The timing of onset of symptoms in people with idiopathic pulmonary fibrosis: a UK general population-based case-control study – Supplementary material

Thomas Hewson, BMedSci

Tricia M McKeever, PhD

Jack E Gibson, PhD

Vidya Navaratnam, PhD

Richard B Hubbard, DM

John P Hutchinson, BMBS

- Summary of patient population and Consort diagram of numbers of exclusions

- Additional tables and figures for cough, consultations for heart failure, consultations for

COPD, sensitivity analyses

- Read codes for exclusions

Summary of patient population

Cases Controls n (%) n (%) Sex Male 1,301 (63.1) 4,580 (63.7)

Female 761 (36.9) 2,607 (36.3) Age group <55 years 87 (4.2) 277 (3.9)

55-64 years 234 (11.4) 803 (11.2) 65-74 years 638 (30.9) 2,227 (31.0)

75-84 years 803 (38.9) 2,864 (39.9) >84 years 300 (14.6) 1,016 (14.1) Smoking category* Current 348 (18.3) 1,158 (18.2)

Ex 810 (42.5) 1,923 (30.3) Never 746 (39.2) 3,269 (51.5) *based on latest record of smoking status prior to diagnosis A Consort diagram of patient selection is shown below. Controls were identified as a 4:1 incidence density sample, matched on age (year of age rather than age-band), sex and GP practice. Each case could have up to four possible controls.

Consort diagram of patient selection

13,906 patients from THIN 2,801 cases 11,105 controls 1,415 patients excluded with inadequate length of data pre-diagnosis (already applied to cases

12,491 patients when selected) 2,801 cases 9,690 controls 96 patients excluded aged 40 or below

12,395 patients 2,774 cases 9,621 controls 153 cases excluded with use of amiodarone or methotrexate 12,242 patients 2,621 cases 9,621 controls 551 cases excluded with record suggesting alternative cause for pulmonary fibrosis 11,691 patients 2,070 cases 9,621 controls 2,442 further patients excluded: cases with no controls, or controls with no case (predominantly) 9,249 patients fibrosis 2,062 cases 7,187 controls Table e2 - Number of IPF cases and controls with consultations for cough within five one-year periods prior to diagnosis date

Years pre- Number with Number (%) with Unadjusted OR Adjusted OR† p value diagnosis adequate records consultation for cough (95% CI) (95% CI) in each time period in each time period Control 7,187 728 (10.1) 1.00 1.00 0-1 Case 2,062 652 (31.6) 4.49 (3.95-5.12) 4.35 (3.79-4.98) <0.001 Control 6,660 591 (8.9) 1.00 1.00 1-2 Case 1,951 363 (18.6) 2.51 (2.16-2.91) 2.40 (2.06-2.81) <0.001 Control 6,187 529 (8.6) 1.00 1.00 2-3 Case 1,859 296 (15.9) 2.11 (1.80-2.48) 2.02 (1.71-2.38) <0.001 Control 5,799 433 (7.5) 1.00 1.00 3-4 Case 1,775 235 (13.2) 1.95 (1.64-2.33) 1.80 (1.51-2.16) <0.001 Control 5,351 370 (6.9) 1.00 1.00 4-5 Case 1,671 206 (12.3) 1.99 (1.65-2.40) 1.78 (1.47-2.17) <0.001 † Adjusted for smoking status

Figure e1 - Number of consultations for cough for IPF cases (right panel) and single matched controls (left panel) over five years prior to diagnosis date

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Table e3 - Number of IPF cases and controls with consultations for heart failure within five one-year periods prior to diagnosis date

Years pre- Number with Number (%) with Unadjusted OR Adjusted OR† p value diagnosis adequate records consultation for heart (95% CI) (95% CI) in each time period failure in each time period Control 7,187 94 (1.3) 1.00 1.00 0-1 Case 2,062 148 (7.2) 6.12 (4.63-8.09) 6.09 (4.43-8.37) <0.001 Control 6,660 73 (1.1) 1.00 1.00 1-2 Case 1,951 58 (3.0) 2.85 (2.00-4.06) 2.53 (1.73-3.69) <0.001 Control 6,187 35 (0.6) 1.00 1.00 2-3 Case 1,859 52 (2.8) 5.55 (3.54-8.71) 6.16 (3.73-10.18) <0.001 Control 5,799 47 (0.8) 1.00 1.00 3-4 Case 1,775 36 (2.0) 2.51 (1.60-3.94) 2.52 (1.56-4.05) <0.001 Control 5,351 33 (0.6) 1.00 1.00 4-5 Case 1,671 31 (1.9) 3.09 (1.85-5.16) 2.74 (1.57-4.77) <0.001 † Adjusted for smoking status

