SUPPLEMENTARY MATERIAL Risk of cancer in patients with thyroid disease and venous thromboembolism

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1 SUPPLEMENTARY MATERIAL Risk of cancer in patients with thyroid disease and venous thromboembolism Diana H Christensen 1 Katalin Veres 1 Anne G Ording 1 Jens Otto L Jørgensen 2 Suzanne C Cannegieter 3 Reimar W Thomsen 1 Henrik T Sørensen 1 1 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark 2 Department of Endocrinology and Internal medicine, Aarhus University Hospital, Aarhus, Denmark 3 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands Table S1: International Classification of Diseases, Eighth Revision (ICD-8) and Tenth Revision (ICD-10) codes used in this study. Table S2: Site-specific standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, by follow-up interval, Denmark, Table S3: Site-specific standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism, by follow-up interval, Denmark, Table S4: Standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, Denmark, , stratified by follow-up of 0-30 days vs days. Table S5: Standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism, Denmark, , stratified by follow-up of 0-30 days vs days Table S6: 1-year standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, excluding cancers detected within the first 30 days after VTE, Denmark, Table S7: 1-year standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism, excluding cancers detected within the first 30 days after VTE, Denmark, Table S8: Absolute one-year cancer risk and standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism (N=575), by follow-up interval, Denmark, , restricted to patients with a maximum of 2 years between first hypothyroid disease diagnosis and first VTE diagnosis. Table S9: Standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, Denmark, , stratified by follow-up of 0-30 days vs days,

2 restricted to patients with a maximum of 2 years between first hypothyroid disease diagnosis and first VTE diagnosis. Table S10: 1-year standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, excluding cancers detected within the first 30 days after VTE, Denmark, , restricted to patients with a maximum of 2 years between first hypothyroid disease diagnosis and first VTE diagnosis. Table S11: Absolute one-year cancer risk and standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism (N=637), by follow-up interval, Denmark, , restricted to patients with a maximum of 2 years between first hyperthyroid disease diagnosis and first VTE diagnosis. Table S12: Standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism, Denmark, , stratified by follow-up of 0-30 days vs days, restricted to patients with a maximum of 2 years between first hyperthyroid disease diagnosis and first VTE diagnosis. Table S13: 1-year standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism excluding cancers detected within the first 30 days after VTE, Denmark, , restricted to patients with a maximum of 2 years between first hyperthyroid disease diagnosis and first VTE diagnosis.

3 Table S1. International Classification of Diseases, Eighth Revision (ICD-8) and Tenth Revision (ICD-10) codes used in this study. Venous thromboembolism Deep venous thrombosis ICD-8: ICD-10: I Pulmonary embolism ICD-8: ICD-10: I26 Thyroid disease Hypothyroidism ICD-8: , , , , ICD-10: E03.2-E03.9, E06.3, E06.5 Hyperthyroidism ICD-8: ICD-10: E05 (excluding E05.4), H052, H062 Cancer ICD-10: DC00.x-DC97.x We grouped cancers as specified in the Annual Cancer Report published by the Danish National Board of Health (available at: /media/sds/filer/find-tal-og-analyser/sygdomme/cancerregisteret/cancerregisteret og-2006.pdf ), excluding carcinoma in situ of the breast, dysplasia and carcinoma in situ of the uterine cervix, mola and neoplasma placenta, polycythemia vera, myelodysplastic syndromes, and other not-otherwise-specified neoplasms of lymphoid and hematopoietic tissue. Charlson Comorbidity Index Score 1 (1 point) Myocardial infarction ICD-8: 410 ICD-10: I21, I22, I23 Congestive heart failure ICD-8: , , , , , ICD-10: I50, I11.0, I13.0, I13.2 Peripheral vascular disease ICD-8: 440, 441, 442, 443, 444, 445 ICD-10: I70, I71, I72, I73, I74, I77 Cerebrovascular disease ICD-8: ICD-10: I60-I69, G45, G46 Dementia ICD-8: , ICD-10: F00-F03, F05.1, G30 Chronic pulmonary disease ICD-8: , ICD-10: J40-J47, J60-J67, J68.4, J70.1, J70.3, J84.1, J92.0, J96.1, J98.2, J98.3 Connective tissue disease ICD-8: 712, 716, 734, 446, ICD-10: M05, M06, M08, M09, M30, M31, M32, M33, M34, M35, M36, D86 Ulcer disease ICD-8: , , ICD-10: K22.1, K25-K28 Mild liver disease ICD-8: 571, , ICD-10: B18, K70.0-K70.3, K70.9, K71, K73, K74, K76.0 Diabetes type 1 and 2 ICD-8: ICD-10: E10-E14, O24 (except O24.4), H36.0 Score 2 (2 points) Hemiplegia ICD-8: 344 ICD-10: G81, G82 Moderate to severe renal disease ICD-8: 403, 404, , 584, , , , 792 ICD-10: 12, I13, N00-N05, N07, N11, N14, N17-N19, Q61 Diabetes mellitus with end-organ damage ICD-8: , , , ICD-10: E10.2-E10.8, E11.2-E11.8

