The paper by Federica Braga and Mauro Panteghini entitled “Utility of measurement uncertainty in medical laboratories” , published in this issue of the Journal, provides welcome light in the shadows of an intriguing and widely debated issue. Despite the numerous papers published in recent years, measurement uncertainty remains a nightmare for many laboratory professionals, particularly those seeking laboratory accreditation according to the ISO 15189:2012 . As correctly highlighted by the authors, “although all medical laboratories seeking ISO 15189:2012 accreditation know that measurement uncertainty (MU) estimate is a specific requirement (clause 126.96.36.199), few know what to do with the calculated MU” . We wish to add that “few are truly aware of how to calculate MU in medical laboratories”.
Most laboratorians express concern about the so-called “bottom-up” approach, which seems appropriate for testing and calibration laboratories working in fields other than medicine and for those seeking accreditation in line with ISO 17025:2017 and 15195:2012 standards , . After decades of increasingly accurate internal quality control (IQC) and external quality assessment/proficiency testing (EQA/PT) practices, the search for any potential source of analytical uncertainty according to the “bottom-up” approach is seen as a complicated and useless challenge, particularly in the light of the impressive improvement achieved in analytical performances in recent decades. Indeed, recent evidence highlights that analytical errors have been reduced, thanks to the availability of reliable analytical performance specifications, valuable tools (IQC, EQA/PT) for monitoring the achievement of analytical goals, and inter-laboratory comparison of performances (benchmark). The vulnerability of the extra-analytical phases of the total testing process (TTP) has now been well demonstrated. More efforts should therefore be made to adopt harmonized quality indicators and related performance characteristics in the pre- and post-analytical phases rather than changing the concepts and tools used to successfully control and improve the analytical phase , .
Particularly in the US, but also in many European laboratories, the shift from the well-known concepts of total allowable error (TAE), imprecision and bias in a search for the Holy Grail of measurement uncertainty is conceived as a complication without any real added value .
Braga and Panteghini strongly recommend the “top-down” approach as a more simple and effective way of estimating the MU of laboratory results, also in view of its recent endorsement in the recently released ISO/TS 20914:2019 .
The authors also emphasize the importance of establishing the magnitude of MU in comparison to the specific use of the measurand in medical decision making and patient management (which should be addressed for diagnostic, prognostic, monitoring and therapy purposes). As stressed elsewhere , a “one size fits all” calculation of MU is inappropriate; rather, MU should be calculated depending on how the “true” value is obtained and applied depending on the type of comparison required for correct result interpretation”. Figure 1 shows our proposal for MU calculation according to different test purposes.
Braga and Panteghini suggest the right approach for defining the “maximum allowable MU” and explain how to deal with bias in clinical measurements, stressing the importance of the traceability framework and the strategic role of in vitro diagnostics (IVD) manufacturers in assigning the MU of calibrators’ value (that includes the ubias) . While we agree with the authors, we wish to raise a further concern: currently only a few IVD manufacturers provide information on the MU of their calibrators. This information should be considered mandatory when evaluating IVD manufacturers’ tenders, and scientific national societies and federations should support further initiatives to raise the awareness of laboratory professionals and IVD manufacturers of the need for metrological traceability of measuring systems to the highest available references, including the assignment of MU value to the calibrators. However, we firmly maintain that medical laboratories need to verify and monitor measurement bias using valuable EQA/PT systems that fulfil category I/IIA criteria. This in turn, encourages laboratory professionals, national scientific societies and federations to focus on the importance of EQA/PT systems as professional tools in measuring and improving quality in all steps of laboratory testing, and raises awareness of the need to demonstrate the commutability of control materials, and target values obtained with (when available) measurement reference systems and by reference laboratories and to adopt harmonized extra-analytical indicators .
The main reasons for MUs’ usefulness, laudably summarize by the authors, are that they: (a) give objective information on the quality of individual laboratory performance; (b) serve as a management tool for the medical laboratory and for IVD manufacturers, obliging them to investigate and eventually fix the identified problems; (c) help the manufacturers of superior products and measuring systems to demonstrate the superiority of their products; (d) identify analytes requiring analytical improvement for their clinical use, and encourage IVD manufacturers to work toward improving the quality of assay performance; (e) lead to the abandonment of poor quality assays (with demonstrated insufficient quality).
However, the authors do not mention another basic clause of the same International Standard: the notification of MU to laboratory users as stated in the footnote to the above-cited clause 188.8.131.52: “upon request, the laboratory shall make its estimates of measurement uncertainty available to laboratory users” .
With regard to the above reported concept, which calls for the calculation of MU according to the different test purposes, although it seems easy to define some measurands used for diagnosis and/or monitoring purposes, for some other measurands used for both aims, the medical laboratory should have a better understanding of the specific aim of the request for the specific patient, context and time, and should consistently calculate and report MU .
The last few years have seen a greater focus on uncertainty in medicine and, as stated, “despite significant advances in diagnostic testing, physicians still face uncertainty in interpretation” . The notification of MU should facilitate the appropriate interpretation of laboratory results, particularly when they are close to the upper (or lower) reference value or to the decision level (cut-off). The management of uncertainty may strengthen the relationship between clinicians, patients and medical laboratories if that uncertainty is communicated effectively. Laboratory professionals should clearly inform all users (physicians and patients) that MU is only a part of the broader uncertainty of laboratory information, which takes into account both pre- and post-analytical issues, such as the quality of the sample/specimen and of the comparator (reference interval/decision limits).
Finally, we stress that uncertainty is ubiquitous in medicine and, as stated by Han and colleagues, “doctors continually have to make decisions on the basis of imperfect data and limited knowledge, which leads to diagnostic uncertainty, coupled with the uncertainty that arises from unpredictable patient responses to treatment and from health care outcomes that are far from binary ”. Laboratory information is playing an increasingly important role in the provision of diagnosis and therapy but, as with any kind of clinical information, all limitations in diagnostic tests influence diagnostic and therapeutic decisions. Each and every user should therefore be aware of this when interpreting the results of an individual patient.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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