BMJ

Confidential: For Review Only

Temporal trends in the use of tests in UK primary care: a retrospective analysis of 250 million tests, 2000 – 2015.

Journal: BMJ

Manuscript ID BMJ.2018.044789

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 26-Apr-2018

Complete List of Authors: O'Sullivan, Jack; University of Oxford, Centre for Evidence-based medicine, Nuffield Department of Primary Care Health Sciences Stevens, Sarah; University of Oxford, Primary Care Health Sciences Hobbs, FD Richard; University of Oxford, Nuffield Department of Primary Care Health Science Salisbury, Chris; University of Bristol, Centre for Academic Primary Care, School of Social and Community Medicine Little, Paul; University of Southampton, Medical School, Goldacre, Ben; University of Oxford, Primary Care Health Sciences Bankhead, Clare; University of Oxford, Nuffield Department of Primary Care Health Sciences Aronson, Jeffrey; University of Oxford, Primary Health Care Perera, Rafael; University of Oxford, Primary Health Care Heneghan, Carl; Oxford University, Primary Health Care

Too much medicine, Primary Care, Imaging, Laboratory tests, , Keywords: Workload

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1 2 3 Temporal trends in the use of tests in UK primary care: a retrospective analysis of 250 million 4 tests, 2000 – 2015. 5 Jack W. O’Sullivan,1,2 Sarah Stevens,2 FD Richard Hobbs,2 Chris Salisbury,3 Paul Little,4 Ben 6 1,2 1,2 1,2 1,2 1,2 7 Goldacre, Clare Bankhead, Jeffrey K. Aronson, Rafael Perera, and Carl Heneghan . 8 9 10 1CentreConfidential: for Evidence-Based Medicine, Nuffield For Department Review of Primary Care HealthOnly Sciences, 11 University of Oxford, OX2 6GG, UK 12 2 13 Nuffield Department of Primary Care Health Sciences, University of Oxford, OX2 6GG, UK 14 3Centre for Academic Primary Care, School of Social and Community Medicine, University of 15 16 Bristol, BS8 2PS, UK 17 4Primary Care and Population Sciences, University of Southampton, Southampton, SO17 1BJ, UK 18 19 20 21 Jack W. O’Sullivan, Clinical Researcher and DPhil Candidate, [email protected] 22 Sarah Stevens, Statistician, [email protected] 23 24 FD Richard Hobbs, Professor of Primary Care Health Sciences, [email protected] 25 26 Chris Salisbury, Professor of Primary Health Care, [email protected] 27 Paul Little, Professor of Primary Care Research, [email protected] 28 29 Ben Goldacre, Senior Clinical Research Fellow, [email protected] 30 31 Clare Bankhead, Associate Professor of Primary Care, [email protected] 32 Jeffrey K. Aronson, Clinical Pharmacologist, [email protected] 33 34 Rafael Perera, Professor of Medical Statistics, [email protected] 35 36 Carl Heneghan, Professor of Evidence-Based Medicine, [email protected] 37 38 39 Correspondence to: Dr Jack W O’Sullivan 40 41 Centre for Evidence-Based Medicine 42 43 Nuffield Department of Primary Care Health Sciences 44 Radcliffe Observatory Quarter, Oxford, OX2 6GG 45 46 [email protected] 47 48 01865 289300 49

50 51 Manuscript word count: 3,565 52 53 Number of references: 31 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 2 of 100

1 2 3 Temporal trends in the use of tests in UK primary care: a retrospective analysis of 250 4 million tests, 2000 – 2015. 5 6 Abstract 7 8 Objectives 9 To assess the temporal change in UK primary care test use and identify tests with the greatest 10 11 increaseConfidential: in use. For Review Only 12 Design 13 14 Retrospective cohort study 15 16 Setting 17 18 UK primary care 19 20 Participants 21 All patients registered to UK General Practices in the Clinical Practice Research Datalink, 22 2000/1 to 2015/16. 23 24 Main outcome measure 25 26 We used data from the Clinical Practice Research Datalink to retrospectively analyse 27 temporal trends in the use of tests from UK general practices from 2000/1 to 2015/16. We 28 calculated crude and age- and sex-standardised rates of total test use and of 44 specific tests. 29 30 Results 31 32 We analysed 262,974,099 tests over 71,436,331 person-years. Age- and sex-adjusted use 33 increased by 8.5% annually (95%CI 7.6 – 9.4%); from 14,869 tests per 10,000 person-years 34 in 2000/1 to 49,267 in 2015/16, a 231% increase. Patients in 2015/16 had on average 5 tests 35 per year, compared with 1.5 in 2000/1. Test use also increased significantly across all age 36 37 groups, in both sexes, all test types (laboratory, imaging, and miscellaneous), and 40 of the 44 38 tests that we studied specifically. 39 40 Conclusion 41 Our findings contribute to a better understanding of primary care activities and can inform 42 43 future resource allocation. The significant increase in test use, which has outstripped 44 population growth, may be both a cause and a consequence of increasing GP workload. The 45 increasing rate of test use in UK general practice is unlikely to be sustainable. Furthermore, 46 the increase in almost all tests we studied specifically and the increase in the number of tests 47 ordered per patient are concerning for overtesting. 48 49 Funding 50 51 National Institute for Health Research. 52 53 Abstract word count: 243 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 3 of 100 BMJ

1 2 3 Introduction 4 5 The NHS is experiencing an unprecedented rise in spending [1]. Since 2003, net expenditure 6 has increased by over £50bn, an approximate 80% rise [1]. These increasing costs threaten 7 the sustainability of the NHS. 8 9 Primary care accounts for 90% of all NHS care [2]. Few studies have explored primary care 10 activities,Confidential: despite their importance and callsFor for urgent Review research [2]. There Only are no official 11 statistics on one of the core services provided by UK General Practitioners (GPs) – the use of 12 tests. Prior research focused on only a few specific tests in a small population sample [3]. 13 14 Tests account for a substantial proportion of the NHS budget – around £2-3bn annually for 15 laboratory tests alone – and influence more than 70% of clinical decisions [4]. We have 16 therefore quantified the temporal changes in the use of tests in UK general practice and have 17 18 identified specific tests for which usage has changed the most. 19 Methods 20 21 Study population 22 23 We obtained electronic health record data from patients registered with general practices 24 contributing to the Clinical Practice Research Datalink (CPRD) during April 1st 2000 to 25 March 31st 2016. The CPRD, a large database of anonymised electronic health records from 26 UK primary care, contains patient-level data covering approximately 7% of the UK 27 28 population [5]. CPRD data have been validated extensively and are representative of the UK 29 population in terms of age, sex [5], and ethnic background [6]. We included patients of any 30 age if their records were acceptable for research purposes (a data quality indicator provided 31 by CPRD) and were registered at practices with continuous high-quality data reporting 32 (CPRD defined up-to-standard) [7] at any time during the study period. The protocol was 33 approved by the Independent Scientific Advisory Committee (ISAC) of the MHRA (ISAC 34 35 protocol number 17_06R; available from the authors on request). Ethics approval for 36 observational research using the CPRD with approval from ISAC was granted by a National 37 Research Ethics Service committee (Trent MultiResearch Ethics Committee, REC reference 38 number 05/MRE04/87). 39 40 Included tests 41 42 We studied all tests recorded in the CPRD primary care record during the study period. The 43 CPRD contains primary care data, while secondary care data is captured in a separate 44 database and was not included in this study. We also excluded physical examination findings, 45 vital signs, and body weights. 46 47 Tests were grouped into one of three groups: laboratory, imaging, or miscellaneous. The 48 miscellaneous group included tests such as spirometry, upper endoscopy, colonoscopy, 49 Papanicolaou smears, and electrocardiography (ECG). To avoid double counting, if the same 50 code was recorded multiple times for the same patient on the same day, it was counted as 51 52 only one test. Similarly, codes that referred to the same test, or separate components of a 53 single test (e.g. individual components of a full blood count), were grouped and counted as 54 one test. 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 4 of 100

1 2 3 We also examined 44 specific tests (28 laboratory, 11 imaging, and five miscellaneous tests), 4 chosen because they are commonly used tests, included in guidelines or in the Quality 5 Outcomes Framework (QOF) (supplementary file). 6 7 Statistical analysis 8 9 The total number of tests recorded in general practice was calculated for each year, stratified 10 by ageConfidential: and sex. We calculated total person-years For ofReview observation in each Onlyage and sex stratum 11 for each year. Patients alive and registered for the entire year contributed 1 person-year of 12 observation to the total. Patients who were born, died, registered, or deregistered during the 13 year were included, but their contribution to the person-year calculation was adjusted 14 15 proportionately (e.g. a patient who was registered and alive for only 6 months contributed 0.5 16 person-years). 17 18 We calculated crude rates of test use per 10,000 person-years in each age and sex stratum for 19 each year. For comparison across years, we standardised crude rates to the mid-2015 UK 20 population [8]. We calculated rates for the total number of tests, each of the 44 specific tests, 21 and the three groups of tests (laboratory, imaging, and miscellaneous). 22 23 Temporal changes in age- and sex-standardised rates were modelled using joinpoint 24 regression [9]. We examined temporal changes from 2000/1 to 2015/16, and, to account for 25 any potential coding inconsistencies early in our study period, we conducted a sensitivity 26 analysis for the period after the introduction of QOF (2004/5 to 2015/16). The locations of 27 significant changes in slope (‘joinpoints’) were identified, as were the annual percentage 28 29 changes (APC) between joinpoints. We also calculated the average annual percentage change 30 (AAPC) [10] across the entire study period (2000/1 to 2015/16) and for the period after the 31 introduction of QOF (2004/5 to 2015/16). 32 33 We also examined the extent of multiple testing per patient for the years 2000/1, 2004/5, and 34 2015/16. We calculated the percentage of test use that was ordered for patients who had one 35 or more tests (up to 100 tests per patient) in each year. We examined the differences between 36 these proportions across years using the chi-square test and have reported the percentage 37 differences with 95% CI and P values. 38 39 We used Stata (version 14.2) for data extraction and cleaning and R (version 3.4.1) for 40 statistical analyses. 41 42 Patient involvement 43 44 The grant supporting this study has a dedicated patient group who were involved in refining 45 the research question and protocol. There is also a patient, public involvement (PPI) focus 46 group scheduled to assist with lay summaries and dissemination of results (upon publication). 47 48 Role of the funding source 49 50 This study was funded by an independent grant from the National Institute for Health 51 Research (NIHR) School of Primary Care Research (Grant reference number: 386). 52 Independent expert peer reviewers provided feedback on the grant application underpinning 53 this study but had no further role in study design, data collection, analysis, interpretation, or 54 55 drafting of the manuscript. 56 Results 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 5 of 100 BMJ

1 2 3 In all, 262,974,099 tests were ordered for 11,082,628 patients over 71,436,331 patient-years 4 from April 1st 2000 to March 31st 2016. 5 6 Total test use 7 8 The age- and sex-adjusted rate of total test use increased from 14,869 tests per 10,000 person- 9 years in 2000/1 to 49,267 in 2015/16 (Table 1, Figure 1), an 8.5% annual increase (95%CI: 10 7.6–9.3%).Confidential: The rate of test use also increased For significantly Review after the introduction Only of QOF, 11 although at a reduced rate; a 4.3% annual increase (95%CI: 3.4–5.1%). The slope of the trend 12 line changed significantly at two points, 2004/5 (P<0.001), and 2008/9 (P=0.004) (Figure 1). 13 14 Total test use by age groups 15 16 Patients aged 45 to 64 had the highest rates of test use across all 16 study years, followed by 17 those aged 65 to 74 and then 25 to 44-year olds (Table 1). Over the 16-year study period, the 18 age- and sex-adjusted rates of test use increased significantly in all age groups, by at least 19 6.5% annually (Table 2). Patients over the age of 85 saw the largest annual increase (11% 20 21 (95%CI: 9.8–12%)), followed by patients aged 75 to 84 (9.8% (95%CI: 8.8–11%)). The rate 22 of test use also increased significantly in all age groups after QOF (Table 2). Patients aged 23 over 85 also saw the greatest annual increase in test use after QOF; 5.7% (95%CI: 4.6–6.8%), 24 followed by 25 to 44-year olds (4.8% (95%CI: 4.0–5.6%)). 25 26 Total test use by sex 27 28 The adjusted rate of test use increased in both men and women over the 16-year study period 29 (Supplementary file). The adjusted rate of use in men increased from 5,733 per 10,000 in 30 2000/1 to 19,528 per 10,000 in 2015/16, an 8.7% annual increase (95%CI: 7.7–9.7%). Usage 31 increased slightly less in women over the same time (8.3% (95%CI: 7.5–9.1%)), although the 32 absolute rate was higher across all years (supplementary file). For the period after the 33 introduction of QOF, usage increased at similar rates in men and women: 4.3% (95%CI: 3.5– 34 35 5.1%) and 4.2% (95%CI: 3.2–5.1%) respectively (supplementary file). 36 Test types 37 38 Laboratory tests were used substantially more often than imaging and miscellaneous tests 39 across the entire study period (Figure 2, Supplementary file). The adjusted rates of laboratory, 40 41 imaging, and miscellaneous tests all increased significantly (Table 3). Laboratory tests saw 42 the greatest increase, from 13,091 tests per 10,000 person-years in 2000/1 to 44,847 in 43 2015/16 (Supplementary file), an 8.7% annual increase (95%CI 7.8–9.6%). Over the same 44 period, the use of imaging and miscellaneous tests increased annually by 5.5% (95%CI: 4.7– 45 6.4%) and 6.3% (95%CI: 5.3–7.3%) respectively. All test types increased significantly after 46 QOF, but less so (Table 3). 47 48 Multiple testing 49 50 The proportion and degree of multiple testing changed significantly over the study period. 51 There was a substantial increase in the number of tests ordered per patient over time 52 (Supplementary file and Figure 3). Of the patients who had at least one test, the proportion 53 that had more than ten tests annually was 23.2% greater in 2015 than in 2000 (95%CI: 23.1– 54 55 23.3%). Similarly, the proportion of patients who had only one test annually was 16.4% less 56 (95%CI: 16.3–16.5%) in 2015/16 than in 2000/1 (Supplementary file). 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 6 of 100

