HEALTH TECHNOLOGY ASSESSMENT

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1 HEALTH TECHNOLOGY ASSESSMENT VOLUME 17 ISSUE 55 NOVEMBER 2013 ISSN Faeca caprotectin testing for differentiating amongst infammatory and non-infammatory bowe diseases: systematic review and economic evauation N Waugh, E Cummins, P Roye, N-B Kandaa, D Shyangdan, R Arasaradnam, C Car and R Johnston DOI /hta17550

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3 Faeca caprotectin testing for differentiating amongst infammatory and non-infammatory bowe diseases: systematic review and economic evauation N Waugh, 1 * E Cummins, 2 P Roye, 1 N-B Kandaa, 1 D Shyangdan, 1 R Arasaradnam, 3 C Car 1 and R Johnston 2 1 Warwick Evidence, Division of Heath Sciences, Warwick Medica Schoo, Coventry, UK 2 McMDC Ltd, Gasgow, UK 3 University Hospita Coventry and Warwickshire, Coventry, UK *Corresponding author Decared competing interests of authors: Ramesh Arasaradnam has received fees for ecturing on the use of caprotectin from Warner Chicott, a pharmaceutica company that is not a manufacturer of caprotectin tests. Pubished November 2013 DOI: /hta17550 This report shoud be referenced as foows: Waugh N, Cummins E, Roye P, Kandaa N-B, Shyangdan D, Arasaradnam R, et a. Faeca caprotectin testing for differentiating amongst infammatory and non-infammatory bowe diseases: systematic review and economic evauation. Heath Techno Assess 2013;17(55). Heath Technoogy Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Cinica Medicine.

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5 Heath Technoogy Assessment NICE TAR and DAR ISSN (Print) ISSN (Onine) Five-year impact factor: Heath Technoogy Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index and is assessed for incusion in the Database of Abstracts of Reviews of Effects. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) ( Editoria contact: nihredit@southampton.ac.uk The fu HTA archive is freey avaiabe to view onine at Print-on-demand copies can be purchased from the report pages of the NIHR Journas Library website: Criteria for incusion in the Heath Technoogy Assessment journa Reports are pubished in Heath Technoogy Assessment (HTA) if (1) they have resuted from work for the HTA programme, and (2) they are of a sufficienty high scientific quaity as assessed by the reviewers and editors. Reviews in Heath Technoogy Assessment are termed systematic when the account of the search appraisa and synthesis methods (to minimise biases and random errors) woud, in theory, permit the repication of the review by others. HTA programme The HTA programme, part of the Nationa Institute for Heath Research (NIHR), was set up in It produces high-quaity research information on the effectiveness, costs and broader impact of heath technoogies for those who use, manage and provide care in the NHS. Heath technoogies are broady defined as a interventions used to promote heath, prevent and treat disease, and improve rehabiitation and ong-term care. The journa is indexed in NHS Evidence via its abstracts incuded in MEDLINE and its Technoogy Assessment Reports inform Nationa Institute for Heath and Care Exceence (NICE) guidance. HTA research is aso an important source of evidence for Nationa Screening Committee (NSC) poicy decisions. For more information about the HTA programme pease visit the website: This report The research reported in this issue of the journa was commissioned and funded by the HTA programme on behaf of NICE as project number 12/48/01. The protoco was agreed in October The assessment report began editoria review in Apri 2013 and was accepted for pubication in August The authors have been whoy responsibe for a data coection, anaysis and interpretation, and for writing up their work. The HTA editors and pubisher have tried to ensure the accuracy of the authors report and woud ike to thank the reviewers for their constructive comments on the draft document. However, they do not accept iabiity for damages or osses arising from materia pubished in this report. This report presents independent research funded by the Nationa Institute for Heath Research (NIHR). The views and opinions expressed by authors in this pubication are those of the authors and do not necessariy refect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. If there are verbatim quotations incuded in this pubication the views and opinions expressed by the interviewees are those of the interviewees and do not necessariy refect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Pubished by the NIHR Journas Library ( produced by Prepress Projects Ltd, Perth, Scotand (

