Review Article

Annals of Clinical Biochemistry

50(4) 306–314
! The Author(s) 2013
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DOI: 10.1177/0004563213476486
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Ask the right question: a critical step for practicing

evidence-based laboratory medicine*

Christopher P Price1 and Robert H Christenson2

Abstract
The purpose of laboratory medicine is to facilitate better decision making in clinical practice and healthcare delivery.
Decision making implies an unresolved issue, problem or unmet need. The most important criterion for any investigation
to be of value in clinical practice is that it addresses an unmet need. The different ways in which laboratory investigations
are utilized in patient care can be represented in the form of questions. It is important that these questions are
articulated to highlight the variables that will impact on the effectiveness of the investigation in the scenario being
considered. These variables include the characteristics of the patient (or population) and clinical setting, the nature of
the decision and action taken on receipt of the test result and the expected outcome. Asking a question is the first step
of the evidence-based laboratory medicine (EBLM) cycle, the other steps being acquiring the evidence, critically apprais-
ing the evidence, applying the evidence and auditing use of the evidence. Getting the question right determines the quality
of the whole process, thus, defines the quality in practice of laboratory medicine. Whilst the main focus of the EBLM
cycle is to provide a strong evidence base for use in clinical practice, it is clear that the five steps are equally applicable in
commissioning, delivery and audit (performance management) of services. Asking the right question is crucial to improv-
ing the quality of evidence, and practice, in laboratory medicine, and should be used in routine laboratory medicine
practice and management throughout healthcare.

Keyword
Diagnostic tests, evidence-based medicine, laboratory medicine, question formulation, PICO

