Bladder pain syndrome: validation of simple tests for diagnosis in women with chronic pelvic pain: BRaVADO study protocol

Background: Bladder pain syndrome (BPS), a condition with no gold standard diagnosis, comprises of a cluster of signs and symptoms. Bladder filling pain and bladder wall tenderness are two basic clinical features, present in a high number of sufferers. This study will validate the performance of these simple tests for BPS in women with chronic pelvic pain (CPP). Methods/design: We will conduct a prospective test validation study amongst women with unexplained CPP presenting to gynaecology outpatient clinics. Two index tests will be performed: patient reported bladder filling pain and bladder wall tenderness on internal pelvic bimanual examination. A final diagnosis of BPS will be made by expert consensus panel. We will assess the rates of index tests in women with CPP; evaluate the correlation between index tests and Pelvic Pain Urgency/ Frequency (PUF) questionnaire results; and determine index test sensitivity and specificity using a range of analytical methods. Assuming a 50% prevalence of BPS and an 80% power approximately 152 subjects will be required exclude sensitivity of < 55% at 70% sensitivity.

The results of this test validation study will be used to identify whether a certain combination of signs and symptoms can accurately diagnose BPS. Trial registration: ISRCTN13028601

Bladder pain syndrome, Chronic pelvic pain, Consensus panel, Latent class analysis, Test validation

Bladder pain syndrome (BPS), formerly known as inter- stitial cystitis and painful bladder syndrome, is a cause of chronic pelvic pain (CPP) and is defined as CPP , bladder pressure or discomfort along with at least one other urinary symptom in the absence of any identifiable path- ology or infection [1,2]. The reported prevalence of BPS is between 5 and 16 per 100,000 of the population with 61% of women pre- senting with CPP being diagnosed with BPS [3-5]. The condition has a large impact on sexual function and quality of life [6]. It has an unknown aetiology and impre- cise characterisation, which makes it difficult to accurately diagnose clinically [7,8]. The diagnosis of BPS can be made by symptoms alone and further classified by cyst- oscopy findings and biopsy results, after exclusion of other confusable diseases like urinary tract infection or overactive bladder [2]. Symptoms include urinary fre- quency, urgency, nocturia and incomplete voiding [9]. Validated questionnaires may be used to help diagnose patients. The two commonly used are the O ’Leary-Sant Interstitial Cystitis Symptom Index/Problem Index and the Pelvic Pain Urgency/ Frequency (PUF) question- naire [10,11]. Neither questionnaire is considered a reli- able predictor of disease or disease severity [11,12]. There is no gold standard test for BPS, which makes for difficulty in choice of study d esign for a diagnostic eva- luation study (Figure 1). The most commonly reported symptoms are bladder/ pelvic pain, urgency, frequency and nocturia but this symp- tom cluster is present in sever al other urinary conditions * Correspondence: [email protected] 1Women’s Health Research Unit, Barts and the London School of Medicine, Queen Mary, University of London, 58 Turner Street, London E1 2AB, UK Full list of author information is available at the end of the article © 2013 Tirlapur et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tirlapur et al. Reproductive Health 2013, 10:61 http://www.reproductive-health-journal.com/content/10/1/61 and is not discriminating of BPS [14]. In practice, the symp- tom of bladder filling pain and the sign of bladder wall ten- derness on vaginal examination have been shown to be present in a high number of patients with BPS, but these have not been incorporated into existing tools [15,16]. This s 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 women with CPP. Methods/design The BRa VADO study will be conducted prospectively and its protocol is reported in accordance with the SPIRIT guidelines [17]. This will be a sub-study of the MEDAL trial (MRI to Establish Diagnosis Against Laparoscopy), which is a multicentre diagnostic test accuracy study car- ried out in United Kingdom to investigate women with unexplained chronic pelvic pain. Trial registration: Ethics and research and develop- ment approvals for this study are covered through the multicentre research ethics committee (REC no: 11/EM/ 0281). The study is sponsored by Queen Mary, Univer- sity of London (Ref no: 007936 QM). Clinical trial regis- tration no: ISRCTN13028601.

1. To determine the rates of the symptom of bladder filling pain and the sign of bladder wall tenderness in women with CPP. 2. To assess the correlation between bladder filling pain, bladder wall tenderness, and the PUF questionnaire (and several component questions within it) in the diagnosis of BPS in CPP. 3. To determine the prevalence of BPS in CPP , using consensus panel to establish reference standard diagnosis. 4. To estimate the accuracy with which a certain combination of signs and symptoms (index tests) can identify the diagnosis of BPS in CPP. Design Prospective test validation study with consensus panel to establish reference diagnosis. Setting Gynaecology outpatient clinics in the United Kingdom. Consider other types of evaluation Will the outcome of the reference standard be available in all study participants? Is there a single

standard providing adequate classification? Is there reliable external information about the degree of imperfection of the

standard? Consider using panel consensus diagnosis or latent class analysis Consider using correction methods for imperfect

standard Consider using composite reference standard Classic diagnostic accuracy study Consider using an alternative reference standard in these subgroups No Is it plausible that the