4 Score 3 (3 points) Moderate to severe liver disease ICD-8: , , , , , , ICD-10: B15.0, B16.0, B16.2, B19.0, K70.4, K72, K76.6, I85 Score 6 (6 points) AIDS ICD-8: ICD-10: B21-B24 Classic provoking/risk factors for VTE Pregnancy ICD-8: ICD-10: O00-O99 Fractures/trauma ICD-8: , ICD-10: S00-T14 Surgery Danish Classification of Surgical Procedures: all codes ( ) NOMESCO Classification of surgical Procedures: All K-codes excluding minor procedures. Obesity ICD-8: ICD-10: E65, E66.0, E66.1, E66.2, E66.8, E66.9 Abbreviations: ICD = International Classification of Diseases, AIDS = Acute immunodeficiency syndrome

5 Supplementary Table S2. Site-specific standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, by follow-up interval, Denmark, days days 0-1 year 1+ year Cancer site N - cancers O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) Large intestine including 12 3/ (1.17; 16.57) 1/ (0.02; 3.91) 4/ (0.56; 5.24) 8/ (0.37; 1.69) rectosigmoid colon Lung, bronchi and trachea / (0.16; 4.69) 2/ (0.11; 3.41) 16/ (0.92; 2.60) Other skin cancer (excluding 7 1/ (0.09; 20.28) 1/ (0.03; 7.50) 2/ (0.24; 7.10) 5/ (0.33; 2.39) basal cell carcinoma) Breast / (0.48; 4.50) 4/ (0.35; 3.29) 16/ (0.59; 1.68) Ovary 5 2/ (1.79; 53.44) 0-2/ (0.48; 14.42) 3/ (0.26; 3.68) Urinary bladder / (0.04; 9.90) 1/ (0.03; 7.24) 10/ (1.36; 5.22) Non-Hodgkin malignant 14 2/ (1.28; 38.25) 6/ (4.34; 25.76) 8/ (4.95; 22.62) 6/ (0.67; 4.00) lymphoma Basal cell carcinoma 31 1/ (0.02; 4.64) 1/ (0.01; 1.72) 2/ (0.05; 1.63) 29/ (0.91; 1.95) Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval Note: Only cancer sites with a minimum of 5 observed cases overall are shown.

