e-figure 1. The design of the study.

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1 e-figure 1. The design of the study. NDM, no diabetes; DM, diabetes; TB, tuberculosis; SN, sputum smear negative; SP, sputum smear positive; AFB, acid fast bacilli.

2 e-figure 2. Representative H&E (A) and Masson s trichrome staining (B) sections of granulomas with differential degrees of fibrotic encapsulation. Class 1+, reduced perinecrotic fibrosis, more multinucleated giant cells ( <200 M thick ) MNGCs; >3 MNGCs per 10 high power fields, HP >3/10 HP), epithelioid cells and inflammatory cells; Class 2+, moderate perinecrotic fibrosis ( M thick), fewer MNGCs (1 2/10 HP), epithelioid cells and inflammatory cells; Class 3+, severe perinecrotic fibrosis (>500 M thick), collagen hyperplasia, absence of MNGCs (0/10 HP), epithelioid cells and inflammatory cells. C. Representative computed tomography (CT) scans at the time of diagnosis.1. a thin-walled cavity (arrow); 2. a thick-walled cavity ; 3. a tree-in-bud appearance (TIB); 4. lobular consolidations (LC), and 5. a thick-walled cavity with a fibrotic band (FB).

e-figure 3. Changes in WBC and RBC indices between NDM-TB and DM-TB groups during TB progression. Horizontal lines represent median values. Gray areas represent normal ranges of the indices.

3 e-figure 3. Changes in WBC and RBC indices between NDM-TB and DM-TB groups during TB progression. Horizontal lines represent median values. Gray areas represent normal ranges of the indices. SN, smear negative TB;SP, smear positive TB;WBC, white blood cell;rbc, red blood cell;hgb, hemoglobin;neu/lym, neutrophil to lymphocyte ratio; Mon/Lym, monocyte to lymphocyte ratio. Differences between groups were analyzed by Mann Whitney tests.

e-figure 4. Changes in antibody isotypes, complements and RBC indices between NDM-TB and DM-TB during TB progression. Horizontal lines represent median values.

4 e-figure 4. Changes in antibody isotypes, complements and RBC indices between NDM-TB and DM-TB during TB progression. Horizontal lines represent median values. Gray areas represent the normal ranges of the indices. SN, smear negative TB;SP, smear positive TB; C3, complement component 3; MCV, erythrocyte mean corpuscular volume;hct, hematocrit; MCH, Mean corpuscular hemoglobin The differences between groups were analyzed by Mann Whitney tests.

5 e-table 1. CT findings of NDM-TB and DM-TB patients Prevalence of CT findings, No. (%) Prevalence of CT findings, No (%) CT findings SN-NDM-TB SN-DM-TB P-value* SP-NDM-TB SP-DM-TB P-value* (n=40) (n=40) (n=87) (n=92) Centrilobular nodule or 9 (22.50) 15(37.50) (57.47) 68 (73.91) a branching Tree-in-bud appearance 9 (22.50) 13 (32.50) (40.23) 49 (53.26) Poorly defined ( fuzzy ) 9 (22.50) 17 (42.50) (42.53) 51 (55.43) nodule Cavity 6 (15.00) 13 (32.50) (67.82) 80 (86.96) a Thin-walled cavity 0 (0.00 ) 2 (5.00) (10.34) 6 (6.52) Thick-walled cavity 5 (12.50 ) 8 (20.00) (43.68) 64 (69.57) <0.001 a Lobular consolidations 34 (85.00) 33 (82.50) (78.16) 80 (86.96) Bronchovascular distortion 1 (2.50) 2 (5.00) (55.17) 55 (59.78) Fibrotic band 24 (60.00) 10 (25.00) a 47 (54.02) 36 (39.13) a Bronchiectasis 3 (7.50) 1 (2.50) (59.77) 58 (63.04) Miliary nodules 0 (0.00) 1 (2.50) (0.03) 3 (3.26) Hilar and mediastinal adenopathy 11 (27.50) 14 (35.00) (16.09) 68 (73.91) <0.001 a Table notes: CT, computed tomography; DM, diabetes mellitus; DM-TB, TB patients with DM; NDM-TB, TB patients without DM; TB: tuberculosis; SN, smear negative; SP, smear positive. * 2 test a P <0.05.