Introduction
‘A prudent question is one-half of wisdom’.
Francis Bacon
The care of patients is a multi-professional team
activity with continuing calls for a more integrated
approach to healthcare.1 At the core of this activity
are the needs and values of those involved in delivering,
and receiving, care – and the information that is shared
between them; optimizing patient outcomes depends on
the quality of the information that is available, the plan
for translation of this information into clinical action
and the effectiveness of communication.2 Asking the
right question improves the quality of communication
between individuals, a point recognized in the
quotation at the head of this article. Thus to provide
the correct information, laboratory professionals must
1
Department of Primary Care Health Sciences, University of Oxford,
Oxford, UK
2
Department of Pathology, University of Maryland School of Medicine,
Baltimore, MD, USA
*This article was prepared at the invitation of the Clinical Sciences
Reviews Committee of the Association for Clinical Biochemistry and
Laboratory Medicine.
Corresponding author:
Christopher P Price, Department of Primary Care Health Sciences,
University of Oxford, New Radcliffe House, Radcliffe Observatory
Quarter, Woodstock Road, Oxford OX2 6GG, UK.
Email: cpprice1@gmail.com
Price and Christenson
be aware of the questions that are posed by clinicians,
which can be broadly categorized as those that (i)
enhance their dialogue with patients and (ii) deliver
the best knowledge on how to effectively deal with a
specific clinical situation. For example, patient-care-
giver communication is recognized as an important
part of the care of patients with cancer.3 Ely et al.4
developed a taxonomy of generic questions asked by
the primary care physician that could be used to help
understand clinical information needs and improve our
ability to meet those needs and answer such questions.
The three most common generic questions reported
were (i) ‘What is the drug of choice for condition x?’,
(ii) ‘What is the cause of symptom x?’ and (iii) ‘What
test is indicated in situation x?’. However, the import-
ance of asking the right question is not limited to the
patient-carer interaction and extends across all aspects
of healthcare from patient involvement, through edu-
cation, research and clinical practice to management
and policymaking.5–10
The Oxford English Dictionary describes a question
as (i) ‘a sentence worded or expressed so as to elicit
information’, (ii) ‘a problem requiring resolution’, or
(ii) ‘a matter or concern depending on conditions’.11
Therefore, asking a question involves clearly articulat-
ing the nature of a problem. In medicine, questions
have been described as background questions or fore-
ground questions;12 the former relates to the knowledge
surrounding the problem (and in the context of labora-
tory medicine, e.g. the pathology of the disease), whilst
the latter relates to the application of the knowledge.
An example of the former would be ‘why does the
serum C-reactive protein concentration rise in rheuma-
toid arthritis?’ An example of the latter would be ‘will
the measurement of C-reactive protein be helpful in the
diagnosis of rheumatoid arthritis?’, or ‘will the meas-
urement of C-reactive protein be helpful in the manage-
ment of rheumatoid arthritis, e.g. for the assessing the
effectiveness of treatments?’ It is the latter style of ques-
tion that is most important in the delivery of health-
care, including laboratory medicine.13–15 This resonates
with the points made by Glasziou et al.16 that Evidence-
Based Medicine is about ‘. . .. trying to improve the
quality of the information on which decisions are based
. . ..’ and ‘. . .. thinking not about mechanisms but about
outcomes. . ..’.
Richardson et al.17 concluded that the majority of
questions asked in clinical practice were about (i) ‘how
to gather clinical findings properly and interpret them
soundly’ (clinical evidence), (ii) ‘how to select and inter-
pret diagnostic tests’ (diagnosis), (iii) ‘how to anticipate
the patients’ likely course’ (prognosis), (iv) ‘how to
select treatments that do more good than harm’ (ther-
apy), (v) ‘how to screen and reduce the risk of disease’
(prevention) and (vi) ‘how to teach yourself, the patient
307
and the family what is needed’ (education). Crucially
these authors stressed the importance of employing a
‘well-built’ clinical question, now common practice in
many areas of medicine.18–20
The evidence-based laboratory medicine
(EBLM) cycle
There are five steps in the practice of evidence-based
medicine proposed by Strauss and Sackett:21 (i) con-
verting the need for information by asking questions
that are clinically relevant and answerable, (ii) finding
the best evidence to answer the question, (iii) critically
appraising the evidence for its validity and usefulness,
(iv) applying the evidence to clinical practice and
(v) audit, evaluating your performance. These steps
have been adapted for use in laboratory medicine as
the EBLM cycle (Figure 1)13,14 and modified to add
an ‘Analyse’ step between the Appraise and Apply
step for Laboratory Medicine Best Practice systematic
reviews.15 Christenson et al.15 have advocated the add-
ition of the ‘Analyse’ element for aggregating the data
