Preanalytical challenges - Time for solutions

Abstract

The European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase (WG-PRE) was originally established in 2013, with the main aims of (i) promoting the importance of quality in the preanalytical phase of the testing process, (ii) establishing best practices and providing guidance for critical activities in the preanalyti-cal phase, (iii) developing and disseminating European surveys for exploring practices concerning preanalytical issues, (iv) organizing meetings, workshops, webinars or specific training courses on preanalytical issues. As education is a core activity of the WG-PRE, a series of European conferences have been organized every second year across Europe. This collective article summarizes the leading concepts expressed during the lectures of the fifth EFLM Preanalytical Conference "Preanalytical Challenges-Time for solutions", held in Zagreb, 22-23 March, 2019. The topics covered include sample stability , preanalytical challenges in hematology testing, feces analysis, bio-banking, liquid profiling, mass spectro-metry, next generation sequencing, laboratory automation , the importance of knowing and measuring the exact sampling time, technology aids in managing inappropriate utilization of laboratory resources, management of hemolyzed samples and preanalytical quality indicators.

Full text

Clin Chem Lab Med 2019; aop
EFLM Paper
Giuseppe Lippi*, Fay Betsou, Janne Cadamuro, Michael Cornes, Michael Fleischhacker,
PalleFruekilde, Michael Neumaier, Mads Nybo, Andrea Padoan, Mario Plebani,
LauraSciacovelli, Pieter Vermeersch, Alexander von Meyer and Ana-Maria Simundic,
onbehalfof the Working Group for Preanalytical Phase (WG-PRE), European Federation
ofClinical Chemistry and Laboratory Medicine (EFLM)
Preanalytical challenges – time for solutions
https://doi.org/10.1515/cclm-2018-1334
Received December 17, 2018; accepted January 8, 2019
Abstract: The European Federation of Clinical Chemis-
try and Laboratory Medicine (EFLM) Working Group for
the Preanalytical Phase (WG-PRE) was originally estab-
lished in 2013, with the main aims of (i) promoting the
importance of quality in the preanalytical phase of the
testing process, (ii) establishing best practices and pro-
viding guidance for critical activities in the preanalyti-
cal phase, (iii) developing and disseminating European
surveys for exploring practices concerning preanalytical
issues, (iv) organizing meetings, workshops, webinars
or specific training courses on preanalytical issues. As
education is a core activity of the WG-PRE, a series of
European conferences have been organized every second
year across Europe. This collective article summarizes
the leading concepts expressed during the lectures of
the fifth EFLM Preanalytical Conference “Preanalytical
Challenges – Time for solutions”, held in Zagreb, 22–23
March, 2019. The topics covered include sample stabil-
ity, preanalytical challenges in hematology testing, feces
analysis, bio-banking, liquid profiling, mass spectro-
metry, next generation sequencing, laboratory automa-
tion, the importance of knowing and measuring the exact
sampling time, technology aids in managing inappropri-
ate utilization of laboratory resources, management of
hemolyzed samples and preanalytical quality indicators.
Keywords: education; errors; laboratory medicine; pre-
analytical phase; quality.
Introduction
The European Federation of Clinical Chemistry and
Laboratory Medicine (EFLM) Working Group for the Pre-
analytical Phase (WG-PRE) was originally established
in 2013, with the main aims of (i) promoting the impor-
tance of quality in the preanalytical phase of the testing
process, (ii) establishing best practices and providing
guidance for critical activities in the preanalytical phase,
(iii) developing and disseminating European surveys for
exploring practices concerning preanalytical issues, (iv)
organizing meetings, workshops, webinars or specific
training courses on preanalytical issues (Table 1) [1]. The
WG-PRE has already achieved many important goals
related to its terms of reference and will continued to do
so in the future, with the purpose of improving the overall
culture of quality in preanalytical phase across Europe
and beyond, a goal than could also be achieved by collab-
orating with other extra-European federations or national
associations [2].