6 Editor-in-Chief of Heath Technoogy Assessment and NIHR Journas Library Professor Tom Waey Director, NIHR Evauation, Trias and Studies and Director of the HTA Programme, UK NIHR Journas Library Editors Professor Ken Stein Chair of HTA Editoria Board and Professor of Pubic Heath, University of Exeter Medica Schoo, UK Professor Andree Le May Chair of NIHR Journas Library Editoria Group (EME, HS&DR, PGfAR, PHR journas) Dr Martin Ashton-Key Consutant in Pubic Heath Medicine/Consutant Advisor, NETSCC, UK Professor Matthias Beck Chair in Pubic Sector Management and Subject Leader (Management Group), Queen s University Management Schoo, Queen s University Befast, UK Professor Aieen Carke Professor of Heath Sciences, Warwick Medica Schoo, University of Warwick, UK Dr Tessa Criy Director, Crysta Bue Consuting Ltd, UK Dr Peter Davidson Director of NETSCC, HTA, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Professor Eaine McCo Director, Newcaste Cinica Trias Unit, Institute of Heath and Society, Newcaste University, UK Professor Wiiam McGuire Professor of Chid Heath, Hu York Medica Schoo, University of York, UK Professor Geoffrey Meads Honorary Professor, Business Schoo, Winchester University and Medica Schoo, University of Warwick, UK Professor Jane Norman Professor of Materna and Feta Heath, University of Edinburgh, UK Professor John Powe Consutant Cinica Adviser, Nationa Institute for Heath and Care Exceence (NICE), UK Professor James Raftery Professor of Heath Technoogy Assessment, Wessex Institute, Facuty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Keijnen Systematic Reviews Ltd, UK Professor Heen Roberts Professoria Research Associate, University Coege London, UK Professor Heen Snooks Professor of Heath Services Research, Institute of Life Science, Coege of Medicine, Swansea University, UK Pease visit the website for a ist of members of the NIHR Journas Library Board: Editoria contact: nihredit@southampton.ac.uk NIHR Journas Library

7 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 Abstract Faeca caprotectin testing for differentiating amongst infammatory and non-infammatory bowe diseases: systematic review and economic evauation N Waugh, 1 * E Cummins, 2 P Roye, 1 N-B Kandaa, 1 D Shyangdan, 1 R Arasaradnam, 3 C Car 1 and R Johnston 2 1 Warwick Evidence, Division of Heath Sciences, Warwick Medica Schoo, Coventry, UK 2 McMDC Ltd, Gasgow, UK 3 University Hospita Coventry and Warwickshire, Coventry, UK *Corresponding author Background: Irritabe bowe syndrome (IBS) is common, and causes pain, boating and diarrhoea and/or constipation. It is a troubesome condition that reduces the quaity of ife but causes no permanent damage. Infammatory bowe disease (IBD) comprises mainy ucerative coitis (UC) and Crohn s disease (CD). Both cause serious compications and may ead to sections of the bowe having to be removed, athough this is more common with CD. The presenting symptoms of IBS and IBD can be simiar. Distinguishing them on cinica signs and symptoms can be difficut. Unti recenty, coonoscopy was often required to rue out IBD. In younger peope, > 60% of coonoscopies showed no abnormaity. Faeca caprotectin (FC) is a protein reeased by the white bood ces, neutrophis, found in infamed areas of the bowe in IBD. Determining the eve of FC in stoo sampes may hep distinguish IBS from IBD. Objective: To review the vaue of FC for distinguishing between IBD and non-ibd. Data sources: Sources incuded MEDLINE, EMBASE, The Cochrane Library, Web of Science, websites of journas and the European Crohn s and Coitis Organisation (conference abstracts 2012 and 2013), and contact with experts. Review methods: Systematic review and economic modeing. Review Manager (RevMan) version 5.2 (The Cochrane Coaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) was used for most anaysis, with statistica anayses done in Stata version 12 (StataCorp LP, Coege Station, TX, USA). Forest pots and receiver operating characteristic curves were produced. Quaity Assessment of Diagnostic Accuracy Studies was used for quaity assessment. Economic modeing was done in Microsoft Exce 2010 (Microsoft Corporation, Redmond, WA, USA). Limitations: Studies were often sma, most used ony one caprotectin cut-off eve, and neary a came from secondary care popuations. Resuts: Twenty-eight studies provided data for 2 2 tabes and were incuded in meta-anayses, with seven in the most important comparison in aduts (IBS vs. IBD) and eight in the key comparison in paediatrics (IBD vs. non-ibd). Most studies used aboratory enzyme-inked immunosorbent assay (ELISA) tests. For distinguishing between IBD and IBS in aduts, these gave pooed sensitivity of 93% and specificity of 94% at FC cut-off eve of 50 µg/g. Sensitivities at that cut-off ranged from 83% to 100%, and specificities from 60% to 100%. For distinguishing between IBD and non-ibd in paediatric popuations with ELISA tests, sensitivities ranged from 95% to 100% at cut-off of 50 µg/g and specificities of 44 93%. Few studies used point-of-care testing but that seemed as reiabe as ELISA, though perhaps ess specific. Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. v