from several studies when ‘Appraise’ has focused on
data from individual studies, whereas it can be con-
sidered as part of the ‘Appraisal’ step. The ‘Analyse’
step was also introduced by Kingsnorth et al.22; how-
ever, they were using an ‘Ask – Acquire/Appraise –
Apply – Analyse –Adapt/Adopt’ cycle, in which the
‘Analyse’ element was applied to the output from the
application of the results from the ‘Acquire/Appraise’
step which could be considered as part of the ‘Assess’
step in the cycle described in Figure 1. The objective of
laboratory medicine is to assist in solving clinical prob-
lems and facilitating clinical decision making and so the
use of laboratory medicine is driven by the existence of
a problem, which can be articulated in a question – or a
problem statement. There are several ways of preparing
a problem statement, probably the simplest being
(i) what is the problem? This should explain why an
PROBLEM
ASK
ACQUIRE
APPRAISE
APPLY
ASSESS
Figure 1. The core of the EBLM cycle.
308
answer is needed; (ii) who has the problem? This should
explain who needs the solution, in what clinical setting,
and who will decide the problem has been solved; and
(iii) how might the problem be resolved? This will
describe the solution and effectively, the business case
for its adoption. The exact nature of the question will,
however, depend on who is asking the questions, e.g.
patient, doctor, manager, policymaker, etc.
The structured question
Richardson et al.17 outlined the structure of the well
formulated question in relation to clinical decision
making which has subsequently become known as the
PICO framework.12–16,23 The framework is built
around the Patient or population of interest, the
Intervention (treatment or diagnostic procedure), the
Comparator (the procedure with which the intervention
Table 1. Types of questions, the generic PICO elements and examples of structured questions relevant to laboratory medicine.
Type of question PICO elements
Screening P – population considered at risk
I – potential screening test
C – current practice
O – detection of patients with disease
Diagnosis P – patient presenting with symptoms
I – a proposed test
C – ‘Gold Standard’ reference method
(may be current practice)
O – diagnostic accuracy of test
Prognosis P – patients with a diagnosis, or population
I – the test of interest
C – *See footnote
O – mortality
Treatment P – patients with diagnosis
I – test of interest
C – no test, i.e. current practice
O – patient outcome metric
Analytical P – patient group of interest
I – new method (e.g. better or worse
imprecision, bias, etc.)
C – current method in use
O – patient outcome metric
Operational P – patient group of interest
I – alternative way to deliver test,
e.g. POCT
C – from central laboratory
O – patient outcome metric
Economic P – patient group of interest
I – new method
C – current practice
O – cost of care
*There is no comparator when assessing prognostic accuracy.
Annals of Clinical Biochemistry 50(4)
of interest is being compared) and the Outcome
expected. This framework can be employed for the dif-
ferent ways in which a test may be used, i.e. screening,
diagnosis (rule-in or rule-out), prognosis, treatment
(both candidacy for a treatment, optimization of treat-
ment regimen, monitoring and compliance). However,
it is important to recognize that when seeking to estab-
lish the utility of a particular test used to support treat-
ment, e.g. blood glucose, HbA1c, natriuretic peptide, in
order to improve the outcome, the use of the test has to
be considered in combination with the treatment, i.e. as
a ‘test-and-act’ intervention.24,25 Examples of ques-
tions, and the PICO elements for the different ways in
which test results can be used are given in Table 1. The
questions can relate to making clinical decisions, e.g.
regarding screening, diagnosis, prognosis and treat-
ment; however, in laboratory medicine there can also
be other types of decisions, e.g. related to analytical
Example of a structured question
In males and females considered at risk of developing type 2 dia-
betes (P), will a measurement of HbA1c (I), compared with the
current practice of no testing (C), lead to earlier detection of
diabetes (O)
In patients with breathlessness presenting in primary care (P), will
a natriuretic peptide test (I) help to rule-in or rule- out a diagnosis
of heart failure (O), when compared with the independent opinion
of two cardiologists (C) (the reference method)
In patients with chronic kidney disease (P), will a serum troponin
measurement (I) indicate the prognosis for the patient (O)
In patients with type 2 diabetes (P), will self-monitoring of blood
glucose (I), compared with current practice of periodic testing at
clinician visit (C), lead to a reduction in the HbA1c concentration
(O)
In patients on the ICU (P), will use of a blood glucose method with
a CV of 2.0% (I), compared with a method with a CV of 4.0% (C)
achieve better glycaemic control, with improved patient morbidity
and mortality (O)
In patients with diabetes (P), will provision of HbA1c testing at the
point of care (I), compared with a central laboratory service (C),
lead to lower HbA1c results (O)
In women aged 16–35 years (P), will screening for Chlamydia infec-
tion (I), compared with no screening (C), lead to a reduction in
