Accepted Manuscript

The role of laboratory in ensuring appropriate test requests

Simona Ferraro, Mauro Panteghini

PII: S0009-9120(17)30038-3
DOI: doi: 10.1016/j.clinbiochem.2017.03.002
Reference: CLB 9491
To appear in: Clinical Biochemistry
Received date: 16 January 2017
Revised date: 3 March 2017
Accepted date: 4 March 2017

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 ACCEPTED MANUSCRIPT

The role of laboratory in ensuring appropriate test requests

Simona Ferraro1, Mauro Panteghini1,2

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1
Clinical Pathology Unit, ‘Luigi Sacco’ University Hospital, and 2 Department of Biomedical and
Clinical Sciences, University of Milan, Milan, Italy

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Corresponding author: Simona Ferraro, UOC Patologia Clinica, Ospedale ‘Luigi Sacco’, ASST
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Fatebenefratelli-Sacco, Via G.B. Grassi 74, Milano, Italy. Phone +39 02 3904 2766; fax +39 02 503
19835; e-mail simona.ferraro@asst-fbf-sacco.it

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ABSTRACT

This review highlights the role of laboratory professionals and the strategies to be promoted in strict
cooperation with clinicians for auditing, monitoring and improving the appropriateness of test
request. The introduction of local pathways and care maps in agreement with international and
national guidelines as well as the implementation of reflex testing and algorithms have a central role
in guiding test request and in correcting the overuse/misuse of tests. Furthermore, removing
obsolete tests from laboratory menu and vetting of restricted tests is recommended to increase cost-

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effectiveness. This saves costs and permits to introduce new biomarkers with increased diagnostic
accuracy with a better impact on patient outcome. An additional issue is concerning the periodicity

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of (re)testing, accounting that only a minority of tests may be ordered as often as necessary. In the

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majority of cases, a minimum retesting interval should be introduced. The availability of effective
computerised order entry systems is relevant in ensuring appropriate test requests and in providing
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an aid by automated rules that may stop inappropriate requests before they reach the laboratory.
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ABBREVIATIONS
GPs: General Practitioners; PSA: prostate specific antigen; BNP: B-type natriuretic peptide; ED:
Emergency Department; HTA: Health Technology Assessment; CK: creatine kinase; AMI: acute
myocardial infarction; AST aspartate aminotransferase; ALT: alanine aminotransferase; PCT:
procalcitonin; ICU: Intensive Care Unit; HbA1c: haemoglobin A1c; TSH: thyroid-stimulating
hormone; CPOE: computerised physician order entry.

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INTRODUCTION

Advising on the optimal use of laboratory tests to improve the clinical effectiveness and
patient outcome is one of the main tasks of laboratory professionals [1]. According to Smellie [2],
to improve the appropriate use of tests, we should first answer a number of relevant questions
concerning: a) the definition of an inappropriate test, b) the estimation of the prevalence of
inappropriate testing, and c) which types of intervention are valuable to reduce the rate of
inappropriate test requests.

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DEFINITION OF AN INAPPROPRIATE TEST

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Current literature largely defines inappropriate laboratory utilization as “any test order in
violation of a guideline produced by a government or professional society” [3]. In a broader sense,
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according to Lundberg, who compared the laboratory test to any other diagnostic or therapeutic
intervention, the appropriateness entails that the delivered benefit to the patient exceeds the
delivered harm (i.e., undesirable effects of testing), and this can be done at a reasonable cost and
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with reasonable risk [4]. Indeed, the right test choice is part of the triad of main elements of value in
laboratory information, together with the right interpretation and the right advice as to what to do
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next with the result (Figure 1). The appropriate request starts the loop of laboratory testing, in which
a laboratory result should enable a decision to be made, which leads to an action being taken,
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yielding an improved clinical and economic outcome for the patient [5]. The majority of laboratory-
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related causes of diagnostic mistakes have been ascribed to overuse, underuse and misuse of
laboratory tests [1, 6, 7] and updated evidence has recently identified test ordering on the top of the
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pre-analytical steps recognized as the most critical and in need of immediate harmonization [8].
Interestingly, a net prevalence of underutilization vs overutilization (error rate, 44.8% vs 20.6%) has
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been suggested [9].