Figure e2 - Number of consultations for heart failure for IPF cases (right panel) and single matched controls (left panel) over five years prior to diagnosis date

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Table e4 - Number of IPF cases and controls with consultations for COPD within five one-year periods prior to diagnosis date

Years pre- Number with Number (%) with Unadjusted OR Adjusted OR† (95% p value diagnosis adequate records consultation for COPD (95% CI) CI) in each time period in each time period Control 7,187 136 (1.9) 1.00 1.00 0-1 Case 2,062 149 (7.2) 4.21 (3.30-5.37) 3.68 (2.83-4.79) <0.001 Control 6,660 120 (1.8) 1.00 1.00 1-2 Case 1,951 80 (4.1) 2.36 (1.76-3.16) 1.94 (1.43-2.63) <0.001 Control 6,187 97 (1.6) 1.00 1.00 2-3 Case 1,859 53 (2.9) 1.91 (1.35-2.69) 1.51 (1.05-2.17) 0.027 Control 5,799 92 (1.6) 1.00 1.00 3-4 Case 1,775 51 (2.9) 1.86 (1.30-2.65) 1.51 (1.05-2.19) 0.028 Control 5,351 68 (1.3) 1.00 1.00 4-5 Case 1,671 38 (2.3) 1.80 (1.20-2.71) 1.45 (0.94-2.23) 0.089 † Adjusted for smoking status

Figure e3 - Number of consultations for COPD for IPF cases (right panel) and single matched controls (left panel) over five years prior to diagnosis date

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Table e5 - Number of IPF cases and controls with consultations for breathlessness (SOB) within five one-year periods prior to diagnosis date (never smokers only)

Years pre- Number with Number (%) with Odds ratio p value diagnosis adequate records consultation for SOB (95% CI) in each time period in each time period Control 1,389 72 (5.2) 1.00 0-1 Case 647 288 (44.5) 17.29 (12.01-24.89) <0.001 Control 1,280 53 (4.1) 1.00 1-2 Case 607 100 (16.5) 5.36 (3.65-7.86) <0.001 Control 1,183 45 (3.8) 1.00 2-3 Case 571 67 (11.7) 4.05 (2.64-6.22) <0.001 Control 1,107 23 (2.1) 1.00 3-4 Case 540 43 (8.0) 5.09 (2.90-8.92) <0.001 Control 1,026 15 (1.5) 1.00 4-5 Case 504 46 (9.1) 7.89 (4.15-15.01) <0.001

Table e6 - Number of IPF cases and controls with consultations for cough within five one-year periods prior to diagnosis date (never smokers only)

Years pre- Number with Number (%) with Odds ratio p value diagnosis adequate records consultation for cough (95% CI) in each time period in each time period Control 1,389 144 (10.4) 1.00 0-1 Case 647 236 (36.5) 5.29 (4.06-6.90) <0.001 Control 1,280 97 (7.6) 1.00 1-2 Case 607 122 (20.1) 3.48 (2.54-4.76) <0.001 Control 1,183 109 (9.2) 1.00 2-3 Case 571 93 (16.3) 2.13 (1.55-2.91) <0.001 Control 1,107 84 (7.6) 1.00 3-4 Case 540 82 (15.2) 2.45 (1.75-3.44) <0.001 Control 1,026 72 (7.0) 1.00 4-5 Case 504 73 (14.5) 2.42 (1.69-3.48) <0.001

Table e7 - Number of IPF cases and controls with consultations for breathlessness (SOB) within five one-year periods prior to diagnosis date (excluding those with any record for heart failure or COPD prior to diagnosis date)

Years pre- Number with Number (%) with Unadjusted OR Adjusted OR† p value diagnosis adequate records consultation for SOB (95% CI) (95% CI) in each time period in each time period Control 6,635 265 (4.0) 1.00 1.00 0-1 Case 1,590 628 (39.5) 19.95 (15.98-24.89) 19.00 (15.05-23.99) <0.001 Control 4,771 145 (3.0) 1.00 1.00 1-2 Case 1,500 184 (12.3) 5.17 (4.05-6.60) 4.77 (3.71-6.13) <0.001 Control 4,424 125 (2.8) 1.00 1.00 2-3 Case 1,425 118 (8.3) 3.26 (2.50-4.25) 2.91 (2.20-3.85) <0.001 Control 4,129 94 (2.3) 1.00 1.00 3-4 Case 1,359 83 (6.1) 3.00 (2.20-4.11) 2.73 (1.97-3.78) <0.001 Control 3,806 74 (1.9) 1.00 1.00 4-5 Case 1,279 73 (5.7) 3.35 (2.36-4.74) 3.17 (2.20-4.58) <0.001 † Adjusted for smoking status