the costs of managing the complications of Chlamydia infection (O)
Price and Christenson
performance, operational or financial decisions. Thus,
whilst from a clinical perspective the outcomes will pri-
marily relate to the patient outcome, there are broader
operational and economic outcomes that should also be
considered.
The PICO framework for the development of a
structured question is also employed in the assessment
of evidence for the development of clinical practice
guidelines advocated by the GRADE Working
Group.26 The reader is referred to the discussion by
Brozek et al.27 regarding the GRADE approach to
grading of evidence for diagnostic tests, and a specific
example is described by Hsu et al.28
Tips on formulating questions
This is not an exact science; however, there are a few
points that offer guidance:
. Succinctly describing the patient or population of
interest is vital, as test results change with the evo-
lution and progression of disease. Failure to do so
risks leaving the study open to patient spectrum bias.
For example, it is well known that patients present-
ing in primary care, when their condition may not
yet be symptomatic or severe, are likely to have a
different spectrum of results compared with those
presenting to the Emergency Department when
their condition is urgent (e.g. natriuretic peptide
levels in breathless patients).29 Similarly results
may vary according to gender, age or lifestyle.
Specifying the characteristics of the patient or popu-
lation is essential;
. When asking a question about risk stratification, e.g.
assessing prognostic performance of a test, the com-
parator is not always used. For example, formulat-
ing a question about the prognostic value of
increased natriuretic peptide values in a population
will likely not include a comparator. This is because
natriuretic peptide results are a continuous variable
so some of the cohort will have very low values and
others comparatively higher values. Comparing the
different natriuretic peptide ‘dose’ levels in the
cohort and the association with outcomes will
serve the comparative function. However, it is fre-
quently helpful to indicate whether it is mortality or
morbidity that is documented, and at a fixed time
(see below for comment on time);
. Outcomes can be considered in terms of impact on
the patient, the care delivery process (operational) or
the cost (economic);
. As noted earlier when assessing the impact of a test
on outcomes, it is important to remember that the
test does not exist in isolation and is only effective
coupled with the treatment. So, in addition to it
309
being a ‘test-and-act’ intervention when evaluating
evidence or practice, it is important to ensure that
both test and treatment are delivered appropriately;
. In a treatment question, a validated surrogate out-
come measure is often used, e.g. HbA1c in relation to
glycaemic control and as a practical alternative to
morbidity and mortality;
. The analytical question typically examines the effect
of differences in method performance, e.g. impreci-
sion or inaccuracy, although the framework can
limit elegant construction of the question. In other
words, in order to investigate the relationship
between method imprecision (or inaccuracy) and
outcome, it will be necessary to define issues such
as total error (bias þ [2SD]) and therefore a range
of imprecision and bias values should be considered.
A relevant analytical question is to define the inter-
vention in terms of a particular assay characteristic
compared with current practice. An example is to
ask if there will be benefit to patients presenting
with signs and symptoms of cardiac ischaemia by
implementing a high-sensitivity troponin method
with superior imprecision compared to use of con-
temporary sensitive assays that are currently the
state-of-the-art methodology;
. The operational questions can look at impact on
patient outcome or on process outcome, e.g. length
of stay, hospital visits, re-hospitalization, emergency
admissions – all valid surrogate process outcomes.
The issues and questions provided above are only
intended as examples; further examples can be found
in the included reference.14 It is worth stressing that the
objective of the structured question is to improve clarity
and specificity in the understanding and communica-
tion of the problems and their resolution in the various
facets of professional practice.15
Variants of the PICO
There have been additions to the PICO framework
described, all with the intention of providing greater
clarity to articulation of the problem. Sometimes an S
to identify the clinical setting is included in the frame-
work, i.e. PICOS; alternatively this can be included in
the description of the patient or population, e.g. a
patient presenting to primary care, the emergency
room, etc. An additional P for pre-test probability (if
that is known) when a test result is used for diagnosis,
i.e. PPICO. A T may be included to emphasize the
importance of time (PICOT); it may be important to
specify time in a number of scenarios, e.g. when a
sample is collected in relation to circadian rhythm, or
in relation to dosing regimen, or the period of follow-
up in a prognostic accuracy study. An additional C may
310 Annals of Clinical Biochemistry 50(4)