*Corresponding author: Prof. Giuseppe Lippi, Section of Clinical
Biochemistry, University Hospital of Verona, Piazzale L.A. Scuro 10,
37134 Verona, Italy, Phone: +0039-045-8124308,
E-mail: giuseppe.lippi@univr.it. https://orcid.org/0000-0001-9523-
9054
Fay Betsou: Integrated Biobank of Luxembourg, Luxembourg,
Luxembourg
Janne Cadamuro: Department of Laboratory Medicine, Paracelsus
Medical University, Salzburg, Austria
Michael Cornes: Worcestershire Acute Hospitals NHS Trust,
Worcester, UK
Michael Fleischhacker: DRK Kliniken Berlin Mitte, Clinic for Internal
Medicine – Department of Pneumology, Berlin, Germany
Palle Fruekilde and Mads Nybo: Department for Clinical
Biochemistry and Pharmacology, Odense University Hospital,
Odense, Denmark
Michael Neumaier: Institute for Clinical Chemistry, Medical Faculty
Mannheim of Heidelberg University, Mannheim, Germany
Andrea Padoan, Mario Plebani and Laura Sciacovelli: Department of
Laboratory Medicine, University Hospital of Padova, Padova, Italy.
https://orcid.org/0000-0003-1284-7885 (A. Padoan);
https://orcid.org/0000-0002-0270-1711 (M. Plebani);
https://orcid.org/0000-0003-3156-1399 (L. Sciacovelli)
Pieter Vermeersch: Laboratory Medicine, University Hospitals
Leuven, Leuven, Belgium
Alexander von Meyer: Kliniken Nordoberpfalz and Klinikum St.
Marien, Weiden and Amberg, Germany
Ana-Maria Simundic: Department of Medical Laboratory Diagnostics,
Clinical Hospital “Sveti Duh”, Zagreb, Croatia
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2 Lippi etal.: Preanalytical challenges – time for solutions
Education, one of the core activities of the WG-PRE,
has been mostly pursued by organizing a series of Euro-
pean conferences every second year across Europe. Four
conferences have already been organized in Parma in 2011
[3], in Zagreb in 2013 [4], in Porto in 2015 [5] and in Amster-
dam in 2017 [6]. These meetings, which have provided a
contribution for improving the quality in the preanalyti-
cal phase, have been the largest such conferences across
Europe, bringing together over 600 participants at the
last occasion. The program of these conferences has been
tailored by the Scientific Committee to provide updated
knowledge in preanalytics and developing an open forum
for interactive discussions and professional improvement.
This fifth collective article is hence the latest of the
opinion papers published by the EFLM WG-PRE following
from the previous Preanalytical Conferences, and sum-
marizes the leading concepts and issues expressed during
the lectures of the fifth EFLM Preanalytical Conference
“Preanalytical Challenges – Time for solutions”, held in
Zagreb, 22–23 March, 2019. The topics covered included
sample stability, preanalytical challenges in hematology
testing, feces analysis, bio-banking, liquid profiling, mass
spectrometry, next generation sequencing and laboratory
automation, the importance of knowing and measuring
the exact sampling time, technology aids in managing
inappropriate utilization of laboratory resources, man-
agement of hemolyzed samples and preanalytical quality
indicators.
Preanalytical challenges
inlaboratory automation
Total laboratory automation (TLA) has recently expanded
dramatically in many laboratories and has a wide variety
of advantages in a high-volume laboratory with 24/7 activ-
ity [7]. The automation solution varies from automated
equipment for the majority of analyses, to cover the
inclusion of an automated sample reception unit and/
or track solution delivering the samples to the analyz-
ers and, finally, to automated transportation facility (e.g.
tube transportation or a vehicle) that delivers samples
directly to reception units. Undoubtedly, automation has
significantly improved efficiency and shortened turna-
round times (TAT) [8] and has also reduced the hands-
on time and thereby the number of (possible) human
errors. Nevertheless, there are still many preanalytical
caveats that laboratory professionals must address [9].