1 2 3 Changes in specific tests 4 5 Renal function tests were the most commonly ordered test for most of the study period 6 (2002/3 to 2015/16) (Supplementary file). Full blood count (FBC) was used most often in 7 2000/1 and 2001/2 and was then the second most frequently ordered test during the rest of the 8 study (2002/3 to 2015/16). Liver function tests were the third most commonly ordered test 9 from 2001/2 to 2015/16, with urine dipstick third in 2000/1. CT pelvis and MRI knee had the 10 lowest adjusted rates of use (MRI knee from 2000/1 to 2006/7 and CT pelvis for the rest). 11 Confidential: For Review Only 12 Over the 16-year study period, MRI knee scans had the highest average annual increase (69% 13 (95%CI: 38–107%), followed by vitamin D tests (54% (95%CI: 50–57%)) and MRI brain 14 15 scans (47% (95%CI: 40–56%)) (Supplementary file). Vitamin D, MRI knee, and CT pelvis 16 had the greatest increases after QOF (Supplementary file). 17 18 Vaginal swab was the only test in which the use fell significantly over the study period (5.2% 19 annual decrease (95%CI: 4.1–6.3%)). Three tests (Papanicolaou smears, lumbar spine x-ray, 20 and urine non-illicit drug testing) had non-significant changes over the same time. The 21 adjusted rates for four tests fell significantly after QOF (creatine kinase, vaginal swab, 22 Papanicolaou smear, and spirometry) (Supplementary file). 23 24 Five temporal patterns in specific test use emerged (Supplementary file). 25 26 • A consistent linear increase: chest , vitamin B12, C-reactive protein 27 (CRP), iron, folate, and ferritin 28 • An initial rapid increase, followed by a less rapid one: lumbar spine MRI, pelvic CT, 29 knee MRI, DEXA, MRI brain, female sex hormones, knee radiography, testosterone, 30 31 clotting, renal function tests, urine albumin–creatinine ratio, bone profile, prostate- 32 specific antigen (PSA), full blood count, and liver function tests) 33 • An initial increase followed by a plateau: , thyroid function tests, 34 Erythrocyte Sedimentation Rate (ESR), upper endoscopy, urine microscopy and 35 culture (MCS), progesterone, spirometry, and oestradiol 36 37 • An ‘inverted U distribution’: glucose, lipids, troponin, urine dipstick, urine 38 microalbumin, colonoscopy, vitamin D, Papanicolaou smears, creatine kinase, pelvic 39 ultrasonography 40 • A fall, an increase and then a fall: lumbar spine x-ray and urine non-illicit drug test 41 42 Two tests (HbA1c and vaginal swab tests) did not adequately fitted any category nor were 43 similar to each other. 44 45 Discussion 46 47 We have analysed the temporal change in test ordering from UK primary care. Total test use 48 increased markedly over time, even after adjustment for population growth; patients in 49 2015/16 had on average 5 tests per year, compared with 1.5 in 2000/1. Test use increased in 50 men and women (by 241% and 226% respectively) and in all age groups; elderly patients had 51 the greatest increase (372% for those over 85). All types of tests (laboratory, imaging, and 52 53 miscellaneous) increased significantly, as did 40 of the 44 tests we studied specifically. 54 Furthermore, there was a significant increase in the number of tests ordered per patient; of the 55 patients who underwent at least one test annually, the proportion that had more than one test 56 increased significantly over time. In light of unprecedented financial strains on the NHS, 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 7 of 100 BMJ

1 2 3 accurate data on core primary care services are essential. These results allow policy makers to 4 assess trends in the use of tests, stratified by the type of test and the age and sex of patients, 5 providing guidance for healthcare resource planning. 6 7 Many factors probably contribute to the increasing use of tests in UK primary care. The 8 workload of UK GPs continues to increase, and may now be at saturation [2]. Increasing test 9 use may be a direct response to the increasing number and length of GP consultations [2], 10 with tests reportedly being used for ‘strategic, non-medical reasons’, such as reassuring 11 Confidential: For Review Only 12 patients and ending consultations [11]. Conversely, greater use of tests is likely to result in 13 more consultations and to contribute to further workload, with more test results to review in 14 non-consultation time. Ordering tests will also beget more testing to follow up abnormal test 15 results, amplified through biological and test variability when multiple investigations are 16 ordered at the same time. 17 18 Increased test use may be a result of both clinician’s [12] and patients [13] overestimation of 19 test’s benefits and underestimations of their harms. Changes to NHS services may also have 20 contributed. Over the study period, GP access to diagnostic tests expanded [14], many 21 22 services were diverted from secondary to primary care [15], and the QOF was introduced. 23 Lastly, increases in test usage may reflect, more broadly, the possible medicolegal 24 consequences of undertesting [16] and the lack of disincentives to overinvestigate. 25 26 Changes in the use of specific tests give further insights into the factors that increase use. The 27 four haematinic tests (iron, ferritin, vitamin B12, and folate) followed the same linear pattern, 28 as did CRP. These tests are typically used for patients with non-specific symptoms [11] and 29 may reflect clinician’s increased desire to rule out disease in these patients. Imaging tests 30 largely followed a pattern of a rapid increase that then diminished. This may reflect changes 31 32 when GPs gain direct access to imaging. Guidelines may explain the temporal pattern of a 33 few tests. For instance, the sharp increase in HbA1c use may be attributable to the World 34 Health Organization’s 2011 guideline supporting the use of HbA1c for diagnosing diabetes 35 mellitus [17]. Similarly, the 2006 Scottish Intercollegiate Guidelines Network (SIGN) 36 guideline recommended a clinical diagnosis of urinary tract infection (UTI) [18], also 37 adopted by NICE, may explain the plateau of urine MCS tests around the same time. For 38 39 most tests, however, further investigation into the causes and appropriateness of these 40 changes is still required. 41 42 Implications 43 Whatever factors contribute to increased test use, our results reflect a dramatic escalation in 44 GP workload. Greater test use is likely to lead to more consultations and an increase in non- 45 46 consultation workload. There are no UK data on the time it takes GPs to review test results. 47 However, an American study suggested that primary-care physicians spend, on average, 2–3 48 minutes reviewing a test (70 minutes a day) [19]. Using this estimate and the approximate 49 average number of patients (7000) and general practitioners (3) per GP practice (which have 50 changed minimally since 2005) [20], we estimate that the average GP spent 1.5–2 hours 51 reviewing test results each workday in 2015/16. This is a 230% increase from the estimated 52 53 2000/1 figure of 25–35 minutes daily. Our results support other evidence suggesting that UK 54 general practice workload is reaching saturation point [2]. 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 8 of 100

1 2 3 Similarly, our results reflect the burden of GP test use on NHS expenditure. Using 4 conservative estimates from NICE [21] (£6 for a laboratory test, £29 for imaging, and £53 for 5 miscellaneous tests), we estimate that test use from general practice cost £2.8bn in 2015/16 6 (£1.8bn for laboratory tests, £400K for imaging, and £600K for miscellaneous tests). 7 Notably, these estimates are likely underestimating the true costs. Our estimates only account 8 9 for the direct cost of tests and do not include the cost of GPs reviewing the result or the 10 administration team processing the result. 11 Confidential: For Review Only 12 Strengths and weaknesses in relation to other studies 13 This appears to be the first comprehensive assessment of changes in use of tests in primary 14 15 care. There are no official statistics on the use of tests in the UK. A 2013 study [3] assessed 16 temporal changes in 29 laboratory tests ordered from UK primary care from 2005 to 2009 in 17 a random sample of 100,000 patients. The authors also calculated an average temporal 18 change for all 29 tests. Our study, in comparison, was not exclusive in its selection of tests or 19 patients – we assessed changes in the use of all tests in all registered patients over a longer 20 period. We also assessed more tests individually and all types of tests over time (laboratory, 21 22 imaging, and miscellaneous). Nevertheless, our results over the same period are similar; we 23 found that all laboratory tests increased from around 3 tests per patient annually in 2005 24 (31,306 per 10,000 person-years) to 4 tests per patient in 2009 (38,758 per 10,000 person- 25 years). Busby et al [3] reported that the ordering of 29 specific laboratory tests increased, on 26 average, from 2.4 tests per patient (23,872 per 10,000 person-years) to 3.0 tests per patient 27 (29,644 per 10,000 person-years) over the same period. Furthermore, our results are in line 28 29 with data from other countries. An Australian study reported a 54% increase in laboratory test 30 ordering from 2000/1 to 2007/8 [22], while in the USA, CT and MRI scans increased by 14% 31 and 26% annually from 1997 to 2006 [23]. 32 33 We have not examined the appropriateness of the changes in total and specific test use. It is 34 plausible that a substantial proportion of the temporal changes we found represents 35 overtesting. Although the definition remains contentious [24], overtesting (also known as ‘too 36 much testing’) is the unnecessary ordering of a test; where the harms outweigh the benefits 37 [25]. Overtesting is thought to be prevalent and increasing in health care systems, particularly 38 39 in developed countries [26,25,27]. Although our results do not explicitly quantify overtesting, 40 we have identified tests with the greatest temporal change in use and display, graphically, the 41 tests that have seen recent, exponential increases in use (figures S10 supplementary file). 42 43 A potential limitation of our analysis is the inconsistency of coding across the study period. 44 To address this, we only included general practices whose data were quality assured by the 45 CPRD. Furthermore, we considered the ordering of a test as either (a) a record indicating that 46 the test had been ordered or (b) evidence of the result of the test (for instance, via a letter or 47 numerical results). Letter correspondence is often incorporated into CPRD, with around 90% 48 compliance [28,29]. We therefore captured tests when the order was not directly documented. 49 50 To mitigate double counting, if the same test appeared in a patient record twice on one day, 51 we matched these data entries and counted only one test. 52 53 The introduction of QOF improved the frequency of data entry in GP records [30]; 90% of 54 GPs were electronically ordering tests from this date [3,31]. Thus, to further investigate any 55 effects of incomplete coding in the early 2000’s, we conducted a sensitivity analysis, 56 restricting the study period to after the introduction of QOF. Comparison of our primary and 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 9 of 100 BMJ

1 2 3 sensitivity analyses shows a consistent direction of results, with the magnitude of increase 4 greater in the main analysis. 5 6 We also believe that the results from our analysis of 44 specific tests support the conclusion 7 that coding before 2004/5 was valid. Three tests (urine drug monitoring, vaginal swabbing, 8 and lumbar spine radiography) fell significantly in use from 2000 to 2003/4. If the data were 9 not coded appropriately, and thus tests were missed before QOF, we would not have 10 anticipated any reductions in test use. The reduction in the use of all three test types 11 Confidential: For Review Only 12 (laboratory, imaging, and miscellaneous) suggests that the data were captured and coded 13 appropriately. 14 15 Nevertheless. even if the earlier period is ignored (2000/1 to 2003/4) our sensitivity analysis 16 suggests the same conclusion: there has been a significant increase in the use of tests over 17 time. We further address this potential limitation in the supplementary file. 18 19 Another potential limitation of our study is the contamination of secondary care data within 20 the CPRD. Given the CPRD’s extensive use and validation as a primary care database and the 21 existence of a dedicated secondary care database (Hospital Episode Statistics), we feel this is 22 unlikely. The temporal trends in Brain and Knee MRI also further support the lack of 23 secondary care data contamination, as described in the supplementary file. 24 25 Further research 26 27 Future research should focus on determining the appropriateness of the temporal changes we 28 have reported. Ideally, this research should use individual patient data to measure 29 appropriateness directly against evidence-based criteria. We suggest an initial focus on the 30 tests with the greatest temporal changes. 31 32 Further research can also investigate factors that increase the use of tests in particular patient 33 groups, such as those older than 85, who had the greatest increase in test ordering. Additional 34 35 research investigating the consequences of accelerating test use, for instance on specialist 36 referral and treatment, would also be valuable. 37 38 Some of our team are involved in delivering OpenPathology.net [27]; an open data tool (like 39 OpenPrescribing.net) that provides easy access to various analytic approaches identifying 40 test-ordering behaviour in primary care. This tool will continue our work exploring temporal 41 trends on a live interface. 42 43 Conclusion 44 45 The use of tests from UK general practices is increasing substantially; across all patient ages, 46 both sexes, all test types, and for most specific tests. These changes have outstripped 47 population growth. In light of unprecedented financial strains on the NHS, these results allow 48 policy makers to assess trends in the use of tests, stratified by the type of test and the age and 49 sex of patients, providing guidance for healthcare resource planning. 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 10 of 100

