Clin Chem Lab Med 2020; aop
Editorial
Mario Plebani, Andrea Padoan and Laura Sciacovelli
Measurement uncertainty: light in the shadows
https://doi.org/10.1515/cclm-2020-0134
The paper by Federica Braga and Mauro Panteghini enti-
tled “Utility of measurement uncertainty in medical labo-
ratories” [1], 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 night-
mare for many laboratory professionals, particularly
those seeking laboratory accreditation according to the
ISO 15189:2012 [2]. 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 5.5.1.4), few
know what to do with the calculated MU” [2]. 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 accredita-
tion in line with ISO 17025:2017 and 15195:2012 standards
[2, 3]. 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 impres-
sive improvement achieved in analytical performances in
recent decades. Indeed, recent evidence highlights that
analytical errors have been reduced, thanks to the avail-
ability of reliable analytical performance specifications,
valuable tools (IQC, EQA/PT) for monitoring the achieve-
ment 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 [4, 5].
Particularly in the US, but also in many European lab-
oratories, 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 [6].
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 [7].
The authors also emphasize the importance of estab-
lishing 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 diag-
nostic, prognostic, monitoring and therapy purposes).
As stressed elsewhere [8], a “one size fits all” calcula-
tion of MU is inappropriate; rather, MU should be calcu-
lated 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 stra-
tegic role of in vitro diagnostics (IVD) manufacturers in
assigning the MU of calibrators’ value (that includes the
ubias) [1]. While we agree with the authors, we wish to raise
a further concern: currently only a few IVD manufactur-
ers 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 profession-
als 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
2      Plebani et al.: Measurement uncertainty: light in the shadows
Figure 1: Proposal for MU calculation according to different test purposes.
obtained with (when available) measurement reference
systems and by reference laboratories and to adopt har-
monized extra-analytical indicators [9].
The main reasons for MUs’ usefulness, laudably
summarize by the authors, are that they: (a) give objec-
tive information on the quality of individual laboratory
performance; (b) serve as a management tool for the
medical laboratory and for IVD manufacturers, oblig-
ing 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 notifica-
tion of MU to laboratory users as stated in the footnote to
the above-cited clause 5.5.1.4: “upon request, the labora-
tory shall make its estimates of measurement uncertainty
available to laboratory users” [2].
With regard to the above reported concept, which
calls for the calculation of MU according to the differ-
ent test purposes, although it seems easy to define some
measurands used for diagnosis and/or monitoring pur-
poses, 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 [10].
The last few years have seen a greater focus on
uncertainty in medicine and, as stated, “despite signifi-
cant advances in diagnostic testing, physicians still face
uncertainty in interpretation” [11]. The notification of MU
should facilitate the appropriate interpretation of labora-
tory 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 effec-
tively. 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 imper-
fect data and limited knowledge, which leads to diagnos-
tic uncertainty, coupled with the uncertainty that arises
from unpredictable patient responses to treatment and
from health care outcomes that are far from binary [12]”.
Laboratory information is playing an increasingly impor-
tant 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.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
 Plebani et al.: Measurement uncertainty: light in the shadows      3
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Corresponding author: Mario Plebani, Department of Laboratory
Medicine, University-Hospital of Padova, 3218 Padova,
Italy; and Department of Medicine-DIMED, Medical School,
University of Padova, Padova, Italy, E-mail: mario.plebani@unipd.it.
https://orcid.org/0000-0002-0270-1711
Andrea Padoan: Department of Laboratory Medicine, University-
Hospital of Padova, Padova, Italy; and Department of Medicine-
DIMED, Medical School, University of Padova, Padova, Italy. https://
orcid.org/0000-0003-1284-7885
Laura Sciacovelli: Department of Laboratory Medicine, University-
Hospital of Padova, Padova, Italy. https://orcid.org/0000-0003-
3156-1399