The more automated the system becomes, the harder it
is to unravel errors and perhaps even to discover them in
the first place. In the worst case, nothing is noticed before
a substantial number of patients are potentially harmed.
Further efforts should therefore be made to focus on pre-
analytical issues within the TLA and facilitating future
decision-making in an increasingly automated laboratory
environment. No doubt, much will still depend on the
specialist knowledge of a laboratory professional, and
continuous dialog with clinicians on a number of matters
will perhaps be even more important in a fully-automated
laboratory to understand and, if necessary, improve test
algorithms, reflex testing, as well as to assure deliverance
of laboratory test results to the right clinician as expedi-
tiously as possible.
The importance of knowing the
exact sampling time and ways to
measure it
Several pre- and postanalytical quality indicators in labo-
ratory medicine are strongly dependent on the time the
sample is collected. The duration of sample transport is
a leading quality indicator, defined by standards such as
the International Organization for Standardization (ISO)
15189:2012. As analytical stability for most laboratory
tests is time- and temperature-dependent, sampling time
information is crucial for qualifying a sample as suitable
for being tested. Moreover, sampling time information is
indispensable when interpreting test results for thera-
peutic drug monitoring, hormones and other parameters
exhibiting circadian variation [10–12].
Despite its unquestionable importance for accurate
analytical and post-analytical sample handling, sampling
time information is often missing. Although the retrieval
and documentation of correct sampling times may be
a major challenge for many medical laboratories, some
Table 1: Terms of reference of the European Federation of Clinical
Chemistry and Laboratory Medicine (EFLM) Working Group for the
Preanalytical Phase (WG-PRE).
– Promoting the importance of quality in the preanalytical phase of
the testing process
– Establishing best practices and providing guidance for critical
activities in the preanalytical phase
– Developing and disseminating European surveys for exploring
practices concerning preanalytical issues
– Organizing meetings, workshops, webinars or specific training
courses on preanalytical issues
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Lippi etal.: Preanalytical challenges – time for solutions 3
facilities have already helped solve this issue. Depend-
ing on the local healthcare environment, the problem
can be addressed in different ways. In some situations,
information technology (IT) solutions may be the most
appropriate approach, whilst a more pragmatic and less
technical approach might be more sensible in other situ-
ations. In any case, human and financial resources need
to be defined and allocated before implementing systems
or processes.
Several different approaches aiming to solve the
problem of retrieving a correct sampling time are cur-
rently being developed or are already in use. In order to
provide high quality analytics and interpretation of labo-
ratory tests, laboratories need to find a suitable approach
for retrieving correct sampling times, fitting properly to
their local environment.
Technology aids in optimizing
utilization of laboratory resources
Although laboratory testing shall be used for the right
patient, using the right test at the right time and with
accurate data interpretation, clinicians or nurses do not
often fulfill a reasonable approach when ordering tests,
especially for inpatients [13]. This may frequently lead to
over- or under-utilization of laboratory resources, thus
potentially jeopardizing patient health. The reasons for an
inappropriate use of laboratory tests include broad labo-
ratory ordering profiles, defensive medicine, insufficient
education, availability-triggered demand, among others
[14]. Test ordering is hence a framework where labora-
tory professionals shall provide their medical expertise,
assisting the selection of the right test and the accurate
interpretation of results, thus more efficiently managing
the demand of laboratory resources. This objective can
be accomplished by educational interventions or using
digital tools integrated in the laboratory information
system (LIS). As the overall number of laboratory profes-
sionals is typically limited in most healthcare settings, the
latter option seems more efficient. Demand management
tools, which have proven to be effective, include labora-
tory diagnostic algorithms, gate-keeping strategies such
as re-testing intervals, harmonization and re-evaluation
of ordering profiles among others [15]. As a reasonable
premise to all efforts made to improve the appropriateness
of laboratory test usage, strategies need to be developed
in close collaboration with clinicians, based on current
evidence and revised/updated on a regular basis. In the
future, laboratory professionals shall need to engage far
more outside of the analytical part of the testing process,
thus providing their vast expertise to benefit patient
outcome.