6 e-table 2. Association of immune, biochemical indices with granuloma caseous necrosis in 67 TB (34NDM, 33DM) patients. Parameters Area of caseous necrosis Odd Ratio (95% CI) P Odd Ratio1 (95% CI) P Odd Ratio 2 (95% CI) P Demographic indices Age (year) (0.860, 0.997) (0.885, 1.046) (0.872, 1.046) Height (cm) (1.000, 1.177) (0.854, 1.114) (0.832, 1.117) Weight (Kg) (1.001, 1.124) (0.818, 1.151) (0.796, 1.150) BMI (0.928, 1.358) (0.889, 1.322) (0.819, 1.254) Immune cells and inflammatory indices WBC ( 10 9 / L) (0.770, 1.437) (0.686, 1.387) (0.619, 1.359) Neu (%) (0.902, 1.046) (0.915, 1.085) (0.907, 1.093) Neu ( 10 9 /L) (0.649, 1.554) (0.590, 1.605) (0.520, 1.600) Mon (%) (0.862, 1.577) (0.793, 1.660) (0.703, 1.504) Mon ( 10 9 /L) (0.159, ) (0.042, ) (0.006, ) Lym (%) (0.927, 1.111) (0.876, 1.088) (0.864, 1.096) Lym ( 10 9 /L) (0.496, 2.645) (0.317, 1.991) (0.246, 1.877) Eo (%) (0.851, 1.283) (0.860, 1.245) (0.881, 1.324) Baso (%) (1.003, ) (0.692, ) (0.554, ) Eo ( 10 9 /L) (0.102, ) (0.075, ) (0.108, ) Baso ( 10 9 /L) (0.000, ) (0.000, ) (0.000, ) Neu/Lym (0.420, 1.778) (0.481, 2.828) (0.440, 3.015) Mon/Lym (0.011, ) (0.004, ) (0.000, ) PLT/Neu (0.974, 1.020) (0.977, 1.024) (0.976, 1.028) PLT/Lym (0.987, 1.008) (0.988, 1.014) (0.989, 1.016) Platelet and coagulation indices PLT ( 10 9 /L) (0.990, 1.005) (0.988, 1.005) (0.989, 1.006) PCT (%) (0.000, 6.366) (0.000, ) (0.000, ) MPV (fl) (0.604, 1.228) (0.619, 1.433) (0.661, 1.977) INR (0.000, 3.406) (0.000, 5.343) (0.000, 4.415) Fibrinogen (g/l) (0.704, 2.200) (0.755, 2.931) (0.443, 2.235) D-Dimer (ng/ml) (0.996, 1.001) (0.996, 1.002) (0.996, 1.003) Glucose and lipid-associated indices TCH (mmol/l) (0.408, 1.243) (0.352, 1.267) (0.363, 1.379) TG (mmol/l) (0.726, 1.975) (0.436, 1.965) (0.301, 1.664) HDL-C (mmol/l) 0.734( 0.217, 2.483) (0.388, ) (0.693, ) ApoA (mmol/l) (0.073, 2.512) (0.165, ) (0.352, ) ApoB (mmol/l) (0.038, 2.625) (0.015, 1.942) (0.013, 2.617) ApoE (mmol/l) (0.946, 1.014) (0.946, 1.028) (0.946, 1.032) LPA (mmol/l) (0.996, 1.001) (0.996, 1.001) (0.995, 1.001) GLU (mmol/l) (0.934, 1.717) (0.828, 1.579) (0.555, 1.250) 0.378

