Traceability and Uncertainty of Measurement for Medical Laboratories

Transcription

QUALITY MANAGEMENT PROGRAM –
LABORATORY SERVICES (QMP–LS)
Ontario Laboratory Accreditation Division (OLA)
Traceability and Uncertainty of
Measurement for Medical Laboratories
© Quality Management Program—Laboratory Services (QMP–LS)
April 2009, Version 1
Dr. Godfrey Moses and Linda Crawford
Ontario Laboratory Accreditation Division
Suite 1510 • 250 Bloor Street East
Toronto, ON Canada M6N 1Y9
Phone 416.323.9540 • Fax 416.323.9324
2009-04-14
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Traceability and Uncertainty of Measurement for Medical Laboratories
TABLE OF CONTENTS
SCOPE .........................................................................................................................................................2
INTRODUCTION .............................................................................................................................................2
TRACEABILITY ..............................................................................................................................................3
DEFINITION .....................................................................................................................................3
CONCEPT ........................................................................................................................................3
OLA REQUIREMENTS ......................................................................................................................3
UNCERTAINTY OF MEASUREMENT .................................................................................................................4
DEFINITION .....................................................................................................................................4
CONCEPT ........................................................................................................................................4
OLA REQUIREMENTS ......................................................................................................................4
HOW TO DETERMINE/CALCULATE ESTIMATES OF UNCERTAINTY OF MEASUREMENT IN THE
MEDICAL LABORATORY ................................................................................................................................5
DETERMINING ESTIMATES OF UNCERTAINTY OF MEASUREMENT BY THE “TOP-DOWN” APPROACH
USING INTRA- AND INTER-LABORATORY DATA ..............................................................................................5
ESTIMATES OF UNCERTAINTY OF MEASUREMENT FOR SOME COMMON MEDICAL
LABORATORY TESTS ....................................................................................................................................7
A. PLASMA OR SERUM GLUCOSE (FASTING PLASMA GLUCOSE).......................................................7
B. ANION GAP (AG)........................................................................................................................8
C. CREATININE CLEARANCE (CCR) ..................................................................................................9
SUMMARY ..................................................................................................................................................10
REFERENCES .............................................................................................................................................10
RECOMMENDED READING ...........................................................................................................................11
© 2009 Quality Management Program—Laboratory Services. All Ontario Laboratory Accreditation program documents are the sole
property and copyright of the Quality Management Program—Laboratory Services, ALL RIGHTS RESERVED. No part of the
material protected by this copyright may be reproduced without written permission from QMP–LS.
The logos and/or symbols used are the property of QMP–LS or other third parties. You are not permitted to use these logos and/or
symbols without written permission from QMP–LS or such third party that may own the logos and/or symbols.
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SCOPE
The purpose of this document is to provide the following information for accredited medical laboratories:
•
•
•
an understanding of the concept of measurement traceability, within which determination of uncertainty of
measurement is required;
an explanation of the applicable accreditation requirements;
suitable ways to obtain uncertainty of measurement results for examinations included within the scope of
medical laboratory accreditation.
INTRODUCTION
Ontario Laboratory Accreditation (OLA) first outlined its expectations with regard to traceability and uncertainty of
measurement in the medical laboratory in QMP–LS News; No. 118, September 2007, (“Traceability and Uncertainty
of Measurement for Medical Laboratories—OLA’s Expectations”).1 The article pointed out that traceability and
uncertainty of measurement ensure valid laboratory measurements, in concert with method validation, quality
control and quality assurance. By establishing both the traceability and uncertainty of measurement of quantitative
measurements, the laboratory establishes and demonstrates the preciseness of its methods, determines if repeat
results are measurably different, and demonstrates that its results are fit-for-purpose (measuring the desired
component).
Ensuring that laboratory measurements are valid requires the use of appropriate reference materials for method
validation, calibration, traceability, estimation of uncertainty and quality control/quality assurance. For medical
testing, traceability and uncertainty of measurement are essential and usually overlapping components.
In order to receive an accreditation certificate from QMP–LS, OLA’s accreditation requirements must be met. The
applicable requirements (version 4.1, July 2008) 2 that specifically address calibration/traceability and uncertainty of
measurement are:
•
•
IV.8.3 for calibration/traceability; and
VI.8 for uncertainty of measurement.
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TRACEABILITY
DEFINITION
Traceability (Tr) – Property of the result of a measurement or value of a standard whereby it can be related to
stated references (usually national or international standards) through an unbroken chain of comparisons all having
stated uncertainties. (Source: Standards Council of Canada CAN-P-1626 Policy on traceability requirements for
calibration sources used by accredited testing laboratories).3
CONCEPT
Traceability provides confidence in the “trueness” of a measurement result, and it is characterized by six
sub-components:
1.
