Bladder ultrasound for diagnosing detrusor overactivity: test accuracy study and economic evaluation

Definition and prevalence

Overactive bladder (OAB) is defined by the International Continence Society and the International Urogynaecology Association1 as a symptom complex of urinary urgency (an intense, sudden desire to void) with or without incontinence, usually with increased urinary frequency or nocturia, but in the absence of infection or other proven pathology. Increased urinary frequency and urgency seem to be more common symptoms of OAB than urinary incontinence (UI). Incontinence may be the most distressing symptom of OAB, but affects only one-third of patients. 2

Overactive bladder affects millions of people worldwide. In the epiLUTS study, OAB prevalence was found to be 12.8%. 3,4 Prevalence and severity of OAB are known to increase with age from 14.9% in the 18- to 29-year group, to 21.3% in the 30- to 39-year group, 32.9% in the 40- to 49-year group, 35.8% in the 50- to 59-year group and up to 39.8% in the 60- to 69-year group. 5 With the increase in longevity owing to advances in health care and the population growth, the burden of OAB is going to increase in the next few decades, with a 9% increase anticipated from 500 million globally in 2013 to 546 million by 2018. 6 Two-thirds of a predominantly female sample of people with OAB had sought treatment in the 6 months prior to a multinational survey. 7

Moderate-to-severe symptoms may have an adverse impact on lifestyle. Affected women tend to cope by restricting fluid intake and ‘toilet mapping’ to control urgency and frequency. 8 Women may avoid sexual contact because of the risk of coital incontinence. 9 These coping strategies can have a deleterious effect on physical, social and emotional health. Low mood and depression due to social restriction and fear of embarrassment are also associated with OAB in women (with and without urgency incontinence), while OAB also has significant financial implications (e.g. cost of pads, prescriptions, time off work, job losses, effects on the family, etc.). 10,11 Urgency or nocturia in the elderly have been linked to a higher risk of falls and fractures. 12

Mixed urinary incontinence

The International Continence Society and International Urogynecology Association describe mixed urinary incontinence (MUI) as a complaint of involuntary loss of urine associated with urgency and also with effort or physical exertion, or on sneezing or coughing. 1 MUI may be urgency-predominant or stress-predominant and accounts for 49% of UI in women. 13 In a study on the prevalence of individual symptoms of MUI, 29% of participants had stress-predominant MUI, 15% of participants had urgency-predominant MUI and 56% (912/1626) of participants had equal severity of urgency- and stress-related MUI. 13 Appropriate categorisation of women into urgency-predominant or stress-predominant MUI has been a matter of great debate. Previous studies have used the Medical, Epidemiological, and Social Aspects of Ageing (MESA) Questionnaire,14 the Urogenital Distress (UI) Inventory15 and visual analogue scale (VAS) scores alongside 7-day bladder diaries to categorise women with mixed incontinence based on the predominant symptom (stress or urgency). 16 However, in routine clinical practice, women are categorised based on which symptoms they consider are more bothersome.

Underlying pathology of overactive bladder

The pathology behind OAB symptoms has been found to be detrusor overactivity (DO) in 54–58% of the cases. The remaining 42–46% of the patients may have other pathologies causing OAB symptoms17 (Table 1).

The pathophysiology of the DO and other causes of OAB have not been understood completely. Enhanced afferent activity generated by the detrusor smooth muscle and the urothelium/lamina propria may be the main mechanism. 18 In vitro studies have shown that spontaneous contractile activity was seen more often in muscle strips from overactive than from normal bladders. 19

According to the myogenic theory, DO may be caused by an intrinsic abnormality of the detrusor muscle rather than a disturbance of its neural control. Detrusor smooth muscle cells may become hyperexcitable, react to minor stimuli and result in untimely bladder contractions resulting in urgency. In isolated bladder preparations from patients with DO, there seems to be increased co-ordination leading to larger amplitude contractions, possibly reflecting changes in intercellular communication. 20

In OAB patients, increase in intravesical pressure secondary to detrusor contractions may cause the symptom of urgency and prompt the woman to increase her urethral closure pressure using her urethral sphincter and pelvic floor musculature. Such isometric contractions against a closed bladder neck and competent sphincter may lead to the hypertrophy of the detrusor. A thickened bladder wall is suggestive of detrusor hypertrophy. 21

Clinical history

Clinical history taking for urinary symptoms includes the type of incontinence (provoked by urgency or activity), duration and severity of symptoms, impact of symptoms on quality of life (QoL), exacerbating factors including diet, fluid and medications, co-existing medical, surgical or gynaecological conditions and the person’s strategies for coping with symptoms. In a semisystematic review, mean sensitivity and specificity of clinical history compared with a reference standard diagnosis made by urodynamics (UDS) was 69% (range 35–96%) and 60% (range 21–97%), respectively, for OAB, and 51% (range 38–84%) and 66% (range 43–96%), respectively, for women with MUI. 22 Mean sensitivity for predicting DO in women with clinical symptoms of OAB was 76%, but the specificity was only 57%. 22 Meta-analytical averages were not presented.

However, in a more methodologically thorough review, Martin et al. 23 reported the pooled sensitivity of clinical history assessment of urgency symptoms, compared with a UDS diagnosis of DO, to be lower at 61% [95% confidence interval (CI) 57% to 65%], and the specificity to be higher at 87% (95% CI 85% to 89%).

History of urinary symptoms alone may not help in the differentiation of the underlying pathology. 24,25 Women go through a thorough clinical assessment to rule out other causes of OAB, for example urogenital atrophy, significant pelvic organ prolapse (POP), and should undergo post-void residual (PVR) ultrasonography to rule out incomplete bladder emptying.

Bladder diaries in the assessment of overactive bladder

Bladder diaries are useful tools in the investigation of lower urinary tract symptoms (LUTS)3 and also to assess treatment response. 26 Episodes of urgency and sensation may also be recorded, along with the activities performed during or immediately preceding the involuntary loss of urine. Severity of incontinence in terms of leakage episodes and pad use may also be reported in bladder diaries. On evaluation of accuracy of bladder diaries in OAB patients against the urodynamic diagnosis of DO, sensitivity and specificity were found to be 0.88 and 0.83, respectively. 27 A high subjective score of urgency, frequent voiding and urgency incontinence episodes (over a 3-day diary period) were strongly associated with urodynamic DO in a multivariate analysis. 28

Clinical use of urodynamics

National Institute for Health and Care Excellence (NICE) guidelines (CG 171)36 advise against the use of multichannel, ambulatory UDS or video UDS prior to commencing conservative management for OABs. However, there are recommendations to perform UDS before proceeding to invasive treatments for DO, for example botulinum toxin serotype A (BTX-A) (Onabotulinum A, Botox™, Allergan Ltd.) or neurostimulation.

Standardisation of the urodynamic assessment

Urodynamics is a skilled procedure, which requires training in setting up the UDS equipment, calibration of the machine, interpreting the pressure/flow recordings and counselling patients. One of the difficulties often encountered during UDS is the ability to identify artefacts and interpret the results. 5 One of the key aspects of maintaining the accuracy of UDS is to ensure that the initial resting pressures are correct and recognised. 8 Previous studies showed that even under ideal test–retest conditions, reliability can be poor for many urodynamic parameters. 9,10 In clinical settings in which UDS is performed, this can be further compromised by inconsistencies in practice. The site-to-site variation in UDS procedure may have resulted from difference in equipment and training of staff. 3 Quality control is a process through which procedure quality is maintained or improved, errors reduced or eliminated and is a crucial element of the good urodynamic practice (GUP) guidelines, which were developed following poor quality control observed during review of UDS traces from multicentre trials by the International Continence Society in 2002. 6

Acceptability of urodynamics

Women experience significant emotional distress in relation to diagnostic evaluation. 37 UDS is an intimate and invasive test13 involving the catheterisation of the bladder and rectum/vagina and some provocative manoeuvres. 13 A significant number of people who undergo UDS find it embarrassing, painful or distressing. 38,39 These feelings can be relieved by appropriate interpersonal skills, communication skills, maintenance of privacy and confidence in the technical ability of the health-care professional. 40 Younger women and those with a history of anxiety or depression, and those receiving a diagnosis of OAB and painful bladder syndrome have been reported to have more negative experiences during UDS. 41 Female patients found that UDS was more embarrassing when carried out by a male examiner, although they felt it less painful than their male counterparts. Patients with higher ‘bother’ scores may not tolerate UDS as well as a patient who has a lower bother score. 38

Evidence for the accuracy of ultrasonographic measurement of bladder wall thickness in diagnosis of detrusor overactivity

There has been conflicting evidence in the literature on the diagnostic accuracy of BWT in diagnosing DO. 47,48 A systematic review identified five studies49–53 of women with OAB symptoms, three of these studies49,52,53 used transvaginal bladder ultrasonography but different UDS methods. 48 In one study of transvaginal bladder ultrasonography from which accuracy data could be extracted, a BWT cut-off point of 5 mm gave a sensitivity of 84% (95% CI 76% to 89%) and specificity of 89% (95% CI 90% to 96%) for identifying DO, compared with video cystourethrography and ambulatory UDS. 49 In another study, BWT varied significantly between UDS-defined lower urinary tract conditions – the mean BWT was 3.78 mm (SD 0.39 mm) for USI, 4.97 mm (SD 0.63 mm) for DO and 6.01 mm (SD 0.73 mm) for bladder outflow obstruction; p < 0.0001. 54 This study reported an area under the receiver operating characteristic (ROC) curve of 0.94 (95% CI 0.89 to 0.99) for the differentiation between USI and DO or bladder outflow obstruction and 0.87 (95% CI 0.78 to 0.97) to differentiate DO and bladder outflow obstruction, suggesting thresholds of 4.1 mm and 5.6 mm, respectively, for maximal diagnostic accuracy. 54 A subsequent update to the review identified seven further studies that have shown a significantly increased BWT in patients with DO than in patients without DO. 27,50,55–59 However, the heterogeneity in the methods, including the standardisation of bladder ultrasonography and of UDS, and poor reporting of the proportions of DO cases identified as well as missed, precludes a formal diagnostic meta-analysis. Other methodological weaknesses of prior studies include unclear description of how bladder ultrasonography and UDS results were blinded to each other, recruitment mainly from a single centre and retrospective design.

Acceptability of bladder ultrasonography

Transvaginal bladder ultrasonography is a less invasive technique than UDS. The acceptability and psychological impact of transvaginal scanning has been extensively studied. In a study of 755 pregnant women undergoing transvaginal scanning, 272 (36%) experienced some pain or physical discomfort,60 the majority (92%) describing it as ‘mild’ or ‘discomforting’, but a small minority found the scan ‘distressing’ (5%), ‘horrible’ (3%) or ‘excruciating’ (1%). The level of psychological trauma, measured by the impact of event score (with ratings of symptoms of avoidance and intrusion) was low, with a mean of 4.3 out of a possible maximum score of 40. The majority of the women (86%) said they would definitely or probably have a repeat scan in the future.

Methodology for determination of the accuracy of bladder ultrasonography

Evaluation of the accuracy of a diagnostic test involves comparing the findings a new test with a reference standard diagnosis, which may be based on one or several pieces of test information. Accuracy focuses on estimating rates of test errors: false negatives – those who have the condition but who wrongly receive a negative test result; and false positives – those who do not have the condition but wrongly receive a positive test result. Sensitivity describes the ability of the test to correctly identify the disease (i.e. not give false-negative results) and specificity the ability to identify those without the disease (i.e. to not give false-positive results). For the evaluation of bladder ultrasonography, the findings of UDS are used for the reference standard as it is the best test for diagnosing DO. For bladder ultrasonography to be considered as a test to replace UDS, it is necessary for the rates of false negatives and false positives to be low (i.e. sensitivity and specificity to be high).

There are many possible sources of bias in accuracy studies68 and we report our study in accordance with the Standards for Reporting of Diagnostic Accuracy statement to ensure that the risk of bias can be assessed. 69 There are three main domains of bias: (1) selection of the sample, (2) verification of the reference standard and (3) completeness of the data. Selection bias may arise if the sample is not suitably representative of the population. This is likely to occur with use of non-consecutive or convenience sampling. The BUS sought to approach all consecutive eligible women. A related issue is that of spectrum bias whereby the accuracy of tests varies among study samples with differences in disease severity (a measurable characteristic). We planned subgroup analysis to explore the variation in test accuracy owing to spectrum composition.