8 ABSTRACT The evidence did not provide any grounds for preferring one test over others on cinica effectiveness grounds. FC testing in primary care coud reduce the need for referra and coonoscopies. Any quaity-adjusted ife-year gains are ikey to be sma because of the ow prevaence of IBD and the high sensitivities of a of the tests, resuting in few fase negatives with IBD. However, considerabe savings coud accrue. Areas of uncertainty incude the optimum management of peope with borderine resuts ( µg/g), most of whom do not have IBD. Repeat testing may be appropriate before referra. Concusions: Faeca caprotectin can be a highy sensitive way of detecting IBD, athough there are inevitaby trade-offs between sensitivity and specificity, with some fase positives (IBS with positive caprotectin) if a ow caprotectin cut-off is used. In most cases, a negative caprotectin rues out IBD, thereby sparing most peope with IBS from having to have invasive investigations, such as coonoscopy. Study registration: PROSPERO CRD Funding: The Nationa Institute for Heath Research Heath Technoogy Assessment programme. vi NIHR Journas Library

9 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 Contents Gossary...ix List of abbreviations....xiii Scientific summary...xv Chapter 1 Introduction 1 The conditions 1 Nationa Institute for Heath and Care Exceence cinica guideine 61 (irritabe bowe syndrome in aduts) 6 Caprotectin 7 Decision probem 10 Methods 14 The NHS Technoogy Adoption Centre piot studies 16 Chapter 2 Resuts of cinica effectiveness review 17 Some issues 17 Previous reviews 19 The tests 30 The comparisons 30 Studies of caprotectin in the differentiation of infammatory bowe disease and irritabe bowe syndrome 32 Studies of caprotectin: organic versus irritabe bowe syndrome 39 Studies of caprotectin: infammatory bowe disease versus non-infammatory bowe disease 42 Studies of caprotectin: organic versus non-organic bowe disease 51 Ranges 51 Choice of test 55 Genera practitioner assessment and referra: impications for modeing 70 Chapter 3 Economics 75 Faeca caprotectin tests economic iterature 75 Quaity of ife 78 Cost utiity modeing 87 Heath-reated quaity of ife 94 Chapter 4 Discussion 123 Principa findings 123 Uncertainties 123 Ongoing research and research needs 130 Concusions 131 Acknowedgements 133 References 135 Appendix 1 Comparison of ucerative coitis, Crohn s disease, irritabe bowe syndrome and coeiac disease Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii

10 CONTENTS Appendix 2 Search strategy 155 Appendix 3 Description of different tests 161 Appendix 4 Quaity assessment tabes 165 Appendix 5 Protoco 171 Appendix 6 Baseine characteristics of a the incuded studies 183 Appendix 7 Cost-effectiveness mode inputs 203 viii NIHR Journas Library

11 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 Gossary Accuracy Accuracy is the probabiity that the test yieds a correct resut: (true positive+true negative)/ (positive+negative). Boating Funess or sweing in the abdomen that often occurs after meas. Constipation A condition in which bowe movements are infrequent, hard and dry, and eimination of faeces is difficut and infrequent. Cost impact The tota cost to the person, the Nationa Heath Service or to society. Cost minimisation anaysis A type of economic evauation used to compare the difference in costs between programmes that have the same heath outcome. Cost-effectiveness anaysis An economic study design in which aternative interventions are compared in terms of cost per unit of effectiveness. Cost-effectiveness mode An expicit mathematica framework which is used to represent cinica decision probems and incorporate evidence from a variety of sources in order to estimate the costs and heath outcomes. Cost-effectiveness The cost per unit of benefit of an intervention. Benefits of different interventions are measured using a singe outcome (e.g. ife-years gained, quaity-adjusted ife-years gained, deaths avoided, heart attacks avoided, cases detected). Cost-of-iness/economic burden studies An anaysis of the tota costs incurred by a society due to a specific disease. Cost consequences anaysis A type of economic evauation, whereby both outcomes and costs of aternative interventions are described, without any attempt to combine the resuts. Cost utiity anaysis A form of cost-effectiveness anaysis in which the units of effectiveness are quaity-adjusted ife-years. Crohn s disease A chronic infammatory disease of the digestive tract that can invove any part of it from the mouth to the anus. It typicay affects the termina ieum as we as demarcated areas of arge bowe, with other areas of the bowe being reativey unaffected. It is often associated with autoimmune disorders outside the bowe, such as rheumatoid arthritis. Diagnostic odds ratio It is defined as the ratio of the odds of the test being positive if the subject has a disease reative to the odds of the test being positive if the subject does not have the disease. Discounting Discounting is a method for adjusting the vaue of costs and outcomes that occur in different time periods into a common time period, usuay the present. Dominance An intervention is said to be dominated if there is an aternative intervention that is both ess costy and more effective. Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ix

