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DIAGNOSTIC STUDIES

Nia Kurniati – Nastiti Kaswandani

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
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Diagnosis

 Typically someone with abnormal symptoms consults a

physician, who will obtain a history of their illness and
examine them for signs of diseases.
 The physician formulates a hypothesis of likely
diagnoses and may or may not order further tests to
clarify the diagnosis

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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What we know
 Diagnosis in practice = basis medical care
 Clinicians make diagnosis following these rule:
 Patient history
 Examination
 Differential diagnosis
 Final diagnosis

 Diagnostic studies should serves practice

 Is an imperfect process: probability rather than certainty.
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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DIAGNOSTIC WORK UP:

Multi-test, multi stage, dynamic

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Diagnostic stages & strategies

Heneghan et al, BMJ 2009

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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Diagnosis

• Probability of the presence of a particular

disease in view of all diagnostic information
(patient history, physical examination and test
results) in order to decide whether treatment
should be initiated or not.
• A diagnostic test is evaluated in isolation
without explicit regard to the clinical context
in which the test is applied.

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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What are tests used for?

• Increase certainty about

presence/absence of
disease
• Disease severity
• Monitor clinical course
• Assess prognosis –
risk/stage within
diagnosis
• Plan treatment e.g.,
location
• Stall for time!
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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 Before ordering a test ask:

 What will you do if the test is positive?
 What will you do if the test is negative?
 If the answers are the same, then don’t
do the test

Myriam Hunink and Paul Glasziou

Decision Making in Health and Medicine (2001)

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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VARIATIONS OF DIAGNOSTIC STUDY

 What is causing my symptoms?
 Estimate probability that target disease is present or
absent given test results
 which tests contribute and to what extent?
 does a new test add information?
 Test evaluation studies:
– technical validity (measurement true)
– clinical validity (diagnostic accuracy)
– clinical utility (improve patient outcome)
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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VARIATIONS OF DIAGNOSTIC STUDY

 Measurement of frailty
 Measurement of knowledge
 Ankle-Brachial Index
 Anxiety index
 Rheumatic Fever

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Diagnostic Study vs. Test Study

 A clinical prediction rule for detecting major depressive
disorder in primary care: the PREDICT-NL study
 Performance of lung ultrasonography in children
with community-acquired pneumonia

Which one is the diagnostic study?

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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TEST RESEARCH

• By “test research” we refer to studies that follow a single-test or

univariable approach, i.e., studies focusing on a particular test to
quantify its sensitivity, specificity, likelihood ratio (LR), or area
under the ROC curve (ROC area).
• test research because it merely quantifies the
“characteristics” of the test rather than the test’s contribution to
estimate the diagnostic probability of disease presence or
absence.

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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DIAGNOSTIC RESEARCH

• Studies that aim to quantify a test’s added contribution beyond

test results readily available to the physician in determining the
presence or absence of a particular disease.
• Diagnostic research commonly evaluates whether a test
discriminates between the presence and absence of a particular
disease, as determined by a reference standard.

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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CLINICAL QUESTION

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Defining the clinical question: PICO or PIRT

• Patient/Problem
How would I describe a group of patients of mine?

• Index test
Which test am I considering?

• Comparator… or …Reference Standard

What is the best reference standard to diagnose the
target condition?

• Outcome….or….Target condition
Which condition do I want to rule in or rule out?

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Examples
 The study aim to measure the efficiency of US in
comparison with that of CXR in defining different kinds
of lung alterations in the various pulmonary sections in
(adult) pneumonia patients.
 What is the level of vitamin D in women with primary
infertility (Anti-Mullerian Hormone positive)

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Diagnostic Accuracy Studies

Series of patients

Index test

Reference standard

Compare the results of the index

test with the reference standard

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Hypothesis testing
 Test study: Lung ultrasound is as good as CXR in
describing lung alterations in pneumonia patients

 Diagnostic study: Genome testing increase the

probability of diagnosis of chemotherapy-respond breast
cancer type

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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STUDY DESIGN

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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STUDY DESIGNS
 Diagnostic study is a part occurrence research
 Two types of occurrence research: descriptive and
causal
 Descriptive: Diagnosis and Prognosis
 Focus on potential diagnostic determinant (no issue of
confounding, may have issue conditionality), with no
inherent hierarchy of determinant except by chronology

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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STUDY DESIGNS
 Cross sectional is good for single test diagnostic
 Multiple test may appear as longitudinal study, although
every test is done cross sectional
 The subjects are tested as a group, acquiring the same
test(s)
 Do not use case-control design
 Normal value? Use survey design

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Designing a study
 Research question
PICO/PIRT
 Study population
– in/exclusion criteria
– sampling
 Tests under study (determinants)
 Disease under study (outcome)
 Sample size
 Design of data analysis

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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IDENTIFYING VARIABLES

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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VARIABLES
 Dependent variable: Diagnosis of interest
(determined by reference test)
 Independent Variables: demographic,
symptoms, sign, initial tests, NEW test
 Use key STARD (Standard for Reporting of
Diagnostic Accuracy Study)