Empirical studies have shown that studies with differential verification, whereby the reference standard use is dependent on the index test result, produce more biased estimates of accuracy than studies with complete verification by the preferred reference standard. 70 Some of the studies of bladder ultrasonography have mixed reference standards according to the results of the index test, which can lead to bias. 44,49,52 This has occurred through using ambulatory UDS in selected subsets of patients selected according to the results of bladder ultrasonography. Although ambulatory UDS is probably a more accurate reference standard than standard UDS, it was available in only a single recruiting centre, and is costly and inconvenient, and thus we could not use it in all centres. We did aim to include a subset of patients in whom ambulatory UDS had been carried out on and use this enhanced reference standard in a sensitivity analysis, but the primary analysis is based on standard UDS assessments. We mandated that both tests were completed to ensure that we had complete data to enable the accuracy assessment to see if bladder ultrasonography can replace UDS. 71

Reproducibility of a test

The accuracy of a diagnostic test relates to its ability to detect differences in measurements between individuals related to disease state (the signal) against a background of variability in measurements caused by measurement error (the noise or analytical variability). Tests may fail when there is little signal or when the magnitude of the noise is high compared with the size of the signal. Studies of reliability and reproducibility provide estimates of analytical variability and allow assessment of the ability of a test to detect real differences of varying magnitude. For imaging studies, there are two core sources of analytical variability: first, relating to the interpretation of images, with variability caused by measurement error within an observer (intraobserver) and between observers (interobserver); and second, relating to the imaging technique.

Any newer diagnostic test developed to assess bladder function accurately should ideally be reliable and reproducible and easy to interpret. Reproducibility of BWT is of particular importance given the fact that the bladder is a distensible organ and its thickness is known to inversely correlate with the amount of urine present in the bladder. 46 Intraobserver and interobserver reproducibility is demonstrated by studying the difference between blinded observers/measurements when exposing the same patient to the technique independently at different points of time. Transabdominal and transperineal measurement of BWT was shown to have higher interobserver variation than transvaginal measurement in a study by Panayi et al. 72 Hence we chose transvaginal measurement of BWT to evaluate diagnostic accuracy in diagnosing DO.

Assessing the acceptability of bladder ultrasonography and urodynamics

Extreme anxiety disrupts and unsettles behaviour by lowering the individual’s concentration and affecting their self-confidence and muscular control. Unsettled behaviour during intimate and invasive tests such as UDS and bladder ultrasonography may have an impact on the level of co-operation gained from the patient, the ability to complete the test and may have an adverse effect on interpretation of test results. 73,74

There is no reported literature on the explicit quantification of the anxiety levels elicited by UDS and very little attention has been paid to the psychological impact of invasive diagnostic testing of lower urinary tract conditions. 26 We aimed to assess state anxiety, defined as a mood state associated with preparation for possible upcoming negative events75 and consider this alongside pain during and shortly after each test.

Effect of tests on subsequent treatment pathway

Pharmacotherapy is considered first-line treatment of OAB, with or without the use of conservative interventions like bladder retraining, pelvic floor muscle training (PFMT) (with or without biofeedback), weight loss and fluid management. The motor nerve supply to the bladder is via the parasympathetic nervous system (via sacral nerves S2, S3, S4),76–78 which stimulates detrusor muscle contraction. This is mediated by acetylcholine acting on muscarinic receptors at the level of the bladder. Cholinergic blockade may abolish or reduce the intensity of detrusor muscle contraction. 79 Various anticholinergic medications differ with respect to efficacy, tolerability and side effect profile. Women taking anticholinergic medications frequently experience adverse effects such as dry mouth, headache, constipation, dizziness, decreased visual acuity and tachycardia. A pharmacological classification of bladder agents used in OAB is:

• Non-selective anticholinergics: tolterodine tartrate, trospium chloride, oxybutynin hydrochloride, propiverine hydrochloride, propantheline bromide.

• M2–M3 selective anticholinergic: solifenacin succinate (Vesicare^®, Astellas).

• M3 selective antagonist: darifenacin hydrobromide (Emselex^®, Merus).

• Beta3 receptor agonist: mirabegron (Betmiga^®, Astellas).

In patients who are refractory to conservative management of OAB (because of either a lack of efficacy or troublesome adverse effects), BTX-A has been used for over a decade with successful outcomes. The majority of patients who commence treatment with BTX-A may require long-term repeat treatments. 80 There is evidence of sustained reductions in UI episodes and increase in volume/void as well as QoL in patients with neurogenic DO81 on repeat (up to five) injections with BTX-A.

Percutaneous tibial nerve stimulation (PTNS) involves stimulation of the posterior tibial nerve in the ankle using a fine-gauge needle, given weekly for 12 weeks and topped up as required. Improvement in OAB symptoms using PTNS is comparable to the effect of antimuscarinics but with a better side effect profile. 82 The studies included in the published systematic review considered only short-term outcomes after initial treatment. 82 In order to recommend PTNS as a practical treatment option, long-term data and health economic analysis are needed. 82 The NICE guideline on UI recommends that PTNS for OAB can be offered only if there has been a multidisciplinary team review, conservative management including OAB drug treatment has not worked adequately and the woman does not want BTX-A or percutaneous sacral nerve stimulation (SNS). 36

Sacral neuromodulation involves implantation of a permanent sacral nerve root stimulator, which is designed to stimulate the third sacral nerve root. It is recommended to patients with refractory OAB who have failed conservative measures (including drugs), who have not responded to BTX-A treatment and have voiding difficulties. 36,83 The surgical treatment for SUI is offered if the PFMT has been unsuccessful or declined and mainly consists of a mid-urethral sling. 36

The impact of a test is whether or not it ultimately improves patient outcomes, by identifying those that need treatment, or differentiating between alternative diagnoses and directing an appropriate treatment. There are widely held concerns that although a UDS DO diagnosis is accurate, it is not clear that it leads to different patient management or predicts patient outcome. There are some studies to suggest that patient-related outcomes are similar whether or not there is an urodynamic diagnosis of DO in patients with OAB, following a variety of treatment options. 84–87

A comparable situation exists for stress incontinence, whereupon non-invasive assessments alone were found to be not inferior to UDS for outcomes at 1 year in a randomised controlled trial (RCT). 61 A meta-analysis has concluded that pre-operative UDS does not influence the likelihood of subjective cure or post-operative complications in women without VD undergoing primary surgery for uncomplicated SUI and so should not be carried out. 88 In a RCT, urodynamic status could not predict treatment outcomes between patients treated with extended-release tolterodine tartrate or placebo. 84

There is a necessity, therefore, to establish the role of UDS and its impact on treatment and patient outcomes in OAB as at present its role is unclear. The BUS provided a unique opportunity to address this question and so, midway through, we proposed an extension to the study. The extension aimed to establish if treatment pathways differed following confirmation of DO based on UDS. Moreover, we sought to assess if the UDS diagnosis had an effect on patient-reported severity and improvement at 6 and 12 months after testing, and whether or not receiving the most appropriate treatment according to the UDS diagnosis improved symptoms.

Economic evaluation of the alternative diagnostic strategies

In addition to evaluating the reproducibility, accuracy and acceptability of bladder ultrasonography, it is important to assess the cost-effectiveness of testing strategies involving bladder ultrasonography, UDS and based on the primary presenting symptom in clinical history alone. The BUS would enable comprehensive primary resource utilisation for bladder ultrasonography and UDS to be collected as part of the study and the extension provided the opportunity to collect outcome data for all women who having reported bladder problems, and the treatment they received, whether or not they had a UDS diagnosis of DO. These data, together with other estimates obtained from the literature,89–92 were used to clarify whether or not the UDS test itself represents an appropriate and justifiable use of health service resources, given the doubt over its predictive ability.

Study sample

Consecutive women attending urogynaecology or urology clinics at either specialised referral centres or district general hospitals were approached for consent to the study. They were eligible for inclusion in the study (Figure 1) if they satisfied the following criteria:

1. Frequency of nine or more voids in 24 hours as reported in a 3-day bladder diary (on at least on one of the days).

2. Urgency (cannot defer the urge to void) recorded on at least two occasions in the 3-day bladder diary.

3. PVR volume ≤ 100 ml on the screening bladder scan.

4. No stress incontinence surgery and/or BTX-A in the past 6 months.

5. Provided written informed consent.

FIGURE 1.

Study flow chart.

Exclusion criteria were:

1. Current pregnancy or up to 6 weeks post partum.

2. Pure symptoms of stress incontinence or stress-predominant mixed incontinence.

3. Evidence of cystitis (dipstick positive for leucocytes/nitrites).

4. Voiding difficulties (e.g. PVR of > 100 ml).

5. Prolapse > grade II (any compartment, as defined by the Pelvic Organ Prolapse (POP) Quantification system). 93

6. Previous UDS assessment in the past 6 months.

7. Use of antimuscarinics for more than 6 months continuously.

8. Current use of antimuscarinics (e.g. tolterodine, solifenacin, oxybutynin). If the woman was taking antimuscarinics at the point of consent, she was eligible if the medication was ceased immediately and there was a delay of at least 2 weeks before the index and reference tests were carried out.

Given the need to fully inform each woman about the study (to provide time for her to consider participation and to avoid burdening her with information at the time of recruitment), a two-stage informed consent strategy was employed. The study information leaflets along with a sample consent form and bladder diaries were posted to all prospective participants with their clinic appointment letter. Research nurses and principal investigators in the recruiting hospitals were trained to reinforce the information provided and answer any questions that the women may have had. The collaborating teams approached patients for recruitment and consent at the time of consultation. We advised the recruiting centres to maintain a screening log of the eligible and ineligible participants was (identification and demographic details and any exclusion criteria).

Demographic and clinical history of the participants was collected prior to testing. This included medical and surgical history, previous treatments, if any, for bladder, bladder diary results and incontinence pad use. The ICIQ-OAB questionnaire67 was also administered prior to testing and then at 6 and 12 months post-testing for use in the long-term follow-up study (see Chapter 6). A generic and preference-based health-related QoL questionnaire, the European Quality of Life-5 Dimensions (EQ-5D),94 was administered at the same time points. The Investigating Choice Experiments CAPability measure for Adults (ICECAP-A) was given at baseline and 6 months only. Questionnaires on the acceptability of the testing were given immediately post-testing (see Chapter 5 for output).

Setting of tests

Urodynamics was carried out by health-care professionals (doctors or nurses) who routinely carry out the procedure in clinical practice. The standard operating procedures (SOPs) (see Appendix 5) and quality assurance processes are described in Chapter 3. For bladder ultrasonography (see Appendix 6), hands-on training was delivered on site at each of the recruiting sites for the clinicians (doctors or sonographers) and two training workshops were carried out at the Birmingham Women’s Hospital.

At centres where ultrasonography was undertaken in the UDS suite, the scan was performed at the same clinic visit but by an independent trained observer blinded to the UDS result. At centres where the scan was to be performed in the radiology department, both diagnostic tests were carried out within 4 weeks of each other. Clinicians performing each of the tests were blinded to the results of the other. The operator performing the UDS recorded the findings and the diagnosis in the UDS test pro forma and the operator performing bladder ultrasonography recorded the BWT measurements in the bladder ultrasonography test. The index test (bladder ultrasonography) was carried out in a scan suite and the UDS carried out in the UDS suite in the majority of the centres. Both data collection forms were then collected by a research nurse/research fellow co-ordinating the recruitment at each centre and were sent to the bladder ultrasonography trial office (Birmingham Clinical Trials Unit) in a sealed envelope.

Index test: bladder wall thickness via ultrasonography

The BWT was measured from a transvaginal scan with the end-firing transvaginal probe in the sagittal plane (midline) introduced 1 cm beyond the vaginal introitus in the midline. BWT measurement involved measuring the inner and outer hyperechoic areas along with the hypoechoic detrusor sandwiched in the middle. 49,95 When the inner and outer hyperechoic areas are excluded and the inner hypoechoic area only is measured, it is classed as DWT. We measured BWT via the transvaginal approach at a volume < 30 ml. The echo-poor central area of the urethra was used as a landmark for BWT scanning. BWT was measured in millimetres using tools provided on the ultrasonography machine at the following three sites perpendicular to the luminal surface of the bladder (Figures 2 and 3):

1. The thickest part of the trigone.

2. The dome of the bladder in the midline.

3. The anterior wall of the bladder.

FIGURE 2.

Bladder wall thickness measurement at trigone.

FIGURE 3.

Dome midline and two lateral measurements on either side.

For the purposes of this study, BWT was to be calculated as the mean of these three measurements. In order to assess whether or not the mean of three values at the dome was similar to the value obtained on dome, anterior wall and trigone, two further measurements of DWT 1 cm on either side of the dome midline were also taken.

Reference standard: urodynamics

All women underwent UDS, using a standardised protocol in accordance with the GUP guidelines of the International Continence Society. 96 Participants attended the UDS clinic with a full bladder. Uroflowmetry was performed with the woman voiding in private and recorded on a gravimetric flow meter. Filling cystometry was then performed with the woman in sitting position. This was then followed by voiding cystometry with the pressure lines in situ (see Appendix 5).

Sample size

A target sample size of 600 participants was determined a priori. The computation was based on presuming a prevalence of 50% for DO,17 providing 300 women for the estimate of sensitivity and 300 for the estimate of specificity. This allows estimation of sensitivities and specificities with 95% CIs of width 10% for sensitivity and specificity values between 70% and 95%, and narrower for higher values.

Data analysis

The primary analysis involved calculations of sensitivity, specificity, predictive values and likelihood ratios (LRs) using a BWT of 5 mm as a cut-off point (≥ 5 mm indicating presence of DO, < 5 mm indicating absence of DO). BWT of 5 mm was chosen as the cut-off point for discriminating DO based on the evidence from previous studies49,97 and was pre-specified in the protocol.