12 GLOSSARY Fagan s nomogram A graph that uses pre-test probabiity of infammatory bowe disease and ikeihood ratios to estimate the probabiity of a patient with a positive test having the condition. Exampes are shown on pages Fase negative Incorrect negative test resut number of diseased persons with a negative test resut. Fase positive Incorrect positive test resut number of non-diseased persons with a positive test resut. Functiona bowe disorder In medicine, the term functiona bowe disorder refers to a group of disorders that are characterised by chronic abdomina compaints without a structura or biochemica cause that coud expain symptoms. Incrementa cost-effectiveness ratio The difference in the mean costs of two interventions in the popuation of interest divided by the difference in the mean outcomes in the popuation of interest. Index test The test of which performance is being evauated. Infammatory bowe disease Genera term for any disease characterised by infammation of the bowe. Two of the most common infammatory bowe diseases are ucerative coitis and Crohn s disease. Likeihood ratios Likeihood ratios combine the information from sensitivity and specificity. The ikeihood ratio for a positive test is the probabiity of an individua with infammatory bowe disease having a positive test (sensitivity) divided by the probabiity of an individua without infammatory bowe disease having a positive test (1 minus specificity). The ikeihood ratio for a negative test is the probabiity of an individua with infammatory bowe disease having a negative test divided by the probabiity of an individua without infammatory bowe disease having a negative test. So, the ikeihood ratio for a negative test=1 sensitivity/ specificity. In those with a positive test, ikeihood ratio positive vaues of 10 are usuay regarded as strong evidence of a disease being present. Meta-anaysis Statistica techniques used to combine the resuts of two or more studies and obtain a combined estimate of effect. Negative predictive vaue The negative predictive vaue of a caprotectin test is the probabiity that a patient with a negative caprotectin test does not have infammatory bowe disease. Positive predictive vaue The positive predictive vaue is defined as the probabiity that a patient with a positive caprotectin test has infammatory bowe disease. Probabiistic sensitivity anaysis Probabiity distributions are assigned to the uncertain parameters and are incorporated into evauation modes based on decision anaytica techniques (e.g. Monte Caro simuation). Quaity of ife An individua s emotiona, socia and physica we-being, and his or her abiity to perform the ordinary tasks of iving. Quaity-adjusted ife-years An index of surviva that is adjusted to account for the patient s quaity of ife during this time. Quaity-adjusted ife-years have the advantage of incorporating changes in both quantity (ongevity/mortaity) and quaity (morbidity, psychoogica, functiona, socia and other factors) of ife. Used to measure benefits in cost utiity anaysis. The quaity-adjusted ife-years gained are the mean quaity-adjusted ife-years associated with one treatment minus the mean quaity-adjusted ife-years associated with an aternative treatment. Receiver operating characteristic curve A graph that iustrates the trade-offs between sensitivity and specificity, which resut from varying the diagnostic threshod. x NIHR Journas Library

13 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 Reference standard The best currenty avaiabe diagnostic test(s), against which the index test is compared. Sensitivity (of a test) The proportion of individuas cassified as positive by the god (or reference) standard, who are correcty identified by the study test. Sensitivity anaysis A means of representing uncertainty in the resuts of economic evauations. Uncertainty may arise from missing data, imprecise estimates or methodoogica controversy. Sensitivity anaysis aso aows for exporing the generaisabiity of resuts to other settings. The anaysis is repeated using different assumptions to examine the effect on the resuts. One-way simpe sensitivity anaysis (univariate anaysis): each parameter is varied individuay in order to isoate the consequences of each parameter on the resuts of the study. Mutiway simpe sensitivity anaysis (scenario anaysis): two or more parameters are varied at the same time, and the overa effect on the resuts is evauated. Specificity (of a test) The proportion of individuas cassified as negative by the god (or reference) standard, who are correcty identified by the study test. Threshod sensitivity anaysis The critica vaue of parameters above or beow which the concusions of the study wi change are identified. True negative Correct negative test resut number of non-diseased persons with a negative test resut. True positive Correct positive test resut number of diseased persons with a positive test resut. Utiity A measure of the strength of an individua s preference for a specific heath state in reation to aternative heath states. The utiity scae assigns numerica vaues on a scae from 0 (death) to 1 (optima or perfect heath). Heath states can be considered worse than death and thus have a negative vaue. Viscera hypersensitivity Enhanced perception or enhanced responsiveness within the gut. Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xi

