MEASUREMENT UNCERTAINTY


Term SI unit


Reference material Reference measuring system International standard How it confers traceability The definition of the SI unit is the reference for traceability


The assigned value of that reference material is what confers traceability


Traceability is conferred by the result produced by this system


A standard material where an assigned value is produced by a harmonisation process, often including all main available methods used in the diagnostic industry to provide a method of calibrating measurement procedures at the manufacturer, and laboratory, level


International harmonisation protocol


International collaborations to develop agreement between methods using a standardised protocol so that results are comparable in the absence of standardisation


Table 2. Methods available to evidence metrological traceability of results. SI – International System of Units.


hierarchy of calibrations is shown to a higher-order reference system including the International System of Units (SI). The use of SI units for laboratory results requires very strict conventions to be followed. We recognised this in recent years in haematology when we moved our haemoglobin units from g/dL to g/L to align with the SI unit of litre, rather than using a prefix (deci) on the denominator of the unit definition. To be complete, MT must be demonstrated to a higher-order reference, either material or procedure, and in an ideal world… both (Table 2). Measurement methods and materials do not themselves confer traceability. The results they produce have the property of traceability. The same can be said for calibrators or international standards.


The SI system of units and laboratory medicine In the early days of clinical laboratory medicine, measurement methods were manual, poorly standardised and very much performed at a local level without much application of harmonisation or standardisation. Standards used to generate results were often derived locally, and differences between centres in the local standards led to significant variation in clinical results. Around the turn of the 20th century,


international efforts began to try to standardise measurement units through the SI units. This system has been steadily implemented into laboratory medicine, including examples such as the mole that are central to many standardised measurement procedures. It is an ongoing project to try to have results for the same measurand reported in the same units, and when possible reporting them in SI units. To ensure the traceability of those results, the local measurement procedures must be calibrated against


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either a reference material – by traceability to the assigned value – or to the results produced by a reference measurement procedure.


Steps in a calibration hierarchy When describing a calibration hierarchy, we are looking at an unbroken series of calibrations from the higher-order standard to the end user method. As can be seen in Figure 1, uncertainty is propagated through the traceability chain, and increases through a series of alternating value transfers (calibrations) from reference procedure to end user measurement procedure. Each successive calibration will add additional uncertainty, and the subsequent value assignment in the next step of the chain


Calibration Hierarchy


Reference Measurement Procedure


Manufacturer master Measurement Procedure


Analyser/method used by laboratory


Local laboratory analyser


Increasing uncertainty


Fig 1. An example of the propagation of uncertainty through a fictional calibration hierarchy. A CRM of known concentration is used to calibrate a reference measurement procedure (a) so that value can be assigned to a matrix matched (to patients) in the subsequent step (b). That calibrator is then used to calibrate a manufacturer master procedure, to which all its subsequent methods are compared (c). Using that method, the manufacturer produces and calibrates a master calibration lot (d), from which all subsequent calibrator lot numbers are compared. If multiple measurement methods are available by the manufacturer, each individual method will require calibration against the master lot (e) and a value can then be assigned for that method for each later calibrator lot (f). We then use that calibrator to calibrate our local analyser using the assigned value – and hopefully uncertainty! (g, h). Finally, the accumulation of all uncertainty is manifested in patient results.


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a. b. c. d. e. f.


g. h.


again will add uncertainty. Uncertainty is calculated using the root sum of squares methodology through each step, resulting in an uncertainty we can apply to patient results through the top-down method (ISO/TS 20914:2019).


Traceability of results to reference method procedures


IVD Manufacturer requirements to demonstrate Metrological Traceability For the laboratory our first questions about MT will be directed to our in vitro diagnostic device (IVD) manufacturers (I won’t talk about laboratory developed tests here!). In order to demonstrate MT, the IVD manufacturer must demonstrate that an appropriate system of units is used for reporting results, be that SI, international units or other units. Within the specifications an indication of the highest order reference procedure in the calibration hierarchy should be made, and how the series of calibrations has ensured that chain is maintained. According to ISO17511:2020 compliance is also reliant on the IVD manufacturer providing specifications for the maximum allowable uncertainty of the method (U(y)


max),


as well as documentation to evidence the method achieves the requirement. Unfortunately, this is variably applied in practice.


Traceability of results to reference materials Certified reference materials (CRM) have a precisely determined assigned value


Calibrate Assign value


CRM


Matrix matched calibrator


Manufacturer calibrator master lot


Manufacturer calibrator (lot to lot)


Patient result


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