Uncertainty of measurement in clinical laboratory sciences.To the Editor:
Random and systematic errors can act together to produce an error of measurement (total error) and generate a doubt (uncertainty) about the true value of the measured quantity.
The international metrological organizations, keeping in mind these facts, have developed the concept of uncertainty of measurement. This concept has become an important issue in general metrology, and by extension, its importance is increasing in clinical laboratory sciences. It is thus important to clarify the concept and to identify the practical difficulties in the use of uncertainty of patients' results.
Uncertainty of measurement (hereafter referred to as uncertainty) is a parameter, associated with the result of a measurement, that characterizes the dispersion of the values that could reasonably be attributed to the measurand (i.e., the measured quantity) (1); in other words Adv. 1. in other words - otherwise stated; "in other words, we are broke"
put differently , uncertainty is numerical information that complements a result of measurement, indicating the magnitude of the doubt about this result. Uncertainty is described by means of one of the following three parameters (2):
* "Standard uncertainty" (u) is the standard deviation that denotes the uncertainty of the result of a single measurement.
* "Combined standard uncertainty" ([u.sub.c]) is the standard deviation that denotes the uncertainty of the result obtained from other results of measurement. It is obtained by combining the standard uncertainties of all individual measurements according to the law of propagation of uncertainty In statistics, propagation of uncertainty (or propagation of error) is the effect of variables' uncertainties (or errors) on the uncertainty of a function based on them. .
* "Expanded uncertainty" (U) is the statistic defining the interval within which the value of the measurand is believed to lie with a particular level of confidence. It is obtained by multiplying the combined standard uncertainty by a coverage factor, k, the choice of which is based on the level of confidence (1 - [alpha]) desired. If k = 2, then 1 - [alpha] [approximately equal to] 0.95; if k = 2.6, then 1 - [alpha] [approximately equal to] 0.99.
The international scientific and standardization bodies recommend that the uncertainty of patients' results obtained in clinical laboratories should be known (3-5); the rationale for this recommendation is that full interpretation of the value of a quantity obtained by measurement also requires evaluation of the doubt attached to its value. The common opinion of these bodies is that clinical laboratories should supply information about the uncertainty of their results of measurement when applicable; ideally, this information should be attached to the patients' results as shown in this example:
S-Almandine aminotransferase; cat.c. = (1.15 [+ or -] 0.23) [micro]kat/L, where 1.15 [micro]kat/L is the result given by the system of measurement, and 0.23 [micro]kat/L is the expanded uncertainty multiplied by 2 as coverage factor. (According to IFCC and IUPAC IUPAC: see International Union of Pure and Applied Chemistry. , S is serum, and cat.c. is the catalytic concentration.)
Institutional guidelines for estimating uncertainty of measurement, containing examples in fields of application other than clinical laboratory sciences, have been published (2, 6-8). An excellent review of uncertainty (and traceability) in clinical chemistry was published recently (9).
Depending on the field of application, uncertainty is attributable to different sets of elements. Each element of uncertainty, expressed as a standard deviation, may be estimated from the probability distribution of values with repeated measurements, termed "type A standard uncertainty", or estimated by use of an assumed probability distribution based on experience or other available information, termed "type B standard uncertainty".
In general, in clinical laboratory sciences the most relevant elements that can contribute to uncertainty for a given system of measurement are:
* Incomplete definition of the particular quantity under measurement,
* Unrepresentative sampling,
* Withdrawal conditions,
* Effects of additives,
* Centrifugation conditions,
* Storage conditions,
* Day-to-day (or between-run) imprecision,
* Systematic error,
* Lack of specificity,
* Values assigned to calibrators
Estimation of the combined uncertainty, expressed as a variance, is the sum of the values, all expressed as variances, corresponding to several of the above elements. Perhaps variances corresponding to these elements can be easily estimated in some clinical laboratories, but for others their evaluation is certainly not easy, as may be derived from the following points:
(a) Manufacturers do not give the uncertainty of the values assigned to calibrators.
(b) In the majority of measurement procedures used in clinical laboratories, the metrological standard deviation varies with the value of the measurand; this phenomenon, called "heteroscedasticity" (the opposite is called homoscedasticity), should be always taken into account when estimating uncertainty.
(c) Premetrological variation should not be considered negligible even when the premetrological process seems to be well standardized (10, 11).
Bearing in mind these points, the following questions arise:
* When will manufacturers supply the uncertainties of the values assigned to calibrators?
* How many clinical laboratories know--or really can know--the mathematical or graphical relationship between metrological standard deviation and concentration for each measurement procedure?
* How many clinical laboratories know--or really can know--the standard deviation of their pre-metrological variation for each quantity?