Preanalytical requirements
inhematology
Laboratory hematology is an essential part of diagnos-
tic reasoning and managed care of most, when not all,
hematologic diseases [16]. As many other areas of labo-
ratory medicine, total quality in hemostasis testing is an
essential premise for obtaining reliable and clinically
usable data. The preanalytical issues related to labora-
tory hematology are frequently similar to those of other
areas of diagnostic testing, and hence include accurate
patient identification, as well as appropriate procedures
for sample collection, handling, transportation and
storage [16]. Unlike clinical chemistry, immunochemistry
and hemostasis testing, however, laboratory hematology
has a unique trait, represented by the need to irrevers-
ibly inhibit blood coagulation, and hence maintain the
sample indefinitely anticoagulated for blood cells enu-
meration, sizing and differentiation. This can be achieved
by using the specific additive ethylenediaminetetraacetic
acid (EDTA). The blood collection tubes for hematologic
testing typically contain dipotassium EDTA (K2-EDTA) in
a powdered state, coated onto the tube walls. The EDTA
mainly acts by irreversibly chelating bivalent ions, espe-
cially ionized calcium (Ca2+), which is essential for the
appropriate development of blood coagulation, through
the establishment of a bridge between negatively charged
phospholipids and the gamma-glutamic acid moiety of
clotting factors [17]. This would hence require a thor-
ough interaction between K2-EDTA and blood during tube
mixing, to ensure that all Ca2+ molecules present in the
blood tube are irreversibly chelated. The use of altera-
tive anticoagulant mixtures for laboratory hematology
(e.g. lithium-heparin or sodium citrate) is usually dis-
couraged, except in specific conditions such as EDTA-
dependent pseudothrombocytopenia [18]. Additional
frequent causes of sample non-conformance, especially
the presence of small clots or interfering substances
such as cell-free hemoglobin (i.e. spurious hemolysis),
bilirubin (i.e. icterus) and turbidity (i.e. lipemia), are
sources of great concern in laboratory hematology, as the
use of whole blood rather than serum or plasma would
make their visual or spectrophotometric identification
rather challenging or virtually unfeasible. This would
need additional tools to be developed (e.g. clot sensors,
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4 Lippi etal.: Preanalytical challenges – time for solutions
algorithms for analyzers, digital morphology), which may
finally help to increase the overall quality in laboratory
hematology.
Preanalytical issues in feces
analysis
Qualitative and quantitative feces analyses are a part
of routine laboratory diagnostics, although this mate-
rial is vulnerable to many sources of variability, related
to matrix heterogeneity, sample stability and prepara-
tion. Feces is characterized by a high intrinsic variabil-
ity in density and texture, both within the same sample
and among specimens collected at different time points
between successive bowel movements [19]. Between-
specimens heterogeneity increases in parallel with time
from one bowel movement and another. Within-stool het-
erogeneity can be limited by collecting a representative
amount of sample and by sampling multiple spots from
different sites within the same specimen. The sampling
technique, usually performed either by sample weight-
ing or apposite devices (dipsticks), is another notable
preanalytical aspect. Although sampling is performed by
trained personnel using dipsticks, a high variability in
the amount of collected sample remains (typically >20%).
Manual weighting appears more accurate, but less prac-
tical for routine analysis, especially in laboratories
analyzing large volumes of samples. Regarding sample
conservation, it has also been recently demonstrated that
fecal calprotectin (fCal) concentration may decrease after
24h by 12% at room temperature and 13% at 4 °C, respec-
tively [20]. Different preanalytical factors of fecal testing
should hence be controlled and standard handling proce-
dures should be followed for obtaining clinically reliable
data. Finally, a compeling need has emerged for develop-
ing harmonization programs aimed at limiting misinter-
pretation of test results.
