{"paper_id":"4a64c58b-f035-4acb-a35b-8c62faffd696","body_text":"S T U D Y P R O T O C O L Open Access\nBladder pain syndrome: validation of simple tests\nfor diagnosis in women with chronic pelvic pain:\nBRaVADO study protocol\nSeema A Tirlapur 1*, Lee Priest 2, Daniel Wojdyla 3, Khalid S Khan 1,4 and On behalf of the MEDAL Study\nAbstract\nBackground: Bladder pain syndrome (BPS), a condition with no gold standard diagnosis, comprises of a cluster of\nsigns and symptoms. Bladder filling pain and bladder wall tenderness are two basic clinical features, present in a\nhigh number of sufferers. This study will validate the performance of these simple tests for BPS in women with\nchronic pelvic pain (CPP).\nMethods/design: We will conduct a prospective test validation study amongst women with unexplained CPP\npresenting to gynaecology outpatient clinics. Two index tests will be performed: patient reported bladder filling\npain and bladder wall tenderness on internal pelvic bimanual examination. A final diagnosis of BPS will be made by\nexpert consensus panel. We will assess the rates of index tests in women with CPP; evaluate the correlation\nbetween index tests and Pelvic Pain Urgency/ Frequency (PUF) questionnaire results; and determine index test\nsensitivity and specificity using a range of analytical methods. Assuming a 50% prevalence of BPS and an 80%\npower approximately 152 subjects will be required exclude sensitivity of < 55% at 70% sensitivity.\nDiscussion: The results of this test validation study will be used to identify whether a certain combination of signs\nand symptoms can accurately diagnose BPS.\nTrial registration: ISRCTN13028601\nKeywords: Bladder pain syndrome, Chronic pelvic pain, Consensus panel, Latent class analysis, Test validation\nBackground\nBladder pain syndrome (BPS), formerly known as inter-\nstitial cystitis and painful bladder syndrome, is a cause of\nchronic pelvic pain (CPP) and is defined as CPP , bladder\npressure or discomfort along with at least one other\nurinary symptom in the absence of any identifiable path-\nology or infection [1,2].\nThe reported prevalence of BPS is between 5 and 16\nper 100,000 of the population with 61% of women pre-\nsenting with CPP being diagnosed with BPS [3-5]. The\ncondition has a large impact on sexual function and\nquality of life [6]. It has an unknown aetiology and impre-\ncise characterisation, which makes it difficult to accurately\ndiagnose clinically [7,8]. The diagnosis of BPS can be\nmade by symptoms alone and further classified by cyst-\noscopy findings and biopsy results, after exclusion of\nother confusable diseases like urinary tract infection or\noveractive bladder [2]. Symptoms include urinary fre-\nquency, urgency, nocturia and incomplete voiding [9].\nValidated questionnaires may be used to help diagnose\npatients. The two commonly used are the O ’Leary-Sant\nInterstitial Cystitis Symptom Index/Problem Index and\nthe Pelvic Pain Urgency/ Frequency (PUF) question-\nnaire [10,11]. Neither questionnaire is considered a reli-\nable predictor of disease or disease severity [11,12].\nThere is no gold standard test for BPS, which makes for\ndifficulty in choice of study d esign for a diagnostic eva-\nluation study (Figure 1).\nThe most commonly reported symptoms are bladder/\npelvic pain, urgency, frequency and nocturia but this symp-\ntom cluster is present in sever al other urinary conditions\n* Correspondence: s.a.tirlapur@qmul.ac.uk\n1Women’s Health Research Unit, Barts and the London School of Medicine,\nQueen Mary, University of London, 58 Turner Street, London E1 2AB, UK\nFull list of author information is available at the end of the article\n© 2013 Tirlapur et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative\nCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication\nwaiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise\nstated.