Bossuyt, et al. Radiology 2015;277:826-32

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Key STARD Terminology

Term Explanation
Medical Test Any method for collecting additional information about
the current or future health status of a patient
Index Test The test under evaluation
Target condition The disease or condition that the index test is expected
to detect
Clinical reference The best available method for establishing the
standard presence or absence of the target condition; a gold
standard would be an error-free reference standard
Sensitivity Proportion of those with the target condition with
positive index test result
Specificity Proportion of those without the target condition with
negative index test result
Intended use of Whether the index test is used for diagnosis, screening,
the test staging, monitoring, surveillance, prediction, prognosis
or other reasons
Role of the test The position of the index test relative to other tests for
the same condition
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Biases in Diagnostic Accuracy Studies…

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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1. Appropriate spectrum of
patients?
Ideally, test should be performed on a
group of patients in whom it will be
applied in the real world clinical
setting
Spectrum bias:
study uses only highly
selected
patients…….perhaps
those in whom you
would really suspect
have the diagnosis Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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Case-control design “Real” diagnostic

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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2. Do all patients get the reference

standard?
Ideally all patients get the reference
standard test
Verification bias:
only some patients get the
reference standard…..probably the
ones in whom you really suspect
have the disease

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Partial Reference Bias

Series of patients

Index test

Ref. Std. A

Compare the results of the index

test with the reference standard,
blinded
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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Differential Reference Bias

Series of patients

Index test

Ref. Std. A Ref. Std. B

Blinded cross-classification

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Incorporation Bias
Series of patients

Index test

Reference standard….. includes

parts of Index test

Blinded cross-classification

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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3. Independent, blind or objective

comparison with the reference
standard?
Ideally, the reference standard is
independent, blind and objective
Observer bias:
test is very
subjective, or done
by person who
knows something
about the patient or
samples Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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Observer Bias
Series of patients

Index test

Reference standard

Unblinded cross-classification

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Flowchart of study

Bossuyt, et al. Radiology

2015;277:826-32

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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ANALYSIS OF DATA

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Study Analysis
 Accuracy study:
 Sensitivity, specificity (generalization)
 To accommodate variation in subjects: multiple sensitivity and
specificity- ROC curve
 Diagnostic model development
 ROC curve
 Model comparisons (multivariable analysis)

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Application analysis
 Predictive Values
 Positive predictive value
 Negative predictive value

 Likelihood ratio

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Sensitivity and
Specificity

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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The 2 by 2 table

Disease
+ -
True False
+ positives positives

Test
False True
- negatives negatives

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The 2 by 2 table: Sensitivity

Disease Proportion of people

+ - WITH the disease

who have a positive
84 a test result.

+ True
positives
So, a test with
84%
Test 16 c sensitivity….
means that
- False
negatives the test
identifies 84
out of 100
Sensitivity = a / a Sensitivity =
people WITH
+c 84/100
the disease
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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The 2 by 2 table: Specificity

Disease
+ - Proportion of people
25 b WITHOUT the
disease who have a
+ False negative test result.
positives
So, a test with
Test 75 d 75%
specificity will
- True
negatives be NEGATIVE
in 75 out of
100 people
Specificity = d / b WITHOUT
Specificity = the
+d disease
75/100
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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The Influenza Example

Disease: Lab Test

+ - There were 61
children who had
27
+ 3 30 influenza…the
rapid test was
positive in 27 of
Test: Rapid themwere 96
There
Test 34 93 127 children who did not
- have influenza… the
rapid test was
negative in 93 of them
61 96 157
Sensitivity = 27/61 = Specificity = 93/96 =
0.44 (44%) 0.97 (97%)
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Tip
• Sensitivity is very straight forward
– ‘The new rapid influenza test was positive in 27 out of 61
children with influenza (sensitivity = 44%)’

• Specificity seems a bit confusing!

– ‘The new rapid influenza test was negative in 93 of the 96
children who did not have influenza (specificity = 97%)’

• So…the false positive rate is sometimes easier

False positive rate = 1 -
– specificity
‘There were 96 children who did not have influenza… the
rapid test was falsely positive in 3 of them’
– So a specificity of 97% means that the new rapid test is
wrong (or falsely positive) in 3% of children

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Ruling In and Ruling Out

High A good test to help in Ruling Out disease
Sensitivity
High sensitivity means there are very few false SnNOUT
negatives – so if the test comes back negative
it’s highly unlikely the person has the disease
High SpecificityA good test to help in Ruling In disease
High specificity means there are very few false SpPIN
positives – so if the test comes back positive it’s
highly likely the person has the disease
Disease: Influenza
+ - +Disease -
a b
27 +
+ 3 True False
positives positives
Test
c d
Test: Rapid Test
- False True
34 93 negatives negatives
-
Sensitivity = Specificity = Sensitivity = Specificity =
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
44% 97% a/a+c
RSUPN Dr. Cipto Mangunkusumo d/b+d
– Fakultas Kedokteran Universitas Indonesia
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Likelihood Ratios

