Traceability to previous standard, with defined uncertainty
WHO guidelines produce standards:
calibrated in a multi-method study (rather than a single, reference method)
With values assigned in International units (rather than mg/ml)
With no imprecision assigned to the ampoule content
prEN/ISO 17511 WHO
Calibration of the current International Reference Preparation for TSH Deviation of any assay result from the mean is composed of two elements; the assay imprecision, and the bias: The WHO multi-method approach, by including all assays, seeks to average out, and therefore eliminate the bias effect. The WHO approach will provide an estimate which is “accurate” but not “ precise” The “reference-method approach will provide an estimate which may be “precise”, but not “ accurate” Method bias, and single method vs multi method calibration
“ the choice of method depends on whether the most important consideration is metrological to minimise imprecision, in which case a single method should be used, or is biological to achieve a “true” overall value, in which case multiple methods should be used”.
To measure in activity (IU) or content (SI units)?
Many biologicals exist in both active and inactive states in plasma, where the activity (IU) rather than content (mol) reflects the clinical situation of the patient. Calibration in less precise biological units would hence be more appropriate than calibration in more precise, clinically irrelevant SI units
Conversely, situations exists where measurement of inactive or total (active plus inactive) analyte (mol) may be more clinically relevant that activity (IU)
WHO standards are established either: - as the first International Standard for any given analyte, in which case in which case the international unit is arbitrarily established for the first time - or as replacement international standards, in which case it is necessary to ensure continuity of the value of the unit;
the second standard is calibrated in terms of the first standard, preserving a line of metrological traceability of the international unit. This approach requires assignment of uncertainty, and the minimization of that uncertainty through the use of defined or even reference methods
the second standard is arbitrarily assigned a value intended to preserve as closely as possible the value of the unit, but where traceability to the first IS is discontinued and re-established to the second. This approach requires an arbitrary assignment without uncertainty, as wide a range of methods as possible, and sometimes reference to additional factors outside the collaborative study (eg standard plasma pools for factor VIII)
The continued usefulness of WHO biological standards shows that the approaches taken by WHO to biological standardisation have served well over a long period of time. The current two classes of reference preparation, the International Standard and WHO Reference Reagents should be maintianed.
As WHO biological standards cover a broad range of uses a range of options should continue to be used in their characterisation. It is essential to define the intended use of a standard prior to initiation of studies. This is to aid in the design of the studies to characterise the material and in the eventual value assignment to the material.