Table e8 - Number of IPF cases and controls with consultations for cough within five one-year periods prior to diagnosis date (excluding those with any record for heart failure or COPD prior to diagnosis date)

Years pre- Number with Number (%) with Unadjusted OR Adjusted OR† p value diagnosis adequate records consultation for cough (95% CI) (95% CI) in each time period in each time period 0-1 Control 6,635 598 (9.0) 1.00 1.00 Case 1,590 492 (30.9) 5.20 (4.44-6.09) 5.09 (4.31-6.00) <0.001 1-2 Control 4,771 375 (7.9) 1.00 1.00 Case 1,500 246 (16.4) 2.44 (2.04-2.93) 2.42 (2.00-2.92) <0.001 2-3 Control 4,424 350 (7.9) 1.00 1.00 Case 1,425 195 (13.7) 1.88 (1.55-2.28) 1.84 (1.51-2.25) <0.001 3-4 Control 4,129 272 (6.6) 1.00 1.00 Case 1,359 149 (11.0) 1.78 (1.44-2.21) 1.71 (1.37-2.13) <0.001 4-5 Control 3,806 229 (6.0) 1.00 1.00 Case 1,279 136 (10.6) 1.92 (1.52-2.42) 1.71 (1.34-2.18) <0.001 † Adjusted for smoking status Read codes for exclusions

