Calibration hierarchy

From the definitions and examples above, it should be clear that metrological traceability is established by a series of comparisons back to a reference value of a quantity. In the mass example it is easy to picture a number of scientists with ever more sophisticated balances comparing one mass with another down the chain of masses from the international prototype of the kilogram to bathroom scales. This is known as a calibration hierarchy. A mass farther up the chain is used to calibrate the next mass down the chain, which in turn can be used to calibrate another mass, and so on, until the final measurement of the mass is made. 

A primary measurement standard is expected to have a known quantity value with minimum uncertainty, although this is not specified as such in the definitions. Because the measurement uncertainty is propagated down the calibration hierarchy, you should start with as small an uncertainty as possible and choose methods to establish purity of primary reference materials with this in mind. 

For a measurement result to be metrologically traceable, the measurement uncertainty at each level of the calibration hierarchy must be known. Therefore, a calibration standard must have a known uncertainty concerning the quantity value. For a CRM this is included in the certificate. The uncertainty is usually in the form of a confidence interval (expanded uncertainty see chapter 6), which is a range about the certified value that contains the value of the measurand witha particular degree of confidence (usually 95%). There should be sufficient information to convert this confidence interval to a standard uncertainty. Usually the coverage factor ( see chapter 6) is 2, corresponding to infinite degrees of freedom in the calculation of measurement uncertainty, and so the confidence interval can be divided by 2 to obtain uc, the combined standard uncertainty. Suppose this CRM is used to calibrate... 

Select calibration hierarchy. By selecting a working calibrator, its calibration hierarchy is determined by the available documentation. Attention should also be paid to the calibration and metrological traceability of measurement results for input quantities to a measurement function measured by accessory equipment such as balances, thermometers, and volumetric ware. 

Keywords Calibration hierarchy Comparability of results Joint Committee on Traceability in Laboratory Medicine Metrological traceability Reference examination system... 

Metrological traceability, according to its definition, is a property of a measurement result or quantity value, and the trace is towards a stated reference through a metrological traceability chain. Its links and relations between them have to be established a priori in the opposite direction from the chosen reference towards the measurement result. This structure is termed a calibration hierarchy. 

The concepts of calibration and especially of metrological traceability were elaborated by physicists as mentioned above. The reference or top of the calibration hierarchy preferably is the definition of an SI unit, which is realized or embodied as a primary measurement standard. By direct comparison, the quantity value of a secondary measurement standard can be established. Subsequent comparisons may furnish quantity values of reference measurement standard, working measurement standard, and routine measurement standard with which the object carrying the measure and is compared to obtain its measurement result which then retrospectively is metrologically traceable to the SI unit. The primary measurement standard, as the definition of metrological traceability says, is preferably an international or national measurement standard. 

Although many elements of measurement in chemistry are by nature physical, such as those involving mass, volume, time, temperature and spectral absorbance, the calibration hierarchy in chemistry is seldom described as a series of comparisons between measurement standards. Rather, a measurement procedure points to a measuring system performing a measurement which assigns a quantity value and measurement uncertainty to a calibrator itself a type of measurement standard which serves to calibrate the next measuring system, operated according to a second measurement procedure, and so on. 

Fig. 1 Full calibration hierarchy providing metrological traceability from measurement results to SI unit definition as the stated reference. MP=measurement procedure, C=calibrator...

The sequence of five types of calibration hierarchy outlined above obviously constitutes decreasingly transparent and generalized traceability chains, and international collaboration is necessary to improve comparability. 

When a calibration hierarchy starts with the definition of an SI unit followed by a primary reference measurement procedure and descends through commutable calibrators and specific and selective measurement procedures full calibration hierarchy above the traceability to an SI unit is automatically ensured. The other four types of hierarchy do not preclude the use of a bona fide SI unit in the expression of a measurement result for a differential or rational quantity, but it is mandatory to specify the top measurement procedure and/or calibrator in the designation for the measurand. For example, amount-of-substance concentration of nitrogen(N) in human plasma by Kjeldahl procedure no. 3 (referring to the laboratory s list of procedures). The result in millimole per litre, however, is not unequivocally comparable with that of another Kjeldahl procedure, because the kinds-of-quanti-ty are differently specified, but the unit is unchanged. 

All five documents provide detailed instructions and obviously apply to various elements of calibration hierarchies. 

At the metrological top, the CGPM defines SI units, and its executive, the CIPM, oversees their dissemination [12], The rather newly established CCQM organizes Key Comparisons of measurements on reference materials among the national metrology institutes to ensure adequate measurement capabilities at the highest metrological level. Several of these materials are relevant to calibration hierarchies in laboratory medicine. 

Abstract The concept of total allowable error , investigated by Westgard and co-workers over a quarter of a century for use in laboratory medicine, comprises bias as well as random elements. Yet, to minimize diagnostic misclassifi-cations, it is necessary to have spatio-temporal comparability of results. This requires trueness obtained through metrological traceability based on a calibration hierarchy. Hereby, the result is associated with a final uncertainty of measurement purged of known... 