6 Supplementary Table S3. Site-specific standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism, by follow-up interval, Denmark, days days 0-1 year 1+ year Cancer site N - cancers O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) Large intestine including 25 4/ (1.76; 16.53) 4/ (0.66; 6.23) 8/ (1.52; 6.96) 17/ (0.85; 2.34) rectosigmoid colon Rectum / (0.73; 3.32) Pancreas 10 3/ (3.34; 47.32) 1/ (0.05; 11.22) 4/ (1.60; 15.02) 6/ (0.63; 3.72) Lung, bronchi and trachea 26 4/ (1.60; 15.04) 2/ (0.13; 3.97) 6/ (0.88; 5.23) 20/ (0.93; 2.34) Malignant melanoma / (0.54; 3.89) Other skin cancer (excluding / (0.30; 8.86) 2/ (0.21; 6.40) 10/ (0.75; 2.90) basal cell carcinoma) Breast / (0.63; 4.55) 5/ (0.46; 3.31) 28/ (1.00; 2.17) Cervix of uterus 7 2/ (3.42; ) 0-2/ (0.94; 28.02) 5/ (1.29; 9.29) Uterus 6 3/ (2.98; 42.24) 1/ (0.05; 10.10) 4/ (1.43; 13.49) 2/ (0.06; 1.88) Ovary 6 3/ (4.04; 57.22) 1/ (0.06; 13.66) 4/ (1.94; 18.26) 2/ (0.09; 2.57) Prostate 13 2/ (0.88; 26.32) 2/ (0.33; 9.86) 4/ (1.08; 10.18) 9/ (0.67; 2.78) Urinary bladder 6 2/ (0.94; 28.05) 1/ (0.04; 8.08) 3/ (0.65; 9.25) 3/ (0.12; 1.73) Non-Hodgkin malignant 7 1/ (0.12; 25.62) 0-1/ (0.03; 7.00) 6/ (0.52; 3.12) lymphoma Metastases and non-specified 7 1/ (0.15; 32.50) 1/ (0.06; 12.32) 2/ (0.39; 11.58) 5/ (0.50; 3.62) cancer in lymph nodes Other cancers with poorly 7 3/ (7.69; ) 2/ (1.17; 34.97) 5/ (5.65; 40.63) 2/ (0.17; 4.96) specified localization and non-specified cancer Basal cell carcinoma 33 1/ (0.02; 4.08) 3/ (0.17; 2.40) 4/ (0.22; 2.04) 29/ (0.70; 1.51) Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval Note: Only cancer sites with a minimum of 5 observed cases overall are shown.

7 Supplementary Table S4. Standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, Denmark, , stratified by follow-up of 0-30 days vs days days days O/E SIR (95% CI) O/E SIR (95% CI) Hypothyroidism 8/ (1.69; 7.70) 6/ (0.57; 3.37) Female 6/ (1.31; 7.75) 6/ (0.69; 4.09) Male 2/ (0.67; 20.13) 0 - Age at venous thromboembolism diagnosis < Age at venous thromboembolism diagnosis / (3.38; 20.05) 3/ (0.49; 6.98) Age at venous thromboembolism diagnosis 75 2/ (0.19; 5.73) 3/ (0.26; 3.71) Comorbidity burden, 1 normal 3/ (0.93; 13.19) 2/ (0.19; 5.64) Comorbidity burden, moderate 4/ (1.14; 10.75) 4/ (0.60; 5.69) Comorbidity burden, high 1/ (0.06; 12.98) 0 - Obesity - 7/ (1.53; 7.87) 5/ (0.47; 3.36) Obesity + 1/ (0.12; 26.04) 1/ (0.06; 13.50) Year of venous thromboembolism diagnosis / (0.10; 20.93) 0 - Year of venous thromboembolism diagnosis / (1.58; 8.10) 6/ (0.65; 3.88) Classic provoking factors, 2 Overall - 8/ (2.22; 10.14) 5/ (0.55; 3.95) Classic provoking factors, Overall + 0-1/ (0.03; 6.01) Recent pregnancy - 8/ (1.69; 7.71) 6/ (0.57; 3.38) Recent pregnancy Recent fracture/trauma - 8/ (1.86; 8.52) 6/ (0.63; 3.73) Recent fracture/trauma Recent surgery - 8/ (2.08; 9.52) 5/ (0.51; 3.70) Recent surgery + 0-1/ (0.03; 7.65) Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; normal = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

