Start4All SCREEN-TB PROTOCOL

Primary Endpoint 1.1: Diagnostic Yield of TB by algorithm, disaggregated by symptom status

• WHO: All participants enrolled in the study (≥10 years)
• WHAT: Number and proportion (out of attempted TB testing) of participants diagnosed with TB (microbiologically confirmed and clinically diagnosed) per diagnostic algorithm pathway
• WHEN: Primary = at completion of diagnostic work-up (Day 1-3); Secondary = confirmed via NTP registry data at treatment initiation
• WHERE: Study healthcare facilities and referral laboratories in Bangladesh, Cameroon, Kenya, Nigeria, Viet Nam
• WHY: To determine incremental case detection across different screening approaches
• HOW MEASURED:

oNumerator = number of TB cases identified; oDenominator = total participants screened by each algorithm (including those with invalid and inconclusive results); oStratification = symptomatic vs asymptomatic (per WHO 4-symptom screen); oCase definitions = WHO TB definitions (microbiologically confirmed, clinicaly diagnose

Primary Endpoint 1.2: Comparative diagnostic accuracy (sensitivity, specificity, PPV, NPV) of (i) CAD CXR-AI as an initial screening tool, (ii) NPOC tongue swab and sputum swab testing as initial screening tools.

• WHO: All participants with interpretable test results
• WHAT: Sensitivity, specificity, PPV, NPV of CAD CXR-AI and NPOC tongue swab and sputum swab as initial screening tools
• WHEN: Calculated after completion of reference standard testing for all participants
• WHERE: Central data analysis
• WHY: To compare performance characteristics of screening tools
• HOW MEASURED:

• Reference standard = LC-NAAT;
• Using standard diagnostic accuracy definitions and reporting all estimates together with 95% confidence intervals;
• Receiver operating characteristic (ROC) curves for CAD CXR-AI thresholds
• Pre-specified handling of indeterminate/uninterpretable results

Secondary Endpoint 1.1: Time from entering healthcare facility to being initiated on TB treatment according to National TB Programme (NTP) register record

• WHO: Participants diagnosed with TB
• WHAT: Time from entering healthcare facility to initiation of TB treatment, using NTP register records
• WHEN: From date of facility attendance (and, where available, reported symptom onset) to date of treatment start
• WHERE: Facility records and NTP registers
• WHY: To evaluate timeliness of linkage to care under different algorithms
• HOW MEASURED: Extract dates of facility attendance (or specimen collection), diagnosis confirmation, and treatment start from registers; calculate time to treatment initiation in days; analyse using descriptive and time-to-event methods; assessment limited to treatment initiation (no post-treatment follow-up).

Secondary Endpoint 1.2: Proportion of individuals screening positive on the diagnostic algorithm who then initiate TB treatment.

• WHO: All participants screening positive on diagnostic algorithms
• WHAT: Proportion who initiate TB treatment
• WHEN: At time of registry-confirmed treatment initiation
• WHERE: NTP registers
• WHY: To determine effectiveness of linkage to care
• HOW MEASURED: Numerator = number starting treatment; Denominator = number screening positive

Secondary Endpoint 2.1: Modelled incremental cost per person diagnosed with TB from a societal perspective (disaggregated by provider and beneficiary), comparing multiple screening and diagnostic algorithms where:

CAD CXR-AI and NPOC are incorporated as initial screening tests Varying CAD thresholds for determining whether pooled or individual LC-NAAT testing is subsequently used are treated as independent and separate initial CAD CXR-AI screening tests

• WHO: All participants enrolled
• WHAT: Direct evaluation of costs and cost-effectiveness of CAD vs NPOC tongue swab and sputum swab as:

• stand-alone initial screening tools
• part of diagnostic algorithms
• WHEN: During study and at study end
• WHERE: Facility costing and central analysis
• WHY: To inform programmatic adoption
• HOW MEASURED: Measured cost per TB case diagnosed, modelled incremental cost-effectiveness ratios

Secondary Endpoint 2.2: Modelled incremental cost per person diagnosed with TB who initiates treatment from a societal perspective (disaggregated by provider and beneficiary), comparing multiple screening and diagnostic algorithms where:

CAD CXR-AI and NPOC are incorporated as initial screening tests Varying CAD thresholds for determining whether pooled or individual LC-NAAT testing is subsequently used are treated as independent and separate initial CAD CXR-AI screening tests

• WHO: All participants enrolled
• WHAT: Direct evaluation of costs and cost-effectiveness of CAD vs NPOC tongue swab and sputum swab as:

• stand-alone initial screening tools
• part of diagnostic algorithms
• WHEN: During study and at study end
• WHERE: Facility costing and central analysis
• WHY: To inform programmatic adoption
• HOW MEASURED: Modelled cost per person who initiates treatment, modelled incremental cost-effectiveness ratios

Secondary Endpoint 3.1: Feasibility and acceptability of CAD CXR-AI and NPOC tongue swab and sputum swab from diverse perspectives including people seeking care, and health system, and policy makers

• WHO: People seeking care, healthcare providers, policymakers
• WHAT: Feasibility, acceptability, and scalability of CAD CXR-AI and NPOC tongue swab and sputum swab
• WHEN: During and after implementation
• WHERE: Study facilities and through qualitative sub-studies
• WHY: To evaluate real-world integration and sustainability
• HOW MEASURED: Participant and provider interviews, FGDs; structured observation; time-motion analysis; metrics such as proportion able to provide samples and proportion of valid results

Secondary Endpoint 4.1: Sensitivity and specificity of CAD-guided pooling relative to individual testing

• WHO: All enrolled participants providing tongue or sputum swabs eligible for both individual and pooled testing.
• WHAT: Diagnostic accuracy (sensitivity, specificity, PPV, NPV) of CAD-guided pooling compared with individual LC-NAAT results as reference.
• WHEN: completion of diagnostic work-up; secondary confirmation against NTP registry data at treatment initiation.
• WHERE: Study facilities and laboratories in Bangladesh, Cameroon, Kenya, Nigeria, Viet Nam.
• WHY: To determine whether CAD-guided pooling maintains diagnostic accuracy while reducing testing volumes.
• HOW MEASURED:

• Numerator (sensitivity) = number of TB-positive pools correctly identified.
• Denominator (specificity) = total number of TB-negative individuals per reference testing.
• Stratification = by CAD score band and specimen type (tongue swab, sputum swab).

Secondary Endpoint 4.2: Proportion of tests saved and associated change in turnaround time

• WHO: All pooled samples from enrolled participants eligible for CAD-guided pooling.
• WHAT: Number and proportion of tests saved by CAD-guided pooling compared with individual and turnaround time for reporting results.
• WHEN: Measured in real-time during study implementation; time recorded from specimen collection to availability of test result.
• WHERE: Study facilities and laboratories in Bangladesh, Cameroon, Kenya, Nigeria, Viet Nam.
• WHY: To assess efficiency gains from pooling strategies and their impact on timeliness of results.
• HOW MEASURED:

• Numerator (tests saved) = number of individual cartridges not required due to pooling.
• Denominator (tests saved) = total number of cartridges that would have been required for individual testing alone.
• Turnaround time = median hours from specimen collection to result availability; stratified by pooled vs individual pathways.

Secondary Endpoint 4.3: Feasibility and acceptability of CAD-guided pooling from perspectives of laboratory staff, providers, and policymakers

• WHO: Laboratory staff, healthcare and policymakers engaged in or overseeing CAD-guided pooling activities.
• WHAT: Perceptions of feasibility (integration into, training , workload, error rates) and acceptability (appropriateness, confidence, value)
• WHEN: During implementation and at study end via interviews, discussions, and surveys.
• WHERE: Healthcare facilities, laboratories, and NTB programme offices in-country.
• WHY: To identify barriers and facilitators to implementation of CAD-guided pooling informing potential scale-up.
• HOW MEASURED:

• Qualitative data: thematically analysed from key informant interviews and focus groups.
• Quantitative data: survey scores on feasibility and acceptability domains (e.g. workload, clarity of purpose, perceived reliability).
• Stratification = by stakeholder group (lab staff, providers, policymakers).