1 2 3 What is already known on this topic 4 5 • There are few data quantifying the use of tests in primary care internationally. High- 6 income countries (Australia, USA) have published reports showing temporal increases 7 [22,23]. 8 • In the UK, one study showed that use of laboratory tests increased from 2005 to 2009, 9 but this was in a limited sample of tests, only assessed laboratory tests and was in a 10 11 Confidential:restricted population [3]. For Review Only 12 What this study adds 13 14 • Test use has increased at an inexorable rate in UK primary care. Total test use has 15 increased markedly over time, in both men and women, in all age groups, across all 16 17 types of tests (laboratory, imaging and miscellaneous) and for 40 of the 44 tests we 18 studied specifically. 19 • There was a significant increase in the number of tests ordered per patient; of the 20 patients who underwent at least one test annually, the proportion that had more than 21 one test increased significantly over time. 22 23 • In light of unprecedented financial strains on the NHS, accurate data on core primary 24 care services are essential. Our results provide policy makers with the data for 25 appropriate future healthcare resource planning. 26 27 Acknowledgements 28 This study was funded by an independent grant from the National Institute for Health 29 30 Research (NIHR) School of Primary Care Research (Grant reference number: 386). JOS is a 31 doctoral student supported by the Clarendon Fund. FDRH is a general practitioner and 32 research lead with the Modality Partnership and Director of the National Institute for Health 33 Research (NIHR) School for Primary Care Research. FDRH acknowledges part funding 34 support from the NIHR School for Primary Care Research, the NIHR Oxford BRC, and the 35 NIHR CLAHRC Oxford. CS is a member of the NIHR Health Services and Delivery 36 37 Research Board and acknowledges support from NIHR CLAHRC West and NHS Bristol 38 Clinical Commissioning Group. CH has received expenses and fees for his media work 39 including BBC Inside Health. He holds grant funding from the NIHR, the NIHR School of 40 Primary Care Research, The Wellcome Trust, and the WHO. He has also received income 41 from the publication of a series of toolkit books published by Blackwells. With some 42 international partners, CEBM jointly runs the EvidenceLive Conference and the 43 44 Overdiagnosis Conference, which are based on a non-profit model. CB is partially supported 45 by the NIHR Biomedical Research Centre, Oxford. 46 47 Contribution statement 48 JOS, CH, RP, BG and FDRH conceived the idea for the research. JOS, RP, CB and SS 49 50 designed the study, which was further refined by GP experts CH, FDRH, PL and CS. JOS 51 drafted the protocol, which all authors contributed and revised critically. JOS and SS were 52 responsible for data management and JOS, SS and RP did the statistical analyses. JOS drafted 53 the manuscript, to which all authors contributed, revised critically and approved. JOS is the 54 guarantee. 55 56 Declarations of interest 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 11 of 100 BMJ

1 2 3 All authors declare no competing interests. 4 5 Ethical approval 6 Ethics approval for observational research using the CPRD with approval from ISAC was 7 8 granted by a National Research Ethics Service committee (Trent MultiResearch Ethics 9 Committee, REC reference number 05/MRE04/87). 10 11 DataConfidential: sharing For Review Only 12 The CPRD is run by the UK’s Department of Health. All the data is available via an 13 application to the CPRD, acquisition of the data is associated with a fee. 14 15 Transparency 16 17 The manuscript’s guarantor (JOS) affirms that the manuscript is an honest, accurate, and 18 transparent account of the study being reported; that no important aspects of the study have 19 been omitted; and that any discrepancies from the study as planned (and, if relevant, 20 21 registered) have been explained. 22 Licence 23 24 The Corresponding Author has the right to grant on behalf of all authors and does grant on 25 behalf of all authors, a worldwide licence 26 27 (http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%202013.do 28 c) to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether 29 known now or created in the future), to i) publish, reproduce, distribute, display and store the 30 Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, 31 include within collections and create summaries, extracts and/or, abstracts of the Contribution 32 and convert or allow conversion into any format including without limitation audio, iii) create 33 34 any other derivative work(s) based in whole or part on the on the Contribution, iv) to exploit 35 all subsidiary rights to exploit all subsidiary rights that currently exist or as may exist in the 36 future in the Contribution, v) the inclusion of electronic links from the Contribution to third 37 party material where-ever it may be located; and, vi) licence any third party to do any or all 38 of the above. 39 40 References 41 42 1 NHS Confederation. Key statistics on the NHS - NHS Confederation. Resources. 43 2016.http://www.nhsconfed.org/resources/key-statistics-on-the-nhs (accessed 19 Aug 44 2016). 45 46 2 Hobbs FDR, Bankhead C, Mukhtar T, et al. Clinical workload in UK primary care: a 47 retrospective analysis of 100 million consultations in England, 2007–14. Lancet 48 2016;387:2323–30. doi:10.1016/S0140-6736(16)00620-6 49 3 Busby J, Schroeder K, Woltersdorf W, et al. Temporal growth and geographic 50 51 variation in the use of laboratory tests by NHS general practices: Using routine data to 52 identify research priorities. Br J Gen Pract 2013;63:256–66. 53 doi:10.3399/bjgp13X665224 54 4 Lord Carter of Coles. Report of the review of NHS services in England. 55 56 2006.http://webarchive.nationalarchives.gov.uk/20130107105354/http:/www.dh.gov.u 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 12 of 100

1 2 3 k/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_0919 4 84.pdf (accessed 5 Jan 2018). 5 6 5 Herrett E, Gallagher AM, Bhaskaran K, et al. Data Resource Profile: Clinical Practice 7 Research Datalink (CPRD). Int J Epidemiol 2015;44:827–36. doi:10.1093/ije/dyv098 8 6 Mathur R, Bhaskaran K, Chaturvedi N, et al. Completeness and usability of ethnicity 9 data in UK-based primary care and hospital databases. J Public Health (Oxf) 10 11 Confidential:2014;36:684–92. doi:10.1093/pubmed/fdt116 For Review Only 12 7 Williams T, van Staa T, Puri S, et al. Recent advances in the utility and use of the 13 General Practice Research Database as an example of a UK Primary Care Data 14 resource. Ther Adv drug Saf 2012;3:89–99. doi:10.1177/2042098611435911 15 16 8 Office for National Statistics. Population Estimates for UK, England and Wales, 17 Scotland and Northern Ireland: mid- 2015. 18 2015.https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration 19 /populationestimates/bulletins/annualmidyearpopulationestimates/mid2015 (accessed 20 21 Aug 2016). 21 22 9 National Cancer Institute. Joinpoint Help Manual, Version 4.5.0.1. 23 2015.http://surveillance.cancer.gov/joinpoint/Joinpoint_Help_4.2.0.0.pdf (accessed 5 24 Jan 2018). 25 26 10 Clegg L, Hankey B, Tiwari R, et al. Estimating average annual per cent change in 27 trend analysis. Stat Med 2009;28:3670–3682. doi:10.1002/sim.3733 28 29 11 Koch H, van Bokhoven MA, ter Riet G, et al. What makes general practitioners order 30 blood tests for patients with unexplained complaints? A cross-sectional study. Eur J 31 Gen Pract 2009;15:22–8. doi:10.1080/13814780902855762 32 33 12 Hoffmann TC, Del Mar C. Clinicians’ expectations of the benefits and harms of 34 treatments, , and tests: A systematic review. JAMA Intern Med 35 2017;177:407–19. doi:10.1001/jamainternmed.2016.8254 36 37 13 Hoffmann TC, Del Mar C. Patients’ Expectations of the Benefits and Harms of 38 Treatments, Screening, and Tests. JAMA Intern Med 2015;175:274. 39 doi:10.1001/jamainternmed.2014.6016 40 14 National Audit Office. Department of Health: Managing high value capital equipment 41 42 in the NHS in England. 43 2011.https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/21 44 3151/Radiotherapy-Services-in-England-2012.pdf (accessed 11 Oct 2017). 45 15 Baird B, Charles A, Honeyman M, et al. Understanding pressures in general practice. 46 King’s Fund. 47 48 2016.https://www.kingsfund.org.uk/sites/default/files/field/field_publication_file/Unde 49 rstanding-GP-pressures-Kings-Fund-May-2016.pdf (accessed 12 Dec 2017). 50 16 Medical Protection Society. Fear of legal action impacting on way GPs practise. 51 2017.http://www.medicalprotection.org/uk/for-members/press-releases/press- 52 53 releases/fear-of-legal-action-impacting-on-way-gps-practise (accessed 8 Mar 2018). 54 17 World Health Organization. Use of glycated haemoglobin (HbA1c) in the diagnosis of 55 diabetes mellitus. 2011. doi:WHO/NMH/CHP/CPM/11.1 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 13 of 100 BMJ

1 2 3 18 Scottish Intercollegiate Guidelines Network. Management of suspected bacterial 4 urinary tract infection in adults. 2012. 5 6 19 Poon E, Gandhi T, Sequist T, et al. ‘I Wish I Had Seen This Test Result Earlier!’ Arch 7 Intern Med 2004;164:2223–8. doi:10.1001/archinte.164.20.2223 8 20 Health & Social Care Information Centre. General Practice Trends in the UK to 2015. 9 2016.http://content.digital.nhs.uk/media/21726/General-Practice-Trends-in-the-UK-to- 10 11 Confidential:2015/pdf/General_Practice_Trends_in_the_UK_to_2015.pdf For Review (accessed Only 5 Jan 2018). 12 21 National Institute for Health and Care Excellence. Routine preoperative tests for 13 elective surgery. 2015.https://www.nice.org.uk/guidance/NG45/documents/guideline- 14 appendices-13 (accessed 15 Jan 2018). 15 16 22 Bayram C, Miller G, Valenti L, et al. Evidence-practice gap in GP pathology test 17 ordering A comparison of BEACH pathology data and Bettering the Evaluation And 18 Care of Health. 19 2009.https://www.health.gov.au/internet/main/publishing.nsf/Content/9C300FE48F87 20 6E95CA257BF0001ACE0E/$File/Evidence-practice gap in GP pathology test 21 22 ordering.pdf (accessed 13 Dec 2018). 23 23 Smith-bindman R, Miglioretti DL, Larson EB. Rising Use Of Diagnostic Medical 24 Imaging In A Large Integrated Health System: The use of imaging has skyrocketed in 25 the past decade, but no one patient population or medical condition is responsible. 26 Health Aff (Millwood) 2009;27:1491–502. doi:10.1377/hlthaff.27.6.1491.Rising 27 28 24 Brodersen J, Schwartz LM, Heneghan C, et al. Overdiagnosis: what it is and what it 29 isn’t. BMJ EBM 2018;23:1–3. doi:10.1136/ebmed-2017-110886 30 31 25 O’Sullivan JW, Albasri A, Nicholson B, et al. Overtesting and undertesting in primary 32 care: a systematic review and meta-analysis. BMJ Open 2018;8:e018557. 33 doi:10.1136/bmjopen-2017-018557 34 35 26 Brownlee S, Chalkidou K, Doust J, et al. Evidence for overuse of medical services 36 around the world. Lancet 2017;6736:1–13. doi:10.1016/S0140-6736(16)32585-5 37 38 27 O’Sullivan JW, Heneghan C, Perera R, et al. Variation in diagnostic test requests and 39 outcomes: a preliminary metric for OpenPathology.net. Sci Rep 2018;8:4752. 40 doi:10.1038/s41598-018-23263-z 41 42 28 Khan NF, Harrison SE, Rose PW. Validity of diagnostic coding within the General 43 Practice Research Database: A systematic review. Br J Gen Pract 2010;60:199–206. 44 doi:10.3399/bjgp10X483562 45 29 Jick H, Jick SS, Derby LE. Validation of information recorded on general practitioner 46 based computerised data resource in the United Kingdom. BMJ 1991;302:766–8. 47 48 doi:10.1136/bmj.302.6779.766 49 30 Mannino DM, Thorn D, Swensen A, et al. Prevalence and outcomes of diabetes, 50 hypertension and cardiovascular disease in COPD. Eur Respir J 2008;32:962–9. 51 doi:10.1183/09031936.00012408 52 53 31 Anonymous. GPRD Users’ Group meeting. Scribe 2005;8:20. 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 14 of 100