Likelihood ratios for the following three ordered categories of BWT were also pre-specified: < 3 mm, ≥ 3 mm to < 5mm, ≥ 5 mm. 98 95% CIs were calculated using binomial exact methods. A ROC curve was constructed and the area under the curve (AUC) computed (with 95% CI) to give an overall estimate of BWT accuracy across all thresholds. Statistical significance was tested by comparing against the uninformative model (i.e. for which AUC = 0.5) using a non-parametric approach. 99 The distributions of BWT measurements in groups with and without a DO diagnosis were depicted using box-and-whisker plots and mean values compared using a two-sample t-test.

A number of sensitivity analyses were performed on the primary population to test the robustness of the results to protocol deviations and missing data. ROC curves and associated AUC values were computed for each analysis. The analyses were:

1. Excluding those patients for whom it was revealed that the UDS test result was not blinded to the results of ultrasonography (to exclude any possible diagnostic review bias).

2. Excluding those patients for whom it was calculated to be more than 4 weeks between index and reference standard tests (to exclude any possible disease progression bias).

3. Including results of incomplete ultrasonographic measurements, that is when not all three components of BWT were recorded (in these cases, if one or two measurements were missing, the average of the remaining values was taken to be BWT; this was to exclude the impact of missing measures).

4. Replacing the original UDS diagnosis with that from the additional ambulatory UDS test when available (this happened only in 14 instances, all from one centre; this analysis was intended to assess the impact of this presumed more sensitive UDS than supine UDS).

5. Using the trigone measurement alone as BWT (to explore whether or not a single measurement was as accurate as the mean of three locations).

6. Excluding those who had ‘provoked DO’ (detrusor pressure rise on provocation testing – 187 cases; this was to assess the impact of iatrogenic DO).

7. Excluding those who had PVR of > 30 ml on BWT testing (34 cases; this was to explore the impact of those with minor degrees of incomplete emptying).

8. Taking the average of dome, 1 cm left of dome and 1 cm right of dome as BWT (to explore whether or not measurements at this location improve accuracy).

In addition, some unplanned exploratory analyses were also performed to gauge the effect of changing the population of interest and also to see which parameters were associated with DO diagnosis. The populations explored were:

1. Women with urgency alone on clinical history (i.e. excluding those with mixed stress/urgency incontinence).

2. Women with ‘pure’ DO only (i.e. not alongside another diagnosis from UDS).

3. Women with ‘wet’ DO only (i.e. not including those with ‘dry’ DO).

Pre-planned subgroup analyses were also performed to compare test accuracy between subgroups. ROC curves were created for each subgroup and associated AUC values compared using a large sample chi-squared test for independent curves. 100 The subgroups used here to dichotomise patient groups were:

1. Previous treatment with antimuscarinics.

2. A clinical history suggesting mixed incontinence.

3. Presence of a UTI in the previous 12 months.

4. Voiding difficulties.

5. Previous incontinence surgery.

6. Body mass index (BMI) (< 25 kg/m², ≥ 25 kg/m²).

Exploratory analyses were undertaken to assess variables associated with a diagnosis of DO using logistic regression. The above six subgroup variables were included along with pre-test International Consultation on Incontinence modular Questionnaire (ICIQ) score, BWT, age, duration of symptoms, ethnicity, number of vaginal deliveries, menopausal status, parity and previous POP surgery. Covariates were considered individually and then in a multivariable analysis. Three multivariable models were constructed: one using all possible explanatory variables, another using all possible explanatory variables but using a multiple imputation approach to generate missing responses101 and another using a backward-step process to eliminate unimportant variables (a level of p = 0.1 was used here as criteria for staying in the model). We also examined whether or not BWT had any relationship with baseline ICIQ-OAB score using a simple linear regression model.

Recruitment

Recruitment of participants started in March 2011 and closed in March 2013. A total of 1310 women were approached. Six hundred and eighty seven women who were eligible and consented to participate were recruited into the study from 22 centres (Table 2 and see Figure 23). This number was slightly higher than the agreed sample size calculation to compensate for a small number of study withdrawals and women without complete index and reference standard test results (Figure 4).

FIGURE 4.

Participant flow diagram.

Characteristics of participants

Characteristics of women who consented to take part in the study are shown in Table 3. The mean age of women was 52.7 years (SD 13.9 years) and the average BMI was 30.6 kg/m² (SD 12.2 kg/m²). A total of 55% (378/687) of the women were post menopausal. According to the clinical history, 33% (226/687) reported only urinary urgency without incontinence and 61% (419/687) had urgency-predominant MUI. The median duration of symptoms was 3.0 years (IQR 1.6–7.0 years).

The reference standard: urodynamics

The number of participants with a complete reference standard diagnosis was 666/687 (97%). The other 21 (3%) decided to withdraw from the study before any testing could take place (see Figure 4). Details of the findings in these tests are given in Table 4. Of these, 399 (60%) were diagnosed with DO (95% CI 56% to 64%) (Table 5). Of the 399, 245 were given further subdiagnosis of ‘wet’ DO (61%) and 154 as ‘dry’ DO (39%). The participants also had their DO diagnosis subcategorised as phasic ‘spontaneous’ DO (detrusor contraction during the filling phase: 182/369, 49%; 30 observations missing), provoked DO (if the detrusor contraction occurred during or after provocative measures such as cough, running water or immersion of hands in cold water: 56/369, 15%) or both spontaneous and provoked (131/369, 36%).

The index test: bladder wall thickness

The number of participants with all three BWT measurements (trigone, dome midline, anterior wall midline) available was 645 (94%). Eleven patients had withdrawn after having UDS but prior to ultrasonography (see Figure 4) and a further 10 (1%) had partial measurements recorded (nine with two out of the three measurements and one with one of the three measurements). Summary statistics and distribution of BWT are provided in Table 6 and Figure 5.

FIGURE 5.

Histogram of BWT measurements (average: trigone/dome midline/anterior wall).

Timing and safety of tests

Six hundred and forty-four participants had both complete index and reference standard results (one had a complete index test but was missing their reference standard, see Figure 4). Of these, 439/644 (68%) had both BWT and UDS performed on the same day. Only a small proportion (26/644, 4%) were performed more than 4 weeks apart. Ninety-seven per cent of reference tests (616/632, 12 observations missing) were confirmed as being blind to the index test. No serious adverse events were reported following either test, although 49/479 (10%) of those responding reported having a UTI within 2 weeks of testing at a 6-month follow-up. Seventy five per cent (36/48, one observation missing) of these were diagnosed by a general practitioner (GP) or in a hospital and resulted in antibiotic use in 83% of cases (39/47, two observations missing).

Estimates of test accuracy

Estimation of the accuracy of BWT showed poor sensitivity, specificity and LRs at all pre-specified cut-off points of 5 mm, < 3 mm/3–5 mm/≥ 5 mm (Tables 7–9). The ROC curve (Figure 6) showed no evidence of discrimination at any threshold between those with and without DO (p = 0.25); the AUC was 0.53, 95% CI 0.48 to 0.57. Furthermore, there was no evidence that the mean BWT measurements were any higher in the DO-positive group than the DO-negative group: 4.85 mm (SD 1.36 mm) versus 4.70 mm (SD 1.29 mm); p = 0.19 (Figure 7) or that it had any relationship with ICIQ-OAB symptoms score when measured at presentation (r = –0.01; p = 0.88).

FIGURE 6.

Receiver operating curve analysis for BWT. AUC = 0.5267.

FIGURE 7.

Box and whisker plot comparing BWT with DO diagnosis.

The planned and unplanned sensitivity analysis described above did not change the interpretation of these findings (see Appendix 2, Figure 23 and Appendix 3, Figures 24–36). There was some evidence, albeit weak, that those diagnosed with ‘wet’ DO had higher BWT than those with ‘dry’ DO (wet 4.94 mm vs. dry 4.69 mm; p = 0.08) (see Appendix 3, Figure 32). However, when the BWT for the wet DO group was analysed alone, the AUC was only 0.55, 95% CI 0.50 to 0.59. There was no evidence that BWT performed any differently in any of the pre-specified subgroups (see Table 45).

In the multivariable exploration of factors possibly associated with DO diagnosis, only higher baseline ICIQ score (i.e. worse symptoms) was associated with DO [odds ratio (OR) 1.21, 95% CI 1.13 to 1.29; p < 0.0001 from the model including all possible variables], that is, the odds of DO diagnosis were increased by 21% for every point increase in ICIQ score. Previous treatment with antimuscarinics and previous history of UTI in the previous 12 months also showed some relationship but these were of borderline statistical significance (see Tables 46 and 47). Despite the evidence of association between ICIQ score and DO diagnosis, ICIQ was not found to be an accurate predictor of DO with an AUC of 0.65 (95% CI 0.61 to 0.70).

Summary of main findings

To date, BUS is the largest diagnostic accuracy study evaluating the diagnostic accuracy of BWT to diagnose DO in women with symptoms of OAB and using transvaginal ultrasonography with a near empty bladder. We could not find any evidence that BWT was of any clinical benefit in women with DO, indeed it appeared to be no better than chance at making this diagnosis with an AUC of 0.53 (95% CI 0.48 to 0.57). Extensive sensitivity analyses and subgroup analyses were carried out but did not alter the interpretation of these findings. Furthermore, BWT had no relationship to ICIQ score upon presentation, indicating that it has no relationship with symptom severity. ICIQ score was shown to have some relationship with DO diagnosis. Based on this evidence, we conclude that BWT is not a useful test in diagnosing DO.

Strengths and limitations of methods

The validity of our findings relied on the quality of the study. The protocol pre-specified key study methods and analyses and was peer reviewed. The study was undertaken with independent oversight with biannual meetings of independent Data Monitoring Committee (DMC) and Study Steering Committees. Blinding of operators performing bladder ultrasonography and UDS was ensured for 97% of the women recruited into the study. Verification bias was minimised by incorporating a complete verification design. Disease progression bias was minimised by conducting BWT and UDS within a short time span of each other, often within the same day. The spectrum variation (recruiting women with varying degree of severity of OAB or urgency-predominant MUI) was a strength of the design, assuring the applicability of the findings to NHS practice.

The study was powered to ensure that estimates of sensitivity and specificity would be made with adequate precision to draw robust conclusions and we recruited beyond the target. Participants in the study were recruited from several centres (university teaching and district general hospitals). Women were of mixed ages, ethnicities and social background, and were recruited from various parts of the UK.

The prevalence of DO in our study was 60%, which was similar to other studies (48% of ‘OAB dry’ and 58% of ‘OAB wet’ women were found to have DO on UDS). 102 The adverse events in our study were UTI in 10% of the population following the UDS procedure. The post UDS rate of UTI was very similar to the other studies so far. 103

As bladder ultrasonography is a relatively new transvaginal scan technique, concerns may be raised on the quality of scan measurements in the study. However, the technique is straightforward to perform with the urinary bladder being an anterior and relatively superficial midline structure. To standardise the performance of bladder ultrasonography, we developed a SOP (see Appendix 5) for carrying out ultrasonography and provided hands-on training at individual recruitment sites to our co-investigators and organised two workshops on BWT measurements. The chief investigator and clinical research fellow were assessed by the main recruiting centre consultant radiologist of 14 years’ experience in the technique of BWT measurement. The collaborators had to be signed off as competent by the chief investigator or clinical research fellow once they had completed at least five scans before recruiting patients into the study.

Good site-to-site reliability is essential for multicentre clinical trials using UDS. With the use of continuous quality improvement and training on standardised urodynamic testing procedures and interpretation guidelines, the technical quality of urodynamic findings were improved. 104 To improve reliability of our gold standard test UDS, we used various proactive measures such as standard urodynamic testing protocols, standard interpretation guidelines and auditing the traces centrally every 6 months to ensure ongoing quality assurance. We are therefore confident of the methods and hence the results.

Concerns about the reference standard

Accuracy measures express how the results of the test under evaluation agree with the outcome of the reference standard. Estimates of diagnostic accuracy are directly influenced by the quality of the reference standard. 105 When the accuracy of the reference standard is unknown, or known to be imperfect, estimates of the sensitivity and specificity or AUC for new diagnostic tests will be biased as misclassifications in the reference standard diagnosis will have been misattributed to errors made by the index test. Our reference standard, UDS, has been shown to have less than perfect reproducibility in previous studies in patients with OAB106,107 and also in healthy women. 108,109 When estimating the test accuracy of BWT against an imperfect reference standard (UDS), the accuracy of BWT may have been biased to an unknown degree, or submerged in the ‘noise’ from the imperfect reference standard. However, the poor accuracy for BWT elicited in our study is unlikely to have been entirely caused by misclassifications made by UDS, as there was no significant relationship between BWT measurements and grades of DO severity or subsequent treatment responses (see Chapter 6). When the test values do not differ among those with varying grades of the target condition, it can be inferred that the lack of accuracy may be an inherent feature of the index test.