Recommendations for managing
hemolyzed samples
Visual inspection of serum indices is highly unreliable
and should be replaced by automated systems. Han-
dling and managing hemolyzed samples may lead to
reporting errors for some very critical analytes and thus
affect clinician reasoning and decision, an example
being when an inaccurate result is reported from a
hemolyzed sample. On the other hand, patients can also
be harmed by an unnecessary suppression of sample
results which are unaffected by the degree of hemolysis
present. Although this is often not so obvious, sample
rejection and subsequent sample re-collection leads to
prolonged TATs, thus depriving a patient from a timely
diagnosis and treatment. Delayed diagnosis may cause
serious harm to patients, jeopardizing their health and
well-being. To minimize patient risk, managing samples
with a certain degree of hemolysis needs to be highly
standardized and preferably even automated, but at the
same time evidence-based and when necessary even per-
sonalized [21, 22]. The appropriate detection and man-
agement of serum indices requires adequate internal
(IQC) and external quality (EQA) control mechanisms.
Monitoring day-to-day variation of HIL indices should
become an essential part of a daily routine in labora-
tories worldwide. Commercial IQC materials have only
recently become available from external suppliers. It
should be noted that laboratories can also use in-house
IQC materials for this purpose, as a cost-effective alterna-
tive. Hence, the EFLM WG-PRE has developed a series of
recommendations [23, 24] for the efficient use of serum
indices, in an attempt to balance the need to produce
high quality laboratory data with a need to improve
patient care and outcome.
Sample stability
Pathology results are involved in most patient path-
ways. It is therefore essential to ensure that laboratory
results are of a high quality. However, laboratories can
only produce results as accurate as the sample quality
allows. Analyte stability is a key part of this, and it is
essential that the time and conditions a sample was
subjected to and the impact on the result are known.
The vocabulary in metrology defines stability as met-
rological properties remaining constant in time. Bio-
marker quantification of stability can be defined as
how much an analyte deviates from initial concentra-
tions over time [25]. Many replicate studies are per-
formed looking at the same analytes. This is because
many studies have been performed on a low number of
samples, with data that is often contradictory or incom-
plete and additional biases are often introduced [26].
The numbers of factors that can affect analyte stability
are many. Stability studies are complex and often dif-
ficult to apply across different healthcare settings and,
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Lippi etal.: Preanalytical challenges – time for solutions 5
for this exact reason, the EFLM WG-PRE is working on
some guidance. Checklist of recommendations of what
needs to be considered and documented when design-
ing a stability study are being produced. This does not
state how a study should be conducted but does state
what information should be included in publications to
allow transferability. This will be followed-up by a tool
to establish the quality of the data from already per-
formed stability studies. These checklists are based on
STARD [27] and should drive standardization and trans-
ferability of future studies.
Preanalytical quality indicators
During the Consensus Conference on “Harmonization
of Quality Indicators in Laboratory Medicine: two years
later” held in Padova (Italy) on October 26, 2016, a list
of quality indicators (QI) has been approved on behalf
of the Working Group “Laboratory Errors and Patient
Safety” (WG-LEPS) of the International Federation of
Clinical Chemistry and Laboratory Medicine (IFCC) [28].
A priority order has also been assigned to each QI, based
on its relevance (related to the critical activities being
monitored) and difficulties in data collection. More spe-
cifically, 26 QIs and 53 measurements concerning key
processes, along with three QIs and five measurements
concerning support processes and outcome measures,
have been finally identified. The higher number of QIs
with priority 1 (i.e. mandatory registration) relates to
activities of the preanalytical phase, thus confirming
the importance of QIs for monitoring and eventually
improving this particularly error-prone part of total
testing process [29]. Additional information collected
during the past few years highlights that (i) a relatively
low number of QIs has been currently implemented, (ii)
difficulties remain in assuring standardized and regular
comprehensive data collection and (iii) a low level of par-
ticipation has been recorded from laboratories belong-
ing to the same country. In order to achieve participation
from more laboratories, there should be further discus-
sion on the best strategy for (i) engaging international
providers of EQAs in the WG-LEPS, thus improving QI
harmonization, (ii) identifying a project leader in each
country for better coordinating of the participation of
national laboratories to the Model of Quality Indicators
(MQI) project and (iii) involving accreditation bodies, so
that the MQI project could be recognized as a suitable
tool for complying with ISO 15189:2012 accreditation
requirements [30].
