Supplementary webappendix

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1 Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Gao L, Lu W, Bai L, et al, for the LATENTTB-NSTM study team. Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study. Lancet Infect Dis 2015; published online Feb 11.

2 Supporting file: Supplementary Figure 1. Study design and schedule. The study involves two phases, encompassing a total of three years ( ). The aim of the baseline survey (Phase 1), reported here, was to screen for active TB and history of TB, and then detect LTBI using IGRA and TST in parallel after excluding those with current TB or with a history of TB. During the follow-up phase (Phase 2), which is currently underway, those detected with LTBI at baseline will be followed for the development of active TB through active case finding. Supplementary Figure 2. The agreement between QFT and TST according to TST cutoff values by study site. The agreement between QFT and TST when using different TST cut-off values was evaluated by Cohen s kappa test. The corresponding kappa coefficient was shown with respect to study site. The cut-off values with the best agreement was observed to be different between the study sites. Supplementary File 1. Determination of sample size Supplementary Table 1. Quality control (QC) of the baseline survey Supplementary Table 2. Positivity of TST and QFT by study site Supplementary Table 3. The agreement between TST and QFT results according to TST cut-off values Supplementary Table 4. The distribution of study participants according to QFT and TST

3 Supplementary Figure 1. Outline of study design and schedule Apr 2013 Oct-Nov 2013 Tuberculin skin test (TST) training Data cleaning Digital Radiography technique training Baseline data analysis Jun 2013 Sampling population verification Quarterly cohort maintenance Home visit or telephone interview; Suspected symptoms investigation; Yearly physical examination Questionnaire survey; Clinical examination; Tuberculin skin test; Digital chest radiography; Interferon-γ release assays; Mar 2013 Study sites selection Protocol preparation May 2013 Laboratory test training Field investigation training Data management training Main preliminary experiment Dec 2013 LTBI cohort establishment Jul-Sep 2013 LTBI prevalence investigation Questionnaire; Clinical examination; Tuberculin skin test; Digital chest radiography; Interferon-γ release assays; Expected output Baseline survey: Epidemiological characteristics of LTBI in rural areas in China Follow-up: Incidence of active pulmonary TB among LTBIs and potential risk factors associated with the disease development

4 Supplementary File 1. As the major objective of this study was acquiring population based data on LTBI prevalence and active TB incidence among LTBI infections but not evaluating potential risk factors associated with LTBI prevalence or active TB incidence. Therefore, sample size for the prospective cohort was calculated to detect well accepted age differences related to TB incidence among population with LTBI. The proportion of elderly ( 60 years) was defined to be 20% of the total population, the expected risk ratio for the development of active TB for elderly with LTBI in the study population was 3.5. Assuming the prevalence of LTBI in the general population was 20% and that the majority of new cases with active TB originate from LTBI infections, TB incidence in LTBIs was estimated to be 40/100,000 per year based on the registered TB incidence in China of 80/100,000 per year. Assuming 20% of lost to follow up for LTBIs during two years period, 4500 individuals were needed in LTBI cohorts with a power of 80% and 95% confidence intervals (CIs). Therefore, the minimum sample size required at baseline was 22,000 in total (5500 in each site). This was increased for each study site according to each site s proportion of migrating peasant workers. Each site s eligible population was inflated by an additional 5% to account for those who refused to participate or failed to be interviewed.

