For Peer Review Only Journal: BMJ Open

BMJ Open

Validation of Chronic Obstructive Pulmonary Disease (COPD) recording in the Clinical Practice Research Datalink (CPRD-GOLD)

For peer review only Journal: BMJ Open

Manuscript ID: bmjopen-2014-005540

Article Type: Research

Date Submitted by the Author: 23-Apr-2014

Complete List of Authors: Quint, Jennifer; London School of Hygeine and Tropical Medicine, Epidemiology M�llerova, Hana; GlaxoSmithKline, Epidemiology Department DiSantostefano, Rachael; GlaxoSmithKline, Worldwide Epidemiology Forbes, Harriet; London school of Hygiene and Tropical Medicine, Epidemiology Department Eaton, Susan; MHRA, Clincal Practice Research Datalink Group Hurst, John; UCL Medical School,, Academic Unit of Respiratory Medicine Davis, Kourtney Smeeth, Liam; London School of Hygiene and Tropical Medicine, Epidemiology and Population Health

Primary Subject Respiratory medicine Heading:

Secondary Subject Heading: Epidemiology

RESPIRATORY MEDICINE (see Thoracic Medicine), THORACIC MEDICINE, Keywords: Chronic airways disease < THORACIC MEDICINE, Epidemiology < THORACIC MEDICINE

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1 2 3 Validation of Chronic Obstructive Pulmonary Disease (COPD) recording in the Clinical 4 Practice Research Datalink (CPRD-GOLD) 5 6 Jennifer K Quint 1, Hana Müllerova 2, Rachael L DiSantostefano 3, Harriet Forbes 1, Susan 7 Eaton 4, John R Hurst 5, Kourtney Davis 2, Liam Smeeth 1. 8 9 1Department of Non-communicable disease Epidemiology, London School of Hygiene and 10 Tropical Medicine, London, UK 11 2 Respiratory Epidemiology, GlaxoSmithKline R&D, Uxbridge, UK 12 3 Respiratory Epidemiology, GlaxoSmithKline R&D, RTP, NC USA 13 4 Clinical Practice Research Datalink Group, Medicines and Healthcare products Regulatory 14 Agency, London, UK 15 5UCL RespiratoryFor Medicine, peer Royal Free Campus,review University College only London Medical 16 School, London, UK 17 18 19 20 Corresponding author: 21 Dr. Jennifer K Quint 22 Department of Non-communicable disease Epidemiology 23 London School of Hygiene and Tropical Medicine 24 Keppel Street, London WC1E 7HT 25 Tel: 0207 927 2622 26 Email: [email protected] 27 28

30 Keywords: COPD, diagnosis of COPD, validation, spirometry, electronic health records 31

33 Word count: 3448 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 48

1 2 3 4 5 ABSTRACT (252 words) 6 7 Background: The optimal method of identifying people with COPD from primary care 8 9 records is not known. We assessed the accuracy of different approaches using the Clinical 10 11 Practice Research Datalink (CPRD). 12 13 Methods: Participants were registered with a CPRD practice between 1st January 2004 and 14 15 31 st DecemberFor 2012. Individuals peer were selectedreview for ≥1 of eight algorithmsonly to identify people 16 17 with COPD. General practitioners were sent a brief questionnaire and additional evidence to 18 19 support a COPD diagnosis was requested. All information received was reviewed 20 21 independently by two respiratory physicians whose opinion was taken as gold standard. The 22 23 primary measure of accuracy was the positive predictive value (PPV); the proportion of 24 25 people identified by each algorithm for whom COPD was confirmed. 26 27 Results: Nine hundred and fifty one questionnaires were sent and 738 (78%) returned. After 28 29 quality control, 696 (73.2%) patients were included in the final analysis. All four algorithms 30 31 including a specific COPD diagnostic code performed well. Using a diagnostic code alone 32 33 the PPV was 86.5% (77.5% to 92.3%) while requiring a diagnosis plus spirometry plus 34 35 36 specific medication the PPV was slightly higher at 89.4% (80.7% to 94.5%) but reduced case 37 38 numbers by 10%. Algorithms without specific diagnostic codes had low PPVs (range 12.2% 39 40 to 44.4%). 41 42 Conclusion: Patients with COPD can be accurately identified from UK primary care records 43 44 using specific diagnostic codes. Requiring spirometry or COPD medications only marginally 45 46 improved accuracy. The high accuracy applies since the introduction of an incentivised 47 48 disease register for COPD as part of QOF (Quality and Outcomes Framework) in 2004. 49 50 51 52 53 54 Article Summary: This paper investigates how individuals with COPD can be accurately 55 56 identified in electronic health records using specific COPD codes alone without additional 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 48 BMJ Open

1 2 3 information (i.e. presence of spirometry or respiratory medications). This information is 4 5 essential for appropriate disease management, epidemiological research of COPD and other 6 7 conditions, where COPD is an important co-morbidity. 8 9 10 11 Strengths and limitations of this study: 12 13 - We have shown that the presence of a specific COPD Read code alone is sufficient to 14 15 identify patientsFor with peerCOPD from electronic review health records. only Minimal precision lost by not 16 17 including spirometry and medications in the algorithm, allows an increase in the number 18 19 of individuals who can potentially be included in a study by up to 10%. 20 21 - We were able to investigate both the accuracy of algorithms when identifying COPD 22 23 patients within the CPRD, and accuracy of the actual GP diagnosis of COPD. 24 25 - The amount of missing data among the responding questionnaires was low, suggesting 26 27 reasonable data quality. 28 29 - Although the overall response rate for this study was acceptable (77.6%), the proportion 30 31 of questionnaires accompanied with additional evidence allowing for adjudication was 32 33 lower. 34 35 36 37 38 39 40 No additional data are available. We would be happy to provide the ISAC protocol to 41 42 reviewers if required. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 48

1 2 3 4 5 INTRODUCTION 6 7 Chronic obstructive pulmonary disease (COPD) represents an enormous health burden 8 9 worldwide. Currently COPD is the 4th leading cause of death and is predicted to become the 10 11 3rd by 2020.[1] There are approximately 835,000 people diagnosed with COPD in the UK 12 13 and an estimated 2,200,000 people remain undiagnosed.[2] 14 15 For peer review only 16 17 Electronic health records in the UK provide an excellent resource in which to study COPD as 18 19 they offer a large cohort size, the presence of disease severity indicators and long-term 20 21 follow-up information on a patient’s integrated medical history. Although multiple studies 22 23 have been undertaken to investigate various aspects of COPD over the last 10 years in 24 25 several electronic health record databases, there is no standard definition used to identify 26 27 COPD in large databases and codelists used to identify patients with COPD vary by author. 28 29 Over ten years ago, the diagnosis of COPD was validated in the Clinical Practice Research 30 31 Datalink (CPRD-GOLD, formerly GPRD) using OXMIS codes.[3] This coding system is now 32 33 obsolete in CPRD and Read codes are used as standard. 34 35 36 37 38 There is no single diagnostic test for COPD. The diagnosis of COPD relies on clinical 39 40 judgement based on a combination of history, physical examination and confirmation of the 41 42 presence of airflow obstruction using spirometry.[4] When retrospectively evaluating the 43 44 accuracy of a COPD diagnosis, commonly used COPD definitions may misclassify patients 45 46 as having COPD. Using multiple diagnostic codes in combination with pharmacy may 47 48 improve the accuracy of identification of COPD patients.[5] Further, over the past 10 years 49 50 the definition of COPD in clinical practice has evolved leading to changes in how COPD is 51 52 diagnosed and the diagnosis recorded. With the introduction of the Quality and Outcomes 53 54 Framework (QOF) codes for COPD in 2004 in England and Wales there are more codes 55 56 available to identify COPD then there were previously. Evaluation of airflow limitation using 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 48 BMJ Open

1 2 3 spirometry is used as standard to confirm COPD diagnosis and severity of COPD is part of 4 5 the annual COPD patient review.[3,6] However, even spirometry if incorrectly performed or 6 7 interpreted can lead to misdiagnosis (both over and under diagnosis of COPD) in 8 9 approximately 20% of cases. It is also recognised that some subgroups of individuals (e.g. 10 11 women and individuals under 50 and over 80) are less likely to have spirometry 12 13 measured.[6] 14 15 For peer review only 16 17 This study aimed to improve our ability to identify patients with COPD within electronic health 18 19 records. We used the CPRD, a widely used collection of computerised medical records 20 21 which is commonly used for clinical and research purposes. CPRD is comparable to other 22 23 electronic health record databases used in the UK. Our objective was to test the accuracy of 24 25 different definitions of COPD in the CPRD using Positive Predictive Value (PPV), by 26 27 comparing the database records with additional information provided by General 28 29 Practitioners (GPs). This work is important for epidemiological research in COPD and 30 31 diseases where COPD is an important co-morbidity as well as for clinical practice. 32 33

34 35 METHODS 36 37 Dataset 38 39 CPRD is the world's largest validated computerized database of anonymized longitudinal 40 41 medical records for primary care. [7,8] Data comprise approximately 14 million patients with 42 43 around 5.4 million of these being currently alive and registered from 660 primary care 44 45 46 practices spread throughout the UK. Records are derived from a widely used GP software 47 48 system and contain complete prescribing and coded diagnostic and clinical information as 49 50 well as information on tests requested, laboratory results and referrals made at or following 51 52 on from each consultation. [9] 53 54 55 56 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 48

1 2 3 4 5 Codelists and algorithms 6 7 Lists of medical codes (Read codes) specific and non-specific for COPD were created prior 8 9 to the study initiation. Specific COPD codes consisted of codes listing either COPD or COPD 10 11 specific entities of emphysema (see supplementary material). Non-specific codes consisted 12 13 of a variety of lung diseases that could potentially be COPD e.g. chronic bronchitis. 14 15 CombinationsFor of codelists peer and additional review material in the form ofonly the presence of spirometry 16 17 or COPD medications (see supplementary material) were used to make up the eight 18 19 algorithms. The first four definitions required a specific COPD diagnosis code, with the first 20 21 three requiring additional documentation (e.g., medication and/or spirometry). The other four 22 23 definitions required non-specific bronchitis or respiratory symptom codes, with the least 24 25 specific definition requiring only respiratory symptom codes. Details regarding each 26 27 algorithm can be found in the supplementary material. Briefly, the eight algorithms were 28 29 defined as follows, from the expected most specific to most sensitive construct: 30 31 32 33 34 1. Specific COPD code and more than one prescription of a COPD medication and 35 36 presence of spirometry (COPD Code + spirometry + COPD medication) 37 38 2. Specific COPD code and presence of spirometry (COPD Code + spirometry) 39 40 3. Specific COPD code and more than one prescription of a COPD medication (COPD 41 42 Code + COPD medication) 43 44 4. Specific COPD code only (COPD Code only) 45 46 5. Non-specific bronchitis code and more than one prescription of a COPD medication 47 48 (Bronchitis + COPD medication) 49 50 6. Non-specific bronchitis code only (Bronchitis only) 51 52 7. Respiratory symptoms and presence of spirometry. Respiratory symptoms consisted 53 54 of persistent cough, sputum production, or dyspnoea. (Symptoms + spirometry) 55 56 8. Respiratory symptom definition only (Symptoms only) 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 48 BMJ Open

1 2 3 The presence of spirometry for inclusion in the algorithm was based on an existence of a 4 5 record of a specific value or a Read code for spirometry rather than examining the actual 6 7 value. We were able to assess interpretation of spirometry in the subset of patients who had 8

9 flow volume loops or clinic letters attached and where actual FEV 1 and FVC values were 10 11 available in CPRD. 12 13 14 15 Study PopulationFor peer review only 16 17 The study population consisted of a random sample of individuals selected from all subjects 18 19 registered in CPRD with cohort entry being on or after the 1 st January 2004. At cohort entry, 20 21 people included had to be: over 35 years old, with at least 1 year historical data, and a 22 23 possible diagnosis of COPD defined as evidence of having ever smoked and a record of a 24 25 least one specific or possible COPD code or respiratory symptoms suggestive of COPD. The 26 27 presence of the algorithms was ascertained during a period between patient cohort entry 28 29 and the 31 st December 2012. Patients had to be alive within 4 months of the last collection 30 31 32 date of CPRD data for the January 2013 data build for inclusion in the analysis so that 33 34 CPRD could access their medical records and additional information. For the main analysis, 35 36 a patient could contribute to one algorithm only. It was possible for an individual to be eligible 37 38 for more than one algorithm depending upon the codes used in their medical record over the 39 40 study period. Individuals were randomly selected from the algorithm with the fewest number 41 42 of participants first and then removed from the cohort so they could not be selected for 43 44 another algorithm. 45 46 47 48 CPRD mailed a short, structured questionnaire to GPs in charge of randomly selected 49 50 patients requesting confirmation of COPD status as well as any available specific information 51 52 from the individual’s medical record including spirometry print outs and hospital respiratory 53 54 outpatient letters (see supplementary material). Data were “twice encrypted” within CPRD to 55 56 ensure anonymity; firstly between practices and CPRD and secondly from CPRD to 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 48

1 2 3 researchers. In the questionnaire the GP was asked whether or not the patient had a 4 5 diagnosis of COPD, what that diagnosis was based on, whether or not the patient had seen 6 7 a respiratory physician and if they had any other respiratory diagnoses. A pilot set of 20 8 9 questionnaires were sent to GPs to assess the quality of the questionnaire. In total, 951 10 11 questionnaires were sent out assuming an 80% response rate. 12 13 14 15 Primary outcomeFor peer review only 16 17 The primary outcome was identification of a diagnosis of COPD according to the pre-defined 18 19 eight algorithms. The gold standard for the diagnosis of COPD was the decision made after 20 21 respiratory physicians independently reviewed the evidence (questionnaire response with or 22 23 without- additional evidence). Where they did not agree, a 3 rd independent physician 24 25 decided. Additionally, GP diagnosis of COPD was validated in a subset of patients where the 26 27 GP provided supportive information including spirometry print-outs and hospital letters. This 28 29 also allowed review of spirometry interpretation in some cases. 30 31

32 33 Analysis 34 35 36 The primary analysis focused on the accuracy of identification of a COPD diagnosis in each 37 38 of the pre-defined algorithms as defined by positive predicted value (PPV); i.e. the proportion 39 40 of “true positives” (individuals with COPD) in each algorithm as determined by the gold 41 42 standard. In addition, within each algorithm, where additional information was provided (lung 43 44 function, hospital clinic letters), we calculated the accuracy of the GP diagnosis of COPD 45 46 relative to the gold standard. This allowed review of spirometry interpretation in some cases. 47 48 49 50 We assessed the impact of commonly occurring co-morbidities on the accuracy of the pre- 51 52 specified algorithms stratifying for cardiovascular co-morbidity, previous asthma diagnosis, 53 54 smoking status and, where possible, Global Initiative for Chronic Obstructive Lung Disease 55 56 (GOLD) staging of airflow limitation severity.[10] Cardiovascular co-morbidity included 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 48 BMJ Open

1 2 3 angina, history of myocardial infarction, previous coronary artery bypass graft / percutaneous 4 5 coronary intervention or heart failure, but not hypertension due to its lack of overlap of 6 7 symptoms that could mimic COPD. All covariates for stratification analysis were derived from 8 9 information available up to cohort entry. 10 11 12 13 As a post hoc analysis individuals were eligible to be placed into multiple algorithms where 14 15 possible, andFor the PPV waspeer calculated for review all individuals who had only a specific COPD code 16 17 compared to those with a specific COPD code and additional information (either spirometry 18 19 or a COPD medication). 20 21 22 23 Assessment of possible trends in COPD diagnosis recording were also evaluated, including 24 25 temporal trends in codes used and diagnostic specificity from 2004 to 2011. In addition, we 26 27 compared our specific COPD codes to those recommended for use by QOF (see 28 29 supplementary material); [11,12] H31% (excluding H3101 (smokers cough), H31y0 (chronic 30 31 tracheitis) and H3122 (acute exacerbation of COPD)) H32% H36-H3z (excluding H3y0 and 32 33 H3y1). 34 35 36 37 38 Sample size calculation 39 40 Our sample size for each algorithm was chosen to achieve accuracy of the true positives or 41 42 PPV ±0.08 based on the reviewing physician judgment as the gold standard. Assuming an 43 44 estimated PPV of 0.85 for any one algorithm, we required a sample of at least 77 individuals 45 46 in each algorithm to achieve the desired accuracy (95% CI ±0.08). All analyses were 47 48 performed using STATA 13. 49 50 51 52 Ethics approval was obtained from ISAC (the Independent Scientific Advisory Committee 53 54 overseeing CPRD); protocol 12_065 and the LSHTM ethics committee. 55 56 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 48

1 2 3 RESULTS 4 5 Nine hundred and fifty one questionnaires were sent to GPs (see Figure 1 for patient 6 7 selection). Of those, 738 (77.6%) were returned, 704 (74.0%) met quality control standards 8 9 and were not duplicates, and 696 (73.2%) could be included in the final analysis (8 had 10 11 “uncertain” COPD diagnosis and no supporting documentation and were therefore 12 13 excluded). 14 15 For peer review only 16 Among those included in the final analysis, additional evidence for the diagnosis of COPD 17 18 was available for 272 patients. This represented 39.1% of the total study population, or 19 20 67.7% of the 402 patients with a confirmed COPD diagnosis in the study. 21 22

23 24 25 Overall, irrespective of the qualifying algorithm, 402 patients (57.8%) were considered to 26 27 have a diagnosis of COPD based on reviewing physician judgment. Table 1 shows the 28 29 characteristics of the 696 patients included in the final analysis who were considered to 30 31 possibly have COPD based on the inclusion criteria. On average, patients were in their mid- 32 33 60s to early 70s across all algorithms. Approximately two-thirds of them were current 34 35 smokers and one-quarter had a history of asthma. Generally, there were fewer patients with 36 37 supporting information and cardiovascular co-morbidity in the less specific algorithms (4-8). 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 48 BMJ Open

1 2 3 4 5 Table 1: Characteristics of the 696 patients included in the final study analysis 6 7 Algorithm COPD Code + COPD Code + COPD Code + COPD Bronchitis + Bronchitis Symptoms + Symptoms 8 spirometry + spirometry COPD Code COPD only spirometry only 9 COPD medication medication only medication 10 Number of 85 (100) 79 (100) 88 (100) 89 (100) 98 (100) 84 (100) 83 (100) 90 (100) 11 individuals (%) For peer review only 12 13 Number (%) with 46 (54.1) 44 (55.7) 48 (54.5) 40 (44.9) 32 (32.7) 18 (21.4) 30 (36.1) 14 (15.6) 14 supporting info 15 16 Mean age 68.7 (11.3) 68.3 71.8 71.1 68.5 (13.1) 67.8 (13.4) 65.9 (11.9) 63.4 (14.1) (11.7) 17 (sd) (10.5) (10.4) 18 19 Male (%) 45 (52.9) 41 (51.9) 40 (45.5) 44 (49.4) 31 (31.6) 29 (34.5) 43 (51.8) 47 (52.2) 20 21 Current smoker 49 (57.7) 50 (63.3) 55 (62.5) 47 (52.8) 66 (67.4) 61 (72.6) 48 (57.8) 58 (64.4) 22 (%) 23 24 GOLD stage * 1 13 (16.3) 14 (18.0) 13 (15.9) 16 (20.5) 17 (28.8) 13 (35.1) 8 (20.0) 4 (36.4) 25 (n=465) 26 2 43 (53.8) 48 (61.5) 41 (50.0) 46 (59.0) 31(52.5) 13 (35.1) 22 (55.0) 5 (45.5) 27 3 18 (22.5) 13 (16.7) 22 (26.8) 12 (15.4) 9 (15.3) 8 (21.6) 8 (20.0) 2 (18.2) 28 4 6 (7.5) 3 (3.9) 6 (7.3) 4 (5.1) 2 (3.4) 3 (8.1) 2 (5.0) 0 (0.0) 29 30 History of 20 (23.5) 22 (27.8) 17 (19.3) 18 (20.2) 20 (20.4) 17 (20.2) 14 (16.9) 9 (10.0) 31 cardiovascular 32 disease 33 34 History of asthma 18 (21.2) 20 (25.3) 16 (18.2) 15 (16.9) 27 (27.6) 23 (27.4) 19 (22.9) 23 (25.6) 35 36 Mean BMI (sd ) N=83 N=78 N=86 N=87 N=98 N=85 N=41 N=17 37 (n=575) 27.5 (5.4) 26.7 (5.8) 26.4 (4.7) 27.8 27.4 (5.1) 28.1 (5.0) 27.1 (4.5) 27.6 (4.7) 38 (5.4) 39 *GOLD staging was ascertained from CPRD records or from supplementary information provided by GPs. 40 11 41 42 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 12 of 48

1 2 3 The number of patients diagnosed with COPD confirmed by the gold standard and the PPV 4 5 for each algorithm is given in Table 2 . The PPV was greatest for algorithms 1-4. Further 6 7 data is available in the supplementary material regarding the effect of co-morbidities (Table 8 9 4), smoking status (Table 5) and GOLD staging (Table 6) on the performance of each 10 11 algorithm. 12 13 14 15 For peer review only 16 17 18 19 Table 2 : The PPV and proportion of patients diagnosed with COPD within each algorithm 20 Algorithm Number of Number Number with PPV and 95% CI questionnaires evaluable confirmed 21 sent out returned COPD 22 (n=951) (n=696) (%) 23 COPD Code + spirometry + 119 85 (71.4) 76 89.4, 80.7-94.5 24 COPD medication 25 COPD Code + spirometry 119 79 (66.4) 67 83.8, 73.7-90.4 26 COPD Code + COPD 119 88 (73.9) 77 87.5, 78.6-93.0 27 medication 28 COPD Code only 119 89 (74.8) 77 86.5, 77.5-92.3 29 Bronchitis + COPD medication 119 98 (82.4) 44 44.4, 34.8-54.5 30 Bronchitis only 119 84 (70.6) 26 29.5, 20.8-40.1 31 Symptoms + spirometry 119 83 (69.7) 37 43.5, 33.2-54.4 32 Symptoms only 118 90 (75.6) 11 12.2, 6.8-20.9 33 34 35 36 37 In a subset of 272 patients where additional evidence was available (in the form of 38 39 spirometry print outs or hospital outpatient letters), we assessed accuracy of GP diagnosis of 40 41 COPD. Overall, the PPV in this group was 95.0% (91.1-97.2), This is broken down by 42 43 algorithm in Table 3. While the presence of supporting evidence improved the PPV in each 44 45 group, algorithms 1-4 were still most accurate. 46 47 48 49 50 51 52

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1 2 3 4 5 Table 3: PPV by algorithm where evidence was available to assess GP compared to physician 6 diagnosis of COPD 7 Algorithm Total Number of Number PPV and 95% CI 8 number patients with with COPD with COPD confirmed according 9 evidence by GOLD standard to GP 10 (N=272) (N=220) 11 COPD Code + spirometry + COPD 46 46 46 100 12 medication 13 COPD Code + spirometry 44 35 33 94.3, 82.4-98.9 14 COPD Code + COPD medication 48 43 41 95.3, 82.4-98.9 15 COPD Code onlyFor peer40 review 34 only 33 97.1, 80.2-99.6 16 Bronchitis + COPD medication 32 21 19 90.5, 66.0-97.9 17 Bronchitis only 18 12 11 91.7, 49.9-99.2 18 Symptoms + spiro metry 30 21 20 95.2, 69.1-99.4 19 Symptoms only 14 8 6 75.0, 27.6-95.9 20 21 22 23 24 Post-hoc analysis 25 26 We repeated the analysis allowing individuals to be put into more than one algorithm and 27 28 tested the PPV of COPD by algorithm relative to the gold standard where individuals were 29 30 identified using only the presence of a specific COPD code (n=457) the PPV was identical to 31 32 if they had a COPD code and evidence either in the form of spirometry or COPD medication 33 34 prescription (n=454); PPV 83.0% (79.0-86.0) for both. In the majority of cases, where a 35 36 specific COPD code had been assigned, there was additional evidence. Only 3 individuals 37 38 had a specific COPD code with no additional evidence. 39 40 41 42 43 44 DISCUSSION 45 46 We tested the accuracy of eight different algorithms for identifying COPD within the CPRD 47 48 among patients with suspected COPD (e.g., >35 years of age, smoking history, and 49 50 recording of respiratory symptoms or COPD codes). The physician reviewer consensus was 51 52 the GOLD standard. The best performing algorithm allowed an accurate ascertainment of 53 54 90% of patients as diagnosed with COPD. This consisted of a combination of a specific 55 56 COPD code, more than one prescription of a COPD medication and spirometry (PPV 89.4, 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 48

1 2 3 95% CI: 80.7-94.5). The worst performing algorithm was represented by presence of 4 5 respiratory symptoms only (PPV12.2, 95%CI: 6.8-20.9). We found that any algorithm 6 7 containing a specific COPD code performed better than those without (Algorithms 1-4). In a 8 9 post hoc analysis, where we allowed individuals to populate more than one algorithm, we 10 11 established that the use of additional information such as spirometry or medications in an 12 13 algorithm to a specific COPD Read code alone did not increase the PPV. This suggests that 14 15 the presenceFor of a specific peer COPD Read codereview alone is sufficient onlyto accurately identify patients 16 17 with COPD from the database. Some study protocols require the presence of obstructive 18 19 spirometry for identification of COPD patients; however, this study demonstrates that it may 20 21 be unnecessary. This is particularly important as certain groups of individuals are less likely 22 23 to have spirometry, namely women and patients <50 and >80 years of age. [6] This is also 24 25 important as the minimal precision lost by not including spirometry and medications in the 26 27 algorithm, allows an increase in the number of individuals who can potentially be included in 28 29 a study. Using the whole of CPRD, we identified individuals with COPD using a specific 30 31 COPD code only compared to a specific code plus medication and spirometry and found an 32 33 increase in potential sample size for study of 10% using a specific COPD code only. 34 35 36 37 38 One of the advantages of this study was our ability to investigate both the accuracy of 39 40 algorithms when identifying COPD patients within the CPRD, and accuracy of the actual GP 41 42 diagnosis of COPD. When validating the GP diagnosis of COPD with a respiratory physician 43 44 diagnosis as gold standard based on extra evidence provided by the GP, there was 45 46 improved accuracy (PPV) across all algorithms, with algorithms 1-4 again performing best. 47 48 This suggests that additional evidence is collected when the GP is reasonably certain that 49 50 the patient has COPD. There was good concordance between GP and physician diagnosis 51 52 suggesting respiratory consultant validation is not always needed. Where there was 53 54 disagreement, this was usually because lung function did not meet criteria for COPD. 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 48 BMJ Open

1 2 3 We found that the diagnostic accuracy of COPD decreased across all algorithms when 4 5 patients also had a diagnosis of cardiovascular disease or asthma (Table 4 online 6 7 supplement). When patients had a concomitant diagnosis of asthma, the presence of 8 9 spirometry was particularly important to improve accuracy of COPD diagnosis. However, 10 11 stratification led to smaller sample sizes, which could have impacted the precision of 12 13 estimates. Unsurprisingly, the addition of the use of any inhaled COPD medication to the 14 15 algorithm didFor not improve peer precision, most review likely due to the overlap only in medications used to 16 17 treat both asthma and COPD (see online supplement). The algorithm accuracy was not 18 19 affected by smoking status (current vs. ex-smoker) (Table 5 online supplement). We only 20 21 included current or former smokers in our analysis, and cannot be sure of the validity of the 22 23 results in a patient who has never smoked. Certainly in the UK, the majority of COPD is 24 25 related to tobacco smoking and we hypothesized that fixed airflow obstruction in a non- 26 27 smoker would most likely be due to chronic asthma. 28 29

30 31 When considering the severity of COPD by GOLD classification, algorithms 2 and 3, i.e. a 32 33 specific COPD code and spirometry or COPD medications had the greatest accuracy for 34 35 36 patients with mild disease (GOLD stage 1) (Table 6 online supplement). PPV increased with 37 38 increasing disease severity. PPV increases with disease prevalence, and the prevalence of 39 40 COPD increased moving from algorithm 8 to algorithm 1. 41 42 43 44 We considered the timing of diagnosis in view of an increased uptake of spirometry in 45 46 primary care in more recent years and changes in QOF requirements over time during our 47 48 study period (Table 7 online supplement). We found that algorithms 1-4 still had the greatest 49 50 accuracy, but the PPV estimates were better for the post 2008 period than pre 2008 period 51 52 (see supplementary material). Non-specific bronchitis codes and symptom codes were more 53 54 likely to be used before 2008 rather than post. This may require consideration when 55 56 developing retrospective cohorts for analysis and otherwise suggests QOF has had a 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 48

1 2 3 positive effect on the consistency of codes used for COPD diagnoses. However, our codes 4 5 were more specific than QOF codes and some of the codes included in QOF were not 6 7 included in our specific COPD codelist, but were included in the non-specific bronchitis 8 9 codes. While we cannot comment on the accuracy of QOF codes, it is important to highlight 10 11 that that some QOF codes are not disease specific and may not be a good way of identifying 12 13 COPD patients from electronic health records as inevitably people without COPD will be 14 15 included. It isFor also important peer to highlight reviewthat Read codes change only over time with new codes 16 17 added and some removed, and this needs consideration when identifying people with 18 19 COPD. 20 21 22 23 There are limited COPD validation studies in electronic health records published in the 24 25 literature to which we can compare our study. Soriano validated COPD in the GPRD in 2001, 26 27 when OXMIS codes were still in use. [3] A Swedish study using a Swedish inpatient registry 28 29 used ICD-9 and ICD-10 codes and identified COPD patients with similar accuracy.[13] A 30 31 Canadian study in the Canadian primary care sentinel surveillance network used algorithms 32 33 to identify several long term conditions and also had a PPV similar to ours for COPD [14]. 34 35 36 However, all of these studies used different codes, algorithms and databases. 37 38 39 40 Our analysis has several limitations. Although the overall response rate for this study was 41 42 acceptable (77.6%), the proportion of questionnaires accompanied with additional evidence 43 44 allowing for adjudication was rather low. We chose PPV as the measure of accuracy in this 45 46 study to allow us to determine the probability that a patient had COPD from their electronic 47 48 health record. PPV is correlated with disease prevalence, and although it is strongly related 49 50 to specificity, the actual estimates of specificity, sensitivity and negative predictive value 51 52 cannot be determined from our data. Further, GP practices are self selecting with respect to 53 54 their contribution to CPRD, however those practices appear to be representative of the UK 55 56 population. Very few patients within contributing practices refuse to participate at an 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 48 BMJ Open

1 2 3 individual level and this is not thought to bias the results. While CPRD is representative of 4 5 the general population, as with all validation studies that require a response, we cannot be 6 7 sure that our sample is representative of GPs who have not responded, although there is 8 9 unlikely to be any difference. The amount of missing data among the responding 10 11 questionnaires was low, suggesting reasonable data quality. One of the other limitations of 12 13 this study is that patients had to be alive to be included; however it is unlikely that coding 14 15 would be differentFor for individuals peer who are review no longer alive. only 16 17 18 19 The algorithm that consisted of a specific COPD code, COPD medication and spirometry 20 21 had the highest PPV; however the PPV was almost as high when a specific COPD code 22 23 alone was used. The poorest performing algorithms were those that involved bronchitis 24 25 codes or respiratory symptoms; we would not recommend using these algorithms to identify 26 27 COPD patients. In conclusion, we have shown that the presence of a specific COPD Read 28 29 code alone is sufficient to identify patients with COPD from electronic health records. 30 31 Minimal precision lost by not including spirometry and medications in the algorithm, allows 32 33 an increase in the number of individuals who can potentially be included in a study by up to 34 35 36 10%. However by not including spirometry in the definition, the ability to stage COPD 37 38 according to GOLD stages may not be possible for all COPD patients included in a study. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 48

1 2 3 Acknowledgments: none 4 5 Funding : This project was funded jointly by GSK and the MRC. JKQ is funded on a MRC 6 7 Population Health Scientist Fellowship. This work was part funded by a MRC Industry 8 9 Partnership award (grant number G0902135). 10 11 Contributorship statement : JKQ, HM, RLD, SE, KD and LS contributed to the conception 12 13 and design, JKQ, HM, JH, to acquisition and analysis, JKQ, HM, RLD, HF, SE, JH, KD and 14 15 LS to interpretationFor of data, peer and JKQ, HM, review RLD, HF, SE, JH, KDonly and LS to the drafting of the 16 17 manuscript. JKQ is responsible for the overall content as guarantor. 18 19 Competing interests: There are no competing interests 20 21 Data Sharing Statement: No additional data are available. We would be happy to provide 22 23 the ISAC protocol to reviewers if required. 24 25 26 27 28 29

30 31

32 33

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1 2 3 Figure 1: Study population 4 5 6 7 8 9 REFERENCES 10 11 1. National Statistics. www.statistics.gov.uk date accessed June 2013. 12 13 14 15 2. ShahabFor LM, Jarvis peer MJ, Britton J, reviewet al. Prevalence, diagnosis only and relation to tobacco 16 17 dependence of chronic obstructive pulmonary disease in a nationally representative 18 19 population sample Thorax 2006;61(12):1043 20 21 22 23 3. Soriano JB, Maier WC, Visick G, et al. Validation of general practitioner-diagnosed 24 25 COPD in the UK General Practice. European Journal of Epidemiology 26 27 2001;17:1075–1080 28 29 30 31 4. NICE guideline COPD http://guidance.nice.org.uk/CG101/QuickRefGuide/pdf/English 32 33 date accessed January 2014. 34 35 36 37 5. Cooke CR, Joo MJ, Anderson SM et al. The validity of using ICD-9 codes and 38 39 pharmacy records to identify patients with chronic obstructive pulmonary disease. 40 41 BMC Health Services Research 2011;11:37 42 43 44 45 6. Smith CJP, Gribbin J, Challen KB, et al. The impact of the 2004 NICE guideline and 46 47 2003General Medical Services contract on COPD in primary care in the UK. Q J Med 48 49 2008;101:145–153. 50 51 52 53 7. CPRD http://www.cprd.com (accessed February 28,2013) 54 55

56 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 48

1 2 3 8. Williams T, VanStaa T, Padmanabhan S et al. Recent advances in utility and use of 4 5 the General Practice Research Database as an example of a UK Primary Care Data 6 7 resource. Ther Adv Drug Saf 2012;3:88–99. 8 9 10 11 9. Tate AR, Beloff N, Al-Radwan B et al. Exploiting the potential of large databases of 12 13 electronic health records for research using rapid search algorithms and an intuitive 14 15 queryFor interface. Jpeer Am Med Inform review Assoc . 2014;21(2):292-8. only 16 17 18 19 10. GOLD 2011 http://www.goldcopd.org/uploads/users/files/GOLD2011_Summary.pdf 20 21 accessed Nov 2013. 22 23 24 25 11. https://mqi.ic.nhs.uk/IndicatorDefaultView.aspx?ref=1.09.03.07 (QOF COPD). 26 27 Accessed Feb 2014. 28 29

30 31 12. http://www.nbmedical.com/pdf/keep_simple_qof_2014-2014.pdf accessed Feb 32 33 2014 34 35 36 37 38 13. Inghammar M, Engström G, Löfdahl C-G et al. Validation of a COPD diagnosis 39 40 from the Swedish Inpatient Registry Scandinavian Journal of Public Health , 2012;40: 41 42 773–776 43 44 14. Kadhim-Saleh A, Green M, WilliamsonT et al. Validation of the Diagnostic 45 46 Algorithms for 5 Chronic Conditions in the Canadian Primary Care Sentinel 47 48 Surveillance Network (CPCSSN): A Kingston Practice-based Research Network 49 50 (PBRN) Report. J Am Board Fam Med 2013;26: 159–167 51 52 53 54 55 56 57 58 20 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 48 BMJ Open

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 228x248mm (300 x 300 DPI) 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 48

1 2 3 4 Supplementary information 5 6 7 8 Algorithms 9 10 1. Specific COPD code and more than one prescription of a COPD medication and 11 presence of spirometry. The first COPD medication had to be prescribed within 4 12 weeks of the COPD diagnostic code. 13 2. Specific COPD code and presence of spirometry 14 3. Specific COPD code and more than one prescription of a COPD medication. The first 15 COPD medication had to be prescribed within 4 weeks of the COPD diagnostic code. 16 4. Specific COPD code only 17 For peer review only 18 5. Non-specific bronchitis codes and more than one prescription of a COPD medication. 19 The first COPD medication had to be prescribed within 4 weeks of the COPD 20 diagnostic code. 21 6. Non-specific bronchitis codes only 22 7. Respiratory symptoms and presence of spirometry. Respiratory symptoms consisted 23 of persistent cough, sputum production, or dyspnoea 24 8. Respiratory symptom definition only 25 26 27 28 29 Specific COPD codes 30 medcode term 31 32 18476 COPD follow-up 33 45771 Chronic obstructive pulmonary disease does not disturb sleep 34 4084 Airways obstructn irreversible 35 794 Emphysema 36 998 Chronic obstructive airways disease 37 1001 Chronic obstructive pulmonary disease 38 5710 Chronic obstructive airways disease NOS 39 9520 Chronic obstructive pulmonary disease monitoring 40 9876 Severe chronic obstructive pulmonary disease 41 10802 Moderate chronic obstructive pulmonary disease 42 10863 Mild chronic obstructive pulmonary disease 43 10980 Centrilobular emphysema 44 45 11287 Chronic obstructive pulmonary disease annual review 46 14798 Emphysematous bronchitis 47 18621 Chronic obstructive pulmonary disease follow-up 48 18792 Chronic obstructive pulmonary disease monitoring admin 49 23492 Chronic bullous emphysema NOS 50 26018 Chronic obstructive pulmonary disease monitoring by nurse 51 26306 Chronic bullous emphysema 52 28755 Chronic obstructive pulmonary disease monitoring 1st letter 53 33450 Emphysema NOS 54 34202 Chronic obstructive pulmonary disease monitoring 2nd letter 55 34215 Chronic obstructive pulmonary disease monitoring 3rd letter 56 37247 Chronic obstructive pulmonary disease NOS 57 58 37371 Chronic obstructive pulmonary disease monitoring due 59 44525 Obstructive chronic bronchitis NOS 60 45998 Chronic obstructive pulmonary disease monitoring by doctor 93568 Very severe chronic obstructive pulmonary disease 12166 Other specified chronic obstructive airways disease