Evidence of the misclassification rates for UDS comes from several studies. 110,111 Homma et al. 107 undertook repeat UDS in DO patients within 2–4 weeks to study reproducibility. There was increase in the volume variables by 10–13% (p < 0.01), absence of involuntary contractions (10%) and a reduction in the maximum detrusor pressure by 18% during the repeat urodynamic test indicating poor reproducibility. 107 In a study of 59 healthy women without LUTS, UDS was repeated immediately after the initial test without removing the catheters and then again 1–5 months later. The mean difference was dispersed away from zero in both immediate and short-term reproducibility indicating poor reproducibility. 112

Placing the results in the context of other research

In an update of the systematic review on the diagnostic accuracy of BWT in diagnosing DO (unpublished data: Suneetha Rachaneni, University of Birmingham, 2015) 21 studies28,49–59,72,97,113–119 have been identified that have investigated the relationship between BWT measured by ultrasonography and DO, results from which for the sensitivity, specificity and AUC for bladder ultrasonography vary from 37% to 91%, 61% to 97% and 0.61–0.91, respectively (see Appendix 7). The studies draw mixed conclusions, ranging from claims that bladder ultrasonography is highly diagnostic, to finding statistically significant but diagnostically weak relationships, to finding no relationship at all. 49,51,54,57,72,117 Our study is the most conclusively negative study of the diagnostic value of bladder ultrasonography to date.

Initial studies have shown transvaginal BWT to be an accurate diagnostic marker for DO. 44,49 For a mean BWT cut-off point of 5 mm, the specificity was calculated to be 89% (95% CI 78.8% to 96.11%) with a sensitivity of 84% (95% CI 75.8% to 89.7%). 49 However, this study used ambulatory UDS (in patients who had normal video UDS) as a secondary diagnostic test in 25% of the study population and this introduced workup bias that might have resulted in inaccurate estimation of sensitivity and specificity of BWT.

Many of the other studies have differences in the tests used and the populations studied and methodological weaknesses, which may explain why their results vary and differ from the finding of this prospective study. Poor reporting renders it difficult to make comparisons with findings in 10 studies that did not report estimates of sensitivity, specificity or area under the ROC curve. These studies typically compared the mean BWT between diagnostic groups and did not interpret the findings against a positivity threshold.

Eight of the studies did not use transvaginal ultrasonography,28,50,51,56,57,114,116,119 but instead used transabdominal or translabial ultrasonography. Some transabdominal ultrasonography studies included men as well as women and usually were undertaken with a full bladder leading to much smaller measures of mean BWT. 116,119

Ten studies made comparisons with healthy controls,28,50,55–59,114–116 two others excluded patients with MUI54,117 and one other enriched with women with equivocal UDS findings. 52 One was undertaken in patients with spinal injuries. 119 It is known that altering the spectrum of patients from that encountered in practice will influence estimates of sensitivity and specificity. 120 Exclusion of the MUI cases and inclusion of healthy controls will lead to overestimation of test accuracy; enrichment of difficult to diagnose cases will underestimate test accuracy.

A key difference between the BUS and all others is the focus on the accuracy of ultrasonography in women who do not have signs of pure SUI. Women with SUI diagnosed by symptoms and diary usually proceed to treatment without further diagnostic investigation, including UDS. 36 Thus, ultrasonography has no role in this group. The BUS focused on identifying women with DO among those who have urgency or mixed incontinence, for which UDS currently is used, to assess whether or not ultrasonography can replace UDS in this context. Women in whom SUI is diagnosed clinically, by symptoms and bladder diary responses, usually proceed to treatment without further diagnostic investigation, including UDS. 36 Thus, ultrasonography has no role in this group. Studies that have assessed the value of ultrasonography to differentiate between pure SUI and OAB have addressed a question that is no longer relevant to clinical practice.

In summary, our study was the largest prospective study to date, it is the only study that recruited a representative sample of women presenting with an urgency-dominant complaint (others have recruited other wider groups), and used service-based (but trained and quality assured) ultrasonography services from across many centres (whereas other studies were all single centre and often tertiary centre based).

Variation in technique of transvaginal bladder wall scanning

Our technique of measuring BWT in the sagittal plane with a transvaginal probe placed at the introitus was easy to learn and perform with visualisation of the urethra as the landmark. Previous studies have described parasagittal measurements of BWT at three places on the bladder wall, with the calculation of an average BWT. 41,109 In one study, DWT instead of BWT was measured by transperineal scanning. 51 The rest of the studies have used transabdominal scanning at various bladder volumes, but we rejected this technique on account of the greater reported interobserver variation. 71

Interpretation of findings

Measuring BWT is not accurate enough to consistently identify those with DO and hence it will not be helpful in reducing the need for UDS. It is believed that spontaneous DO is secondary to pathology in detrusor muscle whereas provoked DO is caused by pathology in the bladder neck. Provoked DO, which was previously called urethral instability, could be caused by primary urethral aetiology or some unknown pathology. 121 As women with spontaneous DO are known to respond better to antimuscarinic treatment122 than those with provoked DO or urethral instability, we carried out sensitivity analyses to evaluate diagnostic accuracy of BWT excluding those with provoked DO. Similar to findings in the study by Serati,113 we did not find any difference in BWT in spontaneous and provoked DO groups. 113

Implications for practice

Given the poor performance for BWT as tool for diagnosing DO, BWT cannot be recommended as a replacement test for UDS.

Recommendations for research

There is some emerging evidence in the literature that the response to invasive therapies may be similar in patients with frequency and urgency with or without urgency incontinence, with or without the observation of DO on UDS. 123–125 The necessity to diagnose DO on UDS and its role in improving patient-related outcome measures needs to be evaluated in future diagnostic RCTs.

Objectives

The objectives of this part of the study were as follows:

1. To audit the quality of UDS traces submitted to the study office at the University of Birmingham Clinical Trials Unit as the reference standard for the patients in the BUS.

2. To assess whether or not recommended changes in UDS practice had been implemented following an initial audit among the recruiting centres for the BUS.

Urodynamic studies

Urodynamic studies were to be performed in a standardised manner as per the GUP guidelines from the International Continence Society6 and a SOP that had been produced for the study based on this (see Chapter 2, The reference standard: urodynamics). For patients at the main centre (Birmingham Women’s Hospital), according to the study protocol, patients were offered ambulatory UDS if they had a normal result from standard multichannel UDS.

Assessment of protocol compliance

An assessment of compliance with the UDS SOP for the BUS and with GUP was performed on 64 (20%) of the first 302 UDS traces received at the study office, between May 2011 and May 2012.

An expert panel, comprising a consultant in urogynaecology and a urogynaecology research nurse from the lead centre, assessed the traces independently. They were blinded to the investigator’s UDS diagnosis, the UDS operator and centre providing the trace, to minimise any bias in the assessment. All participating sites were audited regarding the urodynamic technique used throughout the study.

Traces were randomly selected by the BUS trial co-ordinator from traces supplied by each of the recruiting hospitals, as suggested by the DMC. The expert panel rereviewed UDS traces they had undertaken (the lead centre recruited 37% of all participants into the BUS) but were not aware of which traces were from the lead centre.

Following review, the requirements of the UDS SOP were reiterated to recruiting centres via e-mails and a newsletter and also discussed at BUS training days, which were held 3 months and 15 months into the recruitment period. A total of 6 months after the initial audit, a second audit (June 2012 to December 2012) was performed on a further 60 traces.

Audit standards for urodynamic studies

The traces were reviewed to assess the presence of the following criteria:

• adequate subtraction prior to filling cystometry (i.e. initially bladder and rectal catheters should be zero when open to atmosphere, at the level of upper symphysis)

• sitting position during filling cystometry (recommended as per study protocol)

• the cystometry filling rate was 100 ml/minute to begin with (then slowed as and if necessary)

• a cough pre-void

• a cough post void

• presence of one cough per minute to assess ongoing adequate subtraction of intravesical and abdominal pressures.

In addition, agreement of initial diagnosis between study investigator and expert panel was assessed. The expert panel determined a diagnosis of USI, DO, low compliance, VD or normal, or combinations of these diagnoses.

Statistical analysis

For each study, BWT measurements were analysed using one-way analysis of variance (ANOVA). One-way ANOVA decomposes the total variation observed (SDT2) into that originating from differences between women (SDI2 – individual variability) and that caused by the measurement process (SDA2 – analytical variability). The estimates are linked as SDT=SDA2+SDI2. The SD for analytical variability, SD_A estimates the measurement error.

Two further statistics were computed from these values. The intraclass correlation coefficient (ICC) describes the fraction of the total variance in BWT measurements owing to individual rather than analytical variation (SDI2/SDT2). ICC values lie between zero and one; measurements that are reliable have ICCs approaching one, as the signals (the individual variation) dominate the noise (the analytical variation).

The repeatability coefficient describes the smallest real difference that can be detected with a specified degree of certainty between two measurements and is computed as 2ZSDA2 (in which Z takes the value of 1.96 for a difference which has 95% certainty of being a real effect and not measurement error). Smallest real difference values are given in the units of the original measurement.

The above analyses were all undertaken assuming exchangeability of observers, that is, that the ordering of the measurements has no relevance. Generalisability of these findings relies on the observers being presumed to be representative of those who would make the measurements in practice.

For the purpose of graphical display only, we also display the data in scatterplots and Bland–Altman plots to demonstrate the distribution of measurements and differences between measurements (see Figures 8–13). For these analyses assignment of measurements to particular observers is important. In substudy A, there is a logical choice for the first and second measurements, and the distribution of these differences is of interest. In substudies B and C, measurements made by observer 1 were arbitrarily taken as the first measurement (referred to in Figures 10 and 12 as operator A1) and remaining observers 2 to 6 were taken as the second measurement (referred to in Figures 10 and 12 as operators A2 or A3, respectively).

Substudy A: intraobserver repeatability of the same scans

Paired measurements were available for 37 women. The scatter of measurements is shown in Figure 8 and the distribution of differences in measurements in Figure 9. The later measurements were, on average, higher than the earlier measurements by 0.35 mm (95% CI 0.19 mm to 0.51 mm; p < 0.0001) but without any evidence of a relationship between error and the mean BWT value. Differences in measurements of up to 1.5 mm were observed.

FIGURE 8.

Scatterplot for substudy A.

FIGURE 9.

Bland–Altman analysis for substudy A (limits of agreement and 95% CIs shown). LOA, limit of agreement.

The SD for the analytical variation for intraobserver variability was estimated as 0.42 mm (Table 13). This level of variability compares with a SD of 1.04 mm between individual differences, thus 86% of the total variability observed is attributed to individual variability and 14% to measurement error. With this level of measurement error, differences of over 1.16 mm are 95% likely to be real for this single assessor.

Substudy B: interobserver repeatability of the same scans

Paired assessments were available for 57 women made by six different observers. The distribution of measurements and differences are shown in Figures 10 and 11. Differences as large as 2 mm were observed.

FIGURE 10.

Scatterplot for substudy B.

FIGURE 11.

Bland–Altman analysis for substudy B.

The SD for the analytical variation for intraobserver variability was estimated as 0.35 mm (see Table 13). This level of variability compares with a SD of 1.23 mm between individuals, thus 93% of the total variability observed is attributed to individual variability and 7% to measurement error. With this level of measurement error, differences made by assessors similar to these would need to be at least 0.97 mm to be 95% likely to be real.

Substudy C: interobserver repeatability of different scans

Paired measurements were made for 27 women using three different observers. The design of substudy C included estimation of variation occurring from repeated scans together with the interpretation of scans. The distribution of measurements is shown in Figure 12 and distribution of differences in Figure 13. Maximum differences were again around 2 mm, but they were more common in this substudy than in previous substudies A and B.

FIGURE 12.

Scatterplot for substudy C.

FIGURE 13.

Bland–Altman analysis for substudy C.

The SD for the analytical variation for intravariability of repeated scans was estimated as 0.76 mm (see Table 13). This level of variability compares with a SD of 0.95 mm between individuals, thus 61% of the total variability observed is attributed to individual variability and 39% to measurement error. With this level of measurement error, differences made by assessors similar to these would need to be at least 2.11 mm to be 95% likely to be real.

Main findings

We undertook three separate studies to investigate the reliability and repeatability of measurements of BWT using transvaginal ultrasonography. Our analyses have found that differences of < 2 mm in BWT cannot be safely interpreted as indicating real differences in BWT, such differences are in the realms of those attributable to analytical variability (measurement error). The substudies were also designed to identify the magnitude of the possible sources of the analytical variability. We observed that the process of interpreting scans introduces measurement error of around 1 mm, suggesting that the remaining 1 mm is attributable to a combination of the scanning process and biological variability.

We did not assess whether or not the differences in interpreting the scans arose because of within-observer or between-observer variability. Surprisingly, our estimate of intraobserver variation is greater than that of interobserver variation. As the study samples are not large, and different scans were assessed for these repeat intraobserver measurements, this observation potentially could be explained by the play of chance or confounding. However, problems were also experienced with the quality of recorded images used in substudies A and B from the Birmingham Women’s hospital which were not saved using DICOM software, which may explain this observation and may also explain the finding that second reads of scans in substudy A gave, on average, BWT measures of 0.6 mm greater than the original.