8 Supplementary Table S5. Standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism, Denmark, , stratified by follow-up of 0-30 days vs days days days O/E SIR (95% CI) O/E SIR (95% CI) Hyperthyroidism 27/ (7.32; 16.16) 10/ (1.06; 4.07) Female 21/ (6.75; 16.68) 6/ (0.62; 3.66) Male 6/ (4.34; 25.78) 4/ (1.14; 10.75) Age at venous thromboembolism diagnosis < 60 2/ (1.43; 42.57) 0 - Age at venous thromboembolism diagnosis / (7.80; 26.39) 4/ (0.72; 6.75) Age at venous thromboembolism diagnosis 75 13/ (4.71; 15.15) 6/ (0.82; 4.89) Comorbidity burden, 1 normal 10/ (4.91; 18.87) 5/ (0.87; 6.28) Comorbidity burden, moderate 13/ (6.45; 20.73) 3/ (0.31; 4.46) Comorbidity burden, high 4/ (2.83; 26.62) 2/ (0.34; 10.29) Obesity - 26/ (7.41; 16.63) 9/ (0.97; 4.02) Obesity + 1/ (0.18; 39.53) 1/ (0.09; 20.56) Year of venous thromboembolism diagnosis / (0.08; 17.18) 0 - Year of venous thromboembolism diagnosis / (8.06; 18.08) 10/ (1.22; 4.70) Classic provoking factors, 2 Overall - 20/ (6.45; 16.31) 9/ (1.17; 4.87) Classic provoking factors, Overall + 7/ (5.23; 26.85) 1/ (0.03; 5.51) Recent pregnancy - 27/ (7.32; 16.16) 10/ (1.06; 4.07) Recent pregnancy Recent fracture/trauma - 23/ (6.63; 15.71) 10/ (1.17; 4.50) Recent fracture/trauma + 4/ (4.64; 43.72) 0 - Recent surgery - 21/ (6.47; 15.99) 27/ (1.17; 2.58) Recent surgery + 6/ (5.20; 30.88) 4/ (0.33; 3.10) Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; normal = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

9 Supplementary Table S6. 1-year standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, excluding cancers detected within the first 30 days after VTE, Denmark, year minus 30 days O/E SIR (95% CI) Hypothyroidism 35/ (1.23; 2.45) Female 31/ (1.29; 2.69) Male 4/ (0.31; 2.91) Age at venous thromboembolism diagnosis < 60 6/ (1.55; 9.18) Age at venous thromboembolism diagnosis / (0.94; 3.17) Age at venous thromboembolism diagnosis 75 17/ (0.83; 2.30) Comorbidity burden, 1 normal 13/ (1.01; 3.25) Comorbidity burden, moderate 16/ (1.00; 2.83) Comorbidity burden, high 6/ (0.57; 3.39) Obesity - 31/ (1.19; 2.48) Obesity + 4/ (0.51; 4.80) Year of venous thromboembolism diagnosis / (0.82; 4.87) Year of venous thromboembolism diagnosis / (1.13; 2.42) Classic provoking factors, 2 Overall - 30/ ( ) Classic provoking factors, Overall + 5/ (0.33; 2.41) Recent pregnancy - 35/ (1.23; 2.45) Recent pregnancy Recent fracture/trauma - 34/ (1.31; 2.65) Recent fracture/trauma + 1/ (0.01; 2.88) Recent surgery - 30/ (1.26; 2.66) Recent surgery + 5/ (0.43; 3.07) Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; normal = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