2.
3.
4.
5.
6.
an unbroken chain of comparisons going back to an acceptable national or international set of references;
uncertainty of measurement (calculated or estimated for each step in the chain by agreed methods and stated as
such to allow overall uncertainty to be calculated or estimated for the entire process);
documentation;
competence (evidence of technical competence);
reference to SI Units (where possible, chain of comparisons must end with reference to primary standards that
are traceable to SI units);
calibration intervals (length, number of variables, uncertainty required, frequency of use, etc.).
Merely stating that results are obtained against a manufacturer’s reference material or that the method is
standardized against a standard/reference available from a reference body is not sufficient to ensure traceability
of results.
OLA REQUIREMENTS
OLA requirement IV.8.3 states All calibration material and devices shall be traceable to an accepted reference
standard that is expressed in SI units whenever applicable. The laboratory shall have a mechanism to ensure
accuracy if the information is not available from the manufacturer.2
The guidance information provided with this requirement explains that it is expected that a program for calibration
of measuring systems and verification of trueness will be designed and performed to ensure that results are traceable
to SI units or by reference to a natural constant or other stated reference. Recognizing that traceability to a reference
preparation is not always possible or relevant in medical testing, examples of other means for providing confidence
in the results are suggested:
•
•
•
•
•
participation in inter-laboratory comparisons;
use of suitable reference materials, certified to indicate the characterization of the material;
examination or calibration by another procedure;
ratio or reciprocity-type measurements;
mutual consent standards or methods that are clearly established, specified, characterized and mutually agreed
upon; and
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•
documentation of statements regarding reagents, procedures or the examination system when traceability is
provided by the supplier or manufacturer.
UNCERTAINTY OF MEASUREMENT
DEFINITION
Uncertainty of Measurement (UM) – Parameter, associated with the result of measurement, that characterizes the
dispersion of the values that could reasonably be attributed to the measurand (the quantity intended to be measured).
(Source: National Pathology Accreditation Advisory Council Requirements for the estimation of measurement
uncertainty).4
CONCEPT
Uncertainty of measurement provides quantitative estimates of the level of confidence that a laboratory has in its
analytical precision of test results and therefore represents the expected variability in a laboratory result if the test is
repeated a second time. Both imprecision and bias are taken into account. Hence it is a measure of precision to
which biological variation and a confidence level (coverage probability based on normal distribution) have been
applied. Uncertainty of measurement is reported in standard deviation (SD) units or relative SD expressed as the
coefficient of variation (% CV).
OLA REQUIREMENTS
OLA requirement VI.8 states: The laboratory shall determine the uncertainty of results, where relevant and
possible. Potential sources of error or limiting factors (e.g. sample preparation, calibrators, reference materials,
methods, equipment, environmental conditions, sample condition and operator) shall be taken into account.2
The guidance information states that the laboratory is expected to have determined potential sources of error or
limiting factors where relevant or possible. For quantitative measurements, an estimate of uncertainty is expected.
Additional discipline-specific guidance is available.
OLA’s expectations are consistent with the guidelines of uncertainty of measurement (GUM) concept that, for
completeness, a measurement result must have a quantitative statement of its uncertainty.3,5,6 Estimates of the
uncertainty of the measurement result have several uses, including that pertaining to regulation, but key to the
medical laboratory is its use in assessing the “fit-for-purpose” of test results. The concept of uncertainty of
measurement is relatively new to the medical laboratory. Currently, there is no standardized process for calculating
estimates of uncertainty of measurement results in the medical laboratory.
Therefore, what follows is a practical guide for medical laboratory personnel on how to determine estimates of
uncertainty of measurement. This article does not deal with the definition and classification of laboratory tests,
examinations or with specific requirements of accreditation bodies. It is highly recommended that laboratories
consult national and international standard documents for information when determining estimates of uncertainty of
measurement. OLA does not prescribe one approach over another and the choice of approach to the estimation of
uncertainty of measurement rests with the individual laboratory and the resources and expertise available.
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HOW TO DETERMINE/CALCULATE ESTIMATES OF UNCERTAINTY OF MEASUREMENT IN THE
MEDICAL LABORATORY
Laboratories may select one or a combination of the following for quantitative and semi-quantitative measurements:
a)
The “bottom-up” approach as per GUM (International Organization for Standardization)6 principles, based on
estimates of uncertainty, expressed as standard deviations (SDs), that are assigned to individual steps or
components of the test, examination or procedure used to produce the result and combined to provide an
expanded uncertainty associated with the specific result.