Findings in the context of existing data

Six previous studies on reliability and reproducibility of BWT have used a variety of ultrasonography techniques, including transabdominal56 and translabial51 as well as transvaginal44,56,72,129 (as summarised in Appendix 8). Several of these studies investigated women with different or a mixture of aetiologies, or used levels of bladder filling. Of the transvaginal ultrasonography studies, only two56,72 included assessment of repeated scans as in our third substudy, evaluating 10 and 25 women, respectively. The other two studies44,129 only evaluated the reproducibility of image interpretation (as in our first and second substudy) based on repeated assessment of 10 and 1544 images, respectively.

Comparison of findings between these previous studies and the BUS is complicated owing to the common inappropriate use of Bland–Altman analyses and Pearson’s correlation coefficients. Neither of these methods directly estimates the degree of analytical variability, allowing assessment of the reproducibility of the measurement and the signal-to-noise ratio, although a pseudo estimate of analytical variability can be computed from the SD of the differences. Reporting of the study design and statistical analysis was often incomplete or ambiguous. Khullar et al. ,44 Panayi et al. 72 and Tubaro et al. 129 all reported Bland–Altman analyses from which pseudo estimates of measurement error have been computed (see Appendix 8). Estimates of the SD of analytical variability vary between 0.3 mm and 1.3 mm for interobserver and intraobserver variation for image interpretation (compared with 0.3 mm and 0.4 mm for the BUS), and a SD of 0.4 mm for interobserver variation for repeated scans (compared with 0.8 mm for the BUS)56 only reported Pearson’s correlation coefficients from which no useful measures of reproducibility can be obtained.

Strengths and limitations of the study

The women in our study were recruited prospectively as part of the BUS, which involved good characterisation of symptoms and disease state. They were recruited from standard NHS incontinence clinics and are thus highly likely to be representative of women in whom BWT would be measured as part of the diagnosis of DO. The subsamples in each study appear to be representative of the larger cohort.

Bladder wall thickness measurements were made according to a standardised protocol implemented following a programme of rigorous investigator training implemented in the larger study, which will have minimised variability due to differences in technique.

Both the number of women and the number of assessors limit the precision of the estimates made, although the study was larger than many previously undertaken. The assessors who partook in the intraobserver studies generally had high levels of experience and expertise with the techniques, such that the estimates of operator-dependent analytical variability may be lower than those in standard practice.

In substudies A and B, the use of stored images of the original bladder transvaginal scan was problematic because those not stored using DICOM software were of poorer quality than the original images, as reported in previous interobserver variation studies using ultrasonography. 130 We found that the brightness of echogenic serosa and mucosa were reduced in the stored ultrasound images, making the bladder wall less distinct and reducing the ability to place the callipers accurately. This may have led to overestimation in analytical variation in substudies A and B, particularly in A as no images were stored using DICOM.

Interpretation

Ultrasonographic measurements of BWT have a high level of analytical variation arising from the scanning technique, underlying biological variability and interpretation of images, such that only differences > 2 mm should be interpreted as indicating real changes in BWT. The range of BWT measurements observed in the full cohort ranged from 1 mm to 10 mm. To illustrate the potential impact of measurement error of this magnitude, if a threshold of 5 mm is used to define test positives, those between 3 mm and 5 mm could be misclassified as test negatives through measurement error, and those between 5 mm and 7 mm could be misclassified as test positives. In the BUS cohort of 645 women, 326 had values between 3 mm and < 5 mm, and 217 had values between 5 mm and < 7 mm. These groups constitute 84% of the complete sample. Only 41 women (6%) had BWT measures of ≥ 7 mm and 61 (10%) had measurements of < 3 mm. Thus, for the majority of women included in the study there is a possibility that a transvaginal ultrasonographic measurement of BWT would misclassify them using a 5 mm threshold owing to analytical variation. Rates of potential misclassification for higher or lower thresholds would be lower, but still substantial.

Conclusion

In the presence of high levels of analytical variation for a relatively small measurement of BWT, it is unlikely that BWT measurement on a transvaginal ultrasound has sufficient reliability and reproducibility to be an accurate diagnostic test.

Objectives

In this chapter we describe a comparative evaluation of the acceptability of performing both transvaginal bladder ultrasonography and UDS from the patient’s perspective through the completion of self-reported questionnaires.

Analysis

All responses were compared using paired (UDS vs. bladder ultrasonography) methods. 133 For VAS and STAI-6 scores, mean differences and 95% CIs were calculated with statistical significance determined by a paired t-test. Wilcoxon signed-rank test was used for ordinal responses and McNemar’s test for binary responses. Analysis was performed using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, USA).

Pain during and after the tests

Pain levels following both tests appeared relatively low, although scores during and shortly after UDS were higher than the corresponding scores during and after bladder ultrasonography; these differences were statistically significant (Table 14).

Acceptability

Bladder ultrasonography was rated as more acceptable to the women than UDS (p < 0.001), with the proportion of women who found the test totally acceptable significantly higher (81% vs. 56%). The number reporting an unacceptable test was still relatively low following UDS (2%). More women found the exposure required for UDS more embarrassing than bladder ultrasonography (proportion reporting some embarrassment 64% vs. 48%; p < 0.001). Fewer women felt that they would recommend UDS to a friend than bladder ultrasonography (86% vs. 96%; p < 0.001) and have the same test again (88% vs. 97%; p < 0.001) (Table 15).

Anxiety

Anxiety levels associated with both tests appeared moderate, although the scores were slightly higher with UDS (Table 16).

Strengths and limitations

A strong component of the study was that a large number of patients were recruited and responded to the questionnaires in the study (at least 87% of the 687 recruited). The population were derived from several geographical areas and various ethnicities within the UK (see Chapter 2 for full details). Data collected from multicentre studies may be more applicable and generalisable than that collected from a single centre. Our study provides information to assist in counselling women who may be apprehensive or anxious regarding an invasive test such as UDS.

The study had some limitations. We administered the instrument to measure anxiety only after each test procedure. We could have measured the difference between pre-test and post-test questionnaires to know the anxiety provoked by each procedure. This would have yielded valid data about fluctuations in anxiety state before and after each test and a comparison of the difference would have been ideal.

Participants were also aware of the fact that the diagnoses and management plan were made on the basis of the information gained during UDS. This knowledge of the test may have introduced bias and influenced the participant’s decision to recommend the test or have it repeated again if required. Bladder ultrasonography was used for assessment only and did not aid in the management of a bladder diagnosis.

We used the short-form anxiety questionnaire in this substudy, which only measures state and not trait anxiety. Trait-anxious individuals tend to respond to stressful situations with increases in state anxiety. The higher the levels of trait anxiety, the more likely it is that an individual will experience anxiety in a variety of situations, relative to individuals low in trait anxiety. 142 Anxiety and urgency incontinence appeared to exacerbate each other. 143 High anxiety score on the STAI-6 was a predisposing factor for UI. 144 UI is associated with a reduced QoL and increased anxiety among community-dwelling elderly women. 145 Given the strong relationship between state and trait anxiety, women with higher trait anxiety levels might have experienced greater state anxiety with UDS than bladder ultrasonography.

In addition, we have not studied the impact of the information given to the women before the procedure and how well we prepared the women for each diagnostic test. We sent out information leaflets about both UDS and bladder ultrasonography along with the appointment letters. During the clinic visit, we reinforced the patient’s understanding of each procedure. This is our routine practice based on previous evidence that women were likely to find the test less distressing when they felt they had been given adequate information about it. 134

Interpretation of findings

Our findings of increased pain and embarrassment perceived during UDS highlight the importance of clarifying the role of UDS in the management of women with OAB. The results may also be used by those preparing information material for women undergoing UDS and/or transvaginal ultrasonography, enabling them to give women a realistic picture of how they might feel.

Conclusion

The UDS procedure had statistically significant higher levels of pain and a lower rate of acceptability than the bladder ultrasonography procedure. In spite of this, the majority of the women would have repeat UDS if needed.

Recommendations for future research

The elevated anxiety levels elicited by invasive diagnostic testing on a background of increased trait anxiety due to LUTS need careful evaluation and interpretation. This may improve the support patients receive during invasive diagnostic testing and subsequent patient satisfaction.

Follow-up

The 6- and 12-month follow-up questionnaires were received at a median time of 7 and 20 months (IQRs 6–8 and 15–24 months, respectively) after tests. Results are henceforth referred to as at 7 and 20 months. The study recruited a total of 687 women and questionnaire booklet booklets were returned by 489 (71%) and 475 (69%) participants at the 7- and 20-month time points (Figure 14).

FIGURE 14.

Study flow chart of follow-up of participants after 6 and 12 months.

Urodynamics diagnosis

Of the total number recruited, 666 (97%) had complete UDS testing. On performing UDS, 43% (n = 284) were diagnosed with DO alone, 17% (n = 115) had DO + USI, 14% (n = 92) were diagnosed with USI alone and 26% (n = 175) had normal UDS. Table 17 summarises these frequencies by presenting symptoms.

Long-term symptom responses in the overall group

Fifty-three per cent (248/470) of the participants thought that their bladder problems had improved since going for the tests at 20 months (global impression of improvement question). Analysis of ICIQ responses showed improving scores reflecting declining severity of patients’ symptoms (Table 20). The reduction in the mean ICIQ scores over time from baseline is depicted in Figure 15.

TABLE 20 - ICIQ scores from baseline to 20 months

Time point	Mean ICIQ (SD), n	ICIQ change from baseline: mean (95% CI), p-value
Baseline	9.3 (2.7), 637
7 months	7.3 (3.3), 469	–1.9 (–2.2 to –1.6), p < 0.0001
20 months	7.0 (3.5), 460	–2.2 (–2.5 to –1.9), p < 0.0001

FIGURE 15.

Overall ICIQ scores over time (95% CIs are shown at each time point).

Long-term responses by urodynamics diagnosis

Positive responses to the global impression of improvement question were higher in the USI (35/56, 63%) and DO + USI (48/83, 58%) diagnosis groups than the DO (104/205, 51%) and normal UDS (60/125, 48%) groups, although the importance of diagnosis group was not statistically significant overall (p = 0.2). ICIQ scores were reduced from baseline in all groups at 7 and 20 months (p < 0.001 or less; Table 21 and Figure 16). There was some evidence that ICIQ responses varied between diagnosis groups overall (p = 0.02) and pairwise comparisons between them indicated that the DO + USI group have a greater reduction than the DO group (–1.1 points, 95% CI –1.7 points to –0.4 points; p = 0.002) over both time points. There were no statistically significant differences between the other groups.

TABLE 21 - ICIQ scores by diagnosis groups

Time point	UDS diagnosis
	DO + USI	DO	USI	Nothing
Baseline mean (SD), n	9.8 (2.5), 92	9.8 (2.7), 236	8.9 (2.7), 67	8.2 (2.3), 144
7 months mean (SD), n	6.8 (3.5), 81	8.1 (3.4), 207	7.1 (3.3), 57	6.5 (2.8), 124
20 months mean (SD), n	6.6 (3.6), 82	7.7 (3.8), 199	6.2 (3.3), 55	6.5 (3.1), 123

FIGURE 16.

The ICIQ scores over time by diagnosis group (95% CIs are shown at each time point).

Effect of receiving a medical or surgical treatment concordant with urodynamics diagnosis

Sixty-two per cent and 66% of patients had received a medical or surgical treatment concordant with their UDS diagnosis by 7 and 20 months, respectively (Table 22). At 20 months, 57% (168/296) of patients who had received a concordant treatment responded positively to the global impression of improvement question compared with 45% (69/152) of patients whose treatment was discordant with their diagnosis (OR 1.6, 95% CI 1.1 to 2.3; p = 0.02). There was no overall evidence that this varied by UDS diagnosis (p = 0.1), although positive responses appeared higher in the DO + USI and USI groups (Table 23). ICIQ scores were reduced at 7 and 20 months overall (Table 24 and Figure 17) and the reduction was significantly greater at both time points in those who had received a concordant treatment than those who had received a discordant treatment (–0.5, 95% CI –0.9 to –0.1; p = 0.02). There was no evidence that the effect of receiving a concordant treatment varied by UDS group (p = 0.3; Table 25).