Exploratory Endpoint 1.1: Incremental TB cases detected using newer ultra-sensitive LAM vs. Alere LAM and vs no use of LAM testing among HIV positive patients

• WHO: Presumptive TB patients (positive in one or more SCREEN-TB pathways) with HIV
• WHAT: Number and proportion of participants additionally diagnosed with LAM testing in comparison to LC-NAAT-confirmed TB
• WHEN: At completion of diagnostic work-up (Day 1-3); then confirmed via NTP registry data at treatment initiation
• WHERE: Study facilities and laboratories in Cameroon, Kenya and Nigeria
• WHY: To determine incremental case detection among people living with HIV (PLHIV) vs LC-NAAT
• HOW MEASURED:

• Number of clinically diagnosed TB cases, microbiologically negative and positive by LAM
• Total participants with an HIV positive test and clinically diagnosed with TB but had a negative LC-NAAT result
• CD4 cell counts < 200/mm3, CD4 cell counts < 100/m3
• WHO TB definitions (microbiologically confirmed, clinically diagnosed)

Exploratory Endpoint 1.2: Sensitivity and specificity of the ultra-sensitive LAM vs. Alere LAM (comparator) and of ultra-sensitive LAM compared to LC-NAAT-based reference standard

• WHO: Presumptive TB patients with HIV
• WHAT: Number and proportion of participants correctly diagnosed with ultrasensitive LAM test in comparison to ALERE test using LC-NAAT status and clinical TB diagnosis as the reference.
• WHEN: Completion of diagnostic work-up (Day 1-3); then confirmed via NTP registry data at treatment initiation
• WHERE: Study facilities and laboratories in Cameroon, Kenya and Nigeria
• WHY: To determine sensitivity and specificity of ultrasensitive LAM tests vs ALERE and LC-NAAT among PLHIV
• HOW MEASURED:

• Number of clinically diagnosed TB cases, microbiologically negative and positive by LAM
• Total participants with an HIV positive test and clinically diagnosed with TB but had a negative LC-NAAT result
• CD4 cell counts < 200/mm3, CD4 cell counts < 100/m3
• WHO TB definitions

Exploratory Endpoint 1.3: Error/invalid rates; ease-of-use.

• WHO: People seeking care, healthcare providers
• WHAT: Feasibility, acceptability and scalability of ultrasensitive LAM tests in comparison to Alere
• WHEN: During and after implementation
• WHERE: Study facilities and through qualitative sub-studies
• WHY: To evaluate real-world integration
• HOW MEASURED: Operator questionnaires on technology easy-of-use, structured observation; time-motion analysis; metrics such as proportion able and willing to provide samples and proportion of valid results

Exploratory Endpoint 1.4: Cost per additional case detected;

• WHO: All participants taking part in SCREEN-TB&HIV sub study
• WHAT: Direct evaluation of costs and cost-effectiveness of LAM and CD4 count testing

• stand-alone as initial screening tools among PLHIV presumptive of TB infection
• part of diagnostic algorithms
• WHEN: During study and at study end
• WHERE: Facility costing and central analysis
• WHY: To inform programmatic adoption
• HOW MEASURED: Cost per TB case detected, incremental cost-effectiveness ratios

Exploratory Endpoint 2.1: Diagnostic yield of TB from pooled tongue swabs versus individual tongue swabs

• WHO: All participants (≥10 years) providing tongue swab specimens.
• WHAT: Number and proportion (out of attempted TB testing) of TB diagnoses from pooled tongue swabs compared with individual swabs (reference).
• WHEN: At completion of diagnostic work-up (Day 1-3); confirmation via NTP register at treatment initiation.
• WHERE: Study healthcare facilities and referral laboratories in Bangladesh, Cameroon, Kenya, Nigeria, Viet Nam.
• WHY: To determine whether tongue swab pooling retains diagnostic yield compared with individual testing.
• HOW MEASURED:

• Numerator = TB-positive results from pooled tongue swabs.
• Denominator = total number of individuals tested.
• Reference = individual tongue swab LC-NAAT results.
• Stratification = symptomatic vs asymptomatic.