All effective strategies documented to drive the appropriate test demand imply the
establishment of a close relationship between clinicians and laboratory professionals. Working on
the clinical-laboratory interface is central to increase the clinical efficacy of laboratory testing and
to promote subsequent appropriate actions [1]. By the way, this may actively involve laboratory
professionals both in managing upstream test demand and in down-stream interpretation of
laboratory results [10]. Plebani and Panteghini have prioritized harmonization initiatives at the
clinical-laboratory interface [5]. In particular, the harmonization of test demand, covering the so-
called pre-pre-analytical phase, implies cooperation between clinicians and laboratory professionals

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to achieve: a) local implementation of practice guidelines, b) design and use of common laboratory
test profiles, if any, c) agreed periodicity of (re)testing, d) use of reflex testing and algorithms, and
e) a policy of introducing new tests and discontinuing or replacing obsolete tests [5]. Appropriate
quality assessment programs should be implemented together with a regular auditing of this
activity, in order to share the results of quality indicators with clinicians and to demonstrate their
effectiveness [11].

PREVALENCE OF INAPPROPRIATENESS

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A large variation in clinicians’ requesting behaviour has been demonstrated by auditing data

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on test ordering for inpatients and outpatients in primary and secondary care settings. Data

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published in UK in November 2013 in the National Health System Atlas of Variation in Diagnostic
Services showed large variations in General Practitioners’ (GPs) requesting, which affected both
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common and specialized tests [12]. Marked difference were reported between most and least
requesting groups of GPs for, e.g., prostate specific antigen (PSA) (72-fold difference in annual rate
of requesting), B-type natriuretic peptide (BNP) (89-fold difference), serum creatinine (106-fold
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difference), and fecal calprotectin (446-fold difference) [12]. Even when outliers were removed, a 4
to 5-fold difference in average persisted. Notably, it was difficult to explain such a large variability
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in requesting rate by differences in disease prevalence in different regions and, consequently, to

establish the correct requesting rate. Similar audits performed in Spain in primary care has further
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confirmed the wide test request variability involving both relatively common analytes, such as
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calcium and iron, and specialized tests, such as ferritin and vitamin D [13, 14]. Another survey
involving more specifically tumour marker ordering in general surgery has pointed out that 40-
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50% of all requests were for panels of ≥4 markers and one-third of requests for carbohydrate
antigen 125, the reference marker for ovarian cancer, were for male patients [15].
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Surveys have also clearly documented underuse of appropriate tests. Since 2005, the
European Society of Cardiology recommends excluding suspected heart failure in symptomatic
patients through electrocardiogram and measurement of natriuretic peptides [16]. However, a recent
international survey has revealed that in 2013 20% of surveyed laboratories did not offer this test
in their menu, showing that this type of service is not yet universal [17].
The documented situation calls for efforts in reduction of variation in test requests
addressing the urgent need for harmonization efforts. Indeed, the existence of persistent
unwarranted variations in providing healthcare may directly affects the equity of access to services,
the health outcomes of populations and the efficient use of resources [18].

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An additional source of inappropriateness proven by auditing concerns the failure to follow-

up test results, which also represents a critical safety issue. A meta-analysis of 12 studies reported
that the proportion of test results not followed up for hospitalized patients ranged from 20% to
61.6% and for patients treated in the Emergency Department (ED) ranged from 1% to 75% [19].
Notably, the main problems concerned the follow-up of critical test results, which can result life
threatening if an action is not taken promptly. In many cases, urgent results were never accessed
electronically, missing in the medical records or there was no documentation showing that the
physician was aware of the critical laboratory value and/or had taken a consequent corrective action

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[19]. A comparable missing follow-up of laboratory results was reported in patients moving across
different healthcare settings (e.g., from hospital to outpatient services or for patients first treated in

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the ED and then moved to a clinical ward). In this case, late-arriving results, flawed management

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systems, and practices preventing the appropriate sharing and transferring of information across
healthcare settings increased the risk of missing certain test results, causing problems with the
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continuity of care [19].