TABLE 22 - Proportion of patients who had received a medical or surgical treatment concordant with their UDS diagnosis at 7 and 20 months

UDS diagnosis	Concordant medical or surgical treatment, n/N (%)
7 months
DO + USI	40/71 (56)
DO	113/194 (58)
USI	6/53 (11)
Normal UDS	111/118 (94)
Total	270/436 (62)
20 months
DO + USI	56/82 (68)
DO	121/201 (60)
USI	18/61 (30)
Normal UDS	111/123 (90)
Total	306/467 (66)

TABLE 23 - Proportion of patients reporting improvement in symptoms at 20 months by UDS diagnosis and whether a medical or surgical treatment concordant with this diagnosis had been received

UDS diagnosis	Concordant medical or surgical treatment = no, n/N (%)	Concordant medical or surgical treatment = yes, n/N (%)	OR (95% CI)
DO + USI	8/25 (32)	39/55 (71)	5.2 (1.9 to 14.4)
DO	36/79 (46)	63/118 (53)	1.4 (0.8 to 2.4)
USI	24/41 (59%)	10/14 (71)	1.8 (0.5 to 6.6)
Normal UDS	1/7 (14)	56/109 (51)	6.3 (0.7 to 54.4)
Total	69/152	168/296

TABLE 24 - The ICIQ score responses by whether a medical or surgical treatment concordant with UDS diagnosis had been received

Time point	Concordant medical or surgical treatment = no		Concordant medical or surgical treatment = yes
	Mean (SD), n	Change from baseline: mean (95% CI), p-value	Mean (SD), n	Change from baseline: mean (95% CI), p-value
Baseline	9.3 (2.5)		9.0 (2.8)
7 months	7.7 (3.6), 159	–1.6 (–2.1 to –1.1), p < 0.0001	7.0 (3.2), 261	–2.1 (–2.4 to –1.7), p < 0.0001
20 months	7.3 (3.6), 150	–1.9 (–2.4 to –1.3), p < 0.0001	6.8 (3.5), 289	–2.4 (–2.8 to –2.0), p < 0.0001

FIGURE 17.

The ICIQ scores over time by medical or surgical treatment concordant with UDS diagnosis (95% CIs are shown at each time point).

TABLE 25 - The ICIQ scores by UDS diagnosis and whether a medical or surgical treatment concordant with this diagnosis had been received

UDS diagnosis	Concordant medical or surgical treatment = no		Concordant medical or surgical treatment = yes
	Mean (SD), n	Change from baseline: mean (95% CI), p-value	Mean (SD), n	Change from baseline: mean (95% CI), p-value
DO + USI
Baseline	9.4 (2.1)		9.5 (2.7)
7 months	6.9 (3.2), 28	–2.7 (–4.0 to –1.4), p = 0.0003	6.2 (3.7), 38	–3.4 (–4.5 to –2.3), p < 0.0001
20 months	7.4 (3.6), 26	–1.8 (–3.3 to –0.4), p = 0.02	6.0 (3.4), 53	–3.6 (–4.6 to –2.6), p < 0.0001
DO
Baseline	9.6 (2.8)		9.9 (2.8)
7 months	8.6 (3.6), 79	–1.0 (–1.6 to –0.4), p = 0.002	7.8 (3.3), 111	–2.2 (–2.8 to –1.6), p < 0.0001
20 months	7.6 (3.8), 77	–1.6 (–2.3 to –0.8), p < 0.0001	7.9 (3.8), 115	–2.3 (–3.0 to –1.6), p < 0.0001
USI
Baseline	8.9 (2.4)		9.3 (4.0)
7 months	7.1 (3.4), 45	–1.8 (–2.8 to –0.8), p = 0.0006	6.5 (4.1), 6	–2.8 (–7.8 to 2.1), p = 0.2
20 months	6.4 (3.3), 40	–2.6 (–3.8 to –1.3), p = 0.0001	5.8 (3.1), 14	–2.3 (–4.3 to –0.2), p = 0.03
Normal UDS
Baseline	9.9 (2.0)		8.0 (2.3)
7 months	6.3 (3.5), 7	–3.6 (–6.9 to –0.2), p = 0.04	6.5 (2.8), 106	–1.5 (–1.9 to –1.0), p < 0.0001
20 months	8.1 (3.2). 7	–1.7 (–5.1 to 1.8), p = 0.3	6.3 (3.1), 107	–1.9 (–2.4 to –1.3), p < 0.0001

Relationship between presenting symptoms and long-term outcomes

Positive responses to the global impression of improvement question at 20 months were slightly higher in the urgency + SUI group (56%, 159/286) than the urgency alone group (48%, 86/181) but this difference was not statistically significant (p = 0.09). There was also no evidence that the effect of these presenting symptoms varied by whether or not a treatment concordant with UDS diagnosis had been received (p = 0.2). ICIQ scores were lower at both time points in both groups (Table 26 and Figure 18); however, there was some evidence of the urgency + SUI group improving more than the urgency alone group by 20 months (0.60 points, 95% CI 0.00 points to 1.20 points) but not at 7 months (–0.03 points, 95% CI –0.56 points to 0.51 points).

TABLE 26 - Relationship between ICIQ scores and clinical symptoms

Clinical symptoms	Mean (SD), n	Change from baseline mean (95% CI)	p-value
Urgency + stress
Baseline	9.4 (2.6)
7 months	7.4 (3.4), 286	–1.9 (–2.3 to –1.6)	< 0.0001
20 months	6.9 (3.6), 278	–2.5 (–2.9 to –2.1)	< 0.0001
Urgency alone
Baseline	9.1 (2.8)
7 months	7.3 (3.2), 181	–1.8 (–2.2 to –1.4)	< 0.0001
20 months	7.2 (3.5), 179	–1.8 (–2.3 to –1.3)	< 0.0001

FIGURE 18.

The ICIQ scores over time by presenting symptoms (95% CIs are shown at each time point).

Relationship between bladder wall thickness and long-term outcomes

There was no evidence that BWT had any relationship with the global impression of improvement responses at 20 months (p = 0.4) or ICIQ scores (p = 0.8) over 7 and 20 months (correlation coefficients r = 0.01 at both time points); Figure 19 shows the distribution of scores at 7 months. There was also no evidence of BWT having any interaction effect with (1) UDS diagnosis (global impression of improvement: p = 0.9; ICIQ: p = 0.7) or (2) presenting symptoms (global impression of improvement: p = 0.2; ICIQ: p = 0.5).

FIGURE 19.

Seven months ICIQ scores vs. BWT (r = 0.01).

Summary of main findings

Our analysis demonstrated that UDS diagnosis appeared to have an effect on subsequent treatment. Women with DO were three times more likely to have had bladder relaxants than no treatment compared with women with normal UDS. This might mean that those who were shown to have DO were more likely to be prescribed bladder relaxant tablets or that patient compliance with taking the treatment improved. Women with a diagnosis of DO + USI were 15 times more likely to have USI surgery than no treatment, which may at least partly explain the improved ICIQ scores and global impression of improvement over patients with pure DO.

Numerous studies have demonstrated that a diagnosis of OAB cannot be accurately made based on symptomatology alone. 29,35,149,150 Clement et al. 151 concluded in their Cochrane review that urodynamic testing did change clinical decision-making in women treated for UI (relative risk 5.07, 95% CI 1.87 to 13.74) and more women received drugs in the UDS groups. Contrary to the finding of the Cochrane review, that women were not more likely to undergo surgery, we found that more women with DO + USI had received surgery by the 20-month follow-up. 151 Confirmation of the concurrent pathophysiology of DO + USI may have resulted in more clinicians offering USI surgery when bladder relaxants alone failed to provide improvements.

Over half (53%) of the study population reported an improvement in symptoms and disease-specific scores by a margin that appears clinically meaningful. The ICIQ-OAB provides a brief and robust measure to assess the impact of symptoms of OAB on QoL. In the follow-up of the BUS participants, scores were significantly reduced from baseline by 2.2 points (p < 0.0001). The findings also support ‘responsiveness’ of ICIQ questionnaire to therapy as the change in ICIQ scores was two-thirds of a SD and most studies would accept a difference of half a SD to be a clinically important change. 152

Patients who received a medical or surgical treatment concordant with their UDS findings were more likely to report an improvement in bladder symptoms at 20 months than those who did not (57% vs. 45%; p = 0.02). The improvement reported by those who did not receive a concordant treatment could be for several reasons, such as natural fluctuation of disease state, regression to the mean and Hawthorne effects. 153 The experience of UDS may have helped women to understand their condition better and improve compliance, including with lifestyle measures. 154

The ICIQ scores were reduced at both time points regardless of whether or not the women received a treatment concordant with UDS findings; however, patients receiving a concordant treatment reported a slightly greater reduction (–0.5 points; p = 0.02). There was also some evidence that ICIQ responses were greater in the DO + USI diagnosis group than the DO group (–1.1 points; p = 0.002); that is, women with MUI treated based on UDS diagnoses appear to have greater reductions in symptoms.

There was no evidence that BWT had any relationship with the global impression of improvement responses or ICIQ scores. This concurred with the findings from the BUS which indicated that BWT is not a useful test in the management of these patients.

Strengths and limitations

The patients were followed up for more than 12 months and validated questionnaires were used. This study is one of the few reporting on prospective follow-up in patients with urgency-predominant MUI and suggestive of better prognosis in the MUI group than the DO group.

The response rate for continued follow-up of the BUS cohort was 69% which, although not high, is superior to other studies in the field at over 1-year follow-up. We could only ascertain whether or not women had ever having taken bladder relaxants and could not determine whether or not women were currently taking bladder relaxants. In addition, the number of women having both bladder relaxants and surgery was small and, therefore, could not be reliably distinguished from those who had surgery alone in the analysis. We also did not collect data on therapies, such as supervised intensive PFMT, bladder retraining, lifestyle changes, etc., but we presumed that the conservative treatment was already exhausted before patients were referred for UDS.

As the study is an observational study, it is not possible to directly infer the clinical effectiveness of the therapies from the comparison of whether treatment options were compliant or non-compliant with the UDS diagnosis. There may be other reasons why patients whose treatment did not follow from the diagnosis have different outcomes from those who did, for example reasons related to health states, patient preferences and characteristics.

Interpretations of findings

Urodynamics appears to influence treatment decisions made by clinicians in determining treatment pathways in women presenting with UI. Women treated with medical or surgical interventions based on UDS diagnoses appear to have greater reductions in symptoms than who were not. This was more evident in women with MUI on UDS. In the overall population, half the women reported long-term improvement in symptoms. BWT is not associated with patient management or treatment responses, either global or ICIQ score changes and has no prognostic value as a test in this condition.

Recommendations for research

There is need for randomised trials involving women with OAB or urgency-predominant MUI, comparing treatment based on UDS with treatment based on clinical symptoms and examination alone. 155

Further work needs to be carried out to establish the ‘minimally important clinical difference’ in ICIQ scores to enable its use to quantify response to treatment objectively in clinical practice. This could be done by assessing the changes in the bladder diary variables and the individual ICIQ items. 156

Objectives

The initial objective of the primary study was to evaluate the accuracy of bladder ultrasonography in the diagnosis of DO and to investigate the added value of using the test results alongside the information obtained from routinely used non-invasive tests. These objectives were revised [with agreement of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA)] because bladder ultrasonography was shown in the accuracy study to be of limited diagnostic value. The focus switched instead to the investigation of the accuracy and cost-effectiveness of UDS in the investigation of OAB-like presentations. However, given that the initial objective was to evaluate bladder ultrasonography and given the extent of data collected on this test, for completeness it has been included in the economic analysis.

National Institute for Health and Care Excellence recommends the use of UDS only prior any invasive intervention for OAB,36 based on evidence indicating its limited role in determining the outcome of conservative treatments. 66 Thus, the objective of the model-based economic evaluation of this chapter is to compare the relative cost-effectiveness of undertaking three alternative diagnostic strategies based on (1) UDS, (2) a bladder ultrasonography test or (3) clinical history for women with predominant symptoms of OAB for whom conservative treatments were not effective. Each strategy contains both the test and the subsequent treatment options made based on the results of the test. For brevity, we will refer to the strategies by the test name, but in all instances we consider a strategy as consisting of the test plus the treatment choices, which are made dependent on the test result obtained.

Model structure

In order to maintain patient history and given the short-term nature of the decision problem, the appropriate model structure to describe the options being compared and their treatment pathways is a decision tree. The model was developed in TreeAge Pro 2014 software (TreeAge Software, Inc., Williamstown, MA, USA) and the structure was informed by clinical input and NICE guidelines on the management of UI. 36 Women with a mean age of 55 years (95% CIs 39 years to 71 years) enter the model if they present predominant symptoms of OAB and conservative treatments have not been effective. The term ‘predominant symptoms of OAB’ refers to symptoms of urgency or urgency-related incontinence, possibly accompanied by stress incontinence. Women who have not undergone conservative treatments and women for whom conservative treatments were effective in treating the urgency symptom but the stress symptom remained were not included in the analysis.

In the primary analysis of the model-based economic evaluation, women are assumed to follow one of three alternative strategies for the treatment of their symptoms: (1) based on UDS observation alone, (2) based on bladder ultrasonography test alone and (3) based on clinical history. These are presented in the branches to the right of the decision node (square symbol) in Appendix 9 (see Figure 43). For completeness, pathways for strategies that represent other combinations in which clinical history and diagnostic tests can in theory be used together are also considered. These are illustrated in Appendix 9 (see Figure 44).

Once women enter the model, it is assumed that they proceed from the least invasive (and more common) interventions to the most invasive ones. For the purpose of the model, it is assumed that further conservative treatment is not provided. However, in real life, conservative treatments are ongoing and can be complementary to the more invasive interventions.