Note: Equations on how to calculate uncertainty of measurement by this approach were previously given
(QMP–LS News, No. 118, September 2007).1 The GUM approach involves complex mathematics and is
not the method of choice for routine medical laboratory tests.
b) The “top-down” approach, using available laboratory test performance information, such as method validation,
intra-laboratory and inter-laboratory quality control (QC) data, to calculate estimates of the standard uncertainty
associated with the result produced by overall testing procedure/method.
Note: This approach is preferred for routine medical laboratory tests. The process is described briefly
below. A more detailed account is given in the National Association of Testing Authorities (NATA)
Technical Note.7
c)
Other approaches involve various combinations and/or modifications of the components in (a) and (b), personal
experience and information on certified reference methods or materials.
DETERMINING ESTIMATES OF UNCERTAINTY OF MEASUREMENT BY THE “TOP-DOWN”
APPROACH USING INTRA- AND INTER-LABORATORY DATA
The preferred method is to use performance data from both internal QC (intra-laboratory) and external proficiency
testing (inter-laboratory). For stable and well-established methods or procedures, imprecision is equivalent to the
standard uncertainty of measurement, assuming negligible or no bias. A minimum of six months data is
recommended (in order to ensure that variations due to multiple users, reagents and calibrator lots are captured). For
new methods, a minimum of 30 replicate determinations of appropriate control or reference material is required to
calculate an interim standard deviation (SD). If bias is significant or known, calculate the combined standard
uncertainty as demonstrated below. Also, precision and accuracy data from method validation studies can be used,
as long as there are no significant changes in the procedure following validation; this must be checked when
sufficient data has been accumulated.
1.
Calculate the overall SD of the method from monthly SD’s (imprecision) for at least two levels of QC using the
following equation:
SD = {[(SD2)L1 + (SD2)L2] / 2}1/2 ------------------------- (Equation 1)
where (SD)L1 and (SD)L2 are the average SD of each control level, respectively, for the past 6 months.
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Note: If more than two levels are used depending on QC and clinical decision limits for the method, calculate
the average SD as follows: SD = [(n1 SD12 + n2 SD22 + …. nn SDn2) / (n1 + n2 + ….. nn)]1/2, where n is the
number of control levels. Average SD is the combined standard uncertainty, Uc associated with the result, if bias
is negligible.
Equation 1 shows the calculation of the average imprecision for the two control levels and is generally
applicable to methods where control levels depict performance across the entire analytical measuring ranges of
the methods (AMR). For some methods, such as some immunoassays, with varying imprecision at different
clinical decision limits or cut-points, uncertainty of measurement (SD) must be calculated at each
decision level.
If results are outside of the AMR and are derived from dilution or concentration, add the uncertainty associated
with dilution or concentration to equation 1.
2.
Calculate the standard uncertainty associated with the method, uSD:
uSD =SD (average SD)
3.
If bias is significant and not corrected for, calculate the combined standard uncertainty of the method, Uc:
Uc = [(uSD)2 + (uB)2 ]1/2 ---------------------------------- (Equation 2)
= [(SD)2 + (SEM)2 + (uCref)2]1/2 ---------------------- (Equation 3)
uB = [(SEM2) + (uCref2)]1/2 ------------------------------- (Equation 4)
= [(1/N × SD2) + (uCref)2]1/2 -------------------------- (Equation 5)
uB is standard uncertainty of bias; N is the number of replicate analyses performed (minimum 10), when bias is
determined using certified reference material or calibrator traceable to a reference system; uCref is the standard
uncertainty associated with the reference material or calibrator traceable to a reference method (obtained from
the manufacturer or certifying body); SEM is the relative SD or standard error of the mean of replicate
measurements of the reference material or calibrator. Medical laboratories can purchase certified reference
materials and calculate the SEM by performing replicate analyses (minimum of N=10) for each analyte
(test/examination; SEM = SD/N ½ ). Or calculate the bias, uB, from external quality assessment (EQA)
performance data by determining the average % bias from peer mean for at least three different surveys at
multiple levels per analyte. uCref can be calculated from EQA data as well, using the difference between peer
mean and the reference or all-methods’ mean (AMM). If a dilution or concentration is performed, the
appropriate uncertainty should be added to the combined uncertainty.
4.
Calculate the expanded uncertainty of the method, U. The expanded uncertainty is the combined uncertainty x
k-value, which is taken to be either 2 or 1.96;
U
= Uc × 1.96 (~2) --------------------------------------- (Equation 6)
where U is the 95% confidence interval of uncertainty
5.
Express result as: Measured Results +/− U, (units).