10 Supplementary Table S7. 1-year standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism, excluding cancers detected within the first 30 days after VTE, Denmark, year minus 30 days O/E SIR (95% CI) Hyperhyroidism 41/ (1.28; 2.42) Female 28/ (1.02; 2.23) Male 13/ (1.43; 4.59) Age at venous thromboembolism diagnosis < 60 2/ (0.13; 3.92) Age at venous thromboembolism diagnosis / (1.23; 3.38) Age at venous thromboembolism diagnosis 75 22/ (1.05; 2.54) Comorbidity burden, 1 normal 17/ (1.00; 2.76) Comorbidity burden, moderate 22/ (1.41; 3.41) Comorbidity burden, high 2/ (0.07; 2.14) Obesity - 37/ (1.20; 2.36) Obesity + 4/ (0.78; 7.37) Year of venous thromboembolism diagnosis / (0.51; 3.67) Year of venous thromboembolism diagnosis / (1.27; 2.51) Classic provoking factors, 2 Overall - 36/ (1.42; 2.80) Classic provoking factors, Overall + 5/ (0.31; 2.22) Recent pregnancy - 41/ (1.28; 2.42) Recent pregnancy Recent fracture/trauma - 39/ (1.33; 2.57) Recent fracture/trauma + 2/ (0.11; 3.22) Recent surgery - 36/ (1.33; 2.63)

11 Recent surgery + 5/ (0.40; 2.85) Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; normal = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

12 Supplementary Table S8. Absolute one-year cancer risk and standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism (N=575), by follow-up interval, Denmark, , restricted to patients with a maximum of 2 years between first hypothyroid disease diagnosis and first VTE diagnosis. Absolute risk 0-90 days days 0-1 year 1+ year 1 year AR (%) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) (95% CI) Hypothyroidism 2.85 ( ) 5/ ( ) 11/ ( ) 16/ ( ) 53/ ( ) Female - 5/ ( ) 10/ ( ) 15/ ( ) 45/ ( ) Male - 0-1/ ( ) 1/ ( ) 8/ ( ) Age at venous thromboembolism diagnosis < 60 Age at venous thromboembolism diagnosis Age at venous thromboembolism diagnosis / ( ) 5/ ( ) 13/ ( ) - 5/ ( ) 4/ ( ) 9/ ( ) 13/ ( ) - 0-2/ ( ) 2/ ( ) 27/ ( ) Comorbidity burden, 1 low - 2/ ( ) 6/ ( ) 8/ ( ) 25/ ( ) Comorbidity burden, moderate - 2/ ( ) 2/ ( ) 4/ ( ) 24/ ( ) Comorbidity burden, high - 1/ ( ) 3/ ( ) 4/ ( ) 4/ ( ) Obesity - - 4/ ( ) 9/ ( ) 13/ ( ) 49/ ( ) Obesity + - 1/ ( ) 2/ ( ) 3/ ( ) 4/ ( ) Year of venous thromboembolism diagnosis Year of venous thromboembolism diagnosis Classic provoking factors, 2 Overall - - 1/ ( ) 4/ ( ) 5/ ( ) 18/ ( ) - 4/ ( ) 7/ ( ) 11/ ( ) 35/ ( ) - 5/ ( ) 11/ ( ) 16/ ( ) 42/ ( ) Classic provoking factors, / ( )

13 Overall + Recent pregnancy - - 5/ ( ) 11/ ( ) 16/ ( ) 53/ ( ) Recent pregnancy Recent fracture/trauma ( ) 11/ ( ) 16/ ( ) 52/ ( ) Recent fracture/trauma (.-.) ( ) Recent surgery - - 5/ ( ) 11/ ( ) 16/ ( ) 43/35, ( ) Recent surgery / ( ) Abbreviations: AR = absolute risk; O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; low = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