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1 2 3 38074 Chronic obstructive pulmonary disease monitor phone invite 4 42258 Chronic obstructive pulmonary disease monitoring verb invite 5 6 42313 Health education - chronic obstructive pulmonary disease 7 45770 Chronic obstructive pulmonary disease disturbs sleep 8 45777 Chronic obstructive pulmonary disease clini management plan 9 10 11 12 13 COPD medication codes 14 prodcode productname 15 8 salbutamol 100micrograms/dose inhaler 16 17 salbutamol 100micrograms/dose inhaler cfc free 17 31 ventolin 100microgram/inhalationFor peer reviewinhalation powder (glaxoonly wellcome uk ltd) 18 38 beclometasone 100micrograms/dose inhaler 19 20 99 becotide 100 inhaler (glaxosmithkline uk ltd) 21 218 aminophylline 100 mg cap 22 235 bricanyl 250micrograms/dose inhaler (astrazeneca uk ltd) 23 273 theophylline 200 mg cap 24 282 salbutamol 2mg/5ml oral solution sugar free 25 454 pulmicort 200microgram inhaler (astrazeneca uk ltd) 26 465 salmeterol 25micrograms/dose inhaler 27 510 ventolin 5mg/ml respirator solution (glaxosmithkline uk ltd) 28 549 serevent 25micrograms/dose inhaler (glaxosmithkline uk ltd) 29 555 aminophylline 225mg modified-release tablets 30 590 phyllocontin continus 225mg tablets (napp pharmaceuticals ltd) 31 638 seretide 250 accuhaler (glaxosmithkline uk ltd) 32 33 665 seretide 100 accuhaler (glaxosmithkline uk ltd) 34 674 ventolin 2.5mg nebules (glaxosmithkline uk ltd) 35 696 salbutamol 8mg modified-release capsules 36 719 salmeterol 50micrograms/dose dry powder inhaler 37 746 tiotropium 18 microgram capsule 38 752 carbocisteine 375mg capsules 39 856 ventolin 2mg/5ml syrup (glaxosmithkline uk ltd) 40 860 salbutamol 4mg tablets 41 862 salbulin inhalation powder (3m health care ltd) 42 863 slo-phyllin 125mg capsule (lipha pharmaceuticals ltd) 43 879 theophylline 125mg modified-release capsules 44 880 theophylline 60mg modified-release capsules 45 46 881 salbutamol 2mg tablets 47 882 salbutamol 200microgram inhalation powder capsules 48 883 becodisks 200microgram disc (allen & hanburys ltd) 49 895 beclazone 100 easi-breathe inhaler (teva uk ltd) 50 896 becotide easi-breathe 100microgram/actuation pressurised inhalation (allen & 51 hanburys ltd) 52 898 ventolin evohaler 100 100microgram/inhalation pressurised inhalation (glaxo 53 wellcome uk ltd) 54 907 bricanyl turbohaler 500 500microgram turbohaler (astrazeneca uk ltd) 55 908 pulmicort 400 turbohaler (astrazeneca uk ltd) 56 909 budesonide 200micrograms/dose inhaler 57 910 serevent diskhaler 50microgram inhalation powder (glaxo wellcome uk ltd) 58 59 911 flixotide accuhaler 250 250microgram/inhalation inhalation powder (allen & hanburys 60 ltd) 947 budesonide 50micrograms/actuation refill canister 956 pulmicort 200 turbohaler (astrazeneca uk ltd)

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1 2 3 957 salamol easi-breathe 100microgram/actuation pressurised inhalation (ivax 4 pharmaceuticals uk ltd) 5 6 958 ventolin easi-breathe 100microgram/actuation pressurised inhalation (allen & 7 hanburys ltd) 8 959 budesonide 50micrograms/dose inhaler 9 960 pulmicort 100 turbohaler (astrazeneca uk ltd) 10 987 ventolin 4mg tablet (allen & hanburys ltd) 11 1093 salamol 100microgram/actuation inhalation powder (ivax pharmaceuticals uk ltd) 12 1097 slo-phyllin 60mg capsule (lipha pharmaceuticals ltd) 13 1100 beclazone 100 inhaler (teva uk ltd) 14 1236 becloforte 250micrograms/dose inhaler (glaxosmithkline uk ltd) 15 1242 beclometasone 250micrograms/dose inhaler 16 1243 beclazone 250 easi-breathe inhaler (teva uk ltd) 17 For peer review only 1258 becotide 200 inhaler (glaxosmithkline uk ltd) 18 19 1259 beclometasone 200micrograms/dose inhaler 20 1269 becotide 50microgram/ml nebuliser liquid (allen & hanburys ltd) 21 1346 salbutamol 0.05mg/ml injection 22 1406 becotide 50 inhaler (glaxosmithkline uk ltd) 23 1409 ipratropium bromide 20micrograms/dose inhaler 24 1410 ipratropium bromide 0.25mg/ml 25 1411 ipratropium bromide 250micrograms/ml 26 1412 flixotide 250microgram/actuation inhalation powder (allen & hanburys ltd) 27 1414 salamol 5mg/2.5ml nebuliser liquid steri-neb unit dose vials (teva uk ltd) 28 1415 steri-neb ipratropium 250microgram/ml nebuliser liquid (ivax pharmaceuticals uk ltd) 29 1423 uniphyllin continus 200mg tablets (napp pharmaceuticals ltd) 30 1424 flixotide 250microgram disc (allen & hanburys ltd) 31 32 1426 flixotide 500microgram disc (allen & hanburys ltd) 33 1518 flixotide 50microgram/actuation inhalation powder (allen & hanburys ltd) 34 1537 becotide 200microgram rotacaps (glaxosmithkline uk ltd) 35 1551 beclazone 250 inhaler (teva uk ltd) 36 1552 becloforte easi-breathe 250microgram/actuation pressurised inhalation (allen & 37 hanburys ltd) 38 1619 terbutaline 500micrograms/dose dry powder inhaler 39 1620 terbutaline 250micrograms/dose inhaler 40 1628 terbutaline 250micrograms/actuation refill canister 41 1630 salbutamol 2.5mg/2.5ml nebuliser liquid unit dose vials 42 1635 salbuvent 2mg/5ml oral solution (pharmacia ltd) 43 1642 budesonide 400micrograms/dose dry powder inhaler 44 45 1676 flixotide 125microgram/actuation inhalation powder (allen & hanburys ltd) 46 1680 pulmicort ls 50micrograms/dose inhaler (astrazeneca uk ltd) 47 1698 salbutamol 100micrograms/dose breath actuated inhaler 48 1711 salbutamol 5mg/2.5ml nebuliser liquid unit dose vials 49 1725 beclazone 50 easi-breathe inhaler (teva uk ltd) 50 1727 becotide easi-breathe 50microgram/actuation pressurised inhalation (allen & 51 hanburys ltd) 52 1734 beclometasone 100micrograms/dose breath actuated inhaler 53 1741 salbutamol 100micrograms/dose breath actuated inhaler cfc free 54 1833 theophylline 200mg modified-release tablets 55 1834 theophylline 400mg modified-release tablets 56 1861 aerobec 100 autohaler (meda pharmaceuticals ltd) 57 58 1882 ventodisks 200microgram/blister disc (allen & hanburys ltd) 59 1885 beclazone 200 inhaler (teva uk ltd) 60 1950 ventodisks 400microgram/blister disc (allen & hanburys ltd) 1951 becodisks 400microgram disc (allen & hanburys ltd) 1952 ventolin 400microgram rotacaps (glaxosmithkline uk ltd)

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1 2 3 1956 pulmicort 1mg respules (astrazeneca uk ltd) 4 1957 ventolin 5mg nebules (glaxosmithkline uk ltd) 5 6 1959 pulmicort 0.5mg respules (astrazeneca uk ltd) 7 1972 oxygen bp size af lightweight gas 1360 litres 8 1974 oxis 12 turbohaler (astrazeneca uk ltd) 9 1975 oxis 6 turbohaler (astrazeneca uk ltd) 10 2044 prednisone 2.5 mg tab 11 2092 budesonide 200micrograms/dose dry powder inhaler 12 2124 pulmicort refil 200 mcg inh 13 2125 pulmicort 200microgram refill canister (astrazeneca uk ltd) 14 2147 theophylline 250mg modified-release capsules 15 2148 beclometasone 400microgram disc 16 2149 steri-neb salamol 2.5 mg inh 17 For peer review only 2152 ipratropium bromide with salbutamol 20mcg + 100mcg 18 19 2159 aerobec 50 autohaler (meda pharmaceuticals ltd) 20 2160 beclometasone 50micrograms/dose breath actuated inhaler 21 2224 serevent 50micrograms/dose accuhaler (glaxosmithkline uk ltd) 22 2229 becodisks 100microgram disc (allen & hanburys ltd) 23 2282 fluticasone 500micrograms/dose dry powder inhaler 24 2335 qvar 100 inhaler (teva uk ltd) 25 2368 prednisolone 2.5mg tablet 26 2390 prednisolone e/c 1 mg tab 27 2395 salbutamol 2 mg/5ml syr 28 2437 oxitropium bromide 100micrograms/dose inhaler 29 2440 flixotide accuhaler 500 500microgram/inhalation inhalation powder (allen & hanburys 30 ltd) 31 32 2510 oxygen bp gas 1280 litres 33 2600 beclometasone 250micrograms/dose breath actuated inhaler 34 2655 airomir 100micrograms/dose inhaler (teva uk ltd) 35 2723 fluticasone 25micrograms/dose inhaler 36 2757 slo-phyllin 250mg capsule (lipha pharmaceuticals ltd) 37 2758 bricanyl refill canister (astrazeneca uk ltd) 38 2799 prednisolone 10 mg tab 39 2850 salbutamol 400microgram inhalation powder capsules 40 2851 ventolin 200microgram rotacaps (glaxosmithkline uk ltd) 41 2869 salbutamol 8mg modified-release tablets 42 2892 becloforte 400microgram disks (glaxosmithkline uk ltd) 43 2893 beclometasone 200micrograms disc 44 45 2949 prednisone 5mg tablets 46 2951 fluticasone 250microgram/actuation pressurised inhalation 47 2978 salbutamol 200micrograms/dose dry powder inhaler 48 2992 beclazone 50 inhaler (teva uk ltd) 49 2995 nuelin sa 175mg tablets (meda pharmaceuticals ltd) 50 3018 beclometasone 50micrograms/dose inhaler 51 3059 prednisolone 50 mg tab 52 3065 bextasol inhalation powder (allen & hanburys ltd) 53 3075 becotide 400microgram rotacaps (glaxosmithkline uk ltd) 54 3119 becloforte integra 250microgram/actuation inhaler with compact spacer (glaxo 55 laboratories ltd) 56 3150 beclometasone 100micrograms/actuation extrafine particle cfc free inhaler 57 58 3163 salbutamol 200micrograms disc 59 3188 pulmicort complete 50 mcg inh 60 3189 salbuvent inh inh 3220 qvar 50 autohaler (teva uk ltd) 3254 salbulin 4mg tablet (3m health care ltd)

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1 2 3 3289 flixotide 25micrograms/dose inhaler (glaxosmithkline uk ltd) 4 3297 salmeterol 50micrograms disc 5 6 3322 aerolin inh 400 100 mcg aer 7 3345 sintisone tablet (pharmacia ltd) 8 3347 oxygen bp size f gas 1360 litres 9 3363 becloforte 400microgram disks with diskhaler (glaxosmithkline uk ltd) 10 3388 theophylline 175mg modified-release tablets 11 3442 pulmicort complete 200 mcg inh 12 3443 salbutamol 100microgram/inhalation spacehaler (celltech pharma europe ltd) 13 3534 bricanyl 5mg tablets (astrazeneca uk ltd) 14 3546 qvar 50 inhaler (teva uk ltd) 15 3556 beclometasone 50micrograms with salbutamol 100micrograms/inhalation inhaler 16 3557 prednisone 1mg tablets 17 For peer review only 3570 budesonide 200micrograms/actuation refill canister 18 19 3584 bricanyl 1.5mg/5ml syrup (astrazeneca uk ltd) 20 3666 seretide 500 accuhaler (glaxosmithkline uk ltd) 21 3743 filair 50 inhaler (meda pharmaceuticals ltd) 22 3753 flixotide diskhaler-community pack 250 mcg 23 3758 pulmadil inhalation powder (3m health care ltd) 24 3763 terbutaline respules inh 25 3764 bricanyl respules (5mg/2ml) 2.5 mg/ml inh 26 3786 fenoterol 100micrograms/dose / ipratropium 40micrograms/dose inhaler 27 3838 salbutamol 400mcg/beclometh.100mcg r/cap inh 28 3927 filair 100 inhaler (meda pharmaceuticals ltd) 29 3947 becotide 100microgram rotacaps (glaxosmithkline uk ltd) 30 3988 flixotide diskhaler-community pack 100 mcg 31 32 3989 flixotide 100microgram disc (allen & hanburys ltd) 33 3993 filair forte 250micrograms/dose inhaler (meda pharmaceuticals ltd) 34 3994 salbutamol 4mg modified-release tablets 35 4055 salbulin 2mg/5ml oral solution (3m health care ltd) 36 4131 fluticasone 100microgram disc 37 4132 fluticasone 125microgram/actuation pressurised inhalation 38 4165 zithromax 250mg capsules (pfizer ltd) 39 4171 ventolin 2mg tablet (allen & hanburys ltd) 40 4222 bricanyl 10mg/ml respirator solution (astrazeneca uk ltd) 41 4268 ipratropium bromide 40micrograms/dose inhaler 42 4365 beclometasone 100micrograms disc 43 4412 oxygen bp size g gas 3400 litres 44 45 4413 qvar 100 autohaler (teva uk ltd) 46 4497 ventolin accuhaler 200 200microgram/actuation inhalation powder (glaxo wellcome 47 uk ltd) 48 4499 aerobec 250microgram/actuation pressurised inhalation (meda pharmaceuticals ltd) 49 4514 aminophylline 350mg modified-release tablets 50 4538 oxygen bp size pd gas 300 litres 51 4541 bricanyl sa 7.5mg tablets (astrazeneca uk ltd) 52 4545 pulmicort ls 50microgram refill canister (astrazeneca uk ltd) 53 4593 theophylline 125mg tablets 54 4601 asmabec 100 clickhaler (focus pharmaceuticals ltd) 55 4634 salamol 2.5mg/2.5ml nebuliser liquid steri-neb unit dose vials (teva uk ltd) 56 4640 bricanyl 5mg/2ml nebuliser liquid (astrazeneca uk ltd) 57 58 4665 salbulin 100micrograms/dose inhaler (3m health care ltd) 59 4688 fluticasone 50microgram/actuation pressurised inhalation 60 4759 beclometasone 100microgram inhalation powder capsules 4791 oxygen bp size c gas 170 litres 4801 budesonide 500micrograms/2ml nebuliser liquid unit dose vials

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1 2 3 4803 beclazone 250microgram/actuation inhalation powder (actavis uk ltd) 4 4842 fenoterol 100microgram/actuation inhaler 5 6 4908 ventolin rotahaler (glaxosmithkline uk ltd) 7 4926 flixotide accuhaler 100 100microgram/inhalation inhalation powder (allen & hanburys 8 ltd) 9 4942 budesonide 1mg/2ml nebuliser liquid unit dose vials 10 5057 azithromycin 200mg/5ml oral suspension 11 5116 azithromycin 250mg capsules 12 5143 seretide 50 evohaler (glaxosmithkline uk ltd) 13 5161 seretide 125 evohaler (glaxosmithkline uk ltd) 14 5170 salamol 100micrograms/dose inhaler cfc free (teva uk ltd) 15 5172 seretide 250 evohaler (glaxosmithkline uk ltd) 16 5185 fenoterol 200micrograms/dose inhaler 17 For peer review only 5223 fluticasone 50micrograms/dose inhaler cfc free 18 19 5261 nuelin sa 250 tablets (meda pharmaceuticals ltd) 20 5308 terbutaline 5mg/2ml nebuliser liquid unit dose vials 21 5309 flixotide 50micrograms/dose evohaler (glaxosmithkline uk ltd) 22 5335 zithromax 500mg tablets (pfizer ltd) 23 5453 uniphyllin continus 400mg tablets (napp pharmaceuticals ltd) 24 5516 salamol 100micrograms/dose easi-breathe inhaler (teva uk ltd) 25 5521 beclometasone 200micrograms/dose dry powder inhaler 26 5522 beclometasone 100micrograms/dose dry powder inhaler 27 5551 flixotide 0.5mg/2ml nebules (glaxosmithkline uk ltd) 28 5558 salmeterol 50micrograms with fluticasone 500micrograms cfc free inhaler 29 5580 flixotide accuhaler 50 50microgram/inhalation inhalation powder (allen & hanburys 30 ltd) 31 32 5584 oxygen cylinders size pd (boc ltd) 33 5683 flixotide 250micrograms/dose evohaler (glaxosmithkline uk ltd) 34 5718 flixotide 125micrograms/dose evohaler (glaxosmithkline uk ltd) 35 5740 airomir 100micrograms/dose autohaler (teva uk ltd) 36 5753 salbutamol 400micrograms disc 37 5773 oxygen bp size dd gas 460 litres 38 5780 oxygen cylinders size af (boc ltd) 39 5804 beclometasone 250micrograms/dose dry powder inhaler 40 5822 fluticasone 250micrograms/dose inhaler cfc free 41 5837 salamol steri-neb 5mg/2.5ml nebuliser liquid (numark management ltd) 42 5864 salmeterol 25micrograms with fluticasone 250micrograms cfc free inhaler 43 5885 fluticasone 100micrograms/dose dry powder inhaler 44 45 5889 salamol 100microgram/inhalation inhalation powder (kent pharmaceuticals ltd) 46 5898 salamol steri-neb 2.5mg/2.5ml nebuliser liquid (numark management ltd) 47 5941 uniphyllin continus 300mg tablets (napp pharmaceuticals ltd) 48 5942 salmeterol 50micrograms with fluticasone 250micrograms cfc free inhaler 49 5975 fluticasone 125micrograms/dose inhaler cfc free 50 5976 oxygen bp size dd 460 litre inhalation gas (boc ltd) 51 5992 beclometasone 50micrograms/dose dry powder inhaler 52 6081 ipratropium bromide 20micrograms/dose breath actuated inhaler 53 6276 carbocisteine 250mg/5ml oral solution 54 6315 slo-phyllin 250mg capsules (merck serono ltd) 55 6325 symbicort 200/6 turbohaler (astrazeneca uk ltd) 56 6419 oxygen cylinders size f (boc ltd) 57 58 6420 oxygen bp size d gas 340 litres 59 6423 oxygen bp with integral headset 1360 litre inhalation gas (boc ltd) 60 6462 salbutamol 95micrograms/dose dry powder inhaler 6522 ipratropium bromide 20micrograms/dose inhaler cfc free 6526 formoterol 12microgram inhalation powder capsules with device

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1 2 3 6556 oxygen cylinders size c (boc ltd) 4 6569 salmeterol 25micrograms with fluticasone 125micrograms cfc free inhaler 5 6 6616 salmeterol 25micrograms with fluticasone 50micrograms cfc free inhaler 7 6619 oxygen bp size cd gas 460 litres 8 6719 ipratropium bromide 500micrograms/2ml nebuliser liquid unit dose vials 9 6746 budesonide 400micrograms/dose / formoterol 12micrograms/dose dry powder inhaler 10 6758 ipratropium 250micrograms/1ml nebuliser liquid steri-neb unit dose vials (teva uk ltd) 11 6768 oxygen bp size cd 460 litre inhalation gas (boc ltd) 12 6772 ipratropium bromide 250micrograms/1ml nebuliser liquid unit dose vials 13 6780 symbicort 400/12 turbohaler (astrazeneca uk ltd) 14 6796 budesonide 200micrograms/dose / formoterol 6micrograms/dose dry powder inhaler 15 6802 mucodyne 375mg capsules (sanofi) 16 6848 oxygen cylinders size dd with integral headset 2 and 4litres/minute flow rate (boc ltd) 17 For peer review only 6920 mecysteine 100mg gastro-resistant tablets 18 19 6938 salmeterol 50micrograms with fluticasone 100micrograms dry powder inhaler 20 6976 oxygen bp with integral headset gas 430 litres 21 6988 aminophylline hydrate 100mg modified-release tablets 22 7013 symbicort 100/6 turbohaler (astrazeneca uk ltd) 23 7017 salbutamol 100micrograms/dose dry powder inhaler 24 7031 oxygen bp size e gas 680 litres 25 7042 oxygen cylinders size e (boc ltd) 26 7133 formoterol 12micrograms/dose dry powder inhaler 27 7192 bambuterol 10mg tablets 28 7239 oxygen cylinders size b10s (air products plc) 29 7268 serevent 25micrograms/dose evohaler (glaxosmithkline uk ltd) 30 7270 salmeterol 25micrograms/dose inhaler cfc free 31 32 7452 ventolin .25 mg inj 33 7584 prednisolone 4 mg tab 34 7602 fluticasone 50microgram disc 35 7638 fluticasone 250microgram disc 36 7653 beclometasone 400microgram inhalation powder capsules 37 7710 prednisolone 15 mg tab 38 7711 terbutaline 250micrograms/dose inhaler with spacer 39 7724 betamethasone valerate 100micrograms/actuation inhaler 40 7730 theo-dur 300mg tablets (astrazeneca uk ltd) 41 7731 theo-dur 200mg tablets (astrazeneca uk ltd) 42 7732 theophylline 300mg modified-release tablets 43 7733 theophylline 250mg modified-release tablets 44 45 7788 budesonide 100micrograms/dose dry powder inhaler 46 7832 choline theophyllinate 200mg tablets 47 7841 nuelin 125mg tablets (3m health care ltd) 48 7891 fluticasone 500microgram disc 49 7934 prednisone 30 mg tab 50 7935 maxivent 100microgram/inhalation inhalation powder (ashbourne pharmaceuticals 51 ltd) 52 7948 fluticasone 250micrograms/dose dry powder inhaler 53 7953 terbutaline 1.5mg/5ml oral solution sugar free 54 7954 bricanyl 250micrograms/dose spacer inhaler (astrazeneca uk ltd) 55 7964 beclometasone 50micrograms/ml nebuliser suspension 56 7965 salbutamol 5mg/ml nebuliser liquid 57 58 8012 exirel 15mg capsule (3m health care ltd) 59 8056 aminophylline 100mg tablets 60 8057 aminophylline 100mg modified-release tablets 8111 becloforte vm 250microgram/actuation vm pack (allen & hanburys ltd) 8183 oxygen bp gas 640 litres

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1 2 3 8251 pulmicort refil 50 mg inh 4 8252 pirbuterol 15mg capsule 5 6 8267 sodium cromoglicate 1mg/dose / salbutamol 100micrograms/dose inhaler 7 8333 ipratropium bromide 40microgram inhalation powder capsules 8 8339 fenoterol hydrobromide complete unit inh 9 8429 ventolin i/v 5 mg inj 10 8433 budesonide 100micrograms/actuation inhaler 11 8450 flixotide diskhaler-community pack 50 mcg 12 8504 exirel 15 mg tab 13 8505 oxygen bp gas 6400 litres 14 8522 terbutaline 7.5mg modified-release tablets 15 8572 rimiterol inhaler 16 8635 flixotide 50microgram disc (allen & hanburys ltd) 17 For peer review only 8636 ventolin s/r 8 mg spa 18 19 8676 terbutaline 10mg/ml nebuliser liquid 20 8757 oxygen bp gas 3200 litres 21 8806 phyllocontin continus 350mg tablet (napp pharmaceuticals ltd) 22 8955 theophylline 100 mg tab 23 9018 mucodyne 375mg capsule (aventis pharma) 24 9092 theophylline 350mg modified release tablets 25 9164 fluticasone 50micrograms/dose dry powder inhaler 26 9233 beclometasone 200microgram inhalation powder capsules 27 9270 ipratropium bromide with fenoterol hydrobromide 500micrograms + 1.25mg/4ml 28 9384 salbutamol 4mg modified-release capsules 29 9477 asmabec 100microgram/actuation spacehaler (celltech pharma europe ltd) 30 9571 beclometasone 250micrograms/actuation vortex inhaler 31 32 9577 asmabec 50 clickhaler (focus pharmaceuticals ltd) 33 9599 beclazone 50microgram/actuation inhalation powder (actavis uk ltd) 34 9642 mucodyne 250mg/5ml oral solution (aventis pharma) 35 9651 asmasal 100microgram/inhalation spacehaler (celltech pharma europe ltd) 36 9658 oxitropium bromide 100micrograms/dose breath actuated inhaler 37 9711 formoterol 6micrograms/dose dry powder inhaler 38 9727 prednisolone 50mg tablets 39 9805 salbutamol 5mg/50ml solution for infusion vials 40 9889 oxygen cylinders size g (boc ltd) 41 9895 oxygen bp size df with integral headset gas 1360 litres 42 9906 mucodyne 250mg/5ml syrup (sanofi) 43 9921 beclometasone 100micrograms/dose breath actuated inhaler cfc free 44 45 9943 visclair 100mg gastro-resistant tablets (ranbaxy (uk) ltd) 46 10043 oxygen composite cylinders size b10c with integral headset (air products plc) 47 10053 oxygen connection cubing 1.8m 48 10090 beclometasone 50micrograms/actuation extrafine particle cfc free inhaler 49 10218 budesonide 100micrograms/dose / formoterol 6micrograms/dose dry powder inhaler 50 10321 budesonide 400microgram inhalation powder capsules 51 10331 nuelin 60mg/5ml liquid (3m health care ltd) 52 10353 salbuvent rondo 53 10360 aerocrom inhaler (castlemead healthcare ltd) 54 10407 phyllocontin paediatric continus 100mg tablets (napp pharmaceuticals ltd) 55 10433 theophylline 60mg/5ml oral solution 56 10458 ventolin cr 4mg tablet (allen & hanburys ltd) 57 58 10561 aminophylline 250mg/ml injection 59 10723 theophylline 125mg/5ml syrup 60 10744 theophylline 80 mg eli 10808 mucodyne paediatric 125mg/5ml syrup (sanofi) 10825 terbutaline 5mg tablets

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1 2 3 10831 biophylline 125mg/5ml oral solution (lorex synthelabo ltd) 4 10858 pulmadil auto inhalation powder (3m health care ltd) 5 6 10958 salbutamol .25 mg inj 7 10968 foradil 12microgram inhalation powder capsules with device (novartis 8 pharmaceuticals uk ltd) 9 11046 ipratropium bromide with salbutamol 500micrograms + 2.5mg/2.5ml 10 11149 betnelan 500microgram tablets (focus pharmaceuticals ltd) 11 11198 beclometasons 50 micrograms/actuation vortex inhaler 12 11307 salbutamol 100micrograms/dose / beclometasone 50micrograms/dose inhaler 13 11410 fluticasone 500micrograms/dose / salmeterol 50micrograms/dose dry powder inhaler 14 11478 fluticasone 2mg/2ml nebuliser liquid unit dose vials 15 11497 beclometasone 400micrograms/dose dry powder inhaler 16 11588 fluticasone 125micrograms/dose / salmeterol 25micrograms/dose inhaler cfc free 17 For peer review only 11618 fluticasone 250micrograms/dose / salmeterol 25micrograms/dose inhaler cfc free 18 19 11659 oxygen bp size dd with integral headset gas 460 litres 20 11719 slo-phyllin 60mg capsules (merck serono ltd) 21 11732 beclometasone 50micrograms/dose breath actuated inhaler cfc free 22 11779 ipratropium bromide 40microgram inhalation powder capsules with device 23 11993 pro-vent 300mg capsule (wellcome medical division) 24 12042 ventolin cr 8mg tablet (allen & hanburys ltd) 25 12144 bambuterol 20mg tablets 26 12240 theophylline 300mg modified release capsules 27 12463 pirbuterol 15 mg tab 28 12479 aerolin inh auto refil 100 mcg aer 29 12486 bronchodil 500microgram/dose inhalation powder (viatris pharmaceuticals ltd) 30 12529 fabrol 200mg granules (novartis consumer health uk ltd) 31 32 12563 exirel inhalation powder (3m health care ltd) 33 12699 pecram 225mg modified-release tablet (novartis consumer health uk ltd) 34 12808 fenoterol 100micrograms/dose / ipratropium bromide 40micrograms/dose breath 35 actuated inhaler 36 12822 salbutamol 2.5mg with ipratropium bromide 500micrograms/2.5ml unit dose nebuilser 37 solution 38 12909 salbutamol 100micrograms/dose / ipratropium 20micrograms/dose inhaler 39 12994 fluticasone 50micrograms/dose / salmeterol 25micrograms/dose inhaler cfc free 40 13037 pulvinal beclometasone dipropionate 200micrograms/dose dry powder inhaler (chiesi 41 ltd) 42 13038 pulvinal salbutamol 200micrograms/dose dry powder inhaler (chiesi ltd) 43 13040 fluticasone 250micrograms/dose / salmeterol 50micrograms/dose dry powder inhaler 44 45 13181 easyhaler salbutamol sulphate 100micrograms/dose dry powder inhaler (orion 46 pharma (uk) ltd) 47 13206 oxygen bp with integral headset gas 300 litres 48 13273 fluticasone 100micrograms/dose / salmeterol 50micrograms/dose dry powder inhaler 49 13290 clenil modulite 100micrograms/dose inhaler (chiesi ltd) 50 13307 bricanyl 500microgram/ml injection (astrazeneca uk ltd) 51 13522 prednisolone 2 mg tab 52 13529 amnivent-225 sr tablets (ashbourne pharmaceuticals ltd) 53 13575 bambec 20mg tablets (astrazeneca uk ltd) 54 13615 prednisone 10 mg tab 55 13757 tropiovent steripoule 250microgram/ml nebuliser liquid (ashbourne pharmaceuticals 56 ltd) 57 58 13815 beclazone 100microgram/actuation inhalation powder (actavis uk ltd) 59 13996 salamol 100microgram/inhalation inhalation powder (sandoz ltd) 60 14294 qvar 50micrograms/dose easi-breathe inhaler (teva uk ltd) 14306 formoterol 12micrograms/dose inhaler cfc free 14321 beclometasone 200micrograms/dose inhaler cfc free

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1 2 3 14482 bricanyl 2.5 mg inj 4 14483 terbutaline 500micrograms/ml injection 5 6 14514 zithromax 200mg/5ml oral suspension (pfizer ltd) 7 14524 bdp 250microgram/actuation spacehaler (celltech pharma europe ltd) 8 14525 salbutamol 100micrograms/inhalation vortex inhaler 9 14527 bambec 10mg tablets (astrazeneca uk ltd) 10 14561 salbutamol 400microgram / beclometasone 200microgram inhalation powder 11 capsules 12 14567 asmabec 250 clickhaler (focus pharmaceuticals ltd) 13 14590 asmabec 250microgram/actuation spacehaler (celltech pharma europe ltd) 14 14700 budesonide 400micrograms/actuation inhaler 15 14736 pulvinal beclometasone dipropionate 400micrograms/dose dry powder inhaler (chiesi 16 ltd) 17 For peer review only 14739 norphyllin sr 225mg tablets (teva uk ltd) 18 19 14757 pulvinal beclometasone dipropionate 100micrograms/dose dry powder inhaler (chiesi 20 ltd) 21 14991 aminophylline 250mg/10ml injection 22 15075 bronchodil 20mg tablet (viatris pharmaceuticals ltd) 23 15165 reproterol 500micrograms/dose inhaler 24 15214 oxygen bp size pd 300 litre inhalation gas (medigas ltd) 25 15281 oxygen cylinders size pa2 with integral headset (air products plc) 26 15284 slo-phyllin 125mg capsules (merck serono ltd) 27 15301 carbocisteine 125mg/5ml oral solution 28 15326 beclometasone 100micrograms/dose inhaler cfc free 29 15365 theophylline 10mg/5ml sf elixir 30 15409 theophylline 3 mg sol 31 32 15441 fenoterol hydrobromide .5 % sol 33 15613 salbutamol 500micrograms/1ml solution for injection ampoules 34 15706 beclometasone 100 micrograms/actuation vortex inhaler 35 15979 oxygen bp with integral headset 300 litre inhalation gas (boc ltd) 36 16054 budesonide 200micrograms/actuation breath actuated powder inhaler 37 16124 oxygen cylinders (medigas ltd) 38 16148 clenil modulite 250micrograms/dose inhaler (chiesi ltd) 39 16151 clenil modulite 200micrograms/dose inhaler (chiesi ltd) 40 16158 clenil modulite 50micrograms/dose inhaler (chiesi ltd) 41 16236 pirbuterol acetate inhaler 42 16305 flixotide 2mg/2ml nebules (glaxosmithkline uk ltd) 43 16523 oxygen cylinders size cd with integral headset 0-15litres/minute flow rate (boc ltd) 44 45 16577 easyhaler salbutamol sulphate 200micrograms/dose dry powder inhaler (orion 46 pharma (uk) ltd) 47 16584 beclometasone 50micrograms/dose inhaler cfc free 48 16625 ventide rotacaps (glaxosmithkline uk ltd) 49 16724 prednisone 50 mg tab 50 16994 aminophylline hydrate 350mg modified-release tablets 51 17002 aminophylline hydrate 225mg modified-release tablets 52 17005 oxygen bp size cd with integral headset gas 460 litres 53 17140 aminophylline 200mg tablets 54 17185 ventolin 500micrograms/1ml solution for injection ampoules (glaxosmithkline uk ltd) 55 17465 fluticasone 500micrograms/2ml nebuliser liquid unit dose vials 56 17644 oxygen bp with integral headset gas 2122 litres 57 58 17654 easyhaler beclometasone 200micrograms/dose dry powder inhaler (orion pharma 59 (uk) ltd) 60 17670 easyhaler budesonide 100micrograms/dose dry powder inhaler (orion pharma (uk) ltd) 17696 ventmax sr 4mg capsules (chiesi ltd)

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1 2 3 17874 monovent 1.5mg/5ml oral solution (lagap) 4 17901 bricanyl nebule 2.5 ml 5 6 18140 respontin 500micrograms/2ml nebules (glaxosmithkline uk ltd) 7 18288 choline theophyllinate 100mg tablets 8 18299 fenoterol 1.25mg/4ml / ipratropium 500micrograms/4ml nebuliser liquid unit dose 9 vials 10 18314 aerocrom syncroner with spacer (castlemead healthcare ltd) 11 18394 bdp 50microgram/actuation spacehaler (celltech pharma europe ltd) 12 18421 respontin nebules 250microgram/ml nebuliser liquid (glaxo wellcome uk ltd) 13 18456 salbutamol 200microgram / beclometasone 100microgram inhalation powder 14 capsules 15 18484 ventide paediatric rotacaps (glaxosmithkline uk ltd) 16 18537 budesonide 200microgram inhalation powder capsules 17 For peer review only 18622 salbulin 2mg tablet (3m health care ltd) 18 19 18848 qvar 100micrograms/dose easi-breathe inhaler (teva uk ltd) 20 18937 sabidal sr 270 270 mg tab 21 18968 salbutamol 5mg/5ml solution for infusion ampoules 22 18988 choline theophyllinate 62.5mg/5ml oral solution 23 19031 bdp 100microgram/actuation spacehaler (celltech pharma europe ltd) 24 19121 beclometasone 100micrograms with salbutamol 200micrograms inhalation capsules 25 19376 beclometasone 200micrograms with salbutamol 400micrograms inhalation capsules 26 19389 asmabec 50microgram/actuation spacehaler (celltech pharma europe ltd) 27 19401 beclometasone 250micrograms/actuation inhaler and compact spacer 28 19563 becotide for nebuliser 29 19642 ventolin nebules 30 19649 ventolin rotahaler 31 32 19653 ventolin respirator 33 19726 ventolin s/r 34 19732 cobutolin inh 35 19735 uniphyllin continus 36 19736 becotide susp for nebulisation 37 19737 atrovent nebuliser solution (1ml vial) 38 19799 tulobuterol 2mg 39 19805 atrovent 40 20095 precortisyl forte 25mg tablet (aventis pharma) 41 20225 aminophylline 500 mg inj 42 20670 prednisolone e/c 43 20675 salbutamol rotahaler complete unit 44 45 20680 aerolin autohaler 46 20707 becotide 100 47 20720 atrovent forte 48 20763 becloforte 49 20781 salbutamol u.dose nebulising 2.5mg/2.5ml 50 20803 ipratropium bromide nebuliser solution 51 20812 pulmicort refill 52 20825 spacehaler bdp 250microgram/actuation spacehaler (celltech pharma europe ltd) 53 20838 salbuvent 2mg tablet (pharmacia ltd) 54 21005 beclometasone 250micrograms/dose inhaler cfc free 55 21102 salbutamol 2mg/5ml oral solution (lagap) 56 21330 oxygen composite cylinders size if2 with integral headset (medigas ltd) 57 58 21331 oxygen composite cylinders with integral headset (air products plc) 59 21402 oxygen cylinders size pd (air products plc) 60 21482 beclometasone 100micrograms/dose inhaler (generics (uk) ltd) 21769 lasma 300mg tablet (pharmax ltd) 21833 decortisyl 5mg tablet (roussel laboratories ltd)