1 2 3 Figure captions 4 5 Figure 1: Temporal trends in total test use. APC = Annual Percentage Change 6 Figure 2: Temporal trends in total test use by test type 7 8 Figure 3: Percentage of all tests ordered by annual number of tests received per patient 9 10 11 Confidential: For Review Only 12 Tables 13 14 Table 1 Age and sex adjusted rates of test use per 10,000 person-years 15 Age 2000/1 2001/2 2002/3 20034 2004/5 2005/6 2006/7 2007/8 2008/9 2009/10 2010/11 2011/12 2012/13 2013/14 2014/15 2015/16 16 0 to 127.6 141.0 151.6 189.4 213.8 240.8 249.0 256.7 271.3 274.9 283.8 288.7 295.9 305.2 308.7 299.6 17 4 5 to 18 288.1 319.7 349.0 410.4 458.1 508.0 508.1 532.7 569.3 579.0 605.9 624.5 659.3 696.3 710.3 716.9 14 19 15 to 913.9 1049.0 1174.8 1397.6 1568.7 1723.6 1781.9 1856.1 2034.7 2091.4 2153.6 2281.4 2324.6 2424.1 2466.4 2530.5 20 24 25 to 2844.7 3394.5 3850.5 4641.4 5294.8 5976.8 6243.7 6503.4 7123.9 7318.6 7518.9 7957.2 8091.7 8464.1 8548.2 8720.2 21 44 45 to 22 4839.8 5842.8 6757.0 8306.7 9781.8 10933.8 11700.9 12016.9 12865.4 13266.5 13566.0 14098.0 14391.3 15047.6 14773.2 15233.1 23 64 65 to 3055.9 3820.3 4523.4 5657.1 6775.7 7533.2 8171.3 8401.0 8847.5 9166.2 9288.8 9500.7 9585.0 10039.2 9793.3 10009.8 24 74 75 to 25 1973.5 2517.2 3015.8 3882.2 4727.6 5284.7 5812.9 6087.8 6493.9 6842.9 6999.7 7246.5 7408.2 7834.3 7736.0 7858.4 84 26 85+ 825.6 1077.1 1297.0 1684.2 2096.4 2392.2 2644.9 2825.3 3047.4 3262.8 3356.0 3528.1 3641.0 3902.7 3834.1 3898.5 27 28 Total 14869.0 18161.6 21119.0 26169.0 30916.9 34593.2 37112.7 38480.0 41253.3 42802.4 43772.7 45525.0 46397.0 48713.5 48170.3 49267.0 29 30 31 32 33 Table 2 Average annual percentage increase in rate of test ordering per age group 34 2000/1 to 2015/16 2004/5 to 2015/16 35 Age (95%CI) (95%CI) 36 37 0 to 4 6.5% (5.7% to 7.4%) 3.6% (3.1% to 4.2%) 38 39 5 to 14 6.5% (5.9% to 7.0%) 4.6% (4.2% to 4.9%) 40 41 15 to 24 7.2% (6.5% to 7.9%) 4.5% (3.8% to 5.2%) 42 43 25 to 44 7.6% (6.8% to 8.4%) 4.8% (4.0% to 5.6%) 44 45 45 to 64 7.8% (7.1% to 8.5%) 4.3% (3.7% to 5.1%) 46 65 to 74 8.3% (7.4% to 9.2%) 3.4% (2.6% to 4.4%) 47 48 75 to 84 9.8% (8.8% to 10.8%) 4.7% (3.7% to 5.7%) 49 50 85+ 11.1% (938% to 12.4%) 5.7% (4.6% to 6.8%) 51 52 Total 8.5% (7.6% to 9.3%) 4.3% (3.4% to 5.1%) 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 15 of 100 BMJ

1 2 3 Table 3 Average annual percentage increase in the rate of types of test use 4 5 2000/1 to 2015/16 2004/5 to 2015/16 Test Type 6 (95%CI) (95%CI) 7 8.7% 4.3% Laboratory 8 (7.8% to 9.6%) (3.4% to 5.2%) 9 5.5% 4.0% 10 Imaging (4.7% to 6.4%) (3.0% to 5.0%) 11 Confidential: For Review Only 12 6.3% 1.4% Miscellaneous 13 (5.3% to 7.3%) (0.5% to 2.4%) 14 15 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 https://mc.manuscriptcentral.com/bmj BMJ Page 16 of 100

1 2 3 4 5 6 7 8 9 10 11 Confidential: For Review Only 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 Temporal trends in total test use. APC = Annual Percentage Change 40 149x149mm (300 x 300 DPI) 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 17 of 100 BMJ

1 2 3 4 5 6 7 8 9 10 11 Confidential: For Review Only 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 Percentage of all tests ordered by annual number of tests received per patient 40 149x149mm (300 x 300 DPI) 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj

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Confidential: For Review Only

Figures S10 Temporal trends in specific test use ...... S10Figures Temporal trends in specific test use 34 Figures S9Figures Temporal...... trends in usetest stratified by Gender 33 Table annualAverage S8 percentage increase in specific test...... use 30 Table S7 Age and sex adjusted rates of specific and clustered test use per 10,000 person-years ...... Table and adjusted Age sex S7 rates and of specific clustered per use test 10,000 person-years 28 Table S6 Multiple testing over the years ...... Table Multiple testing S6 over the years 27 Table and ...... adjusted Age sex S5 rates use of test per test 10,000, typeby 26 Table and Age Sex ...... S4 Adjusted rates use of test per 10,000person-years, stratified by sex 25 Text S3: Extended Discussion ...... Text S3: Extended Discussion 23 Text S2 Extended included tests ...... Text S2 Extended included tests 21 Supplementary file Supplementary Contents ...... Test S1 of included list tests 2 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only

Arteriography arteryof carotid Arteriography Arthrography of knee Arthrography Barium enemaBarium Barium follow through Barium Barium meal Barium Barium swallow Barium Bone densitometry Bone Brain isotope studiesBrain Breast contrast radiog contrast Breast Bronchography Cardiac isotope studies isotope Cardiac Carotid artery artery Carotid Carotid artery doppler artery Carotid CAT scan - abdomen - scan CAT CAT scan - face - scan CAT CAT scan - neck - scan CAT CAT scan - thorax - scan CAT

Arteriography upper- limbArteriography Arteriography lower- limbArteriography Arm arteriographyArm Antenatal scan Antenatal Angiocardiography ABPI - Ankle index - pressure brachial ABPI Abdominal fistulography Abdominal fistulography Abdominal aortography Abdominal aortography

10. 9. 11. 8. 7. 12. 6. 5. 13. 4. 14. 3. 2. 15. 1. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. Test S1 list of included tests S1Test list of included within of tests total List tests Imaging 2 Page 19 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 20 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only CAT scan - whole body whole - scan CAT Cholecystogram Cholecystogram Cineradiography - - GIT Cineradiography Cineradiography - - GUTCineradiography Cineradiography - joints - Cineradiography Cineradiography - tract- resp. Cineradiography Computed angiography of coronary of coronary arteries angiography Computed tomography Computed tomography arteriogram of thorax arteriogram Computed tomography Computed tomography abdomen Computed tomography Computed tomography brain Computed tomography Computed tomography chest Computed tomography Computed tomography bladdergall Computed tomography Computed tomography head/sinusesComputed tomography Computed tomography kidney Computed tomography Computed tomography lower limb Computed tomography Computed tomography neckComputed tomography Computed tomography pelvisComputed tomography Computed tomography shoulder Computed tomography Computed tomography sternoclavicular jointComputed tomography Computed tomography upper limb Computed tomography Computed tomography urinary tract urinary Computed tomography Computed tomography pelvisComputed tomography Computed tomography pulmonary pulmonary angiographyComputed tomography Computerised bone densimetry bone Computerised Contrast neurodiography neurodiography Contrast Contrast radiog.abd.cavity radiog.abd.cavity Contrast Contrast radiog.larynx/tracheaContrast Contrast radiog.peritoneal cav radiog.peritoneal Contrast Contrast radiogr. oropharynx radiogr. Contrast Contrast radiogr.abdom.cavity Contrast

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. 3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Contrast radiogr.nasopharynx radiogr.nasopharynx Contrast Contrast radiogr.resp.organsContrast Contrast radiography - ducts - radiography Contrast Contrast radiography GIT radiography Contrast Contrast radiography head/neck radiography Contrast Coronary arteriography Coronary CSF isotope study isotope CSF Dental radiographyDental Doppler ultrasound of vessels ultrasound Doppler of extremities Dual-energy X-ray absorptiometry X-ray (DEXA)Dual-energy Dynam.non-im.isotope: brain brain Dynam.non-im.isotope: Dynam.non-im.isotope: heartDynam.non-im.isotope: Dynam.non-im.isotope: liver Dynam.non-im.isotope: Dynam.non-im.isotope: thoraxDynam.non-im.isotope: Dynam.non-im.isotope: thyroidDynam.non-im.isotope: Dynam.non-im.isotope: urinaryDynam.non-im.isotope: Dynam.non-im.isotope:blood floDynam.non-im.isotope:blood Echocardiogram Elbow Elbow arthrogram Encephalography Femoral arteriography Femoral Head fistulography Head Heart isotope studiesHeart Hip arthrogram Hip arthrogram Hormone radioassay-parathyroid Hormone Hormone radioassay-sex/placentHormone Hormone radioassay - - radioassay adrenalHormone Hormone radioassay - pituitary - radioassay Hormone Hormone radioassay - thyroid - radioassay Hormone Hypothalamus hormone radioass. hormone Hypothalamus

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Confidential: For Review Only Liver isotope studies Liver Leg arteriography Leg Left toe brachial pressure brachial toe index Left Left posterior tibial doppler posterior pressureLeft Left peroneal doppler pressure doppler peroneal Left Left dorsalis pedis doppler pedis dorsalis pressureLeft Left brachial doppler pressure doppler brachial Left Left anterior pressure tibial doppler Left Knee arthrographyKnee Kids.,urets, bladder bladder abdoKids.,urets, xray Isotope static Isotope Isotope stat parathyroid scan Isotope Isotope scan spleenIsotope Isotope phlebography Isotope Isotope lymphographyIsotope Isotope lung perfusion scan Isotope Isotope dynamic scan liver Isotope

Hysterography Hysterography Hysterosalpingography I-V pyelographyI-V Intervertebral disc arthrogram Intervertebral Intravenous cystographyIntravenous Intravenous pyelographyIntravenous Intravenous urogramIntravenous Isotope iron absorptionB12 + Isotope Isotope bone scanIsotope Isotope brain angiographyIsotope Isotope diagnostic radiologyIsotope Isotope distribut.static scan Isotope Isotope dynamic heart scan Isotope

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Confidential: For Review Only Plethysmography Plethysmography Percutaneous cystographyPercutaneous Per-oral Per-oral Optical coherence tomography coherence Optical Octreotide scanOctreotide Nuchal scan Nuchal Neck fistulography Neck Myocardial perfusion scan Myocardial MRI of upper limb MRI MRI of thoraxMRI MRI of thoracic spine of thoracic MRI MRI of shoulderMRI MRI of lumbar spineMRI MRI of lower limb MRI MRI of knee MRI MRI of femur MRI MRI of cervical spine of cervical MRI MRI of Brain MRI MRI abdomen MRI Micturating cystogramMicturating Mammary ductogram Mammary Mammary contrast radiog contrast Mammary Male genital venogram genital Male Male genital contrast radiog. genital Male Lymph isotope studiesLymph Lung isotope studies isotope Lung Lower limb venogram Lower Lower limb arteriogramLower

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Confidential: For Review Only Ultrasound scan of Achilles scan Ultrasound tendon Ultrasound of scrotumUltrasound Ultrasound of bladderUltrasound Ultrasound of abdomen Ultrasound Ultrasonic doppler for fetal heart sounds for heart doppler fetal Ultrasonic Ultra-sound scan scan obstetric- Ultra-sound Transrectal ultrasound scan of prostate ultrasound Transrectal Thalamus hormone radioassay hormone Thalamus Temporomandibular arthrogramTemporomandibular Tc99m-MAG3 renogram Tc99m-MAG3 Tc99m-DTPA renogramTc99m-DTPA Tc99m-DMSA renal study renal Tc99m-DMSA Tc-99m hexamethylpropyleneamine oxime leucocyte scan oxime leucocyte hexamethylpropyleneamine Tc-99m Tc-99m hexamethylpropyleneamine oxime leucocyte knee scan oxime leucocyte hexamethylpropyleneamine Tc-99m Tc-99m hexamethylpropyleneamine oxime leucocyte hip scan oxime hexamethylpropyleneamine leucocyte Tc-99m Tc-99m hexamethylpropyleneamine oxime leucocyte bowel scan oxime leucocyte hexamethylpropyleneamine Tc-99m Skeletal surveySkeletal Sinuses contrast radiography Sinuses contrast Sialography Shoulder arthrogram arthrogram Shoulder Right toe brachial pressure index pressure brachial toe Right Right posterior tibial doppler pressure tibial doppler posterior Right Right dorsalis pedis pedis dorsalis doppler pressureRight Right brachial doppler pressure doppler brachial Right Right anterior tibial doppler pressure anterior Right Renal soft tis. X-ray Renal Renal isotope studies Renal Renal arteriographyRenal Quantitative ultrasound scan of heel scan ultrasound Quantitative