be included in an outcome study to verify that a change
in practice has been adopted with the intervention
being tested, i.e. PICCO. Some of these variants are
more applicable to reviewing evidence rather than
when formulating the question at the outset, e.g. deal-
ing with a clinical query.
EBLM and relevant questions
There are five stages in the EBLM cycle, starting with
asking the question (Figure 1). The basic structure
should be viewed as a problem resolution cycle and in
so doing it can be applied to a wide range of activities
involving laboratory medicine (Table 2). Thus whilst
the principles of evidence-based medicine (from which
EBLM has evolved) were originally focussed on the
interaction between patient and clinician (and asso-
ciated education and research), this culture of evi-
dence-based practice can be applied to all aspects of
professional activity in laboratory medicine from stra-
tegic thinking and commissioning of services,30 to daily
practice, quality improvement31 and organizational

Table 2. Illustrating the range of health professionals asking questions, the settings in which they may be
asked and range of issues being addressed.

Questioner Setting Type of questions

Patient  Home  Use of tests

Government
Commissioner/purchaser
Provider organization
Clinician/nurse/carer
Laboratory director
Laboratory manager
Clinical scientist
 Health centre  Meaning of results
 Hospital  Prognosis
 Long term planning  Health promotion programmes
 Short term crisis  Screening programmes
 Improving quality
Annual review and planning cycle  Prioritization of services
 Planning  Resource prioritization
 Quality improvement  Resource utilization
 Routine management - Investment
- disinvestment
 Primary care  Screening
 Ambulatory care  Diagnosis
 Emergency care  Prognosis
 Treatment
- selection
- optimization
- monitoring
- compliance
 Strategic planning  Choice of tests
 Quality improvement  Appropriate use of tests
 Research and development  Audit of utilization
 Identification of unmet needs
 Study design
 Critical appraisal of evidence
 Accreditation  Mode of delivery
 Process management  Resource utilization
 Workload management  Health economics of testing
 Financial management  Audit of utilization
 Duty biochemist  Choice of tests
- clinical queries  Meaning of results
 Background knowledge  Choice of action on results
- aetiology  Appropriate utilization of tests
- risk factors  Improve knowledge
- prevalence - relevance of tests
 Method validation  Intended utility of test
- Imprecision - impact of imprecision
- bias - impact of bias
- interferences  as above
 Research and development
Price and Christenson
Commissioning PROBLEM Audit
(performance
management)
Seng strategic
Idenfy the
direcon and ASK queson
pathway design
ACQUIRE Crically
appraise
Specifying
evidence
service
APPRAISE
Audit pracce
Contracng
APPLY Modify pracce
Evaluang
impact/outcomes ASSESS Apply to pracce
Figure 2. Illustrating how asking the right question is the first
step in the practice of EBLM (inner column), and in commis-
sioning (left column) and audit (performance management) (right
column) of laboratory medicine services.
research32 – as well as personal development through
education, training and research. The concordance of
the steps in the EBLM cycle with the steps in commis-
sioning and performance management (audit) of diag-
nostic services is illustrated in Figure 2. Thus in the case
of audit (the right-hand column), it is important to
understand the process being audited and so the ques-
tion is crucial. It is then important to understand the
evidence base that underpins the utility of the test and
the ‘diagnostic process’ being reviewed, e.g. if auditing
the use of a test you need to understand why the test is
being used, the patient characteristics, the clinical setting
– as well as the decisions and actions informed by the
result. This helps to inform the data collected for
the audit. The data are then reviewed in the context of
the evidence base and the clinical guideline (protocol)
for that test’s utility(ies), and practice modified accord-
ing to the outcome of the data review. This cycle can
then be used to design local performance management
and continuous quality improvement initiatives – link-
ing closely to the broader annual review and strategic
planning cycle. The emphasis then transfers to the com-
missioning (left-hand column) cycle, where the use of the
laboratory medicine service to address unmet commis-
sioning or providing needs should be considered, e.g. the
use of point-of-care testing to address length of stay in
the Emergency Department or in the management of
patients with long-term conditions in primary care.
Establishing the need is followed by development of
the business case and specification of the service –
informed by the evidence base, including an economic
assessment. Monitoring adoption, in essence perform-
ance management of the service, has many of the simila-
rities to audit as noted earlier. Successful completion of
311
each step of the EBLM cycle in all of these activities is
predicated in each case on the clarity with which the
problem and question to be addressed are articulated.
Translating EBLM into routine practice
A strategy for translating EBLM into routine practice
makes a number of basic assumptions (i) laboratory
medicine is part of a clinical team so test information
can be converted to action; (ii) the main goal is to add
value to the care pathway; (iii) a test is only used
because there is a problem or unmet need; (iv) the
result is acted upon at the appropriate time; and
(v) resource utilization is managed across the care path-
way. These assumptions may appear obvious but they
do not necessarily reflect practice in all health systems,
at all times.24 Thus, on the one hand additional testing
is expected as part of junior doctors gaining experience,
whilst on the other hand many health systems manage
laboratory services on a fee-for-service basis, regarding
laboratories as profit centres – and in that respect may
encourage over-testing. This notwithstanding, the
raison d’eˆtre of laboratory medicine should be improv-