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1 2 3 21859 asmaven 100microgram inhalation powder (berk pharmaceuticals ltd) 4 22080 aminophylline 20 ml inj 5 6 22225 beclomethasone /salbutamol 7 22313 ventmax sr 8mg capsules (chiesi ltd) 8 22430 spacehaler salbutamol 100microgram/inhalation spacehaler (celltech pharma europe 9 ltd) 10 22467 salbutamol respirator soln 11 22512 salbutamol inhaler 12 22550 duovent 13 22661 pirbuterol 10mg capsule 14 22663 respacal 2mg tablet (ucb pharma ltd) 15 22669 choline theophyllinate 270 mg tab 16 22790 reproterol 10mg/ml respirator solution 17 For peer review only 22828 carbocisteine 750mg/5ml forte oral solution 18 19 23269 maxivent 2.5mg/2.5ml nebuliser liquid unit dose steripoule vials (ashbourne 20 pharmaceuticals ltd) 21 23337 oxygen cylinder f size 1280 litres 22 23512 precortisyl 5mg tablet (hoechst marion roussel) 23 23567 respontin 250micrograms/1ml nebules (glaxosmithkline uk ltd) 24 23572 aminophylline sr 225mg modified-release tablet (ivax pharmaceuticals uk ltd) 25 23675 pulmicort l.s. refil 26 23688 ventolin rotacaps 27 23709 ipratropium 500micrograms/2ml nebuliser liquid steri-neb unit dose vials (teva uk ltd) 28 23741 novolizer budesonide 200microgram/actuation pressurised inhalation (meda 29 pharmaceuticals ltd) 30 23787 exirel 10mg capsule (3m health care ltd) 31 32 23905 oxygen cylinders size d (boc ltd) 33 23961 ipratropium bromide 250microgram/ml inhalation vapour (galen ltd) 34 24219 becotide rotacaps 35 24380 sodium cromoglicate 1mg/dose / salbutamol 100micrograms/dose inhaler with spacer 36 24418 biophylline 350mg tablet (lorex synthelabo ltd) 37 24456 carbocisteine 375mg tablets 38 24645 ventolin 5mg/5ml solution for infusion ampoules (glaxosmithkline uk ltd) 39 24660 betamethasone valerate 40 24674 biophylline 500mg tablet (lorex synthelabo ltd) 41 24716 prednisolone e/c 42 24898 spacehaler bdp 100microgram/actuation spacehaler (celltech pharma europe ltd) 43 25020 ipratropium bromide (forte) 44 45 25073 salbutamol 46 25093 theophylline s/r 47 25204 beclometasone 100micrograms/dose inhaler (a a h pharmaceuticals ltd) 48 25218 salbutamol cfc/free b/a 49 25272 precortisyl 1mg tablet (hoechst marion roussel) 50 25339 maxivent 5mg/2.5ml nebuliser liquid unit dose steripoule vials (ashbourne 51 pharmaceuticals ltd) 52 25784 atimos modulite 12micrograms/dose inhaler (chiesi ltd) 53 25820 bronchodil 10mg/5ml oral solution (viatris pharmaceuticals ltd) 54 25821 exirel 7.5mg/5ml oral solution (3m health care ltd) 55 25829 pirbuterol 7.5mg/5ml oral solution 56 26063 beclometasone 100micrograms/dose inhaler (teva uk ltd) 57 58 26079 uniphyllin paediatric continus 59 26420 exirel 10 mg tab 60 26525 ventolin 26616 ipratropium bromide with fenoterol hydrobromide 0micrograms + 100micrograms/actuation

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1 2 3 26665 pulmicort complete 4 26716 airomir autohaler cfc free b/a 5 6 26829 brelomax 2mg tablet (abbott laboratories ltd) 7 26873 cobutolin 2mg tablet (actavis uk ltd) 8 27040 phyllocontin continus 9 27188 easyhaler budesonide 200micrograms/dose dry powder inhaler (orion pharma (uk) 10 ltd) 11 27301 bromhexine hcl 8mg tablets 12 27340 salbuvent 0.5mg/ml injection (pharmacia ltd) 13 27505 ipratropium bromide with fenoterol hydrobromide 40micrograms + 14 100micrograms/actuation 15 27525 becotide 50 16 27558 choledyl 17 For peer review only 27573 ventolin 18 19 27583 pulmicort 20 27679 beclometasone 100microgram/actuation pressurised inhalation (approved 21 prescription services ltd) 22 27842 aminophylline 2 ml inj 23 27889 prednisolone 24 27915 fluticasone prop disk refill 25 27959 prednisolone 26 27962 deltastab 1mg tablet (waymade healthcare plc) 27 28073 beclometasone 250microgram/actuation pressurised inhalation (approved 28 prescription services ltd) 29 28241 aminophylline 250mg/10ml solution for injection minijet pre-filled syringes (ucb 30 pharma ltd) 31 32 28376 prednisolone 2.5mg gastro-resistant tablet (biorex laboratories ltd) 33 28508 salbutamol 100microgram/inhalation inhalation powder (ivax pharmaceuticals uk ltd) 34 28577 ventolin 50microgram/ml injection (allen & hanburys ltd) 35 28640 beclometasone 100microgram/actuation inhalation powder (actavis uk ltd) 36 28761 spacehaler bdp 50microgram/actuation spacehaler (celltech pharma europe ltd) 37 28859 deltastab 5mg tablet (waymade healthcare plc) 38 28881 salbutamol 2mg/5ml oral solution sugar free (a a h pharmaceuticals ltd) 39 29267 salbuvent 4mg tablet (pharmacia ltd) 40 29273 aminophylline 225mg modified-release tablet (hillcross pharmaceuticals ltd) 41 29325 beclometasone 250micrograms/dose inhaler (generics (uk) ltd) 42 30118 salbutamol 100micrograms/dose inhaler cfc free (teva uk ltd) 43 30204 salbutamol 200micrograms inahalation capsules 44 45 30210 beclometasone 250micrograms/dose inhaler (teva uk ltd) 46 30212 salbutamol cyclohaler 47 30229 ipratropium bromide 250microgram/ml nebuliser liquid (galen ltd) 48 30230 salbutamol 100micrograms/actuation breath actuated inhaler 49 30238 beclometasone 50microgram/actuation pressurised inhalation (approved prescription 50 services ltd) 51 30240 aerolin autohaler 100microgram/actuation pressurised inhalation (3m health care ltd) 52 30390 deltastab 2 mg tab 53 30596 aminophylline 225mg modified-release tablet (actavis uk ltd) 54 30649 easyhaler budesonide 400micrograms/dose dry powder inhaler (orion pharma (uk) 55 ltd) 56 30971 decortisyl 25 mg tab 57 58 31082 salbuvent 5mg/ml respirator solution (pharmacia ltd) 59 31290 salbulin cfc free 60 31327 prednisolone steaglate 6.65mg tablet 31758 uniphyllin continus 31774 beclometasone 50micrograms/dose inhaler (generics (uk) ltd)

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1 2 3 31845 salapin 2mg/5ml syrup (pinewood healthcare) 4 31933 salbutamol 100micrograms/dose inhaler (a a h pharmaceuticals ltd) 5 6 32050 salbutamol 400 cyclocaps (teva uk ltd) 7 32102 salbutamol 4mg tablets (a a h pharmaceuticals ltd) 8 32461 choline theophyllinate 90 mg tab 9 32812 numotac 10mg tablet (3m health care ltd) 10 32874 beclometasone 50microgram/actuation inhalation powder (actavis uk ltd) 11 32893 theophylline 100mg/lysine 74mg mg tab 12 33089 salbutamol 100micrograms/dose inhaler (kent pharmaceuticals ltd) 13 33258 beclometasone 250micrograms/dose inhaler (a a h pharmaceuticals ltd) 14 33373 salbutamol 200 cyclocaps (teva uk ltd) 15 33588 salbutamol 100micrograms/dose inhaler (generics (uk) ltd) 16 33691 prednisolone 5mg gastro-resistant tablet (biorex laboratories ltd) 17 For peer review only 33817 salbutamol 100micrograms/dose inhaler cfc free (actavis uk ltd) 18 19 33849 beclometasone 100microgram/actuation inhalation powder (neo laboratories ltd) 20 33888 azithromycin 250mg tablets 21 33988 prednisolone 5mg tablet (co-pharma ltd) 22 33990 prednisolone 5mg tablet (ivax pharmaceuticals uk ltd) 23 34018 salbutamol 5mg/2.5ml nebuliser liquid (galen ltd) 24 34029 salbutamol 400micrograms inahalation capsules 25 34109 prednisolone 5 mg gastro-resistant tablet 26 34134 aerolin 400 100microgram/actuation inhalation powder (3m health care ltd) 27 34162 salbutamol 2.5mg/2.5ml nebuliser liquid (galen ltd) 28 34310 salbutamol 100micrograms/dose inhaler cfc free (a a h pharmaceuticals ltd) 29 34311 salbutamol 100microgram/inhalation inhalation powder (berk pharmaceuticals ltd) 30 34315 beclometasone 250microgram/actuation inhalation powder (actavis uk ltd) 31 32 34428 beclometasone 50microgram/actuation inhalation powder (neo laboratories ltd) 33 34618 salbutamol 2mg tablets (actavis uk ltd) 34 34619 salbutamol 100microgram/inhalation inhalation powder (kent pharmaceuticals ltd) 35 34631 prednisolone 1mg tablet (co-pharma ltd) 36 34702 salbutamol 100microgram/inhalation inhalation powder (c p pharmaceuticals ltd) 37 34739 beclometasone 50micrograms/dose inhaler (teva uk ltd) 38 34794 beclometasone 200micrograms/dose inhaler (a a h pharmaceuticals ltd) 39 34859 beclometasone 250microgram/actuation inhalation powder (neo laboratories ltd) 40 34914 prednisolone 1mg tablet (celltech pharma europe ltd) 41 34919 beclometasone 50micrograms/dose inhaler (a a h pharmaceuticals ltd) 42 34938 salbutamol 4mg tablets (actavis uk ltd) 43 35011 tiotropium bromide 18microgram inhalation powder capsules 44 45 35014 tiotropium bromide 18microgram inhalation powder capsules with device 46 35015 erdosteine 300mg capsules 47 35071 becodisks 200microgram (glaxosmithkline uk ltd) 48 35106 becodisks 100microgram with diskhaler (glaxosmithkline uk ltd) 49 35107 beclometasone 400microgram inhalation powder blisters with device 50 35113 beclometasone 200microgram inhalation powder blisters 51 35118 becodisks 400microgram with diskhaler (glaxosmithkline uk ltd) 52 35165 serevent 50microgram disks with diskhaler (glaxosmithkline uk ltd) 53 35178 erdotin 300mg capsules (galen ltd) 54 35225 flixotide 100microgram disks with diskhaler (glaxosmithkline uk ltd) 55 35288 beclometasone 400microgram inhalation powder blisters 56 35293 beclometasone 200microgram inhalation powder blisters with device 57 58 35299 becodisks 400microgram (glaxosmithkline uk ltd) 59 35374 flixotide 500microgram disks (glaxosmithkline uk ltd) 60 35392 flixotide 500microgram disks with diskhaler (glaxosmithkline uk ltd) 35408 becodisks 100microgram (glaxosmithkline uk ltd) 35430 becodisks 200microgram with diskhaler (glaxosmithkline uk ltd)

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1 2 3 35461 flixotide 250microgram disks with diskhaler (glaxosmithkline uk ltd) 4 35503 salmeterol 50microgram inhalation powder blisters 5 6 35510 budesonide 200micrograms/dose dry powder inhalation cartridge with device 7 35522 bricanyl 500micrograms/1ml solution for injection ampoules (astrazeneca uk ltd) 8 35542 salmeterol 50microgram inhalation powder blisters with device 9 35557 ipramol nebuliser solution 2.5ml steri-neb unit dose vials (teva uk ltd) 10 35566 oxygen bp with set gas 1360 litres 11 35580 beclometasone 100microgram inhalation powder blisters with device 12 35602 budesonide 200micrograms/dose dry powder inhalation cartridge 13 35611 flixotide 250microgram disks (glaxosmithkline uk ltd) 14 35631 budelin novolizer 200micrograms/dose inhalation powder (meda pharmaceuticals ltd) 15 35638 fluticasone 100microgram inhalation powder blisters with device 16 35652 beclometasone 100microgram inhalation powder blisters 17 For peer review only 35700 fluticasone 500microgram inhalation powder blisters with device 18 19 35724 budelin novolizer 200micrograms/dose inhalation powder refill (meda 20 pharmaceuticals ltd) 21 35725 formoterol easyhaler 12micrograms/dose dry powder inhaler (orion pharma (uk) ltd) 22 35744 bricanyl 2.5mg/5ml solution for injection ampoules (astrazeneca uk ltd) 23 35772 fluticasone 100microgram inhalation powder blisters 24 35825 serevent 50microgram disks (glaxosmithkline uk ltd) 25 35861 terbutaline 2.5mg/5ml solution for injection ampoules 26 35862 terbutaline 500micrograms/1ml solution for injection ampoules 27 35905 fluticasone 250microgram inhalation powder blisters 28 35986 flixotide 50microgram disks (glaxosmithkline uk ltd) 29 36021 fluticasone 50microgram inhalation powder blisters with device 30 36090 flixotide 100microgram disks (glaxosmithkline uk ltd) 31 32 36290 flixotide 50microgram disks with diskhaler (glaxosmithkline uk ltd) 33 36401 fluticasone 250microgram inhalation powder blisters with device 34 36462 fluticasone 500microgram inhalation powder blisters 35 36677 reproterol 10mg/5ml oral solution 36 36864 tiotropium bromide 2.5micrograms/dose solution for inhalation cartridge with device 37 cfc free 38 37432 fostair 100micrograms/dose/6micrograms/dose inhaler (chiesi ltd) 39 37447 fluticasone 50microgram inhalation powder blisters 40 37470 beclometasone 100micrograms/dose / formoterol 6micrograms/dose inhaler cfc free 41 37612 terbutaline 5mg/2ml nebuliser liquid unit dose vials (galen ltd) 42 37791 ipratropium bromide 250microgram/ml 43 38079 salbutamol 100micrograms/dose dry powder inhalation cartridge with device 44 45 38097 salbutamol cyclocaps 200microgram inhalation powder (dupont pharmaceuticals ltd) 46 38120 theophylline 500mg modified release tablets 47 38136 salbulin novolizer 100micrograms/dose inhalation powder (meda pharmaceuticals ltd) 48 38214 salbutamol 100micrograms/dose dry powder inhalation cartridge 49 38226 salbulin novolizer 100micrograms/dose inhalation powder refill (meda 50 pharmaceuticals ltd) 51 38407 prednisolone 20mg tablet 52 38416 salbutamol cyclocaps 400microgram inhalation powder (dupont pharmaceuticals ltd) 53 38419 terbutaline 1.5mg/5ml oral solution sugar free (a a h pharmaceuticals ltd) 54 39040 phyllocontin forte continus 350mg tablets (napp pharmaceuticals ltd) 55 39099 pulmicort 100micrograms/dose inhaler cfc free (astrazeneca uk ltd) 56 39102 budesonide 100micrograms/dose inhaler cfc free 57 58 39200 aerobec forte 250 autohaler (meda pharmaceuticals ltd) 59 39879 budesonide 200micrograms/dose inhaler cfc free 60 40057 pulmicort 200micrograms/dose inhaler cfc free (astrazeneca uk ltd) 40177 ipratropium bromide 250microgram/ml nebuliser liquid (hillcross pharmaceuticals ltd) 40218 azithromycin 500mg tablets (teva uk ltd)

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1 2 3 40599 salbutamol 5mg/2.5ml nebuliser liquid unit dose steripoule vials (galen ltd) 4 40637 ipratropium 250micrograms/1ml nebuliser liquid unit dose steripoule vials (galen ltd) 5 6 40655 salbuvent 100microgram/actuation inhalation powder (pharmacia ltd) 7 40709 salbutamol 2.5mg/2.5ml nebuliser liquid unit dose vials (a a h pharmaceuticals ltd) 8 40832 ipratropium 500micrograms/2ml nebuliser liquid unit dose steripoule vials (galen ltd) 9 41269 beclometasone 400 cyclocaps (teva uk ltd) 10 41412 beclometasone 400micrograms/actuation inhaler 11 41548 salbutamol 2mg tablets (approved prescription services ltd) 12 41549 salbutamol 2mg tablet (c p pharmaceuticals ltd) 13 41691 salbutamol 2mg/5ml oral solution sugar free (sandoz ltd) 14 41832 monovent 1.5mg/5ml syrup (sandoz ltd) 15 42103 tulobuterol 1mg/5ml sugar free syrup 16 42279 salbutamol 2.5mg/2.5ml nebuliser liquid unit dose steripoule vials (galen ltd) 17 For peer review only 42497 salbutamol 8mg tablet 18 19 42511 aminophylline 25mg/ml injection (celltech pharma europe ltd) 20 42830 ventolin 100micrograms/dose evohaler (glaxosmithkline uk ltd) 21 42858 ventolin 200micrograms/dose accuhaler (glaxosmithkline uk ltd) 22 42867 terbutaline 1.5mg/5ml oral solution (sandoz ltd) 23 42886 bricanyl 500micrograms/dose turbohaler (astrazeneca uk ltd) 24 42910 aminophylline 250mg/10ml solution for injection ampoules (martindale 25 pharmaceuticals ltd) 26 42928 flixotide 100micrograms/dose accuhaler (glaxosmithkline uk ltd) 27 42985 flixotide 50micrograms/dose accuhaler (glaxosmithkline uk ltd) 28 42994 flixotide 250micrograms/dose accuhaler (glaxosmithkline uk ltd) 29 43046 salipraneb 0.5mg/2.5mg nebuliser solution 2.5ml ampoules (arrow generics ltd) 30 43074 flixotide 500micrograms/dose accuhaler (glaxosmithkline uk ltd) 31 32 43085 bricanyl 5mg/2ml respules (astrazeneca uk ltd) 33 43400 clamelle 500mg tablets (actavis uk ltd) 34 43544 prednisone 5mg tablet (knoll ltd) 35 43738 indacaterol 150microgram inhalation powder capsules with device 36 43794 nebusal 7% inhalation solution 4ml ampoules (forest laboratories uk ltd) 37 43870 sodium chloride 7% inhalation solution 4ml ampoules 38 43893 onbrez breezhaler 150microgram inhalation powder capsules with device (novartis 39 pharmaceuticals uk ltd) 40 44064 onbrez breezhaler 300microgram inhalation powder capsules with device (novartis 41 pharmaceuticals uk ltd) 42 44173 roflumilast 500microgram tablets 43 44380 prednisone 1mg modified-release tablets 44 45 44431 daxas 500microgram tablets (takeda uk ltd) 46 44713 salbutamol 100microgram/inhalation inhalation powder (celltech pharma europe ltd) 47 45302 prednisolone 5mg tablet (biorex laboratories ltd) 48 45610 indacaterol 300microgram inhalation powder capsules with device 49 45863 salbutamol 5mg/2.5ml nebuliser liquid (generics (uk) ltd) 50 46157 beclometasone 200 cyclocaps (teva uk ltd) 51 46551 salbutamol 100microgram/inhalation inhalation powder (neo laboratories ltd) 52 46695 azithromycin 500mg tablet (hillcross pharmaceuticals ltd) 53 49016 sodium chloride 7% inhalation solution 4ml vials 54 49045 nebusal 7% inhalation solution 4ml vials (forest laboratories uk ltd) 55 49530 azithromycin 200mg/5ml oral suspension (sandoz ltd) 56 50508 mucodyne 250mg/5ml syrup (sigma pharmaceuticals plc) 57 58 52029 zithromax 250mg capsules (mawdsley-brooks & company ltd) 59 53303 carbocisteine 375mg capsules (arrow generics ltd) 60

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1 2 3 Spirometry codes 4 medcode readterm 5 6 6118 spirometry 7 10336 spirometry reversibility 8 10337 spirometry screening 9 10420 spirometry reversibility negative 10 10492 spirometry reversibility positive 11 13683 referral for spirometry 12 14453 forced expiratory volume - fev 13 19428 chronic obstructive pulmonary disease excluded by spirometry 14 26241 spirometry indicated 15 29015 spirometry 16 45993 incentive spirometry 17 For peer review only 102522 post bronchodilator spirometry 18 19 6091 Percent predicted FEV1 20 8512 FEV1/FVC percent 21 10320 Forced expired volume in 1 second 22 11078 FEV1/FVC > 70% of predicted 23 14455 FEV1/FVC ratio normal 24 14456 FEV1/FVC ratio 25 19830 FEV1 after bronchodilation 26 19832 FEV1/FVC ratio after bronchodilator 27 23237 FEV1 before bronchodilation 28 23285 FEV1/FVC ratio abnormal 29 25083 FEV1/FVC < 70% of predicted 30 27141 FEV1/FVC ratio before bronchodilator 31 32 43040 FEV1 pre steroids 33 43041 FEV1 post steroids 34 58632 FEV1/FVC ratio pre steroids 35 58633 FEV1/FVC ratio post steroids 36 99777 Forced expired volume in 1 second reversibility 37 100391 Forced expired volume in 1 second percentage change 38 101079 Percentage predicted FEV1 after bronchodilation 39 40 41 Non-specific bronchitis codes / Frequent winter bronchitis 42 medcode readterm 43 148 bronchitis unspecified 44 45 152 wheezy bronchitis 46 3243 chronic bronchitis 47 3480 bronchitis nos 48 4519 h/o: bronchitis 49 5798 chronic asthmatic bronchitis 50 5909 chronic wheezy bronchitis 51 7092 recurrent wheezy bronchitis 52 11150 mucopurulent chronic bronchitis 53 13247 fh: bronchitis 54 13262 fh: bronchitis/coad 55 14798 emphysematous bronchitis 56 15157 chronic bronchitis nos 57 58 15626 chronic catarrhal bronchitis 59 17359 chest infection - unspecified bronchitis 60 24248 mixed simple and mucopurulent chronic bronchitis 25603 simple chronic bronchitis 27819 obstructive chronic bronchitis

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1 2 3 37959 fetid chronic bronchitis 4 40159 purulent chronic bronchitis 5 6 44525 obstructive chronic bronchitis nos 7 61118 simple chronic bronchitis nos 8 61513 mucopurulent chronic bronchitis nos 9 62913 [v]screening for chronic bronchitis or emphysema 10 66043 other chronic bronchitis 11 68066 other chronic bronchitis nos 12 202167 INFLUENZAL BRONCHITIS 13 207165 Acute streptococcal bronchitis 14 207166 Acute viral bronchitis unspecified 15 216109 Acute membranous bronchitis 16 216111 Acute bronchitis due to mycoplasma pneumoniae 17 For peer review only 216112 Acute bronchitis NOS 18 19 216141 Chest infection - unspecified bronchopneumonia 20 220234 BRONCHITIS FIBRINOUS ACUTE 21 225216 Acute pseudomembranous bronchitis 22 225241 Bronchitis NOS 23 234340 Acute bronchitis due to rhinovirus 24 239395 H/O: bronchitis 25 243349 Acute bronchitis and bronchiolitis 26 243350 Acute pneumococcal bronchitis 27 243351 Acute bronchitis due to echovirus 28 243389 Bronchitis unspecified 29 261710 Acute wheezy bronchitis 30 261711 Acute purulent bronchitis 31 32 261712 Acute croupous bronchitis 33 261713 Acute bronchitis due to respiratory syncytial virus 34 271007 Acute bronchitis due to coxsackievirus 35 280054 Acute fibrinous bronchitis 36 280055 Acute bronchitis due to parainfluenza virus 37 280082 Chest infection - unspecified bronchitis 38 289164 Acute bronchitis 39 289165 Acute neisseria catarrhalis bronchitis 40 289166 Subacute bronchitis unspecified 41 289233 [X]Acute bronchitis due to other specified organisms 42 293231 BRONCHITIS SUBACUTE 43 298435 Acute haemophilus influenzae bronchitis 44 45 298436 Acute bacterial bronchitis unspecified 46 298440 Acute bronchitis or bronchiolitis NOS 47 303952 BRONCHITIS ACUTE 48 303954 VIRAL BRONCHITIS 49 303963 BRONCHOPNEUMONIA 50 306525 BRONCHITIS PURULENT 51 306528 CATARRHAL BRONCHITIS 52 308788 Acute bronchitis 53 54 55 Respiratory symptom codes 56

57 58 Wheeze 59 medcode readterm 60 152 wheezy bronchitis 173 wheezing 2210 [d]wheezing

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1 2 3 2891 wheezing symptom 4 4836 nocturnal cough / wheeze 5 6 5861 o/e - expiratory wheeze 7 5909 chronic wheezy bronchitis 8 5978 acute wheezy bronchitis 9 7092 recurrent wheezy bronchitis 10 42317 increasing exercise wheeze 11 100954 [d]mild wheeze 12 101037 [d]moderate wheeze 13 101073 [d]severe wheeze 14 101421 [d]very severe wheeze 15 102480 on examination - inspiratory wheeze 16 For peer review only 17 18 19 Chronic cough 20 medcode readterm 21 92 cough 22 292 chesty cough 23 1025 bronchial cough 24 1160 [d]cough 25 1234 productive cough nos 26 1273 c/o - cough 27 1612 chronic cough 28 3068 night cough present 29 3628 persistent cough 30 3645 coughing up phlegm 31 32 4070 morning cough 33 4836 nocturnal cough / wheeze 34 4931 dry cough 35 7706 productive cough -clear sputum 36 7707 cough symptom nos 37 7708 productive cough-yellow sputum 38 7773 productive cough -green sputum 39 16717 smokers' cough 40 22318 difficulty in coughing up sputum 41 29318 evening cough 42 43795 unexplained cough 43 60903 cough aggravates symptom 44 45 100333 cough on exercise 46 47 48 49 Exertional breathlessness 50 medcode readterm 51 735 [d]breathlessness 52 1429 breathlessness 53 3092 [d]dyspnoea 54 5175 breathlessness symptom 55 5896 dyspnoea - symptom 56 6326 breathless - moderate exertion 57 58 7000 o/e - dyspnoea 59 7932 breathless - mild exertion 60 19426 mrc breathlessness scale: grade 3 19427 mrc breathlessness scale: grade 2 19429 mrc breathlessness scale: grade 5

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1 2 3 19430 mrc breathlessness scale: grade 4 4 19432 mrc breathlessness scale: grade 1 5 6 21801 breathlessness nos 7 24889 breathless - strenuous exertion 8 31143 breathless - at rest 9 42287 borg breathlessness score: 6 severe (+) 10 53771 dyspnoea on exertion 11 57193 borg breathlessness score: 3 moderate 12 57759 borg breathlessness score: 2 slight 13 59860 borg breathlessness score: 4 somewhat severe 14 64049 borg breathlessness score: 5 severe 15 67566 borg breathlessness score: 9 very, very sev (almost maximal) 16 68707 borg breathlessness score: 1 very slight 17 For peer review only 70061 borg breathlessness score: 7 very severe 18 19 70818 borg breathlessness score: 0.5 very, very slight 20 72334 borg breathlessness score: 8 very severe (+) 21 101843 borg breathlessness score: 10 maximal 22 741 [D]Shortness of breath 23 2563 [D]Respiratory distress 24 2575 Short of breath on exertion 25 2931 Difficulty breathing 26 4822 Shortness of breath 27 5349 Shortness of breath symptom 28 9297 [D]Respiratory insufficiency 29 22094 Short of breath dressing/undressing 30 40813 Unable to complete a sentence in one breath 31 32 33 Sputum codes 34 medcode readterm 35 292 chesty cough 36 1025 bronchial cough 37 1234 productive cough nos 38 3645 coughing up phlegm 39 7706 productive cough -clear sputum 40 7708 productive cough-yellow sputum 41 7773 productive cough -green sputum 42 22318 difficulty in coughing up sputum 43 1251 [d]abnormal sputum 44 45 3727 sputum sent for c/s 46 8287 sputum sample obtained 47 8760 [d]positive culture findings in sputum 48 9807 sputum - symptom 49 14804 sputum appears infected 50 15430 [d]sputum abnormal - colour 51 16026 sputum examination: abnormal 52 18964 sputum clearance 53 20086 [d]sputum abnormal - amount 54 22318 difficulty in coughing up sputum 55 23582 [d]abnormal sputum nos 56 24181 sputum: mucopurulent 57 58 29294 sputum appears normal 59 30754 yellow sputum 60 30904 sputum sent for examination 31417 sputum - not infected 35577 sputum examination - general

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1 2 3 36515 [d]abnormal sputum - tenacious 4 36880 green sputum 5 6 40201 sputum microscopy: nad 7 40202 mucoid sputum - o/e 8 42573 clear sputum 9 43270 sputum evidence of infection 10 43272 sputum examination nos 11 44214 [d]sputum abnormal - odour 12 49029 sputum gen. exam. nos 13 49694 sputum: organism on gram stain 14 52806 sputum: frothy/watery 15 54177 sputum: excessive - mucoid 16 61079 sputum inspection nos 17 For peer review only 91680 expectoration of induced sputum from respiratory tract 18 19 100484 volume of sputum 20 100524 moderate sputum 21 100629 white sputum 22 100647 copious sputum 23 100931 brown sputum 24 101782 profuse sputum 25 103209 grey sputum 26 27 28 QOF codes 29 30 H3... Chronic obstructive pulmonary disease 31 H31.. Chronic bronchitis 32 33 H310. Simple chronic bronchitis 34 H3100 Chronic catarrhal bronchitis 35 H310z Simple chronic bronchitis NOS 36 H311. Mucopurulent chronic bronchitis 37 H3110 Purulent chronic bronchitis 38 H3111 Fetid chronic bronchitis 39 H311z Mucopurulent chronic bronchitis NOS 40 H312. Obstructive chronic bronchitis 41 H3120 Chronic asthmatic bronchitis 42 H3121 Emphysematous bronchitis 43 H3123 Bronchiolitis obliterans 44 H312z Obstructive chronic bronchitis NOS 45 46 H313. Mixed simple and mucopurulent chronic bronchitis 47 H31y. Other chronic bronchitis 48 H31y1 Chronic tracheobronchitis 49 H31yz Other chronic bronchitis NOS 50 H31z. Chronic bronchitis NOS 51 H32.. Emphysema 52 H320. Chronic bullous emphysema 53 H3200 Segmental bullous emphysema 54 H3201 Zonal bullous emphysema 55 H3202 Giant bullous emphysema 56 H3203 Bullous emphysema with collapse 57 H320z Chronic bullous emphysema NOS 58 59 H321. Panlobular emphysema 60 H322. Centrilobular emphysema H32y. Other emphysema H32y0 Acute vesicular emphysema

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1 2 3 H32y1 Atrophic (senile) emphysema 4 H32y2 MacLeod's unilateral emphysema 5 6 H32yz Other emphysema NOS 7 H32z. Emphysema NOS 8 H36.. Mild chronic obstructive pulmonary disease 9 H37.. Moderate chronic obstructive pulmonary disease 10 H38.. Severe chronic obstructive pulmonary disease 11 H39.. Very severe chronic obstructive pulmonary disease 12 H3A.. End stage chronic obstructive airways disease (v23) 13 H3y.. Other specified chronic obstructive airways disease 14 H3y0. Chronic obstructive pulmonary disease with acute lower respiratory 15 infection (v23) 16 H3y1. Chronic obstructive pulmonary disease with acute exacerbation, 17 For peer review only unspecified (v23) 18 19 H3z.. Chronic obstructive airways disease NOS 20 21 22 23 24 GP Questionnaire 25 26 1. Do you think this patient has COPD? Yes / No / Uncertain 27 2. What was the diagnosis of COPD based on? (please circle all that apply) 28 Smoking history symptoms spirometry other (please describe) 29 3. Has a respiratory physician seen the patient and confirmed a diagnosis of COPD? 30 4. Does the patient have any other respiratory condition? 31 If yes, than what? 32

33 34

35 36

37 38

39 40

41 42 Table 4: The PPV and proportion of patients diagnosed with COPD who also had cardiovascular 43 disease or asthma 44 Algorithm Number Number PPV and 95% Number Number PPV and 95% CI 45 with confirmed CI with confirmed 46 CVDx COPD asthma COPD 47 COPD Code + 20 17 85.0, 59.6-95.6 18 14 72.2, 45.3-89.1 48 spirometry + COPD 49 medication 50 COPD Code + 24 20 83.3, 61.1-94.1 20 14 70.0, 45.0-87.0 51 spirometry 52 COPD Code + 18 16 88.9, 61.1-97.6 16 9 56.3, 29.8-79.6 53 COPD medication 54 COPD Code only 18 16 88.9, 61.1-97.6 15 12 80.0, 48.8-94.4 55 Bronchitis + COPD 21 8 38.1, 19.1-61.7 27 4 14.8, 5.3-35.1 56 medication 57 Bronchitis only 19 8 42.1, 21.1-66.5 23 6 26.1, 11.4-49.1 58 59 Symptoms + 15 9 60.0, 31.8-82.9 19 4 21.1, 7.3-47.3 60 spirometry Symptoms only 9 2 22.2, 3.9-67.0 23 2 8.7, 1.9-31.4

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1 2 3 Table 5: The PPV and proportion of patients diagnosed with COPD who were current smokers 4 Algorithm Number Number PPV and 95% CI 5 current confirmed COPD 6 smokers 7 COPD Code + 49 44 89.9, 77.1-95.8 8 spirometry + COPD 9 medication 10 COPD Code + 51 39 76.5, 62.5-86.4 11 spirometry 12 COPD Code + COPD 55 46 83.6, 71.0-91.4 13 medication 14 COPD Code only 47 41 87.2, 73.8-94.3 15 Bronchitis + COPD 67 34 50.7, 38.7-62.7 16 medication 17 Bronchitis only For64 peer review19 only29.7, 19.6-42.3 18 Symptoms + 50 20 40.0, 27.1-54.5 19 spirometry 20 Symptoms only 58 6 10.3, 4.6-21.7 21 22 23

26 27 28 29 30 31 32 Table 6: The PPV and proportion of patients diagnosed with COPD by COPD severity 33 Algorithm GOLD 1 GOLD 2 GOLD 3 GOLD 4 34 Number Number confirmed, Number Number 35 confirmed, (PPV (PPV and 95% CI) confirmed, (PPV confirmed, 36 and 95% CI) and 95% CI) (PPV and 95% 37 CI) 38 COPD Code + spirometry 9, 34, 22, 6, 39 + COPD medication (69.2, 36.5-89.8) (87.2, 71.8-94.8) (100) (100) 40 41 COPD Code + spirometry 8, 35, 20, 3, 42 (66.7, 32.9-89.1) (83.3, 68.2-92.1) (100) (75, 4.1-99.5) 43 44 COPD Code + COPD 14, 32 20, 6, 45 medication (82.4, 53.7-94.9) (84.2, 68.1-93.0) (95.2, 69.1-99.4) (100) 46 47 COPD Code only 14, 37, 14, 3, 48 (82.4, 53.7-94.9) (86.0, 71.5-93.8) (93.3, 58.4-99.3) (100) 49 Bronchitis + COPD 7, 20, 11, 2, 50 medication (36.8, 17.3-62.0) (76.9, 55.6-89.9) (91.7, 49.9-99.2) (100) 51 52 Bronchitis only 3, 7, 10 1, 53 (20.0, 5.6-51.2) (63.6, 28.8-83.3) (100) (100) 54 55 Symptoms + spirometry 4, 19, 10 1, 56 (57.1, 15.0-90.9) (90.5, 66.0-97.9) (90.9, 46.3-99.1) (100) 57 58 Symptoms only 2, 6, 0 0 59 (40, 3.8-91.9) (100) 60

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1 2 3 4 Table 7: The PPV and proportion of patients diagnosed with COPD by timing of diagnosis 5 Algorithm 2004 to end 2008 Post 2008 6 7 Number Number PPV and 95% Number Number PPV and 95% 8 in confirmed CI in confirmed CI 9 algorithm COPD algorithm COPD 10 COPD Code + 32 28 87.5, 69.8-95.5 53 48 90.6, 78.7-96.1 11 spirometry + 12 COPD medication 13 COPD Code + 14 11 78.6, 46.0-94.0 66 56 84.8, 73.7-91.8 14 spirometry 15 COPD Code + 27 23 85.2, 64.9-94.7 61 54 88.5, 77.4-94.5 16 COPD medication 17 COPD Code onlyFor 21 peer16 review76.2, 51.7-90.5 only68 61 89.7, 79.6-95.1 18 Bronchitis + COPD 94 42 44.7, 34.8-55.0 5 2 40.0, 3.8-91.9 19 medication 20 Bronchitis only 83 22 26.5, 18.0-37.2 5 4 80.0, 11.1-99.2 21 Symptoms + 63 28 44.4, 32.4-57.1 22 9 40.9, 21.6-63.5 22 spirometry 23 Symptoms only 64 10 15.6, 8.5-27.0 26 1 3.8, 0.47-25.4 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 STROBE Statement—checklist of items that should be included in reports of observational studies 3 4 5 Item No Recommendation 6 7 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 8 Pg 1 and 2 (b) Provide in the abstract an informative and balanced summary of what was done 9 and what was found 10 11 Introduction 12 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 13 Pg 3 14 Objectives 3 State specific objectives, including any prespecified hypotheses 15 Pg 4 For peer review only 16 17 Methods 18 Study design 4 Present key elements of study design early in the paper 19 Pg 4 20 21 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 22 Pg 4 exposure, follow-up, and data collection 23 Participants 6 (a) Cohort study —Give the eligibility criteria, and the sources and methods of 24 Pg 6 selection of participants. Describe methods of follow-up 25 26 Case-control study —Give the eligibility criteria, and the sources and methods of 27 case ascertainment and control selection. Give the rationale for the choice of cases 28 and controls 29 Cross-sectional study —Give the eligibility criteria, and the sources and methods of 30 selection of participants 31 32 (b) Cohort study —For matched studies, give matching criteria and number of 33 exposed and unexposed 34 Case-control study —For matched studies, give matching criteria and the number of 35 controls per case 36 37 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect 38 Pg 5,7 modifiers. Give diagnostic criteria, if applicable 39 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 40 measurement assessment (measurement). Describe comparability of assessment methods if there 41 Pg 7 is more than one group 42 43 Bias 9 Describe any efforts to address potential sources of bias 44 Pg 6 45 Study size 10 Explain how the study size was arrived at 46 Pg 8 47 48 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 49 Pg 7 and 8 describe which groupings were chosen and why 50 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 51 Pg 7 and 8 (b) Describe any methods used to examine subgroups and interactions 52 53 (c) Explain how missing data were addressed 54 (d) Cohort study —If applicable, explain how loss to follow-up was addressed 55 Case-control study —If applicable, explain how matching of cases and controls was 56 addressed 57 Cross-sectional study —If applicable, describe analytical methods taking account of 58 59 sampling strategy 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 Page 47 of 48 BMJ Open