A calibration hierarchy must be defined to allow metrological traceability, preferably to a unit of the International System of Units (SI). Traceability involves plugging into a reference measurement system of reference procedures and commutable calibration materials. 

The necessary anchor for the trueness of a measurement procedure is obtained by strict metrological traceability of result, based on a calibration hierarchy. The... 

In physics, the use of calibration hierarchies is well established and is used in any laboratory, e.g. for balances, volumetric equipment, spectrometer wavelengths, cuvette light path lengths, thermometers, barometers and clocks. 

According to EN/ISO 17511 [4] traceability of a value attributed to a routine sample, a calibrator or a control material is established by a series of comparative measurements using measurement procedures and reference materials in a chain of decreasing hierarchical order (Fig. 1). The figure demonstrates the calibration hierarchy from top to bottom and the traceability chain from bottom to top. Since each link in the chain contributes to the uncertainty of the result it is advisable to omit as many steps as possible. In terms of metrology it would be ideal to omit all in-between steps of the traceability chain and to measure the routine sample directly using a primary reference procedure. This of course is not feasible. 

In many instances a selected and agreed reference measurement procedure forms the basis of the definition of the quantity and thereby represents the top of the calibration hierarchy. This is particularly true for establishing reference systems for the catalytic concentrations of enzymes. In 1999 members of the IFCC working group and some enzyme reference laboratories decided to establish new 37 C measurement procedures as IFCC reference procedures on the basis of the existing 30 C IFCC procedures and to certify enzyme reference materials for AFT, AST, GGT, CK, FD and amylase in collaboration with the IRMM. The enzymes having IFCC reference measurement procedures have catalytic concentra-... 

Figure 14-39 The calibration hierarchy from a primary method to a routine method. The uncertainty increases from top to bottom.

Note 2 Metrological traceability requires an established calibration hierarchy. 

Note 3 Specification of the reference must include the time at which this reference was used in establishing the calibration hierarchy, along with any other relevant metrological information about the reference, such as when the first calibration in the calibration hierarchy was performed. 

Fig. 1 Illustrating a calibration hierarchy, also known as a traceability...

EAL-G12 describes in detail the components of a calibration hierarchy whereby an instrument calibration made at a local level, such as an industrial in-house calibration laboratory, is linked to a national standard by a chain of comparisons, with each step explicitly supported by appropriate documentation. The document gives a number of excellent detailed examples for various types of measuring instruments, including ... 

Figure 1 illustrates a simple calibration hierarchy for a manufactured product that is required to conform with stated requirements. 

The calibration hierarchy is the sequence of calibrations from a reference to the final measuring system, where the outcome of each calibration depends on the outcome of the previous calibration [13]. This hierarchy requires that for measurements incorporating more than one input quantity in the measurement model (e.g., pH, 7), each input quantity must itself be metrologically traceable. In addition, each measurement and derived quantity is listed with an evaluated uncertainty that captures the uncertainties of the measurements and of the calibration hierarchy. Also, because the propagation of variances is additive, measurement uncertainty increases throughout the calibration hierarchy fiomthe RM (which is ideally a certified reference material aka CRM) to the sample. A statement describing the uncertainty is essential, as a measured quantity value unaccompanied by a measurement uncertainty is not only useless, but it is potentially dangerous because the measured value may be misinterpreted or misused. 

Rigorously, the measurand of Fourier transform instruments is the frequency and amplitude of an image current and in quadrupole and time-of-flight instruments it is the ion multiplier ou ut current. In practice, the instrument manufacturer provides die customer die traceable calibration hierarchy information relevant to accounting for the / vs. m/z spectrum. The investigator must verify die claimed traceability of the insttument. The final traceability to the instrument performance (i.e., mass calibration) remains the responsibility of the laboratory operator. 

In summary, HX-MS measurements of Type A analytes can be firmly based in the SI, and the HX-MS instmment and analysis method can be traced through the calibration hierarchy to fundamental standards. Assured that this rigorous foundation can exist, the development of validated measurement methods and RM for use in proteolytic fragmentation HX-MS is sensible. 

Thus far, no national standards laboratory (e.g., NIST) or private standards organization has issued, or recommended, suitable proteins for use in an HX-MS calibration hierarchy. This absence is not surprising, as investigators using HX-MS have yet to settle on a set of consensus standard RM. In view of the rapid expansion in the use of HX-MS for research applications and its likely future applications as a quality control for biopharmaceuticals, perhaps it is time for the HX-MS community, the national standards laboratories, and RM producers to devote resources to identifying and characterizing proteins that can serve as suitable reference proteins. 

Figure 4 Calibration hierarchy and metrological traceability to SI (The terms and definitions taken from ISO 17511 2003 In vitro diagnostic medical devices - Measurement of quantities in biological samples - Metrological traceability of values assigned to calibrators and control materials.) (Reproduced with permission from International Organization for standardization, ISO. This standard can be obtained from any ISO member and from the website, www.iso.org ISO.)...

Note 2 Metrological traceability requires an established calibration hierarchy. Metrological traceability to a measurement unit... 

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