* Is there heteroscedasticity for premetrological variation, and if it exists, can it be evaluated?
* When a clinical laboratory has produced biological reference values according to IFCC recommendation, should systematic error be referred to as the conventional true value of the calibrators used during the production of reference values?
Although some of the most relevant elements contributing to uncertainty can potentially be evaluated in clinical laboratories, the effort required to undertake such an endeavor might be so great that it will be difficult to bring into general use the uncertainty of patients' results.
(1.) International Bureau of Weights and Measures The International Bureau of Weights and Measures is the English translation of the name of the Bureau international des poids et mesures (BIPM), a standards organisation, one of the three organisations established to maintain the International System of Units (SI) , International Electrotechnical Commission See IEC.
(standard, body) International Electrotechnical Commission - (IEC) A standardisation body at the same level as ISO. , International Organization for Standardization International Organization for Standardization (ISO)
Organization for determining standards in most technical and nontechnical fields. Founded in Geneva in 1947, its membership includes more than 100 countries. , International Organization of Legal Metrology The International Organization of Legal Metrology or Organization Internationale de Métrologie Légale (OIML) is an intergovernmental treaty organization. It is made up of approximately 60 nations from around the world. . , International Federation of Clinical Chemistry, International Union of Pure and Applied Chemistry International Union of Pure and Applied Chemistry (IUPAC), an international organization est. 1919 to advance the chemical sciences and contribute to the application of chemistry to the service of humanity. , International Union of Pure and Applied Physics The International Union of Pure and Applied Physics (IUPAP) is an international non-governmental organization devoted to the advancement of physics. It was established in 1922 and the first General Assembly was held in 1923 in Paris. . International vocabulary of basic and general terms in metrology Geneva Geneva, canton and city, Switzerland
Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva. : ISO (1) See ISO speed.
(2) (International Organization for Standardization, Geneva, Switzerland, www.iso.ch) An organization that sets international standards, founded in 1946. The U.S. member body is ANSI. , 1993.
(2.) International Organization for Standardization, International Electrotechnical Commission, International Organization of Legal Metrology, International Bureau of Weights and Measures. Guide to the expression of uncertainty in measurement. Geneva: ISO, 1993.
(3.) International Union of Pure and Applied Chemistry, International Federation of Clinical Chemistry. Compendium of terminology and nomenclature of properties in clinical laboratory sciences. Recommendations 1995. [Prepared for publication by JC Rigg, SS Brown, R Dybkaer, H Olesen.] Oxford: Blackwell Science, 1995.
(4.) European Committee for Standardization. Medical informatics-expression of the results of measurement in health sciences. ENV 12435. Brussels: CEN, 1997.
(5.) International Organization for Standardization. Quality management in the medical laboratory. ISO/DIS 15189. Geneva: ISO, 2000.
(6.) Taylor BN, Kuyatt CE. National Institute of Standards and Technology. Guidelines for evaluating and expressing the uncertainty of NIST measurement results. NIST Technical Note 1297, 1994 edition. http://physlab.nist.gov/ Pubs/guidelines/outline.html (accessed March 22, 1999).
(7.) Eurachem. Quantifying uncertainty in analytical measurement. London: Eurachem, British Standards Institute (body, standard) British Standards Institute - (BSI) The British member of ISO. , 1995.
(8.) Deutsches Institut fur Normung. Basic concepts in metrology. Evaluating measurements of a single measurand and expression of uncertainty. DIN 1319-3. Berlin: DIN, 1996.
(9.) Kristiansen J, Christensen JM. Traceability and uncertainty in analytical measurements. Ann Clin Biochem 1998;35:371-9.
(10.) Fuentes-Arderiu X, Acebes-Frieyro G, Gavaso-Navarro L, Castineiras-Lacambra MJ. Pre-metrological (pre-analytical) variation of some biochemical quantities. Clin Chem Lab Med 1999; 37:987-9.
(11.) Fuentes-Arderiu X, Gonzalez-Alba JM, Baltuille-Peiron F, Navarro-Moreno MA. Premetrological variation of thyrotropin thyrotropin (thī'rätrō`pĭn) or thyroid-stimulating hormone (TSH), hormone released by the anterior pituitary gland that stimulates the thyroid gland to release thyroxine. , thyroxine (non-protein bound), and triiodothyronine triiodothyronine /tri·io·do·thy·ro·nine/ (tri?i-o?do-thi´ro-nen) one of the thyroid hormones, an organic iodine-containing compound liberated from thyroglobulin by hydrolysis. It has several times the biological activity of thyroxine. concentrations in serum. Clin Chem 2000;46:431-2.
Servei de Bioquimica Clinica
Ciutat Sanitaria i
Universitaria de Bellvitge
08907 L'Hospitalet de Llobregat