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ESTIMATES OF UNCERTAINTY OF MEASUREMENT FOR SOME COMMON MEDICAL
LABORATORY TESTS
A. PLASMA OR SERUM GLUCOSE (FASTING PLASMA GLUCOSE)
The values used in the following examples are not real results and are used for illustrative purposes only.
Fasting plasma or serum glucose (FPG) (indicative of impaired glucose utilization) = 6.8 mmol/L; CV = 2.0%
or SD = 0.14 mmol/L; uBref (calibrator bias/uncertainty relative to a reference system) = 2.0% or 0.1 mmol/L;
SEM (method bias/uncertainty of the test method) = 2.0 % or 0.1 mmol/L; acceptable sources are peer group
data from EQA or proficiency testing (PT) programs, replicate analyses of certified reference material or
accuracy surveys with frozen serum samples and manufacturers and reference laboratories.
The combined uncertainty of fasting plasma glucose is:
uSDFPG = Standard Uncertainty = [(uSD)2 + (uB)2]1/2 mmol/L]
= [(SD)2 + (SEM)2 + (uBref)2]1/2
= [(0.14)2 + (0.1)2 + (0.1)2]1/2
= [(0.02) + (0.01) + (0.01)]1/2
= 0.2 mmol/L
The expanded uncertainty of fasting plasma glucose, UFPG is:
UFPG
= 0.2 × 1.96 or Um = 0.2 × 2 = 0.4 mmol/L, representing a 95% confidence interval of uncertainty.
At a fasting plasma glucose 6.8 mmol/L, the UFPG = 0.4 mmol/L
i.e., the fasting plasma or serum glucose = 6.8 +/− 0.4 mmol/L (95% CI = 6.4 − 7.2 mmol/L)
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B. ANION GAP (AG)
Estimates of uncertainty of measurement derived from other measurement results, often termed inputs, are
combined uncertainties of the independent inputs. If inputs interact by addition or subtraction, SD must be used.
However, if they interact by multiplication or division, CV must be used in the determination (see
next example).
For routine use, the anion gap, AG is derived as follows:
AG = [Na – (Cl + HCO3)] mmol/L
AG result is 14 mmol/L derived from [Na 140 – (Cl 105 + HCO3 21)] = 14 mmol/L
Inputs interact by addition and subtraction, standard uncertainty is SD: SD’s for Na, Cl and HCO3 for level 1 or
level 2 QC derived from equation 1 are:
Na+
= 1.0 mmol/L; Cl = 1.2 mmol/L; HCO3 = 0.9 mmol/L
The standard uncertainty of the anion gap, uSDAG is:
uSDAG1 = [(1.02 + 1.22 + 0.92)]1/2 = 2 mmol/L
The expanded uncertainty of the anion gap, UAG, is:
= uSDAG × 1.96 or uSDAG × 2 = 4 mmol/L, representing a 95% confidence interval of uncertainty.
UAG
The number 1.96 or 2 is called the coverage factor as previously described. UAG is equivalent to the
total error (TE) in the absence of a systematic error (SE).
At an AG of 14 mmol/L, the UAG = 4 mmol/L
i.e., the anion gap = 14 +/− 4 mmol/L (95% CI = 10 – 18 mmol/L)
As an exercise, using your own laboratory information and the appropriate formulae, determine the expanded
uncertainties for the following tests:
1.
Calc. LDL-Chol = Total Chol – HDL-Chol – VLDL-Chol (Trig)
2.
Osmol Gap = Measured Osmol – Calculated Osmol
Calculated Osmol = Na + Glucose + Urea
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C. CREATININE CLEARANCE (CCR)
For routine use, creatinine clearance (Ccr) is derived as follows:
= [Ucr (umol/L) × Vol (mL)] / [t(min) × Scr(umol/L)] mL/min
Ccr
Ccr is the creatinine clearance, Ucr, the urine creatinine, Vol, the volume of urine, Scr, the serum creatinine and t,
the collection time.
Because inputs interact by multiplication or division, CV must be used in determining uncertainty of
measurement here.
Typical CV’s are Ucr = 2.3%; Vol = 10%; Scr = 3.5%; t = 1%
The standard uncertainty of creatinine clearance, uCVCcr is
uCVCcr = [(2.32 + 102 + 3.52 + 12)]1/2 = 11%
SDCcr
= uCVCcr × Ccr
= 11% × 80 = 8.8 mL/min
The expanded uncertainty of creatinine clearance, UCcr is:
UCcr
= SDCcr × 1.96 or SDCcr × 2 = 18
At a Ccr of 80 mL/min, the UCcr = 18 mL/min
i.e., the creatinine clearance = 80 +/− 18 mL/min (95% CI = 62 – 98 mL/min)
As an exercise, using your own laboratory information and the appropriate formulae, determine the expanded
uncertainties for the following tests:
1.