INTERVENTIONS TO IMPROVE APPROPRIATENESS IN TEST REQUEST

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A wide body of literature describes actions and strategies that can be employed to improve
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test ordering [20]. Here, we describe some options, summarized in Table 1, related to practical
approaches we applied in our professional experience that proved to be effective.
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Developing and disseminating practice care maps and clinical pathways

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Usually, international and national guidelines aim to achieve the “right balance” between
hazards of under-testing and of over-testing, considering both the risk of missing, not monitoring or
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treating a disease as well as the risk of complicating diagnosis and/or treatment since false positive
results likely trigger additional (often more costly) investigations. We previously underlined the
advantages of promoting interaction between clinicians and laboratory professionals early on in
preparation of guidelines when they include the use of laboratory tests [1]. Crucial to appropriate
application of laboratory tests is laboratorians’ role in closely scrutinizing proposed assays and
limiting their clinical use before the evidence for them is solid [21, 22]. It has been reported that the
inclusion of laboratory professionals in the guideline development process increases the focus on
important laboratory-related items concerning all phases of the examination process, including the

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pre-pre-analytical one [23]. Consequently, this may reduce inappropriate laboratory test use as well
as increase the quality of laboratory information.
With these premises in mind, in order to become effective at the local level and finally
achieve efficacy of care, recommendations by national and international guidelines should firstly
drive to efficiency of care (Figure 2) [24]. To this aim, the guideline recommendations should be
translated into more pragmatic local care maps/clinical pathways, extensively stating how, when,
where and why specific tests should or should not be ordered. As an example, Table 2 reports the
basic concepts we agreed in partnership with clinicians, when recommendations on the correct use

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of tumour markers were implemented in our institution [25]. In general, we recommended that one
marker is usually enough for disease management, and thus we established that no more than two

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different tumour markers should be requested in the same transaction. Importantly, before making

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any final decision related to the (in)appropriateness of request, blocked orders asking for >2 tumour
markers were always discussed with the requesting clinicians. By introducing these
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recommendations, we immediately experienced a large decrease in the number of ordered tests (in
average, -40%), without any negative clinical impact [26]. However, in a more recent study, we
have shown that the release of local recommendations to guide tumour marker ordering is not
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enough to curb the excess of requests and maintain the appropriateness, but this should be supported
by strict monitoring on a daily basis by laboratory professionals as well as a continuous consultation
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with requesting clinicians [27]. In reviewing the persisting level of inappropriateness of tumour
marker ordering, 6 years after the introduction of local recommendations, we showed that clinicians
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initially deleted 43% of the originally ordered markers, but for a relevant proportion, they
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immediately reintegrated some in a second request. This evidence confirms the deep-rooted belief
that measuring more markers provides better diagnostic power or may be of aid when characterizing
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complex patients. Unfortunately, this is in contrast with the biological features of most tumour
markers (limited predictive value), which often prevent performing an accurate
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identification/exclusion of malignancies, particularly when the test is applied to low-risk

individuals.
In the mentioned study, we also tried to estimate the impact and the dimension of tumour
marker inappropriateness. By considering the updated epidemiological estimates of tumour
incidence and prevalence in Milan, the expected total number of tumour marker tests per year
amounts to ~126,000, if tumour marker ordering would fulfil recommendations. By comparing this
estimate with the number of markers currently performed in Milan clinical laboratories (~350,000),
we estimated that performed tumour marker tests exceed the justified ones by approximately 3-fold
[27].

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Using the Health Technology Assessment (HTA) approach

If guidelines by professional societies or expert groups are lacking, corrective actions can be
planned using the HTA approach, which enables healthcare providers to tackle the issue of test
requests as a “healthcare problem”, by considering the position of stakeholders involved in
ordering, performing, interpreting the test, and receiving its results [28]. In our experience, we used
HTA for introducing local recommendations to reduce the overuse of vitamin B12, folate and

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homocysteine testing [29, 30]. For instance, for vitamin B12, in compliance with ethical concerns
and association with adverse outcome occurrences, we identified haemodialysis patients and

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pregnant women as those groups preferentially requiring B12 testing [31]. For folate determination,