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Confidential: For Review Only X-ray abdomenX-ray Vitamin B12 isotope studies Vitamin B12 Ventriculography contrast- Ventriculography azygos - Venography Venogram - renal Venogram Urethrography Ultrasound scan of wrist scan Ultrasound Ultrasound scan of upper scan arm Ultrasound Ultrasound scan of upper scan abdomenUltrasound Ultrasound scan of thyroid scan Ultrasound Ultrasound scan of thigh scan Ultrasound Ultrasound scan of salivary of salivary glands scan Ultrasound Ultrasound scan of sacral scan Ultrasound spine Ultrasound scan of popliteal artery scan Ultrasound Ultrasound scan of pelvis scan Ultrasound Ultrasound scan of lower scan leg Ultrasound Ultrasound scan of liver scan Ultrasound Ultrasound can of can kidneysUltrasound Ultrasound scan of hand scan Ultrasound Ultrasound scan of bladder gall scan Ultrasound Ultrasound scan of forearm scan Ultrasound Ultrasound scan of foot scan Ultrasound Ultrasound scan of fingers scan Ultrasound Ultrasound scan of elbow scan Ultrasound Ultrasound scan of chest of chest scan wall Ultrasound Ultrasound scan of chest scan Ultrasound Ultrasound scan of calcaneum scan Ultrasound Ultrasound scan of buttock scan Ultrasound Ultrasound scan of back scan Ultrasound Ultrasound scan of aorta scan Ultrasound

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Confidential: For Review Only X-ray of toesX-ray X-ray of radius/ulnaX-ray X-ray of radiusX-ray X-ray neck of femur X-ray X-ray nasal/malar X-ray X-ray metatarsal bones metatarsal X-ray X-ray metacarpalsX-ray X-ray maxillary sinuses maxillary X-ray X-ray X-ray X-ray X-ray X-ray lumbar spine lumbar X-ray X-ray knee X-ray X-ray jawX-ray X-ray humerusX-ray X-ray hip/leg X-ray X-ray hip joint X-ray X-ray head of humerusX-ray X-ray head of femur X-ray X-ray handX-ray X-ray sinusesfrontal X-ray X-ray foot X-ray X-ray femur X-ray X-ray facial sinuses facial X-ray X-ray elbowX-ray X-ray coccyx X-ray X-ray clavicle X-ray X-ray chestX-ray X-ray spinecervical X-ray X-ray carpus X-ray X-ray jointankle X-ray

236. 235. 234. 233. 232. 231. 230. 229. 228. 227. 226. 225. 224. 223. 222. 221. 220. 219. 218. 217. 216. 215. 214. 213. 212. 211. 210. 209. 208. 207. 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only X-ray thoracic spine thoracic X-ray X-ray thoracic thoracic cage X-ray X-ray temporomandib.jnt X-ray X-ray teethX-ray X-ray tarsusX-ray X-ray sternum X-ray X-ray skullX-ray X-ray sternoclavicular jointX-ray X-ray shoulder/armX-ray X-ray shoulder joint X-ray X-ray shaft humerus of X-ray X-ray shaft femur of X-ray X-ray scapula X-ray X-ray scaphoidX-ray X-ray sacrum/coccyx X-ray X-ray sacrumX-ray X-ray sacro-iliac joint X-ray X-ray ribs X-ray X-ray radiusX-ray X-ray pubisX-ray X-ray phalanges of toes phalanges X-ray X-ray pelvis X-ray X-ray orbit X-ray X-ray of wristX-ray X-ray of ulnaX-ray

B12 levelsB12 Alpha fetoprotein Alpha Acid phosphatase Acid

3. 2. 1. 261. 260. 259. 258. 257. 256. 255. 254. 253. 252. 251. 250. 249. 248. 247. 246. 245. 244. 243. 242. 241. 240. 239. 238. 237. Laboratory 10 Page 27 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 28 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Luteinising hormone Luteinising Lithium levelsLithium Phenobarbitone Phenytoin Prolactin level level Prolactin Prostatic acid phosphatase acid Prostatic Reticulocytes Reticulocytes Theophylline Theophylline Total protein protein Total Valproate Valproate Amniocentesis Amniocentesis Clotting testsClotting Faecal occult blood Faecal Glandular fever test fever Glandular Pregnancy testPregnancy Seminal analysisSeminal Serology Serology Sputum culture Stool culture Eye swabEye Cervical swab Cervical Nose swab Nose Penile swabPenile Skin swab

Lactate dehydrogenase Lactate Human chorionic chorionic gonadotropin Human Follicle stimulating hormone stimulating Follicle Digoxin bloodDigoxin level Serum chlorideSerum Carbemazepine monitoring Carbemazepine

10. 9. 11. 8. 7. 12. 6. 5. 13. 4. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Throat swab Throat Wound swab Rubella test Rubella Tuberculin testTuberculin Amylase Amylase Uric acid blood level acid Uric Anti mitochondrial antibodiesAnti mitochondrial Anti nuclear antibodies Anti nuclear Blood group antibodies Blood group Syphilis testSyphilis Viral studies Viral Guthrie test test Guthrie Immunoglobulin Immunoglobulin Plasma electrophoresis electrophoresis Plasma Rheumatoid factor Rheumatoid Chemical function tests function Chemical Examination of faeces Examination faeces of Synovial fluid examination fluid Synovial Bone marrow examination Bone Sputum examination Amniotic fluid examination Amniotic examination fluid SH-antigen (hepatitis b) testSH-antigen HIV testHIV Infection titres Infection Anti smooth autoantibodies muscle Thyroid autoantibodies Thyroid DNA binding binding autoantibodies DNA Cardiac enzymesCardiac Serum osmolality osmolality Serum Serum globinSerum

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. 61. 62. 63. 12 Page 29 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 30 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Blood trace elements / trace vitaminsBlood Histology Other autoantibodies Other Hepatitis a test a Hepatitis Other bacteriology tests bacteriology Other Microscopy for malarial for parasitesMicroscopy Fructosamine Fructosamine Urethral swabUrethral Antostreptolysin o titreAntostreptolysin Radioallergosorbent (RAST) test Radioallergosorbent Lipoprotein electrophoresisLipoprotein Lupus erythematosus (LE) erythematosus cellsLupus Gonadotrophin Serum cortisol Serum Sex hormone binding globulinSex binding hormone Other immunology tests immunology Other Tricyclics Plasma viscosity viscosity Plasma Toxicology Toxicology Serum amino acids amino Serum Blood Blood gases Vomit examination Vomit examination Calculus examination examination Calculus Haemoglobin variantsHaemoglobin Legionella antibody antibody test Legionella Immuno electrophoresis Immuno Feto-placental hormones Feto-placental Serum bicarbonateSerum Skin prick testSkin prick Serum fibrinogen level fibrinogen Serum

64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Pleural fluid examination fluid examination Pleural Disaccharidase tolerance testDisaccharidase Serum lactate Serum Serum aldosterone Serum Anion gap Anion gap Serum noradrenalineSerum Serum adrenalineSerum Thrombin timeThrombin Sickle cell disease screen disease cell Sickle Schilling test b12 absorption- Schilling Serum cyclosporinSerum Serum paracetamolSerum Enzymes/specific proteinEnzymes/specific Tumour markers Tumour markers Serum insulin insulin Serum Microscopy culture sensitivities culture & Microscopy Sputum cytology Sputum cytology Serum growth hormone growth Serum Gastrointestinal hormonesGastrointestinal Complement tests Complement tests Parietal cell autoantibodes cell Parietal Ascitic fluid examination examination fluid Ascitic Methotrexate Methotrexate Blood alcohol level alcohol Blood

Transfer coefficient for coefficient COTransfer Serum parathyroid hormone parathyroid Serum HLA tissue typing tissue HLA Blood lead level lead Blood Chlamydia Cerebro-spinal fluid examinationCerebro-spinal

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Confidential: For Review Only Toxoplasma Toxoplasma Leptospira Mycoplasma Virus: serology Virus: serology Chlamydia Chlamydia Hepatitis B surface surface antigen B Hepatitis C. Difficile toxin C. Difficile A Helicobacter pylori antibody pylori Helicobacter Helicobacter pylori serology pylori Helicobacter HTLV Rubella Rubella Pentagastrin test Pentagastrin Nitrogen testbalance Nitrogen Short tetracosactrin test Short tetracosactrin D-xylose absorption test absorption D-xylose Disaccharidase tolerance testsDisaccharidase Synacthen test Synacthen Schilling test Schilling Ear swab Ear Ante-natal blood testsAnte-natal Haematology screening tests screening Haematology Genetic observations Genetic Biochemical screening tests screening Biochemical Hepatitis B Antibody B Hepatitis Immunology screening tests screening Immunology Serum amiodarone amiodarone Serum Serum adrenocorticotrophic hormone adrenocorticotrophic Serum Carboxyhaemoglobin Serum reninSerum Adrenal autoantibodies Adrenal

153. 152. 151. 150. 149. 148. 147. 146. 145. 144. 143. 142. 141. 140. 139. 138. 137. 136. 135. 134. 133. 132. 131. 130. 129. 128. 127. 126. 125. 124. 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Serum IgG anticardiolipins level Serum IgG Nasopharyngeal virology swabNasopharyngeal Borrelia Rapid human immunodeficiency virus antibody immunodeficiency human Rapid Infleunza A virus A virus Infleunza Camplobacter serology Camplobacter Tropheryma whipplei Tropheryma West Nile Influenza Influenza Human T-lymphotropic T-lymphotropic virus Human Dengue virus Dengue Hepatitis D Hepatitis Respiratory syncytial virus syncytial Respiratory Bordetella Hepatitis G Hepatitis Parasite Hepatitis E Hepatitis Brucella Hepatitis CHepatitis Malaria Malaria Treponema pallidum haemaglutinationTreponema HIV Yersinia Aspergillus Aspergillus Epstein-Barr virusEpstein-Barr Fungus serologyFungus Human hepes virus hepes Human Rubella Rubella IgM Syphilis Syphilis Legionella

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Confidential: For Review Only Centromere antibody antibody level Centromere Anti-thrombin III level Anti-thrombin III TSH receptor antibody level antibody TSH receptor Liver autoantibody level autoantibody Liver Cytoplasmic anti-neutrophil cytoplasmic antibody antibody level anti-neutrophil cytoplasmic Cytoplasmic Anti-cyclic citrullinated peptide antibody level antibody citrullinated peptide Anti-cyclic Skin antibody levelSkin antibody Anti liver kidney microsomal antibody level microsomal antibody kidney Anti liver Anti-neutrophil cytoplasmic antibody screen antibody cytoplasmic Anti-neutrophil Human leucocyte antigen antibody level antigen leucocyte antibody Human Extractable nuclear antigen antibody level antigen nuclear antibody Extractable Intrinsic factor antibody screen antibody factor Intrinsic Anti-nuclear IgG antibody level antibody Anti-nuclear IgG Thyroid peroxidase antibody level peroxidase antibody Thyroid Islet level antibody cell Islet Lupus anticoagulant screen Lupus Albumin autoantibody level Albumin autoantibody Anti-gliadin antibody level Anti-gliadin Serum endomysium antibodies endomysium Serum Reticulin R1 autoantibody titre R1Reticulin autoantibody Anti-neutrophil cytoplasmic antibody level antibody cytoplasmic Anti-neutrophil Lupus circulating anticoagulant index circulating anticoagulant Lupus Microsomal autoantibodies autoantibodies Microsomal Thyroglobulin autoantibodies Thyroglobulin Serum IgM anticardiolipins level Serum IgM DS DNA antibody by by ELISA antibody DS DNA Mitochondrial antibody level antibody Mitochondrial Coeliac disease screen disease Coeliac Serum anti-cardiolipin level anti-cardiolipin Serum Autoantibody titre positive titre Autoantibody

213. 212. 211. 210. 209. 208. 207. 206. 205. 204. 203. 202. 201. 200. 199. 198. 197. 196. 195. 194. 193. 192. 191. 190. 189. 188. 187. 186. 185. 184. 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Histone antibody level antibody Histone Ri antibody levelRi antibody Yo antibody levelYo antibody Pemphigus antibody level antibody Pemphigus Pemphigoid antibody level antibody Pemphigoid U-snRNP Antibody level Antibody U-snRNP Parathyroid antibody level Parathyroid Platelet antibodies test antibodies Platelet Glycolipid antibody level Glycolipid Cold antibody levelCold antibody Serum anti-ganglioside M1 level M1 level anti-ganglioside Serum Ganglioside antibody level antibody Ganglioside ALKM - Anti liver kidney level microsomal kidney Anti liver antibody - ALKM Serum Ro 02-0683 numberSerum Acetyl choline receptor antibody level choline receptor antibody Acetyl Paraneoplastic antibody level antibody Paraneoplastic ssDNA binding autoantibody level autoantibody binding ssDNA Anti-tissue transglutaminase level Anti-tissue transglutaminase Intrinsic factor antibodyfactor Intrinsic GBM antibody level antibody GBM Proteinase 3 antibody level 3 antibody Proteinase Serum glomerular basement membrane antibody level basement antibody membrane glomerular Serum Myeloperoxidase antibody level antibody Myeloperoxidase Striated muscle antibody level antibody muscle Striated IgA antibody level antibody IgA Intrinsic factor antibody level antibody factor Intrinsic Anti-B autoantibody level autoantibody Anti-B Anti -Hb antibody level antibody Anti -Hb Anti-nuclear antibody level antibody Anti-nuclear dsDNA binding autoantibody level binding autoantibody dsDNA

