, and proficiency testing aid in determining long-term trending. The practical benefits of these technical and management quality improvements are seen on a daily basis in the laboratory. Faster identification and resolution of issues regarding methods, personnel or equipment, improved customer satisfaction, meeting quality requirements of specialized customers, and overall increased laboratory business are all the result of implementing an effective quality system.     

Metrology in laboratory medicine – Reference measurement systems

 The medical laboratory must provide results of measurements that are comparable over space and time in order to aid medical diagnosis and therapy. Thus, metrological traceability, preferably to the SI, is necessary. The task is formidable due to the many disciplines involved, the high production rate, short request-to-report time, small sample volumes, microheterogeneity of many analytes, and complex matrices. The prerequisite reference measurement systems include definition of measurand, unit of measurement (when applicable), consecutive levels of measurement procedures and calibrators in a calibration hierarchy, international organizations, reference measurement laboratories, dedicated manufacturers, written standards and guides for the medical laboratory, production of reference materials, internal and external quality control schemes, and increasingly accreditation. The present availability of reference measurement procedures and primary calibrators is shown to be insufficient to obtain international comparability of all types of quantity in laboratory medicine. Received: 19 April 2000 / Accepted: 3 July 2000     

Establishing measurement traceability in clinical chemistry

Measurement traceability is probably the most important tool for achievement of comparability in clinical chemistry. As stipulated by the In Vitro Diagnostica Directive of the European Union and several ISO standards, values assigned to calibrators and control materials must be traceable to reference materials and/or reference procedures of higher order. In the German proficiency testing system, statutory use of reference measurement procedures for several measurands has been in force since 1988. As a result, reference procedures are now regularly applied for the setting up of target values in the control samples of internal and external quality assessment and for assigning values to the manufacturers calibrator and control materials. Noticeably, the comparability of results obtained by different diagnostic tests has greatly improved for the measurement of many metabolites and substrates, e.g. creatinine, cholesterol, uric acid, total glycerol and urea. For many measurands in laboratory medicine the implementation of the concept of traceability proves to be much more difficult; this mainly concerns the measurement of proteins, in particular enzymes, proteo-hormones, tumour markers and cardiac markers. For such measurands the analyte must first of all be distinctively defined before a reference system can be established which comprises reference procedures, reference materials and networks of reference laboratories.Presented at the CCQM Workshop on Traceability 16–17 April 2002 at the BIPM, Sèvres, France     

External quality assessment schemes for clinical laboratories

 The clinical routine laboratory generally utilizes cheap, easy and rapid measurement procedures ("methods") in order to meet the requirement for the production of many analytical results (500–3000 per day) of hundreds of different types. The measurement procedures are optimized for the analysis of native patients' samples, but are frequently sensitive to deviation of the composition of the matrix from that in normal fresh samples. The inherent lack of stability of patient samples means that control samples need to be stabilized. The method of stabilization is critical. Furthermore, the method of "spiking" samples with pathological material is a matter of concern. Generally, minimally processed patients' samples should be used in external quality assessment (EQA) schemes. Consensus values are currently the most popular for use as a guide to the best results from participating laboratories in EQA schemes; these often work fairly well. However, the uncertainty and traceability of this type of value is unknown, and in some cases may even be misleading, tending to preserve bad routine methods when these are dominant in the participating laboratories. Reference measurement procedure (RMP) values are recommended to provide scientifically based information, to facilitate the proper choice of methods in the routine laboratories, and to validate the suitability of control materials in EQA schemes. The present paper provides selected examples from a study comparing consensus values with RMP values on lyophilized sera, and also presents results on a fresh frozen thawed serum for the study of commutability. Received: 8 November 1995 Accepted: 8 May 1996     

Participation in IAEA proficiency test exercise on major,minor and trace elements in ancient Chinese ceramic (IAEA-CU-2006-06) using low power research reactor

A proficiency test (PT) exercise was offered by the International Atomic Energy Agency (IAEA) for major, minor and trace elements in Chinese ceramic reference material (IAEA-CU-2006-06). Neutron activation analysis (NAA) laboratory at PINSTECH, Pakistan participated in the exercise and submitted the results for 28 elements. The aim of participation was to develop a suitable methodology for accurate measurement of as many elements as possible in ceramic material using a low power reactor (PARR-2) as this would help future investigation in a project on the authenticity of art objects, for provenance, conservation and management of ancient cultural heritage of the country. After receiving the final report of the PT exercise, a critical review of our data and final scoring of each element is made to check the suitability of our methodology and reliability of the acquired data. Most of the reported results passed different statistical evaluation criterion such as relative bias, z-score and u-scores and ratio of our results and IAEA target values. One element (Yb) falls in the unacceptable range of relative bias and z-scores. Hf and Tb showed slightly high z-scores within the questionable range. Ho, Mo and Sn were determined during this study but their results were not submitted to the IAEA. The confidence of accuracy observed for most of the elements in ceramic material has made it mandatory to report their results as information values.     