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15 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 List of abbreviations 6-MP 6-mercaptopurine FOBT faeca occut bood testing AQoL Assessment of Quaity of Life GI gastrointestina ASA aminosaicyic acid GP genera practitioner ASCA AUC anti-saccharomyces cerevisiae antibodies area under the curve HASA HASB high-dose aminosaicyic acid high-dose aminosaicyic acid with becometasone BaFT BSG BWUS CBT CD CDAI CE barium foow-through British Society of Gastroenteroogy bowe wa utrasonography measurement cognitive behavioura therapy Crohn s disease Crohn s Disease Activity Index conformité Européenne (European Conformity) HAST Hb HCSC HLA HODaR HRQoL HUI high-dose aminosaicyic acid with a topica aminosaicyic acid haemogobin Hospita and Community Services Costs human eucocyte antigen Heath Outcomes Data Repository heath-reated quaity of ife heath utiity index CEAF CEP CI CRC cost-effectiveness acceptabiity frontier Centre for Evidence-based Purchasing confidence interva coorecta cancer IBD IBDQ IBS IBS-A infammatory bowe disease Infammatory Bowe Disease Questionnaire irritabe bowe syndrome irritabe bowe syndromeaternating type CRP C-reactive protein IBS-C irritabe bowe syndrome-constipation CT computed tomography IBS-D irritabe bowe syndrome-diarrhoea DOR diagnostic odds ratio IBS-M irritabe bowe syndrome-mixed ELISA EQ-5D ERG ESR FBC FC FDA FL enzyme-inked immunosorbent assay European Quaity of Life-5 Dimensions Evidence Review Group erythrocyte sedimentation rate fu bood count faeca caprotectin Food and Drug Administration faeca actoferrin ICC ICER IDDM IP IQR LASA LR MRI NA intracass correation coefficient incrementa cost-effectiveness ratio insuin-dependent diabetes meitus intestina permeabiity interquartie range ow-dose aminosaicyic acid ikeihood ratio magnetic resonance imaging not avaiabe Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xiii

16 LIST OF ABBREVIATIONS NICE NLR NPV NSAID NTAC OBD OR Nationa Institute for Heath and Care Exceence negative ikeihood ratio negative predictive vaue non-steroida anti-infammatory drug NHS Technoogy Adoption Centre organic bowe disease odds ratio SBFT SD SE SF-36 SF-6D SG SROC sma bowe foow-through standard deviation standard error Short Form questionnaire-36 items Short Form questionnaire-6 Dimensions standard gambe summary receiver operating characteristic panca perinucear anti-neutrophi cytopasmic antibodies SSRI seective serotonin reuptake inhibitor PCDAI PIBD PLR POCT PPI PPV Paediatric Crohn s Disease Activity Index paediatric infammatory bowe disease positive ikeihood ratio point-of-care testing proton pump inhibitor positive predictive vaue TA TCA TNF TRFIA TSH TTG technoogy appraisa tricycic antidepressant tumour necrosis factor time-resoved fuorimetric immunoassay thyroid-stimuating hormone tissue transgutaminase (a test for coeiac disease) PSA probabiistic sensitivity anaysis TTO time trade-off QALY quaity-adjusted ife-year UC ucerative coitis QoL quaity of ife UCAI Ucerative Coitis Activity Index QUADAS Quaity Assessment of Diagnostic Accuracy Studies UCDAI Ucerative Coitis Disease Activity Index RCT randomised controed tria VAS visua anaogue scae ROC receiver operating characteristic YHEC York Heath Economics Consortium RR reative risk xiv NIHR Journas Library

17 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 Scientific summary Background Lower abdomina symptoms such as pain, diarrhoea and boating are common and are usuay due to irritabe bowe syndrome (IBS), a troubesome condition that interferes with activities of daiy ife but which does not have serious consequences. Around 10% of the popuation have symptoms suggestive of IBS, athough ony about haf consut their genera practitioners (GPs). The symptoms of IBS can resembe those of infammatory bowe disease (IBD), mainy Crohn s disease (CD) and ucerative coitis (UC). These diseases have serious compications, incuding a high risk of compications requiring surgery and an increased risk of coorecta cancer. However, the symptoms of IBD can be different in chidren, many of whom present with non-specific symptoms, such as mid abdomina discomfort, ethargy, weight oss or growth impairment. In a arge UK and Ireand study, ony 25% of chidren with CD presented with the usua triad of diarrhoea, abdomina pain and weight oss. Deays in diagnosis were common, with over one-quarter of patients with CD taking over 1 year to be diagnosed. About 25% of peope with IBD deveop it under the age of 17 years. Irritabe bowe syndrome is often diagnosed on the basis of signs and symptoms, without a need for further investigations, but distinction from IBD on cinica grounds is often not possibe. Distinguishing between IBD and IBS has often required referra to speciaist care for coonoscopy, an invasive and unpeasant investigation requiring sedation, usuay carried out on a day case basis, at a cost of around 650 (incuding speciaist referra and day case endoscopy). Some centres have reported that > 60% of coonoscopies in younger patients have been norma, and in retrospect, not necessary. Caprotectin is a protein reeased by the white bood ces invoved in infammation of the bowe. It is stabe in faeces and can be measured by aboratory tests, and more recenty by point-of-care testing (POCT). It indicates infammation in the bowe. This review examines the cinica effectiveness and cost-effectiveness of FC testing in heping to distinguish between functiona disorders, such as IBS and organic disorders, such as IBD. In aduts, the differentiation is most often between IBS and IBD. In chidren, there is a different range of conditions. Perspectives on the use of caprotectin testing wi vary with setting. GPs wi see far more cases of IBS than IBD, and for them caprotectin testing offers evidence to rue out IBD. A negative caprotectin wi impy IBS. So GPs wi be ooking for parameters such as sensitivity (for IBD) and negative predictive vaue (NPV), to provide a basis for a decision not to refer. Gastroenteroogists in adut cinics wi be seeing a seected group of patients, referred by GPs, with a suspicion of IBD. Gastroenteroogists wi be ooking for positive evidence of IBD in order to decide whether to proceed to further investigations, incuding coonoscopy and biopsy, and possiby aso gastroscopy and other tests. They may find a positive predictive vaue or a positive diagnostic odds ratio more usefu. It shoud be noted that diagnosis wi be made on the whoe cinica picture, not on the basis of caprotectin resuts aone. The same genera principes wi appy to the different case mix seen in paediatric gastroenteroogy. The proportion with IBD is higher, but a norma or near-norma caprotectin eve may contribute to a decision not to proceed to invasive procedures such as endoscopy. Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xv