14G1.00 H/O: rheumatoid arthritis 14GC.00 History of connective tissue disease 2G27.00 O/E-hands-rheumatoid spindling 38DZ000 Disease activity score 28 joint in rheumatoid arthritis 43F1.00 Rheumatoid factor positive 66H..12 Rheumatism monitoring 66H..13 Rheumatoid arthrit. monitoring 66HB000 Rheumatoid arthritis annual review 7P20300 Delivery of rehabilitation for rheumatoid arthritis 9hR..00 Exception reporting: rheumatoid arthritis quality indicators 9hR0.00 Except rheumatoid arthritis quality indicator: pt unsuitable 9hR1.00 Except rheumatoid arthritis qual indicator: informed dissent 9mM..00 Rheumatoid arthritis monitoring invitation 9mM0.00 Rheumatoid arthritis monitoring invitation first letter 9mM1.00 Rheumatoid arthritis monitoring invitation second letter 9mM2.00 Rheumatoid arthritis monitoring invitation third letter 9mM3.00 Rheumatoid arthritis monitoring verbal invitation 9mM4.00 Rheumatoid arthritis monitoring telephone invitation A521.00 Varicella pneumonitis AD04.00 Toxoplasma pneumonitis AD5..00 Sarcoidosis AD50.00 Sarcoidosis of lung AD51.00 Sarcoidosis of lymph nodes AD52.00 Sarcoidosis of lung with sarcoidosis of lymph nodes AD53.00 Sarcoidosis of skin AD54.00 Sarcoidosis of inferior turbinates AD55.00 Sarcoid arthropathy Cyu0600 [X]Sarcoidosis of other and combined sites F013.00 Meningitis due to sarcoidosis F326300 Multiple cranial nerve palsies in sarcoidosis F371.00 Polyneuropathy in collagen vascular disease F371000 Polyneuropathy in disseminated lupus erythematosus F371200 Polyneuropathy in rheumatoid arthritis F371z00 Polyneuropathy in collagen vascular disease NOS F374900 Polyneuropathy in sarcoidosis F396100 Myopathy due to disseminated lupus erythematosus F396400 Myopathy due to rheumatoid arthritis F396500 Myopathy due to sarcoidosis F396600 Myopathy due to scleroderma F4D3300 Eyelid discoid lupus erythematosus G558300 Sarcoid heart disease G5y7.00 Sarcoid myocarditis G5y8.00 Rheumatoid myocarditis G5yA.00 Rheumatoid carditis H263.00 Pneumonitis, unspecified H35..00 Extrinsic allergic alveolitis H35..11 Hypersensitivity pneumonitis H350.00 Farmers' lung H351.00 Bagassosis H352.00 Bird-fancier's lung H353.00 Suberosis ( cork-handlers' lung ) H354.00 Malt workers' lung H355.00 Mushroom workers' lung H356.00 Maple bark strippers' lung H357.00 "Ventilation" pneumonitis H35y.00 Other allergic alveolitis H35yz00 Other allergic alveolitis NOS H35z.00 Allergic alveolitis and pneumonitis NOS H35z000 Allergic extrinsic alveolitis NOS H35z100 Hypersensitivity pneumonitis NOS H35zz00 Allergic alveolitis and pneumonitis NOS H4...00 Lung disease due to external agents H4...11 Pneumoconioses H4...12 Occupational lung disease H40..00 Coal workers' pneumoconiosis H41..00 Asbestosis H410.00 Pleural plaque disease due to asbestosis H410.11 Asbestos-induced pleural plaque H41z.00 Asbestosis NOS H42..00 Silica and silicate pneumoconiosis H420.00 Talc pneumoconiosis H421.00 Simple silicosis H422.00 Complicated silicosis H423.00 Massive silicotic fibrosis H42z.00 Silica pneumoconiosis NOS H43..00 Pneumoconiosis due to other inorganic dust H430.00 Aluminosis of lung H431.00 Bauxite fibrosis of lung H432.00 Berylliosis H433.00 Graphite fibrosis of lung H434.00 Siderosis H435.00 Stannosis H43z.00 Pneumoconiosis due to inorganic dust NOS H44..00 Pneumopathy due to inhalation of other dust H45..00 Pneumoconiosis NOS H450.00 Pneumoconiosis associated with tuberculosis H46..00 Respiratory disease due to chemical fumes and vapours H48..00 Progressive massive fibrosis H4y..00 Other specified lung diseases due to external agent H4y0.00 Acute pulmonary radiation disease H4y1.00 Chronic pulmonary radiation disease H4y1000 Chronic pulmonary fibrosis following radiation H4y1z00 Chronic pulmonary radiation disease NOS H4y2.00 Drug-induced interstitial lung disorders H4y2000 Acute drug-induced interstitial lung disorders H4y2100 Chronic drug-induced interstitial lung disorders H4yz.00 External agent causing respiratory conditions NOS H4z..00 Pulmonary alveolar proteinosis H561.00 Idiopathic pulmonary haemosiderosis H562.00 Pulmonary alveolar microlithiasis H564.00 Bronchiolitis obliterans organising pneumonia H564.11 Cryptogenic organising pneumonia H57..00 Lung involvement in diseases EC H570.00 Rheumatoid lung H571.00 Rheumatic pneumonia H572.00 Lung disease with systemic sclerosis H57y.00 Lung disease with diseases EC H57y000 Pulmonary amyloidosis H57y100 Lung disease with polymyositis H57y200 Pulmonary sarcoidosis H57y400 Lung disease with systemic lupus erythematosus H58y500 Respiratory bronchiolitis associated interstitial lung dis H58y600 Interstitial lung disease due to collagen vascular disease H58y700 Interstitial lung disease due to connective tissue disease Hyu4.00 [X]Lung diseases due to external agents Hyu4000 [X]Pneumoconiosis due to other dust containing silica Hyu4100 [X]Pneumoconiosis due to other specified inorganic dusts Hyu4300 [X]Hypersensitivity pneumonitis due to other organic dusts Hyu4800 [X]Chronic+other pulmonary manifestations due to radiation Hyu4900 [X]Respiratory conditions/other specified external agents Hyu4A00 [X]Respiratory conditions due to unspecified external agent J63A.00 Hepatic granulomas in sarcoidosis K01x400 Nephrotic syndrome in systemic lupus erythematosus K01x411 Lupus nephritis M154.00 Lupus erythematosus M154000 Lupus erythematosus chronicus M154100 Discoid lupus erythematosus M154200 Lupus erythematosus migrans M154300 Lupus erythematosus nodularis M154400 Lupus erythematosus profundus M154500 Lupus erythematosus tumidus M154600 Lupus erythematosus unguium mutilans M154700 Subacute cutaneous lupus erythematosus M154z00 Lupus erythematosus NOS M210.00 Circumscribed scleroderma M210000 Unspecified circumscribed scleroderma M210400 Linear scleroderma M210z00 Circumscribed scleroderma NOS Myu7800 [X]Other local lupus erythematosus N....00 Musculoskeletal and connective tissue diseases N....11 Connective tissue diseases N00..00 Diffuse diseases of connective tissue N00..11 Collagen diseases N000.00 Systemic lupus erythematosus N000000 Disseminated lupus erythematosus N000300 Systemic lupus erythematosus with organ or sys involv N000400 Systemic lupus erythematosus with pericarditis N000500 Neonatal lupus erythematosus N000z00 Systemic lupus erythematosus NOS N001.00 Scleroderma N001.11 Acrosclerosis N001.12 Systemic sclerosis N001000 Progressive systemic sclerosis N001100 CREST syndrome N003.00 Dermatomyositis N003.11 Poikilodermatomyositis N003000 Juvenile dermatomyositis N003100 Dermatopolymyositis in neoplastic disease N003X00 Dermatopolymyositis, unspecified N004.00 Polymyositis N00y.00 Other specified diffuse collagen diseases N00z.00 Collagen disease NOS N04..00 Rheumatoid arthritis and other inflammatory polyarthropathy N040.00 Rheumatoid arthritis N040000 Rheumatoid arthritis of cervical spine N040100 Other rheumatoid arthritis of spine N040200 Rheumatoid arthritis of shoulder N040300 Rheumatoid arthritis of sternoclavicular joint N040400 Rheumatoid arthritis of acromioclavicular joint N040500 Rheumatoid arthritis of elbow N040600 Rheumatoid arthritis of distal radio-ulnar joint N040700 Rheumatoid arthritis of wrist N040800 Rheumatoid arthritis of MCP joint N040900 Rheumatoid arthritis of PIP joint of finger N040A00 Rheumatoid arthritis of DIP joint of finger N040B00 Rheumatoid arthritis of hip N040C00 Rheumatoid arthritis of sacro-iliac joint N040D00 Rheumatoid arthritis of knee N040E00 Rheumatoid arthritis of tibio-fibular joint N040F00 Rheumatoid arthritis of ankle N040G00 Rheumatoid arthritis of subtalar joint N040H00 Rheumatoid arthritis of talonavicular joint N040J00 Rheumatoid arthritis of other tarsal joint N040K00 Rheumatoid arthritis of 1st MTP joint N040L00 Rheumatoid arthritis of lesser MTP joint N040M00 Rheumatoid arthritis of IP joint of toe N040N00 Rheumatoid vasculitis N040P00 Seronegative rheumatoid arthritis N040Q00 Rheumatoid bursitis N040R00 Rheumatoid nodule N040S00 Rheumatoid arthritis - multiple joint N040T00 Flare of rheumatoid arthritis N042.00 Other rheumatoid arthropathy + visceral/systemic involvement N042000 Rheumatic carditis N042100 Rheumatoid lung disease N042200 Rheumatoid nodule N042z00 Rheumatoid arthropathy + visceral/systemic involvement NOS N043.00 Juvenile rheumatoid arthritis - Still's disease N043000 Juvenile rheumatoid arthropathy unspecified N043100 Acute polyarticular juvenile rheumatoid arthritis N043200 Pauciarticular juvenile rheumatoid arthritis N043300 Monarticular juvenile rheumatoid arthritis N043z00 Juvenile rheumatoid arthritis NOS N044.00 Chronic post-rheumatic arthropathy N044.12 Nodular fibrositis of chronic rheumatic disease N045500 Juvenile rheumatoid arthritis N047.00 Seropositive errosive rheumatoid arthritis N04X.00 Seropositive rheumatoid arthritis, unspecified N04y000 Rheumatoid lung N04y011 Caplan's syndrome N04y012 Fibrosing alveolitis associated with rheumatoid arthritis N233200 Myositis in sarcoidosis Nyu1000 [X]Rheumatoid arthritis+involvement/other organs or systems Nyu1100 [X]Other seropositive rheumatoid arthritis Nyu1200 [X]Other specified rheumatoid arthritis Nyu1G00 [X]Seropositive rheumatoid arthritis, unspecified Nyu4.00 [X]Systemic connective tissue disorders Nyu4300 [X]Other forms of systemic lupus erythematosus Nyu4400 [X]Other dermatomyositis Nyu4500 [X]Other forms of systemic sclerosis Nyu4700 [X]Other systemic diseases of connective tissue Nyu4800 [X]Dermato(poly)myositis in neoplastic disease CE Nyu4C00 [X]Systemic disorders/connective tissue in other diseases CE Nyu4E00 [X]Dermatopolymyositis, unspecified Nyu4F00 [X]Mixed connective tissue disease Nyu8900 [X]Myositis in sarcoidosis classified elsewhere Nz...00 Musculoskeletal and connective tissue diseases NOS Q471100 Scleroderma in newborn

Plus any prescription reference for methotrexate or amiodarone