\nTirlapur et al. Reproductive Health 2013, 10:61\nhttp://www.reproductive-health-journal.com/content/10/1/61\n\nand is not discriminating of BPS [14]. In practice, the symp-\ntom of bladder filling pain and the sign of bladder wall ten-\nderness on vaginal examination have been shown to be\npresent in a high number of patients with BPS, but these\nhave not been incorporated into existing tools [15,16]. This\ns t u d yw i l lv a l i d a t et h eu s eo ft h e s es i m p l et e s t sf o rB P Si n\nwomen with CPP.\nMethods/design\nThe BRa VADO study will be conducted prospectively and\nits protocol is reported in accordance with the SPIRIT\nguidelines [17]. This will be a sub-study of the MEDAL\ntrial (MRI to Establish Diagnosis Against Laparoscopy),\nwhich is a multicentre diagnostic test accuracy study car-\nried out in United Kingdom to investigate women with\nunexplained chronic pelvic pain.\nTrial registration: Ethics and research and develop-\nment approvals for this study are covered through the\nmulticentre research ethics committee (REC no: 11/EM/\n0281). The study is sponsored by Queen Mary, Univer-\nsity of London (Ref no: 007936 QM). Clinical trial regis-\ntration no: ISRCTN13028601.\nObjectives:\n1. To determine the rates of the symptom of bladder\nfilling pain and the sign of bladder wall tenderness\nin women with CPP.\n2. To assess the correlation between bladder filling\npain, bladder wall tenderness, and the PUF\nquestionnaire (and several component questions\nwithin it) in the diagnosis of BPS in CPP.\n3. To determine the prevalence of BPS in CPP ,\nusing consensus panel to establish reference\nstandard diagnosis.\n4. To estimate the accuracy with which a certain\ncombination of signs and symptoms (index tests)\ncan identify the diagnosis of BPS in CPP.\nDesign\nProspective test validation study with consensus panel to\nestablish reference diagnosis.\nSetting\nGynaecology outpatient clinics in the United Kingdom.\nConsider other \ntypes of evaluation\nWill the outcome of \nthe reference \nstandard be available \nin all study \nparticipants?\nIs there a single \nreference standard \nproviding adequate \nclassification?\nIs there reliable \nexternal information \nabout the degree of \nimperfection of the \nreference standard?\nConsider using \npanel consensus \ndiagnosis or \nlatent class analysis\nConsider using \ncorrection methods \nfor imperfect \nreference standard\nConsider using \ncomposite reference \nstandard\nClassic\ndiagnostic accuracy \nstudy\nConsider using an \nalternative reference \nstandard in these \nsubgroups\nNo\nIs it plausible that the \nreference standard \noutcomes are\nmissing (completely) \nat random?\nYes\nConsider imputing \nmissing outcome on \nreference standard \nor correct accuracy \nestimates\nAre there specific \nsubgroups in which \nthis reference \nstandard cannot be \napplied?\nIs there a-priori \nconsensus what \ncombination of test \nresults provide \nadequate \nclassification? \nIs there a preferred \nreference standard \nbut providing \ninadequate \nclassification?\nYes\nNo\nIs accuracy sufficient for \nanswering the question?\nCan multiple tests \nprovide adequate \nclassification? \nNo\nNo\nYes\nYes\nNo\nYes\nNo\nYes\nYes\nNo\nYes\nYes\nNo\nFigure 1 Flow diagram showing the possible options for researchers when there is no clear reference standard in diagnostic accuracy\nstudies [13].\nTirlapur et al. Reproductive Health 2013, 10:61 Page 2 of 8\nhttp://www.reproductive-health-journal.com/content/10/1/61\n\nParticipant eligibility\nWomen presenting to secondary care with unexplained\nCPP. The inclusion criteria are women aged 16 or older\nwho are referred to secondary care with unexplained CPP\nand have the ability to understand adequate English to\ngive informed consent. Exclusion criteria are pregnancy, a\nprevious hysterectomy, a proven urinary tract infection on\nurine dipstick and a previous diagnosis of BPS.\nIndex tests:\n1. Bladder filling pain will be assessed through a\npatient questionnaire (Figure 2). There is also\nassessment of pain when the bladder is full to\ndiscriminate the two.