Setting quality specifications for the future with newer approaches to defining uncertainty in laboratory medicine.

When describing the performance of procedures and the reliability of their results, ISO terminology should be used. Results should be universally comparable and this requires metrological traceability. The concomitant uncertainty (inversely) indicating reliability should be obtained in a universal and transparent fashion, and should be combinable. Therefore, the approach of the "Guide to the expression of uncertainty in measurement", leading to a result without known bias and a combined standard uncertainty, has advantages over the allowable total error concept, incorporating procedural bias.

Terminological problems around "accuracy" and "uncertainty".

The consistent description and treatment of metrological data in laboratory medicine are hampered by the lack of a systematic, universally accepted nomenclature and by variations in the conceptual understanding of uncertainty. The differences between the classical approach to a result as consisting of a true value plus errors and the new approach of a measured corrected value with uncertainty based on a detailed uncertainty budget are discussed. The various definitions of some relevant concepts, including "accuracy", the new concept "trueness", and "precision", are contrasted, and proposed modification are presented.

Clinical laboratory work--concepts and terms.

An appropriate term is sought for the concept embracing the different types of clinical laboratory work. The defining characteristics of the concept are therefore described, i.e. site, goal, objectives, activity, field, and participating professionals. It is proposed that the superordinate concept should be "medicine" while the subordinate concept under discussion is defined on the basis of the characteristics, thereby distinguishing it from coordinate concepts, i.e. from other branches of medicine. The principles used for establishing existing terms in other branches of medicine are presented, together with a discussion of existing terms in the clinical laboratory field. It is suggested that the current term 'laboratory medicine' has several advantages. The workplace may be called a 'department of laboratory medicine' or 'clinical (or medical) laboratory'. It is further suggested that the term 'clinical chemistry' should not generally be replaced by 'clinical biochemistry'.

Vocabulary for use in measurement procedures and description of reference materials in laboratory medicine.

The preparation of written records of measurement procedures and descriptions of reference materials requires order, scientific and practical expertise, exactness, and completeness. Realizing the importance of adequate documentation in science, practice, and industrial development, the European Committee for Standardization (CEN) has drafted two European Standards on the two subjects, presenting the structure and contents of such documents. The standards, however, do not provide guidance to the proper use of quantities, units, equations, numerical values, and terminology. Laboratory workers writing procedures and descriptions of materials have various educational backgrounds, so that it may be difficult to achieve harmonization of presentation and language. The present text provides an overview of structure of such documents (with reference to the CEN standards), some principles of quantities and units, a common vocabulary (based on authoritative international standards and recommendations), 144 named and defined concepts, and an extensive bibliography.

Quantities and units for biological reference materials used with in vitro diagnostic measuring systems for antibodies.

The WHO International Reference Materials (IRM), whether International Biological Standards (IS) (formerly International Reference Preparations (IRP)) or International Biological Reference Reagents (IRR), have served a good purpose in standardizing bioprocedures by defining international units of bioactivity or potency where dimensions seem difficult to establish. Especially for in vitro diagnostic procedures, the trend is towards measuring biochemically informative molecular-based quantities (involving the unit mole) when some chemical entity of a component can be defined. The use of a standard, with a value assigned by any procedure, as a calibrant in other procedures does not assure traceability and valid diagnostic results if the component (analyte) is microheterogeneous to a varying degree or there are varying matrix effects. Only experiment can demonstrate commutability of the material.

Properties and units in the clinical laboratory sciences. V. Properties and units in thrombosis and haemostasis: ISTH-IUPAC-IFCC recommendations 1995.

For historical reasons, the terms used in the nomenclature for properties in thrombosis and haemostasis differ according to 'school' of thought. This hampers communication. In collaboration, The Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis and the Committee (Commission) of Quantities and Units (in Clinical Chemistry) have prepared a set of recommended systematic names for properties in that domain. For use in electronic transmission each property has been given a code value.

Reference materials and reference measurement systems in laboratory medicine. Harmonization of nomenclature and definitions in reference measurement systems.

Reliability of clinical laboratory results is obtained through quality assurance in both their production and transmission. The former involves a reference measurement system of reference materials and reference measurement procedures with metrological and statistical verification of results. The latter requires that sender and receiver have access to a common terminology. Thus, two data banks are required. A plurilingual systematic vocabulary related to the reference measurement system, giving concepts with terms and definitions concerning measurement standards, reference measurement procedures, internal quality control, external quality assessment, probability and statistics-mainly based on existing authoritative publications. The material should be processed by standard scientific terminological procedure and offered to pertinent organizations and specialists for comment before finalization and authorization. A multilingual collection of systematic names for properties examined by the branches of Laboratory Medicine, such as clinical chemistry, clinical immunology, clinical microbiology, clinical pharmacology, haematology and blood banking, and histochemistry and cytology. The database should function as a reference to consultation and as a link in the transmission of data between local laboratory "dialects". This should be based on the ongoing comprehensive IUPAC/IFCC project for forming names in collaboration with relevant scientific organisations and area specialists. The relational data base including "run-time" software would be accessed by e-mail (gopher or other storage medium).