standard outcomes are missing (completely) at random? Yes Consider imputing missing outcome on

standard or correct accuracy estimates Are there specific subgroups in which this reference standard cannot be applied? Is there a-priori consensus what combination of test

provide adequate classification? Is there a preferred

standard but providing inadequate classification? Yes No Is accuracy sufficient for answering the question? Can multiple tests provide adequate classification? No No Yes Yes No Yes No Yes Yes No Yes Yes No Figure 1 Flow diagram showing the possible options for researchers when there is no clear reference standard in diagnostic accuracy studies [13]. Tirlapur et al. Reproductive Health 2013, 10:61 Page 2 of 8 http://www.reproductive-health-journal.com/content/10/1/61 Participant eligibility Women presenting to secondary care with unexplained CPP. The inclusion criteria are women aged 16 or older who are referred to secondary care with unexplained CPP and have the ability to understand adequate English to give informed consent. Exclusion criteria are pregnancy, a previous hysterectomy, a proven urinary tract infection on urine dipstick and a previous diagnosis of BPS. Index tests: 1. Bladder filling pain will be assessed through a patient questionnaire (Figure 2). There is also assessment of pain when the bladder is full to discriminate the two. 2. Bladder base tenderness will be assessed by specialists in gynaecology as part of a routine vaginal examination. This is the sensation of pain when the bladder wall is palpated, rather than a sensation of discomfort.

tests There is no gold standard test for diagnosis. We will have an expert consensus panel in the study. The panel will be made of 3 national specialists in urogynaecology. The diag- nosis determined by the panel will be a symptom-based diagnosis of BPS through patient self-reporting symptoms captured in a range of validated questionnaires. Figure 3 shows the proforma to be used for the consensus panels. Recruitment All eligible patients will be invited to participate in the study. They will be consented by named research staff at all participating centres, according to the MEDAL proto- col version 1.2. There will be consecutive recruitment of all eligible patients to minimise selection bias (Figure 4). Sample size The power estimation for such test validation studies is not straightforward. Estimates of prevalence of BPS vary. A recent systematic review suggested the prevalence of BPS in women with CPP is as high as 61% [3,4]. Since the exact prevalence in unknown, a range of sample sizes have been calculated based on various levels of prevalence (T able 1). There are no published estimates of sensitivity, as defined as having a positive index test and actually hav- ing BPS. We use a 95% confidence interval and exact test to estimate sample sizes, excluding a sensitivity range of less than 45% to 65% with a power of 80%. For example, assuming a 50% prevalence of BPS and an 80% power ap- proximately 152 subjects will be required exclude sensitiv- ity of < 55% at 70% sensitivity. Proposed time schedule Table 2 shows the study timeline with recruitment com- mencing August 2012 and study end date of September 2014 [17]. Data collection Data will be collected on the pre-designed data collection forms and inputted into the central database. Quality assur- ance testing will take place with double data entry, visual cross validation, data completeness checks and protocol ad- herence. All patients will undergo a diagnostic laparoscopy and cystoscopy, if deemed clinically necessary. Information will be collected about co-existing causes of CPP. The in- formation collected will be represented in a STARD flow diagram (Figure 4). Data analyses Patient characteristics will be recorded. We will provide descriptive statistics with ranges and standard deviations as appropriate. Statistical analyses will compute sensitivity, specificity and predictive values using consensus panel a. b. Figure 2 Index test questions. a . Bladder filling pain. b. Bladder wall tenderness. Tirlapur et al. Reproductive Health 2013, 10:61 Page 3 of 8 http://www.reproductive-health-journal.com/content/10/1/61 Figure 3 Consensus panel assessment form for symptom-based diagnosis of bladder pain syndrome. Figure 4 Study flow chart in accordance with the STARD reporting guidelines [18]. Tirlapur et al. Reproductive Health 2013, 10:61 Page 4 of 8 http://www.reproductive-health-journal.com/content/10/1/61 diagnosis as reference. We will consider several approaches to test validation [13]. The flow diagram in Figure 1 shows how we arrived at the proposed data analyses method- ology. In the absence of a single reference standard to pro- vide adequate diagnostic classification and the lack of information regarding the degree of imperfection of the

standards, multiple tests can be used. As there is no consensus on pre-defined rules to define the target con- dition, we will use an expert panel diagnosis. Accuracy is concurrent criterion validit y. In order to avoid incorpor- ation bias, we will not include the index tests as part of the symptom based diagnosis. From the certainty scores of diagnosis we will calculate median and confidence interval scores, and kappa for inter-rater reliability. We will report all estimates of test performance with confidence intervals. We will also explore the use of latent class analysis, which is a statistical test that allows evaluation of a new test in the absence of a gold standard [19]. Data monitoring Data monitoring will be undertaken in accordance with guidelines for diagnostic studies [20]. Quality testing with range checks for data values and standard operating proce- dures will be used to maintain accurate data reporting and monitoring. Regular data monitoring committee meetings will be scheduled with a group of independent experts.