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we showed that the cost-effectiveness of the test is maximized when the request is oriented to
subjects suggestive/at risk for deficiency, becoming low if the test is used as a screening tool or for
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monitoring of vitamin intake/supplementation [32]. Incidentally, these conclusions should not be
generalized to those countries following folic acid fortification policies, where it is indeed no more
cost-effective to test folate in the face of deficiency prevalence <1% and where it has been
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suggested to phase out serum folate test ordering from clinical use [33].
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Removing obsolete tests

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Removing tests that offer little incremental information would save money, avoid additional
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investigations arising from incidental and clinically irrelevant abnormalities, and improve the risk to
benefit ratio [5]. For instance, deleting myoglobin, total creatine kinase (CK) and CK-MB
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isoenzyme determinations from laboratory order forms in patients admitted to ED with suspected
acute coronary syndrome leads to significant cost saving and reduces possible confusion in data
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interpretation and patient management. When we took action against the redundant request of
biomarkers no longer recommended for acute myocardial infarction (AMI) diagnosis, the overall
testing costs were reduced by 105,000 € per annum [34]. By comparing the rate of laboratories
still offering biomarkers additional to cardiac troponin as part of their cardiac order profile, a recent
survey has recorded a significant reduction from 2010 to 2013 of laboratories retaining CK and
aspartate aminotransferase (AST) in their cardiac test repertoire [35]. However, in spite of the
contemporary recommendations reporting cardiac troponin as the sole diagnostic biomarker for
AMI, a consistent number of laboratories are still using CK-MB isoenzyme activity measurements

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(~30%), myoglobin (~20%) and, incredibly, lactate dehydrogenase/hydroxybutyrate dehydrogenase

assays (~15%) [35].

Avoiding pathophysiologic duplications and implementing reflex testing

There are pairs of tests that are jointly ordered several times per day in many laboratories,
although in most cases there are no pathophysiologic reasons for associating these requests, making
this routine procedure an important source of redundant duplications (Table 3) [36]. For instance,

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the two aminotransferases [AST and alanine aminotransferase (ALT)] are usually ordered together
when hepatocellular damage is suspected, although it is well known that ALT alone would be

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sufficient, being more liver-specific and with an activity persisting longer than AST after an acute

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injury [37]. The incremental benefit of routine determination of AST, in addition to ALT, is very
limited [38]. Optimally, laboratories reporting abnormal ALT results (e.g., higher than twice the
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upper reference limit) should offer AST as a reflex test and calculate the AST-to-ALT ratio because
it provides useful diagnostic and prognostic information [39]. A recent study, considering all
possible combinations of eight tests commonly used to screen liver involvement, has shown that the
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best information can be obtained by associating ALT with alkaline phosphatase, when the purpose
of testing is to exclude liver disease in primary care subjects. For this scope, AST was inefficient
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[40].
The optimal management of free PSA requests using reflex testing may also become a
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source of substantial savings. International guidelines have recommended the determination of free
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PSA only when the total PSA concentrations in serum ranges between 4 to 10 µg/L (revised after
the assay recalibration using the WHO standard to 3-10 µg/L) to differentiate benign hyperplasia
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from prostate cancer [41]. By auditing free PSA requests in our institution, we reported that only
15% of those complied with this recommendation, with an economic waste for the National Health
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Care System of 50,000 € per year [42]. These data supported the activation of reflex testing
allowing free PSA determination only when total PSA is within the recommended range and
labelling as inappropriate the free PSA requests in samples with total PSA exceeding the limits of
the recommended interval (Figure 3).
Measurement of conjugated bilirubin in serum is also consolidated as a reflex test only when
the total bilirubin concentration is higher than the upper reference limit [43]. To similarly seek for
increasing the appropriateness of total bilirubin ordering, we recently introduced in our laboratory a
reflective algorithm using the assessment of icteric index as front-line test for the identification of
blood samples with abnormal total bilirubin concentrations, which are the only ones that need the

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measurement of total bilirubin [44, 45]. The application of optimal cut-off for the icteric index that
reliably excludes abnormal total bilirubin concentrations allowed the accurate “zero-cost” detection
of samples with normal total bilirubin concentrations, avoiding direct measurements in 40% of
bilirubin orders in our clinical setting [46].

