Evidence-Based Medicine:

Diagnosis of Helicobacter pylori

infection
 Clinical Question
• How accurate are tests used to diagnose
disease?
• Diagnostic tests:
– A test performed in a laboratory
– Clinical information obtained from history,
physical examination, and imaging procedures
– A constellation of findings
 What is diagnosis?

• Increase certainty about

presence/absence of
disease
• Disease severity
• Monitor clinical course
• Assess prognosis –
risk/stage

• Stall for time!

Clinical Scenario
• The patient is a middle aged male with symptoms of
dyspepsia. Your first concern in managing this
patient is to determine if the dyspepsia is related to
peptic ulcer disease. This generally requires
endoscopy, which is a minimally invasive, but a
relatively expensive diagnostic test. To decrease the
use of endoscopy, you have been considering the
strategy of testing for H. pylori, treating those that
are positive, and then doing an endoscopy on those
that remain symptomatic.
 Clinical Scenario
• The standard laboratory ELISA has been the favored
screening test for H. pylori but this test can take days
to accomplish. Recently you have read about more
convenient in-office or "near patient" whole-blood
tests (such as FlexSure) that can show results within
hours.
• Before you consider a change in practice, you want
to find out if the these "near patient" tests, such as
FlexSure, are as sensitive as the "gold standard"
ELISA test for detecting H. pylori.
 Steps in Practicing
EBM

1. Convert the need for information into an

answerable question.
2. Track down the best evidence with which to
answer that question.
3. Critically appraise the evidence for its validity,
impact, and applicability.
4. Integrate the evidence with our clinical
expertise and our patient’s characteristics and
values.
5. Evaluating our effectiveness and efficiency in
executing steps 1–4 and seeking ways to
improve them both for next time.
 The clinical question: PICO

Patient or Intervention Comparison Outcome

Problem
Adults with The "near Gold Diagnosis of
suspected H. patient" standard: the Helicobacter
pylori whole-blood ELISA assay pylori
tests such as infection
FlexSure
 The clinical question

• In adults with suspected H. pylori, are the

"near patient" whole-blood tests such as
FlexSure, as accurate as the ELISA assay in
aiding diagnosis?
 Steps in Practicing
EBM

1. Convert the need for information into an

answerable question.
2. Track down the best evidence with which to
answer that question.
3. Critically appraise the evidence for its validity,
impact, and applicability.
4. Integrate the evidence with our clinical
expertise and our patient’s characteristics and
values.
5. Evaluating our effectiveness and efficiency in
executing steps 1–4 and seeking ways to
improve them both for next time.
 The search strategy
• Pubmed database:
(http://www.ncbi.nlm.nih.gov/sites/entrez?db=
pubmed)
• Using the Clinical Queries function of PubMed:
– Key words:
• “h pylori” AND
• “flexsure”
– Clinical Study Categories: “Diagnosis”
– Scope: “Narrow”
✔
 The Evidence
• Duggan AE, Elliott, C. Logan RF. Testing for
Helicobacter pylori infection: validation and
diagnostic yield of a near patient test in
primary care. BMJ. 319(7219):1236-9,1999
Nov 6.
• Testing for Helicobacter pylori infection -
validation and diagnostic yield of a near
patient test in primary care.pdf
 Steps in Practicing
EBM

1. Convert the need for information into an

answerable question.
2. Track down the best evidence with which to
answer that question.
3. Critically appraise the evidence for its
validity, impact, and applicability.
4. Integrate the evidence with our clinical
expertise and our patient’s characteristics and
values.
5. Evaluating our effectiveness and efficiency in
executing steps 1–4 and seeking ways to
improve them both for next time.
 Appraising the Evidence
1. Is this evidence about the accuracy of a
diagnostic test valid?
2. Does this (valid) evidence demonstrate an
important ability of this test to accurately
distinguish patients who do and do not have
a specific disorder?
3. Can I apply this valid, important diagnostic
test to a specific patient?
Is this evidence about the accuracy of a
diagnostic test valid?
Is this evidence about the accuracy of
a diagnostic test valid?

1. Measurement
– Was the reference (“gold”) standard measured
independently, i.e. blind to our target test?
• Yes. A 7ml blood sample was taken from each
patient. The FlexSure test was administered at the
various sites. Then the remaining blood test was sent
to University Hospital were all samples were also
tested with the ELISA assay by a single operator
blinded to the FlexSure results. (under Methods, p.
1237).
Is this evidence about the accuracy of
a diagnostic test valid?

2. Representative
– Was the diagnostic test evaluated in an
appropriate spectrum of patients (those in
whom we would use it in practice)?
• Yes. Patients were from an appropriate spectrum
representing a wide range of ages, duration and
severity of symptoms. Patients were recruited
from 43 general practices in England.
Is this evidence about the accuracy of
a diagnostic test valid?

