STUDY DESIGN FOR DIAGNOSTIC STUDY FOR MELIOIDOSIS

Dr Direk Limmathurotsakul, MD MSc PhD

Introduction: 3 phases of study design

Laboratory

phase

- develop test

- test with few

cases and healthy

controls

- prove of concept

Case-control

phase

- test with definite

cases and definite

controls

- calculate

Se & Sp

Prospective

phase

- test with disease-

suspected

patients

- calculate Se, Sp,

PPV & NPV

Introduction: 3 phases of study design

Laboratory

phase

- develop test

- test with few

cases and healthy

controls

- prove of concept

Case-control

phase

- test with definite

cases and definite

controls

- calculate

Se & Sp

Prospective

phase

- test with disease-

suspected

patients

- calculate Se, Sp,

PPV & NPV

Look promising

Introduction: 3 phases of study design

Laboratory

phase

- develop test

- test with few

cases and healthy

controls

- prove of concept

Case-control

phase

- test with definite

cases and definite

controls

- calculate

Se & Sp

Prospective

phase

- test with disease-

suspected

patients

- calculate Se, Sp,

PPV & NPV

Look promising Look good

Introduction: 3 phases of study design

Laboratory

phase

- develop test

- test with few

cases and healthy

controls

- prove of concept

Case-control

phase

- test with definite

cases and definite

controls

- calculate

Se & Sp

Prospective

phase

- test with disease-

suspected

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

• 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