Vetting of restricted tests

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Applying gating policies is an additional important option that laboratories have to promote
and preserve the cost-benefit, particularly for complex and costly tests. Procalcitonin (PCT), a test
which results can help to diagnose bacterial infection and decide about starting or stopping

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antibiotic treatment, represents a nice example [47]. Although PCT assays are now available on

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several automated analytical platforms, the lack of consistent scientific evidence together with the
relatively high test costs do not permit to recommend adding PCT testing to standard clinical
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practice [48]. A systematic review of the literature, focused on the economic evaluation of PCT use
in critical care setting, has shown that PCT-guided strategies were associated with a significant
reduction (on average, 2 days) on duration of antibiotic utilization, allowing to lower costs per
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patient treatment episode (in average, -470 Can$) in comparison to the standard strategy of care
[49]. However, as Yealy and Fine have noted, “the issue of whether the likely cost-savings
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attributed to reduced antibiotic use (and reduced antibiotic-related adverse effects) would outweigh
the accrued costs of PCT testing remains undefined.” [50]. To compare PCT costs (40 € per test in
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our institution) with the cost of antibiotic treatment for infections in intensive care unit (ICU)
patients (ranging from 114 to 384 € daily [49, 51]), it is unfortunately not diriment: the optimal use
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of PCT in ICU patients requires indeed daily measurements of this marker [52]. In this still doubtful
situation, in order to warrant the cost-effectiveness of PCT test and to increase its appropriateness,
the ordering should fulfil a restricted policy. In our institution, PCT can be ordered only by ICU, as
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an aid in decision for continuing or stopping of antibiotics, and by Neonatology, as an aid in

diagnosing late-onset sepsis in neonates. For all other clinical wards, the PCT request has to be
preventively approved by laboratory specialists, who should be contacted by phone by clinical
requestors to discuss about the clinical suspicion supporting the PCT request in addition to other
already available tests (e.g., C-reactive protein).

Restricting retesting by applying minimum retesting intervals

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An additional intervention concerns the periodicity of retesting (i.e., the minimum time
before a test should be repeated, based on the properties of the test and the clinical situation in
which it is used), accounting that only a minority of tests may be ordered as often as necessary [53].
In the majority of cases, a minimum retesting interval should be introduced by using, e.g.,
automated rejection rules, to reduce unnecessary repeat of tests, thereby improving workload and
expenditure and influencing clinician-requesting behaviour [1, 54]. The consensus
recommendations released by the UK Association for Clinical Biochemistry and Laboratory
Medicine for minimum retesting intervals in clinical biochemistry may represent a sound reference

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for defining monitoring periodicity of testing and implementing rejection rules [55].
Recently, Morgen and Naugler have estimated the rate of inappropriate repeats of six

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laboratory tests [total cholesterol, haemoglobin A1c (HbA1c), thyroid-stimulating hormone (TSH),

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vitamin B12, vitamin D and ferritin] in their laboratory [56]. 16.4% of requests were judged as
inappropriate, ranging from 7.2% for TSH to 35.8% for ferritin [56]. The estimated annual savings
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achievable eliminating the inappropriate testing in the authors’ institution was between 0.57 and
2.15 millions Can$, corresponding to a national annual cost of 160 million Can$ [56].
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UNDERUTILIZATION IN LABORATORY TESTING: AN UNDERAPPRECIATED

PROBLEM
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‘‘Inappropriate’’ and ‘‘overutilization’’ are sometimes used as synonyms for inappropriate

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testing. Indeed, the majority of the proposed interventions are directed to cut tests, refuse requests,
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or act towards cost savings actions. The damage of inappropriateness is, however, far beyond the
mere consumption of reagents: it is the damage of misdiagnosis, generation of incorrect treatment
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pathways, length of hospital stays, and finally worse outcomes. In causing harm and leading to
medical errors, underutilization of laboratory tests may have similar effects when compared to
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overutilization, resulting in morbidity due to delayed or missed diagnoses [9]. While there are
relatively robust data demonstrating overuse of laboratory tests, corresponding data focusing on the
underuse of testing are relatively scant. Lamixan et al. [57] found that approximately 30% of their
patients with newly diagnosed diabetes did not receive a repeat HbA1c test within one year of the
initial test, suggesting a suboptimal metabolic monitoring. In another study, the guideline-
recommended D-dimer as the initial screening test for venous thromboembolism diagnosis were
underused resulting in downstream overutilization of the expensive spiral computerized
tomographic scan [58]. Laboratory monitoring of adverse drug reactions is also often lacking,

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decreasing the possibility of highlighting organ damage and therefore reducing related morbidity
[59].