\n2. Bladder base tenderness will be assessed by\nspecialists in gynaecology as part of a routine vaginal\nexamination. This is the sensation of pain when the\nbladder wall is palpated, rather than a sensation of\ndiscomfort.\nReference tests\nThere is no gold standard test for diagnosis. We will have\nan expert consensus panel in the study. The panel will be\nmade of 3 national specialists in urogynaecology. The diag-\nnosis determined by the panel will be a symptom-based\ndiagnosis of BPS through patient self-reporting symptoms\ncaptured in a range of validated questionnaires. Figure 3\nshows the proforma to be used for the consensus panels.\nRecruitment\nAll eligible patients will be invited to participate in the\nstudy. They will be consented by named research staff at\nall participating centres, according to the MEDAL proto-\ncol version 1.2. There will be consecutive recruitment of\nall eligible patients to minimise selection bias (Figure 4).\nSample size\nThe power estimation for such test validation studies is\nnot straightforward. Estimates of prevalence of BPS vary.\nA recent systematic review suggested the prevalence of\nBPS in women with CPP is as high as 61% [3,4]. Since the\nexact prevalence in unknown, a range of sample sizes have\nbeen calculated based on various levels of prevalence\n(T able 1). There are no published estimates of sensitivity,\nas defined as having a positive index test and actually hav-\ning BPS. We use a 95% confidence interval and exact test\nto estimate sample sizes, excluding a sensitivity range of\nless than 45% to 65% with a power of 80%. For example,\nassuming a 50% prevalence of BPS and an 80% power ap-\nproximately 152 subjects will be required exclude sensitiv-\nity of < 55% at 70% sensitivity.\nProposed time schedule\nTable 2 shows the study timeline with recruitment com-\nmencing August 2012 and study end date of September\n2014 [17].\nData collection\nData will be collected on the pre-designed data collection\nforms and inputted into the central database. Quality assur-\nance testing will take place with double data entry, visual\ncross validation, data completeness checks and protocol ad-\nherence. All patients will undergo a diagnostic laparoscopy\nand cystoscopy, if deemed clinically necessary. Information\nwill be collected about co-existing causes of CPP. The in-\nformation collected will be represented in a STARD flow\ndiagram (Figure 4).\nData analyses\nPatient characteristics will be recorded. We will provide\ndescriptive statistics with ranges and standard deviations\nas appropriate. Statistical analyses will compute sensitivity,\nspecificity and predictive values using consensus panel\na.\nb.\nFigure 2 Index test questions. a . Bladder filling pain. b. Bladder wall tenderness.\nTirlapur et al. Reproductive Health 2013, 10:61 Page 3 of 8\nhttp://www.reproductive-health-journal.com/content/10/1/61\n\nFigure 3 Consensus panel assessment form for symptom-based diagnosis of bladder pain syndrome.\nFigure 4 Study flow chart in accordance with the STARD reporting guidelines [18].\nTirlapur et al. Reproductive Health 2013, 10:61 Page 4 of 8\nhttp://www.reproductive-health-journal.com/content/10/1/61\n\ndiagnosis as reference. We will consider several approaches\nto test validation [13]. The flow diagram in Figure 1 shows\nhow we arrived at the proposed data analyses method-\nology. In the absence of a single reference standard to pro-\nvide adequate diagnostic classification and the lack of\ninformation regarding the degree of imperfection of the\nreference standards, multiple tests can be used. As there is\nno consensus on pre-defined rules to define the target con-\ndition, we will use an expert panel diagnosis. Accuracy is\nconcurrent criterion validit y. In order to avoid incorpor-\nation bias, we will not include the index tests as part of the\nsymptom based diagnosis. From the certainty scores of\ndiagnosis we will calculate median and confidence interval\nscores, and kappa for inter-rater reliability. We will report\nall estimates of test performance with confidence intervals.