7 Red blood cell-associated indices RBC ( / L) (0.414, 5.246) (0.041, 1.587) (0.031, 1.977) HGB (g/l) (0.971, 1.046) (0.902, 1.011) (0.904, 1.024) HCT (%) (0.000, ) (0.000, ) (0.000, ) MCV (fl) (0.829, 1.101) (0.794, 1.140) (0.794, 1.151) MCH (pg) (0.652, 1.366) (0.532, 1.289) (0.577, 1.513) MCHC (g/l) (0.969, 1.028) (0.941, 1.034) (0.956, 1.051) Table notes: BMI, body mass index; WBC, white blood cell; Neu (%), percentage of neutrophil; Neu ( 10 9 /L), counts of neutrophil; Mon (%), percentage of monocyte; Mon ( 10 9 /L), counts of monocyte; Lym (%), percentage of lymphocyte; Lym ( 10 9 /L), counts of lymphocyte; Eo (%), percentage of eosinophil; Baso (%), percentage of basophil; Eo ( 10 9 /L), counts of eosinophil; Baso ( 10 9 /L), counts of basophil; Neu/Lym, neutrophil to lymphocyte ratio; Mon/Lym, monocyte to lymphocyte ratio; PLT/Neu, platelet to neutrophil ratio; PLT/Lym, platelet to lymphocyte ratio; PLT, counts of platelets; PCT, plateletcrit; MPV, Mean platelet volume; INR, international normalized ratio; TCH, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol; ApoA, apolipoprotein A; ApoB, apolipoprotein B; ApoE, apolipoprotein E; LPA, lipoprotein A; GLU, fasting glucose level; RBC, red blood cell; HGB, hemoglobin; HCT, red blood cell specific volume; MCV, erythrocyte mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration. Odd ratios are calculated from binary logistic analysis. Patients were divided into two groups according to the 15.2 mm 2 or >15.2 mm 2 caseous necrotic areas of the granuloma under 5 microscope observation. aor1, odd ratios after adjusted for gender, age and BMI; aor2, odd ratios after adjusted for gender, age, BMI and NDM/DM status. Bold numbers indicate a P value of < 0.05.

8 e-table 3. Association analysis of immune and biochemical indices with extent of peri-necrosis fibro-encapsulation of granuloma in 67 TB (34NDM, 33DM) patients. Parameters Fibro-encapsulation Odd Ratio (95% CI) P Odd Ratio1 (95%CI) P Odd Ratio 2 (95%CI) P Demographic indices Male a (1.082, 9.895) (0.747, 7.526) (0.727, 9.159) Weight (kg) (0.932, 1.024) (0.833, 1.115) (0.806, 1.118) Height (cm) (0.902, 1.039) (0.858, 1.080) (0.828, 1.080) Age (year) (0.951, 1.086) (0.908, 1.053) (0.897, 1.059) BMI (0.883, 1.215) (0.864, 1.195) (0.777, 1.122) Immune cell and inflammatory indices WBC ( 10 9 / L) (0.769, 1.346) (0.747, 1.351) ( 0.654, 1.296) Neu (%) (0.939, 1.078) (0.943, 1.099) (0.936, 1.113) Neu ( 10 9 /L) (0.654, 1.464) (0.685, 1.621) (0.588, 1.579) Lym (%) (0.917, 1.085) (0.874, 1.059) (0.857, 1.066) Lym ( 10 9 /L) (0.453, 1.978) (0.360, 1.719) (0.256, 1.533) Mon (%) (0.775, 1.290) (0.710, 1.250) (0.592, 1.134) Mon ( 10 9 /L) (0.037, ) ( 0.025, ) (0.001, 4.019) Eo (%) (0.791, 1.149) (0.876, 1.278) (0.918, 1.336) Baso (%) (0.557, ) (0.368, ) (0.209, ) Eo ( 10 9 /L) (0.015, 7.588) (0.019, 7.779) (0.220, ) Baso ( 10 9 /L) (0.002, ) (0.000, ) (0.001, ) Neu/Lym (0.457, 1.874) (0.622, 3.198) (0.572, 3.493) Mon/Lym (0.002, ) (0.001, ) (0.000, ) PLT/Neu (0.974, 1.016) (0.976, 1.020) (0.977, 1.027) PLT/Lym (0.986, 1.006) (0.988, 1.010) (0.989, 1.012) Platelet and coagulation indices PLT ( 10 9 /L) (0.990, 1.004) (0.990, 1.005) (0.990, 1.007) PCT (%) (0.000, 6.366) (0.000, ) (0.000, ) MPV (fl) (0.845, 1.591) (0.661, 1.350) (0.726, 1.820) PT (seconds) (0.333, 1.233) (0.308, 1.449) (0.283, 1.527) INR (0.000,74.194) (0.000, ) (0.000, ) Fibrinogen (g/l) (0.863, 2.566) (0.959, 3.272) (0.575, 2.450) D-Dimmer (ng/ml) b (0.994, 1.000) (0.994, 1.000) (0.994, 1.001) Glucose and lipid-associated indices TCH (mmol/l) (0.483, 1.349) (0.485, 1.466) (0.508, 1.678) TG (mmol/l) (0.810, 2.289) (0.674, 2.725) (0.529, 2.568) LDL-C (mmol/l) 0.617(0.328, 1.159) (0.342, 1.273) (0.396, 1.597) ApoB (mmol/l) (0.070, 3.570) (0.060, 4.193) (0.075, 8.345) ApoE (mmol/l) (0.992, 1.059) (0.944, 1.018) (0.940, 1.021) LPA (mmol/l) (0.999, 1.003) (0.997, 1.002) (0.996, 1.002) GLU (mmol/l) (0.946, 1.577) (0.879, 1.475) (0.541, 1.111) 0.165