5 Supplementary table 1. Quality Control (QC) of the Baseline Survey Key Points of QC a Eligible participant identification Inform consent and questionnaire Blood Collection QC Measures Number of not meeting requirements/total number of undergoing QC (%) Site A Site B Site C Site D To repeat door-to-door survey randomly in 10 household in each site 4/10 (40.0%) 1/10 (10.0%) 0/10 (0%) 0/10 (0%) To check the completeness of inform consent and the authenticity and integrity of the questionnaires (randomly sampling 10% daily) To guarantees the volume of the collected blood and the environment temperature for blood samples transport and storage (randomly sampling 10% daily) 60/605 (9.9%) 72/720 (10.0%) 7/657 (1.1%) 38/675 (5.6%) 0/569 (0%) 32/424 (7.5%) 0/581 (0%) 1/676 (0.1%) TST Digital radiography QFT Data Input Data Cleaning chest To check the performance of TST (dose of PPD, location of injection, environment temperature for PPD storage, etc.) (randomly sampling 10% daily) To repeat the measurement of tuberculin reaction size (randomly sampling 10% daily) 2/624 (0.3%) 0/528 (0%) 0/606 (0%) 3/697 (0.4%) 1/754 (0.1%) 1/563 (0.2%) 0/606 (0%) 8/554 (1.4%) Re-read 10% of the digital chest radiography images independently by the experts group 45/75 (60.0% b ) 89/154 (57.8% b ) 471/691(68.2% b ) 111/185 (57.8% b ) To monitor the operation of the test independently by experienced laboratory technicians 2/140 (1.4%) NA 0/576 (0%) NA Repeat all the samples with indeterminate results 57/5445 (1.0%) c 90/5439 (1.7%) c 202/5486 (3.7%) c 265/5525 (4.8%) c Repeat 3% of the detected samples randomly To check the authenticity and integrity of the inputted data (randomly sampling 10% daily) 164/166 (98.8% b ) 219/220 (99.5% b ) 164/168 (97.6% b ) 54/775 (7.0%) 3/591 (0.5%) 12/502 (2.4%) 161/165 (97.6% b ) 4/363 (1.1%) d 2/540 (0.4%) e 10/447 (2.2%) f To check the integrity of the data for each participant 516 g /5445 (9.5%) 104 g /5439 (1.9%) 203 g /5486 (3.7%) 57 g /5525 (1.0%) 707 h /5445 To check the authenticity of the data for each participant 773 h 512 h /5486 /5439 (14.2%) 534 h /5525 (9.7%) (13.0%) (9.3%) Abbreviation: NA, not available; TST, tuberculin skin test; QFT, QuantiFERON-TB Gold In-Tube. a, Besides the key points listed above, the QC work has also been done on the following procedures: samples processing and storage, data entry, and the performance of taking digital chest radiography; b, concordance rate; c, the total of Individuals had the QFT-GIT results; d, the inputted QC of QFT-GIT; e, the inputted QC of PPD Injecting and measuring of the tuberculin reaction size; f the inputted QC of digital chest radiography; g, the number of individuals lack any results; h, the number of individuals had any inaccurate results. Supplementary Table 2 (a). Positivity of QFT by site Total 5-9 years years years years years years years 70 years N % n % n % n % n % n % n % n % n % p

6 Total Negative <0.001 Positive Indeterminate Site A Negative <0.001 Positive Indeterminate Site B Negative <0.001 Positive Indeterminate Site C Negative <0.001 Positive Indeterminate Site D Negative <0.001 Positive Indeterminate Abbreviation: QFT, QuantiFERON-TB Gold In-Tube.

7 Supplementary Table 2 (b). Positivity of TST by site Total 5-9 years years years years years years years 70 years N % n % n % n % n % n % n % n % n % p Total < 5mm < mm mm mm Site A < 5mm < mm mm mm Site B < 5mm < mm mm mm Site C < 5mm < mm mm mm Site D < 5mm < mm mm mm Abbreviation: TST, tuberculin skin test.

8 Supplementary Table 3. The agreement between TST and QFT results according to TST cutoff values QFT-* QFT+ Concordant (%) Cohen s К TST < 5mm TST 5mm TST < 6mm TST 6mm TST < 7mm TST 7mm TST < 8mm TST 8mm TST < 9mm TST 9mm TST < 10mm TST 10mm TST < 11mm TST 11mm TST < 12mm TST 12mm TST < 13mm TST 13mm TST < 14mm TST 14mm TST < 15mm TST 15mm TST < 16mm TST 16mm TST < 17mm TST 17mm TST < 18mm TST 18mm TST < 19mm TST 19mm TST < 20mm TST 20mm Abbreviation: QFT, QuantiFERON-TB Gold In-Tube; TST, tuberculin skin test. *Indeterminate results were grouped into negatives.

9 Kappa Supplementary Figure 2. The agreement between QFT and TST according to TST cutoff values by study site Total Site A Site B Site C Site D TST cutoff values

10 Supplementary Table 4. The distribution of study participants according to QFT and TST QFT TST < 5mm 5-9mm 10-14mm 15mm n % (column/row) n % (column/row) n % (column/row) n % (column/row) Total Negative / / / /9.50 <0.001 Positive / / / /60.90 Indeterminate // / / /9.52 Male Negative / / / /10.27 <0.001 Positive / / / /60.78 Indeterminate / / / /8.94 Female Negative / / / /8.87 <0.001 Positive / / / /61.03 Indeterminate / / / /9.76 p for χ 2 test Abbreviation: QFT, QuantiFERON-TB Gold In-Tube; TST, tuberculin skin test.