Application of IUPAC-IFCC recommendations on quantities and units to WHO biological reference materials for diagnostic use. International Union of Pure and Applied Chemistry (IUPAC) and International Federation of Clinical Chemistry (IFCC).

This document deals with the nature of WHO biological reference materials, their development for the control of therapeutic substances and recommendations to improve their application in diagnosis. The nature of international units specified by WHO biological reference materials is contrasted with that of SI units, and the method for assigning values in international units to such reference materials is described. The document recommends the use of SI units (mole) with existing and proposed WHO biological reference materials whenever the elementary entity of the stated component can be recognized. It also recommends that the description of quantities having no recognized kind-of-quantity with a definable dimension should be clearly distinguished by the term "arbitrary" and include a reference to the procedure and calibrator used. The WHO is urged to involve appropriate non-governmental organizations in advising on the need for, and the suitability of international reference materials.

Result, error and uncertainty.

Several recent documents, from international standardization bodies, present the philosophical and statistical background for understanding the components of a measured value and its uncertainty, as well as the relevant nomenclature for their description. The value is the output of a function relating values from reading, calibrator, corrections and influence quantities. The corrected value may be regarded as the sum of a true value, bias of measurement procedure, laboratory deviation, and random error; in some cases there are also biases from aberrant sample and undetected mistakes. The contributions of laboratory deviation and random error vary with the precision conditions that must be specified. The uncertainty measures are no longer a sum of systematic errors and the positive square root of quadratically added random errors. Now, the measured corrected value is the best estimate and the components of its uncertainty, one from each input, are all expressed as statistically or non-statistically derived variances that are combined according to the function relating the input values. The positive square root of the outcome is the combined standard uncertainty that is regarded as a standard deviation from which an expanded uncertainty may be obtained by multiplying with a coverage factor.

Quality assurance, accreditation, and certification: needs and possibilities.

Demonstrable quality of laboratory services entails two parts. First, one needs a quality policy statement, identification of user needs, choice of measurement procedures, reference measurement system to provide traceability, control materials, and proficiency testing with materials having reference-measurement-assigned values. Second, it may be useful to obtain recognition of competence in addition to the director's certificate, such as Good Laboratory Practice (when studying toxicity of chemicals), ISO 9000 certification of a self-defined quality system, nongovernmental professional accreditation, or, most demanding, governmental accreditation according to European Standard EN 45,001 with some modifications. These require external quality audit; ISO and EN also require a quality manual, which is valuable documentation in any case.

Application of IUPAC-IFCC recommendations on quantities and units to WHO biological reference materials for diagnostic use: recommendations 1994.

This document deals with the nature of WHO biological reference materials, their development for the control of the therapeutic substances, and recommendations to improve their application in diagnosis. The nature of international units specified by WHO biological reference materials is contrasted with that of SI units, and the method for assigning values in international units to such reference materials is described. The document recommends the use of SI units (mole) with existing and proposed WHO biological reference materials whenever the elementary entity of the stated component can be recognized. It also recommends that the description of quantities having no recognized kind-of-quantity with a definable dimension should be clearly distinguished by the term "arbitrary" and include a reference to the procedure and calibrator used. The WHO is urged to involve appropriate nongovernmental organizations in advising on the need for, and the suitability of, international reference materials.

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.

A systematic nomenclature for quantities of the haemostatic system.

The complex interplay of coagulation factors, fibrinolytic factors, and inhibitors characterizing the haemostatic system causes difficulties for devising useful measures of its status in a patient as well as for their calibration, comparability, and nomenclature. The latter problem is addressed by constructing examples of systematic generic quantity names based on IUPAC and IFCC recommendations having the general format "System-Component; kind of quantity" and considering the possibilities for each of these three items with both single and multiple components. The kinds of quantity comprise mass concentration, (amount-of-) substance concentration, catalytic (activity) concentration, time, relative arbitrary (amount-of-) substance concentration, relative time, and reciprocal relative time. For the coagulation system, the relative time specified by the use of thromboplastin reference material WHO 67/40 and the characterization of other thromboplastins by comparison with that reference material is discussed. A descriptive systematic name for international sensitivity index (ISI) is orthogonal regression slope (ORS). The recalculated value for the relative time of coagulation of a sample using any thromboplastin and its ORS is currently called international normalized ratio (INR), but is simply a relative time with the ORS specified.

Reference materials--a main element in a coherent reference measurement system.

The analytical reliability of any measurement procedure requires a specifically designed, coherent reference measurement system, including interrelated measurement procedures and measurement standards such as reference materials. The latter may be characterized by three sets of characteristics. The general characteristics comprise origin, mode of production, physical state and phase, homogeneity, physical form, container, additives, storage conditions, stability, and dangerous properties. The specific characteristics describe molecular composition, analyte, purity, matrix, quantity of interest (including scale), assigned value, and uncertainty of measurement. The additional characteristics concern the way in which values for other characteristics were obtained, the hierarchical position of the material, certificate, instructions for use, and intended function. The problem areas of reference materials comprise definition of the appropriate analyte, purification, matrix, assignment of values, and nomenclature. The present ambiguous terminology is presented and a systematic structure of descriptive names is proposed (tab. 1).