1 2 (e) Describe any sensitivity analyses 3 Continued on next page 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml2 BMJ Open Page 48 of 48

1 2 3 Results 4 5 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, 6 Pg 9 examined for eligibility, confirmed eligible, included in the study, completing follow-up, 7 and analysed 8 (b) Give reasons for non-participation at each stage 9 (c) Consider use of a flow diagram 10 11 Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and 12 Pg 9 and 10 information on exposures and potential confounders 13 (b) Indicate number of participants with missing data for each variable of interest 14 (c) Cohort study —Summarise follow-up time (eg, average and total amount) 15 For peer review only 16 Outcome data 15* Cohort study —Report numbers of outcome events or summary measures over time 17 Pg 11 Case-control study—Report numbers in each exposure category, or summary measures of 18 exposure 19 Cross-sectional study—Report numbers of outcome events or summary measures 20 21 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their 22 Pg 10-12 precision (eg, 95% confidence interval). Make clear which confounders were adjusted for 23 and why they were included 24 (b) Report category boundaries when continuous variables were categorized 25 26 (c) If relevant, consider translating estimates of relative risk into absolute risk for a 27 meaningful time period 28 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 29 Supplementary analyses 30 material 31 32 Discussion 33 Key results 18 Summarise key results with reference to study objectives 34 Pg 12 35 36 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or 37 Pg 15 imprecision. Discuss both direction and magnitude of any potential bias 38 Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, 39 Pg 12-15 multiplicity of analyses, results from similar studies, and other relevant evidence 40 41 Generalisability 21 Discuss the generalisability (external validity) of the study results 42 Pg 15 43 Other information 44 Funding 22 Give the source of funding and the role of the funders for the present study and, if 45 46 Pg 17 applicable, for the original study on which the present article is based 47 48 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and 49 unexposed groups in cohort and cross-sectional studies. 50

51 52 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 53 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 54 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 55 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 56 57 available at www.strobe-statement.org. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml3 BMJ Open

Validation of Chronic Obstructive Pulmonary Disease (COPD) recording in the Clinical Practice Research Datalink (CPRD-GOLD)

For peer review only Journal: BMJ Open

Manuscript ID: bmjopen2014005540.R1

Article Type: Research

Date Submitted by the Author: 29May2014

Primary Subject Respiratory medicine Heading:

Secondary Subject Heading: Epidemiology

RESPIRATORY MEDICINE (see Thoracic Medicine), THORACIC MEDICINE, Keywords: Chronic airways disease < THORACIC MEDICINE, Epidemiology < THORACIC MEDICINE

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1 2 3 Validation of Chronic Obstructive Pulmonary Disease (COPD) recording in the Clinical 4 Practice Research Datalink (CPRD-GOLD) 5 6 Jennifer K Quint 1, Hana Müllerova 2, Rachael L DiSantostefano 3, Harriet Forbes 1, Susan 7 Eaton 4, John R Hurst 5, Kourtney Davis 2, Liam Smeeth 1. 8 9 1Department of Non-communicable disease Epidemiology, London School of Hygiene and 10 Tropical Medicine, London, UK 11 2 Respiratory Epidemiology, GlaxoSmithKline R&D, Uxbridge, UK 12 3 Respiratory Epidemiology, GlaxoSmithKline R&D, RTP, NC USA 13 4 Clinical Practice Research Datalink Group, Medicines and Healthcare products Regulatory 14 Agency, London, UK 15 5UCL RespiratoryFor Medicine, peer Royal Free Campus,review University College only London Medical 16 School, London, UK 17 18 19 20 Corresponding author: 21 Dr. Jennifer K Quint 22 Department of Noncommunicable disease Epidemiology 23 London School of Hygiene and Tropical Medicine 24 Keppel Street, London WC1E 7HT 25 Tel: 0207 927 2622 26 Email: [email protected] 27

29 30 31 Keywords: COPD, diagnosis of COPD, validation, spirometry, electronic health records 32 33 34 Word count: 3448 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 70

1 2 3 ABSTRACT 4 5 Objectives: The optimal method of identifying people with COPD from electronic primary 6 7 care records is not known. We assessed the accuracy of different approaches using the 8 9 Clinical Practice Research Datalink (CPRD), a UK electronic health record database. 10 11 Setting: Nine hundred and fifty one participants registered with a CPRD practice in the UK 12 13 between 1st January 2004 and 31 st December 2012. Individuals were selected for ≥1 of eight 14 15 algorithms toFor identify people peer with COPD. review General practitioners only were sent a brief 16 17 questionnaire and additional evidence to support a COPD diagnosis was requested. All 18 19 information received was reviewed independently by two respiratory physicians whose 20 21 opinion was taken as gold standard. 22 23 Primary outcome measure: The primary measure of accuracy was the positive predictive 24 25 value (PPV); the proportion of people identified by each algorithm for whom COPD was 26 27 confirmed. 28 29 Results: Nine hundred and fifty one questionnaires were sent and 738 (78%) returned. After 30 31 quality control, 696 (73.2%) patients were included in the final analysis. All four algorithms 32 33 including a specific COPD diagnostic code performed well. Using a diagnostic code alone 34 35 36 the PPV was 86.5% (77.5% to 92.3%) while requiring a diagnosis plus spirometry plus 37 38 specific medication the PPV was slightly higher at 89.4% (80.7% to 94.5%) but reduced case 39 40 numbers by 10%. Algorithms without specific diagnostic codes had low PPVs (range 12.2% 41 42 to 44.4%). 43 44 Conclusion: Patients with COPD can be accurately identified from UK primary care records 45 46 using specific diagnostic codes. Requiring spirometry or COPD medications only marginally 47 48 improved accuracy. The high accuracy applies since the introduction of an incentivised 49 50 disease register for COPD as part of QOF (Quality and Outcomes Framework) in 2004. 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 70 BMJ Open

1 2 3 Article Summary: This paper investigates how individuals with COPD can be accurately 4 5 identified in electronic health records using specific COPD codes alone without additional 6 7 information (i.e. presence of spirometry or respiratory medications). This information is 8 9 essential for appropriate disease management, epidemiological research of COPD and other 10 11 conditions, where COPD is an important comorbidity. 12 13 14 15 Strengths andFor limitations peer of this study: review only 16 17 We have shown that the presence of a specific COPD Read code alone is sufficient to 18 19 identify patients with COPD from electronic health records. Minimal precision lost by not 20 21 including spirometry and medications in the algorithm, allows an increase in the number 22 23 of individuals who can potentially be included in a study by up to 10%. 24 25 We were able to investigate both the accuracy of algorithms when identifying COPD 26 27 patients within the CPRD, and accuracy of the actual GP diagnosis of COPD. 28 29 The amount of missing data among the responding questionnaires was low, suggesting 30 31 reasonable data quality. 32 33 Although the overall response rate for this study was acceptable (77.6%), the proportion 34 35 36 of questionnaires accompanied with additional evidence allowing for adjudication was 37 38 lower. 39 40 41 42 43 44 No additional data are available. We would be happy to provide the ISAC protocol to 45 46 reviewers if required. 47 48 49 50 51 52 53 54 55 56 57 58 INTRODUCTION 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 70

1 2 3 Chronic obstructive pulmonary disease (COPD) represents an enormous health burden 4 5 worldwide. Currently COPD is the 4th leading cause of death and is predicted to become the 6 7 3rd by 2020.[1] There are approximately 835,000 people diagnosed with COPD in the UK 8 9 and an estimated 2,200,000 people remain undiagnosed.[2,3] 10 11 12 13 Electronic health records in the UK provide an excellent resource in which to study COPD as 14 15 they offer a largeFor cohort size,peer the presence review of disease severity onlyindicators and longterm 16 17 followup information on a patient’s integrated medical history. Although multiple studies 18 19 have been undertaken to investigate various aspects of COPD over the last 10 years in 20 21 several electronic health record databases, there is no standard definition used to identify 22 23 COPD in large databases and codelists used to identify patients with COPD vary by author. 24 25 Over ten years ago, the diagnosis of COPD was validated in the Clinical Practice Research 26 27 Datalink (CPRDGOLD, formerly GPRD) using OXMIS codes.[4] This coding system is now 28 29 obsolete in CPRD and Read codes are used as standard. 30 31

32 33 There is no single diagnostic test for COPD. The diagnosis of COPD relies on clinical 34 35 36 judgement based on a combination of history, physical examination and confirmation of the 37 38 presence of airflow obstruction using spirometry.[5] When retrospectively evaluating the 39 40 accuracy of a COPD diagnosis, commonly used COPD definitions may misclassify patients 41 42 as having COPD. Using multiple diagnostic codes in combination with pharmacy may 43 44 improve the accuracy of identification of COPD patients.[6] Further, over the past 10 years 45 46 the definition of COPD in clinical practice has evolved leading to changes in how COPD is 47 48 diagnosed and the diagnosis recorded. With the introduction of the Quality and Outcomes 49 50 Framework (QOF) codes for COPD in 2004 in England and Wales there are more codes 51 52 available to identify COPD then there were previously. QOF is a voluntary incentive scheme 53 54 for primary care physicians (GPs) in the UK which contains indicators against which GP 55 56 practices can score points and hence be rewarded for how well they care for patients. [7] 57 58 Evaluation of airflow limitation using spirometry is used as standard to confirm COPD 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 70 BMJ Open

1 2 3 diagnosis and severity of COPD is part of the annual COPD patient review.[3,8] However, 4 5 even spirometry if incorrectly performed or interpreted can lead to misdiagnosis (both over 6 7 and under diagnosis of COPD) in approximately 20% of cases. It is also recognised that 8 9 some subgroups of individuals (e.g. women and individuals under 50 and over 80) are less 10 11 likely to have spirometry measured.[8] 12 13 14 15 This study aimedFor to improve peer our ability toreview identify patients with onlyCOPD within electronic health 16 17 records. We used the CPRD, a widely used collection of computerised medical records 18 19 which is commonly used for clinical and research purposes. CPRD is comparable to other 20 21 electronic health record databases used in the UK. Our objective was to test the accuracy of 22 23 different definitions of COPD in the CPRD using Positive Predictive Value (PPV), by 24 25 comparing the database records with additional information provided by General 26 27 Practitioners (GPs). This work is important for epidemiological research in COPD and 28 29 diseases where COPD is an important comorbidity as well as for clinical practice. 30 31

32 33 METHODS 34 35 Dataset 36 37 CPRD is the world's largest validated computerized database of anonymized longitudinal 38 39 medical records for primary care. [9,10] Data comprise approximately 14 million patients with 40 41 around 5.4 million of these being currently alive and registered from 660 primary care 42 43 practices spread throughout the UK. Records are derived from a widely used GP software 44 45 46 system and contain complete prescribing and coded diagnostic and clinical information as 47 48 well as information on tests requested, laboratory results and referrals made at or following 49 50 on from each consultation. [11] 51 52 Codelists and algorithms 53 54 Lists of medical codes (Read codes) specific and nonspecific for COPD were created prior 55 56 to the study initiation. Read codes are a hierarchical clinical coding system of over 80,000 57 58 terms that are used in general practice in the UK and are entered by the GP into Vision 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 70

1 2 3 Software. [12] These data are then uploaded by CPRD after they have been processed and 4 5 quality checked added to the CPRD database for research use. Specific COPD codes 6 7 consisted of codes listing either COPD or COPD specific entities of emphysema (see 8 9 supplementary material for specific codes included). Nonspecific codes consisted of a 10 11 variety of lung diseases that could potentially be COPD e.g. chronic bronchitis. 12 13 Combinations of codelists and additional material in the form of the presence of spirometry 14 15 or COPD medicationsFor (see peer supplementary review material) were used only to make up the eight 16 17 algorithms. The first four definitions required a specific COPD diagnosis code, with the first 18 19 three requiring additional documentation (e.g., medication and/or spirometry). The other four 20 21 definitions required nonspecific bronchitis or respiratory symptom codes, with the least 22 23 specific definition requiring only respiratory symptom codes. Details regarding each 24 25 algorithm can be found in the supplementary material. Briefly, the eight algorithms were 26 27 defined as follows, from the expected most specific to most sensitive construct: 28 29

30 31 32 1. Specific COPD code and more than one prescription of a COPD medication and 33 34 presence of spirometry ( COPD Code + spirometry + COPD medication) 35 36 2. Specific COPD code and presence of spirometry ( COPD Code + spirometry) 37 38 3. Specific COPD code and more than one prescription of a COPD medication ( COPD 39 40 Code + COPD medication) 41 4. Specific COPD code only ( COPD Code only) 42 43 44 5. Nonspecific bronchitis code and more than one prescription of a COPD medication 45 46 (Bronchitis + COPD medication) 47 48 6. Nonspecific bronchitis code only ( Bronchitis only) 49 50 7. Respiratory symptoms and presence of spirometry. Respiratory symptoms consisted 51 52 of persistent cough, sputum production, or dyspnoea. ( Symptoms + spirometry) 53 54 8. Respiratory symptom definition only ( Symptoms only) 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 70 BMJ Open

9 flow volume loops or clinic letters attached and where actual FEV 1 and FVC values were 10 11 available in CPRD. 12 13 14 15 Study PopulationFor peer review only 16 17 The study population consisted of a random sample of individuals selected from all subjects 18 19 registered in CPRD with cohort entry being on or after the 1 st January 2004. At cohort entry, 20 21 people included had to be: over 35 years old, with at least 1 year historical data, and a 22 23 possible diagnosis of COPD defined as evidence of having ever smoked and a record of a 24 25 least one specific or possible COPD code or respiratory symptoms suggestive of COPD. The 26 27 presence of the algorithms was ascertained during a period between patient cohort entry 28 29 and the 31 st December 2012. Patients had to be alive within 4 months of the last collection 30 31 32 date of CPRD data for the January 2013 data build for inclusion in the analysis so that 33 34 CPRD could access their medical records and additional information. For the main analysis, 35 36 a patient could contribute to one algorithm only. It was possible for an individual to be eligible 37 38 for more than one algorithm depending upon the codes used in their medical record over the 39 40 study period. Individuals were randomly selected from the algorithm with the fewest number 41 42 of participants first and then removed from the cohort so they could not be selected for 43 44 another algorithm. 45 46 47 48 CPRD mailed a short, structured questionnaire to GPs in charge of randomly selected 49 50 patients requesting confirmation of COPD status as well as any available specific information 51 52 from the individual’s medical record including spirometry print outs and hospital respiratory 53 54 outpatient letters (see supplementary material). Data were “twice encrypted” within CPRD to 55 56 ensure anonymity; firstly between practices and CPRD and secondly from CPRD to 57 58 researchers. In the questionnaire the GP was asked whether or not the patient had a 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 70

1 2 3 diagnosis of COPD, what that diagnosis was based on, whether or not the patient had seen 4 5 a respiratory physician and if they had any other respiratory diagnoses. A pilot set of 20 6 7 questionnaires were sent to GPs to assess the quality of the questionnaire. In total, 951 8 9 questionnaires were sent out assuming an 80% response rate. 10 11 12 13 Primary outcome 14 15 The primary Foroutcome was peer identification ofreview a diagnosis of COPD only according to the predefined 16 17 eight algorithms. The gold standard for the diagnosis of COPD was the decision made after 18 19 respiratory physicians independently reviewed the evidence from the GP (questionnaire 20 21 response with or without additional evidence). Where they did not agree, a 3 rd independent 22 23 physician decided. Additionally, GP diagnosis of COPD was validated in a subset of patients 24 25 where the GP provided supportive information including spirometry printouts and hospital 26 27 letters. This also allowed review of spirometry interpretation in some cases. Although we 28 29 used two respiratory physicians independently as the gold standard for diagnosing COPD, 30 31 this was done by reviewing the questionnaire sent to the GP (see appendix) as well as any 32 33 additional information the GP sent which supported that diagnosis. This supporting 34 35 36 information ranged from free text in the GP database to spirometry printouts done in the GP 37 38 surgery to letters from secondary care. Therefore we were not solely relying on information 39 40 from secondary care to make the diagnosis unless the GP decided to share that information. 41 42 In this way we were able to include and validate the diagnosis of COPD in people who were 43 44 not seen in secondary care. 45 46 Analysis 47 48 The primary analysis focused on the accuracy of identification of a COPD diagnosis in each 49 50 of the predefined algorithms as defined by positive predicted value (PPV); i.e. the proportion 51 52 of “true positives” (individuals with COPD) in each algorithm as determined by the gold 53 54 standard. In addition, within each algorithm, where additional information was provided (lung 55 56 function, hospital clinic letters), we calculated the accuracy of the GP diagnosis of COPD 57 58 relative to the gold standard. This allowed review of spirometry interpretation in some cases. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 70 BMJ Open

1 2 3 4 5 We assessed the impact of commonly occurring comorbidities on the accuracy of the pre 6 7 specified algorithms stratifying for cardiovascular comorbidity, previous asthma diagnosis, 8 9 smoking status and, where possible, Global Initiative for Chronic Obstructive Lung Disease 10 11 (GOLD) staging of airflow limitation severity.[13] Cardiovascular comorbidity included 12 13 angina, history of myocardial infarction, previous coronary artery bypass graft / percutaneous 14 15 coronary interventionFor or heartpeer failure, but review not hypertension due only to its lack of overlap of 16 17 symptoms that could mimic COPD. All covariates for stratification analysis were derived from 18 19 information available up to cohort entry. 20 21 22 23 As a post hoc analysis individuals were eligible to be placed into multiple algorithms where 24 25 possible, and the PPV was calculated for all individuals who had a specific COPD code 26 27 compared to those with a specific COPD code and additional information (either spirometry 28 29 or a COPD medication). 30 31

32 33 Assessment of possible trends in COPD diagnosis recording were also evaluated, including 34 35 36 temporal trends in codes used and diagnostic specificity from 2004 to 2011. In addition, we 37 38 compared our specific COPD codes to those recommended for use by QOF (see 39 40 supplementary material); [14,15] H31% (excluding H3101 (smokers cough), H31y0 (chronic 41 42 tracheitis) and H3122 (acute exacerbation of COPD)) H32% H36H3z (excluding H3y0 and 43 44 H3y1). 45 46 47 48 Sample size calculation 49 50 Our sample size for each algorithm was chosen to achieve accuracy of the true positives or 51 52 PPV ±0.08 based on the reviewing physician judgment as the gold standard. Assuming an 53 54 estimated PPV of 0.85 for any one algorithm, we required a sample of at least 77 individuals 55 56 in each algorithm to achieve the desired accuracy (95% CI ±0.08). All analyses were 57 58 performed using STATA 13. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 70

1 2 3 4 5 Ethics approval was obtained from ISAC (the Independent Scientific Advisory Committee 6 7 overseeing CPRD); protocol 12_065 and the LSHTM ethics committee. 8 9 10 11 RESULTS 12 13 Nine hundred and fifty one questionnaires were sent to GPs (see Figure 1 for patient 14 15 For peer review only 16 selection). Of those, 738 (77.6%) were returned, 704 (74.0%) met quality control standards 17 18 and were not duplicates, and 696 (73.2%) could be included in the final analysis (8 had 19 20 “uncertain” COPD diagnosis and no supporting documentation and were therefore 21 22 excluded). 23 24 25 Among those included in the final analysis, additional evidence for the diagnosis of COPD 26 27 was available for 272 patients. This represented 39.1% of the total study population, or 28 29 67.7% of the 402 patients with a confirmed COPD diagnosis in the study. 30 31 32 33 Overall, irrespective of the qualifying algorithm, 402 patients (57.8%) were considered to 34 35 have a diagnosis of COPD based on reviewing physician judgment. Table 1 shows the 36 37 characteristics of the 696 patients included in the final analysis who were considered to 38 39 possibly have COPD based on the inclusion criteria. On average, patients were in their mid 40 41 60s to early 70s across all algorithms. Approximately twothirds of them were current 42 43 smokers and onequarter had a history of asthma. Generally, there were fewer patients with 44 45 supporting information and cardiovascular comorbidity in the less specific algorithms (48). 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 70 BMJ Open

1 2 3 4 5 Table 1: Characteristics of the 696 patients included in the final study analysis 6 7 Algorithm COPD Code + COPD Code + COPD Code + COPD Bronchitis + Bronchitis Symptoms + Symptoms 8 spirometry + spirometry COPD Code COPD only spirometry only 9 COPD medication medication only medication 10 Number of 85 (100) 79 (100) 88 (100) 89 (100) 98 (100) 84 (100) 83 (100) 90 (100) 11 individuals (%) For peer review only 12 13 Number (%) with 46 (54.1) 44 (55.7) 48 (54.5) 40 (44.9) 32 (32.7) 18 (21.4) 30 (36.1) 14 (15.6) 14 supporting info 15 16 Mean age 68.7 (11.3) 68.3 71.8 71.1 68.5 (13.1) 67.8 (13.4) 65.9 (11.9) 63.4 (14.1) (sd) (11.7) (10.5) (10.4) 17 18 19 Male (%) 45 (52.9) 41 (51.9) 40 (45.5) 44 (49.4) 31 (31.6) 29 (34.5) 43 (51.8) 47 (52.2) 20 21 Current smoker 49 (57.7) 50 (63.3) 55 (62.5) 47 (52.8) 66 (67.4) 61 (72.6) 48 (57.8) 58 (64.4) 22 (%) 23 24 GOLD stage* 1 13 (16.3) 14 (18.0) 13 (15.9) 16 (20.5) 17 (28.8) 13 (35.1) 8 (20.0) 4 (36.4) 25 (n=465) 26 2 43 (53.8) 48 (61.5) 41 (50.0) 46 (59.0) 31(52.5) 13 (35.1) 22 (55.0) 5 (45.5) 27 3 18 (22.5) 13 (16.7) 22 (26.8) 12 (15.4) 9 (15.3) 8 (21.6) 8 (20.0) 2 (18.2) 28 4 6 (7.5) 3 (3.9) 6 (7.3) 4 (5.1) 2 (3.4) 3 (8.1) 2 (5.0) 0 (0.0) 29 30 History of 20 (23.5) 22 (27.8) 17 (19.3) 18 (20.2) 20 (20.4) 17 (20.2) 14 (16.9) 9 (10.0) 31 cardiovascular 32 disease 33 34 History of asthma 18 (21.2) 20 (25.3) 16 (18.2) 15 (16.9) 27 (27.6) 23 (27.4) 19 (22.9) 23 (25.6) 35 36 Mean BMI (sd) N=83 N=78 N=86 N=87 N=98 N=85 N=41 N=17 37 (n=575) 27.5 (5.4) 26.7 (5.8) 26.4 (4.7) 27.8 27.4 (5.1) 28.1 (5.0) 27.1 (4.5) 27.6 (4.7) 38 (5.4) 39 *GOLD staging was ascertained from CPRD records or from supplementary information provided by GPs. 40 41 42 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 12 of 70

1 2 3 The number of patients diagnosed with COPD confirmed by the gold standard and the PPV 4 5 for each algorithm is given in Table 2 . The PPV was greatest for algorithms 14. Further 6 7 data is available in the supplementary material regarding the effect of comorbidities ( Table 8 9 S1 ), smoking status ( Table S2 ) and GOLD staging ( Table S3 ) on the performance of each 10 11 algorithm. 12 13 14 15 For peer review only 16 17 18 19 Table 2 : The PPV and proportion of patients diagnosed with COPD within each algorithm 20 Algorithm Number of Number Number with PPV and 95% CI questionnaires evaluable confirmed 21 sent out returned COPD 22 (n=951) (n=696) (%) 23 COPD Code + spirometry + 119 85 (71.4) 76 89.4, 80.794.5 24 COPD medication 25 COPD Code + spirometry 119 79 (66.4) 67 83.8, 73.790.4 26 COPD Code + COPD 119 88 (73.9) 77 87.5, 78.693.0 27 medication 28 COPD Code only 119 89 (74.8) 77 86.5, 77.592.3 29 Bronchitis + COPD medication 119 98 (82.4) 44 44.4, 34.854.5 30 Bronchitis only 119 84 (70.6) 26 29.5, 20.840.1 31 Symptoms + spirometry 119 83 (69.7) 37 43.5, 33.254.4 32 Symptoms only 118 90 (75.6) 11 12.2, 6.820.9 33 34 35 36 37 In a subset of 272 patients where additional evidence was available (in the form of 38 39 spirometry print outs or hospital outpatient letters), we assessed accuracy of GP diagnosis of 40 41 COPD. Overall, the PPV in this group was 95.0% (91.197.2), This is broken down by 42 43 algorithm in Table 3 . While the presence of supporting evidence improved the PPV in each 44 45 group, algorithms 14 were still most accurate. 46 47 48 49 50 51 52

54 55 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 70 BMJ Open

1 2 3 Table 3 : PPV by algorithm where evidence was available to assess GP compared to physician 4 diagnosis of COPD 5 Algorithm Total Number of Number PPV and 95% CI 6 number patients with with COPD 7 with COPD confirmed according 8 evidence by GOLD standard to GP (N=272) (N=220) 9 COPD Code + spirometry + COPD 46 46 46 100 10 medication 11 COPD Code + s pirometry 44 35 33 94.3, 82.498.9 12 COPD Code + COPD medication 48 43 41 95.3, 82.498.9 13 COPD Code only 40 34 33 97.1, 80.299.6 14 Bronchitis + COPD medication 32 21 19 90.5, 66.097.9 15 Bronchitis onlyFor peer18 review 12 only 11 91.7, 49.999.2 16 Symptoms + spirome try 30 21 20 95.2, 69.199.4 17 Symptoms only 14 8 6 75.0, 27.695.9 18 19 20 21 22 Post-hoc analysis 23 24 We repeated the analysis allowing individuals to be put into more than one algorithm and 25 26 tested the PPV of COPD by algorithm relative to the gold standard where individuals were 27 28 identified using only the presence of a specific COPD code (n=457) the PPV was identical to 29 30 if they had a COPD code and evidence either in the form of spirometry or COPD medication 31 32 prescription (n=454); PPV 83.0% (79.086.0) for both. In the majority of cases, where a 33 34 specific COPD code had been assigned, there was additional evidence. Only 3 individuals 35 36 had a specific COPD code with no additional evidence. 37 38 39 40 41 42 DISCUSSION 43 44 We tested the accuracy of eight different algorithms for identifying COPD within the CPRD 45 46 among patients with suspected COPD (e.g., >35 years of age, smoking history, and 47 48 recording of respiratory symptoms or COPD codes). The physician reviewer consensus was 49 50 the GOLD standard. The best performing algorithm allowed an accurate ascertainment of 51 52 90% of patients as diagnosed with COPD. This consisted of a combination of a specific 53 54 COPD code, more than one prescription of a COPD medication and spirometry (PPV 89.4, 55 56 95% CI: 80.794.5). The worst performing algorithm was represented by presence of 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 70

1 2 3 respiratory symptoms only (PPV12.2, 95%CI: 6.820.9). We found that any algorithm 4 5 containing a specific COPD code performed better than those without (Algorithms 14). In a 6 7 post hoc analysis, where we allowed individuals to populate more than one algorithm, we 8 9 established that the use of additional information such as spirometry or medications in an 10 11 algorithm to a specific COPD Read code alone did not increase the PPV. This suggests that 12 13 the presence of a specific COPD Read code alone is sufficient to accurately identify patients 14 15 with COPD fromFor the database. peer Some study review protocols require theonly presence of obstructive 16 17 spirometry for identification of COPD patients; however, this study demonstrates that it may 18 19 be unnecessary. This is particularly important as certain groups of individuals are less likely 20 21 to have spirometry, namely women and patients <50 and >80 years of age. [8] This is also 22 23 important as the minimal precision lost by not including spirometry and medications in the 24 25 algorithm, allows an increase in the number of individuals who can potentially be included in 26 27 a study. Using the whole of CPRD, we identified individuals with COPD using a specific 28 29 COPD code only compared to a specific code plus medication and spirometry and found an 30 31 increase in potential sample size for study of 10% using a specific COPD code only. 32 33

34 35 36 One of the advantages of this study was our ability to investigate both the accuracy of 37 38 algorithms when identifying COPD patients within the CPRD, and accuracy of the actual GP 39 40 diagnosis of COPD. When validating the GP diagnosis of COPD with a respiratory physician 41 42 diagnosis as gold standard based on extra evidence provided by the GP, there was 43 44 improved accuracy (PPV) across all algorithms, with algorithms 14 again performing best. 45 46 This suggests that additional evidence is collected when the GP is reasonably certain that 47 48 the patient has COPD. There was good concordance between GP and physician diagnosis 49 50 suggesting respiratory consultant validation is not always needed. Where there was 51 52 disagreement, this was usually because lung function did not meet criteria for COPD. 53 54 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 70 BMJ Open

1 2 3 We found that the diagnostic accuracy of COPD decreased across all algorithms when 4 5 patients also had a diagnosis of cardiovascular disease or asthma (Table S1 online 6 7 supplement). When patients had a concomitant diagnosis of asthma, the presence of 8 9 spirometry was particularly important to improve accuracy of COPD diagnosis. However, 10 11 stratification led to smaller sample sizes, which could have impacted the precision of 12 13 estimates. Unsurprisingly, the addition of the use of any inhaled COPD medication to the 14 15 algorithm didFor not improve peer precision, most review likely due to the overlap only in medications used to 16 17 treat both asthma and COPD (see online supplement). The algorithm accuracy was not 18 19 affected by smoking status (current vs. exsmoker) (Table S2 online supplement). We only 20 21 included current or former smokers in our analysis, and cannot be sure of the validity of the 22 23 results in a patient who has never smoked. Certainly in the UK, the majority of COPD is 24 25 related to tobacco smoking and we hypothesized that fixed airflow obstruction in a non 26 27 smoker would most likely be due to chronic asthma. 28 29

30 31 When considering the severity of COPD by GOLD classification, algorithms 2 and 3, i.e. a 32 33 specific COPD code and spirometry or COPD medications had the greatest accuracy for 34 35 36 patients with mild disease (GOLD stage 1) (Table S3 online supplement). PPV increased 37 38 with increasing disease severity. PPV increases with disease prevalence, and the 39 40 prevalence of COPD increased moving from algorithm 8 to algorithm 1. 41 42 43 44 We considered the timing of diagnosis in view of an increased uptake of spirometry in 45 46 primary care in more recent years and changes in QOF requirements over time during our 47 48 study period (Table S4 online supplement). We found that algorithms 14 still had the 49 50 greatest accuracy, but the PPV estimates were better for the post 2008 period than pre 2008 51 52 period (see supplementary material). Nonspecific bronchitis codes and symptom codes 53 54 were more likely to be used before 2008 rather than post. This may require consideration 55 56 when developing retrospective cohorts for analysis and otherwise suggests QOF has had a 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 70

1 2 3 positive effect on the consistency of codes used for COPD diagnoses. However, our codes 4 5 were more specific than QOF codes and some of the codes included in QOF were not 6 7 included in our specific COPD codelist, but were included in the nonspecific bronchitis 8 9 codes. While we cannot comment on the accuracy of QOF codes, it is important to highlight 10 11 that that some QOF codes are not disease specific and may not be a good way of identifying 12 13 COPD patients from electronic health records as inevitably people without COPD will be 14 15 included. It isFor also important peer to highlight reviewthat Read codes change only over time with new codes 16 17 added and some removed, and this needs consideration when identifying people with 18 19 COPD. 20 21 22 23 There are limited COPD validation studies in electronic health records published in the 24 25 literature to which we can compare our study. Soriano validated COPD in the GPRD in 2001, 26 27 when OXMIS codes were still in use. [4] A Swedish study using a Swedish inpatient registry 28 29 used ICD9 and ICD10 codes and identified COPD patients with similar accuracy.[16] A 30 31 Canadian study in the Canadian primary care sentinel surveillance network used algorithms 32 33 to identify several long term conditions and also had a PPV similar to ours for COPD [17]. 34 35 36 However, all of these studies used different codes, algorithms and databases. 37 38 39 40 Our analysis has several limitations. Although the overall response rate for this study was 41 42 acceptable (77.6%), the proportion of questionnaires accompanied with additional evidence 43 44 allowing for adjudication was rather low. We chose PPV as the measure of accuracy in this 45 46 study to allow us to determine the probability that a patient had COPD from their electronic 47 48 health record. PPV is correlated with disease prevalence, and although it is strongly related 49 50 to specificity, the actual estimates of specificity, sensitivity and negative predictive value 51 52 cannot be determined from our data. Further, GP practices are self selecting with respect to 53 54 their contribution to CPRD, however those practices appear to be representative of the UK 55 56 population. Very few patients within contributing practices refuse to participate at an 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 70 BMJ Open

1 2 3 4 5 Acknowledgments: none 6 7 Competing interests: none 8 9 Funding : This project was funded jointly by GSK and the MRC. JKQ is funded on a MRC 10 11 Population Health Scientist Fellowship. This work was part funded by a MRC Industry 12 13 Partnership award (grant number G0902135). 14 15 ContributorshipFor statement peer: JKQ, HM, RLD,review SE, KD and LS contributedonly to the conception 16 17 and design, JKQ, HM, JH, to acquisition and analysis, JKQ, HM, RLD, HF, SE, JH, KD and 18 19 LS to interpretation of data, and JKQ, HM, RLD, HF, SE, JH, KD and LS to the drafting of the 20 21 manuscript. JKQ is responsible for the overall content as guarantor. 22 23 Data Sharing Statement: No additional data are available. We would be happy to provide 24 25 the ISAC protocol to reviewers if required. 26 27 28 29

30 31

32 33 Figure legend 34 35 36 Figure 1: Study population 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 70 BMJ Open

1 2 3 REFERENCES 4 5 1. National Statistics. www.statistics.gov.uk date accessed June 2013. 6 7 8 9 2. Shahab LM, Jarvis MJ, Britton J, et al. Prevalence, diagnosis and relation to tobacco 10 11 dependence of chronic obstructive pulmonary disease in a nationally representative 12 13 population sample Thorax 2006;61(12):1043 14 15 For peer review only 16 17 3. file:///C:/Users/ENCDJQUI/Downloads/Invisible-Lives-report.pdf Invisible Lives. 18 19 Chronic Obstructive Pulmonary Disease (COPD) – finding the missing millions. 20 21 British Lung Foundation. November 2007. Accessed February 2014. 22 23 24 25 4. Soriano JB, Maier WC, Visick G, et al. Validation of general practitionerdiagnosed 26 27 COPD in the UK General Practice. European Journal of Epidemiology 28 29 2001;17:1075–1080 30 31

32 33 5. NICE guideline COPD http://guidance.nice.org.uk/CG101/QuickRefGuide/pdf/English 34 35 36 date accessed January 2014. 37 38 39 40 6. Cooke CR, Joo MJ, Anderson SM et al. The validity of using ICD9 codes and 41 42 pharmacy records to identify patients with chronic obstructive pulmonary disease. 43 44 BMC Health Services Research 2011;11:37 45 46 47 48 7. Smith CJP, Gribbin J, Challen KB, et al. The impact of the 2004 NICE guideline and 49 50 2003General Medical Services contract on COPD in primary care in the UK. Q J Med 51 52 2008;101:145–153. 53 54 55 56 8. http://www.nice.org.uk/aboutnice/qof/qof.jsp. Accessed January 2014 . 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 70

1 2 3 4 5 9. CPRD http://www.cprd.com (accessed February 28,2013) 6 7 8 9 10. Williams T, VanStaa T, Padmanabhan S et al. Recent advances in utility and use of 10 11 the General Practice Research Database as an example of a UK Primary Care Data 12 13 resource. Ther Adv Drug Saf 2012;3:88–99. 14 15 For peer review only 16 17 11. Tate AR, Beloff N, AlRadwan B et al. Exploiting the potential of large databases of 18 19 electronic health records for research using rapid search algorithms and an intuitive 20 21 query interface. J Am Med Inform Assoc . 2014;21(2):2928. 22 23 24 25 12. Chisholm J. The Read clinical classification. BMJ, 1990. 300(6732):1092. 26 27 28 29 13. GOLD 2011 http://www.goldcopd.org/uploads/users/files/GOLD2011_Summary.pdf 30 31 accessed Nov 2013. 32 33

34 35 36 14. https://mqi.ic.nhs.uk/IndicatorDefaultView.aspx?ref=1.09.03.07 (QOF COPD). Accessed 37 38 Feb 2014. 39 40 41 42 15. http://www.nbmedical.com/pdf/keep_simple_qof_2014-2014.pdf accessed Feb 2014 43 44 45 46 16. Inghammar M, Engström G, Löfdahl CG et al. Validation of a COPD diagnosis 47 48 from the Swedish Inpatient Registry Scandinavian Journal of Public Health , 2012;40: 49 50 773–776 51 52 17. KadhimSaleh A, Green M, WilliamsonT et al. Validation of the Diagnostic 53 54 Algorithms for 5 Chronic Conditions in the Canadian Primary Care Sentinel 55 56 57 58 20 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 70 BMJ Open

1 2 3 Surveillance Network (CPCSSN): A Kingston Practicebased Research Network 4 5 (PBRN) Report. J Am Board Fam Med 2013;26: 159–167 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 21 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 70