18 SCIENTIFIC SUMMARY Methods Systematic review and economic modeing. A broad search strategy was run in severa databases. Studies that provided sufficient data for cacuation of sensitivity, specificity and other diagnostic outcomes were identified. Review Manager (RevMan) version 5.2 (The Cochrane Coaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) was used to generate paired forest pots and receiver operating characteristic (ROC) curves. Stata 12 (StataCorp LP, Coege Station, TX, USA) was used to produce ikeihood ratios, areas under the curve (AUC) and nomograms. The quaity of studies was assessed using Quaity Assessment of Diagnostic Accuracy Studies. We sought studies in which the reference test was endoscopy with histoogy. Resuts Cinica effectiveness of caprotectin testing The primary studies presented data for different groups of conditions, some providing a direct comparison of IBS and IBD, but others comparing a wider range of organic conditions. Neary a of the evidence comes from studies in speciaist care. Seven studies gave resuts that compared IBS and IBD, at eight cut-off eves, ranging from 8 to 150 µg/g, a in aduts. Sensitivity was consistenty high (usuay 100% at eves of < 50 µg/g, ranging from 83% to 100% at a cut-off of 50 µg/g) but specificity was more varied (51% to 100%), especiay at ower eves of FC. Eeven studies, mosty from paediatrics, reported IBD versus non-ibd, with eight cut-off eves. They showed consistenty high sensitivity at ower cut-offs: neary a over 90%, with most at the 50 µg/g cut-off having sensitivities of 100%. Specificity was much more varied, ranging from 44% to 93% at a 50 µg/g cut-off. Two reports by the York Heath Economics Consortium (YHEC) were very usefu. The first, from 2010, concuded that FC was a reiabe marker of infammation of the bowe, that high sensitivity was very important and that fase positives were preferabe to fase negatives, that the cut-off shoud be 50 µg/g, and, in economic terms, that caprotectin dominated (more correct diagnoses at ess cost) bood tests such as erythrocyte sedimentation rate and C-reactive protein. The second YHEC report provided data on the use of caprotectin testing in routine care and on how it contributed to fina diagnosis. One finding was that when GPs were sure a patient had IBS, they were usuay right 95% of such patients had norma caprotectin eves. Choice of cut-off eves The commonest eve for defining normaity was 50 µg/g. If sensitivity was deemed of paramount importance (in order not to miss any cases of IBD), that eve coud be used. Some aduts with IBS have raised caprotectin eves and woud be fase positives, who might be referred for endoscopy as?ibd. However, there is some evidence that organic pathoogy is rare with eves of < 150 µg/g, and cinica consensus is that if there are aduts with IBD but caprotectin eves of < 150 µg/g, they are ikey to have ow-grade IBD and woud come to no harm if simpy monitored by repeated caprotectins, with referra if the eve rose. In theory, a very sensitive approach might ead to peope with IBS being fase positives and undergoing endoscopy, and a ess sensitive approach might mean missing a few peope with IBD, with more serious consequences. In practice, cinicians wi appy cinica nous and observation, and that wi reduce coonoscopies in fase positives. Decisions wi not be made purey on FC resuts. xvi NIHR Journas Library