3. Ascertainment
– Was the reference standard ascertained
regardless of the diagnostic test result?
• Yes, 389 of 394 patients were tested by the
reference standard ELISA assay regardless of the
results of the FlexSure test. 5 patients did not
have serum available for the ELISA testing. (See
Results p. 1237).
Are the results of this study valid?

• This is a well designed study according to ACP

Journal Club.
 Does this (valid) evidence
demonstrate an important ability of
this test to accurately distinguish
patients who do and do not have a
specific disorder?
 2 x 2 Table
Disease Totals
Present Absent
Diagnostic Positive a b a+b
Test Negative c d c+d
Totals a+c b+d a+b+c+d

Sensitvity = a/(a+c).
Specificity = d/(b+d).
Positive Predictive Value = a/(a+b).
Negative Predictive Value = d/(c+d).
 Technical vs. Clinical Precision
• “Baby Jeff”: The case of screening for
muscular dystrophy
• Technical Precision of CPK test:
– Sensitivity (ability to rule out disease): 100%
– Specificity (ability to identify disease): 99.98%
• But,
– The prevalence of MD is 1 in 5000 (0.02%)
 Does Baby Jeff have M.D.?

• Of 100,000 males, 20 will have M.D.

• (1 in 5,000, or 0.02% prevalence)
– The test will correctly identify all 20 who have
the disease (sensitivity = 100%)
 Does Baby Jeff have M.D.?

• Of the 99,980 without M.D.

– Specificity = 99.98%
– 99,980 x 0.9998 = 99,960 will be negative
– Therefore, false positives = 20
 “. . . The Rest of the Story”

• Therefore,
– Out of 100,000 infants, 20 will be truly positive
and 20 will be false positive
– Positive predictive value = 50%
– The child with a positive screening test only
has a 50/50 chance of actually having MD!

• HARM!
 Another Example: Lyme Disease
• Antibody assay
– Sensitivity= 95%; specificity= 95%
• High Lyme Disease prevalence (20%)
– Positive predictive value = 83%
• Low Lyme Disease prevalence (2%)
– Positive predictive value = 28%

Brown SL. JAMA 1999;282:62-6.

Another Example: Mammography
• Mammography in women between 40-50 yrs
• If 100,000 women are screened:

6,034 mammograms will be abnormal

5,998 (99.4%) will be false-positive
36 will actually have breast cancer

Why? Prevalence = 0.036%

Hamm RM. J Fam Pract 1998;47:44-52.
 What are the results?
Results were available for 375 patients (9 patients
had indeterminate ELISA results, 5 had invalid
FlexSure results, and 8 had no serum available).
36% of patients had H. pylori infection.

H. pylori ELISA Totals

Positive Negative
FlexSure Positive 90 5 95
FlexSure negative 44 236 280
Totals 134 241 375
 Technical precision
H. pylori ELISA Totals
Positive Negative
FlexSure Positive 90 5 95
FlexSure negative 44 236 280
Totals 134 241 375

Sensitivity: measures the proportion of patients with

the disease who also test positive for the disease in
this study.
Sensitivity = true positive / all disease positives =
90/134 = 67% ► 67% of the patient who had H. pylori
infection, tested positive for the disease
 Technical precision
H. pylori ELISA Totals
Positive Negative
FlexSure Positive 90 5 95
FlexSure negative 44 236 280
Totals 134 241 375

Specificity: measures the proportion of patients without

the disease who also test negative for the disease in
this study.
Specificity = true negative / all disease negatives =
236/241= 98% ► 98% of the patients who did not have
H. pylori, tested negative for the disease.
 Clinical precision
H. pylori ELISA Totals
Positive Negative
FlexSure Positive 90 5 95
FlexSure negative 44 236 280
Totals 134 241 375

Positive Predictive Value: measures the proportion of

patients tested positive for the disease who have H.
pylori.
Positive Predictive Value = true positive / all tested
positive = 90/95= 95% ► 95% of the patients who
tested positive for the disease have H. pylori.
 Clinical precision
H. pylori ELISA Totals
Positive Negative
FlexSure Positive 90 5 95
FlexSure negative 44 236 280
Totals 134 241 375

Negative Predictive Value: measures the proportion of

patients test negative for the disease who do not have the
disease.
Negative Predictive Value = true negative / all tested
negatives = 236/280= 84% ► 84% of the patients tested
negative for the disease who did not have H. pylori.
 Technical Precision
• Specificity: Remember SpPin
When a test has a high Specificity, a
Positive test rules IN the disorder.
• Sensitivity: Remember SnNout
When a test has a high Sensitivity, a
Negative result rules OUT the disorder.
Can I apply this valid, important
diagnostic test to a specific
patient?
 Are the results of this diagnostic
study applicable to my patient?