14 Supplementary Table S9. Standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, Denmark, , stratified by follow-up of 0-30 days vs days, restricted to patients with a maximum of 2 years between first hypothyroid disease diagnosis and first VTE diagnosis days days O/E SIR (95% CI) O/E SIR (95% CI) Hypothyroidism 3/ ( ) 2/ ( ) Female 3/ ( ) 2/ ( ) Male Age at venous thromboembolism diagnosis < Age at venous thromboembolism diagnosis / ( ) 2/ ( ) Age at venous thromboembolism diagnosis Comorbidity burden, 1 low 1/ ( ) 1/ ( ) Comorbidity burden, moderate 1/ ( ) 1/ ( ) Comorbidity burden, high 1/ ( ) 0 - Obesity - 2/ ( ) 2/ ( ) Obesity + 1/ ( ) 0 - Year of venous thromboembolism diagnosis / ( ) 0 - Year of venous thromboembolism diagnosis / ( ) 2/ ( ) Classic provoking factors, 2 Overall - 3/ ( ) 2/ ( ) Classic provoking factors, Overall Recent pregnancy - 3/ ( ) 2/ ( ) Recent pregnancy Recent fracture/trauma - 3/ ( ) ( ) Recent fracture/trauma Recent surgery - 3/ ( ) 2/ ( ) Recent surgery Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; low = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

15 Supplementary Table S10. 1-year standardized incidence ratios of cancer in patients with venous thromboembolism and hypothyroidism, excluding cancers detected within the first 30 days after VTE, Denmark, , restricted to patients with a maximum of 2 years between first hypothyroid disease diagnosis and first VTE diagnosis. 0-1 year minus 30 days O/E SIR (95% CI) Hypothyroidism 13/ ( ) Female 12/ ( ) Male 1/ ( ) Age at venous thromboembolism diagnosis < 60 5/ ( ) Age at venous thromboembolism diagnosis / ( ) Age at venous thromboembolism diagnosis 75 2/ ( ) Comorbidity burden, 1 low 7/ ( ) Comorbidity burden, moderate 3/ ( ) Comorbidity burden, high 3/ ( ) Obesity - 11/ ( ) Obesity + 2/ ( ) Year of venous thromboembolism diagnosis / ( ) Year of venous thromboembolism diagnosis / ( ) Classic provoking factors, 2 Overall - 13/ ( ) Classic provoking factors, Overall Recent pregnancy - 13/ ( ) Recent pregnancy Recent fracture/trauma - 13/ ( ) Recent fracture/trauma Recent surgery - 13/ ( ) Recent surgery Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; normal = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

16 Supplementary Table S11. Absolute one-year cancer risk and standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism (N=637), by follow-up interval, Denmark, , restricted to patients with a maximum of 2 years between first hyperthyroid disease diagnosis and first VTE diagnosis. Absolute risk 0-90 days days 0-1 year 1+ year 1 year AR (%) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) O/E SIR (95% CI) (95% CI) Hyperthyroidism 4.12 ( ) 18/ ( ) 8/ ( ) 26/ ( ) 82/ ( ) Female - 15/ ( ) 4/ ( ) 19/ ( ) 65/ ( ) Male - 3/ ( ) 4/ ( ) 7/ ( ) 17/ ( ) Age at venous thromboembolism diagnosis < 60 Age at venous thromboembolism diagnosis Age at venous thromboembolism diagnosis (.-.) (.-.) (.-.) 18/ ( ) - 6/ ( ) 4/ ( ) 10/ ( ) 42/ ( ) - 12/ ( ) 4/ ( ) 16/ ( ) 22/ ( ) Comorbidity burden, 1 low - 9/ ( ) 3/ ( ) 12/ ( ) 57/ ( ) Comorbidity burden, moderate - 7/ ( ) 5/ ( ) 12/ ( ) 21/ ( ) Comorbidity burden, high - 2/ ( ) 0-2/ ( ) 4/ ( ) Obesity / ( ) 7/ ( ) 24/ ( ) 79/ ( ) Obesity + - 1/ ( ) 1/ ( ) 2/ ( ) 3/ ( ) Year of venous thromboembolism diagnosis Year of venous thromboembolism diagnosis Classic provoking factors, 2 Overall - - 1/ ( ) 3/ ( ) 4/ ( ) 32/ ( ) - 17/ ( ) 5/ ( ) 22/ ( ) 50/ ( ) - 15/ ( ) 7/ ( ) 22/ ( ) 60/ ( ) Classic provoking factors, - 3/ ( ) 1/ ( ) 4/ ( ) 22/ ( )