19 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 In paediatric age groups, with a different spectrum of conditions, a cut-off eve of 50 µg/g gives amost 100% sensitivity but specificity varying from 44% to 94%. One study reported that a cut-off eve of 100 µg/g gave sensitivity of ony 86%, specificity 91%. Another study recommended a cut-off eve of 200 µg/g as being most usefu in routine practice. Cost-effectiveness NHS Technoogy Adoption Centre piot study Resuts from the piot project show that caprotectin testing coud reduce costs of referra and investigation of patients under 60 years with chronic diarrhoea by over 60%, if a patients with negative tests are managed in primary care as IBS, with those with borderine and positive tests being referred to gastroenteroogy. This reduction is simiar to the proportions of coonoscopies reported as norma from some other UK centres. Review of previous studies Previous economic anayses have typicay concuded that caprotectin testing is cost saving compared with the situation without it. Given test specificities and the assumed prevaences of IBD in the presenting popuation, the additiona cost of the caprotectin testing is more than offset by the reduction in the cost of unnecessary coonoscopies. Externa Assessment Group: primary care The Externa Assessment Group (EAG) deveoped a de novo cost-effectiveness mode for the use of caprotectin testing for distinguishing between IBS and IBD in the primary care setting. This had an initia sequence of tests, with associated sensitivities and specificities, with positive resuts being referred to outpatient assessment and coonoscopy. Those testing positive were assumed to go on to an outpatient appointment and coonoscopy. Coonoscopy was associated with a sight risk of beeds and perforation, with the atter having a very sma mortaity risk. Subsequent to testing, patients coud receive induction and maintenance treatment for IBS, CD and UC. Fase negatives coud spend a period of time being unsuccessfuy treated for IBS before re-presenting for testing. A key uncertainty in the modeing was whether caprotectin testing woud resut in a wider group of patients being considered for testing than in the absence of caprotectin testing. This was expored through an aternative presenting popuation scenario anaysis that doubed the number who woud be tested compared with the number who woud have been previousy considered for referra in the absence of caprotectin testing. The base case of the modeing assumed that without caprotectin testing a of those referred from primary care woud go through an outpatient assessment and on to receive a coonoscopy. Without caprotectin testing, GP cinica assessment can be highy sensitive in referring IBD. However, this may be at the cost of ow specificity, with many fase positives (peope with IBS) referred to gastroenteroogy. GPs without caprotectin testing might refer about 20%, most without IBD. The rates of fase positives referred after caprotectin testing woud be much ower: 5.1% and 5.6%, respectivey. Faeca caprotectin testing is estimated to resut in cost savings. In theory, sma quaity-adjusted ife-year (QALY) gains coud accrue but these are too sma to be significant, because of the ow prevaence of IBD and the high sensitivities of a the tests, resuting in few fase negatives with IBD. Sensitivity anayses suggest that caprotectin testing resuts in patient gains and remains cost saving compared with GP assessment without caprotectin testing, up to an IBD prevaence of 25%. At this point, Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xvii

20 SCIENTIFIC SUMMARY the ess-than-perfect sensitivity ELISA testing resuts in very sight QALY osses compared with GP assessment without caprotectin testing, athough cost savings of around 63 per patient on average remain. The cost savings from caprotectin testing woud be much reduced if the numbers tested were doube those referred in the absence of caprotectin testing, resuting in sight cost savings or broad cost neutraity. Increases beyond a doubing woud be ikey to resut in additiona costs from caprotectin testing. The savings from increased specificity of GP referra when given access to caprotectin testing depend argey on reduced coonoscopies. Scenario anaysis shows that increasing the specificity of speciaist assessment reduces the number of coonoscopies, with the cost savings from caprotectin testing faing. With a 95% specificity for outpatient assessment, the cost savings fe to around 10. Given ack of data, no modeing of repeat testing after indeterminate resuts was done. The impact of this on costs woud mainy be determined by the caprotectin eves among patients with IBS who had an indeterminate resut from their first test. If eves fe, the second test woud resut in fewer referras and so coud resut in cost savings. Secondary care The mode deveoped was aso appied to differentiating IBD from non-ibd in the mainy paediatric secondary care setting. Despite the higher IBD prevaence in the paediatric popuation, the main test differences sti ie in the number of coonoscopies. Without caprotectin testing, a 52.1% of non-ibd patients receive a coonoscopy compared with 13.5% for the ELISA with the 50 µg/g cut-off, and ony 9.4% for ELISA with the 100 µg/g cut-off. The additiona ELISA test costs are more than offset by the savings from reduced coonoscopies. Compared with a having a coonoscopy, ELISA with the 50 µg/g cut-off is estimated to save 205 on average, whereas ELISA with the 100 µg/g cut-off is estimated to save 240. Trivia QALY gains of around QALYs may occur with ELISA compared with universa coonoscopy, these being sighty arger the 50 µg/g cut-off owing to its better sensitivity. But given the additiona average 35 cost, the cost-effectiveness estimate using the 50 µg/g cut-off compared with the 100 µg/g cut-off is 35,000 per QALY. It shoud be stressed that the QALY differences between the strategies are very sma and they may be better considered as equivaent. Research needs There is a ack of studies in primary care popuations, and on the proportion of patients with ower bowe symptoms that woud be tested if FC testing was avaiabe to GPs. Many peope have intermediate caprotectin eves ( µg/g) and foow-up studies are required to determine the most usefu cut-off eve. Some peope with IBS have raised caprotectin eves. The reasons for that are not cear. Concusions The Nationa Institute for Heath and Care Exceence (NICE) scope raised questions, abbreviated in itaic text beow: Is caprotectin testing a reiabe way of differentiating infammatory diseases of the bowe from non-infammatory ones? xviii NIHR Journas Library