\nWe will also explore the use of latent class analysis, which\nis a statistical test that allows evaluation of a new test in\nthe absence of a gold standard [19].\nData monitoring\nData monitoring will be undertaken in accordance with\nguidelines for diagnostic studies [20]. Quality testing with\nrange checks for data values and standard operating proce-\ndures will be used to maintain accurate data reporting and\nmonitoring. Regular data monitoring committee meetings\nwill be scheduled with a group of independent experts.\nDiscussion\nThe results of this test validation study will be used to\nidentify whether a certain co mbination of signs and symp-\ntoms can accurately predict the diagnosis of BPS. In 2011\nthe American Urological Association produced their guide-\nlines for diagnosis and management of BPS, which are\nsummarised in Figure 5 [21]. Since then, cystoscopic find-\nings have been discredited a s a negative cystoscopy does\nnot exclude BPS and cystoscopi cf i n d i n g sd on o tc o r r e l a t e\nwell with disease severity or histopathology [22,23]. For\nTable 1 Study power calculations at various assumptions\nSample size\nSensitivity Sensitivity\nto exclude\nNo. of patients\nwith BPS\nTotal number of patients\n40% prevalence 50% prevalence 60% prevalence\n60% 45% 82 205 164 137\n65% 50% 78 195 156 130\n70% 55% 76 190 152 127\n75% 60% 73 183 146 122\n80% 65% 69 173 132 115\nTable 2 A schematic diagram showing the timeline for study participation [17]\nTIMEPOINT -t1 0\nt1 t2 t3 t4 tx\n(July 2012) (August 2012)\nPre-study Enrolment PatientVisit 1 PatientVisit 2 Reference diagnosis Analysis Study end\nENROLMENT:\nEligibility screen X\nInformed consent X\nScreening log X\nUrine screen X\nINTERVENTIONS:\nBladder filling pain X\nBladder wall tenderness X\nASSESSMENTS:\nValidated questionnaires XX\nVaginal examination X\nDiagnostic laparoscopy X\nExpert panel (reference diagnosis) X\nDATA ANALYSIS X\nCOMPLETE REPORT X\nTirlapur et al. Reproductive Health 2013, 10:61 Page 5 of 8\nhttp://www.reproductive-health-journal.com/content/10/1/61\n\nFigure 5 A summary of the American urological association guidelines [21].\nTirlapur et al. Reproductive Health 2013, 10:61 Page 6 of 8\nhttp://www.reproductive-health-journal.com/content/10/1/61\n\nthis reason cystoscopy and bladder biopsy can no longer\nbe used as a gold standard diagnostic tool for the condi-\ntion. According to the 2011 guidelines, initial treatment\nwith pain management, behavioural modifications, patient\neducation and physical therapies can be commenced after\nbasic assessment consisting of history, pain assessment,\nphysical examination and urinalysis. Cystoscopy and hydro-\ndistension are recommended as a fourth-line treatment for\nBPS as this investigation may provide limited diagnostic\nand therapeutic benefit [24]. If a cluster of signs and symp-\ntoms could accurately predict BPS this could be incorpo-\nrated into the basic clinical assessment and would help\nclinicians diagnose the condition and initiate treatments\nwithout lengthy delays performing investigations, which are\noften not discriminatory.\nEthics approval\nThe study has ethical approval from the National Re-\nsearch Ethics Service (NRES) Committee East Midlands -\nNottingham 1, United Kingdom (Ref 11/EM/0281).\nAbbreviations\nBPS: Bladder pain syndrome; CPP: Chronic pelvic pain; MEDAL: MRI to\nestablish diagnosis against laparoscopy; NIHR: National institute of health\nresearch; PUF: Pelvic pain urgency/ frequency.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthors’ contributions\nSAT drafted and revised the protocol and manuscript. LP revised manuscript.\nDW provided statistical guidance on latent class analysis and sample size\ncalculations. KSK conceived and designed the study and applied for funding.