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Likelihood ratios

Probability of clinical finding in patients with disease

LR =
Probability of same finding in patients without disease

Example:
If 80% of people with a cold have a
runny nose
and 10% of people without a cold
have a runny nose,
then the LR for runny nose is:
80%/10% = 8
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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Likelihood ratios

Positive likelihood ratio (LR+)

How much more likely is a positive test to be
found in a person with the disease than in a
person without it?
LR+ = sens/(1-
spec)

Negative likelihood ratio (LR-)

How much more likely is a negative test to be
found in a person without the disease than in a
person with it?
LR- =
(1-sens)/(spec
)
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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What do likelihood ratios mean?

LR=1 LR>10 =
LR<0.1 = strong
strong No positive test
negative test diagnostic result
result value

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Diagnosis of Appendicitis
Rovsing’s sign
McBurney’s point If palpation of the left
lower quadrant of a
person's abdomen
results in more pain in
Psoasthe right lower quadrant
sign
Abdominal pain
resulting from passively
extending the thigh of a
patient or asking the
patient to actively flex
his thigh at the hip
Ashdown’s sign
Pain when driving over speed
bumps Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
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For Example

(LR+ = 3.4)

(LR- = 0.4)

Speed bump test (Ashdown’s sign):

LR+ = 1.4
LR- = 0.1
McGee:
Clinical Evidence
Epidemiology based Physical
and Evidence-Based Diagnosis
Medicine (CEEBM) Unit (Saunders
Elsevier)
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Predictive Values

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Positive and Negative Predictive Value

Disease PPV = Proportion of

+ - people with a
positive test who
a b have the disease.
PPV = a / a +
+ True
positives
False
positives
b

Test c d
NPV = d / c +
- False
negatives
True
negatives
d
NPV = Proportion of
people with a
negative test who do
not have the disease.

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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The Influenza Example

Disease: Lab Test

+ - PPV = 27/30 =
90%
27
+ 3 30

Test: Rapid NPV = 93/127 =

Test 34 93 127 73%
-
61 96 157

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Predictive Value: Natural Frequencies

Your father went to his doctor

and was told that his test for a
disease was positive. He is
really worried, and comes to
ask you for help!
After doing some reading, you find that for men of his age:
The prevalence of the disease is 30%
The test has a sensitivity of 50% and specificity of 90%

“Tell me what’s the chance I have this disease?”

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Predictive Value

• 100% Likely

Disease has a
prevalence of 30%.
• 50% Maybe
The test has
sensitivity of 50%
and specificity of
90%.
• 0% Unlikely

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Natural Frequencies

Disease has a prevalence of 30%.

The test has sensitivity of 50% and specificity of
90%.
Given a positive test, what is the probability your
dad has the disease

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

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Prevalence of 30%, Sensitivity of 50%, Specificity of 90%

Sensitiv
Disease ity = 22 people
+ve
30 50% 15 test
positive……
…

100 Testing +ve of whom 15

have the
disease

Disease -
70 7
False
ve positive So, chance
of disease is
rate =
15/22 =
10% 68%
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
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Prevalence of 4%, Sensitivity of 50%, Specificity of 90%

Sensiti
Disease vity = 11.6 people
+ve
4 50% 2 test
positive……
…

100 Testing +ve of whom 2

have the
disease

Disease -
96 9.6
False
ve positive So, chance
of disease is
rate =
2/11.6 =
10% 17%
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective

Positive and Negative Predictive Value

NOTE
• PPV and NPV are not intrinsic to the test – they
also depend on the prevalence!

• NPV and PPV should only be used if the ratio of

the number of patients with the disease
and the number of patients without the
disease is equivalent to the prevalence of
the diseases in the studied population

• Likelihood Ratio – it does not depend on

prevalence
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective

ROC Curve / AUC

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
 Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective

Study examples
 Patients suspected of Deep Venous Thrombosis (DVT)
 General practicioner:
 Patient history
 Physical examination
 D-dimer test
 2086 patients, 20% DVT

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
 Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective

Study example (2)

Basic Prediction Model Extended Prediction
Model
Male gender Male gender
Oral contraception use Oral contraception use
Leg trauma Leg trauma
Malignancy Malignancy
Vein distention Vein distention
Recent surgery Recent surgery
Difference in calf Difference in calf
circumference circumference
D-dimer test

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
 Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective

Study example (3)

 Green line: basic model

 Red line: Extended model
(Basic model + D-dimer)
 Dash line: reference

 AUC basic model = 0.72 (0.70-

0.75)
 AUC extended model = 0.87
(0.85-0.89)
Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit
RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia
 Competence and Credible, Excel in Organization, Excel in Operation, Beyond Expectations, Management by Objective

Finish

Clinical Epidemiology and Evidence-Based Medicine (CEEBM) Unit

RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Indonesia