243. 242. 241. 240. 239. 238. 237. 236. 235. 234. 233. 232. 231. 230. 229. 228. 227. 226. 225. 224. 223. 222. 221. 220. 219. 218. 217. 216. 215. 214. 18 Page 35 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 36 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Tartrate labile acid serum level phosphatase Tartrate Serum P1 phenotypeSerum - Plasma beta 2 microglobulin beta Plasma level Leucocyte level phosphatase alkaline Leucocyte Serum lipase lipase Serum Serum haptoglobin screen haptoglobin Serum Plasma amylase level amylase Plasma Enzymes/specific proteins NOSEnzymes/specific Serum cholinesterase level cholinesterase Serum Serum pseudocholinesteraseSerum Serum beta 2 microglobulin beta Serum level Serum A1 - acid acid - glycoprotein A1 Serum Serum immunoreactive trypsin level trypsin immunoreactive Serum Serum A1 - antitrypsin - A1 Serum Serum haptoglobinSerum Serum caeruloplasmin Serum Serum angiotensin converting enzyme level enzyme converting angiotensin Serum Serum transferrinSerum Plasma cholinesterase level cholinesterase Plasma Serum amylase level amylase Serum Squamous cell carcinoma antigen level antigen carcinoma Squamous cell Plasma chromogranin A level chromogranin Plasma CA153 level CA153 level CA199 level CA199 level Carcinoembryonic antigen Carcinoembryonic level Carbohydrate 125antigen level Carbohydrate CMV IgG antibody level antibody CMV IgG CMV IgM antibody level antibody CMV IgM Serum voltage-gated calcium channel antibody level calcium channel voltage-gated Serum Sperm antibody level antibody Sperm

273. 272. 271. 270. 269. 268. 267. 266. 265. 264. 263. 262. 261. 260. 259. 258. 257. 256. 255. 254. 253. 252. 251. 250. 249. 248. 247. 246. 245. 244. 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Urine vanillylmandelic acid/creatinine ratio acid/creatinine vanillylmandelic Urine Urine: Bence Jones' protein Bence Urine: Thiopurine methyltransferase enzyme activity methyltransferase Thiopurine Serum orosomucoid level orosomucoid Serum Faecal trypsin level trypsin Faecal Serum glutamate D.H. glutamate Serum

Intraocular pressure right pressure Intraocular Intraocular pressure left pressure Intraocular Electroencephalography (EEG)Electroencephalography Nerve studies conduction Nerve Electrocardiogram (ECG) Electrocardiogram ECG exercise ECG ambulatory ECG ambulatory Pap smearPap Diabetic retinopathy screening retinopathy Diabetic Colonoscopy Bronchoscopy Spirometry Upper endoscopyUpper Vaginal smear Vaginal

10. 9. 8. 11. 7. 6. 5. 12. 4. 3. 2. 13. 1. 14. 279. 278. 277. 276. 275. 274. Miscellaneous

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Page 38 of 100 the slope between between the slope nnual of (APC) change percentage BMJ

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Confidential: For Review Only scellaneous tests (supplementary file). file). Twenty-five tests (supplementary selected based scellaneous in use 1. Specific onon their were the following tests criteria: guidance Locations of a significant change in temporal slope were identified (aa ”joinpoint‘) in temporal identified the slope were significant and of a change Locations Text S2 Extended Text tests included in age change modelled sex-standardised ratesTemporal and with joinpoint were models consists regression of straight [1].Joinpoint regression joinpoint The significant line. joinpoints slope in the a change trend of connected programme location of the are by which the estimated lines - of hypothesis the the maximum alternative zero of joinpoints number a null hypothesis model of and tests whether from starts joinpoints significant for model has sequentially residual until statistically the squares sum of applied a model a [2,3]. lower specified tests are Permutation test is level at of each overall type the error the significance to control multipleI adjusted performed, are tests [3]. fit is reached Because of best level [2]. (0.05) a joinpoints of observationsspecified number upon the of is maximum number dependent a The in the model, for model our recommended allowed, as [2]. was maximum of 2 joinpoints (QOF), National Outcomes Framework of in is stated following Institute care or more Quality Health the one guidelines/frameworks: of primary Not Do Do Wiselyguidelines. or NICE or onetwo most (NICE), Choosing frequent were of the Excellence laboratory Clinical 2. They and 3. were They directly (OUH)). Hospital Oxford (data attained University from from care tests ordered identified primary Oxfordshire imaging by and public involvement(PPI). group our patient in consultation and of one identified part with GPs tests as as test butcleaning as data 19 tests return ordered typically were A further that are (ALT), Alanine aminotransferase function liver test returns for Aspartarte a results. instance, results Alkaline For (AST), many aminotransferase codes individual others, have Read (GGT) of which transferase all amongst (ALP) recorded and are and Gamma phosphatase glutamyl data Selection before of theseThe analysis. additional tests occurred in Supplementaryspecific full codes listedseparately. are Text above S1. to be ordered GPs. by to exclude we chloride, unlikely tests Uric were tests serum were: acid bloodgoing level, These Originally, data examination, Practitioner bloodfluid ascitic review,anion expert before General gases, test. Upon further bicarbonate, wasgap, Schilling of total or analysis concluded least decided at it tests. Expert tests in was the temporal review GP that itanalysed, these to include is likely 21 joinpoints was determined. Thus, our calculated APC represent the between the APC change joinpoints. annual the of calculated for Calculation Thus, our joinpoints represent determined. percentage years was time intervals. and for between same comparison time the interval of over tests comparison the annual To determine for AAPC allows over study period change the entire post-QOF average percentage period(2000/1 the the (2004/5 calculated over to to 2015/16) and 2015/16) we equal to the APCsweights AAPC within weighted is computedof the average change. a the joinpoint percentage The with model, as the annual interval in trend the changes over were there joinpoint that if the model indicates is [4]. of the thus even valid respective length APC intervals. It selected and 11 imaging tests, we tests (28 laboratory, in utilisation of specific 44 specific change five other, the temporal To examine mi 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only plausible that these tests are ordered by UK General Practitioner and tests would be inappropriate. by and exclusion General these Practitioner ordered of UK was that given stated testsalso are that these plausible It is very tests, inclusion the up by of total of tests in proportion the total test analysis unlikely made above use test to affect these the the tiny results. 22 Page 39 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 40 of 100 s guide s guide ‘ [8,9],

[13]. abnormal test results are recorded accurately in CPRD recorded accurately are results test abnormal all BMJ since the since mid 90‘s to late least utilised tests respectively). It should be noted that the other MRI test in our should other the MRI noted that be It utilised respectively). least tests rd https://mc.manuscriptcentral.com/bmj systematic review reports that review systematic A The CPRD contains primary care data, did not care if requested CPRD primary care (we The to secondary contains linkage with additional For General Practices to be included in the CPRD, they must report ”significant clinical events‘ clinical must included report to be ”significant Practices CPRD, in the they General For

Confidential: For Review Only 4.5.0.1. 5 Jan (accessed 2018). 2015.http://surveillance.cancer.gov/joinpoint/Joinpoint_Help_4.2.0.0.pdf [14]. A separate study [9] reports that from 2000 the proportion of abnormal results, out of the total number of tests ordered, has remained tests ordered, remained has of number total out results, of the of abnormal [9] 2000 the proportion that from [14]. study reports A separate of that the test results 2000-20042005 all These in CPRD results constant coding from from 27.0% suggest onwards). relatively and (28.7% consistent abnormal results) and 2000. been (normal has from References 1 Program. Joinpoint Research Branch, user Surveillance Applications and Cancer. Statistical National Methodology Institute Text S3: Extended Discussion S3: Extended Text measures throughout many to ensure of coding that the taken consistency Wethe study period have the is consistent. manuscript, in the As stated Practices includes General with robust, valid test fromCPRD and of the data up-to-date only [5]. ordering two perspectives: Weconsidered also is often numerical lettercorrespondence test been the result ordered via a or having instance, results). the test of the and of record (for Letter a compliance points into CPRD, 90% also [6,7]. we believe around those with main manuscripts, the following incorporated in the stated Beyond support the validity of coding. further coding. Significant clinical event 23 including test ordering. test ordering. including data contamination. care Secondary but unlikely, the CPRD it is beyond of datait Thus, validation aim data, was secondary as linked attain and quality study). of our given the in trends clinicians. of the temporal by Assessment care secondary we teststwo present ordering ordered reflects test possible, of our that some secondary care MRI access tests provision MRI) is little, suggests (Knee The Brain direct if any, specific and of there in our data. contamination been has access direct [10], inconsistent 2005/6 the UK for GP occurred around MRI around MRIs to increase national effort but substantial in the substantial and reflected are in brain[11,12], changes the same knee MRIs ofMRIs increase these Brain around Knee, rate and time. The are 2005 very our results least,from (the 3 low before and Independent validation of in test Independent codes CPRD. validation analysis (Lumbar spine) has been available direct GPs direct available spine) (Lumbar for has been access analysis 2 4.5.0.1. Version Manual, Joinpoint Help Cancer Institute. National 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

Br J Br J œ 51.

19 :335 Br Genera J œ 3682. 2000; Int J Epidemiol Int J 28 :3670 Stat Med 2009; œ experience one institutionat experience A - ‘ 6 :435 Stat Med 66. doi:10.3399/bjgp13X665224 œ 66. doi:10.3399/bjgp13X665224 63 :256 2005;:331:256. BMJ 2013; BMJ Br J Gen Pract Gen Br J https://mc.manuscriptcentral.com/bmj 90. doi:10.1259/bjr/88267089 œ 90. doi:10.1259/bjr/88267089 14. doi:10.1111/j.1365-2125.2009.03537.x œ 14. doi:10.1111/j.1365-2125.2009.03537.x 69 :4 Data Resource Profile: Clinical Practice Research Datalink Profile: Research Clinical Practice (CPRD). Data Resource Validation and validity of diagnoses in the General Practice Research Database: A Research in the General Practice of diagnoses validity and Validation Temporal growth and geographic variation in the use of laboratory tests by NHS general tests by NHS of use in the general laboratory and growth variation geographic Temporal 82 :687 et al. et 2010; et al. et et al. et Estimating average per analysis. in trend change cent annual average Estimating 2009; Permutation tests for joipoint regression with applications to cancer rates. rates. to cancer with applications joipoint for regression tests Permutation et al. et œ 8. doi:10.1136/bmj.302.6779.766 et al. et 206. doi:10.3399/bjgp10X483562 œ 206. doi:10.3399/bjgp10X483562 Br Radiol J 302 :766 Br J Clin Pharmacol 60 :199 1991; 6.http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med4&NEWS=N&AN=9406494 œ 6.http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med4&NEWS=N&AN=9406494 œ 36. doi:10.1093/ije/dyv098 BMJ Confidential: 2010; For Review Only 47 :575 44 :827 7.https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/136578/dh_4127152.pdf 7.https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/136578/dh_4127152.pdf 1997; systematic review. review. systematic http://www.vision3.homecall.co.uk/general/GPR Data Recording Data Guidelines.pdf http://www.vision3.homecall.co.uk/general/GPR Kingdom. Kingdom. retrospective analysis. retrospective Gen Pract Gen 2015; doi:10.1002/(SICI)1097-0258(20000215)19:33.3.CO;2-Q doi:10.1002/(SICI)1097-0258(20000215)19:33.3.CO;2-Q practices: Using routine data to identify Usingresearch routine to identify priorities. data practices: doi:10.1002/sim.3733 14 Schoonen WM, SL, E, Thomas Herrett 13 practitioners. lumbar for direct of the general imaging access spine: DC. Magnetic resonance R, S, Watura Chawda Lloyd