Exploratory Endpoint 2.2: Diagnostic yield of TB from pooled tongue swabs versus individual sputum swabs

• WHO: All participants (≥10 years) providing tongue swab specimens.
• WHAT: Number and proportion (out of attempted TB testing) of TB diagnoses from pooled sputum swabs compared with individual swabs (reference).
• WHEN: At completion of diagnostic work-up (Day 1-3); confirmation via NTP register at treatment initiation.
• WHERE: Study healthcare facilities and referral laboratories in Bangladesh, Cameroon, Kenya, Nigeria, Viet Nam.
• WHY: To determine whether sputum swab pooling retains diagnostic yield compared with individual testing.
• HOW MEASURED:

• Numerator = TB-positive results from pooled sputum swabs.
• Denominator = total number of individuals tested.
• Reference = individual sputum swab LC-NAAT results.
• Stratification = symptomatic vs asymptomatic.

Exploratory Endpoint 2.3:

Comparative diagnostic accuracy (sensitivity, specificity, PPV, NPV) of tongue vs sputum pooling

• WHO: All participants providing both tongue and sputum swabs.
• WHAT: Accuracy of pooled tongue vs sputum swab testing relative to individual results.
• WHEN: At completion of diagnostic work-up (Day 1-3).
• WHERE: Study sites as above.
• WHY: To identify whether tongue or sputum pooling offers better performance.
• HOW MEASURED:

• Sensitivity, specificity, PPV, NPV calculated against individual swab results.
• Stratification = by symptom status and CAD score band.

Exploratory Endpoint 2.4: Invalid or error rate of pooled vs individual testing

• WHO: All pooled and individual swab samples tested.
• WHAT: Proportion of invalid/error results in pooled vs individual testing.
• WHEN: During study implementation, measured in real-time.
• WHERE: Study labs across all participating countries.
• WHY: To assess whether pooling increases technical error rates.
• HOW MEASURED:

• Numerator = number of invalid/error results.
• Denominator = total tests conducted (pooled or individual).

Exploratory Endpoint 2.5: Efficiency outcomes (tests saved, cartridge use, estimated cost savings)

• WHO: All swab tests (tongue and sputum) eligible for pooling.
• WHAT: Number of cartridges/tests saved and estimated cost savings compared with individual-only testing.
• WHEN: Throughout study implementation.
• WHERE: All study sites and labs.
• WHY: To measure efficiency benefits of pooling strategies.
• HOW MEASURED:

• Numerator = cartridges saved by pooling.
• Denominator = total that would have been used for individual-only testing.
• Costs = estimated from provider and beneficiary perspectives.

Secondary Endpoint 3.1: Feasibility and acceptability of CAD CXR-AI and NPOC tongue swab and sputum swab from diverse perspectives including people seeking care, and health system, and policy makers

• WHO: People seeking care, healthcare providers, policymakers
• WHAT: Feasibility, acceptability, and scalability of CAD CXR-AI and NPOC tongue swab and sputum swab
• WHEN: During and after implementation
• WHERE: Study facilities and through qualitative sub-studies
• WHY: To evaluate real-world integration and sustainability
• HOW MEASURED: Participant and provider interviews, FGDs; structured observation; time-motion analysis; metrics such as proportion able to provide samples and proportion of valid results

Exploratory Endpoint 3.2: Diagnostic accuracy of self-collected tongue swabs

• WHO: Participants who completed self-swab and had individual results available.
• WHAT: Sensitivity, specificity, PPV, NPV of self-swabs relative to HCW-swabs as reference.
• WHEN: At completion of diagnostic work-up (Day 1-3); confirmation via NTP register at treatment initiation.
• WHERE: Study healthcare facilities in all countries.
• WHY: To assess whether self-collection achieves comparable diagnostic yield to HCW collection.
• HOW MEASURED: Standard accuracy metrics using HCW swabs and final diagnostic algorithm as reference.