As a first-line surgical intervention for the treatment of OAB caused by DO (diagnosed as DO by UDS, or a positive bladder ultrasonography test, or as urgency with or without urgency incontinence, or clinical history) women go through either BTX-A injections or PTNS depending on patient and physician preferences. If these interventions are not effective, the second-line intervention is determined through a peripheral nerve evaluation (PNE), which is the first stage of the SNS. The outcome then determines whether or not a permanent implantation of a stimulation device (stage II) will be given. If this is not indicated, women are assumed to undergo either BTX-A injections or PTNS depending on which of the two has not been applied earlier in the treatment pathway.

The treatment of SUI (USI diagnosed only by UDS) involves a sling surgery as a first-line intervention and Burch colposuspension as a second-line surgical treatment.

In cases of MUI (diagnosed as DO + USI by UDS, a negative bladder ultrasonography test, or urgency-dominant MUI clinical history) women can opt for BTX-A injections prior to the sling surgery and Burch colposuspension as a second-line surgical treatment.

Women who are diagnosed with a normal bladder, despite the existence of symptoms, can be identified by UDS only. These women are assumed to remain symptomatic without further interventions.

For the strategies bladder ultrasonography test and clinical history, when treatment either for OAB or MUI is initiated, women are assumed to receive invasive interventions as a result of a misdiagnosis. The same is assumed for women who have low compliance only or VD only despite the predominant symptoms of OAB. The treatment pathways for each syndrome in the UDS strategy are illustrated in Appendix 9 (see Figures 45–47). The pathways for the diagnostic strategies of bladder ultrasonography test and clinical history are shown in Appendix 9 (see Figures 48–51).

Model assumptions

To carry out the model-based analysis some further pragmatic assumptions were required. These are presented below.

• Diagnostic tests may be repeated once in each treatment pathway before the second-line interventions and intervention strategies will change if the second test contradicts the original test.

• In the UDS and bladder ultrasonography strategies, treatment is assumed to be initiated 3 months after the diagnostic test, but instantly in the case of clinical assessment. Three months was selected as an arbitrary cut-off point below the maximum of 18 weeks used in the NHS157 to reflect the waiting time for a subsequent visit for a first-line intervention.

• Symptoms of VD and low compliance that can accompany DO, MUI or SUI are assumed to not have an impact on the clinical effectiveness of interventions.

• Women diagnosed with VD require self-catheterisation training.

• A woman can have up to three BTX-A injections at yearly intervals.

• Subjective cure from BTX-A entails the possibility of acquiring voiding difficulties that will require self-catheterisation training.

• PTNS is offered in 12 sessions, a week apart, in the final 3 months. If it is successful, a monthly session is required for the rest of the model period in order for its clinical effectiveness to be maintained.

• In the case of SNS, a proportion of women will require a revision of the surgery and maintenance or removal of the implanted neurostimulator device, depending on the time between SNS surgery and the end of the model period. These were assumed to take place at the end of the model period.

• De novo DO or urgency UI is a possible outcome of an antistress incontinence surgery. It is described as the development of a new OAB-related symptom in women who did not demonstrate DO in their pre-operative evaluation. Given that women entering the model have predominant symptoms of OAB, de novo DO or urgency UI is not modelled.

• If a woman becomes subjectively cured, improvements are assumed to be maintained throughout the model period.

Clinical data

The prevalence and accuracy data used in the model are based on the results of the primary study using UDS as a reference standard. These are presented in Tables 27–30. The probability of each intervention being clinically effective is presented in Table 31. Data on the effectiveness of PTNS in women with DO,82 the clinical effectiveness of sling surgery in women with SUI160 and MUI,161 as well as the clinical effectiveness of colposuspension in women with SUI164 were drawn from meta-analyses. The probability of SNS being effective in women with DO was taken from a systematic review. 89 Observational studies were used to inform the probability of three repetitive BTX-A injections being effective in women with DO158 and the cure rate of colposuspension in women with MUI. 163 From the former observational study, the proportion of women that become subjectively cured after three BTX-A injections (56.8%), the disaggregation of the overall effectiveness across the three injections and the drop-out rate after each injection were used in the model (Table 32). In the absence of relevant literature, the disaggregation of the overall effectiveness across the three injections and the drop-out rate after each injection were assumed to be the same if BTX-A was offered in women with other syndromes.

A literature search was undertaken to identify the clinical effectiveness of interventions modelled in a situation of a misdiagnosis. Apart from the clinical effectiveness of a sling surgery in women with DO identified in a published economic evaluation,90 there was limited robust evidence to inform the model about the clinical effectiveness of BTX-A in women with MUI and SUI or the clinical effectiveness of PTNS and SNS in women with MUI or SUI. For this reason, these values were elicited from the anonymous expert opinion of eight study collaborators on 18 June 2014. Expert opinion is a legitimate source of information in decision modelling when other information is not available. Given that the parameters of interest apply to very rare circumstances, it was appropriate to decide in advance to use a beta distribution and use a simple approach to elicitation, asking for most likely value as well as lowest and highest, interpreting these as mean and lower and upper limits of a 95% CI. Use of more elaborate elicitation techniques165 was judged to be unlikely to make an appreciable difference to the modelling.

Other data used in the model are presented in Table 33. The proportion of women that proceed to an implantation of a neurostimulator device (SNS stage II) after a PNE was informed by a systematic review. 88 SNS often requires a revision of the surgery and this was assumed to vary across time. More specifically, 9% of women undergoing a SNS surgery are assumed to require a revision of the surgery within 2 years from the surgery and 33% after 3–5 years. These values were taken from two systematic reviews. 90,166 The probability of removal of the implanted device and the probability that a maintenance surgery will be required ≥ 2 years after surgery were also taken from these systematic reviews. In addition, VD is a possible adverse event after a subjective cure from BTX-A injections and the proportion of women acquiring VD was taken from a RCT. 91 Finally, the proportion of women with a diagnosis of MUI that choose BTX-A injections prior to a sling surgery and women with a diagnosis of DO (or OAB) of that choose BTX-A injections instead of PTNS were informed by the anonymous collaborators of this study.

Cost data

Information from the NHS Reference Costs 2012–1330 and Curtis92 was used to parameterise the cost component of the decision model. Costs were calculated in 2012–13 UK Great British pounds (£). These costs of different interventions modelled are presented in Table 34. Costs selected from the NHS Reference Costs have been calculated based on the weighted average value of elective inpatient and day-case costs and the proportion of patients in each group. An exception is in the case of the evaluation stage of the SNS, which is offered as a day case. Unit costs from the urology category were selected instead of the average across different medical specialties, apart from the case of bladder ultrasonography for which only a total Healthcare Resource Group (HRG) cost was available. The cost of three BTX-A injections has been calculated by multiplying the unit cost of each injection (£912, 95% CI £704 to £1060) by the proportion of women undergoing each injection. This has been calculated based on the proportions of women becoming subjectively cured and dropping out after each BTX-A injection, which combines information from Tables 31 to 32. Information about the mean cost and 95% CIs for three BTX-A injections across the different syndromes is illustrated in Table 35.

Outcomes

To examine whether or not a diagnostic test is a cost-effective component in the treatment pathway for women with predominant symptoms of OAB, three different outcomes were considered: (1) women successfully treated, as determined by subjective symptoms, (2) DO cases detected and (3) quality-adjusted life-years (QALYs) based on the best available QoL data in the literature. The third combines quantity with QoL, which is measured using utility weights. A review of the Cost-Effectiveness Analysis Registry167 using the terms ‘overactive bladder’, ‘urinary incontinence’ and ‘detrusor overactivity’ was performed to identify relevant utility weights for the outcomes experienced at a time point beyond the primary study end point. Eighteen studies168–186 were identified and utility weights from one study168 were selected to represent the QoL for subjective cure. This study was selected because the utility values were obtained with a sound theoretical approach (time trade-off) and were relevant to the symptoms of OAB and the type of interventions modelled. 169 Utility weights from other studies were not considered, either because they were focusing on a population with OAB that was undergoing conservative treatments rather than invasive170–176 or because they were focusing on women with SUI. 177–182 In four more studies,183–186 the values of 0.95 and 0.73 were used to represent the utility of continent and incontinent state for a relevant population and interventions, but these were not considered appropriate because the former value in reality represents the utility weight of people with no chronic condition187 and the latter is based on women with SUI. 188 In the model, women who remain symptomatic were assumed to maintain their initial QoL, which was informed by the primary study. Thus, no QoL decrements were allowed to occur after diagnostic tests or after surgeries, even when they were the outcome of a misdiagnosis. The QoL scores used in the model are shown in Table 36. QALYs were estimated combining the utility weights with estimates of the duration of different health states.

Analysis

The decision model was constructed to investigate the cost-effectiveness of UDS compared with the diagnostic strategies, the bladder ultrasonography test and clinical history alone. Two separate economic analyses are carried out. The primary analysis provides a comparative evaluation of the costs and benefits of the UDS, bladder ultrasonography and clinical history diagnostic strategies. In a secondary analysis, all the different ways in which clinical history and a diagnostic test (UDS, bladder ultrasonography test) can be used together are explored. This allows the exploration of whether or not a diagnostic test in selective subgroups of women with predominant symptoms of OAB is a more cost-effective strategy than the three strategies explored in the primary analysis.

In both primary and secondary analyses, subjective cure is used for the identification of women successfully treated and UDS has been used as a reference standard. In the UDS arm, women with ‘normal’ or ‘other’ observations are assumed to remain symptomatic throughout the model period. However, in the case of bladder ultrasonography and clinical history, these women receive treatment for OAB or MUI as a result of a misdiagnosis. In such a situation, women were assumed to have a probability of becoming asymptomatic mainly as a result of a placebo effect. In the absence of robust evidence to inform this probability, the smallest figure of Table 31 (0.143, 95% CI 0.133 to 0.375) was selected.

The analyses were carried out from the perspective of the UK NHS and the primary outcome is in terms of cost per woman successfully treated. Other outcomes included in the analysis are cost per DO case detected and cost per QALY. The latter is the recommended outcome for economic evaluations in the UK. 189 Results presented in terms of QALYs represent an additional analysis and were not part of the principal objective of the study. Results are presented in terms of incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability frontiers (CEAFs). A 5-year time horizon was considered appropriate to reflect all key differences, in terms of costs and benefits, for the options compared. Costs and QALYs accruing beyond 12 months were discounted at a rate of 3.5% per year. According to NICE,36 based on existing evidence,66 UDS should not be applied prior to the initiation of conservative treatments but only when these are not effective and women are expected to proceed to more invasive interventions. For this reason, the decision model is focusing on the subgroup population of the primary study that had been taking conservative treatment before enrolling into the study and had complete accuracy data on the three strategies modelled (n = 209).

Deterministic and probabilistic sensitivity analyses (PSAs) are performed to explore the effects of the inherent uncertainty in parameter estimates on model results. In deterministic sensitivity analysis, one or more parameters are varied while keeping the remaining at their baseline value. Although deterministic sensitivity analyses can be helpful to identify which model inputs are important in driving a decision or identify threshold values, comprehensive representation can be obtained by undertaking a PSA, in which the uncertainty around a parameter is represented with a probability distribution. 190,191 In the PSA, using 10,000 repeated random draws from those distributions, a Monte Carlo simulation of the model provides an indication of how variation in the model parameters leads to a variation in the results generated. Beta and Dirichlet distributions were used for binomial and multinomial data, respectively (see Tables 27–33 and Table 36) and a Gamma distribution for costs (see Table 34). The parameters of each distribution are shown in the corresponding tables.

Deterministic sensitivity analyses

A number of deterministic sensitivity analyses were conducted in both the primary and secondary analyses. These deterministic analyses include both univariate and multivariate analyses to assess the impact of any uncertainty in model parameters on the final results. Three univariate analyses and four multivariate analyses were conducted based on the following justifications:

1. Univariate analyses

   1. Reducing the cost of UDS from £401 (95% CI £216 to £462) to £173. The base-case value was calculated based on the weighted average value of elective inpatient and day-care costs for a urological intervention and the proportion of patients in each group. The value used in this sensitivity analysis represents the weighted average value of total HRGs. 30

   2. Increasing the cost of sling surgery by 50% to account for possible adverse events such as bladder injury, vaginal erosion or groin pain. 160

   3. Lowering the utility weight of women subjectively cured from 0.92 to 0.84. This value is drawn from the BUS and represents the EQ-5D QoL score of those women that scored below four in the ICIQ (low bother).

2. Multivariate analyses

   1. Changing the accuracy data. The main analyses use UDS as a reference standard, which possibly leads to an overestimation of its diagnostic accuracy. In addition, urinary diaries can complement clinical history and provide a more accurate clinical assessment. The accuracy of UDS was reduced using evidence from an economic evaluation,64 which reports 14% probability of false-positive diagnoses for MUI when DO or SUI are the true conditions and 25% probability of false-positive diagnoses for SUI when MUI is the true condition. Similarly, a systematic review150 has reported that clinical history and information from diaries detect 53.4% of women with DO, increasing the accuracy of clinical history by five percentage points.