1 2 3 Validation of Chronic Obstructive Pulmonary Disease (COPD) recording in the Clinical 4 Practice Research Datalink (CPRD-GOLD) 5 6 Jennifer K Quint 1, Hana Müllerova 2, Rachael L DiSantostefano 3, Harriet Forbes 1, Susan 7 Eaton 4, John R Hurst 5, Kourtney Davis 2, Liam Smeeth 1. 8 9 1Department of Non-communicable disease Epidemiology, London School of Hygiene and 10 Tropical Medicine, London, UK 11 2 Respiratory Epidemiology, GlaxoSmithKline R&D, Uxbridge, UK 12 3 Respiratory Epidemiology, GlaxoSmithKline R&D, RTP, NC USA 13 4 Clinical Practice Research Datalink Group, Medicines and Healthcare products Regulatory 14 Agency, London, UK 15 5UCL RespiratoryFor Medicine, peer Royal Free Campus,review University College only London Medical 16 School, London, UK 17 18 19 20 Corresponding author: 21 Dr. Jennifer K Quint 22 Department of Noncommunicable disease Epidemiology 23 London School of Hygiene and Tropical Medicine 24 Keppel Street, London WC1E 7HT 25 Tel: 0207 927 2622 26 Email: [email protected] 27 28

30 Keywords: COPD, diagnosis of COPD, validation, spirometry, electronic health records 31

33 Word count: 3448 34 35 36 37 38 39 40 Contributorship statement : JKQ, HM, RLD, SE, KD and LS contributed to the conception 41 42 and design, JKQ, HM, JH, to acquisition and analysis, JKQ, HM, RLD, HF, SE, JH, KD and 43 44 LS to interpretation of data, and JKQ, HM, RLD, HF, SE, JH, KD and LS to the drafting of the 45 46 manuscript. JKQ is responsible for the overall content as guarantor. 47 48 49 50 51 52 53 54 55 56 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 70 BMJ Open

1 2 3 ABSTRACT 4 5 Objectives: The optimal method of identifying people with COPD from electronic primary 6 7 care records is not known. We assessed the accuracy of different approaches using the 8 9 Clinical Practice Research Datalink (CPRD), a UK electronic health record database. 10 11 Setting: Nine hundred and fifty one participants registered with a CPRD practice in the UK 12 13 between 1st January 2004 and 31 st December 2012. Individuals were selected for ≥1 of eight 14 15 algorithms toFor identify people peer with COPD. review General practitioners only were sent a brief 16 17 questionnaire and additional evidence to support a COPD diagnosis was requested. All 18 19 information received was reviewed independently by two respiratory physicians whose 20 21 opinion was taken as gold standard. 22 23 Primary outcome measure: The primary measure of accuracy was the positive predictive 24 25 value (PPV); the proportion of people identified by each algorithm for whom COPD was 26 27 confirmed. 28 29 Results: Nine hundred and fifty one questionnaires were sent and 738 (78%) returned. After 30 31 quality control, 696 (73.2%) patients were included in the final analysis. All four algorithms 32 33 including a specific COPD diagnostic code performed well. Using a diagnostic code alone 34 35 36 the PPV was 86.5% (77.5% to 92.3%) while requiring a diagnosis plus spirometry plus 37 38 specific medication the PPV was slightly higher at 89.4% (80.7% to 94.5%) but reduced case 39 40 numbers by 10%. Algorithms without specific diagnostic codes had low PPVs (range 12.2% 41 42 to 44.4%). 43 44 Conclusion: Patients with COPD can be accurately identified from UK primary care records 45 46 using specific diagnostic codes. Requiring spirometry or COPD medications only marginally 47 48 improved accuracy. The high accuracy applies since the introduction of an incentivised 49 50 disease register for COPD as part of QOF (Quality and Outcomes Framework) in 2004. 51 52 53 54 55 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 70

1 2 3 Article Summary: This paper investigates how individuals with COPD can be accurately 4 5 identified in electronic health records using specific COPD codes alone without additional 6 7 information (i.e. presence of spirometry or respiratory medications). This information is 8 9 essential for appropriate disease management, epidemiological research of COPD and other 10 11 conditions, where COPD is an important comorbidity. 12 13 14 15 Strengths andFor limitations peer of this study: review only 16 17 We have shown that the presence of a specific COPD Read code alone is sufficient to 18 19 identify patients with COPD from electronic health records. Minimal precision lost by not 20 21 including spirometry and medications in the algorithm, allows an increase in the number 22 23 of individuals who can potentially be included in a study by up to 10%. 24 25 We were able to investigate both the accuracy of algorithms when identifying COPD 26 27 patients within the CPRD, and accuracy of the actual GP diagnosis of COPD. 28 29 The amount of missing data among the responding questionnaires was low, suggesting 30 31 reasonable data quality. 32 33 Although the overall response rate for this study was acceptable (77.6%), the proportion 34 35 36 of questionnaires accompanied with additional evidence allowing for adjudication was 37 38 lower. 39 40 41 42 43 44 No additional data are available. We would be happy to provide the ISAC protocol to 45 46 reviewers if required. 47 48 49 50 51 52 53 54 55 56 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 70 BMJ Open

1 2 3 INTRODUCTION 4 5 Chronic obstructive pulmonary disease (COPD) represents an enormous health burden 6 7 worldwide. Currently COPD is the 4th leading cause of death and is predicted to become the 8 9 3rd by 2020.[1] There are approximately 835,000 people diagnosed with COPD in the UK 10 11 and an estimated 2,200,000 people remain undiagnosed.[2,3] 12 13 14 15 Electronic healthFor records peer in the UK provide review an excellent resource only in which to study COPD as 16 17 they offer a large cohort size, the presence of disease severity indicators and longterm 18 19 followup information on a patient’s integrated medical history. Although multiple studies 20 21 have been undertaken to investigate various aspects of COPD over the last 10 years in 22 23 several electronic health record databases, there is no standard definition used to identify 24 25 COPD in large databases and codelists used to identify patients with COPD vary by author. 26 27 Over ten years ago, the diagnosis of COPD was validated in the Clinical Practice Research 28 29 Datalink (CPRDGOLD, formerly GPRD) using OXMIS codes.[4] This coding system is now 30 31 obsolete in CPRD and Read codes are used as standard. 32 33

34 35 36 There is no single diagnostic test for COPD. The diagnosis of COPD relies on clinical 37 38 judgement based on a combination of history, physical examination and confirmation of the 39 40 presence of airflow obstruction using spirometry.[5] When retrospectively evaluating the 41 42 accuracy of a COPD diagnosis, commonly used COPD definitions may misclassify patients 43 44 as having COPD. Using multiple diagnostic codes in combination with pharmacy may 45 46 improve the accuracy of identification of COPD patients.[6] Further, over the past 10 years 47 48 the definition of COPD in clinical practice has evolved leading to changes in how COPD is 49 50 diagnosed and the diagnosis recorded. With the introduction of the Quality and Outcomes 51 52 Framework (QOF) codes for COPD in 2004 in England and Wales there are more codes 53 54 available to identify COPD then there were previously. QOF is a voluntary incentive scheme 55 56 for primary care physicians (GPs) in the UK which contains indicators against which GP 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 70

1 2 3 practices can score points and hence be rewarded for how well they care for patients. [7] 4 5 Evaluation of airflow limitation using spirometry is used as standard to confirm COPD 6 7 diagnosis and severity of COPD is part of the annual COPD patient review.[3,8] However, 8 9 even spirometry if incorrectly performed or interpreted can lead to misdiagnosis (both over 10 11 and under diagnosis of COPD) in approximately 20% of cases. It is also recognised that 12 13 some subgroups of individuals (e.g. women and individuals under 50 and over 80) are less 14 15 likely to haveFor spirometry peermeasured.[8] review only 16 17 18 19 This study aimed to improve our ability to identify patients with COPD within electronic health 20 21 records. We used the CPRD, a widely used collection of computerised medical records 22 23 which is commonly used for clinical and research purposes. CPRD is comparable to other 24 25 electronic health record databases used in the UK. Our objective was to test the accuracy of 26 27 different definitions of COPD in the CPRD using Positive Predictive Value (PPV), by 28 29 comparing the database records with additional information provided by General 30 31 Practitioners (GPs). This work is important for epidemiological research in COPD and 32 33 diseases where COPD is an important comorbidity as well as for clinical practice. 34 35

36 37 METHODS 38 39 Dataset 40 41 CPRD is the world's largest validated computerized database of anonymized longitudinal 42 43 medical records for primary care. [9,10] Data comprise approximately 14 million patients with 44 45 46 around 5.4 million of these being currently alive and registered from 660 primary care 47 48 practices spread throughout the UK. Records are derived from a widely used GP software 49 50 system and contain complete prescribing and coded diagnostic and clinical information as 51 52 well as information on tests requested, laboratory results and referrals made at or following 53 54 on from each consultation. [11] 55 56 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 70 BMJ Open

1 2 3 Codelists and algorithms 4 5 Lists of medical codes (Read codes) specific and nonspecific for COPD were created prior 6 7 to the study initiation. Read codes are a hierarchical clinical coding system of over 80,000 8 9 terms that are used in general practice in the UK and are entered by the GP into Vision 10 11 Software. [12] These data are then uploaded by CPRD after they have been processed and 12 13 quality checked added to the CPRD database for research use. Specific COPD codes 14 15 consisted of Forcodes listing peer either COPD orreview COPD specific entities only of emphysema (see 16 17 supplementary material for specific codes included ). Nonspecific codes consisted of a 18 19 variety of lung diseases that could potentially be COPD e.g. chronic bronchitis. 20 21 Combinations of codelists and additional material in the form of the presence of spirometry 22 23 or COPD medications (see supplementary material) were used to make up the eight 24 25 algorithms. The first four definitions required a specific COPD diagnosis code, with the first 26 27 three requiring additional documentation (e.g., medication and/or spirometry). The other four 28 29 definitions required nonspecific bronchitis or respiratory symptom codes, with the least 30 31 specific definition requiring only respiratory symptom codes. Details regarding each 32 33 algorithm can be found in the supplementary material. Briefly, the eight algorithms were 34 35 36 defined as follows, from the expected most specific to most sensitive construct: 37 38 39 40 1. Specific COPD code and more than one prescription of a COPD medication and 41 42 presence of spirometry (COPD Code + spirometry + COPD medication) 43 44 2. Specific COPD code and presence of spirometry (COPD Code + spirometry) 45 46 3. Specific COPD code and more than one prescription of a COPD medication (COPD 47 48 Code + COPD medication) 49 50 4. Specific COPD code only (COPD Code only) 51 52 5. Nonspecific bronchitis code and more than one prescription of a COPD medication 53 54 (Bronchitis + COPD medication) 55 56 6. Nonspecific bronchitis code only (Bronchitis only) 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 70

1 2 3 7. Respiratory symptoms and presence of spirometry. Respiratory symptoms consisted 4 5 of persistent cough, sputum production, or dyspnoea. (Symptoms + spirometry) 6 7 8. Respiratory symptom definition only (Symptoms only) 8 9 10 11 The presence of spirometry for inclusion in the algorithm was based on an existence of a 12 13 record of a specific value or a Read code for spirometry rather than examining the actual 14 15 value. We wereFor able to assesspeer interpretation review of spirometry in theonly subset of patients who had 16 17 flow volume loops or clinic letters attached and where actual FEV 1 and FVC values were 18 19 available in CPRD. 20 21 22 23 Study Population 24 25 The study population consisted of a random sample of individuals selected from all subjects 26 27 registered in CPRD with cohort entry being on or after the 1 st January 2004. At cohort entry, 28 29 people included had to be: over 35 years old, with at least 1 year historical data, and a 30 31 32 possible diagnosis of COPD defined as evidence of having ever smoked and a record of a 33 34 least one specific or possible COPD code or respiratory symptoms suggestive of COPD. The 35 36 presence of the algorithms was ascertained during a period between patient cohort entry

37 st 38 and the 31 December 2012. Patients had to be alive within 4 months of the last collection 39 40 date of CPRD data for the January 2013 data build for inclusion in the analysis so that 41 42 CPRD could access their medical records and additional information. For the main analysis, 43 44 a patient could contribute to one algorithm only. It was possible for an individual to be eligible 45 46 for more than one algorithm depending upon the codes used in their medical record over the 47 48 study period. Individuals were randomly selected from the algorithm with the fewest number 49 50 of participants first and then removed from the cohort so they could not be selected for 51 52 another algorithm. 53 54 55 56 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 70 BMJ Open

1 2 3 CPRD mailed a short, structured questionnaire to GPs in charge of randomly selected 4 5 patients requesting confirmation of COPD status as well as any available specific information 6 7 from the individual’s medical record including spirometry print outs and hospital respiratory 8 9 outpatient letters (see supplementary material). Data were “twice encrypted” within CPRD to 10 11 ensure anonymity; firstly between practices and CPRD and secondly from CPRD to 12 13 researchers. In the questionnaire the GP was asked whether or not the patient had a 14 15 diagnosis of ForCOPD, what peer that diagnosis reviewwas based on, whether only or not the patient had seen 16 17 a respiratory physician and if they had any other respiratory diagnoses. A pilot set of 20 18 19 questionnaires were sent to GPs to assess the quality of the questionnaire. In total, 951 20 21 questionnaires were sent out assuming an 80% response rate. 22 23 24 25 Primary outcome 26 27 The primary outcome was identification of a diagnosis of COPD according to the predefined 28 29 eight algorithms. The gold standard for the diagnosis of COPD was the decision made after 30 31 respiratory physicians independently reviewed the evidence from the GP (questionnaire 32 33 response with or without additional evidence). Where they did not agree, a 3 rd independent 34 35 36 physician decided. Additionally, GP diagnosis of COPD was validated in a subset of patients 37 38 where the GP provided supportive information including spirometry printouts and hospital 39 40 letters. This also allowed review of spirometry interpretation in some cases. Although we 41 42 used two respiratory physicians independently as the gold standard for diagnosing COPD, 43 44 this was done by reviewing the questionnaire sent to the GP (see appendix) as well as any 45 46 additional information the GP sent which supported that diagnosis. This supporting 47 48 information ranged from free text in the GP database to spirometry printouts done in the GP 49 50 surgery to letters from secondary care. Therefore we were not solely relying on information 51 52 from secondary care to make the diagnosis unless the GP decided to share that information. 53 54 In this way we were able to include and validate the diagnosis of COPD in people who were 55 56 not seen in secondary care. 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 70

1 2 3 Analysis 4 5 The primary analysis focused on the accuracy of identification of a COPD diagnosis in each 6 7 of the predefined algorithms as defined by positive predicted value (PPV); i.e. the proportion 8 9 of “true positives” (individuals with COPD) in each algorithm as determined by the gold 10 11 standard. In addition, within each algorithm, where additional information was provided (lung 12 13 function, hospital clinic letters), we calculated the accuracy of the GP diagnosis of COPD 14 15 relative to theFor gold standard. peer This allowed review review of spirometry only interpretation in some cases. 16 17 18 19 We assessed the impact of commonly occurring comorbidities on the accuracy of the pre 20 21 specified algorithms stratifying for cardiovascular comorbidity, previous asthma diagnosis, 22 23 smoking status and, where possible, Global Initiative for Chronic Obstructive Lung Disease 24 25 (GOLD) staging of airflow limitation severity.[13] Cardiovascular comorbidity included 26 27 angina, history of myocardial infarction, previous coronary artery bypass graft / percutaneous 28 29 coronary intervention or heart failure, but not hypertension due to its lack of overlap of 30 31 symptoms that could mimic COPD. All covariates for stratification analysis were derived from 32 33 information available up to cohort entry. 34 35 36 37 38 As a post hoc analysis individuals were eligible to be placed into multiple algorithms where 39 40 possible, and the PPV was calculated for all individuals who had a specific COPD code 41 42 compared to those with a specific COPD code and additional information (either spirometry 43 44 or a COPD medication). 45 46 47 48 Assessment of possible trends in COPD diagnosis recording were also evaluated, including 49 50 temporal trends in codes used and diagnostic specificity from 2004 to 2011. In addition, we 51 52 compared our specific COPD codes to those recommended for use by QOF (see 53 54 supplementary material); [14,15] H31% (excluding H3101 (smokers cough), H31y0 (chronic 55 56 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 70 BMJ Open

1 2 3 tracheitis) and H3122 (acute exacerbation of COPD)) H32% H36H3z (excluding H3y0 and 4 5 H3y1). 6 7 8 9 Sample size calculation 10 11 Our sample size for each algorithm was chosen to achieve accuracy of the true positives or 12 13 PPV ±0.08 based on the reviewing physician judgment as the gold standard. Assuming an 14 15 estimated PPVFor of 0.85 forpeer any one algorithm, review we required a sample only of at least 77 individuals 16 17 in each algorithm to achieve the desired accuracy (95% CI ±0.08). All analyses were 18 19 performed using STATA 13. 20 21 22 23 Ethics approval was obtained from ISAC (the Independent Scientific Advisory Committee 24 25 overseeing CPRD); protocol 12_065 and the LSHTM ethics committee. 26 27 28 29 30 RESULTS 31 32 Nine hundred and fifty one questionnaires were sent to GPs (see Figure 1 for patient 33 34 selection). Of those, 738 (77.6%) were returned, 704 (74.0%) met quality control standards 35 36 and were not duplicates, and 696 (73.2%) could be included in the final analysis (8 had 37 38 “uncertain” COPD diagnosis and no supporting documentation and were therefore 39 40 excluded). 41 42 43 Among those included in the final analysis, additional evidence for the diagnosis of COPD 44 45 was available for 272 patients. This represented 39.1% of the total study population, or 46 47 67.7% of the 402 patients with a confirmed COPD diagnosis in the study. 48 49 50 51 Overall, irrespective of the qualifying algorithm, 402 patients (57.8%) were considered to 52 53 have a diagnosis of COPD based on reviewing physician judgment. Table 1 shows the 54 55 characteristics of the 696 patients included in the final analysis who were considered to 56 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 70

1 2 3 possibly have COPD based on the inclusion criteria. On average, patients were in their mid 4 5 60s to early 70s across all algorithms. Approximately twothirds of them were current 6 7 smokers and onequarter had a history of asthma. Generally, there were fewer patients with 8 9 supporting information and cardiovascular comorbidity in the less specific algorithms (48). 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 70 BMJ Open

1 2 3 4 5 Table 1: Characteristics of the 696 patients included in the final study analysis 6 7 Algorithm COPD Code + COPD Code + COPD Code + COPD Bronchitis + Bronchitis Symptoms + Symptoms 8 spirometry + spirometry COPD Code COPD only spirometry only 9 COPD medication medication only medication 10 Number of 85 (100) 79 (100) 88 (100) 89 (100) 98 (100) 84 (100) 83 (100) 90 (100) 11 individuals (%) For peer review only 12 13 Number (%) with 46 (54.1) 44 (55.7) 48 (54.5) 40 (44.9) 32 (32.7) 18 (21.4) 30 (36.1) 14 (15.6) 14 supporting info 15 16 Mean age 68.7 (11.3) 68.3 71.8 71.1 68.5 (13.1) 67.8 (13.4) 65.9 (11.9) 63.4 (14.1) (sd) (11.7) (10.5) (10.4) 17 18 19 Male (%) 45 (52.9) 41 (51.9) 40 (45.5) 44 (49.4) 31 (31.6) 29 (34.5) 43 (51.8) 47 (52.2) 20 21 Current smoker 49 (57.7) 50 (63.3) 55 (62.5) 47 (52.8) 66 (67.4) 61 (72.6) 48 (57.8) 58 (64.4) 22 (%) 23 24 GOLD stage * 1 13 (16.3) 14 (18.0) 13 (15.9) 16 (20.5) 17 (28.8) 13 (35.1) 8 (20.0) 4 (36.4) 25 (n=465) 26 2 43 (53.8) 48 (61.5) 41 (50.0) 46 (59.0) 31(52.5) 13 (35.1) 22 (55.0) 5 (45.5) 27 3 18 (22.5) 13 (16.7) 22 (26.8) 12 (15.4) 9 (15.3) 8 (21.6) 8 (20.0) 2 (18.2) 28 4 6 (7.5) 3 (3.9) 6 (7.3) 4 (5.1) 2 (3.4) 3 (8.1) 2 (5.0) 0 (0.0) 29 30 History of 20 (23.5) 22 (27.8) 17 (19.3) 18 (20.2) 20 (20.4) 17 (20.2) 14 (16.9) 9 (10.0) 31 cardiovascular 32 disease 33 34 History of asthma 18 (21.2) 20 (25.3) 16 (18.2) 15 (16.9) 27 (27.6) 23 (27.4) 19 (22.9) 23 (25.6) 35 36 Mean BMI (sd) N=83 N=78 N=86 N=87 N=98 N=85 N=41 N=17 37 (n=575) 27.5 (5.4) 26.7 (5.8) 26.4 (4.7) 27.8 27.4 (5.1) 28.1 (5.0) 27.1 (4.5) 27.6 (4.7) 38 (5.4) 39 *GOLD staging was ascertained from CPRD records or from supplementary information provided by GPs. 40 12 41 42 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 34 of 70

1 2 3 The number of patients diagnosed with COPD confirmed by the gold standard and the PPV 4 5 for each algorithm is given in Table 2 . The PPV was greatest for algorithms 14. Further 6 7 data is available in the supplementary material regarding the effect of comorbidities (Table 8 9 S1 ), smoking status (Table S2 ) and GOLD staging (Table S3 ) on the performance of each 10 11 algorithm. 12 13 14 15 For peer review only 16 17 18 19 Table 2 : The PPV and proportion of patients diagnosed with COPD within each algorithm 20 Algorithm Number of Number Number wi th PPV and 95% CI questionnaires evaluable confirmed 21 sent out returned COPD 22 (n=951) (n=696) (%) 23 COPD Code + spirometry + 119 85 (71.4) 76 89.4, 80.794.5 24 COPD medication 25 COPD Code + spirometry 119 79 (66.4) 67 83.8, 73.790.4 26 COPD Code + COPD 119 88 (73.9) 77 87.5, 78.693.0 27 medication 28 COPD Code only 119 89 (74.8) 77 86.5, 77.592.3 29 Bronchitis + COPD medication 119 98 (82.4) 44 44.4, 34.854.5 30 Bronchitis only 119 84 (70.6) 26 29.5, 20.840.1 31 Symptoms + spirometry 119 83 (69.7) 37 43.5, 33.254.4 32 Symptoms only 118 90 (75.6) 11 12.2, 6.820.9 33 34 35 36 37 In a subset of 272 patients where additional evidence was available (in the form of 38 39 spirometry print outs or hospital outpatient letters), we assessed accuracy of GP diagnosis of 40 41 COPD. Overall, the PPV in this group was 95.0% (91.197.2), This is broken down by 42 43 algorithm in Table 3. While the presence of supporting evidence improved the PPV in each 44 45 group, algorithms 14 were still most accurate. 46 47 48 49 50 51 52

54 55 56 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 70 BMJ Open

1 2 3 Table 3: PPV by algorithm where evidence was available to assess GP compared to physician 4 diagnosis of COPD 5 Algorithm Total Number of Number PPV and 95% CI 6 number patients with with COPD 7 with COPD confirmed according 8 evidence by GOLD standard to GP (N=272) (N=220) 9 COPD Code + spirometry + COPD 46 46 46 100 10 medication 11 COPD Code + spirometry 44 35 33 94.3, 82.498.9 12 COPD Code + COPD medication 48 43 41 95.3, 82.498.9 13 COPD Code only 40 34 33 97.1, 80.299.6 14 Bronchitis + COPD medication 32 21 19 90.5, 66.097.9 15 Bronchitis onlyFor peer18 review 12 only 11 91.7, 49.999.2 16 Symptoms + spirometry 30 21 20 95.2, 69.199.4 17 Symptoms only 14 8 6 75.0, 27.695.9 18 19 20 21 22 Post-hoc analysis 23 24 We repeated the analysis allowing individuals to be put into more than one algorithm and 25 26 tested the PPV of COPD by algorithm relative to the gold standard where individuals were 27 28 identified using only the presence of a specific COPD code (n=457) the PPV was identical to 29 30 if they had a COPD code and evidence either in the form of spirometry or COPD medication 31 32 prescription (n=454); PPV 83.0% (79.086.0) for both. In the majority of cases, where a 33 34 specific COPD code had been assigned, there was additional evidence. Only 3 individuals 35 36 had a specific COPD code with no additional evidence. 37 38 39 40 41 42 DISCUSSION 43 44 We tested the accuracy of eight different algorithms for identifying COPD within the CPRD 45 46 among patients with suspected COPD (e.g., >35 years of age, smoking history, and 47 48 recording of respiratory symptoms or COPD codes). The physician reviewer consensus was 49 50 the GOLD standard. The best performing algorithm allowed an accurate ascertainment of 51 52 90% of patients as diagnosed with COPD. This consisted of a combination of a specific 53 54 COPD code, more than one prescription of a COPD medication and spirometry (PPV 89.4, 55 56 95% CI: 80.794.5). The worst performing algorithm was represented by presence of 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 70

34 35 36 One of the advantages of this study was our ability to investigate both the accuracy of 37 38 algorithms when identifying COPD patients within the CPRD, and accuracy of the actual GP 39 40 diagnosis of COPD. When validating the GP diagnosis of COPD with a respiratory physician 41 42 diagnosis as gold standard based on extra evidence provided by the GP, there was 43 44 improved accuracy (PPV) across all algorithms, with algorithms 14 again performing best. 45 46 This suggests that additional evidence is collected when the GP is reasonably certain that 47 48 the patient has COPD. There was good concordance between GP and physician diagnosis 49 50 suggesting respiratory consultant validation is not always needed. Where there was 51 52 disagreement, this was usually because lung function did not meet criteria for COPD. 53 54 55 56 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 70 BMJ Open

30 31 When considering the severity of COPD by GOLD classification, algorithms 2 and 3, i.e. a 32 33 specific COPD code and spirometry or COPD medications had the greatest accuracy for 34 35 36 patients with mild disease (GOLD stage 1) (Table S3 online supplement). PPV increased 37 38 with increasing disease severity. PPV increases with disease prevalence, and the 39 40 prevalence of COPD increased moving from algorithm 8 to algorithm 1. 41 42 43 44 We considered the timing of diagnosis in view of an increased uptake of spirometry in 45 46 primary care in more recent years and changes in QOF requirements over time during our 47 48 study period (Table S4 online supplement). We found that algorithms 14 still had the 49 50 greatest accuracy, but the PPV estimates were better for the post 2008 period than pre 2008 51 52 period (see supplementary material). Nonspecific bronchitis codes and symptom codes 53 54 were more likely to be used before 2008 rather than post. This may require consideration 55 56 when developing retrospective cohorts for analysis and otherwise suggests QOF has had a 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 70

1 2 3 positive effect on the consistency of codes used for COPD diagnoses. However, our codes 4 5 were more specific than QOF codes and some of the codes included in QOF were not 6 7 included in our specific COPD codelist, but were included in the nonspecific bronchitis 8 9 codes. While we cannot comment on the accuracy of QOF codes, it is important to highlight 10 11 that that some QOF codes are not disease specific and may not be a good way of identifying 12 13 COPD patients from electronic health records as inevitably people without COPD will be 14 15 included. It isFor also important peer to highlight reviewthat Read codes change only over time with new codes 16 17 added and some removed, and this needs consideration when identifying people with 18 19 COPD. 20 21 22 23 There are limited COPD validation studies in electronic health records published in the 24 25 literature to which we can compare our study. Soriano validated COPD in the GPRD in 2001, 26 27 when OXMIS codes were still in use. [4] A Swedish study using a Swedish inpatient registry 28 29 used ICD9 and ICD10 codes and identified COPD patients with similar accuracy.[16] A 30 31 Canadian study in the Canadian primary care sentinel surveillance network used algorithms 32 33 to identify several long term conditions and also had a PPV similar to ours for COPD [17]. 34 35 36 However, all of these studies used different codes, algorithms and databases. 37 38 39 40 Our analysis has several limitations. Although the overall response rate for this study was 41 42 acceptable (77.6%), the proportion of questionnaires accompanied with additional evidence 43 44 allowing for adjudication was rather low. We chose PPV as the measure of accuracy in this 45 46 study to allow us to determine the probability that a patient had COPD from their electronic 47 48 health record. PPV is correlated with disease prevalence, and although it is strongly related 49 50 to specificity, the actual estimates of specificity, sensitivity and negative predictive value 51 52 cannot be determined from our data. Further, GP practices are self selecting with respect to 53 54 their contribution to CPRD, however those practices appear to be representative of the UK 55 56 population. Very few patients within contributing practices refuse to participate at an 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 70 BMJ Open

1 2 3 individual level and this is not thought to bias the results. While CPRD is representative of 4 5 the general population, as with all validation studies that require a response, we cannot be 6 7 sure that our sample is representative of GPs who have not responded, although there is 8 9 unlikely to be any difference. The amount of missing data among the responding 10 11 questionnaires was low, suggesting reasonable data quality. One of the other limitations of 12 13 this study is that patients had to be alive to be included; however it is unlikely that coding 14 15 would be differentFor for individuals peer who are review no longer alive. only 16 17 18 19 The algorithm that consisted of a specific COPD code, COPD medication and spirometry 20 21 had the highest PPV; however the PPV was almost as high when a specific COPD code 22 23 alone was used. The poorest performing algorithms were those that involved bronchitis 24 25 codes or respiratory symptoms; we would not recommend using these algorithms to identify 26 27 COPD patients. In conclusion, we have shown that the presence of a specific COPD Read 28 29 code alone is sufficient to identify patients with COPD from electronic health records. 30 31 Minimal precision lost by not including spirometry and medications in the algorithm, allows 32 33 an increase in the number of individuals who can potentially be included in a study by up to 34 35 36 10%. However by not including spirometry in the definition, the ability to stage COPD 37 38 according to GOLD stages may not be possible for all COPD patients included in a study. 39 40 41 42 Acknowledgments: none 43 44 Competing interests: none 45 46 Funding : This project was funded jointly by GSK and the MRC. JKQ is funded on a MRC 47 48 Population Health Scientist Fellowship. This work was part funded by a MRC Industry 49 50 Partnership award (grant number G0902135). 51 52 53 54 Figure 1: Study population 55 56 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 70

1 2 3 4 REFERENCES 5 6 1. National Statistics. www.statistics.gov.uk date accessed June 2013. 7 8 9 10 11 2. Shahab LM, Jarvis MJ, Britton J, et al. Prevalence, diagnosis and relation to tobacco 12 13 dependence of chronic obstructive pulmonary disease in a nationally representative 14 15 populationFor sample peer Thorax 2006;61(12):1043 review only 16 17 18 19 3. file:///C:/Users/ENCDJQUI/Downloads/InvisibleLivesreport.pdf Invisible Lives. 20 21 Chronic Obstructive Pulmonary Disease (COPD) – finding the missing millions. 22 23 British Lung Foundation. November 2007. Accessed February 2014. 24 25 26 27 4. Soriano JB, Maier WC, Visick G, et al. Validation of general practitionerdiagnosed 28 29 COPD in the UK General Practice. European Journal of Epidemiology 30 31 2001;17:1075–1080 32 33 34 35 5. NICE guideline COPD http://guidance.nice.org.uk/CG101/QuickRefGuide/pdf/English 36 37 date accessed January 2014. 38 39 40 41 6. Cooke CR, Joo MJ, Anderson SM et al. The validity of using ICD9 codes and 42 43 pharmacy records to identify patients with chronic obstructive pulmonary disease. 44 45 BMC Health Services Research 2011;11:37 46 47 48 49 7. Smith CJP, Gribbin J, Challen KB, et al. The impact of the 2004 NICE guideline and 50 51 2003General Medical Services contract on COPD in primary care in the UK. Q J Med 52 53 2008;101:145–153. 54 55

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1 2 3 8. http://www.nice.org.uk/aboutnice/qof/qof.jsp. Accessed January 2014 . 4 5 6 7 9. CPRD http://www.cprd.com (accessed February 28,2013) 8 9 10 11 10. Williams T, VanStaa T, Padmanabhan S et al. Recent advances in utility and use of 12 13 the General Practice Research Database as an example of a UK Primary Care Data 14 15 resource.For Ther Advpeer Drug Saf 2012;3:88–99. review only 16 17 18 19 11. Tate AR, Beloff N, AlRadwan B et al. Exploiting the potential of large databases of 20 21 electronic health records for research using rapid search algorithms and an intuitive 22 23 query interface. J Am Med Inform Assoc . 2014;21(2):2928. 24 25 26 27 12. Chisholm J. The Read clinical classification. BMJ, 1990. 300(6732):1092. 28 29

30 31 13. GOLD 2011 http://www.goldcopd.org/uploads/users/files/GOLD2011_Summary.pdf 32 33 accessed Nov 2013. 34 35 36 37 38 14. https://mqi.ic.nhs.uk/IndicatorDefaultView.aspx?ref=1.09.03.07 (QOF COPD). 39 40 Accessed Feb 2014. 41 42 43 44 15. http://www.nbmedical.com/pdf/keep_simple_qof_20142014.pdf accessed Feb 45 46 2014 47 48 49 50 16. Inghammar M, Engström G, Löfdahl CG et al. Validation of a COPD diagnosis 51 52 from the Swedish Inpatient Registry Scandinavian Journal of Public Health , 2012;40: 53 54 773–776 55 56 57 58 20 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 70

1 2 3 17. KadhimSaleh A, Green M, WilliamsonT et al. Validation of the Diagnostic 4 5 Algorithms for 5 Chronic Conditions in the Canadian Primary Care Sentinel 6 7 Surveillance Network (CPCSSN): A Kingston Practicebased Research Network 8 9 (PBRN) Report. J Am Board Fam Med 2013;26: 159–167 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 21 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 70 BMJ Open

1 2 3 Supplementary information 4 5 6 7 Algorithms 8 9 1. Specific COPD code and more than one prescription of a COPD medication and 10 presence of spirometry. The first COPD medication had to be prescribed within 4 11 weeks of the COPD diagnostic code. 12 2. Specific COPD code and presence of spirometry 13 3. Specific COPD code and more than one prescription of a COPD medication. The first 14 COPD medication had to be prescribed within 4 weeks of the COPD diagnostic code. 15 4. SpecificFor COPD codepeer only review only 16 5. Non-specific bronchitis codes and more than one prescription of a COPD medication. 17 The first COPD medication had to be prescribed within 4 weeks of the COPD 18 diagnostic code. 19 6. Non-specific bronchitis codes only 20 7. Respiratory symptoms and presence of spirometry. Respiratory symptoms consisted 21 of persistent cough, sputum production, or dyspnoea 22 8. Respiratory symptom definition only 23

24 25 26 27 Specific COPD codes 28 medcode term 29 18476 COPD follow-up 30 45771 Chronic obstructive pulmonary disease does not disturb sleep 31 4084 Airways obstructn irreversible 32 794 Emphysema 33 998 Chronic obstructive airways disease 34 1001 Chronic obstructive pulmonary disease 35 36 5710 Chronic obstructive airways disease NOS 37 9520 Chronic obstructive pulmonary disease monitoring 38 9876 Severe chronic obstructive pulmonary disease 39 10802 Moderate chronic obstructive pulmonary disease 40 10863 Mild chronic obstructive pulmonary disease 41 10980 Centrilobular emphysema 42 11287 Chronic obstructive pulmonary disease annual review 43 14798 Emphysematous bronchitis 44 18621 Chronic obstructive pulmonary disease follow-up 45 18792 Chronic obstructive pulmonary disease monitoring admin 46 23492 Chronic bullous emphysema NOS 47 26018 Chronic obstructive pulmonary disease monitoring by nurse 48 26306 Chronic bullous emphysema 49 28755 Chronic obstructive pulmonary disease monitoring 1st letter 50 33450 Emphysema NOS 51 34202 Chronic obstructive pulmonary disease monitoring 2nd letter 52 34215 Chronic obstructive pulmonary disease monitoring 3rd letter 53 37247 Chronic obstructive pulmonary disease NOS 54 37371 Chronic obstructive pulmonary disease monitoring due 55 44525 Obstructive chronic bronchitis NOS 56 45998 Chronic obstructive pulmonary disease monitoring by doctor 57 93568 Very severe chronic obstructive pulmonary disease 58 12166 Other specified chronic obstructive airways disease 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 70 BMJ Open

1 2 3 38074 Chronic obstructive pulmonary disease monitor phone invite 4 42258 Chronic obstructive pulmonary disease monitoring verb invite 5 42313 Health education - chronic obstructive pulmonary disease 6 45770 Chronic obstructive pulmonary disease disturbs sleep 7 45777 Chronic obstructive pulmonary disease clini management plan 8 9 10 11 12 COPD medication codes 13 prodcode productname 14 8 salbutamol 100micrograms/dose inhaler 15 17 salbutamolFor 100micrograms/dose peer reviewinhaler cfc free only 16 31 ventolin 100microgram/inhalation inhalation powder (glaxo wellcome uk ltd) 17 38 beclometasone 100micrograms/dose inhaler 18 99 becotide 100 inhaler (glaxosmithkline uk ltd) 19 218 aminophylline 100 mg cap 20 235 bricanyl 250micrograms/dose inhaler (astrazeneca uk ltd) 21 273 theophylline 200 mg cap 22 282 salbutamol 2mg/5ml oral solution sugar free 23 454 pulmicort 200microgram inhaler (astrazeneca uk ltd) 24 465 salmeterol 25micrograms/dose inhaler 25 510 ventolin 5mg/ml respirator solution (glaxosmithkline uk ltd) 26 549 serevent 25micrograms/dose inhaler (glaxosmithkline uk ltd) 27 555 aminophylline 225mg modified-release tablets 28 590 phyllocontin continus 225mg tablets (napp pharmaceuticals ltd) 29 638 seretide 250 accuhaler (glaxosmithkline uk ltd) 30 665 seretide 100 accuhaler (glaxosmithkline uk ltd) 31 674 ventolin 2.5mg nebules (glaxosmithkline uk ltd) 32 696 salbutamol 8mg modified-release capsules 33 719 salmeterol 50micrograms/dose dry powder inhaler 34 746 tiotropium 18 microgram capsule 35 752 carbocisteine 375mg capsules 36 856 ventolin 2mg/5ml syrup (glaxosmithkline uk ltd) 37 860 salbutamol 4mg tablets 38 862 salbulin inhalation powder (3m health care ltd) 39 40 863 slo-phyllin 125mg capsule (lipha pharmaceuticals ltd) 41 879 theophylline 125mg modified-release capsules 42 880 theophylline 60mg modified-release capsules 43 881 salbutamol 2mg tablets 44 882 salbutamol 200microgram inhalation powder capsules 45 883 becodisks 200microgram disc (allen & hanburys ltd) 46 895 beclazone 100 easi-breathe inhaler (teva uk ltd) 47 896 becotide easi-breathe 100microgram/actuation pressurised inhalation (allen & 48 hanburys ltd) 49 898 ventolin evohaler 100 100microgram/inhalation pressurised inhalation (glaxo 50 wellcome uk ltd) 51 907 bricanyl turbohaler 500 500microgram turbohaler (astrazeneca uk ltd) 52 908 pulmicort 400 turbohaler (astrazeneca uk ltd) 53 909 budesonide 200micrograms/dose inhaler 54 910 serevent diskhaler 50microgram inhalation powder (glaxo wellcome uk ltd) 55 911 flixotide accuhaler 250 250microgram/inhalation inhalation powder (allen & hanburys 56 ltd) 57 947 budesonide 50micrograms/actuation refill canister 58 956 pulmicort 200 turbohaler (astrazeneca uk ltd) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 70