ing health outcomes and so the assumptions are appro-
priate attributes at the core of a laboratory medicine
service. A recent paper makes the same point when
describing a framework for designing and evaluating
trials for assessing the value of diagnostic tests
opened with the statement ‘The value of a diagnostic
test is not simply measured by its accuracy, but depends
on how it affects patient health’.33 If the laboratory
medicine services are to be innovative, and used cor-
rectly, then the assumptions above should reflect rou-
tine practice.
The easiest way to illustrate how EBLM can be
translated into practice is with the introduction of a
new test. There are a number of generic questions to
ask of the requestor at this point, set out below with
some explanatory notes.
. Why do you want the test?
. What will you do with the result?
. What decision will you make?
. What action will you take?
. What outcome would you expect?
. Is the test any good, i.e. is there any evidence
available?
. What will be the cost?
. What additional benefits might be expected, and
where in the care pathway?
The responses to these questions help to (i) establish
the nature of the problem or unmet need, (ii) review the
evidence to demonstrate that the need can be met,
312
(iii) develop the business case and (iv) set out the
requirements for adoption and implementation, if the
business case is successful. The questions are relevant to
any number of problems that might be experienced and
they reflect the use of the test and the complementary
activities across the care pathway, with the potential for
solutions with clinical, operational and/or economic
impact. However, insofar as the questions reflect the
use of the test across the care pathway they can also
be used to inform audit, performance management and
continuous quality improvement activities. They also
provide a framework for many of the enquiries made
of the laboratory, e.g. to the duty biochemist/doctor
and accessing the knowledge base.
This approach is illustrated in the request for the
introduction of natriuretic peptide testing – where the
request was made by the local cardiac network man-
ager.30 The local need was based on a combination of
poor access to echocardiography for patients present-
ing in primary care with suspected heart failure and
awareness of a revised clinical guideline supported by
a good evidence base for the use of a natriuretic peptide
as the first line test. The PICO question developed is the
second in Table 1. The discussion with stakeholders
established the requirement and provided the basis of
the answers to the first seven questions outlined above
and enabled the development of the business case for
adoption of the test, as well as the framework for the
implementation and performance management of the
service. This involved details of current practice includ-
ing time to diagnosis from initial presentation, cost of
current diagnostic pathway, level of activity, number of
patients presenting with suspected heart failure,
number of patients on heart failure register and cost
of natriuretic peptide test. These data together with
the evidence from a relevant systematic review29 were
used to model the revised pathway and establish the
economic elements of the business case. The core of
the business case was the reduction in time to diagnosis
as well as the additional benefits of a significant reduc-
tion in the requirement for echocardiography and asso-
ciated outpatient clinic visits – the savings being used to
fund the natriuretic peptide service as well as reduction
in overall cost to the commissioner/purchaser. The ini-
tial discussion also highlighted additional clinical
questions around the potential use of the test for
(i) screening women receiving chemotherapy for
breast cancer and at risk of developing heart failure,
(ii) screening other patient groups at risk of developing
heart failure and (iii) guiding therapy in patients diag-
nosed with heart failure. This provided the opportunity
for business cases to be developed including the extent
of the relevant evidence base, to be submitted to the
local annual strategic review and prioritization process.
Annals of Clinical Biochemistry 50(4)
The core of translating EBLM into routine practice
is the link between articulation of the problem (the
question), the quality of the evidence, the decision
made on receipt of the result and the action taken.
This has then to be evaluated within the context of
the delivery and performance management of an inte-
grated healthcare service, i.e. integrated care pathways.
The practical questions outlined above can be adapted
to address clinical, operational and economic issues as
outlined in Table 2, across the full spectrum of health-
care – from policymaking to delivery.
Conclusions
In routine laboratory practice, it is recognized that (i) the
evidence base is poor,34 and (ii) there are many reports
of both under- and over-utilization of tests; the second
observation is an obvious corollary of the first! Over
a decade ago, George Lundberg35 alluded to this prob-
lem when identifying the need for an outcomes agenda
for laboratory medicine. There is also a recognized prob-
lem around translation of evidence into routine practice
with the associated transformational change,36 a prob-
lem not limited to laboratory medicine.37 The demand
for evidence-based practice extends to laboratory medi-
cine as one of the tools for improving the quality of
healthcare. The practice of EBLM is the core for all
of the facets of laboratory medicine from commissioning
of a service through to audit and continuous quality
improvement. The starting point in all cases remains
identifying unmet needs and the articulation of the prob-
lem (the problem statement) through clinical questions.
Acknowledgements
None.
Declaration of conflicting interests
None.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Ethical approval
Not required.
Guarantor
CPP.
Contributorship
The authors contributed equally to the content of this review.
Price and Christenson
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