\nHe revised the protocol and manuscript. All authors read and approved the\nfinal manuscript.\nAuthor’s information\nSeema Anushka Tirlapur BSc, MBChB – Clinical research fellow in obstetrics\nand gynaecology at Queen Mary, University of London.\nLee Priest BSc (Hons), MPhil – Trial Coordinator at Birmingham Clinical Trials\nUnit, University of Birmingham.\nDaniel Wojdyla MSc – Clinical statistician, Centro Rosarino de Estudios\nPerinatales, Argentina.\nKhalid S Khan MSc, MRCOG, MMed - Professor of women ’s health and clinical\nepidemiology at Queen Mary, University of London.\nAcknowledgements\nThe BRAVADO study is a sub-study within the MEDAL study (MRI to establish\na diagnosis in chronic pelvic pain) (http://www.controlledtrials.com/\nISRCTN13028601/medal), a project funded by the National Institute for Health\nResearch Health Technology Assessment (NIHR HTA) (ref: 09/22/50). The\nviews and opinions expressed are those of the authors and do not necessar-\nily reflect those of the HTA programme, NIHR, NHS or Department of Health.\nThe MEDAL study management group includes Khalid Khan, Jane Daniels,\nJon Deeks, Elizabeth Ball, Teresita Beeston, Lee Middleton, Lee Priest, Julia\nSeeley, Anushka Tirlapur and Julie Dodds.\nFunding\nSAT is a clinical research fellow, funded by the NIHR Health Technology\nAssessment Programme (ref: 09/22/50).\nAuthor details\n1Women’s Health Research Unit, Barts and the London School of Medicine,\nQueen Mary, University of London, 58 Turner Street, London E1 2AB, UK.\n2Birmingham Clinical Trials Unit, School of Cancer Sciences, Robert Aitken\nInstitute, University of Birmingham, Birmingham B15 2TT, UK. 3Centro\nRosarino de Estudios Perinatales (CREP), Moreno 878, Rosario S2000DKR,\nSanta Fe, Argentina. 4WE1 2AB and Barts Health NHS Trust, The Royal\nLondon Hospital, Whitechapel Road, London E1 1BB, UK.\nReceived: 25 October 2013 Accepted: 15 November 2013\nPublished: 4 December 2013\nReferences\n1. 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Biostatistics 2007, 8(2):474–484.\n20. Daniels J, Gray J, Pattison H, Roberts T, Edwards E, Milner P, et al:\nRapid testing for group B streptococcus during labour: a test accuracy\nstudy with evaluation of acceptability and cost-effectiveness.\nHealth Technol Assess 2009,\n13(42):1–154. iii-iv.\nTirlapur et al. Reproductive Health 2013, 10:61 Page 7 of 8\nhttp://www.reproductive-health-journal.com/content/10/1/61\n\n21. Hanno PM, Burks DA, Clemens JQ, Dmochowski RR, Erickson D, Fitzgerald MP,\net al: AUA guideline for the diagnosis and treatment of interstitial cystitis/\nbladder pain syndrome. JU r o l2011, 185(6):2162–2170.\n22. Messing E, Pauk D, Schaeffer A, Nieweglowski M, Nyberg LM, Landis JR, et al:\nAssociations among cystoscopic findings and symptoms and physical\nexamination findings in women enrolled in the interstitial cystitis data base\n(ICDB) study. Urology 1997, 49(5A Suppl):81–85.\n23. Denson MA, Griebling TL, Cohen MB, Kreder KJ: Comparison of cystoscopic\nand histological findings in patients with suspected interstitial cystitis.\nJ Urol 2000, 164(6):1908–1911.\n24. Ottem DP, Teichman JM: What is the value of cystoscopy with\nhydrodistension for interstitial cystitis? Urology 2005, 66(3):494–499.\ndoi:10.1186/1742-4755-10-61\nCite this article as: Tirlapur et al. : Bladder pain syndrome: validation of\nsimple tests for diagnosis in women with chronic pelvic pain: BRaVADO\nstudy protocol. Reproductive Health 2013 10:61.\nSubmit your next manuscript to BioMed Central\nand take full advantage of: \n• Convenient online submission\n• Thorough peer review\n• No space constraints or color figure charges\n• Immediate publication on acceptance\n• Inclusion in PubMed, CAS, Scopus and Google Scholar\n• Research which is freely available for redistribution\nSubmit your manuscript at \nwww.biomedcentral.com/submit\nTirlapur et al. Reproductive Health 2013, 10:61 Page 8 of 8\nhttp://www.reproductive-health-journal.com/content/10/1/61","source_license":"CC0","license_restricted":false}