Keeping pace with patient safety by developing and qualifying higher-order reference measurement procedures for laboratory measurement standardization

Obtaining comparability among different in vitro diagnostic (IVD) measurement procedures is a priority in order to avoid result misinterpretation and patient harm [1]. The agreed principle to achieve standardization of laboratory measurements is represented by establishing metrological traceability of results on clinical samples to higher-order references of suitable quality [2]. The key higher-order elements are certified reference materials and reference measurement procedures (RMP), together with reference laboratory services using these RMPs [3]. The International Vocabulary of Metrology (VIM) defines the reference measurement procedure (RMP) as a “measurement procedure accepted as providing measurement results fit for their intended use in assessing measurement trueness of measured quantity values obtained from other measurement procedures for quantities of the same kind, in calibration, or in characterizing reference materials” [4]. To become an RMP, a measurement procedure requires a clearly planned design, with a detailed documentation of the individual working steps, and should be thoroughly investigated for all requirements described in the International Organization for Standardization (ISO) 15193:2009 standard [5] and supporting the implementation of a calibration hierarchy as described in ISO 17511:2020 [6]. Among others, the measurement uncertainty (MU) should be sufficiently low for accurately assigning values to reference materials to be used as common calibrators in the calibration hierarchy [7]. For many clinical measurands, isotope dilution mass spectrometry is the analytical principle used to achieve an RMP.

The Joint Committee for Traceability in Laboratory Medicine (JCTLM) database is designed to support the introduction of higher-order references and to represent transparently the current state-of-the-art for all components, including certified reference materials, RMPs, and reference measurement services. To fulfill its purpose, the JCTLM uses appropriate ISO standards and a third-party independent review process [8]. At present, the JCTLM database lists 249 RMPs for approximately 160 measurands. For JCTLM to review RMPs for compliance with ISO requirements, these should include detailed experimental setup and procedure descriptions, validation and traceability data and a thorough description of the MU evaluation [9]. In addition, the JCTLM requires evidence of the extent of equivalence through a comparison with already listed higher-order reference(s), if any, when new candidate reference materials or RMPs are nominated in order to avoid the introduction of a bias in the calibration hierarchies of commercially available IVD measurement procedures that will use different higher-order reference options [8].

The JCTLM has a requirement that an RMP nominated for listing is made publicly available by publication in a scientific journal. The principle behind is that available RMPs must be made accessible to all stakeholders, such that their independent use and dissemination is possible. Publications must be peer reviewed and should be accompanied by supplementary materials with detailed operational instructions. This requirement also applies to modifications to an existing published RMP or a new RMP similar to an existing published RMP. Within the field of measurements science, even small changes to methods can impact the accuracy and MU of results, and the modifications need to be documented and their impact on the measurement results validated. The JCTLM has issued a request to journals to support scientists developing and validating both new and modified RMPs by being open to accept submissions of such papers to peer-review and publication through their journals. In line with this concept, this issue of Clinical Chemistry and Laboratory Medicine is publishing a series of papers describing candidate RMPs based on liquid chromatography isotope dilution mass spectrometry [10], [11], [12], [13], [14], [15], [16].

An aspect not yet completely considered when higher-order references are established is that their use should be closely associated with the setting of targets for MU to provide test results that are clinically suitable [6], 8]. In particular, the MU of certified reference material values or that related to clinical samples characterized by an RMP should be small enough, when combined with other MU sources of the total MU budget, i.e., IVD calibrator and random variability generated by medical laboratory, to permit the fulfilment of maximum allowable MU at the level of patient results (MAU) [17]. A model for the definition of limits for combined MU across the entire metrological traceability chain was proposed, suggesting that the higher-order references should display an MU at most equal to one-third of MAU to leave enough MU budget for the IVD manufacturer’s calibrators and the imprecision of the IVD measurement procedure as implemented by each individual laboratory to produce acceptable results in terms of MU on clinical samples [18]. With this regard, the authors of the published papers should be congratulated for taking care of this important, although often neglected aspect and applying this concept helping to characterize the quality of their candidate RMPs. Table 1 summarizes the MAUs for the measurands that are covered in the publications.

In conclusion, the availability of published candidate RMPs is a pre-requisite for third-party review and listing in the JCTLM database of higher metrological order reference materials, methods and services. With the current issue, the CCLM is responding to the JCTLM’s request to facilitate the publication of such papers, with the ultimate goal of providing a significant contribution to supporting standardization in laboratory medicine for the benefit of patient care.