STUDY DESIGN FOR
DIAGNOSTIC STUDY FOR MELIOIDOSIS
Dr Direk Limmathurotsakul, MD MSc PhD
Introduction: 3 phases of study design
Laboratory
phase
Case-control
phase
Prospective
phase
- develop test
- test with few
cases and healthy
controls
- prove of concept
- test with definite
cases and definite
controls
- calculate
Se & Sp
- test with diseasesuspected
patients
- calculate Se, Sp,
PPV & NPV
Introduction: 3 phases of study design
Laboratory
phase
Case-control
phase
Prospective
phase
- develop test
- test with few
cases and healthy
controls
- prove of concept
- test with definite
cases and definite
controls
- calculate
Se & Sp
- test with diseasesuspected
patients
- calculate Se, Sp,
PPV & NPV
Look promising
Introduction: 3 phases of study design
Laboratory
phase
Case-control
phase
Prospective
phase
- develop test
- test with few
cases and healthy
controls
- prove of concept
- test with definite
cases and definite
controls
- calculate
Se & Sp
- test with diseasesuspected
patients
- calculate Se, Sp,
PPV & NPV
Look promising
Look good
Introduction: 3 phases of study design
Laboratory
phase
Case-control
phase
Prospective
phase
- develop test
- test with few
cases and healthy
controls
- prove of concept
- test with definite
cases and definite
controls
- calculate
Se & Sp
- test with diseasesuspected
patients
- calculate Se, Sp,
PPV & NPV
Look promising
Look good
Look rubbish
(GS problem)
Good guideline
Good guideline
• Recommendation 1: Access index test’s ability to predict
patient-relevant outcomes instead of test accuracy
• Recommendation 2: Access the concordance of difference
tests instead of test accuracy
• Recommendation 3: Qualify the interpretation of “naïve”
estimates of the index test’s performance
• Recommendation 4: Imperfect gold standard model
Recommended design for melioidosis
• Define need
For example, estimate Se, Sp, PPV and NPV in a prospective
design (to represent the real clinical situation)
• Define study population (that we would like to infer the
estimated accuracy to)
• Next: select reference standard
Recommended design for melioidosis
• If there are more than one population, at least 2 diagnostic
tests (3 tests are preferred)
Those 2 tests should be based on 2 different biological
mechanism (e.g. one antigen detection [culture] and one
antibody detection [IHA])
• If there is only one population, at least 3 diagnostic tests (5
tests are preferred)
Those 3 tests should be based on 3 different biological
mechanism (e.g. one antigen detection [culture / PCR assays],
one antibody detection [IHA/ELISA], one clinical detection
[ultrasonogram/CT scan])
Recommended design for melioidosis
• Consider repeated sampling and convalescent specimens
• Day 4 and Day 7 specimens may have clinical implication for
changing the diagnosis and treatment
• Day 14 and Day 28 specimens may have clinical implication for
starting oral treatment regimen
• Consider long-term outcome for relapse/recurrent infection
• Four-fold rising is arbitrary and based on imperfect gold
standard. This should be evaluated with better approach
• Adequate sample size is required (enough diseased patients
for sensitivity estimation is important than the total number)
Recommended design for melioidosis
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Select sites
Appoint study team
Train staff
Provide GCP
Conduct QC and monitoring
Collect data
Perform analysis
Report results using STARD checklist
Disseminate results
END