THE WAY FORWARD: STOPPING INAPPROPRIATE REQUESTS BEFORE THEY

REACH THE LABORATORY

According to Fryer and Smellie, to effectively manage demands for laboratory tests and
reduce inappropriate requesting it is mandatory the activation of preventative strategies stopping

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inappropriate requests before they could reach the laboratory [20]. Accordingly, institutions should
fully exploit the potential of electronic requesting acting as “enabling factor” for reinforcing

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educational messages and sustaining their effects over time. For any institution trying to achieve

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optimum patient care (and control costs), the appropriate design of information systems for
computerised physician order entry (CPOE) is critical and, consequently, laboratory professionals
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must insist that information system vendors provide effective systems to assist in the institutions’
endeavours to ensure appropriate test requests. On the other hand, the performance of CPOE
systems represents a new challenge when considering the clinicians’ satisfaction with clinical
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laboratory services [60]. Working to optimize CPOE systems, also involving clinicians, may
therefore increase the rate of acceptance and satisfaction. Other technological tools such as
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laboratory information systems and patient databases have certainly a role for improving laboratory
test utilization.
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CONCLUSIONS
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Previously, we highlighted that laboratory professionals should be continuously engaged in

auditing, monitoring and improving the appropriateness of test requests by promoting a cooperation
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on the clinical-laboratory interface and introducing different educational tools enabling clinicians to
increase their knowledge on test use [1]. Tools such as CPOE guidelines and on-line help, audit,
consensus definition of laboratory test profiles according to diagnosis-related problems may provide
meaningful aid. These activities are quite relevant in modern laboratory medicine, helping to
counteract the vision of laboratory testing as a “commodity”. Laboratory professionals have to
evaluate the impact of laboratory testing in terms of clinical efficacy and effectiveness in addition to
efficiency, and provide and employ quality indicators linking laboratory testing to patients’ and
economic outcomes [61].

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Table1. Types of interventions to improve appropriateness in test request

 Developing and disseminating practice care maps (agreed in partnership with clinicians)
 Using the Health Technology Assessment (HTA) approach when guidelines are lacking
 Deleting obsolete tests from laboratory order forms
 Avoiding pathophysiologic duplications and implementing reflex testing
 Applying gating policies and “traffic light” systems (particularly for complex and costly tests)

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 Restricting retesting by applying minimum retesting intervals

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Table 2. General concepts and main outcomes supporting recommendations for the correct

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use of tumour markers (TMs) in our institution
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Basic concepts
 With few exceptions, TMs should not be requested and used for diagnostic purposes
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 When appropriately used, TMs may provide relevant information on treatment efficacy and
on residual disease after treatment
 In general, organ-appropriate TMs exist and one TM is enough for disease evaluation and
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monitoring
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Main outcomes
 To homogenise the possible clinical benefits associated to the TMs request
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 To decrease the rate of inappropriateness of TMs request (e.g., requests performed for
tumour diagnosis or use of TMs not recommended for specific tumours)
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To decrease costs both direct and indirect, i.e., economic and social, associated with the
TMs inappropriate use, with consequent better rationalization of resources.

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Table 3. The "famous pairs" in Laboratory Medicine

 Serum creatinine and urea

 Erythrocyte sedimentation rate and C-reactive protein
 Aspartate aminotransferase and alanine aminotransferase
 Total and conjugated bilirubin
 Amylase and lipase

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 Prothrombin time and activated partial thromboplastin time
 Free T3 and free T4

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 Total and free prostate specific antigen
 Ferritin and transferrin saturation

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Figure legends

Figure 1. The triad of elements of value in laboratory information.

Figure 2. Steps describing the loop linking the preparation of international and national guidelines
and the corresponding local release of care maps/clinical pathways.

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Figure 3. Investigational algorithm for prostatic cancer in use at our institution.

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PSA, prostate specific antigen.

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Fig. 2
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Fig. 3

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