Preanalytical real-world experience
with mass spectrometry
Liquid chromatography-tandem mass spectrometry
(LC-MS/MS) has been used for decades for specialized,
anti-doping, toxicology and clinical chemistry testing
due to its high selectivity, sensitivity and method adapt-
ability of this technology [31]. It is often postulated that
the full advantage of LC-MS/MS technology can only be
achieved with highly specialized personnel. Although
this may be true for the method-development phase,
this is not necessary the case following implementation
in an accredited routine clinical chemistry environment.
LC-MS/MS technology is a powerful tool when used in a
standardized continuous setting, with strict guidelines
from sampling to result dispatch. Incorrect sampling and
handling often compromises both selectivity and specific-
ity [32]. A neglected fact is that the use of gel-containing
blood collecting tubes poses a very high risk for interfer-
ence, either by introducing high levels of noise or, more
frequently, partly concealing the components of interest,
and thus posing a risk for falsely low results. Local expe-
riences reveal that therapeutic drug monitoring (TDM)
results can be dependent on the collecting tube manu-
facturer. Even changes in the composition of the phase-
separation reagent within the same product-line, can have
huge impact on analysis performance. Additional factors
such as type of sampling tube from various manufacturer
pose a massive validation effort which overwhelms most
laboratories, thus only one or two sample matrixes are
usually validated for routine analysis [33]. Full- or semi-
automated LC-MS/MS is emerging and will become more
available in a few years as application menus expand.
This expansion is strongly facilitated by correspondence
with clinical societies as well as clinical guidelines recom-
mending the use of LC-MS/MS methods.
Standardization of blood draw for
liquid profiling
The US Food and Drug Administration (FDA) approval of
the first blood-based genetic test for detecting gene muta-
tions of epidermal growth factor receptor (EGFR) in non-
small cell lung cancer (NSCLC) has been a milestone for
the management of cancer patients. Thus, the genetic
characterization of cell-free DNA has become a routine
application for the care of NSCLC patients. Additionally,
liquid profiling has been deemed useful in clinical studies
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6 Lippi etal.: Preanalytical challenges – time for solutions
for therapy monitoring, prognostic and predictive evalu-
ation of patients’ solid tumors other than lung cancer
[34]. Nevertheless, many unresolved preanalytical issues
remain. It is particularly important to define the optimal
method for blood drawing and sample handling before
plasma preparation. The use of EDTA blood tubes is still
considered the gold standard, although their applica-
tion for liquid profiling is suboptimal. Blood drawn into
these tubes cannot be stored (not to mention shipped to
a remote laboratory) and plasma preparation should be
performed without delay (maximum 4–6h when stored
at room temperature) [35]. In the last few years several
companies have developed new blood draw tubes which
are better suited for liquid profiling purposes. These sta-
bilize blood cells, prevent them from lysing and thus from
“contaminating” cell-free DNA/RNA with cellular nucleic
acids. A more detailed description of data achieved so far
and comparison of new tubes with EDTA has been recently
reviewed elsewhere [36].
Managing preanalytical variables
inbio-banking
The work of biobanks essentially consists of processing
biological materials. The input is a collected specimen
and the output is a sample to be stored for future analyses.