9 Red blood cell-associated indices RBC ( / L) b (0.221, 2.364) (0.037, 1.004) (0.020, 0.998) HGB (g/l) (0.961, 1.029) (0.921, 1.013) (0.923, 1.025) HCT (%) (0.000, ) (0.000, ) (0.000, ) MCV (fl) (0.806, 1.047) (0.907, 1.249) (0.899, 1.267) MCH (pg) (0.922, 1.842) (0.747, 1.681) (0.878, 2.243) MCHC (g/l) (0.974, 1.027) (0.961, 1.027) (0.979, 1.045) Table notes: BMI, body mass index; WBC, white blood cell; Neu (%), percentage of neutrophil; Neu ( 10 9 /L), counts of neutrophil; Mon (%), percentage of monocyte; Mon ( 10 9 /L), counts of monocyte; Lym (%), percentage of lymphocyte; Lym ( 10 9 /L), counts of lymphocyte; Eo (%), percentage of eosinophil; Baso (%), percentage of basophil; Eo ( 10 9 /L), counts of eosinophil; Baso ( 10 9 /L), counts of basophil; Neu/Lym, neutrophil to lymphocyte ratio; Mon/ Lym, monocyte to lymphocyte ratio; PLT/Neu, platelet to neutrophil ratio; PLT/Lym, platelet to lymphocyte ratio; PLT, counts of platelets; PCT, plateletcrit; MPV, Mean platelet volume; INR, international normalized ratio; TCH, total cholesterol; TG, triglyceride; ApoA, apolipoprotein A; ApoB, apolipoprotein B; ApoE, apolipoprotein E; LPA, lipoprotein A; GLU, fasting glucose level; RBC, red blood cell; HGB, hemoglobin; HCT, red blood cell specific volume; MCV, erythrocyte mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration. Odd ratios are calculated from binary logistic analysis. Patients were divided into two groups with slight (1+) and moderate plus severe (2+ plus 3+ ) fibro-encapsulation. aor1, odd ratios after adjusted for gender, age and BMI; aor2, odd ratios after adjusted for gender, age, BMI and NDM/DM status. Bold numbers indicate a P value of < a female as reference. b indice with P<0.05, but the value of aor ratio (95% CI) includes /close to