1. Is the diagnostic test available, affordable,

accurate, and precise in our setting?
• Yes
 Are the results of this diagnostic
study applicable to my patient?

2. Can we generate a clinically sensible estimate of

our patient’s pre-test probability?
a. From personal experience, prevalence statistics,
practice databases, or primary studies.
• Yes
b. Are the study patients similar to our own?
• Yes
c. Is it unlikely that the disease possibilities have changed
since this evidence was gathered?
• Yes
 Test-Treatment Thresholds

Do not Do not
test Test, and treat
test
on the basis of
Do not the test result Get on
with
treat
treatment
0 .10 .20 .30 .40 .50 .60 .70 .80 .90

A B
Prevalence (pre-test probability) of target disorder
 Clinical Probability
Clinical features of
presentation including High Post-Test
characteristics of Probability
patient, history, and
exam. Knowing
Test (can include
distinct features likelihood ratio
of presentation in allows you to
Pre-Test history or calculate post-
Probability examination). test probability

Low Post-Test
Probability
 Pre-test Probability
• Definition: The probability that a person has a particular
disease before any test results are obtained. The pretest
probability for large groups of people (such as the population
of a city) is the same as the prevalence of the disease in that
group.
• Example: For example, breast biopsy is a highly accurate test
for finding out whether a breast lump is breast cancer. The
pretest probability of breast cancer in a group of women who
have been referred for breast biopsy is estimated to be 20
percent. This means that a person who has a biopsy because
of a suspicious breast lump has a 20 percent chance that the
breast lump will be cancerous even before the test is
performed.
 Likelihood Ratio
H. pylori ELISA Totals
Positive Negative
FlexSure Positive 90 5 95
FlexSure negative 44 236 280
Totals 134 241 375

Likelihood Ratio+ = sens/(1-spec) = 67/(100-98) = 67/2 = 33.5

Likelihood Ratio- = (1-sens)/spec = (100-67)/98 = 33/98 = 0.34
Prevalence = (a+c)/(a+b+c+d) = 134/375 = 35.7%
Study pre-test odds = prevalence/(1-prevalence) = 35.7/64.3 = 0.56
Post-test odds = pre-test odds x likelihood ratio = 0.56 x 33.5 = 18.76
Post-test probability = post-test odds/(post-test odds +1) = 18.76/19.76 = 0.95
 Are the results of this diagnostic
study applicable to my patient?

3. Will the resulting post-test probabilities

affect our management and help our
patient?
1. Could it move us across a test-treatment
threshold?
• Yes, from pre-test probability of 35.7% to post-test
probability of 94.9%
 Are the results of this diagnostic
study applicable to my patient?

3. Will the resulting post-test probabilities affect our

management and help our patient? (cont.)
2. Would our patient be a willing partner in carrying it
out?
• Probably yes
3. Would the consequences of the test help our patient
reach his or her goals in all this?
• Yes, reassurance when negative, labeling and possibly
generating awful diagnostic and prognostic news if positive,
leading to further diagnostic tests and treatments, etc.
 Steps in Practicing
EBM

1. Convert the need for information into an

answerable question.
2. Track down the best evidence with which to
answer that question.
3. Critically appraise the evidence for its validity,
impact, and applicability.
4. Integrate the evidence with our clinical
expertise and our patient’s characteristics
and values.
5. Evaluating our effectiveness and efficiency in
executing steps 1–4 and seeking ways to
improve them both for next time.
How can I apply the results to patient
care?
• The in-office or "near patient" test had
excellent specificity (98%) but a sensitivity of
only 67%, which means that one third of
patients infected with H. pylori and a
proportionate number of those with peptic
ulcer would be missed. The authors conclude
that tests with such poor sensitivity should
not be used for the test-and-treat strategy
(remember SpPin and SnNout!).
 How can I apply the results to patient
care?
• An alternate approach exists, however. Given its
high specificity, the in-office test could be used
to rapidly and reliably diagnose two thirds of
infected patients; the more sensitive laboratory
ELISA could be reserved for those with negative
results. However, the cost-effectiveness of this
strategy would be highly dependent on the
relative costs of the tests (the in-office test
would have to be much less expensive than the
ELISA) and on the prevalence of H. pylori in the
population (the fewer people infected, the larger
the number who would need a second test).
How can I apply the results to patient
care?
• All of these factors should be considered
before an in-office test is used for the test-
and-treat strategy.
 Steps in Practicing
EBM

1. Convert the need for information into an

answerable question.
2. Track down the best evidence with which to
answer that question.
3. Critically appraise the evidence for its validity,
impact, and applicability.
4. Integrate the evidence with our clinical
expertise and our patient’s characteristics and
values.
5. Evaluating our effectiveness and efficiency
in executing steps 1–4 and seeking ways to
improve them both for next time.
Questions?