12 strategy. 2006; health best research health: of health. national for Best a new research Department 3 MP, Feuer EJ, Kim H-J, Fay 24 8 2004. for GPRD vision users. Agency. recording Healthcare Regulatory guidelines and Products Medicines London: 9 Woltersdorf K, J, W, Busby Schroeder 7 practitioner computerised based on information of recorded Jickgeneral in the JickLE. Validation data SS,resource United H, Derby 11 of vows to decrease, times Health. A. Waiting Department scans for Barrett 10 for WM. practitioners: 12 to Open MRI general access years AL, C,Burnett Gedroyc Gough-Palmer 6 A systematic Research within Database: review. Practice the coding of diagnostic NF, General SE,Harrison PW. Rose Khan Validity 4 Hankey Tiwari R, B, L, Clegg 5 K, AM, E, Gallagher Bhaskaran Herrett Page 41 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 4.3% 4.3% 4.2% 5.1%) 5.1%) 5.1%) (3.5% to to (3.5% to (3.2% 2015/16: 2015/16: (95%CI) (95%CI) 2004/5 to to 2004/5 Page 42 of 100 8.3% 8.3% 8.7% 9.1%) 9.1%) 9.7%) 2015/16 2015/16 (7.5% to to (7.5% to (7.7% (95%CI) (95%CI) 2000/1 to to 2000/1 29739.1 29739.1 19527.9 2015/16 2015/16 29096.6 29096.6 19073.7 2014/15 2014/15 29224.1 29224.1 19489.4 2013/14 2013/14 27795.6 27795.6 18601.4 2012/13 2012/13 27304.3 27304.3 18220.8 2011/12 2011/12 26196.4 26196.4 17576.3 2010/11 2010/11 25592.5 25592.5 17209.9 2009/10 2009/10 BMJ 2008/9 2008/9 24688.1 24688.1 16565.2 2007/8 2007/8 23005.9 23005.9 15474.1 https://mc.manuscriptcentral.com/bmj 2006/7 2006/7 22195.4 22195.4 14917.3 2005/6 2005/6 20702.0 20702.0 13891.2 2004/5 2004/5 18455.2 18455.2 12461.6 2003/4 2003/4 15779.6 15779.6 10389.3 Confidential: For Review Only 8315.5 8315.5 2002/3 2002/3 12803.5 12803.5 7095.9 7095.9 2001/2 2001/2 11065.7 11065.7 use of test rates Adjusted Table 10,000 person-years, by stratified and S4 per sex Sex Age 25 9135.6 9135.6 5733.4 2000/1 2000/1

Male Male Female Female 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 2259.1 2259.1 1696.2 44847.0 44847.0 2015/14 2271.4 2271.4 1734.3 43725.2 43725.2 2014/15 2277.5 2277.5 1796.9 44234.9 44234.9 2013/14 2287.4 2287.4 1786.4 41953.7 41953.7 2012/13 2181.8 2181.8 1755.2 41256.9 41256.9 2011/12 2113.3 2113.3 1758.6 39633.6 39633.6 2010/11 2077.2 2077.2 1745.4 38757.5 38757.5 2009/10 1940.2 1940.2 1776.2 37360.2 37360.2 2008/9 1810.0 1810.0 1703.3 34840.1 34840.1 2007/8 BMJ 1762.1 1762.1 1639.2 33609.1 33609.1 2006/7 1648.0 1648.0 1553.7 https://mc.manuscriptcentral.com/bmj 31306.2 31306.2 2005/6 1449.0 1449.0 1501.5 27898.3 27898.3 2004/5 1351.4 1351.4 1222.7 23533.8 23533.8 2003/4 984.1 984.1 1189.5 1189.5 18893.7 18893.7 2002/3 843.5 843.5 1084.3 1084.3 16196.9 16196.9 Confidential:2001/2 For Review Only 716.1 716.1 1035.5 1035.5 13091.2 13091.2 2000/1 Table S5 Age and sex adjusted rates of test use per 10,000, by test type use of 10,000, by test test per rates Table and S5 adjusted sex Age 26 Imaging Imaging Laboratory Laboratory Test Test type Miscellaneous Miscellaneous Page 43 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 44 of 100 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p value -4.8% -4.8% -2.6% -2.0% 0.20% 0.20% 0.63% 0.88% -1.78% -1.78% -1.39% -0.97% -0.32% (95%CI) (-4.7% to -4.9%) to -4.9%) (-4.7% (0.16% to 0.24%) 0.24%) to (0.16% 0.67%) to (0.59% 0.92%) to (0.84% (-2.55% to -2.7%) to -2.7%) (-2.55% to -2.1%) (-1.99% (-0.93% to -1.0%) to -1.0%) (-0.93% (-1.74% to -1.82%) to -1.82%) (-1.74% to -1.43%) (-1.34% to -0.37%) (-0.27% 12.1% (12.0% to 12.2%) to 12.2%) 12.1% (12.0% Absolute percentage change: 2004/5 2015/16to p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p value BMJ -6.2% -6.2% -3.5% -2.3% -0.2% 0.86% 0.86% 1.59% 2.07% 2.18% -16.4% -16.4% -1.35% (0.82% to 0.9%) 0.9%) to (0.82% 2.1%) to (2.03% (-1.3% to -1.4%) to -1.4%) (-1.3% (-6.1% to -6.3%) to -6.3%) (-6.1% to -3.6%) (-3.4% (1.54% to 1.64%) 1.64%) to (1.54% (2.14% to 2.22%) 2.22%) to (2.14% (-2.27% to -2.4%) to -2.4%) (-2.27% to -0.3%) (-0.18% (-16.3% to -16.5%) to -16.5%) (-16.3% 2015/16 (95%CI) change: 2000/1 to 23.2% (23.1% to 23.3%) to 23.3%) 23.2% (23.1% Absolute percentage https://mc.manuscriptcentral.com/bmj 33% 33% 9.0% 9.0% 5.6% 4.7% 4.5% 4.8% 5.1% 5.0% 4.8% 4.3% 19.5% 19.5% 2015/16 21% 21% 7.7% 7.7% 6.4% 5.9% 5.8% 5.4% 4.8% 4.1% 3.5% 24.2% 24.2% 11.6% 2004/5 9.1% 9.1% 7.0% 5.8% 5.0% 4.2% 3.4% 2.7% 2.2% 9.5% 35.8% 35.8% 15.2% 2000/1 1 1 2 3 4 5 6 7 8 9 10 >10 >10 Annual number ofnumber per patient

Confidential:tests received For Review Only Table S6 Multiple testing over the yearsTable testing S6 over Multiple 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 7.8 7.8 9.1 87.9 87.9 98.1 20.1 46.1 91.0 11.8 60.3 2015 2015 339.3 339.3 924.4 140.5 930.6 780.7 166.3 1331.5 1331.5 1676.7 1027.2 4272.1 1887.4 1711.1 2434.2 4002.8 6.4 6.4 8.4 90.3 90.3 19.3 48.8 90.2 11.5 60.3 2014 2014 360.3 360.3 894.7 106.2 140.4 864.1 705.4 133.9 1266.8 1266.8 1649.2 1031.6 4270.1 2068.1 1514.1 2457.0 3940.4 5.3 5.3 8.6 93.8 17.3 48.7 96.2 10.5 60.9 2013 2013 349.9 349.9 848.4 118.0 142.2 792.4 650.7 120.5 1259.1 1259.1 1614.8 1059.6 4304.5 2373.7 1380.0 2706.0 4024.8 4.6 4.6 9.4 7.7 99.1 99.1 17.2 43.8 91.4 57.8 2012 2012 367.6 367.6 788.9 120.7 130.0 698.2 586.8 109.2 1228.8 1228.8 1499.2 1048.1 4119.7 2463.9 1100.3 2574.1 3844.3 3.7 3.7 9.6 7.7 96.4 96.4 17.5 38.8 93.7 99.3 57.5 2011 2011 316.2 316.2 752.1 134.8 135.5 636.7 513.1 955.7 1189.8 1189.8 1419.4 1050.5 4073.9 2562.8 2549.7 3790.1 1.3 1.3 8.3 7.0 93.5 93.5 15.7 38.1 93.0 97.3 57.0 2010 2010 300.2 300.2 691.9 176.1 127.1 565.9 449.5 908.5 1125.2 1125.2 1351.4 1015.2 3897.8 2524.9 2510.8 3650.1 0.5 0.5 7.0 5.9 93.1 93.1 15.5 40.1 95.0 83.6 54.9 2009 2009 290.8 290.8 635.0 191.2 123.7 500.2 381.2 860.3 1123.1 1123.1 1269.3 1016.8 3736.9 2506.5 2545.2 3558.8 0.4 0.4 5.9 4.7 91.0 91.0 14.5 34.7 94.1 76.3 48.1 2008 2008 290.2 290.2 587.7 207.9 991.3 121.8 437.0 322.1 826.9 1104.1 1104.1 1182.6 3632.0 2480.7 2555.3 3495.9 0.4 0.4 4.3 2.9 83.6 83.6 12.6 31.6 88.9 61.7 41.9 2007 2007 278.9 278.9 514.6 216.5 938.4 113.3 362.5 267.9 794.4 1031.8 1031.8 1073.6 3383.3 2325.2 2457.5 3291.5 BMJ 0.3 0.3 1.6 0.1 80.2 80.2 13.3 29.0 86.5 52.8 36.8 2006 2006 990.7 990.7 270.7 979.1 470.6 218.3 916.8 114.6 307.8 235.8 773.7 3249.1 3249.1 2312.0 2519.1 3229.2 0.3 0.3 1.1 0.0 77.2 77.2 14.1 27.2 81.9 45.1 32.5 2005 2005 901.3 901.3 270.1 873.4 421.4 201.3 898.6 112.1 267.3 209.6 760.8 3077.1 3077.1 2234.7 2401.9 2988.9 0.3 0.3 0.3 0.0 68.1 68.1 13.9 27.6 77.2 37.5 24.1 2004 2004 781.6 781.6 246.8 756.5 344.2 163.8 820.4 102.6 215.1 178.6 713.6 https://mc.manuscriptcentral.com/bmj 2775.3 2775.3 2046.9 2233.8 2609.9 9.3 9.3 0.3 0.1 0.0 58.1 58.1 26.3 59.2 95.6 29.1 17.4 2003 2003 615.5 615.5 231.8 663.0 260.7 108.8 752.0 176.8 144.4 620.0 2507.4 2507.4 1838.3 1824.3 2146.6 4.7 4.7 0.1 0.1 0.0 49.9 49.9 70.4 21.7 37.5 83.3 22.6 12.4 2002 2002 436.7 436.7 223.4 571.3 193.5 642.8 126.3 107.7 517.5 2159.7 2159.7 1490.9 1425.4 1651.3 3.3 3.3 0.1 0.1 0.0 9.9 42.3 42.3 50.1 18.7 25.5 77.4 96.3 88.0 20.7 2001 2001 367.6 367.6 217.7 511.4 137.2 591.4 434.8 1920.7 1920.7 1240.1 1174.2 1339.8 2.3 2.3 0.1 0.1 0.0 7.4 33.9 33.9 91.6 31.6 11.4 17.6 68.3 68.6 64.5 16.7 2000 2000 279.1 279.1 196.4 421.9 501.1 961.9 366.8 933.1 977.7 1607.7 1607.7 Confidential: For Review Only Iron Iron Test Test Folate Folate Lipids Lipids DEXA DEXA HbA1c HbA1c Ferritin Ferritin Glucose Glucose CT Brain Brain CT CT Pelvis Pelvis CT MRI Knee Knee MRI MRI Brain MRI Chest x-ray Chest x-ray Erythrocyte Erythrocyte Bone Profile Profile Bone Colonoscopy Colonoscopy Clotting tests tests Clotting Creatine Kinase Kinase Creatine Echocardiogram Echocardiogram Full Blood Count Blood Count Full sedimentation rate rate sedimentation C-Reactive Protein Protein C-Reactive MRI Lumbar Spine Spine Lumbar MRI Liver Function Tests Tests Function Liver Female Sex Hormones Hormones Sex Female use per of 10,000 test specific and rates Table clustered and S7 person-years adjusted sex Age 28 Page 45 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 46 of 100 48.0 48.0 82.6 35.7 72.5 17.1 96.3 12.9 51.0 54.3 326.4 326.4 700.7 564.4 168.4 924.4 119.3 811.7 181.9 103.6 4854.6 4854.6 2424.0 1548.2 49.1 49.1 82.2 35.7 72.3 17.7 91.2 13.5 63.3 53.8 331.5 331.5 740.9 675.1 225.8 964.8 128.5 733.0 204.2 101.1 4758.0 4758.0 2393.1 1690.9 49.0 85.6 35.9 73.3 19.5 91.4 16.4 76.0 56.2 352.6 352.6 781.7 680.2 310.9 962.5 136.9 676.9 191.4 100.0 4799.9 4799.9 2498.3 1855.8 48.7 48.7 75.0 35.3 65.0 19.2 91.1 19.8 79.8 95.4 54.3 321.9 321.9 817.5 558.9 318.8 918.3 134.5 609.8 135.0 4565.6 4565.6 2389.2 1841.8 52.2 52.2 88.6 35.9 63.3 21.1 88.2 18.2 90.5 81.7 96.8 56.0 319.8 319.8 789.2 544.5 337.4 920.8 135.5 534.2 4527.7 4527.7 2372.2 1904.7 50.8 50.8 97.0 32.8 57.9 19.8 88.9 16.9 94.7 52.3 93.9 56.8 316.8 316.8 805.0 497.3 336.2 949.9 124.8 470.1 4366.6 4366.6 2279.7 1888.0 51.0 51.0 30.3 53.1 18.0 84.7 15.9 26.3 90.1 59.5 105.2 105.2 311.5 809.3 481.1 367.6 975.6 115.9 105.9 401.1 4277.1 4277.1 2248.8 1936.4 50.9 50.9 28.9 45.2 18.1 83.1 11.2 98.4 13.8 86.3 62.4 116.0 116.0 296.6 847.8 276.1 282.7 956.5 108.4 343.8 4178.5 4178.5 2187.6 1781.3 9.5 9.5 8.0 47.3 47.3 26.8 38.8 17.8 74.5 91.2 79.7 60.3 123.6 123.6 264.4 832.7 242.5 265.3 899.0 102.2 286.6 3988.6 3988.6 2032.2 1712.1 BMJ 8.8 8.8 5.5 47.6 47.6 26.8 35.8 18.3 72.6 84.3 74.0 60.3 117.9 117.9 248.4 857.1 225.4 253.7 866.6 106.5 252.7 3920.4 3920.4 1995.1 1674.3 8.4 8.4 2.8 46.5 46.5 26.2 34.4 17.2 70.1 83.1 69.1 61.1 107.0 107.0 235.3 848.8 179.7 239.3 783.2 111.4 225.3 3571.2 3571.2 1934.2 1536.5 7.5 7.5 2.1 42.7 42.7 84.1 23.1 30.3 13.6 68.0 75.4 61.1 56.9 213.0 213.0 880.7 143.0 205.5 712.6 109.7 191.6 https://mc.manuscriptcentral.com/bmj 3216.9 3216.9 1755.0 1448.3 9.0 9.0 7.3 1.4 40.2 40.2 92.5 20.1 28.8 66.2 42.1 69.3 56.5 54.0 187.7 187.7 675.6 116.5 682.6 129.2 157.6 2753.8 2753.8 1523.6 1445.8 4.5 4.5 6.0 7.2 0.9 37.8 37.8 96.3 16.9 24.1 61.1 46.8 63.4 50.8 52.7 149.7 149.7 518.3 615.9 150.9 117.4 2188.1 2188.1 1223.2 1293.5 2.5 2.5 7.9 9.5 0.5 35.0 35.0 87.8 15.2 20.5 52.3 23.1 58.9 98.4 49.7 54.0 128.4 128.4 453.6 552.8 148.5 1826.8 1826.8 1068.3 1157.0 1.0 1.0 6.5 9.9 0.3 29.9 29.9 61.1 13.0 15.6 41.1 13.1 51.3 75.4 46.1 56.1 102.6 102.6 418.7 862.0 476.1 133.9 1422.1 1422.1 1023.9 Confidential: For Review Only Troponin Troponin US Pelvis Pelvis US Oestradiol Oestradiol Vitamin D D Vitamin Pap Smear Pap Smear Spirometry Spirometry Urine MCS MCS Urine X-ray Knee X-ray Testosterone Testosterone Vitamin B12 B12 Vitamin Progesterone Progesterone Vaginal Swab Vaginal Swab Urine Dipstick Dipstick Urine Urine Albumin Albumin Urine Albumin Urine Renal Function Function Renal Creatinine ratio ratio Creatinine Upper Endoscopy Endoscopy Upper X-ray Lumber Spine Lumber X-ray Urine non-illicit drugs drugs non-illicit Urine Thyroid Function Tests Tests Function Thyroid Prostate Specific Antigen Antigen Specific Prostate 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 2 2 1 4 5 3 7 8 9 6 40 35 10 26 11 33 13 16 15 12 19 Rank %increase 2004/5 to 2015/16 to 2015/16 2004/5 %increase Rank 1.4% (0.2% to 2.5%) 2.5%) to 1.4% (0.2% 9.8%) to 8.6% (7.3% 5.8%) to 5.4% (4.9% 7.1%) to 6.0% (5.0% 5.0%) to 4.5% (4.1% 0.8% (-0.6% to 2.3%) 2.3%) to 0.8% (-0.6% 7.1%) to 3.3% (-0.3% 9.4% (8.5% to 10.3%) 10.3%) to 9.4% (8.5% 10.1%) to 9.0% (8.0% 10.6%) to 8.9% (7.1% -1.0% (-4.8% to 3.0%) to 3.0%) -1.0% (-4.8% 15.6% (8.8% to 22.8%) 22.8%) to 15.6% (8.8% 46.5% (27.5% to 68.2%) to 68.2%) 46.5% (27.5% to 53.3%) 49.6% (45.9% to 39.2%) 33.8% (28.7% to 54.4%) 37.1% (21.7% to 15.2%) 14.4% (13.6% to 15.2%) 14.4% (13.5% to 14.8%) 14.0% (13.2% to 16.8%) 14.7% (12.7% 2004/5 to 2015/16: Post QOF QOF Post to 2015/16: 2004/5 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 BMJ Rank %increase 2000/1 to 2015/16 to 2015/16 2000/1 %increase Rank https://mc.manuscriptcentral.com/bmj 2000/1 to 2015/16 to 2015/16 2000/1 9.7% (8.2% to 11.2%) 11.2%) to 9.7% (8.2% 10.3%) to 9.5% (8.7% 11.0% (9.5% to 12.4%) 12.4%) to 11.0% (9.5% 14.5%) to 10.0% (5.7% 53.7% (50.2% to 57.3%) to 57.3%) 53.7% (50.2% to 55.5%) 47.3% (39.5% to 74.6%) 44.6% (19.8% to 41.7%) 28.4% (16.4% to 28.7%) 20.3% (12.3% to 20.9%) 19.2% (17.6% to 21.6%) 18.8% (16.1% to 19.0%) 17.7% (16.5% to 18.2%) 17.0% (15.9% to 17.6%) 16.5% (15.4% to 20.3%) 16.3% (12.4% to 18.2%) 16.4% (14.7% to 16.6%) 15.4% (14.3% to 12.8%) 11.4% (10.1% to 11.7%) 10.9% (10.1% 69.0% (38.4% to 106.5%) to 106.5%) 69.0% (38.4%