1 2 3 957 salamol easi-breathe 100microgram/actuation pressurised inhalation (ivax 4 pharmaceuticals uk ltd) 5 958 ventolin easi-breathe 100microgram/actuation pressurised inhalation (allen & 6 hanburys ltd) 7 959 budesonide 50micrograms/dose inhaler 8 960 pulmicort 100 turbohaler (astrazeneca uk ltd) 9 987 ventolin 4mg tablet (allen & hanburys ltd) 10 1093 salamol 100microgram/actuation inhalation powder (ivax pharmaceuticals uk ltd) 11 1097 slo-phyllin 60mg capsule (lipha pharmaceuticals ltd) 12 1100 beclazone 100 inhaler (teva uk ltd) 13 1236 becloforte 250micrograms/dose inhaler (glaxosmithkline uk ltd) 14 1242 beclometasone 250micrograms/dose inhaler 15 1243 beclazoneFor 250 easi-breathe peer inhaler review (teva uk ltd) only 16 1258 becotide 200 inhaler (glaxosmithkline uk ltd) 17 1259 beclometasone 200micrograms/dose inhaler 18 1269 becotide 50microgram/ml nebuliser liquid (allen & hanburys ltd) 19 1346 salbutamol 0.05mg/ml injection 20 1406 becotide 50 inhaler (glaxosmithkline uk ltd) 21 1409 ipratropium bromide 20micrograms/dose inhaler 22 1410 ipratropium bromide 0.25mg/ml 23 1411 ipratropium bromide 250micrograms/ml 24 1412 flixotide 250microgram/actuation inhalation powder (allen & hanburys ltd) 25 1414 salamol 5mg/2.5ml nebuliser liquid steri-neb unit dose vials (teva uk ltd) 26 1415 steri-neb ipratropium 250microgram/ml nebuliser liquid (ivax pharmaceuticals uk ltd) 27 1423 uniphyllin continus 200mg tablets (napp pharmaceuticals ltd) 28 1424 flixotide 250microgram disc (allen & hanburys ltd) 29 1426 flixotide 500microgram disc (allen & hanburys ltd) 30 1518 flixotide 50microgram/actuation inhalation powder (allen & hanburys ltd) 31 1537 becotide 200microgram rotacaps (glaxosmithkline uk ltd) 32 1551 beclazone 250 inhaler (teva uk ltd) 33 1552 becloforte easi-breathe 250microgram/actuation pressurised inhalation (allen & 34 35 hanburys ltd) 36 1619 terbutaline 500micrograms/dose dry powder inhaler 37 1620 terbutaline 250micrograms/dose inhaler 38 1628 terbutaline 250micrograms/actuation refill canister 39 1630 salbutamol 2.5mg/2.5ml nebuliser liquid unit dose vials 40 1635 salbuvent 2mg/5ml oral solution (pharmacia ltd) 41 1642 budesonide 400micrograms/dose dry powder inhaler 42 1676 flixotide 125microgram/actuation inhalation powder (allen & hanburys ltd) 43 1680 pulmicort ls 50micrograms/dose inhaler (astrazeneca uk ltd) 44 1698 salbutamol 100micrograms/dose breath actuated inhaler 45 1711 salbutamol 5mg/2.5ml nebuliser liquid unit dose vials 46 1725 beclazone 50 easi-breathe inhaler (teva uk ltd) 47 1727 becotide easi-breathe 50microgram/actuation pressurised inhalation (allen & 48 hanburys ltd) 49 1734 beclometasone 100micrograms/dose breath actuated inhaler 50 1741 salbutamol 100micrograms/dose breath actuated inhaler cfc free 51 1833 theophylline 200mg modified-release tablets 52 1834 theophylline 400mg modified-release tablets 53 1861 aerobec 100 autohaler (meda pharmaceuticals ltd) 54 1882 ventodisks 200microgram/blister disc (allen & hanburys ltd) 55 1885 beclazone 200 inhaler (teva uk ltd) 56 1950 ventodisks 400microgram/blister disc (allen & hanburys ltd) 57 1951 becodisks 400microgram disc (allen & hanburys ltd) 58 1952 ventolin 400microgram rotacaps (glaxosmithkline uk ltd) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 70 BMJ Open

1 2 3 1956 pulmicort 1mg respules (astrazeneca uk ltd) 4 1957 ventolin 5mg nebules (glaxosmithkline uk ltd) 5 1959 pulmicort 0.5mg respules (astrazeneca uk ltd) 6 1972 oxygen bp size af lightweight gas 1360 litres 7 1974 oxis 12 turbohaler (astrazeneca uk ltd) 8 1975 oxis 6 turbohaler (astrazeneca uk ltd) 9 2044 prednisone 2.5 mg tab 10 2092 budesonide 200micrograms/dose dry powder inhaler 11 2124 pulmicort refil 200 mcg inh 12 2125 pulmicort 200microgram refill canister (astrazeneca uk ltd) 13 2147 theophylline 250mg modified-release capsules 14 2148 beclometasone 400microgram disc 15 2149 steri-nebFor salamol peer 2.5 mg inh review only 16 2152 ipratropium bromide with salbutamol 20mcg + 100mcg 17 2159 aerobec 50 autohaler (meda pharmaceuticals ltd) 18 2160 beclometasone 50micrograms/dose breath actuated inhaler 19 2224 serevent 50micrograms/dose accuhaler (glaxosmithkline uk ltd) 20 2229 becodisks 100microgram disc (allen & hanburys ltd) 21 2282 fluticasone 500micrograms/dose dry powder inhaler 22 2335 qvar 100 inhaler (teva uk ltd) 23 2368 prednisolone 2.5mg tablet 24 2390 prednisolone e/c 1 mg tab 25 2395 salbutamol 2 mg/5ml syr 26 2437 oxitropium bromide 100micrograms/dose inhaler 27 2440 flixotide accuhaler 500 500microgram/inhalation inhalation powder (allen & hanburys 28 ltd) 29 2510 oxygen bp gas 1280 litres 30 2600 beclometasone 250micrograms/dose breath actuated inhaler 31 2655 airomir 100micrograms/dose inhaler (teva uk ltd) 32 2723 fluticasone 25micrograms/dose inhaler 33 2757 slo-phyllin 250mg capsule (lipha pharmaceuticals ltd) 34 35 2758 bricanyl refill canister (astrazeneca uk ltd) 36 2799 prednisolone 10 mg tab 37 2850 salbutamol 400microgram inhalation powder capsules 38 2851 ventolin 200microgram rotacaps (glaxosmithkline uk ltd) 39 2869 salbutamol 8mg modified-release tablets 40 2892 becloforte 400microgram disks (glaxosmithkline uk ltd) 41 2893 beclometasone 200micrograms disc 42 2949 prednisone 5mg tablets 43 2951 fluticasone 250microgram/actuation pressurised inhalation 44 2978 salbutamol 200micrograms/dose dry powder inhaler 45 2992 beclazone 50 inhaler (teva uk ltd) 46 2995 nuelin sa 175mg tablets (meda pharmaceuticals ltd) 47 3018 beclometasone 50micrograms/dose inhaler 48 3059 prednisolone 50 mg tab 49 3065 bextasol inhalation powder (allen & hanburys ltd) 50 3075 becotide 400microgram rotacaps (glaxosmithkline uk ltd) 51 3119 becloforte integra 250microgram/actuation inhaler with compact spacer (glaxo 52 laboratories ltd) 53 3150 beclometasone 100micrograms/actuation extrafine particle cfc free inhaler 54 3163 salbutamol 200micrograms disc 55 3188 pulmicort complete 50 mcg inh 56 3189 salbuvent inh inh 57 3220 qvar 50 autohaler (teva uk ltd) 58 3254 salbulin 4mg tablet (3m health care ltd) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48 of 70

1 2 3 3289 flixotide 25micrograms/dose inhaler (glaxosmithkline uk ltd) 4 3297 salmeterol 50micrograms disc 5 3322 aerolin inh 400 100 mcg aer 6 3345 sintisone tablet (pharmacia ltd) 7 3347 oxygen bp size f gas 1360 litres 8 3363 becloforte 400microgram disks with diskhaler (glaxosmithkline uk ltd) 9 3388 theophylline 175mg modified-release tablets 10 3442 pulmicort complete 200 mcg inh 11 3443 salbutamol 100microgram/inhalation spacehaler (celltech pharma europe ltd) 12 3534 bricanyl 5mg tablets (astrazeneca uk ltd) 13 3546 qvar 50 inhaler (teva uk ltd) 14 3556 beclometasone 50micrograms with salbutamol 100micrograms/inhalation inhaler 15 3557 prednisoneFor 1mg tabletspeer review only 16 3570 budesonide 200micrograms/actuation refill canister 17 3584 bricanyl 1.5mg/5ml syrup (astrazeneca uk ltd) 18 3666 seretide 500 accuhaler (glaxosmithkline uk ltd) 19 3743 filair 50 inhaler (meda pharmaceuticals ltd) 20 3753 flixotide diskhaler-community pack 250 mcg 21 3758 pulmadil inhalation powder (3m health care ltd) 22 3763 terbutaline respules inh 23 3764 bricanyl respules (5mg/2ml) 2.5 mg/ml inh 24 3786 fenoterol 100micrograms/dose / ipratropium 40micrograms/dose inhaler 25 3838 salbutamol 400mcg/beclometh.100mcg r/cap inh 26 3927 filair 100 inhaler (meda pharmaceuticals ltd) 27 3947 becotide 100microgram rotacaps (glaxosmithkline uk ltd) 28 3988 flixotide diskhaler-community pack 100 mcg 29 3989 flixotide 100microgram disc (allen & hanburys ltd) 30 3993 filair forte 250micrograms/dose inhaler (meda pharmaceuticals ltd) 31 3994 salbutamol 4mg modified-release tablets 32 4055 salbulin 2mg/5ml oral solution (3m health care ltd) 33 4131 fluticasone 100microgram disc 34 35 4132 fluticasone 125microgram/actuation pressurised inhalation 36 4165 zithromax 250mg capsules (pfizer ltd) 37 4171 ventolin 2mg tablet (allen & hanburys ltd) 38 4222 bricanyl 10mg/ml respirator solution (astrazeneca uk ltd) 39 4268 ipratropium bromide 40micrograms/dose inhaler 40 4365 beclometasone 100micrograms disc 41 4412 oxygen bp size g gas 3400 litres 42 4413 qvar 100 autohaler (teva uk ltd) 43 4497 ventolin accuhaler 200 200microgram/actuation inhalation powder (glaxo wellcome 44 uk ltd) 45 4499 aerobec 250microgram/actuation pressurised inhalation (meda pharmaceuticals ltd) 46 4514 aminophylline 350mg modified-release tablets 47 4538 oxygen bp size pd gas 300 litres 48 4541 bricanyl sa 7.5mg tablets (astrazeneca uk ltd) 49 4545 pulmicort ls 50microgram refill canister (astrazeneca uk ltd) 50 4593 theophylline 125mg tablets 51 4601 asmabec 100 clickhaler (focus pharmaceuticals ltd) 52 4634 salamol 2.5mg/2.5ml nebuliser liquid steri-neb unit dose vials (teva uk ltd) 53 4640 bricanyl 5mg/2ml nebuliser liquid (astrazeneca uk ltd) 54 4665 salbulin 100micrograms/dose inhaler (3m health care ltd) 55 4688 fluticasone 50microgram/actuation pressurised inhalation 56 4759 beclometasone 100microgram inhalation powder capsules 57 4791 oxygen bp size c gas 170 litres 58 4801 budesonide 500micrograms/2ml nebuliser liquid unit dose vials 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 70 BMJ Open

1 2 3 4803 beclazone 250microgram/actuation inhalation powder (actavis uk ltd) 4 4842 fenoterol 100microgram/actuation inhaler 5 4908 ventolin rotahaler (glaxosmithkline uk ltd) 6 4926 flixotide accuhaler 100 100microgram/inhalation inhalation powder (allen & hanburys 7 ltd) 8 4942 budesonide 1mg/2ml nebuliser liquid unit dose vials 9 5057 azithromycin 200mg/5ml oral suspension 10 5116 azithromycin 250mg capsules 11 5143 seretide 50 evohaler (glaxosmithkline uk ltd) 12 5161 seretide 125 evohaler (glaxosmithkline uk ltd) 13 5170 salamol 100micrograms/dose inhaler cfc free (teva uk ltd) 14 5172 seretide 250 evohaler (glaxosmithkline uk ltd) 15 5185 fenoterolFor 200micrograms/dose peer inhalerreview only 16 5223 fluticasone 50micrograms/dose inhaler cfc free 17 5261 nuelin sa 250 tablets (meda pharmaceuticals ltd) 18 5308 terbutaline 5mg/2ml nebuliser liquid unit dose vials 19 5309 flixotide 50micrograms/dose evohaler (glaxosmithkline uk ltd) 20 5335 zithromax 500mg tablets (pfizer ltd) 21 5453 uniphyllin continus 400mg tablets (napp pharmaceuticals ltd) 22 5516 salamol 100micrograms/dose easi-breathe inhaler (teva uk ltd) 23 5521 beclometasone 200micrograms/dose dry powder inhaler 24 5522 beclometasone 100micrograms/dose dry powder inhaler 25 5551 flixotide 0.5mg/2ml nebules (glaxosmithkline uk ltd) 26 5558 salmeterol 50micrograms with fluticasone 500micrograms cfc free inhaler 27 5580 flixotide accuhaler 50 50microgram/inhalation inhalation powder (allen & hanburys 28 ltd) 29 5584 oxygen cylinders size pd (boc ltd) 30 5683 flixotide 250micrograms/dose evohaler (glaxosmithkline uk ltd) 31 5718 flixotide 125micrograms/dose evohaler (glaxosmithkline uk ltd) 32 5740 airomir 100micrograms/dose autohaler (teva uk ltd) 33 5753 salbutamol 400micrograms disc 34 35 5773 oxygen bp size dd gas 460 litres 36 5780 oxygen cylinders size af (boc ltd) 37 5804 beclometasone 250micrograms/dose dry powder inhaler 38 5822 fluticasone 250micrograms/dose inhaler cfc free 39 5837 salamol steri-neb 5mg/2.5ml nebuliser liquid (numark management ltd) 40 5864 salmeterol 25micrograms with fluticasone 250micrograms cfc free inhaler 41 5885 fluticasone 100micrograms/dose dry powder inhaler 42 5889 salamol 100microgram/inhalation inhalation powder (kent pharmaceuticals ltd) 43 5898 salamol steri-neb 2.5mg/2.5ml nebuliser liquid (numark management ltd) 44 5941 uniphyllin continus 300mg tablets (napp pharmaceuticals ltd) 45 5942 salmeterol 50micrograms with fluticasone 250micrograms cfc free inhaler 46 5975 fluticasone 125micrograms/dose inhaler cfc free 47 5976 oxygen bp size dd 460 litre inhalation gas (boc ltd) 48 5992 beclometasone 50micrograms/dose dry powder inhaler 49 6081 ipratropium bromide 20micrograms/dose breath actuated inhaler 50 6276 carbocisteine 250mg/5ml oral solution 51 6315 slo-phyllin 250mg capsules (merck serono ltd) 52 6325 symbicort 200/6 turbohaler (astrazeneca uk ltd) 53 6419 oxygen cylinders size f (boc ltd) 54 6420 oxygen bp size d gas 340 litres 55 6423 oxygen bp with integral headset 1360 litre inhalation gas (boc ltd) 56 6462 salbutamol 95micrograms/dose dry powder inhaler 57 6522 ipratropium bromide 20micrograms/dose inhaler cfc free 58 6526 formoterol 12microgram inhalation powder capsules with device 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50 of 70

1 2 3 6556 oxygen cylinders size c (boc ltd) 4 6569 salmeterol 25micrograms with fluticasone 125micrograms cfc free inhaler 5 6616 salmeterol 25micrograms with fluticasone 50micrograms cfc free inhaler 6 6619 oxygen bp size cd gas 460 litres 7 6719 ipratropium bromide 500micrograms/2ml nebuliser liquid unit dose vials 8 6746 budesonide 400micrograms/dose / formoterol 12micrograms/dose dry powder inhaler 9 6758 ipratropium 250micrograms/1ml nebuliser liquid steri-neb unit dose vials (teva uk ltd) 10 6768 oxygen bp size cd 460 litre inhalation gas (boc ltd) 11 6772 ipratropium bromide 250micrograms/1ml nebuliser liquid unit dose vials 12 6780 symbicort 400/12 turbohaler (astrazeneca uk ltd) 13 6796 budesonide 200micrograms/dose / formoterol 6micrograms/dose dry powder inhaler 14 6802 mucodyne 375mg capsules (sanofi) 15 6848 oxygenFor cylinders peersize dd with integral review headset 2 and 4litres/minute only flow rate (boc ltd) 16 6920 mecysteine 100mg gastro-resistant tablets 17 6938 salmeterol 50micrograms with fluticasone 100micrograms dry powder inhaler 18 6976 oxygen bp with integral headset gas 430 litres 19 6988 aminophylline hydrate 100mg modified-release tablets 20 7013 symbicort 100/6 turbohaler (astrazeneca uk ltd) 21 7017 salbutamol 100micrograms/dose dry powder inhaler 22 7031 oxygen bp size e gas 680 litres 23 7042 oxygen cylinders size e (boc ltd) 24 7133 formoterol 12micrograms/dose dry powder inhaler 25 7192 bambuterol 10mg tablets 26 7239 oxygen cylinders size b10s (air products plc) 27 7268 serevent 25micrograms/dose evohaler (glaxosmithkline uk ltd) 28 7270 salmeterol 25micrograms/dose inhaler cfc free 29 7452 ventolin .25 mg inj 30 7584 prednisolone 4 mg tab 31 7602 fluticasone 50microgram disc 32 7638 fluticasone 250microgram disc 33 7653 beclometasone 400microgram inhalation powder capsules 34 35 7710 prednisolone 15 mg tab 36 7711 terbutaline 250micrograms/dose inhaler with spacer 37 7724 betamethasone valerate 100micrograms/actuation inhaler 38 7730 theo-dur 300mg tablets (astrazeneca uk ltd) 39 7731 theo-dur 200mg tablets (astrazeneca uk ltd) 40 7732 theophylline 300mg modified-release tablets 41 7733 theophylline 250mg modified-release tablets 42 7788 budesonide 100micrograms/dose dry powder inhaler 43 7832 choline theophyllinate 200mg tablets 44 7841 nuelin 125mg tablets (3m health care ltd) 45 7891 fluticasone 500microgram disc 46 7934 prednisone 30 mg tab 47 7935 maxivent 100microgram/inhalation inhalation powder (ashbourne pharmaceuticals 48 ltd) 49 7948 fluticasone 250micrograms/dose dry powder inhaler 50 7953 terbutaline 1.5mg/5ml oral solution sugar free 51 7954 bricanyl 250micrograms/dose spacer inhaler (astrazeneca uk ltd) 52 7964 beclometasone 50micrograms/ml nebuliser suspension 53 7965 salbutamol 5mg/ml nebuliser liquid 54 8012 exirel 15mg capsule (3m health care ltd) 55 8056 aminophylline 100mg tablets 56 8057 aminophylline 100mg modified-release tablets 57 8111 becloforte vm 250microgram/actuation vm pack (allen & hanburys ltd) 58 8183 oxygen bp gas 640 litres 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 70 BMJ Open

1 2 3 8251 pulmicort refil 50 mg inh 4 8252 pirbuterol 15mg capsule 5 8267 sodium cromoglicate 1mg/dose / salbutamol 100micrograms/dose inhaler 6 8333 ipratropium bromide 40microgram inhalation powder capsules 7 8339 fenoterol hydrobromide complete unit inh 8 8429 ventolin i/v 5 mg inj 9 8433 budesonide 100micrograms/actuation inhaler 10 8450 flixotide diskhaler-community pack 50 mcg 11 8504 exirel 15 mg tab 12 8505 oxygen bp gas 6400 litres 13 8522 terbutaline 7.5mg modified-release tablets 14 8572 rimiterol inhaler 15 8635 flixotideFor 50microgram peer disc (allen review& hanburys ltd) only 16 8636 ventolin s/r 8 mg spa 17 8676 terbutaline 10mg/ml nebuliser liquid 18 8757 oxygen bp gas 3200 litres 19 8806 phyllocontin continus 350mg tablet (napp pharmaceuticals ltd) 20 8955 theophylline 100 mg tab 21 9018 mucodyne 375mg capsule (aventis pharma) 22 9092 theophylline 350mg modified release tablets 23 9164 fluticasone 50micrograms/dose dry powder inhaler 24 9233 beclometasone 200microgram inhalation powder capsules 25 9270 ipratropium bromide with fenoterol hydrobromide 500micrograms + 1.25mg/4ml 26 9384 salbutamol 4mg modified-release capsules 27 9477 asmabec 100microgram/actuation spacehaler (celltech pharma europe ltd) 28 9571 beclometasone 250micrograms/actuation vortex inhaler 29 9577 asmabec 50 clickhaler (focus pharmaceuticals ltd) 30 9599 beclazone 50microgram/actuation inhalation powder (actavis uk ltd) 31 9642 mucodyne 250mg/5ml oral solution (aventis pharma) 32 9651 asmasal 100microgram/inhalation spacehaler (celltech pharma europe ltd) 33 9658 oxitropium bromide 100micrograms/dose breath actuated inhaler 34 35 9711 formoterol 6micrograms/dose dry powder inhaler 36 9727 prednisolone 50mg tablets 37 9805 salbutamol 5mg/50ml solution for infusion vials 38 9889 oxygen cylinders size g (boc ltd) 39 9895 oxygen bp size df with integral headset gas 1360 litres 40 9906 mucodyne 250mg/5ml syrup (sanofi) 41 9921 beclometasone 100micrograms/dose breath actuated inhaler cfc free 42 9943 visclair 100mg gastro-resistant tablets (ranbaxy (uk) ltd) 43 10043 oxygen composite cylinders size b10c with integral headset (air products plc) 44 10053 oxygen connection cubing 1.8m 45 10090 beclometasone 50micrograms/actuation extrafine particle cfc free inhaler 46 10218 budesonide 100micrograms/dose / formoterol 6micrograms/dose dry powder inhaler 47 10321 budesonide 400microgram inhalation powder capsules 48 10331 nuelin 60mg/5ml liquid (3m health care ltd) 49 10353 salbuvent rondo 50 10360 aerocrom inhaler (castlemead healthcare ltd) 51 10407 phyllocontin paediatric continus 100mg tablets (napp pharmaceuticals ltd) 52 10433 theophylline 60mg/5ml oral solution 53 10458 ventolin cr 4mg tablet (allen & hanburys ltd) 54 10561 aminophylline 250mg/ml injection 55 10723 theophylline 125mg/5ml syrup 56 10744 theophylline 80 mg eli 57 10808 mucodyne paediatric 125mg/5ml syrup (sanofi) 58 10825 terbutaline 5mg tablets 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 52 of 70

1 2 3 10831 biophylline 125mg/5ml oral solution (lorex synthelabo ltd) 4 10858 pulmadil auto inhalation powder (3m health care ltd) 5 10958 salbutamol .25 mg inj 6 10968 foradil 12microgram inhalation powder capsules with device (novartis 7 pharmaceuticals uk ltd) 8 11046 ipratropium bromide with salbutamol 500micrograms + 2.5mg/2.5ml 9 11149 betnelan 500microgram tablets (focus pharmaceuticals ltd) 10 11198 beclometasons 50 micrograms/actuation vortex inhaler 11 11307 salbutamol 100micrograms/dose / beclometasone 50micrograms/dose inhaler 12 11410 fluticasone 500micrograms/dose / salmeterol 50micrograms/dose dry powder inhaler 13 11478 fluticasone 2mg/2ml nebuliser liquid unit dose vials 14 11497 beclometasone 400micrograms/dose dry powder inhaler 15 11588 fluticasoneFor 125micrograms/dose peer review/ salmeterol 25micrograms/dose only inhaler cfc free 16 11618 fluticasone 250micrograms/dose / salmeterol 25micrograms/dose inhaler cfc free 17 11659 oxygen bp size dd with integral headset gas 460 litres 18 11719 slo-phyllin 60mg capsules (merck serono ltd) 19 11732 beclometasone 50micrograms/dose breath actuated inhaler cfc free 20 11779 ipratropium bromide 40microgram inhalation powder capsules with device 21 11993 pro-vent 300mg capsule (wellcome medical division) 22 12042 ventolin cr 8mg tablet (allen & hanburys ltd) 23 12144 bambuterol 20mg tablets 24 12240 theophylline 300mg modified release capsules 25 12463 pirbuterol 15 mg tab 26 12479 aerolin inh auto refil 100 mcg aer 27 12486 bronchodil 500microgram/dose inhalation powder (viatris pharmaceuticals ltd) 28 12529 fabrol 200mg granules (novartis consumer health uk ltd) 29 12563 exirel inhalation powder (3m health care ltd) 30 12699 pecram 225mg modified-release tablet (novartis consumer health uk ltd) 31 12808 fenoterol 100micrograms/dose / ipratropium bromide 40micrograms/dose breath 32 actuated inhaler 33 12822 salbutamol 2.5mg with ipratropium bromide 500micrograms/2.5ml unit dose nebuilser 34 35 solution 36 12909 salbutamol 100micrograms/dose / ipratropium 20micrograms/dose inhaler 37 12994 fluticasone 50micrograms/dose / salmeterol 25micrograms/dose inhaler cfc free 38 13037 pulvinal beclometasone dipropionate 200micrograms/dose dry powder inhaler (chiesi 39 ltd) 40 13038 pulvinal salbutamol 200micrograms/dose dry powder inhaler (chiesi ltd) 41 13040 fluticasone 250micrograms/dose / salmeterol 50micrograms/dose dry powder inhaler 42 13181 easyhaler salbutamol sulphate 100micrograms/dose dry powder inhaler (orion 43 pharma (uk) ltd) 44 13206 oxygen bp with integral headset gas 300 litres 45 13273 fluticasone 100micrograms/dose / salmeterol 50micrograms/dose dry powder inhaler 46 13290 clenil modulite 100micrograms/dose inhaler (chiesi ltd) 47 13307 bricanyl 500microgram/ml injection (astrazeneca uk ltd) 48 13522 prednisolone 2 mg tab 49 13529 amnivent-225 sr tablets (ashbourne pharmaceuticals ltd) 50 13575 bambec 20mg tablets (astrazeneca uk ltd) 51 13615 prednisone 10 mg tab 52 13757 tropiovent steripoule 250microgram/ml nebuliser liquid (ashbourne pharmaceuticals 53 ltd) 54 13815 beclazone 100microgram/actuation inhalation powder (actavis uk ltd) 55 13996 salamol 100microgram/inhalation inhalation powder (sandoz ltd) 56 14294 qvar 50micrograms/dose easi-breathe inhaler (teva uk ltd) 57 14306 formoterol 12micrograms/dose inhaler cfc free 58 14321 beclometasone 200micrograms/dose inhaler cfc free 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 53 of 70 BMJ Open

1 2 3 14482 bricanyl 2.5 mg inj 4 14483 terbutaline 500micrograms/ml injection 5 14514 zithromax 200mg/5ml oral suspension (pfizer ltd) 6 14524 bdp 250microgram/actuation spacehaler (celltech pharma europe ltd) 7 14525 salbutamol 100micrograms/inhalation vortex inhaler 8 14527 bambec 10mg tablets (astrazeneca uk ltd) 9 14561 salbutamol 400microgram / beclometasone 200microgram inhalation powder 10 capsules 11 14567 asmabec 250 clickhaler (focus pharmaceuticals ltd) 12 14590 asmabec 250microgram/actuation spacehaler (celltech pharma europe ltd) 13 14700 budesonide 400micrograms/actuation inhaler 14 14736 pulvinal beclometasone dipropionate 400micrograms/dose dry powder inhaler (chiesi 15 ltd) For peer review only 16 14739 norphyllin sr 225mg tablets (teva uk ltd) 17 14757 pulvinal beclometasone dipropionate 100micrograms/dose dry powder inhaler (chiesi 18 ltd) 19 14991 aminophylline 250mg/10ml injection 20 15075 bronchodil 20mg tablet (viatris pharmaceuticals ltd) 21 15165 reproterol 500micrograms/dose inhaler 22 15214 oxygen bp size pd 300 litre inhalation gas (medigas ltd) 23 15281 oxygen cylinders size pa2 with integral headset (air products plc) 24 15284 slo-phyllin 125mg capsules (merck serono ltd) 25 15301 carbocisteine 125mg/5ml oral solution 26 15326 beclometasone 100micrograms/dose inhaler cfc free 27 15365 theophylline 10mg/5ml sf elixir 28 15409 theophylline 3 mg sol 29 15441 fenoterol hydrobromide .5 % sol 30 15613 salbutamol 500micrograms/1ml solution for injection ampoules 31 15706 beclometasone 100 micrograms/actuation vortex inhaler 32 15979 oxygen bp with integral headset 300 litre inhalation gas (boc ltd) 33 16054 budesonide 200micrograms/actuation breath actuated powder inhaler 34 35 16124 oxygen cylinders (medigas ltd) 36 16148 clenil modulite 250micrograms/dose inhaler (chiesi ltd) 37 16151 clenil modulite 200micrograms/dose inhaler (chiesi ltd) 38 16158 clenil modulite 50micrograms/dose inhaler (chiesi ltd) 39 16236 pirbuterol acetate inhaler 40 16305 flixotide 2mg/2ml nebules (glaxosmithkline uk ltd) 41 16523 oxygen cylinders size cd with integral headset 0-15litres/minute flow rate (boc ltd) 42 16577 easyhaler salbutamol sulphate 200micrograms/dose dry powder inhaler (orion 43 pharma (uk) ltd) 44 16584 beclometasone 50micrograms/dose inhaler cfc free 45 16625 ventide rotacaps (glaxosmithkline uk ltd) 46 16724 prednisone 50 mg tab 47 16994 aminophylline hydrate 350mg modified-release tablets 48 17002 aminophylline hydrate 225mg modified-release tablets 49 17005 oxygen bp size cd with integral headset gas 460 litres 50 17140 aminophylline 200mg tablets 51 17185 ventolin 500micrograms/1ml solution for injection ampoules (glaxosmithkline uk ltd) 52 17465 fluticasone 500micrograms/2ml nebuliser liquid unit dose vials 53 17644 oxygen bp with integral headset gas 2122 litres 54 17654 easyhaler beclometasone 200micrograms/dose dry powder inhaler (orion pharma 55 (uk) ltd) 56 17670 easyhaler budesonide 100micrograms/dose dry powder inhaler (orion pharma (uk) 57 ltd) 58 17696 ventmax sr 4mg capsules (chiesi ltd) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 54 of 70

1 2 3 17874 monovent 1.5mg/5ml oral solution (lagap) 4 17901 bricanyl nebule 2.5 ml 5 18140 respontin 500micrograms/2ml nebules (glaxosmithkline uk ltd) 6 18288 choline theophyllinate 100mg tablets 7 18299 fenoterol 1.25mg/4ml / ipratropium 500micrograms/4ml nebuliser liquid unit dose 8 vials 9 18314 aerocrom syncroner with spacer (castlemead healthcare ltd) 10 18394 bdp 50microgram/actuation spacehaler (celltech pharma europe ltd) 11 18421 respontin nebules 250microgram/ml nebuliser liquid (glaxo wellcome uk ltd) 12 18456 salbutamol 200microgram / beclometasone 100microgram inhalation powder 13 capsules 14 18484 ventide paediatric rotacaps (glaxosmithkline uk ltd) 15 18537 budesonideFor 200microgram peer inhalation review powder capsules only 16 18622 salbulin 2mg tablet (3m health care ltd) 17 18848 qvar 100micrograms/dose easi-breathe inhaler (teva uk ltd) 18 18937 sabidal sr 270 270 mg tab 19 18968 salbutamol 5mg/5ml solution for infusion ampoules 20 18988 choline theophyllinate 62.5mg/5ml oral solution 21 19031 bdp 100microgram/actuation spacehaler (celltech pharma europe ltd) 22 19121 beclometasone 100micrograms with salbutamol 200micrograms inhalation capsules 23 19376 beclometasone 200micrograms with salbutamol 400micrograms inhalation capsules 24 19389 asmabec 50microgram/actuation spacehaler (celltech pharma europe ltd) 25 19401 beclometasone 250micrograms/actuation inhaler and compact spacer 26 19563 becotide for nebuliser 27 19642 ventolin nebules 28 19649 ventolin rotahaler 29 19653 ventolin respirator 30 19726 ventolin s/r 31 19732 cobutolin inh 32 19735 uniphyllin continus 33 19736 becotide susp for nebulisation 34 35 19737 atrovent nebuliser solution (1ml vial) 36 19799 tulobuterol 2mg 37 19805 atrovent 38 20095 precortisyl forte 25mg tablet (aventis pharma) 39 20225 aminophylline 500 mg inj 40 20670 prednisolone e/c 41 20675 salbutamol rotahaler complete unit 42 20680 aerolin autohaler 43 20707 becotide 100 44 20720 atrovent forte 45 20763 becloforte 46 20781 salbutamol u.dose nebulising 2.5mg/2.5ml 47 20803 ipratropium bromide nebuliser solution 48 20812 pulmicort refill 49 20825 spacehaler bdp 250microgram/actuation spacehaler (celltech pharma europe ltd) 50 20838 salbuvent 2mg tablet (pharmacia ltd) 51 21005 beclometasone 250micrograms/dose inhaler cfc free 52 21102 salbutamol 2mg/5ml oral solution (lagap) 53 21330 oxygen composite cylinders size if2 with integral headset (medigas ltd) 54 21331 oxygen composite cylinders with integral headset (air products plc) 55 21402 oxygen cylinders size pd (air products plc) 56 21482 beclometasone 100micrograms/dose inhaler (generics (uk) ltd) 57 21769 lasma 300mg tablet (pharmax ltd) 58 21833 decortisyl 5mg tablet (roussel laboratories ltd) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 55 of 70 BMJ Open

1 2 3 21859 asmaven 100microgram inhalation powder (berk pharmaceuticals ltd) 4 22080 aminophylline 20 ml inj 5 22225 beclomethasone /salbutamol 6 22313 ventmax sr 8mg capsules (chiesi ltd) 7 22430 spacehaler salbutamol 100microgram/inhalation spacehaler (celltech pharma europe 8 ltd) 9 22467 salbutamol respirator soln 10 22512 salbutamol inhaler 11 22550 duovent 12 22661 pirbuterol 10mg capsule 13 22663 respacal 2mg tablet (ucb pharma ltd) 14 22669 choline theophyllinate 270 mg tab 15 22790 reproterolFor 10mg/ml peer respirator solution review only 16 22828 carbocisteine 750mg/5ml forte oral solution 17 23269 maxivent 2.5mg/2.5ml nebuliser liquid unit dose steripoule vials (ashbourne 18 pharmaceuticals ltd) 19 23337 oxygen cylinder f size 1280 litres 20 23512 precortisyl 5mg tablet (hoechst marion roussel) 21 23567 respontin 250micrograms/1ml nebules (glaxosmithkline uk ltd) 22 23572 aminophylline sr 225mg modified-release tablet (ivax pharmaceuticals uk ltd) 23 23675 pulmicort l.s. refil 24 23688 ventolin rotacaps 25 23709 ipratropium 500micrograms/2ml nebuliser liquid steri-neb unit dose vials (teva uk ltd) 26 23741 novolizer budesonide 200microgram/actuation pressurised inhalation (meda 27 pharmaceuticals ltd) 28 23787 exirel 10mg capsule (3m health care ltd) 29 23905 oxygen cylinders size d (boc ltd) 30 23961 ipratropium bromide 250microgram/ml inhalation vapour (galen ltd) 31 24219 becotide rotacaps 32 24380 sodium cromoglicate 1mg/dose / salbutamol 100micrograms/dose inhaler with spacer 33 24418 biophylline 350mg tablet (lorex synthelabo ltd) 34 35 24456 carbocisteine 375mg tablets 36 24645 ventolin 5mg/5ml solution for infusion ampoules (glaxosmithkline uk ltd) 37 24660 betamethasone valerate 38 24674 biophylline 500mg tablet (lorex synthelabo ltd) 39 24716 prednisolone e/c 40 24898 spacehaler bdp 100microgram/actuation spacehaler (celltech pharma europe ltd) 41 25020 ipratropium bromide (forte) 42 25073 salbutamol 43 25093 theophylline s/r 44 25204 beclometasone 100micrograms/dose inhaler (a a h pharmaceuticals ltd) 45 25218 salbutamol cfc/free b/a 46 25272 precortisyl 1mg tablet (hoechst marion roussel) 47 25339 maxivent 5mg/2.5ml nebuliser liquid unit dose steripoule vials (ashbourne 48 pharmaceuticals ltd) 49 25784 atimos modulite 12micrograms/dose inhaler (chiesi ltd) 50 25820 bronchodil 10mg/5ml oral solution (viatris pharmaceuticals ltd) 51 25821 exirel 7.5mg/5ml oral solution (3m health care ltd) 52 25829 pirbuterol 7.5mg/5ml oral solution 53 26063 beclometasone 100micrograms/dose inhaler (teva uk ltd) 54 26079 uniphyllin paediatric continus 55 26420 exirel 10 mg tab 56 26525 ventolin 57 26616 ipratropium bromide with fenoterol hydrobromide 0micrograms + 58 100micrograms/actuation 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 56 of 70