17 Overall + Recent pregnancy ( ) 8/ ( ) 26/ ( ) ( ) Recent pregnancy Recent fracture/trauma / ( ) 8/ ( ) 25/ ( ) 76/ ( ) Recent fracture/trauma + - 1/ ( ) 0-1/ ( ) 6/ ( ) Recent surgery / ( ) 7/ ( ) 23/ ( ) 63/ ( ) Recent surgery + - 2/ ( ) 1/ ( ) 3/ ( ) 119/ ( ) Abbreviations: AR = absolute risk; O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; low = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

18 Supplementary Table S12. Standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism, Denmark, , stratified by follow-up of 0-30 days vs days, restricted to patients with a maximum of 2 years between first hyperthyroid disease diagnosis and first VTE diagnosis days days O/E SIR (95% CI) O/E SIR (95% CI) Hyperthyroidism 12/ ( ) 6/ ( ) Female 11/ ( ) 4/ ( ) Male 1/ ( ) 2/ ( ) Age at venous thromboembolism diagnosis < (.-.) (.-.) Age at venous thromboembolism diagnosis / ( ) 2/ ( ) Age at venous thromboembolism diagnosis 75 8/ ( ) 4/ ( ) Comorbidity burden, 1 low 5/ ( ) 4/ ( ) Comorbidity burden, moderate 6/ ( ) 1/ ( ) Comorbidity burden, high 1/ ( ) 1/ ( ) Obesity - 12/ ( ) 5/ ( ) Obesity (.-.) 1/ ( ) Year of venous thromboembolism diagnosis / ( ) (.-.) Year of venous thromboembolism diagnosis ( ) 6/ ( ) Classic provoking factors, 2 Overall - 9/ ( ) 6/ ( ) Classic provoking factors, Overall + 3/ ( ) 0 - Recent pregnancy - 12/ ( ) 6/ ( ) Recent pregnancy Recent fracture/trauma - 11/ ( ) 6/ ( ) Recent fracture/trauma + 1/ ( ) (.-.) Recent surgery - 10/ ( ) 6/ ( ) Recent surgery + 2/ ( ) 0 - Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; low = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

19 Supplementary Table S13. 1-year standardized incidence ratios of cancer in patients with venous thromboembolism and hyperthyroidism excluding cancers detected within the first 30 days after VTE, Denmark, , restricted to patients with a maximum of 2 years between first hyperthyroid disease diagnosis and first VTE diagnosis. 0-1 year minus 30 days O/E SIR (95% CI) Hyperhyroidism 14/ ( ) Female 8/ ( ) Male 6/ ( ) Age at venous thromboembolism diagnosis < (.-.) Age at venous thromboembolism diagnosis / ( ) Age at venous thromboembolism diagnosis 75 8/ ( ) Comorbidity burden, 1 low 7/ ( ) Comorbidity burden, moderate 6/ ( ) Comorbidity burden, high 1/ ( ) Obesity - 12/ ( ) Obesity + 2/ ( ) Year of venous thromboembolism diagnosis / ( ) Year of venous thromboembolism diagnosis / ( ) Classic provoking factors, 2 Overall - 13/ ( ) Classic provoking factors, Overall Recent pregnancy - 14/ ( ) Recent pregnancy Recent fracture/trauma - 14/ ( ) Recent fracture/trauma (.-.) Recent surgery - 13/ ( ) Recent surgery Abbreviations: O/E = observed number/expected number; SIR = standardized incidence ratio; CI = confidence interval 1 3 categories of comorbidity burden based on the Charlson Comorbidity Index; normal = 0 points, moderate = 1-2 points, and high = 3 or more points. Cancer was excluded from the comorbidity index. 2 Within the 3 months prior to a venous thromboembolism diagnosis.

20