Urine albumin creatinine ratio (ACR)
ACR = Ualb (mg/L) / Ucr (mmol/L) mg/mmol
2.
Urine cadmium creatinine ratio (CdCR)
CdCR = Ucd (umol/L) / Ucr (mmol/L) umol/mmol
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SUMMARY
Compliant with OLA accreditation requirements, medical laboratories must establish traceability and estimate the
uncertainty associated with all quantitative measurement results and express it as follows:
Measurand (analyte): Value +/– U units
U is the expanded uncertainty and units are typically SI or internationally accepted non-SI units.
The expanded uncertainty, U, represents the range of values within which the true value produced by the
measurement method lies. U is calculated by multiplying the combined standard uncertainty by a coverage factor, k.
The magnitude of the coverage factor depends on the confidence level assigned to the range of values. For most
medical laboratory procedures, k is taken as 1.96 or 2, signifying a 95% confidence limit.
When using the top-down approach to determining uncertainty of measurement, for stable and well-established
methods, it is important to note that this approach does not include uncertainty associated with the pre-analytical
process, such as patient preparation or sampling. However, estimates are compared with clinical decision limits or
goals, which encompass the pre-analytic process.
Several approaches have been proposed for determining the expanded uncertainty of measurement results in the
medical laboratory. The “top-down” approach using laboratory method performance data is recommended.
Regardless of the approach used, medical laboratories must have a documented process for assessing the
fit-for-purpose of uncertainty of measurement, as well as for continuously monitoring the effectiveness.
References
1.
Crawford L, Moses G. Traceability and uncertainty of measurement for medical laboratories—OLA’s
expectations. QMP–LS News [newsletter on the Internet]. 2007 Sept (no. 118); p. 1. Available from:
http://www.qmpls.org/pub_resources/publications/qmpls_news/pdf/qmplsnews118.pdf
2.
Quality Management Program—Laboratory Services. Ontario Laboratory Accreditation Division. Ontario
Laboratory Accreditation Requirements and Guidance Information, 2008 Version 4.1. Ontario (Canada):
QMP-LS; 2008.
3.
Standards Council of Canada (SCC). CAN-P-1626 PALCAN Policy on Traceability Requirements for Calibration
Sources Used by Accredited Testing Laboratories. Ottawa: Standards Council of Canada; November 2006 [cited
2007 August 14]. Available from http://www.scc.ca/Asset/iu_files/criteria/1626_e.pdf.
4.
National Pathology Accreditation Advisory Council (NPAAC). Requirements for the estimation of
measurement uncertainty. Canberra: Commonwealth of Australia, Australian Government Department of
Health & Ageing; 2007. ISBN 1-74186-164-0.
5.
International Organization for Standardization. ISO/IEC 17025:2005 General requirements for the competence
of testing and calibration laboratories. 2nd ed. Geneva: International Organization for Standardization; 2005.
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6.
International Organization for Standardization. ISO/IEC 98:1995 Guide to the expression of uncertainty in
measurement (GUM). Geneva: International Organization for Standardization; 1995.
7. National Association of Testing Authorities (NATA). Technical Note #33 - Guidelines for estimating and
reporting measurement uncertainty of chemical test results. 2006 Jul 3.
RECOMMENDED READING
1.
Australian Government Attorney General’s Department [homepage on the Internet]. Australia: Commonwealth
of Australia; c2005. Available from: http://www.ag.gov.au/.
2.
Physics Laboratory Physical Reference Data [database on the Internet]. Gaithersburg (MD): National Institute
of Standards and Technology (NIST). Recommendation INC-1 (1980) – Expression of experimental
uncertainties. Available from: http://physics.nist.gov/cuu/index.html.
3.
International Organization for Standardization (ISO) [homepage on the Internet]. Geneva: International
Organization for Standardization; c2009. Available from: http://www.iso.org.
4.
The American Association for Laboratory Accreditation (A2LA) [homepage on the Internet]. Frederick (MD):
The American Association for Laboratory Accreditation; c2002. P102 – A2LA Policy on Measurement
Traceability; 2008 October 22; [about 2 screens]. Available from:
http://www.a2la.org/policies/A2LA_p102.pdf.
5.
White GH. Basics of estimating measurement uncertainty. Clin Biochem Rev. 2008;29 Suppl i:S53–S60.

Traceability and Uncertainty of Measurement for Medical Laboratories

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