MRI versus laparoscopy to diagnose the main causes of chronic pelvic pain in women: a test-accuracy study and economic evaluation

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 09/22/50. The contractual start date was in October 2011. The draft report began editorial review in August 2016 and was accepted for publication in November 2017. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Elizabeth Ball declares UK travel reimbursement from Shire Medical (Lexington, MA, USA) outside the submitted work. Jonathan J Deeks was Deputy Chairperson of the National Institute for Health Research Health Technology Assessment (HTA) Commissioning Board (2011–16) and the HTA Efficient Study Designs Board (2016).

Copyright statement

© Queen’s Printer and Controller of HMSO 2018. This work was produced by Khan et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2018 Queen’s Printer and Controller of HMSO

Background

Diagnosis of the cause of chronic pelvic pain

A troublesome clinical issue is the lack of accurate tools to efficiently diagnose and direct cases of women. 23 The Royal College of Obstetricians and Gynaecologists (RCOG) guidelines on the management of CPP provide a number of suggested initial investigations, including history, microbiological screening and vaginal examination, all with weak evidence (levels B or C) for recommendations. 20 If no cause of pain is found, the first port of call is often to perform a diagnostic laparoscopy.

Treatment of chronic pelvic pain

As diagnoses emerge through careful history and examination and directed investigation, so may treatment strategies. These should be tailored to the needs of individual women, whatever the cause. A multidisciplinary approach is considered ideal for achieving this. Chronic symptoms need long-term management and a multimodal approach.

Some clinicians prefer that a diagnostic and therapeutic investigation is performed as part of a single procedure – sometimes referred to as ‘see-and-treat’ laparoscopy. 49,50 For example, adhesiolysis may be performed in what started as a diagnostic procedure. 51 Depending on the severity and corresponding patient consent, endometriosis may be treated at the time of diagnosis by either electrocoagulation, laser vaporisation or excision. 52 Endometrioma and benign ovarian cysts are usually excised. 53 The type of treatment offered may depend on the extent of the disease and surgical expertise. Surgical removal of deep-infiltrating endometriosis is highly specialised and, in the UK, undertaken in accredited specialist centres. Preoperative MRI scans can aid the planning of this complex surgery.

Other conditions observed at laparoscopy are not amenable to immediate laparoscopic treatment, for example myomectomy for subserosal fibroids. 54 Few surgeons attempt uterine-sparing surgery for adenomyosis, as a result of it frequently being diffused throughout the myometrium.

A diagnostic laparoscopy may also provide the opportunity to undertake other investigations, such as a cystoscopy, if symptoms are suggestive of bladder or intrauterine conditions. Some gynaecologists may also use the cover of a general anaesthetic to perform investigations capable of being performed as an outpatient procedure, such as hysteroscopy or insertion of a levonorgestrel-releasing intrauterine system.

Medical treatments are also options for CPP, irrespective of surgical intervention. The combined oral contraceptive pill is used post laparoscopy for prevention of the recurrence of endometriosis, as are long-acting reversible contraceptives. 55–57 Gabapentin is used for women with no identifiable cause of pain, although evidence for its efficacy is limited. 58

Overview of the Magnetic resonance imaging for Establishing Diagnosis Against Laparoscopy study

The MRI for Establishing Diagnosis Against Laparoscopy (MEDAL) study recruited women from 26 UK hospitals (as listed in Appendix 1, Table 29). An outline of the test-accuracy study design is shown in Figure 1. MRI was undertaken before laparoscopy, but the resulting report and images were not to be provided to the gynaecologist, unless there was a critical finding, such as suspected malignancy. This blinding was necessary in order not to distort clinical practice and avoid verification bias arising from knowledge of this index test. A diagnostic laparoscopy was performed and, together with information from the history, examination and ultrasound, produced a post-laparoscopy diagnosis (Figure 2). Information was collected from those who were not eligible for the test-accuracy study. Follow-up information was elicited directly from participants at 6 months.

FIGURE 1.

The MEDAL study flow chart. IRRC, Independent Radiology Review Committee.

FIGURE 2.

Patient pathway and data points through the MEDAL study. GP, general practitioner.

An economic evaluation was performed to establish the cost-effectiveness of MRI as an alternative to laparoscopy for the sensitivity and specificity values of the various target conditions.

Rationale for the Magnetic resonance imaging for Establishing Diagnosis Against Laparoscopy study

There is a perception that diagnostic laparoscopy, an invasive, expensive and potentially risky procedure, is used far too frequently in the NHS, as a significant proportion of women have no pathology identified. 59 The procedure is associated with an approximate 3% risk of minor complications (e.g. nausea and vomiting, shoulder-tip pain) and a 0.24% risk of unanticipated injury causing major complications (e.g. bowel perforation), resulting in two-thirds of women requiring laparotomy. 59–61 There is an estimated risk of death of 3.3 to 8 per 100,000 women,59,61 and payments in medical negligence cases totalled £24.3M in one survey published in 2000. 62

Magnetic resonance imaging is easily accessible, less invasive and cheaper than surgery. In some circumstances, MRI may add a diagnostic benefit over laparoscopy, such as in the cases of severe deep-infiltrating endometriosis and adenomyosis. MRI may also be used to triage cases, so that therapeutic laparoscopy could be better planned. The aim of the MEDAL study was to determine the proportion of women for whom MRI could remove the need for a laparoscopy or, in other words, for whom MRI could be a replacement for laparoscopy.