21 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 Yes. The majority of younger adut patients seen with ower abdomina symptoms in genera practice have IBS, and the absence of infammation as indicated by a negative caprotectin test means that IBD is very unikey. They coud be managed in primary care and spared further investigations. What are the optima cut-offs for use in primary and secondary care? The same cut-off shoud be used in primary and secondary care currenty 50 µg/g for ELISA tests but needing to be reviewed as evidence accumuates. This is based on ensuring high sensitivity, and not missing peope with IBD. Peope with borderine eves of µg/g coud be monitored initiay, with repeat caprotectin testing but some of this group wi progress to definite IBD. How do the rapid point-of-care tests compare with the aboratory tests? There is currenty insufficient evidence on either diagnostic reiabiity or cost-effectiveness considerations for preferring one test over another. How wi caprotectin testing perform in primary care? Sensitivity and specificity wi be as good in primary care but the ower prevaence wi increase the NPV. The main benefit woud be to confirm the cinica diagnosis of IBS by GPs. Making caprotectin testing avaiabe to GPs coud reduce the number of younger aduts referred to speciaist care, and the need for unpeasant invasive investigations, such as coonoscopy. Impact in secondary care? In secondary care, caprotectin testing coud consideraby reduce the number of coonoscopies required. In various studies, over 60% of coonoscopies in this group of adut patients have been norma. Caprotectin testing can aso reduce the need for coonoscopy in chidren who do not have IBD, and coud reduce diagnostic deays in those who do. It coud aso reduce oss of work time for parents and oss of schoo time for chidren. Study registration This study is registered as PROSPERO CRD Funding Funding for this study was provided by the Heath Technoogy Assessment programme of the Nationa Institute for Heath Research. Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xix

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23 DOI: /hta17550 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 55 Chapter 1 Introduction The conditions Chronic abdomina pain or discomfort, accompanied by diarrhoea or constipation, is common. The symptoms can be due to a number of different conditions, some more serious than others. The conditions incude irritabe bowe syndrome (IBS) and infammatory bowe disease (IBD). The commonest forms of the atter are ucerative coitis (UC) and Crohn s disease (CD, sometimes caed regiona ieitis, but that term is miseading because CD can have a much wider distribution). Lower bowe symptoms are very common in genera practice. Most patients have IBS, a troubesome and painfu condition that reduces the quaity of ife (QoL) but which does not have serious effects in terms of structura damage to the bowe. However, some patients have IBD, which can ead to serious compications. Most patients with CD wi require surgery within 5 years. It is important to distinguish IBD from IBS so that patients with the former can be appropriatey managed and monitored. IBD is characterised by infammation of the bowe, which is not seen in most patients with IBS. Unfortunatey, the symptoms of IBD and IBS are often simiar, and, unti recenty, definitive diagnosis was often made ony after invasive coonoscopy and perhaps other investigations. Faeca caprotectin (FC) testing identifies patients with infammation of the bowe, who need referra to speciaist care. The majority of younger patients with ower gastrointestina (GI) symptoms have IBS, and if the absence of infammation can be rued out by a negative caprotectin test, they can then be managed in primary care and spared further investigations. The most common symptoms of IBS incude recurrent coicky abdomina pain or cramping fet in the ower abdomen and reieved by defecation. There may be abdomina distension (boating) and atered bowe habit episodes of diarrhoea and constipation. Features supporting a diagnosis of IBS incude: symptoms > 6 months boating associated with other, non-gi probems symptoms worsened by stress no weight oss. The Rome criteria (Rome II, 1 Rome III 2 ) subdivide IBS into diarrhoea predominant (IBS-D), constipation predominant (IBS-C) or mixed (IBS-M), with roughy one-third of patients in each group. Irritabe bowe syndrome is very common affecting perhaps 15% of the UK popuation athough many peope who have it never consut their genera practitioners (GPs) about it. IBS-D is the commonest form. It is commonest in young women, with an odds ratio (OR) in women to men of The IBS-C form is commoner in women than in men. The underying mechanism is not known. Peope who have it are constitutionay we and do not ose weight. It is a troubesome but not a serious condition, in the sense that it does not ead to serious adverse events. But it can be painfu and disruptive of norma activities, and peope with IBS have a reduced QoL, reported to be reduced by 26%, 4 and 30% if severe. 5 QoL is reduced because of symptoms that disturb work and seep, and anxiety. It eads to 9 22 ost days of work per year. 6 Akehurst et a. 7 report that in the Trent Region, peope with IBS had reduced QoL compared with age-matched, sex-matched and sociay matched contros, refected in every dimension of both Short form-36 (SF-36) and European Quaity of Life-5 Dimensions (EQ-5D). They had more time off work than peope without IBS, and imposed 123 more costs per year on the NHS. 7 The effect on QoL depends on Queen s Printer and Controer of HMSO This work was produced by Waugh et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 1