1 2 3 26665 pulmicort complete 4 26716 airomir autohaler cfc free b/a 5 26829 brelomax 2mg tablet (abbott laboratories ltd) 6 26873 cobutolin 2mg tablet (actavis uk ltd) 7 27040 phyllocontin continus 8 27188 easyhaler budesonide 200micrograms/dose dry powder inhaler (orion pharma (uk) 9 ltd) 10 27301 bromhexine hcl 8mg tablets 11 27340 salbuvent 0.5mg/ml injection (pharmacia ltd) 12 27505 ipratropium bromide with fenoterol hydrobromide 40micrograms + 13 100micrograms/actuation 14 27525 becotide 50 15 27558 choledylFor peer review only 16 27573 ventolin 17 27583 pulmicort 18 27679 beclometasone 100microgram/actuation pressurised inhalation (approved 19 prescription services ltd) 20 27842 aminophylline 2 ml inj 21 27889 prednisolone 22 27915 fluticasone prop disk refill 23 27959 prednisolone 24 27962 deltastab 1mg tablet (waymade healthcare plc) 25 28073 beclometasone 250microgram/actuation pressurised inhalation (approved 26 prescription services ltd) 27 28241 aminophylline 250mg/10ml solution for injection minijet pre-filled syringes (ucb 28 pharma ltd) 29 28376 prednisolone 2.5mg gastro-resistant tablet (biorex laboratories ltd) 30 28508 salbutamol 100microgram/inhalation inhalation powder (ivax pharmaceuticals uk ltd) 31 28577 ventolin 50microgram/ml injection (allen & hanburys ltd) 32 28640 beclometasone 100microgram/actuation inhalation powder (actavis uk ltd) 33 28761 spacehaler bdp 50microgram/actuation spacehaler (celltech pharma europe ltd) 34 35 28859 deltastab 5mg tablet (waymade healthcare plc) 36 28881 salbutamol 2mg/5ml oral solution sugar free (a a h pharmaceuticals ltd) 37 29267 salbuvent 4mg tablet (pharmacia ltd) 38 29273 aminophylline 225mg modified-release tablet (hillcross pharmaceuticals ltd) 39 29325 beclometasone 250micrograms/dose inhaler (generics (uk) ltd) 40 30118 salbutamol 100micrograms/dose inhaler cfc free (teva uk ltd) 41 30204 salbutamol 200micrograms inahalation capsules 42 30210 beclometasone 250micrograms/dose inhaler (teva uk ltd) 43 30212 salbutamol cyclohaler 44 30229 ipratropium bromide 250microgram/ml nebuliser liquid (galen ltd) 45 30230 salbutamol 100micrograms/actuation breath actuated inhaler 46 30238 beclometasone 50microgram/actuation pressurised inhalation (approved prescription 47 services ltd) 48 30240 aerolin autohaler 100microgram/actuation pressurised inhalation (3m health care ltd) 49 30390 deltastab 2 mg tab 50 30596 aminophylline 225mg modified-release tablet (actavis uk ltd) 51 30649 easyhaler budesonide 400micrograms/dose dry powder inhaler (orion pharma (uk) 52 ltd) 53 30971 decortisyl 25 mg tab 54 31082 salbuvent 5mg/ml respirator solution (pharmacia ltd) 55 31290 salbulin cfc free 56 31327 prednisolone steaglate 6.65mg tablet 57 31758 uniphyllin continus 58 31774 beclometasone 50micrograms/dose inhaler (generics (uk) ltd) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 57 of 70 BMJ Open

1 2 3 31845 salapin 2mg/5ml syrup (pinewood healthcare) 4 31933 salbutamol 100micrograms/dose inhaler (a a h pharmaceuticals ltd) 5 32050 salbutamol 400 cyclocaps (teva uk ltd) 6 32102 salbutamol 4mg tablets (a a h pharmaceuticals ltd) 7 32461 choline theophyllinate 90 mg tab 8 32812 numotac 10mg tablet (3m health care ltd) 9 32874 beclometasone 50microgram/actuation inhalation powder (actavis uk ltd) 10 32893 theophylline 100mg/lysine 74mg mg tab 11 33089 salbutamol 100micrograms/dose inhaler (kent pharmaceuticals ltd) 12 33258 beclometasone 250micrograms/dose inhaler (a a h pharmaceuticals ltd) 13 33373 salbutamol 200 cyclocaps (teva uk ltd) 14 33588 salbutamol 100micrograms/dose inhaler (generics (uk) ltd) 15 33691 prednisoloneFor 5mg peer gastro-resistant review tablet (biorex laboratories only ltd) 16 33817 salbutamol 100micrograms/dose inhaler cfc free (actavis uk ltd) 17 33849 beclometasone 100microgram/actuation inhalation powder (neo laboratories ltd) 18 33888 azithromycin 250mg tablets 19 33988 prednisolone 5mg tablet (co-pharma ltd) 20 33990 prednisolone 5mg tablet (ivax pharmaceuticals uk ltd) 21 34018 salbutamol 5mg/2.5ml nebuliser liquid (galen ltd) 22 34029 salbutamol 400micrograms inahalation capsules 23 34109 prednisolone 5 mg gastro-resistant tablet 24 34134 aerolin 400 100microgram/actuation inhalation powder (3m health care ltd) 25 34162 salbutamol 2.5mg/2.5ml nebuliser liquid (galen ltd) 26 34310 salbutamol 100micrograms/dose inhaler cfc free (a a h pharmaceuticals ltd) 27 34311 salbutamol 100microgram/inhalation inhalation powder (berk pharmaceuticals ltd) 28 34315 beclometasone 250microgram/actuation inhalation powder (actavis uk ltd) 29 34428 beclometasone 50microgram/actuation inhalation powder (neo laboratories ltd) 30 34618 salbutamol 2mg tablets (actavis uk ltd) 31 34619 salbutamol 100microgram/inhalation inhalation powder (kent pharmaceuticals ltd) 32 34631 prednisolone 1mg tablet (co-pharma ltd) 33 34702 salbutamol 100microgram/inhalation inhalation powder (c p pharmaceuticals ltd) 34 35 34739 beclometasone 50micrograms/dose inhaler (teva uk ltd) 36 34794 beclometasone 200micrograms/dose inhaler (a a h pharmaceuticals ltd) 37 34859 beclometasone 250microgram/actuation inhalation powder (neo laboratories ltd) 38 34914 prednisolone 1mg tablet (celltech pharma europe ltd) 39 34919 beclometasone 50micrograms/dose inhaler (a a h pharmaceuticals ltd) 40 34938 salbutamol 4mg tablets (actavis uk ltd) 41 35011 tiotropium bromide 18microgram inhalation powder capsules 42 35014 tiotropium bromide 18microgram inhalation powder capsules with device 43 35015 erdosteine 300mg capsules 44 35071 becodisks 200microgram (glaxosmithkline uk ltd) 45 35106 becodisks 100microgram with diskhaler (glaxosmithkline uk ltd) 46 35107 beclometasone 400microgram inhalation powder blisters with device 47 35113 beclometasone 200microgram inhalation powder blisters 48 35118 becodisks 400microgram with diskhaler (glaxosmithkline uk ltd) 49 35165 serevent 50microgram disks with diskhaler (glaxosmithkline uk ltd) 50 35178 erdotin 300mg capsules (galen ltd) 51 35225 flixotide 100microgram disks with diskhaler (glaxosmithkline uk ltd) 52 35288 beclometasone 400microgram inhalation powder blisters 53 35293 beclometasone 200microgram inhalation powder blisters with device 54 35299 becodisks 400microgram (glaxosmithkline uk ltd) 55 35374 flixotide 500microgram disks (glaxosmithkline uk ltd) 56 35392 flixotide 500microgram disks with diskhaler (glaxosmithkline uk ltd) 57 35408 becodisks 100microgram (glaxosmithkline uk ltd) 58 35430 becodisks 200microgram with diskhaler (glaxosmithkline uk ltd) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 58 of 70

1 2 3 35461 flixotide 250microgram disks with diskhaler (glaxosmithkline uk ltd) 4 35503 salmeterol 50microgram inhalation powder blisters 5 35510 budesonide 200micrograms/dose dry powder inhalation cartridge with device 6 35522 bricanyl 500micrograms/1ml solution for injection ampoules (astrazeneca uk ltd) 7 35542 salmeterol 50microgram inhalation powder blisters with device 8 35557 ipramol nebuliser solution 2.5ml steri-neb unit dose vials (teva uk ltd) 9 35566 oxygen bp with set gas 1360 litres 10 35580 beclometasone 100microgram inhalation powder blisters with device 11 35602 budesonide 200micrograms/dose dry powder inhalation cartridge 12 35611 flixotide 250microgram disks (glaxosmithkline uk ltd) 13 35631 budelin novolizer 200micrograms/dose inhalation powder (meda pharmaceuticals ltd) 14 35638 fluticasone 100microgram inhalation powder blisters with device 15 35652 beclometasoneFor 100microgrampeer inhalationreview powder blisters only 16 35700 fluticasone 500microgram inhalation powder blisters with device 17 35724 budelin novolizer 200micrograms/dose inhalation powder refill (meda 18 pharmaceuticals ltd) 19 35725 formoterol easyhaler 12micrograms/dose dry powder inhaler (orion pharma (uk) ltd) 20 35744 bricanyl 2.5mg/5ml solution for injection ampoules (astrazeneca uk ltd) 21 35772 fluticasone 100microgram inhalation powder blisters 22 35825 serevent 50microgram disks (glaxosmithkline uk ltd) 23 35861 terbutaline 2.5mg/5ml solution for injection ampoules 24 35862 terbutaline 500micrograms/1ml solution for injection ampoules 25 35905 fluticasone 250microgram inhalation powder blisters 26 35986 flixotide 50microgram disks (glaxosmithkline uk ltd) 27 36021 fluticasone 50microgram inhalation powder blisters with device 28 36090 flixotide 100microgram disks (glaxosmithkline uk ltd) 29 36290 flixotide 50microgram disks with diskhaler (glaxosmithkline uk ltd) 30 36401 fluticasone 250microgram inhalation powder blisters with device 31 36462 fluticasone 500microgram inhalation powder blisters 32 36677 reproterol 10mg/5ml oral solution 33 36864 tiotropium bromide 2.5micrograms/dose solution for inhalation cartridge with device 34 35 cfc free 36 37432 fostair 100micrograms/dose/6micrograms/dose inhaler (chiesi ltd) 37 37447 fluticasone 50microgram inhalation powder blisters 38 37470 beclometasone 100micrograms/dose / formoterol 6micrograms/dose inhaler cfc free 39 37612 terbutaline 5mg/2ml nebuliser liquid unit dose vials (galen ltd) 40 37791 ipratropium bromide 250microgram/ml 41 38079 salbutamol 100micrograms/dose dry powder inhalation cartridge with device 42 38097 salbutamol cyclocaps 200microgram inhalation powder (dupont pharmaceuticals ltd) 43 38120 theophylline 500mg modified release tablets 44 38136 salbulin novolizer 100micrograms/dose inhalation powder (meda pharmaceuticals ltd) 45 38214 salbutamol 100micrograms/dose dry powder inhalation cartridge 46 38226 salbulin novolizer 100micrograms/dose inhalation powder refill (meda 47 pharmaceuticals ltd) 48 38407 prednisolone 20mg tablet 49 38416 salbutamol cyclocaps 400microgram inhalation powder (dupont pharmaceuticals ltd) 50 38419 terbutaline 1.5mg/5ml oral solution sugar free (a a h pharmaceuticals ltd) 51 39040 phyllocontin forte continus 350mg tablets (napp pharmaceuticals ltd) 52 39099 pulmicort 100micrograms/dose inhaler cfc free (astrazeneca uk ltd) 53 39102 budesonide 100micrograms/dose inhaler cfc free 54 39200 aerobec forte 250 autohaler (meda pharmaceuticals ltd) 55 39879 budesonide 200micrograms/dose inhaler cfc free 56 40057 pulmicort 200micrograms/dose inhaler cfc free (astrazeneca uk ltd) 57 40177 ipratropium bromide 250microgram/ml nebuliser liquid (hillcross pharmaceuticals ltd) 58 40218 azithromycin 500mg tablets (teva uk ltd) 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 59 of 70 BMJ Open

1 2 3 40599 salbutamol 5mg/2.5ml nebuliser liquid unit dose steripoule vials (galen ltd) 4 40637 ipratropium 250micrograms/1ml nebuliser liquid unit dose steripoule vials (galen ltd) 5 40655 salbuvent 100microgram/actuation inhalation powder (pharmacia ltd) 6 40709 salbutamol 2.5mg/2.5ml nebuliser liquid unit dose vials (a a h pharmaceuticals ltd) 7 40832 ipratropium 500micrograms/2ml nebuliser liquid unit dose steripoule vials (galen ltd) 8 41269 beclometasone 400 cyclocaps (teva uk ltd) 9 41412 beclometasone 400micrograms/actuation inhaler 10 41548 salbutamol 2mg tablets (approved prescription services ltd) 11 41549 salbutamol 2mg tablet (c p pharmaceuticals ltd) 12 41691 salbutamol 2mg/5ml oral solution sugar free (sandoz ltd) 13 41832 monovent 1.5mg/5ml syrup (sandoz ltd) 14 42103 tulobuterol 1mg/5ml sugar free syrup 15 42279 salbutamolFor 2.5mg/2.5ml peer nebuliser review liquid unit dose steripoule only vials (galen ltd) 16 42497 salbutamol 8mg tablet 17 42511 aminophylline 25mg/ml injection (celltech pharma europe ltd) 18 42830 ventolin 100micrograms/dose evohaler (glaxosmithkline uk ltd) 19 42858 ventolin 200micrograms/dose accuhaler (glaxosmithkline uk ltd) 20 42867 terbutaline 1.5mg/5ml oral solution (sandoz ltd) 21 42886 bricanyl 500micrograms/dose turbohaler (astrazeneca uk ltd) 22 42910 aminophylline 250mg/10ml solution for injection ampoules (martindale 23 pharmaceuticals ltd) 24 42928 flixotide 100micrograms/dose accuhaler (glaxosmithkline uk ltd) 25 42985 flixotide 50micrograms/dose accuhaler (glaxosmithkline uk ltd) 26 42994 flixotide 250micrograms/dose accuhaler (glaxosmithkline uk ltd) 27 43046 salipraneb 0.5mg/2.5mg nebuliser solution 2.5ml ampoules (arrow generics ltd) 28 43074 flixotide 500micrograms/dose accuhaler (glaxosmithkline uk ltd) 29 43085 bricanyl 5mg/2ml respules (astrazeneca uk ltd) 30 43400 clamelle 500mg tablets (actavis uk ltd) 31 43544 prednisone 5mg tablet (knoll ltd) 32 43738 indacaterol 150microgram inhalation powder capsules with device 33 43794 nebusal 7% inhalation solution 4ml ampoules (forest laboratories uk ltd) 34 35 43870 sodium chloride 7% inhalation solution 4ml ampoules 36 43893 onbrez breezhaler 150microgram inhalation powder capsules with device (novartis 37 pharmaceuticals uk ltd) 38 44064 onbrez breezhaler 300microgram inhalation powder capsules with device (novartis 39 pharmaceuticals uk ltd) 40 44173 roflumilast 500microgram tablets 41 44380 prednisone 1mg modified-release tablets 42 44431 daxas 500microgram tablets (takeda uk ltd) 43 44713 salbutamol 100microgram/inhalation inhalation powder (celltech pharma europe ltd) 44 45302 prednisolone 5mg tablet (biorex laboratories ltd) 45 45610 indacaterol 300microgram inhalation powder capsules with device 46 45863 salbutamol 5mg/2.5ml nebuliser liquid (generics (uk) ltd) 47 46157 beclometasone 200 cyclocaps (teva uk ltd) 48 46551 salbutamol 100microgram/inhalation inhalation powder (neo laboratories ltd) 49 46695 azithromycin 500mg tablet (hillcross pharmaceuticals ltd) 50 49016 sodium chloride 7% inhalation solution 4ml vials 51 49045 nebusal 7% inhalation solution 4ml vials (forest laboratories uk ltd) 52 49530 azithromycin 200mg/5ml oral suspension (sandoz ltd) 53 50508 mucodyne 250mg/5ml syrup (sigma pharmaceuticals plc) 54 52029 zithromax 250mg capsules (mawdsley-brooks & company ltd) 55 53303 carbocisteine 375mg capsules (arrow generics ltd) 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 60 of 70

1 2 3 Spirometry codes 4 medcode readterm 5 6118 spirometry 6 10336 spirometry reversibility 7 10337 spirometry screening 8 10420 spirometry reversibility negative 9 10492 spirometry reversibility positive 10 13683 referral for spirometry 11 14453 forced expiratory volume - fev 12 19428 chronic obstructive pulmonary disease excluded by spirometry 13 26241 spirometry indicated 14 29015 spirometry 15 45993 incentiveFor spirometry peer review only 16 102522 post bronchodilator spirometry 17 6091 Percent predicted FEV1 18 8512 FEV1/FVC percent 19 10320 Forced expired volume in 1 second 20 11078 FEV1/FVC > 70% of predicted 21 14455 FEV1/FVC ratio normal 22 14456 FEV1/FVC ratio 23 19830 FEV1 after bronchodilation 24 19832 FEV1/FVC ratio after bronchodilator 25 23237 FEV1 before bronchodilation 26 23285 FEV1/FVC ratio abnormal 27 25083 FEV1/FVC < 70% of predicted 28 27141 FEV1/FVC ratio before bronchodilator 29 43040 FEV1 pre steroids 30 43041 FEV1 post steroids 31 58632 FEV1/FVC ratio pre steroids 32 58633 FEV1/FVC ratio post steroids 33 99777 Forced expired volume in 1 second reversibility 34 35 100391 Forced expired volume in 1 second percentage change 36 101079 Percentage predicted FEV1 after bronchodilation 37 38 39 Non-specific bronchitis codes / Frequent winter bronchitis 40 medcode readterm 41 148 bronchitis unspecified 42 152 wheezy bronchitis 43 3243 chronic bronchitis 44 3480 bronchitis nos 45 4519 h/o: bronchitis 46 5798 chronic asthmatic bronchitis 47 5909 chronic wheezy bronchitis 48 7092 recurrent wheezy bronchitis 49 11150 mucopurulent chronic bronchitis 50 13247 fh: bronchitis 51 13262 fh: bronchitis/coad 52 14798 emphysematous bronchitis 53 15157 chronic bronchitis nos 54 15626 chronic catarrhal bronchitis 55 17359 chest infection - unspecified bronchitis 56 24248 mixed simple and mucopurulent chronic bronchitis 57 25603 simple chronic bronchitis 58 27819 obstructive chronic bronchitis 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 61 of 70 BMJ Open

1 2 3 37959 fetid chronic bronchitis 4 40159 purulent chronic bronchitis 5 44525 obstructive chronic bronchitis nos 6 61118 simple chronic bronchitis nos 7 61513 mucopurulent chronic bronchitis nos 8 62913 [v]screening for chronic bronchitis or emphysema 9 66043 other chronic bronchitis 10 68066 other chronic bronchitis nos 11 202167 INFLUENZAL BRONCHITIS 12 207165 Acute streptococcal bronchitis 13 207166 Acute viral bronchitis unspecified 14 216109 Acute membranous bronchitis 15 216111 For Acute bronchitis peer due to mycoplasmareview pneumoniae only 16 216112 Acute bronchitis NOS 17 216141 Chest infection - unspecified bronchopneumonia 18 220234 BRONCHITIS FIBRINOUS ACUTE 19 225216 Acute pseudomembranous bronchitis 20 225241 Bronchitis NOS 21 234340 Acute bronchitis due to rhinovirus 22 239395 H/O: bronchitis 23 243349 Acute bronchitis and bronchiolitis 24 243350 Acute pneumococcal bronchitis 25 243351 Acute bronchitis due to echovirus 26 243389 Bronchitis unspecified 27 261710 Acute wheezy bronchitis 28 261711 Acute purulent bronchitis 29 261712 Acute croupous bronchitis 30 261713 Acute bronchitis due to respiratory syncytial virus 31 271007 Acute bronchitis due to coxsackievirus 32 280054 Acute fibrinous bronchitis 33 280055 Acute bronchitis due to parainfluenza virus 34 35 280082 Chest infection - unspecified bronchitis 36 289164 Acute bronchitis 37 289165 Acute neisseria catarrhalis bronchitis 38 289166 Subacute bronchitis unspecified 39 289233 [X]Acute bronchitis due to other specified organisms 40 293231 BRONCHITIS SUBACUTE 41 298435 Acute haemophilus influenzae bronchitis 42 298436 Acute bacterial bronchitis unspecified 43 298440 Acute bronchitis or bronchiolitis NOS 44 303952 BRONCHITIS ACUTE 45 303954 VIRAL BRONCHITIS 46 303963 BRONCHOPNEUMONIA 47 306525 BRONCHITIS PURULENT 48 306528 CATARRHAL BRONCHITIS 49 308788 Acute bronchitis 50 51 52 Respiratory symptom codes 53 54 Wheeze 55 medcode readterm 56 152 wheezy bronchitis 57 173 wheezing 58 2210 [d]wheezing 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 62 of 70

1 2 3 2891 wheezing symptom 4 4836 nocturnal cough / wheeze 5 5861 o/e - expiratory wheeze 6 5909 chronic wheezy bronchitis 7 5978 acute wheezy bronchitis 8 7092 recurrent wheezy bronchitis 9 42317 increasing exercise wheeze 10 100954 [d]mild wheeze 11 101037 [d]moderate wheeze 12 101073 [d]severe wheeze 13 101421 [d]very severe wheeze 14 102480 on examination - inspiratory wheeze 15 For peer review only 16 17 Chronic cough 18 medcode readterm 19 92 cough 20 292 chesty cough 21 1025 bronchial cough 22 1160 [d]cough 23 1234 productive cough nos 24 1273 c/o - cough 25 1612 chronic cough 26 3068 night cough present 27 3628 persistent cough 28 3645 coughing up phlegm 29 4070 morning cough 30 4836 nocturnal cough / wheeze 31 4931 dry cough 32 7706 productive cough -clear sputum 33 7707 cough symptom nos 34 35 7708 productive cough-yellow sputum 36 7773 productive cough -green sputum 37 16717 smokers' cough 38 22318 difficulty in coughing up sputum 39 29318 evening cough 40 43795 unexplained cough 41 60903 cough aggravates symptom 42 100333 cough on exercise 43 44 45 46 Exertional breathlessness 47 medcode readterm 48 735 [d]breathlessness 49 1429 breathlessness 50 3092 [d]dyspnoea 51 5175 breathlessness symptom 52 5896 dyspnoea - symptom 53 6326 breathless - moderate exertion 54 7000 o/e - dyspnoea 55 7932 breathless - mild exertion 56 19426 mrc breathlessness scale: grade 3 57 19427 mrc breathlessness scale: grade 2 58 19429 mrc breathlessness scale: grade 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 63 of 70 BMJ Open

1 2 3 19430 mrc breathlessness scale: grade 4 4 19432 mrc breathlessness scale: grade 1 5 21801 breathlessness nos 6 24889 breathless - strenuous exertion 7 31143 breathless - at rest 8 42287 borg breathlessness score: 6 severe (+) 9 53771 dyspnoea on exertion 10 57193 borg breathlessness score: 3 moderate 11 57759 borg breathlessness score: 2 slight 12 59860 borg breathlessness score: 4 somewhat severe 13 64049 borg breathlessness score: 5 severe 14 67566 borg breathlessness score: 9 very, very sev (almost maximal) 15 68707 borg Forbreathlessness peer score: 1 very review slight only 16 70061 borg breathlessness score: 7 very severe 17 70818 borg breathlessness score: 0.5 very, very slight 18 72334 borg breathlessness score: 8 very severe (+) 19 101843 borg breathlessness score: 10 maximal 20 741 [D]Shortness of breath 21 2563 [D]Respiratory distress 22 2575 Short of breath on exertion 23 2931 Difficulty breathing 24 4822 Shortness of breath 25 5349 Shortness of breath symptom 26 9297 [D]Respiratory insufficiency 27 22094 Short of breath dressing/undressing 28 40813 Unable to complete a sentence in one breath 29

30 Sputum codes 31 medcode readterm 32 292 chesty cough 33 1025 bronchial cough 34 35 1234 productive cough nos 36 3645 coughing up phlegm 37 7706 productive cough -clear sputum 38 7708 productive cough-yellow sputum 39 7773 productive cough -green sputum 40 22318 difficulty in coughing up sputum 41 1251 [d]abnormal sputum 42 3727 sputum sent for c/s 43 8287 sputum sample obtained 44 8760 [d]positive culture findings in sputum 45 9807 sputum - symptom 46 14804 sputum appears infected 47 15430 [d]sputum abnormal - colour 48 16026 sputum examination: abnormal 49 18964 sputum clearance 50 20086 [d]sputum abnormal - amount 51 22318 difficulty in coughing up sputum 52 23582 [d]abnormal sputum nos 53 24181 sputum: mucopurulent 54 29294 sputum appears normal 55 30754 yellow sputum 56 30904 sputum sent for examination 57 31417 sputum - not infected 58 35577 sputum examination - general 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 64 of 70

1 2 3 36515 [d]abnormal sputum - tenacious 4 36880 green sputum 5 40201 sputum microscopy: nad 6 40202 mucoid sputum - o/e 7 42573 clear sputum 8 43270 sputum evidence of infection 9 43272 sputum examination nos 10 44214 [d]sputum abnormal - odour 11 49029 sputum gen. exam. nos 12 49694 sputum: organism on gram stain 13 52806 sputum: frothy/watery 14 54177 sputum: excessive - mucoid 15 61079 sputumFor inspection peer nos review only 16 91680 expectoration of induced sputum from respiratory tract 17 100484 volume of sputum 18 100524 moderate sputum 19 100629 white sputum 20 100647 copious sputum 21 100931 brown sputum 22 101782 profuse sputum 23 103209 grey sputum 24 25 26 QOF codes 27 28 H3... Chronic obstructive pulmonary disease 29 H31.. Chronic bronchitis 30 H310. Simple chronic bronchitis 31 H3100 Chronic catarrhal bronchitis 32 H310z Simple chronic bronchitis NOS 33 H311. Mucopurulent chronic bronchitis 34 H3110 Purulent chronic bronchitis 35 H3111 Fetid chronic bronchitis 36 H311z Mucopurulent chronic bronchitis NOS 37 H312. Obstructive chronic bronchitis 38 H3120 Chronic asthmatic bronchitis 39 40 H3121 Emphysematous bronchitis 41 H3123 Bronchiolitis obliterans 42 H312z Obstructive chronic bronchitis NOS 43 H313. Mixed simple and mucopurulent chronic bronchitis 44 H31y. Other chronic bronchitis 45 H31y1 Chronic tracheobronchitis 46 H31yz Other chronic bronchitis NOS 47 H31z. Chronic bronchitis NOS 48 H32.. Emphysema 49 H320. Chronic bullous emphysema 50 H3200 Segmental bullous emphysema 51 H3201 Zonal bullous emphysema 52 H3202 Giant bullous emphysema 53 H3203 Bullous emphysema with collapse 54 H320z Chronic bullous emphysema NOS 55 H321. Panlobular emphysema 56 H322. Centrilobular emphysema 57 H32y. Other emphysema 58 H32y0 Acute vesicular emphysema 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 65 of 70 BMJ Open

1 2 3 H32y1 Atrophic (senile) emphysema 4 H32y2 MacLeod's unilateral emphysema 5 H32yz Other emphysema NOS 6 H32z. Emphysema NOS 7 H36.. Mild chronic obstructive pulmonary disease 8 H37.. Moderate chronic obstructive pulmonary disease 9 H38.. Severe chronic obstructive pulmonary disease 10 H39.. Very severe chronic obstructive pulmonary disease 11 H3A.. End stage chronic obstructive airways disease (v23) 12 H3y.. Other specified chronic obstructive airways disease 13 H3y0. Chronic obstructive pulmonary disease with acute lower respiratory 14 infection (v23) 15 H3y1.For Chronic obstructive peer pulmonary review disease with acute only exacerbation, 16 unspecified (v23) 17 H3z.. Chronic obstructive airways disease NOS 18 19 20 21 22 GP Questionnaire 23 24 1. Do you think this patient has COPD? Yes / No / Uncertain 25 2. What was the diagnosis of COPD based on? (please circle all that apply) 26 Smoking history symptoms spirometry other (please describe) 27 3. Has a respiratory physician seen the patient and confirmed a diagnosis of COPD? 28 4. Does the patient have any other respiratory condition? 29 If yes, than what? 30 31 32 33 34 35 36 37 38 39 40 Table S1: The PPV and proportion of patients diagnosed with COPD who also had cardiovascular 41 disease or asthma 42 Algorithm Number Number PPV and 95% Number Number PPV and 95% CI with confirmed CI with confirmed 43 CVDx COPD asthma COPD 44 COPD Code + 20 17 85.0, 59.6-95.6 18 14 72.2, 45.3-89.1 45 spirometry + COPD 46 medication 47 COPD Code + 24 20 83.3, 61.1-94.1 20 14 70.0, 45.0-87.0 48 spirometry 49 COPD Code + 18 16 88.9, 61.1-97.6 16 9 56.3, 29.8-79.6 50 COPD medication 51 COPD Code only 18 16 88.9, 61.1-97.6 15 12 80.0, 48.8-94.4 52 Bronchitis + COPD 21 8 38.1, 19.1-61.7 27 4 14.8, 5.3-35.1 53 medication 54 Bronchitis only 19 8 42.1, 21.1-66.5 23 6 26.1, 11.4-49.1 55 Symptoms + 15 9 60.0, 31.8-82.9 19 4 21.1, 7.3-47.3 56 spirometry 57 Symptoms only 9 2 22.2, 3.9-67.0 23 2 8.7, 1.9-31.4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 66 of 70

1 2 3 Table S2: The PPV and proportion of patients diagnosed with COPD who were current smokers 4 Algorithm Number Number PPV and 95% CI 5 current confirmed COPD 6 smokers 7 COPD Code + 49 44 89.9, 77.1-95.8 8 spirometry + COPD medication 9 COPD Code + 51 39 76.5, 62.5-86.4 10 spirometry 11 COPD Code + COPD 55 46 83.6, 71.0-91.4 12 medication 13 COPD Code only 47 41 87.2, 73.8-94.3 14 Bronchitis + COPD 67 34 50.7, 38.7-62.7 15 medication For peer review only 16 Bronchitis only 64 19 29.7, 19.6-42.3 17 Symptoms + 50 20 40.0, 27.1-54.5 18 spirometry 19 Symptoms only 58 6 10.3, 4.6-21.7 20 21 22 23 24 25

27 28 29 30 Table S3: The PPV and proportion of patients diagnosed with COPD by COPD severity 31 Algorithm GOLD 1 GOLD 2 GOLD 3 GOLD 4 32 Number Number confirmed, Number Number 33 confirmed, (PPV (PPV and 95% CI) confirmed, (PPV confirmed, 34 and 95% CI) and 95% CI) (PPV and 95% 35 CI) 36 COPD Code + spirometry 9, 34, 22, 6, 37 + COPD medication (69.2, 36.5-89.8) (87.2, 71.8-94.8) (100) (100) 38 39 COPD Code + spirometry 8, 35, 20, 3, (66.7, 32.9-89.1) (83.3, 68.2-92.1) (100) (75, 4.1-99.5) 40 41 COPD Code + COPD 14, 32 20, 6, 42 medication (82.4, 53.7-94.9) (84.2, 68.1-93.0) (95.2, 69.1-99.4) (100) 43 44 COPD Code only 14, 37, 14, 3, 45 (82.4, 53.7-94.9) (86.0, 71.5-93.8) (93.3, 58.4-99.3) (100) 46 Bronchitis + COPD 7, 20, 11, 2, 47 medication (36.8, 17.3-62.0) (76.9, 55.6-89.9) (91.7, 49.9-99.2) (100) 48 49 Bronchitis only 3, 7, 10 1, 50 (20.0, 5.6-51.2) (63.6, 28.8-83.3) (100) (100) 51 52 Symptoms + spirometry 4, 19, 10 1, 53 (57.1, 15.0-90.9) (90.5, 66.0-97.9) (90.9, 46.3-99.1) (100) 54 Symptoms only 2, 6, 0 0 55 (40, 3.8-91.9) (100) 56

57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 67 of 70 BMJ Open

1 2 3 4 Table S4 : The PPV and proportion of patients diagnosed with COPD by timing of diagnosis 5 Algorithm 2004 to end 2008 Post 2008 6 7 Number Number PPV and 95% Number Number PPV and 95% in confirmed CI in confirmed CI 8 algorithm COPD algorithm COPD 9 COPD Code + 32 28 87.5, 69.8-95.5 53 48 90.6, 78.7-96.1 10 spirometry + 11 COPD medication 12 COPD Code + 14 11 78.6, 46.0-94.0 66 56 84.8, 73.7-91.8 13 spirometry 14 COPD Code + 27 23 85.2, 64.9-94.7 61 54 88.5, 77.4-94.5 15 COPD medicationFor peer review only 16 COPD Code only 21 16 76.2, 51.7-90.5 68 61 89.7, 79.6-95.1 17 Bronchitis + COPD 94 42 44.7, 34.8-55.0 5 2 40.0, 3.8-91.9 18 medication 19 Bronchitis only 83 22 26.5, 18.0-37.2 5 4 80.0, 11.1-99.2 20 Symptoms + 63 28 44.4, 32.4-57.1 22 9 40.9, 21.6-63.5 21 spirometry 22 Symptoms only 64 10 15.6, 8.5-27.0 26 1 3.8, 0.47-25.4 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 68 of 70

Validation of Chronic Obstructive Pulmonary Disease (COPD) recording in the Clinical Practice Research Datalink (CPRD-GOLD)

For peer review only Journal: BMJ Open

Manuscript ID: bmjopen2014005540.R2

Article Type: Research

Date Submitted by the Author: 20Jun2014

Primary Subject Respiratory medicine Heading:

Secondary Subject Heading: Epidemiology

RESPIRATORY MEDICINE (see Thoracic Medicine), THORACIC MEDICINE, Keywords: Chronic airways disease < THORACIC MEDICINE, Epidemiology < THORACIC MEDICINE

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 69 BMJ Open

1 2 3 Validation of Chronic Obstructive Pulmonary Disease (COPD) recording in the Clinical 4 Practice Research Datalink (CPRD-GOLD) 5 6 Jennifer K Quint 1, Hana Müllerova 2, Rachael L DiSantostefano 3, Harriet Forbes 1, Susan 7 Eaton 4, John R Hurst 5, Kourtney Davis 2, Liam Smeeth 1. 8 9 1Department of Non-communicable disease Epidemiology, London School of Hygiene and 10 Tropical Medicine, London, UK 11 2 Respiratory Epidemiology, GlaxoSmithKline R&D, Uxbridge, UK 12 3 Respiratory Epidemiology, GlaxoSmithKline R&D, RTP, NC USA 13 4 Clinical Practice Research Datalink Group, Medicines and Healthcare products Regulatory 14 Agency, London, UK 15 5UCL RespiratoryFor Medicine, peer Royal Free Campus,review University College only London Medical 16 School, London, UK 17 18 19 20 Corresponding author: 21 Dr. Jennifer K Quint 22 Department of Noncommunicable disease Epidemiology 23 London School of Hygiene and Tropical Medicine 24 Keppel Street, London WC1E 7HT 25 Tel: 0207 927 2622 26 Email: [email protected] 27

1 2 3 Article Summary: This paper investigates how individuals with COPD can be accurately 4 5 identified in electronic health records using specific COPD codes alone without additional 6 7 information (i.e. presence of spirometry or respiratory medications). This information is 8 9 essential for appropriate disease management, epidemiological research of COPD and other 10 11 conditions, where COPD is an important comorbidity. 12 13 14 15 Strengths andFor limitations peer of this study: review only 16 17 We have shown that the presence of a specific COPD Read code alone is sufficient to 18 19 identify patients with COPD from electronic health records. Minimal precision lost by not 20 21 including spirometry and medications in the algorithm, allows an increase in the number 22 23 of individuals who can potentially be included in a study by up to 10%. 24 25 We were able to investigate both the accuracy of algorithms when identifying COPD 26 27 patients within the CPRD, and accuracy of the actual GP diagnosis of COPD. 28 29 The amount of missing data among the responding questionnaires was low, suggesting 30 31 reasonable data quality. 32 33 Although the overall response rate for this study was acceptable (77.6%), the proportion 34 35 36 of questionnaires accompanied with additional evidence allowing for adjudication was 37 38 lower. 39 40 41 42 ‘ 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 69