Many biobanks are embedded in clinical diagnostic labo-
ratories, and in this case may be called “clinical biobanks”
or “clinical biobank laboratories”. What is considered as
the “pre-examination” or “preanalytical phase” in clinical
laboratories, largely corresponds to what, here, is called
“processing”. An accreditation standard ISO 20387:2018
(Biotechnology – Biobanking – General requirements
for biobanking) has recently been published. It speci-
fies general requirements for competence, impartiality
and consistent operation of biobanks, including quality
control requirements to ensure biological material
and data collections of appropriate quality. Processing
methods are the core activity of biobanks and deserve
dedicated quality management. The quality management
of the preanalytical phase in biobanks includes some new
concepts such as the validation of each processing method
for reproducibility, robustness, fitness-for-purpose and
stability of output specimens [37]. The development and
implementation of “in-process quality control materials”
is part of the continuous quality assurance, as well as par-
ticipation in EQA “processing schemes” [38]. The purpose
of most of the samples produced by biobanks is not their
use in clinical diagnostics, but rather in research projects.
Therefore, the analytical methods used for validation of
processing methods are generally not clinical diagnostic
assays, but techniques designed to assess the fitness-for-
purpose of specimens for different categories of down-
stream research applications [39].
Next generation preanalytics:
biomolecular quality and IT
approaches
The importance of the preanalytical phase for the overall
accuracy and precision of laboratory results is now
increasingly being appreciated not only by the laboratory,
but also by the sender. Numerous influential factors have
been described ranking from indication for testing, prepa-
ration for sampling, correct sampling procedures, sample
transport and finally the required steps to secure preana-
lytics within the laboratory prior to testing [40].
The prime criterion for sound preanalytics is the main-
tenance of biomolecular specimen quality. However, there
is neither consensus about how to measure it, nor what
suitable parameters may be for that purpose. Plasma/
serum can be considered the most complex (liquid)
“tissue” by far with hundreds of thousands of different
analytes circulating in bodily fluids at any given time. For
example, protein biomarker concentrations in the blood
are known to span 12 orders of magnitude between, for
example, hemoglobin and interleukin-6 [41], and have
very different stabilities in clinical samples. Many metab-
olites cannot be measured under routine conditions due
to very short half-lives [42]. In order to assess the clinical
validity of a laboratory test result, two variables need to be
met. Firstly, the stability of a given analyte in a biological
sample needs to be known, while it must be appreciated
that its rate of decay may vary under different health con-
ditions in the patient. Secondly, the time-to-analysis needs
to be known, while it must be appreciated that important
environmental conditions may vary prior to testing.
How to meet ISO 15189
preanalytical requirements?
ISO15189 describes the quality management system
requirements for medical laboratories [43, 44]. A recent
survey of European medical laboratories by the EFLM
WG-PRE found that almost half of all participants were
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Lippi etal.: Preanalytical challenges – time for solutions 7
accredited according to ISO 15189:2012. This number has
increased in the recent years, at least in part because
accreditation according to ISO 15189 is mandatory in many
European countries. An important difference with ISO
17025, which describes the requirements for testing and
calibration laboratories, is the explicit requirement to con-
tinually improve the effectiveness of preanalytical, analyt-
ical and postanalytical processes. Somewhat surprisingly,
almost 10% of participants in the recent WG-PRE survey
indicated not monitoring any preanalytical quality indica-
tors. However, the ISO 15189:2012 requires the establish-
ment of quality indicators for monitoring and evaluating
critical aspects of the preanalytical phase (4.14.7). At the
same time, complaints have been raised about differing
interpretations by auditors of preanalytical requirements.
This suggests that guidance about implementing preana-
lytical requirements of ISO 15189:2012might be useful.
Conclusions
In conclusion of this collective article “Preanalytical Chal-
lenges – Time for solutions”, we wish to thank all our
contributors, we sincerely hope that this document may
be of interest for the readership of Clinical Chemistry and
Laboratory Medicine and will provide meaningful support
for identifying the issues and opportunities to improve the
quality in the preanalytical phase.
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.
Competing interests: The funding organization(s) played
no role in the study design; in the collection, analysis, and
interpretation of data; in the writing of the report; or in the
decision to submit the report for publication.
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