Confidential: For Review Only

Iron Iron Folate Folate DEXA DEXA HbA1c HbA1c Ferritin Ferritin Troponin Troponin CT Brain Brain CT CT Pelvis Pelvis CT MRI Knee Knee MRI D Vitamin MRI Brain MRI Bone Profile Profile Bone Testosterone Testosterone Vitamin B12 B12 Vitamin Urine Albumin Albumin Urine Echocardiogram Echocardiogram C-Reactive Protein Protein C-Reactive MRI Lumbar Spine Spine Lumbar MRI Liver Function Tests Tests Function Liver Urine Albumin Creatinine ratio Creatinine Albumin Urine Table S8 Average annual percentage increase in increase use specific percentage annual test Table S8 Average 30 Page 47 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 48 of 100 14 22 23 44 24 29 37 21 31 18 20 28 27 32 41 39 30 25 36 34 17 42 38 43 -0.9% (-1.8% to 0%) to 0%) -0.9% (-1.8% 7.6% (6.9% to 8.3%) 8.3%) to 7.6% (6.9% 5.1%) to 4.2% (3.3% 5.8%) to 4.2% (2.6% 5.0%) to 4.0% (3.0% 3.6%) to 2.7% (1.8% 4.9%) to 4.2% (3.4% 3.4%) to 2.3% (1.2% 5.3%) to 4.8% (4.3% 5.8%) to 4.5% (3.3% 3.9%) to 3.1% (2.3% 3.8%) to 3.2% (2.7% 3.0%) to 2.2% (1.4% 3.1%) to 2.5% (1.9% 4.5%) to 3.9% (3.3% 8.9%) to 4.9% (1.0% 0.2% (-0.8% to 1.1%) 1.1%) to 0.2% (-0.8% 1.9%) to 0.8% (-0.2% 2.5%) to 1.0% (-0.4% -0.6% (-1.4% to 0.2%) to 0.2%) -0.6% (-1.4% -5.4% (-8.7% to -2.0%) to -2.0%) -5.4% (-8.7% to -0.6%) -1.3% (-2.0% to -4.1%) -5.2% (-6.3% -2.6% ( -4.9% to -0.2%) to -0.2%) -2.6% -4.9% ( 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 BMJ https://mc.manuscriptcentral.com/bmj 9.3% (8.7% to 9.9% 9.9% to 9.3% (8.7% 8.6% (7.4% to 9.9%) 9.9%) to 8.6% (7.4% 9.9%) to 8.1% (6.3% 8.2%) to 7.1% (6.0% 8.1%) to 7.1% (6.1% 7.6%) to 6.6% (5.7% 7.2%) to 6.5% (5.8% 7.2%) to 6.1% (5.1% 6.3%) to 5.9% (5.4% 6.6%) to 5.6% (4.6% 7.0%) to 5.6% (4.1% 5.8%) to 5.0% (4.2% 5.4%) to 4.7% (3.9% 5.9%) to 4.7% (3.6% 5.5%) to 4.5% (3.5% 5.0%) to 4.3% (3.6% 4.5%) to 3.9% (3.3% 4.4%) to 3.1% (1.8% 4.1%) to 2.9% (1.6% 1.4% (-2.3% to 5.2%) 5.2%) to 1.4% (-2.3% 7.6% (4.1% to 11.3%) 11.3%) to 7.6% (4.1% -0.1% (-2.5% to 2.3%) to 2.3%) -0.1% (-2.5% to 1.1%) -0.3% (-1.7% -5.2% (-6.3% to -4.1%) to -4.1%) -5.2% (-6.3%

Confidential: For Review Only Lipids Lipids Glucose Glucose Oestradiol Oestradiol Pap Smear Pap Smear Spirometry Spirometry Urine MCS MCS Urine Chest x-ray X-ray Knee X-ray Progesterone Progesterone Colonoscopy Colonoscopy Clotting tests tests Clotting Vaginal Swab Swab Vaginal Urine Dipstick Dipstick Urine Renal Function Function Renal Creatine Kinase Kinase Creatine Full Blood Count Blood Count Full Ultrasound Pelvis Pelvis Ultrasound Upper Endoscopy Endoscopy Upper X-ray Lumbar Spine Spine Lumbar X-ray Urine non-illicit drugs drugs non-illicit Urine Female Sex Hormones Hormones Sex Female Thyroid Function Tests Tests Function Thyroid Prostate Specific Antigen Antigen Specific Prostate Erythrocyte sedimentation rate rate sedimentation Erythrocyte 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 32 Page 49 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 50 of 100

2008: 7.2%, 2008-2015:7.2%, 2.7% 2008: œ 2008: 7.3%, 2008: 2.4% 2008-2015:7.3%, œ BMJ 2004: 20.1%, 2004 2004: 20.1%, œ 2004: 22.1%, 200422.1%, 2004: œ https://mc.manuscriptcentral.com/bmj Male: Male: APC: 2000 Female: Female: 2000 APC:

Confidential: For Review Only Figures S9 trends Temporal Figures use in by test stratified Gender 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only Figures S10 trends in use Temporal specificFigures test increase Pattern: linear Consistent, 34 Page 51 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 52 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 36 Page 53 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 54 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 38 Page 55 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 56 of 100

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Confidential: For Review Only 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 40 Page 57 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 58 of 100

BMJ https://mc.manuscriptcentral.com/bmj Pattern: Rapid increase and then increased less quickly Pattern: and Rapid thenincrease increased

Confidential: For Review Only 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 42 Page 59 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 60 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 43 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 44 Page 61 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 62 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 45 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 46 Page 63 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 64 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 47 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 48 Page 65 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 66 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 50 Page 67 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 68 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 52 Page 69 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 70 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 54 Page 71 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 72 of 100

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ Pattern: Plateau https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 56 Page 73 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 74 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 57 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 58 Page 75 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 76 of 100

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Confidential: For Review Only 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 60 Page 77 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 78 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 61 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 62 Page 79 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 80 of 100 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 63 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 64 Page 81 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 82 of 100 BMJ Pattern: Inverted U distribution U Pattern: Inverted https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 66 Page 83 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 84 of 100

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Confidential: For Review Only 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 68 Page 85 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 86 of 100

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Confidential: For Review Only 69 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 70 Page 87 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 88 of 100

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Confidential: For Review Only 71 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 72 Page 89 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 90 of 100

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Confidential: For Review Only 73 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 74 Page 91 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 92 of 100

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 75 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj Pattern: A fall, an increase and then a fall Pattern:A fall, an increase

Confidential: For Review Only 76 Page 93 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 94 of 100

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Confidential: For Review Only 77 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 78 Page 95 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 96 of 100

BMJ Pattern: Exceptions Pattern:Exceptions https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 79 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 BMJ https://mc.manuscriptcentral.com/bmj

Confidential: For Review Only 80 Page 97 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 Page 98 of 100

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Confidential: For Review Only 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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

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Confidential: For Review Only 82 Page 99 of 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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