   2. Changing the rates of clinical effectiveness elicited from expert opinion to their lowest value.

   3. Changing the rates of clinical effectiveness elicited from expert opinion to their highest value.

   4. Assuming one diagnostic test is offered prior to the initiation of the first-line interventions in line with NICE guidelines. 36

Primary analysis

The costs and outcomes of each strategy in the primary analysis are shown in Table 37. In terms of cost, UDS is the least expensive strategy (£4524) with clinical history and bladder ultrasonography costing an additional £1278 (£5801) and £1424 (£5947), respectively. In terms of outcomes, treatment based on clinical history appeared to be the most effective strategy apart from the number of DO cases detected, for which UDS was more effective (as DO is an urodynamic observation rather than a clinical symptom, a DO diagnosis is never made based on clinical history).

It is important to note that the total cost per patient (from £4524 to £5947) greatly exceeds the cost of the initial tests (£401 for UDS or £51 for bladder ultrasonography) and thus the major determinants of the costs are the treatment selections made based on the results of the tests.

In the deterministic analysis, the bladder ultrasonography test strategy was dominated by the other two strategies as it was the most expensive and least effective strategy across all outcomes explored in the analysis. In the remainder of this subsection, the results of the incremental analysis are described with more information provided about the cost for an additional unit of outcome between the strategies compared. Dominated strategies, such as bladder ultrasonography, are not described as a part of the incremental analysis.

Secondary analysis

In this analysis, apart from the main strategies explored in the primary analysis, four further strategies that use a diagnostic test as an adjunct to the clinical history have been included. In these strategies, a diagnostic test (UDS, bladder ultrasonography) is conducted when clinical history has indicated either OAB or MUI. This analysis aims to provide a further insight into the cost-effectiveness of performing a diagnostic test only in selective subgroups of the population modelled. When UDS is used as an adjunct to the clinical history if OAB or MUI has been indicated from patient history, the strategies have been termed as clinical history and UDS in OAB and clinical history and UDS in MUI, respectively. Similarly, when the bladder ultrasonography test complements clinical history, the terms clinical history and BUS in OAB as well as clinical history and BUS in MUI are used.

The mean estimated costs and outcomes for each of the seven strategies compared in the secondary analysis are presented in Table 37. In terms of cost, UDS is again the least expensive strategy with a mean cost of £4524. In terms of outcomes, conducting a diagnostic test when clinical history suggests MUI appears to be more effective in all three outcomes considered in the analysis. More specifically, performing bladder ultrasonography if the patient’s history indicates MUI is the most effective strategy when the outcome is measured in women successfully treated, while conducting UDS if MUI is indicated by the clinical history is the most effective strategy when the outcome is measured in terms of QALYs and DO cases detected.

Principal findings

The results of the deterministic analysis suggest that a patient management strategy based on using bladder ultrasonography to select treatment options is more costly and less effective than the strategies based on UDS and clinical history. Given that the results of the main study show that bladder ultrasonography is of limited diagnostic value, the uncertainty around the deterministic results of this strategy was not explored in a PSA.

With regard to the other two strategies, treating according to the primary symptoms in clinical history is more effective than UDS, leading to an additional 26 cases per 10,000 women successfully treated and 0.02 QALYs gained per woman. This comes at an additional cost of approximately £1300 per woman arising from the costs of the treatments used. Given current acceptable thresholds, this additional cost would not be justified by the clinical gain. In terms of DO cases detected, UDS detects more cases than clinical history at a lower cost. Thus, the results of the primary analysis suggest that UDS would be the preferred strategy on cost-effectiveness grounds for women with predominant symptoms of OAB. This result holds for all three outcome measures used in the primary analysis. This finding has arisen because, although the UDS test itself adds to the cost of clinical history, basing treatment decisions on the UDS leads to more efficient use of expensive interventions than basing decisions on clinical history alone.

In the secondary analysis, the strategy of giving UDS to women with a clinical history of MUI is more effective than universal UDS. The selective use was shown to result in an additional 309 cases per 10,000 women successfully treated and the QALY gain per woman was 0.05. The additional cost per woman was £600. This strategy would be considered value for money according to acceptable thresholds in the UK. Based on cost per DO case detected, UDS was not deemed cost-effective for these women given the ICER of £62,000. This is not a surprising finding as DO is an urodynamic observation and not a clinical symptom.

Univariate and multivariate sensitivity analyses were performed to explore the robustness of the model results to changes in the assumptions made. Conclusions drawn from the main analysis remained robust to all sensitivity analyses apart from the scenario in which the highest effectiveness rates were assumed in cases of misdiagnosis.

Strengths and limitations of the study

The prevalence and accuracy data were estimated in the primary study and the main clinical pathways were parameterised with clinical effectiveness data mostly from systematic reviews and meta-analyses. In addition, costs were drawn from national sources and the development of the model relied on national guidelines. These are likely to enhance the generalisability of the study’s findings. Finally, all assumptions used in the model were agreed a priori and key assumptions have been tested in sensitivity analyses.

However, there are a few weaknesses. Instead of clinical history, the best alternative strategy to compare the cost-effectiveness of UDS with could have been clinical assessment. Urinary diaries, for example, are used to complement clinical history and provide a joint decision based on clinicians’ assessment rather than on patient’s history alone. Furthermore, ambulatory UDS has been shown to be more sensitive in detecting DO,194 or generally the underlying syndrome of UI,195,196 than conventional UDS and thus the results of the economic evaluation may overstate the cost-effectiveness of UDS, as it has been used as a reference standard. Ambulatory UDS was used as part of the primary study in situations of a negative UDS, but in the subgroup population used for the model, the number of observations were not enough to be tested in a sensitivity analysis (n = 7).

A further limitation relates to the QoL estimates used for the outcomes experienced beyond the primary study end point. In the absence of robust utility weights, it was assumed that women maintain their QoL if an invasive intervention is not successful and that all women have a utility score of 0.92 once they become subjectively cured. In reality, however, utility decrements can occur after invasive and poorly tolerated diagnostic strategies, such as UDS or surgeries. In addition, utility gains tend to differ between different syndromes and severity of symptoms. Despite the low accuracy of the QALY estimates used in the model, there was a significant consistency between the results obtained from the primary outcome (cost per woman successfully treated) and the results obtained using QALYs.

Furthermore, in the absence of available literature on the clinical effectiveness of the different interventions modelled in situations of misdiagnosis, values had to be elicited from expert opinion (see Clinical data). Probabilistic and deterministic sensitivity analyses were undertaken to reduce the uncertainty around these parameter estimates and explore their impact on conclusions drawn. Another limitation relates to the fact that the order of the interventions modelled for the treatment of women with predominant symptoms of OAB might be slightly different in practice. For example, after an unsuccessful sling surgery, instead of going through a Burch colposuspension, women may repeat the sling surgery. However, such differences are not expected to significantly impact on the results of the model. Finally, the syndromes of OAB, SUI and MUI are often associated with substantial personal costs. These costs are not included in economic analyses conducted from a health-care perspective and thus economic evaluations from a societal perspective could shed further light onto the cost-effectiveness of the alternative diagnostic strategies for women with predominant symptoms of OAB.

Strengths and limitations in relation to other studies

Economic evaluations that have explored the role of UDS in the treatment of women with predominant symptoms of SUI65 or genuine SUI64,89 have concluded that UDS is not a cost-effective diagnostic test. However, for women with predominant symptoms of OAB, relevant economic evidence on the role of UDS is lacking, while clinical evidence remains inconclusive. 17,29,66

The results of the economic evaluation of this chapter suggest that UDS has a role to play in the treatment pathway of women with OAB. An investigation into whether or not a diagnostic test is more cost-effective when performed in only specific subgroups of women concluded that the most cost-effective diagnostic strategy is to perform UDS in women with a clinical history of mixed incontinence. This finding seems to be further supported by evidence from clinical studies indicating that in women with OAB only an urodynamic observation of DO does not have an impact on the outcome of more invasive interventions,84,86,197 but also from evidence indicating that mixed urinary symptoms tend to be more common than mixed UI on UDS. 13,198 The magnitude of DO appears to be close to 50%,198 as it was also found in the primary study (55%).

Meaning of the study

The results of the economic evaluation showed that UDS is a cost-effective diagnostic strategy for women with predominant symptoms of OAB for whom conservative treatments were not effective. The primary analysis suggested that UDS is the most cost-effective strategy across all outcomes providing significant cost-savings for a small reduction in outcome. The secondary analysis suggested that selective UDS, restricting its use to women with a clinical history of MUI, is a cost-effective strategy.

Unanswered questions and future research

In this study, UDS was used as the reference standard, which may have led to an overestimation of its diagnostic accuracy. Evidence suggests that ambulatory UDS is more sensitive in detecting DO194 and other syndromes of UI. 195,196 Furthermore, a more appropriate comparator for UDS would have been the clinical assessment, which would provide an overall clinical diagnosis based on the clinical history (validated questionnaires) and urinary diaries. Thus, a comparative evaluation of the costs and benefits of UDS and clinical assessment using ambulatory UDS as a reference standard would help gain further insight into the cost-effectiveness of UDS in women with predominant symptoms of OAB.

Furthermore, there are significant inconsistencies in the instruments used in the literature to capture QoL in women with urinary symptoms. Disease-specific instruments, such as the incontinence-specific QoL questionnaire and other non-preference-based measures that are often used in women with OAB symptoms, offer limited usefulness as outcome measures in cost-effectiveness analyses;199 although, mapping algorithms have now started to be developed. 200 Nevertheless, for conditions such as OAB, in which symptoms can also be associated with non-health impacts (e.g. embarrassment), instruments that go beyond health and capture wider changes in individual’s QoL may be deemed more pertinent. An example is the ICECAP-A measure,201 which incorporates capability attributes on Attachment, Security, Role, Enjoyment and Control. Further research is required in the use of such instruments in women with urinary symptoms.

Finally, it appears that further research is needed to resolve current decision uncertainty around the cost-effectiveness of UDS in all women with predominant symptoms of OAB or in only those with a clinical history of MUI. A measure of the maximum possible value of any such research is the expected value of perfect information (EVPI). EVPI is estimated from the difference between the expected net benefit with perfect and current information, and multiplied by the size of the population that could benefit from additional information. Based on estimates of prevalence of women with predominant symptoms of OAB in the UK202–204 and an incidence rate of 6% (54,000 women),205 while assuming a time horizon of 10 years and an annual discount rate of 3.5%, the EVPI was estimated at almost £36M and £77M at a WTP threshold of £28,000 per additional woman successfully treated for the primary and secondary analyses, respectively (see Appendix 10, Figures 67 and 68). These figures reflect the large expected opportunity loss associated with current decision uncertainty and the need for further primary research.

Post-void residual

• Identify entire bladder in sagittal plane, measure longest anteroposterior dimension and then cranio–caudal dimension perpendicular to this (Figure 39).

• Rotate probe through 90° and measure axial dimension (Figure 40).

• Most machines are now able to generate volumes automatically (need to select this before starting with callipers).

• If not available, use the following to standardise calculations: cranio–caudal (H) × anterior–posterior (D) × transverse diameter (W) × 0.5233 (prolate ellipsoid) = PVR volume.

FIGURE 39.

Transvaginal scan in sagittal section to measure the anteroposterior and cranio–caudal dimensions of the bladder.

FIGURE 40.

Transvaginal ultrasound in coronal section to measure the axial dimension of the bladder.

Bladder wall thickness assessment

• Measurement should be obtained in sagittal plane with vesicoureteric junction on margin of screen (probe may need to be introduced slightly further).

• Three × measurements: at the dome, anterior wall and trigone need to be obtained. Then also measure BWT at dome 1 cm to the left and right of midline (Figures 41 and 42).

• The same image should be stored twice: with and without callipers.

• Any focal areas of thickening need separate assessment and evaluation.

• It is not always possible to see the anterior wall or trigone well, as many women with bladder problems often have an irregular bladder outline, but it is always possible to see the dome.

• If the whole of the bladder is not visible on one image (as is preferable), there may be the need to angle anteriorly or posteriorly and measure the trigone or anterior wall thickness.

• Patients with significant cystocoeles may find complete emptying difficult and trigone may be difficult to visualise adequately.

• It is important to document any additional findings (e.g. diverticuli, cystocoeles, focal masses).

FIGURE 41.

Transvaginal scan with callipers showing measurements on the dome, anterior wall and trigone.

FIGURE 42.

Transvaginal scan showing the three dome measurements.

Providing electronic images

Anonymised electronic images for each patient should be provided, labelled clearly with study identifier as the only identifier. These images should be as follows:

1. PVR image 1 WITH callipers.

2. PVR image 1 WITHOUT callipers.

3. PVR image 2 WITH callipers.

4. PVR image 2 WITHOUT callipers.

5. BWT image 1 WITH callipers.

6. BWT image 1 WITHOUT callipers.

7. BWT image 2 (optional) WITH callipers.

8. BWT image 2 (optional) WITHOUT callipers.

For optimal quality these should be sent to Birmingham Clinical Trials Unit on disc or memory stick, ideally in DICOM format.

Failing this JPEG (Joint Photographic Experts Group) images will be accepted.

If downloadable images are not possible, please supply a print out of each image listed above, ensuring that the print quality is optimal (what is seen on screen).