The results of this test validation study will be used to identify whether a certain co mbination of signs and symp- toms can accurately predict the diagnosis of BPS. In 2011 the American Urological Association produced their guide- lines for diagnosis and management of BPS, which are summarised in Figure 5 [21]. Since then, cystoscopic find- ings have been discredited a s a negative cystoscopy does not exclude BPS and cystoscopi cf i n d i n g sd on o tc o r r e l a t e well with disease severity or histopathology [22,23]. For Table 1 Study power calculations at various assumptions Sample size Sensitivity Sensitivity to exclude No. of patients with BPS Total number of patients 40% prevalence 50% prevalence 60% prevalence 60% 45% 82 205 164 137 65% 50% 78 195 156 130 70% 55% 76 190 152 127 75% 60% 73 183 146 122 80% 65% 69 173 132 115 Table 2 A schematic diagram showing the timeline for study participation [17] TIMEPOINT -t1 0 t1 t2 t3 t4 tx (July 2012) (August 2012) Pre-study Enrolment PatientVisit 1 PatientVisit 2 Reference diagnosis Analysis Study end ENROLMENT: Eligibility screen X Informed consent X Screening log X Urine screen X INTERVENTIONS: Bladder filling pain X Bladder wall tenderness X ASSESSMENTS: Validated questionnaires XX Vaginal examination X Diagnostic laparoscopy X Expert panel (reference diagnosis) X DATA ANALYSIS X COMPLETE REPORT X Tirlapur et al. Reproductive Health 2013, 10:61 Page 5 of 8 http://www.reproductive-health-journal.com/content/10/1/61 Figure 5 A summary of the American urological association guidelines [21]. Tirlapur et al. Reproductive Health 2013, 10:61 Page 6 of 8 http://www.reproductive-health-journal.com/content/10/1/61 this reason cystoscopy and bladder biopsy can no longer be used as a gold standard diagnostic tool for the condi- tion. According to the 2011 guidelines, initial treatment with pain management, behavioural modifications, patient education and physical therapies can be commenced after basic assessment consisting of history, pain assessment, physical examination and urinalysis. Cystoscopy and hydro- distension are recommended as a fourth-line treatment for BPS as this investigation may provide limited diagnostic and therapeutic benefit [24]. If a cluster of signs and symp- toms could accurately predict BPS this could be incorpo- rated into the basic clinical assessment and would help clinicians diagnose the condition and initiate treatments without lengthy delays performing investigations, which are often not discriminatory. Ethics approval The study has ethical approval from the National Re- search Ethics Service (NRES) Committee East Midlands - Nottingham 1, United Kingdom (Ref 11/EM/0281). Abbreviations BPS: Bladder pain syndrome; CPP: Chronic pelvic pain; MEDAL: MRI to establish diagnosis against laparoscopy; NIHR: National institute of health research; PUF: Pelvic pain urgency/ frequency. Competing interests The authors declare that they have no competing interests. Authors’ contributions SAT drafted and revised the protocol and manuscript. LP revised manuscript. DW provided statistical guidance on latent class analysis and sample size calculations. KSK conceived and designed the study and applied for funding. He revised the protocol and manuscript. All authors read and approved the final manuscript. Author’s information Seema Anushka Tirlapur BSc, MBChB – Clinical research fellow in obstetrics and gynaecology at Queen Mary, University of London. Lee Priest BSc (Hons), MPhil – Trial Coordinator at Birmingham Clinical Trials Unit, University of Birmingham. Daniel Wojdyla MSc – Clinical statistician, Centro Rosarino de Estudios Perinatales, Argentina. Khalid S Khan MSc, MRCOG, MMed - Professor of women ’s health and clinical epidemiology at Queen Mary, University of London.

The BRAVADO study is a sub-study within the MEDAL study (MRI to establish a diagnosis in chronic pelvic pain) (http://www.controlledtrials.com/ ISRCTN13028601/medal), a project funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) (ref: 09/22/50). The views and opinions expressed are those of the authors and do not necessar- ily reflect those of the HTA programme, NIHR, NHS or Department of Health. The MEDAL study management group includes Khalid Khan, Jane Daniels, Jon Deeks, Elizabeth Ball, Teresita Beeston, Lee Middleton, Lee Priest, Julia Seeley, Anushka Tirlapur and Julie Dodds. Funding SAT is a clinical research fellow, funded by the NIHR Health Technology Assessment Programme (ref: 09/22/50). Author details 1Women’s Health Research Unit, Barts and the London School of Medicine, Queen Mary, University of London, 58 Turner Street, London E1 2AB, UK. 2Birmingham Clinical Trials Unit, School of Cancer Sciences, Robert Aitken Institute, University of Birmingham, Birmingham B15 2TT, UK. 3Centro Rosarino de Estudios Perinatales (CREP), Moreno 878, Rosario S2000DKR, Santa Fe, Argentina. 4WE1 2AB and Barts Health NHS Trust, The Royal London Hospital, Whitechapel Road, London E1 1BB, UK. Received: 25 October 2013 Accepted: 15 November 2013 Published: 4 December 2013

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