Exploratory Endpoint 3.3: Diagnostic accuracy of HCW-collected tongue swabs

• WHO: All participants (≥10 years) eligible for both self- and HCW-collected swabs.
• WHAT: Number and proportion of TB diagnoses from self-collected vs HCW-collected swabs with HCW swabs evaluated against an LC-NAAT-based reference standard.
• WHEN: At completion of diagnostic work-up (Day 1-3); confirmation via NTP register at treatment initiation.
• WHERE: Study healthcare facilities in all countries.
• WHY: To assess whether self-collection achieves comparable diagnostic yield to HCW collection.
• HOW MEASURED: Standard accuracy metrics using HCW swabs and final diagnostic algorithm as reference.

Exploratory Endpoint 4.1: Diagnostic yield of TB by swab order (1 through 4)

• WHO: All participants providing four sequential tongue swabs.
• WHAT: Number and proportion of TB-positive results for each swab order (1-4).
• WHEN: At completion of diagnostic work-up (Day 1-3).
• WHERE: Study healthcare facilities and labs in all countries.
• WHY: To evaluate whether diagnostic yield varies by swab sequence.
• HOW MEASURED:

• Numerator = TB-positive results per swab order.
• Denominator = total tests attempted.

Exploratory Endpoint 4.2: Diagnostic accuracy using first swab only, 1-2 combined, 1-3 combined, 1-4 combined

• WHO: Participants with complete sequential swab sets.
• WHAT: Sensitivity, specificity, PPV, NPV across cumulative swab combinations.
• WHEN: At completion of diagnostic work-up.
• WHERE: Study sites.
• WHY: To determine optimal number of swabs required for reliable detection.
• HOW MEASURED: Accuracy statistics estimated using LC-NAAT as the reference standard.

Exploratory Endpoint 4.3: Incremental diagnostic yield by swab order (additional positives with each subsequent swab)

• WHO: Participants with sequential swab sets.
• WHAT: Number of additional TB-positive results detected as each swab is added (e.g. swab 2 beyond swab 1, etc).
• WHEN: Day 1-3 diagnostic period.
• WHERE: All study sites.
• WHY: To quantify added value of each extra swab for diagnostic sensitivity.
• HOW MEASURED:

• Incremental positives = TB-positive cases detected by swab n but missed by swabs 1 to n-1.
• Denominator = total participants tested.

Exploratory Endpoint 5.1: Incremental diagnostic yield of TB compared with sputum collection without the Lung Flute ECO device

• WHO: Participants enrolled in SCREEN-TB who are unable or have difficulty producing sputum at baseline.
• WHAT: Difference in the proportion of participants with TB detected on diagnostic testing using sputum collected with the Lung Flute ECO device compared with sputum collection without the device.
• WHEN: Assessed after completion of diagnostic testing.
• WHERE: Central data analysis and across participating SCREEN-TB countries.
• WHY: To determine whether the Lung Flute ECO increases TB detection among people with difficulty producing sputum in community-based screening settings.
• HOW MEASURED: Comparison of TB yield on diagnostic tests performed on sputum collected with versus without the Lung Flute ECO device, with confidence intervals and pre-specified handling of invalid results.

Exploratory Endpoint 5.2 : Incremental yield of participants able to produce sputum greater than 1 mL compared with sputum collection without the Lung Flute ECO device

• WHO: Adults and adolescents enrolled in SCREEN-TB who are unable or have difficulty producing sputum at baseline.
• WHAT: Difference in the proportion of participants able to produce sputum volume greater than 1 mL with the Lung Flute ECO device compared with without the device.
• WHEN: Assessed at the sputum collection visit.
• WHERE: Central data analysis and across participating SCREEN-TB countries.
• WHY: To determine whether the Lung Flute ECO improves sputum provision among people with difficulty producing sputum.
• HOW MEASURED:

Comparison of proportions producing sputum volume greater than 1 mL with versus without the Lung Flute ECO device

Secondary Endpoint 6.1: Incremental cost per DALY averted (by diagnostic algorithm)

• WHO: All participants enrolled
• WHAT: Direct evaluation of costs and cost-effectiveness of CAD vs NPOC tongue swab and sputum swab as:

• stand-alone initial screening tools
• part of diagnostic algorithms
• WHEN: During study and at study end
• WHERE: Facility costing and central analysis
• WHY: To inform global policy
• HOW MEASURED: Modelled incremental cost per DALY averted