10 e-table 4. Association of immune and biochemical indices with sputum bacteria counts in 139 SP-TB (67NDM, 72DM) patients. Parameters Sputum bacteria counts Odd Ratio (95% CI) P Odd Ratio 1 (95%CI) P Odd Ratio 2 (95%CI) P Demographic indices Male a (0.184, 1.117) (0.188, 1.205) (0.154, 1.075) Age (year) (0.975, 1.029) (0.969, 1.026) (0.966, 1.025) Height (cm) (0.955, 1.044) (0.992, 1.148) (0.993, 1.154) Weight (Kg) (0.946, 1.014) (0.975, 1.199) (0.971, 1.204) BMI b (0.825, 1.040) (0.827, 1.049) (0.767, 0.995) Immune cell and inflammatory indices Neu (%) (0.991, 1.064) (0.987, 1.068) (0.982, 1.064) Lym (%) (0.933, 1.013) (0.929, 1.016) (0.929, 1.018) Lym ( 10 9 /L) (0.670, 1.993) (0.784, 2.719) (0.707, 2.600) Mon (%) (0.941, 1.231) (0.956, 1.273) (0.967, 1.310) Eo ( 10 9 /L) (0.001, 1.004) (0.002, 1.409) (0.002, 1.512) Baso ( 10 9 /L) (0.000, 1.020) (0.000, ) (0.000, ) Neu/Lym (0.975, 1.145) (0.955, 1.144) (0.955, 1.143) PLT/Lym (1.000, 1.004) (0.999, 1.004) (0.999, 1.005) PLT/Neu (0.986, 1.010) (0.982, 1.008) (0.985, 1.014) CRP (mg/l) b (1.001, 1.018) (1.002, 1.021) (1.001, 1.020) ESR (mm/h) b (1.006, 1.029) (1.007, 1.032) (1.005, 1.031) Immune globins and complements IGG (g/l) (0.988, 1.181) (0.994, 1.197) (0.971, 1.182) IGA (g/l) (0.897, 1.457) (0.928, 1.567) (0.877, 1.513) IGM (g/l) (0.472, 1.337) (0.443, 1.277) (0.382, 1.204) C3 (g/l) (0.579, 4.995) (0.716, 7.769) (0.362, 4.854) C4 (g/l (0.015, ) (0.014, ) (0.002, 6.252) TRF (g/l) (0.403, 1.269) (0.427, 1.428) (0.305, 1.146) Platelet and coagulation indices PLT ( 10 9 /L) b (1.001, 1.009) (1.002, 1.010) (1.002, 1.010) PT (seconds) (0.703, 1.369) (0.685, 1.385) (0.715, 1.488) INR (0.250, ) (0.200, ) (0.436, ) Fibrinogen (g/l) (0.844, 1.472) (0.872, 1.577) (0.826, 1.541) D-Dimmer (ng/ml) (1.000, 1.000) (1.000, 1.000) (1.000, 1.000) FDP (mg/l) (0.984, 1.089) (0.985, 1.095) (0.990, 1.114) Glucose and lipid-associated indices TCH (mmol/l) (0.676, 1.359) ( 0.695, 1.486) (0.632, 1.425) TG (mmol/l) (0.755, 3.179) (0.839, 4.064) (0.920, 4.845) HDL-C (mmol/l) (0.163, 1.399) (0.113, 1.107) (0.112, 1.137) LDL-C (mmol/l) (0.730, 1.630) (0.774, 1.875) (0.659, 1.698) ApoB (mmol/l) (0.465, 6.929) (0.593, ) (0.429, ) ApoE (mmol/l) (0.986, 1.036) (0.979, 1.032) (0.983, 1.038) LPA (mmol/l) (0.999, 1.001) (0.999, 1.001) (0.998, 1.001) 0.562

11 GLU (mmol/l) (0.956, 1.132) (0.976, 1.187) (0.871, 1.105) GA-L (%) (0.995, 1.086) (1.005, 1.107) (0.944, 1.077) Red blood cell-associated indices RBC ( / L) (0.560, 1.526) (0.612, 2.041) (0.498, 1.767) HGB (g/l) b (0.958, 0.995) (0.955, 1.000) (0.949, 0.996) MCHC (g/l) (0.971, 1.027) (0.976, 1.037) (0.968, 1.031) Table notes: BMI, body mass index; Neu (%), percentage of neutrophil; Lym (%), percentage of lymphocyte; Lym ( 10 9 /L), counts of lymphocyte; Mon (%), percentage of monocyte; Eo ( 10 9 /L), counts of eosinophil; Baso ( 10 9 /L), counts of basophil; Neu/Lym, neutrophil to lymphocyte ratio; PLT/Lym, platelet to lymphocyte ratio; PLT/Neu, platelet to neutrophil ratio; CRP, C- reactionprotein; ESR, erythrocyte sedimentation rate; IGG, Immunoglobulin G; IGA, Immunoglobulin A; IGM, Immunoglobulin M; C3, complement component 3; C4, complement component 4; TRF, transferrin; PLT, counts of platelets; PT, prothrombin time; INR, international normalized ratio; FDP, Fibrinogen degradation product; TCH, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; ApoB, apolipoprotein B; ApoE, apolipoprotein E; GLU, fasting glucose level; GA-L (%), percentage of glycosylated hemoglobin; RBC, red blood cell; HGB, hemoglobin; MCHC, mean corpuscular hemoglobin concentration. Odd ratios are calculated from binary logistic analysis. Patients were divided into two groups according to less (class 1 and 2) and more (class 3 and 4 ) sputum bacteria amounts. aor1, odd ratios after adjusted for gender, age and BMI; aor2, odd ratios after adjusted for gender, age, BMI and NDM/DM status. Bold numbers indicate a P value of < a female as reference; b indice with P<0.05, but the value of aor ratio (95% CI) includes /close to

Hamilton Regional Laboratory Medicine Program

Hamilton Regional Laboratory Medicine Program Created: April 2002 of Review: February 2004 of Review: June 2006 of Review: July 2007, St. Joseph s Healthcare went live with Meditech as of June18, 2007. of Review: August 2009 of Review: December 2011;