34 35 36 There is no single diagnostic test for COPD. The diagnosis of COPD relies on clinical 37 38 judgement based on a combination of history, physical examination and confirmation of the 39 40 presence of airflow obstruction using spirometry.[5] When retrospectively evaluating the 41 42 accuracy of a COPD diagnosis, commonly used COPD definitions may misclassify patients 43 44 as having COPD. Using multiple diagnostic codes in combination with pharmacy may 45 46 improve the accuracy of identification of COPD patients.[6] Further, over the past 10 years 47 48 the definition of COPD in clinical practice has evolved leading to changes in how COPD is 49 50 diagnosed and the diagnosis recorded. With the introduction of the Quality and Outcomes 51 52 Framework (QOF) codes for COPD in 2004 in England and Wales there are more codes 53 54 available to identify COPD then there were previously. QOF is a voluntary incentive scheme 55 56 for primary care physicians (GPs) in the UK which contains indicators against which GP 57 58 practices can score points and hence be rewarded for how well they care for patients. [7] 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 69 BMJ Open

1 2 3 Evaluation of airflow limitation using spirometry is used as standard to confirm COPD 4 5 diagnosis and severity of COPD is part of the annual COPD patient review.[3,8] However, 6 7 even spirometry if incorrectly performed or interpreted can lead to misdiagnosis (both over 8 9 and under diagnosis of COPD) in approximately 20% of cases. It is also recognised that 10 11 some subgroups of individuals (e.g. women and individuals under 50 and over 80) are less 12 13 likely to have spirometry measured.[8] 14 15 For peer review only 16 17 This study aimed to improve our ability to identify patients with COPD within electronic health 18 19 records. We used the CPRD, a widely used collection of computerised medical records 20 21 which is commonly used for clinical and research purposes. CPRD is comparable to other 22 23 electronic health record databases used in the UK. Our objective was to test the accuracy of 24 25 different definitions of COPD in the CPRD using Positive Predictive Value (PPV), by 26 27 comparing the database records with additional information provided by General 28 29 Practitioners (GPs). This work is important for epidemiological research in COPD and 30 31 diseases where COPD is an important comorbidity as well as for clinical practice. 32 33

34 35 METHODS 36 37 Dataset 38 39 CPRD is the world's largest validated computerized database of anonymized longitudinal 40 41 medical records for primary care. [9,10] Data comprise approximately 14 million patients with 42 43 around 5.4 million of these being currently alive and registered from 660 primary care 44 45 46 practices spread throughout the UK. Records are derived from a widely used GP software 47 48 system and contain complete prescribing and coded diagnostic and clinical information as 49 50 well as information on tests requested, laboratory results and referrals made at or following 51 52 on from each consultation. [11] 53 54 Codelists and algorithms 55 56 Lists of medical codes (Read codes) specific and nonspecific for COPD were created prior 57 58 to the study initiation. Read codes are a hierarchical clinical coding system of over 80,000 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 69

1 2 3 terms that are used in general practice in the UK and are entered by the GP into Vision 4 5 Software. [12] These data are then uploaded by CPRD after they have been processed and 6 7 quality checked added to the CPRD database for research use. Specific COPD codes 8 9 consisted of codes listing either COPD or COPD specific entities of emphysema (see 10 11 supplementary material for specific codes included). Nonspecific codes consisted of a 12 13 variety of lung diseases that could potentially be COPD e.g. chronic bronchitis. 14 15 CombinationsFor of codelists peer and additional review material in the form ofonly the presence of spirometry 16 17 or COPD medications (see supplementary material) were used to make up the eight 18 19 algorithms. The first four definitions required a specific COPD diagnosis code, with the first 20 21 three requiring additional documentation (e.g., medication and/or spirometry). The other four 22 23 definitions required nonspecific bronchitis or respiratory symptom codes, with the least 24 25 specific definition requiring only respiratory symptom codes. Details regarding each 26 27 algorithm can be found in the supplementary material. Briefly, the eight algorithms were 28 29 defined as follows, from the expected most specific to most sensitive construct: 30 31 32 33 34 1. Specific COPD code and more than one prescription of a COPD medication and 35 36 presence of spirometry ( COPD Code + spirometry + COPD medication) 37 38 2. Specific COPD code and presence of spirometry ( COPD Code + spirometry) 39 40 3. Specific COPD code and more than one prescription of a COPD medication ( COPD 41 42 Code + COPD medication) 43 44 4. Specific COPD code only ( COPD Code only) 45 46 5. Nonspecific bronchitis code and more than one prescription of a COPD medication 47 48 (Bronchitis + COPD medication) 49 50 6. Nonspecific bronchitis code only ( Bronchitis only) 51 52 7. Respiratory symptoms and presence of spirometry. Respiratory symptoms consisted 53 54 of persistent cough, sputum production, or dyspnoea. ( Symptoms + spirometry) 55 56 8. Respiratory symptom definition only ( Symptoms only) 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 69 BMJ Open

9 flow volume loops or clinic letters attached and where actual FEV 1 and FVC values were 10 11 available in CPRD. 12 13 14 15 Study PopulationFor peer review only 16 17 The study population consisted of a random sample of individuals selected from all subjects 18 19 registered in CPRD with cohort entry being on or after the 1 st January 2004. At cohort entry, 20 21 people included had to be: over 35 years old, with at least 1 year historical data, and a 22 23 possible diagnosis of COPD defined as evidence of having ever smoked and a record of a 24 25 least one specific or possible COPD code or respiratory symptoms suggestive of COPD. The 26 27 presence of the algorithms was ascertained during a period between patient cohort entry 28 29 and the 31 st December 2012. Patients had to be alive within 4 months of the last collection 30 31 32 date of CPRD data for the January 2013 data build for inclusion in the analysis so that 33 34 CPRD could access their medical records and additional information. For the main analysis, 35 36 a patient could contribute to one algorithm only. It was possible for an individual to be eligible 37 38 for more than one algorithm depending upon the codes used in their medical record over the 39 40 study period. Individuals were randomly selected from the algorithm with the fewest number 41 42 of participants first and then removed from the cohort so they could not be selected for 43 44 another algorithm. 45 46 47 48 CPRD mailed a short, structured questionnaire to GPs in charge of randomly selected 49 50 patients requesting confirmation of COPD status as well as any available specific information 51 52 from the individual’s medical record including spirometry print outs and hospital respiratory 53 54 outpatient letters (see supplementary material). Data were “twice encrypted” within CPRD to 55 56 ensure anonymity; firstly between practices and CPRD and secondly from CPRD to 57 58 researchers. In the questionnaire the GP was asked whether or not the patient had a 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 69

1 2 3 4 5 Table 1: Characteristics of the 696 patients included in the final study analysis 6 7 Algorithm COPD Code + COPD Code + COPD Code + COPD Bronchitis + Bronchitis Symptoms + Symptoms 8 spirometry + spirometry COPD Code COPD only spirometry only 9 COPD medication medication only medication 10 Number of 85 (100) 79 (100) 88 (100) 89 (100) 98 (100) 84 (100) 83 (100) 90 (100) 11 individuals (%) For peer review only 12 13 Number (%) with 46 (54.1) 44 (55.7) 48 (54.5) 40 (44.9) 32 (32.7) 18 (21.4) 30 (36.1) 14 (15.6) 14 supporting info 15 16 Mean age 68.7 (11.3) 68.3 71.8 71.1 68.5 (13.1) 67.8 (13.4) 65.9 (11.9) 63.4 (14.1) (sd) (11.7) (10.5) (10.4) 17 18 19 Male (%) 45 (52.9) 41 (51.9) 40 (45.5) 44 (49.4) 31 (31.6) 29 (34.5) 43 (51.8) 47 (52.2) 20 21 Current smoker 49 (57.7) 50 (63.3) 55 (62.5) 47 (52.8) 66 (67.4) 61 (72.6) 48 (57.8) 58 (64.4) 22 (%) 23 24 GOLD stage* 1 13 (16.3) 14 (18.0) 13 (15.9) 16 (20.5) 17 (28.8) 13 (35.1) 8 (20.0) 4 (36.4) 25 (n=465) 26 2 43 (53.8) 48 (61.5) 41 (50.0) 46 (59.0) 31(52.5) 13 (35.1) 22 (55.0) 5 (45.5) 27 3 18 (22.5) 13 (16.7) 22 (26.8) 12 (15.4) 9 (15.3) 8 (21.6) 8 (20.0) 2 (18.2) 28 4 6 (7.5) 3 (3.9) 6 (7.3) 4 (5.1) 2 (3.4) 3 (8.1) 2 (5.0) 0 (0.0) 29 30 History of 20 (23.5) 22 (27.8) 17 (19.3) 18 (20.2) 20 (20.4) 17 (20.2) 14 (16.9) 9 (10.0) 31 cardiovascular 32 disease 33 34 History of asthma 18 (21.2) 20 (25.3) 16 (18.2) 15 (16.9) 27 (27.6) 23 (27.4) 19 (22.9) 23 (25.6) 35 36 Mean BMI (sd) N=83 N=78 N=86 N=87 N=98 N=85 N=41 N=17 37 (n=575) 27.5 (5.4) 26.7 (5.8) 26.4 (4.7) 27.8 27.4 (5.1) 28.1 (5.0) 27.1 (4.5) 27.6 (4.7) 38 (5.4) 39 *GOLD staging was ascertained from CPRD records or from supplementary information provided by GPs. 40 41 42 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 12 of 69

54 55 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 69 BMJ Open

1 2 3 Table 3 : PPV by algorithm where evidence was available to assess GP compared to physician 4 diagnosis of COPD 5 Algorithm Total Number of Number PPV and 95% CI 6 number patients with with COPD 7 with COPD confirmed according 8 evidence by GOLD standard to GP (N=272) (N=220) 9 COPD Code + spirometry + COPD 46 46 46 100 10 medication 11 COPD Code + spirometry 44 35 33 94.3, 82.498.9 12 COPD Code + COPD medication 48 43 41 95.3, 82.498.9 13 COPD Code only 40 34 33 97.1, 80.299.6 14 Bronchitis + COPD medication 32 21 19 90.5, 66.097.9 15 Bronchitis onlyFor peer18 review 12 only 11 91.7, 49.999.2 16 Symptoms + spirometry 30 21 20 95.2, 69.199.4 17 Symptoms only 14 8 6 75.0, 27.695.9 18 19 20 21 22 Post-hoc analysis 23 24 We repeated the analysis allowing individuals to be put into more than one algorithm and 25 26 tested the PPV of COPD by algorithm relative to the gold standard where individuals were 27 28 identified using only the presence of a specific COPD code (n=457) the PPV was identical to 29 30 if they had a COPD code and evidence either in the form of spirometry or COPD medication 31 32 prescription (n=454); PPV 83.0% (79.086.0) for both. In the majority of cases, where a 33 34 specific COPD code had been assigned, there was additional evidence. Only 3 individuals 35 36 had a specific COPD code with no additional evidence. 37 38 39 40 41 42 DISCUSSION 43 44 We tested the accuracy of eight different algorithms for identifying COPD within the CPRD 45 46 among patients with suspected COPD (e.g., >35 years of age, smoking history, and 47 48 recording of respiratory symptoms or COPD codes). The physician reviewer consensus was 49 50 the GOLD standard. The best performing algorithm allowed an accurate ascertainment of 51 52 90% of patients as diagnosed with COPD. This consisted of a combination of a specific 53 54 COPD code, more than one prescription of a COPD medication and spirometry (PPV 89.4, 55 56 95% CI: 80.794.5). The worst performing algorithm was represented by presence of 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 69

34 35 36 One of the advantages of this study was our ability to investigate both the accuracy of 37 38 algorithms when identifying COPD patients within the CPRD, and accuracy of the actual GP 39 40 diagnosis of COPD. When validating the GP diagnosis of COPD with a respiratory physician 41 42 diagnosis as gold standard based on extra evidence provided by the GP, there was 43 44 improved accuracy (PPV) across all algorithms, with algorithms 14 again performing best. 45 46 This suggests that additional evidence is collected when the GP is reasonably certain that 47 48 the patient has COPD. There was good concordance between GP and respiratory physician 49 50 diagnosis suggesting respiratory consultant validation is not always needed. Where there 51 52 was disagreement, this was usually because lung function did not meet criteria for COPD. 53 54 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 69 BMJ Open

1 2 3 We found that the diagnostic accuracy of COPD decreased across all algorithms when 4 5 patients also had a diagnosis of cardiovascular disease or asthma (Table S1 online 6 7 supplement). When patients had a concomitant diagnosis of asthma, the presence of 8 9 spirometry was particularly important to improve accuracy of COPD diagnosis. This was 10 11 predominantly due to the fact spirometry had been misinterpreted. However, stratification led 12 13 to smaller sample sizes, which could have impacted the precision of estimates. 14 15 Unsurprisingly,For the addition peer of the use ofreview any inhaled COPD medication only to the algorithm did 16 17 not improve precision, most likely due to the overlap in medications used to treat both 18 19 asthma and COPD (see online supplement). The algorithm accuracy was not affected by 20 21 smoking status (current vs. exsmoker) (Table S2 online supplement). We only included 22 23 current or former smokers in our analysis, and cannot be sure of the validity of the results in 24 25 a patient who has never smoked. Certainly in the UK, the majority of COPD is related to 26 27 tobacco smoking and we hypothesized that fixed airflow obstruction in a nonsmoker would 28 29 most likely be due to chronic asthma. 30 31

32 33 When considering the severity of COPD by GOLD classification, algorithms 2 and 3, i.e. a 34 35 36 specific COPD code and spirometry or COPD medications had the greatest accuracy for 37 38 patients with mild disease (GOLD stage 1) (Table S3 online supplement). PPV increased 39 40 with increasing disease severity. PPV increases with disease prevalence, and the 41 42 prevalence of COPD increased moving from algorithm 8 to algorithm 1. 43 44 45 46 We considered the timing of diagnosis in view of an increased uptake of spirometry in 47 48 primary care in more recent years and changes in QOF requirements over time during our 49 50 study period (Table S4 online supplement). We found that algorithms 14 still had the 51 52 greatest accuracy, but the PPV estimates were better for the post 2008 period than pre 2008 53 54 period (see supplementary material). Nonspecific bronchitis codes and symptom codes 55 56 were more likely to be used before 2008 rather than post. This may require consideration 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 69

1 2 3 when developing retrospective cohorts for analysis and otherwise suggests QOF has had a 4 5 positive effect on the consistency of codes used for COPD diagnoses. However, our codes 6 7 were more specific than QOF codes and some of the codes included in QOF were not 8 9 included in our specific COPD codelist, but were included in the nonspecific bronchitis 10 11 codes. While we cannot comment on the accuracy of QOF codes, it is important to highlight 12 13 that that some QOF codes are not disease specific and may not be a good way of identifying 14 15 COPD patientsFor from electronic peer health records review as inevitably people only without COPD will be 16 17 included. It is also important to highlight that Read codes change over time with new codes 18 19 added and some removed, and this needs consideration when identifying people with 20 21 COPD. 22 23 24 25 There are limited COPD validation studies in electronic health records published in the 26 27 literature to which we can compare our study. Soriano validated COPD in the GPRD in 2001, 28 29 when OXMIS codes were still in use. [4] A Swedish study using a Swedish inpatient registry 30 31 used ICD9 and ICD10 codes and identified COPD patients with similar accuracy.[16] A 32 33 Canadian study in the Canadian primary care sentinel surveillance network used algorithms 34 35 36 to identify several long term conditions and also had a PPV similar to ours for COPD [17]. 37 38 However, all of these studies used different codes, algorithms and databases. 39 40 41 42 Our analysis has several limitations. We appreciate that using the gold standard of GP 43 44 questionnaire and respiratory physician review is not perfect as when asked about whether 45 46 or not a specific patient has a certain diagnosis, the GP is most likely to simply look in the 47 48 electronic health record and see if that diagnosis has been record. However, there is no 49 50 alternative. The overall response rate for this study was acceptable (77.6%), the proportion 51 52 of questionnaires accompanied with additional evidence allowing for adjudication was rather 53 54 low. We chose PPV as the measure of accuracy in this study to allow us to determine the 55 56 probability that a patient had COPD from their electronic health record. PPV is correlated 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 69 BMJ Open

1 2 3 with disease prevalence, and although it is strongly related to specificity, the actual 4 5 estimates of specificity, sensitivity and negative predictive value cannot be determined from 6 7 our data. Further, GP practices are self selecting with respect to their contribution to CPRD, 8 9 however those practices appear to be representative of the UK population. Very few patients 10 11 within contributing practices refuse to participate at an individual level and this is not thought 12 13 to bias the results. While CPRD is representative of the general population, as with all 14 15 validation studiesFor that require peer a response, review we cannot be sure thatonly our sample is 16 17 representative of GPs who have not responded, although there is unlikely to be any 18 19 difference. The amount of missing data among the responding questionnaires was low, 20 21 suggesting reasonable data quality. One of the other limitations of this study is that patients 22 23 had to be alive to be included; however it is unlikely that coding would be different for 24 25 individuals who are no longer alive. 26 27 28 29 The algorithm that consisted of a specific COPD code, COPD medication and spirometry 30 31 had the highest PPV; however the PPV was almost as high when a specific COPD code 32 33 alone was used. The poorest performing algorithms were those that involved bronchitis 34 35 36 codes or respiratory symptoms; we would not recommend using these algorithms to identify 37 38 COPD patients. In conclusion, we have shown that the presence of a specific COPD Read 39 40 code alone is sufficient to identify patients with COPD from electronic health records such as 41 42 CPRD. Minimal precision lost by not including spirometry and medications in the algorithm, 43 44 allows an increase in the number of individuals who can potentially be included in a study by 45 46 up to 10%. However by not including spirometry in the definition, the ability to stage COPD 47 48 according to GOLD stages may not be possible for all COPD patients included in a study. 49 50 51 52 53 54 55 56 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 69

1 2 3 4 5 Acknowledgments: none 6 7 Contributorship statement : JKQ, HM, RLD, SE, KD and LS contributed to the conception 8 9 and design, JKQ, HM, JH, to acquisition and analysis, JKQ, HM, RLD, HF, SE, JH, KD and 10 11 LS to interpretation of data, and JKQ, HM, RLD, HF, SE, JH, KD and LS to the drafting of the 12 13 manuscript. JKQ is responsible for the overall content as guarantor. 14 15 Competing Forinterests: nonepeer review only 16 17 Funding : This project was funded jointly by GSK and the MRC. JKQ is funded on a MRC 18 19 Population Health Scientist Fellowship. This work was part funded by a MRC Industry 20 21 Partnership award (grant number G0902135). 22 23 Data Sharing Statement: No additional data are available. 24 25 26 27 28 29

30 31

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1 2 3 Surveillance Network (CPCSSN): A Kingston Practicebased Research Network 4 5 (PBRN) Report. J Am Board Fam Med 2013;26: 159–167 6 7 8 9 10 11 Figure 1: Study population 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 21 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 69

1 2 3 Validation of Chronic Obstructive Pulmonary Disease (COPD) recording in the Clinical 4 Practice Research Datalink (CPRD-GOLD) 5 6 Jennifer K Quint 1, Hana Müllerova 2, Rachael L DiSantostefano 3, Harriet Forbes 1, Susan 7 Eaton 4, John R Hurst 5, Kourtney Davis 2, Liam Smeeth 1. 8 9 1Department of Non-communicable disease Epidemiology, London School of Hygiene and 10 Tropical Medicine, London, UK 11 2 Respiratory Epidemiology, GlaxoSmithKline R&D, Uxbridge, UK 12 3 Respiratory Epidemiology, GlaxoSmithKline R&D, RTP, NC USA 13 4 Clinical Practice Research Datalink Group, Medicines and Healthcare products Regulatory 14 Agency, London, UK 15 5UCL RespiratoryFor Medicine, peer Royal Free Campus,review University College only London Medical 16 School, London, UK 17 18 19 20 Corresponding author: 21 Dr. Jennifer K Quint 22 Department of Noncommunicable disease Epidemiology 23 London School of Hygiene and Tropical Medicine 24 Keppel Street, London WC1E 7HT 25 Tel: 0207 927 2622 26 Email: [email protected] 27

29 30 31 Keywords: COPD, diagnosis of COPD, validation, spirometry, electronic health records 32 33 34 Word count: 3448 35 36 37 38 39 40 Contributorship statement : JKQ, HM, RLD, SE, KD and LS contributed to the conception 41 42 and design, JKQ, HM, JH, to acquisition and analysis, JKQ, HM, RLD, HF, SE, JH, KD and 43 44 LS to interpretation of data, and JKQ, HM, RLD, HF, SE, JH, KD and LS to the drafting of the 45 46 manuscript. JKQ is responsible for the overall content as guarantor. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 69 BMJ Open

9 flow volume loops or clinic letters attached and where actual FEV 1 and FVC values were 10 11 available in CPRD. 12 13 14 15 Study PopulationFor peer review only 16 17 The study population consisted of a random sample of individuals selected from all subjects 18 19 registered in CPRD with cohort entry being on or after the 1 st January 2004. At cohort entry, 20 21 people included had to be: over 35 years old, with at least 1 year historical data, and a 22 23 possible diagnosis of COPD defined as evidence of having ever smoked and a record of a 24 25 least one specific or possible COPD code or respiratory symptoms suggestive of COPD. The 26 27 presence of the algorithms was ascertained during a period between patient cohort entry 28 29 and the 31 st December 2012. Patients had to be alive within 4 months of the last collection 30 31 32 date of CPRD data for the January 2013 data build for inclusion in the analysis so that 33 34 CPRD could access their medical records and additional information. For the main analysis, 35 36 a patient could contribute to one algorithm only. It was possible for an individual to be eligible 37 38 for more than one algorithm depending upon the codes used in their medical record over the 39 40 study period. Individuals were randomly selected from the algorithm with the fewest number 41 42 of participants first and then removed from the cohort so they could not be selected for 43 44 another algorithm. 45 46 47 48 CPRD mailed a short, structured questionnaire to GPs in charge of randomly selected 49 50 patients requesting confirmation of COPD status as well as any available specific information 51 52 from the individual’s medical record including spirometry print outs and hospital respiratory 53 54 outpatient letters (see supplementary material). Data were “twice encrypted” within CPRD to 55 56 ensure anonymity; firstly between practices and CPRD and secondly from CPRD to 57 58 researchers. In the questionnaire the GP was asked whether or not the patient had a 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 69 BMJ Open

1 2 3 4 5 Table 1: Characteristics of the 696 patients included in the final study analysis 6 7 Algorithm COPD Code + COPD Code + COPD Code + COPD Bronchitis + Bronchi tis Symptoms + Symptoms 8 spirometry + spirometry COPD Code COPD only spirometry only 9 COPD medication medication only medication 10 Number of 85 (100) 79 (100) 88 (100) 89 (100) 98 (100) 84 (100) 83 (100) 90 (100) 11 individuals (%) For peer review only 12 13 Number (%) with 46 (54.1) 44 (55.7) 48 (54.5) 40 (44.9) 32 (32.7) 18 (21.4) 30 (36.1) 14 (15.6) 14 supporting info 15 16 Mean age 68.7 (11.3) 68.3 71.8 71.1 68.5 (13.1) 67.8 (13.4) 65.9 (11.9) 63.4 (14.1) (sd) (11.7) (10.5) (10.4) 17 18 19 Male (%) 45 (52.9) 41 (51.9) 40 (45.5) 44 (49.4) 31 (31.6) 29 (34.5) 43 (51.8) 47 (52.2) 20 21 Current sm oker 49 (57.7) 50 (63.3) 55 (62.5) 47 (52.8) 66 (67.4) 61 (72.6) 48 (57.8) 58 (64.4) 22 (%) 23 24 GOLD stage* 1 13 (16.3) 14 (18.0) 13 (15.9) 16 (20.5) 17 (28.8) 13 (35.1) 8 (20.0) 4 (36.4) 25 (n=465) 26 2 43 (53.8) 48 (61.5) 41 (50.0) 46 (59.0) 31(52.5) 13 (35.1) 22 (55.0) 5 (45.5) 27 3 18 (22.5) 13 (16.7) 22 (26.8) 12 (15.4) 9 (15.3) 8 (21.6) 8 (20.0) 2 (18.2) 28 4 6 (7.5) 3 (3.9) 6 (7.3) 4 (5.1) 2 (3.4) 3 (8.1) 2 (5.0) 0 (0.0) 29 30 History of 20 (23.5) 22 (27.8) 17 (19.3) 18 (20.2) 20 (20.4) 17 (20.2) 14 (16.9) 9 (10.0) 31 cardiovascular 32 disease 33 34 History of asthma 18 (21.2) 20 (25.3) 16 (18.2) 15 (16.9) 27 (27.6) 23 (27.4) 19 (22.9) 23 (25.6) 35 36 Mean BMI (sd) N=83 N=78 N=86 N=87 N=98 N=85 N=41 N=17 37 (n=575) 27.5 (5.4) 26.7 (5.8) 26.4 (4.7) 27.8 27.4 (5.1) 28.1 (5.0) 27.1 (4.5) 27.6 (4.7) 38 (5.4) 39 *GOLD staging was ascertained from CPRD records or from supplementary information provided by GPs. 40 41 42 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 33 of 69 BMJ Open

1 2 3 The number of patients diagnosed with COPD confirmed by the gold standard and the PPV 4 5 for each algorithm is given in Table 2 . The PPV was greatest for algorithms 14. Further 6 7 data is available in the supplementary material regarding the effect of comorbidities ( Table 8 9 S1 ), smoking status ( Table S2 ) and GOLD staging ( Table S3 ) on the performance of each 10 11 algorithm. 12 13 14 15 For peer review only 16 17 18 19 Table 2 : The PPV and proportion of patients diagnosed with COPD within each algorithm 20 Algorithm Number of Number Number with PPV and 95% CI questionnaires evaluable confirmed 21 sent out returned COPD 22 (n=951) (n=696) (%) 23 COPD Code + spirometry + 119 85 (71.4) 76 89.4, 80.794.5 24 COPD medication 25 COPD Code + spirometry 119 79 (66.4) 67 83.8, 73.790.4 26 COPD Code + COPD 119 88 (73.9) 77 87.5, 78.693.0 27 medication 28 COPD Code only 119 89 (74.8) 77 86.5, 77.592.3 29 Bronchitis + COPD medication 119 98 (82.4) 44 44.4, 34.854.5 30 Bronchitis only 119 84 (70.6) 26 29.5, 20.840.1 31 Symptoms + spirometry 119 83 (69.7) 37 43.5, 33.254.4 32 Symptoms onl y 118 90 (75.6) 11 12.2, 6.820.9 33 34 35 36 37 In a subset of 272 patients where additional evidence was available (in the form of 38 39 spirometry print outs or hospital outpatient letters), we assessed accuracy of GP diagnosis of 40 41 COPD. Overall, the PPV in this group was 95.0% (91.197.2), This is broken down by 42 43 algorithm in Table 3 . While the presence of supporting evidence improved the PPV in each 44 45 group, algorithms 14 were still most accurate. 46 47 48 49 50 51 52

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1 2 3 Table 3 : PPV by algorithm where evidence was available to assess GP compared to physician 4 diagnosis of COPD 5 Algorithm Total Number of Number PPV and 95% CI 6 number patients with with COPD 7 with COPD confirmed according 8 evidence by GOLD standard to GP (N=272) (N=220) 9 COPD Code + spirometry + COPD 46 46 46 100 10 medication 11 COPD Code + spirometry 44 35 33 94.3, 82.498.9 12 COPD Code + COPD medication 48 43 41 95.3, 82.498.9 13 COPD Code only 40 34 33 97.1, 80.299.6 14 Bronchitis + COPD medication 32 21 19 90.5, 66.097.9 15 Bronchitis onlyFor peer18 review 12 only 11 91.7, 49.999.2 16 Symptoms + spirometry 30 21 20 95.2, 69.199.4 17 Symptoms only 14 8 6 75.0, 27.695.9 18 19 20 21 22 Post-hoc analysis 23 24 We repeated the analysis allowing individuals to be put into more than one algorithm and 25 26 tested the PPV of COPD by algorithm relative to the gold standard where individuals were 27 28 identified using only the presence of a specific COPD code (n=457) the PPV was identical to 29 30 if they had a COPD code and evidence either in the form of spirometry or COPD medication 31 32 prescription (n=454); PPV 83.0% (79.086.0) for both. In the majority of cases, where a 33 34 specific COPD code had been assigned, there was additional evidence. Only 3 individuals 35 36 had a specific COPD code with no additional evidence. 37 38 39 40 41 42 DISCUSSION 43 44 We tested the accuracy of eight different algorithms for identifying COPD within the CPRD 45 46 among patients with suspected COPD (e.g., >35 years of age, smoking history, and 47 48 recording of respiratory symptoms or COPD codes). The physician reviewer consensus was 49 50 the GOLD standard. The best performing algorithm allowed an accurate ascertainment of 51 52 90% of patients as diagnosed with COPD. This consisted of a combination of a specific 53 54 COPD code, more than one prescription of a COPD medication and spirometry (PPV 89.4, 55 56 95% CI: 80.794.5). The worst performing algorithm was represented by presence of 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 69 BMJ Open

34 35 36 One of the advantages of this study was our ability to investigate both the accuracy of 37 38 algorithms when identifying COPD patients within the CPRD, and accuracy of the actual GP 39 40 diagnosis of COPD. When validating the GP diagnosis of COPD with a respiratory physician 41 42 diagnosis as gold standard based on extra evidence provided by the GP, there was 43 44 improved accuracy (PPV) across all algorithms, with algorithms 14 again performing best. 45 46 This suggests that additional evidence is collected when the GP is reasonably certain that 47 48 the patient has COPD. There was good concordance between GP and respiratory physician 49 50 diagnosis suggesting respiratory consultant validation is not always needed. Where there 51 52 was disagreement, this was usually because lung function did not meet criteria for COPD. 53 54 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 69

1 2 3 We found that the diagnostic accuracy of COPD decreased across all algorithms when 4 5 patients also had a diagnosis of cardiovascular disease or asthma (Table S1 online 6 7 supplement). When patients had a concomitant diagnosis of asthma, the presence of 8 9 spirometry was particularly important to improve accuracy of COPD diagnosis. This was 10 11 predominantly due to the fact spirometry had been misinterpreted. However, stratification led 12 13 to smaller sample sizes, which could have impacted the precision of estimates. 14 15 Unsurprisingly,For the addition peer of the use ofreview any inhaled COPD medication only to the algorithm did 16 17 not improve precision, most likely due to the overlap in medications used to treat both 18 19 asthma and COPD (see online supplement). The algorithm accuracy was not affected by 20 21 smoking status (current vs. exsmoker) (Table S2 online supplement). We only included 22 23 current or former smokers in our analysis, and cannot be sure of the validity of the results in 24 25 a patient who has never smoked. Certainly in the UK, the majority of COPD is related to 26 27 tobacco smoking and we hypothesized that fixed airflow obstruction in a nonsmoker would 28 29 most likely be due to chronic asthma. 30 31

1 2 3 when developing retrospective cohorts for analysis and otherwise suggests QOF has had a 4 5 positive effect on the consistency of codes used for COPD diagnoses. However, our codes 6 7 were more specific than QOF codes and some of the codes included in QOF were not 8 9 included in our specific COPD codelist, but were included in the nonspecific bronchitis 10 11 codes. While we cannot comment on the accuracy of QOF codes, it is important to highlight 12 13 that that some QOF codes are not disease specific and may not be a good way of identifying 14 15 COPD patientsFor from electronic peer health records review as inevitably people only without COPD will be 16 17 included. It is also important to highlight that Read codes change over time with new codes 18 19 added and some removed, and this needs consideration when identifying people with 20 21 COPD. 22 23 24 25 There are limited COPD validation studies in electronic health records published in the 26 27 literature to which we can compare our study. Soriano validated COPD in the GPRD in 2001, 28 29 when OXMIS codes were still in use. [4] A Swedish study using a Swedish inpatient registry 30 31 used ICD9 and ICD10 codes and identified COPD patients with similar accuracy.[16] A 32 33 Canadian study in the Canadian primary care sentinel surveillance network used algorithms 34 35 36 to identify several long term conditions and also had a PPV similar to ours for COPD [17]. 37 38 However, all of these studies used different codes, algorithms and databases. 39 40 41 42 Our analysis has several limitations. We appreciate that using the gold standard of GP 43 44 questionnaire and respiratory physician review is not perfect as when asked about whether 45 46 or not a specific patient has a certain diagnosis, the GP is most likely to simply look in the 47 48 electronic health record and see if that diagnosis has been record. However, there is no 49 50 alternative. T he overall response rate for this study was acceptable (77.6%), the proportion 51 52 of questionnaires accompanied with additional evidence allowing for adjudication was rather 53 54 low. We chose PPV as the measure of accuracy in this study to allow us to determine the 55 56 probability that a patient had COPD from their electronic health record. PPV is correlated 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 69

1 2 3 with disease prevalence, and although it is strongly related to specificity, the actual 4 5 estimates of specificity, sensitivity and negative predictive value cannot be determined from 6 7 our data. Further, GP practices are self selecting with respect to their contribution to CPRD, 8 9 however those practices appear to be representative of the UK population. Very few patients 10 11 within contributing practices refuse to participate at an individual level and this is not thought 12 13 to bias the results. While CPRD is representative of the general population, as with all 14 15 validation studiesFor that require peer a response, review we cannot be sure thatonly our sample is 16 17 representative of GPs who have not responded, although there is unlikely to be any 18 19 difference. The amount of missing data among the responding questionnaires was low, 20 21 suggesting reasonable data quality. One of the other limitations of this study is that patients 22 23 had to be alive to be included; however it is unlikely that coding would be different for 24 25 individuals who are no longer alive. 26 27 28 29 The algorithm that consisted of a specific COPD code, COPD medication and spirometry 30 31 had the highest PPV; however the PPV was almost as high when a specific COPD code 32 33 alone was used. The poorest performing algorithms were those that involved bronchitis 34 35 36 codes or respiratory symptoms; we would not recommend using these algorithms to identify 37 38 COPD patients. In conclusion, we have shown that the presence of a specific COPD Read 39 40 code alone is sufficient to identify patients with COPD from electronic health records such as 41 42 CPRD . Minimal precision lost by not including spirometry and medications in the algorithm, 43 44 allows an increase in the number of individuals who can potentially be included in a study by 45 46 up to 10%. However by not including spirometry in the definition, the ability to stage COPD 47 48 according to GOLD stages may not be possible for all COPD patients included in a study. 49 50 51 52 Acknowledgments: none 53 54 Competing interests: none 55 56 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 69 BMJ Open

1 2 3 Funding : This project was funded jointly by GSK and the MRC. JKQ is funded on a MRC 4 5 Population Health Scientist Fellowship. This work was part funded by a MRC Industry 6 7 Partnership award (grant number G0902135). 8 9 10 11 Figure 1: Study population 12 13 14 15 For peer review only 16 17 REFERENCES 18 19 1. National Statistics. www.statistics.gov.uk date accessed June 2013. 20 21 22 23 2. Shahab LM, Jarvis MJ, Britton J, et al. Prevalence, diagnosis and relation to tobacco 24 25 dependence of chronic obstructive pulmonary disease in a nationally representative 26 27 population sample Thorax 2006;61(12):1043 28 29 30 31 3. file:///C:/Users/ENCDJQUI/Downloads/Invisible-Lives-report.pdf Invisible Lives. 32 33 Chronic Obstructive Pulmonary Disease (COPD) – finding the missing millions. 34 35 British Lung Foundation. November 2007. Accessed February 2014. 36 37 38 39 4. Soriano JB, Maier WC, Visick G, et al. Validation of general practitionerdiagnosed 40 41 COPD in the UK General Practice. European Journal of Epidemiology 42 43 2001;17:1075–1080 44 45 46 47 5. NICE guideline COPD http://guidance.nice.org.uk/CG101/QuickRefGuide/pdf/English 48 49 date accessed January 2014. 50 51 52 53 54 55 56 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 69

1 2 3 6. Cooke CR, Joo MJ, Anderson SM et al. The validity of using ICD9 codes and 4 5 pharmacy records to identify patients with chronic obstructive pulmonary disease. 6 7 BMC Health Services Research 2011;11:37 8 9 10 11 7. Smith CJP, Gribbin J, Challen KB, et al. The impact of the 2004 NICE guideline and 12 13 2003General Medical Services contract on COPD in primary care in the UK. Q J Med 14 15 2008;101:145–153.For peer review only 16 17 18 19 8. http://www.nice.org.uk/aboutnice/qof/qof.jsp. Accessed January 2014 . 20 21 22 23 9. CPRD http://www.cprd.com (accessed February 28,2013) 24 25 26 27 10. Williams T, VanStaa T, Padmanabhan S et al. Recent advances in utility and use of 28 29 the General Practice Research Database as an example of a UK Primary Care Data 30 31 resource. Ther Adv Drug Saf 2012;3:88–99. 32 33

34 35 36 11. Tate AR, Beloff N, AlRadwan B et al. Exploiting the potential of large databases of 37 38 electronic health records for research using rapid search algorithms and an intuitive 39 40 query interface. J Am Med Inform Assoc . 2014;21(2):2928. 41 42 43 44 12. Chisholm J. The Read clinical classification. BMJ, 1990. 300(6732):1092. 45 46 47 48 13. GOLD 2011 http://www.goldcopd.org/uploads/users/files/GOLD2011_Summary.pdf 49 50 accessed Nov 2013. 51 52 53 54 14. https://mqi.ic.nhs.uk/IndicatorDefaultView.aspx?ref=1.09.03.07 (QOF COPD). Accessed 55 56 Feb 2014. 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 69 BMJ Open

1 2 3 4 5 15. http://www.nbmedical.com/pdf/keep_simple_qof_2014-2014.pdf accessed Feb 2014 6 7 8 9 16. Inghammar M, Engström G, Löfdahl CG et al. Validation of a COPD diagnosis 10 11 from the Swedish Inpatient Registry Scandinavian Journal of Public Health , 2012;40: 12 13 773–776 14 15 17. KadhimSalehFor peerA, Green M, WilliamsonTreview et al. Validation only of the Diagnostic 16 17 Algorithms for 5 Chronic Conditions in the Canadian Primary Care Sentinel 18 19 Surveillance Network (CPCSSN): A Kingston Practicebased Research Network 20 21 (PBRN) Report. J Am Board Fam Med 2013;26: 159–167 22 23 24 25 26 27 28 29

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