Quality assurance in analytical measurement

 The peculiarities of analytical measurement require to check characteristics of the error (its components) of the obtained analysis results to assure the quality of the measurements. This article deals with the various quality assurance procedures and algorithms which are used to check the quality indices, i.e. the accuracy, reproducibility, certainty and repeatability of analytical measurements: These procedures include: laboratory rapid control; Intra-laboratory statistical control (statistical selection control by alternative attribute, statistical selection control by quantity method of periodic check of the analysis procedure for conformity to the specified requirements) and external control (inter-laboratory control checks, inter-laboratory comparison tests, and intra-laboratory control algorithms carried out by the appropriate supervisory body.) in the separately taken laboratory. The respective algorithms, control plans and control requirements, specified according to the different control aims and assurance tasks, enable the quality and certianty of analytical information obtained in laboratories in Russia to be assured. Received: 9 November 1998 / Accepted: 24 November 1998     

Preparation of conducting electrodes from biological samples for multi-element trace analysis by spark-source mass spectrometry or emission spectrometry

Four decomposition procedures frequently used for biological material (dry ashing, open wet digestion, wet digestion in a teflon bomb and low-temperature ashing) are optimized for the conversion of biological samples to conducting electrodes suitable for multi-element trace determinations by spark-source mass spectrometry or emission spectrometry. The optimized procedures are evaluated with respect to contamination, retention and preconcentration of the trace elements, homogeneity of the electrodes and precision of the final results. Both dry-ashing methods are prone to losses by volatilization; simple dry ashing suffers from contamination problems during electrode preparation. Wet digestion gives better precision; digestion with nitric/sulfuric acids in an open flask is the method of choice for most elements being simpler and giving lower blanks than the bomb method.     

Criteria for the development of biological reference materials

Summary A review is presented of factors to be considered in the development of biological reference materials. Some guidelines are offered regarding approaches to the generation of the varied materials required for analytical quality control. Major considerations in such an endeavour are the goal of the undertaking and role of the final product, selection of candidate materials, preparation, characterization and certification. Selection of materials should be from those important to commerce and consumers, and related to various regulatory, clinical, environmental, and research activities. They should adequately represent the different choices and types of foodstuffs, clinical materials and environmental materials, such as soils, sewage sludges, plant and animal tissues, of interest in different regions of the world.Acquisition can be from commercial sources or the result of in-house preparation, with attention to stability enhancement if required and maintenance of native analyte levels by minimization of contamination. The approach to chemical and physical characterization relies on the measurement philosophy, selection of analytes, their speciation, and selection of analytical methods and analysts for establishment of homogeneity and quantitative levels. Throughout the overall task of RM development there is a requirement for a critical approach by critical analytical and measurement scientists and the involvement of national RM agencies in order to produce top quality control materials.

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Kriterien für die Entwicklung von biologischen Referenzmaterialien

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Contribution No. 88-50 from Land Resource Research Centre     

Quality issues in proficiency testing

 Proficiency testing is a means of assessing the ability of laboratories to competently perform specific tests and/or measurements. It supplements a laboratory's own internal quality control procedure by providing an additional external audit of their testing capability and provides laboratories with a sound basis for continuous improvement. It is also a means towards achieving comparability of measurement between laboratories. Participation is one of the few ways in which a laboratory can compare its performance with that of other laboratories. Good performance in proficiency testing schemes provides independent evidence and hence reassurance to the laboratory and its clients that its procedures, test methods and other laboratory operations are under control. For test results to have any credibility, they must be traceable to a standard of measurement, preferably in terms of SI units, and must be accompanied by a statement of uncertainty. Analytical chemists are coming to realise that this is just as true in their field as it is for physical measurements, and applies equally to proficiency testing results and laboratory test reports. Recent approaches toward ensuring the quality and comparability of proficiency testing schemes and the means of evaluating proficiency test results are described. These have led to the drafting of guidelines and subsequently to the development of international requirements for the competence of scheme providers. Received: 2 January 1999 · Accepted: 7 April 1999     

Biological variation data are necessary prerequisites for objective autoverification of clinical laboratory data

The wealth of quantitative data on random biological variation has been used for setting quality specifications, assessing the utility of conventional reference values, and deciding of the significance of changes in serial laboratory results. Most analytes have marked individuality and this makes conventional population-based reference values of low utility. In consequence, reference limits are not ideal for autoverification strategies. Clinical decision limits may be better criteria for holding results for verification by laboratory professionals. Changes in serial results are significant only when the reference change value is exceeded. Such values can be generated by all laboratories and can be implemented, not only to flag reports, but also in delta checking and autoverification since these are objective rather than empirical. We have put these considerations into operation into our laboratory. Apart from special cases, our general approach is that results flagged as having changed 0.05<P<0.01, flagged as just outside the reference limits, or not flagged in any way, are autoverified and reported to the user without intervention. Only results outside pre-set clinical limits and those that have changed highly significantly P<0.01 are held for verification by clinical scientists and medical staff. This strategy allows autoverification of ca. 60% of reports. Received: 15 May 2002 Accepted: 17 July 2002 Presented at the European Conference on Quality in the Spotlight in Medical Laboratories, 7–9 October 2001, Antwerp, Belgium Correspondence to C. G. Fraser     

Comparison of strategies to quantify uncertainty of lead measurements in biological tissue at mg kg<Superscript>–1</Superscript> level

The expression of measurement uncertainty in analytical chemistry still presents some difficulties. According to the various guides and standards, several approaches are possible. This paper present two referenced approaches applied to the determination of Pb in a biological tissue at the mg kg^–1 level. Estimations were achieved, either from inter-laboratory precision data, or from the uncertainty propagation equation applied to the measurements of a single laboratory. When comparing final values, for an average concentration of about 2.0 mg kg^–1, expanded uncertainties range from ±0.05 mg kg^–1 up to ±0.31 mg kg^–1, i.e. by a factor of 6. Obviously, both approaches of estimating uncertainty do not cover the same sources of uncertainty and it is interesting to try to understand better these discrepancies in order to try to define realistic guidelines for analysts. Moreover the experimental results of the study are given where a wide number of techniques is applied. Received: 5 May 2002 Accepted: 17 June 2002 Correspondence to M. Feinberg