For MRI to be used in routine clinical practice for the evaluation of CPP, imaging protocols and reporting need to be standardised to allow homogeneous MRI performance between centres and to limit acquisition and interobserver variability. Currently, there are no routinely used standardised reporting guidelines for CPP in the UK. 63 Guided by the MEDAL study, members of the study panel have proposed a template for the standardised reporting of CPP. 63

Following various treatment options, such as the oral contraceptive pill or hormone treatment, some women will undergo laparoscopy resulting in 50% of women having a negative laparoscopy with no pathological cause of pain identified. 8 Although a negative laparoscopy may fail to identify the pathology, it may have a reassuring effect on the patient. A laparoscopy may also have the potential to be a ‘see-and-treat’ laparoscopy if superficial peritoneal endometriosis is observed; MRI would add no benefit in that case.

The choice of study design

Test-accuracy studies are designed to generate measures of accuracy by comparison of the index test with a reference standard, a test that confirms or refutes the presence or absence of disease beyond reasonable doubt. Classical test-accuracy studies require that the target condition is independently verified by the reference test, which must provide a definitive diagnosis, be applicable in all cases and preferably be performed alongside the index test. Complete verification of the presence or absence of a target condition is essential to reduce bias and to maximise the statistical power of the study. By comparing the index test with the reference standard, the result of the index test can be categorised as a true positive, a false positive, a true negative or a false negative. Measures of index test accuracy, including sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratios, can be computed. 64

Verification of the reference standard is frequently dichotomised as disease present/disease absent. In the MEDAL study, we aimed to determine the accuracy of MRI in the differential diagnosis of the causes of CPP. There is a range of potential target conditions and, correspondingly, of reference diagnoses. MRI will visualise the various conditions with different degrees of accuracy (Table 2). To determine the sensitivity of MRI for each pathology would require a large number of participants, to accommodate the low prevalence of some conditions. Furthermore, some pathologies are not independent of each other and could frequently be concurrently observed; for example, endometriosis can give rise to adhesions from fibrotic tissue. Therefore, the principal research question is how frequently does a MRI scan correctly predict the reference diagnosis, thereby removing the need for a laparoscopy or, conversely, what diagnoses cannot be accurately ruled out by a MRI scan and require laparoscopic investigation?

In the context of the MEDAL study, there were a number of target conditions to be considered, not all of which had a perfect reference standard of identification against which to make a differential diagnosis. There was a risk of partial or differential verification of the underlying causes, with their inherent biases. There are several proposed study designs that overcome the problems of an imperfect reference diagnosis. 67 In the absence of a single ‘gold standard’ test, the results of several imperfect tests or observations can be combined to create a composite reference standard. These can be combined according to a predefined algorithm or a consensus diagnosis obtained from considering all the information.

We employed a panel (consensus) diagnosis in which a group of experts determined the presence or absence of the target condition based on several sources of information captured along the patient pathway. This was an acceptable way of addressing the problem of achieving a diagnosis from multiple sources of information and of subjective assessment of that information, as a diagnosis is achieved by consensus. 68 A final diagnosis can be obtained for all women and the panel method reflects the clinical reality, in which several items of information are synthesised by the clinician. The results of this methodology can be viewed as being generalisable to clinical practice.

To establish whether or not MRI can replace laparoscopy, a paired design was employed, in which both tests were compared with the reference standard. As sensitivity and specificity can vary across subgroups, the two tests and the reference standard are best performed in the same population. 68 It is feasible to perform MRI and laparoscopy in women with CPP and, although MRI does not interfere with laparoscopy, the paired design is preferable to a randomised trial. 69 As MRI would precede laparoscopy, it can also be viewed as a triage test, directing only women with a specific condition towards a laparoscopic confirmation or operative laparoscopic procedure. A fully paired study design is also appropriate for this type of diagnostic situation.

The certainty with which gynaecologists have made their diagnoses will be measured and compared as a secondary measure of diagnostic efficacy. In order to be clinically effective, tests should contribute to the diagnostician’s decision-making,70 for example, by changing a differential diagnosis, strengthening an existing hypothesis or simply reassuring the clinician. Although accuracy is the chief concern, the extent to which clinicians make use of test results also relies on their confidence that the test has contributed usefully to a diagnosis. The MEDAL study therefore evaluated the diagnostic impact of MRI and of laparoscopy by conducting a:

1. before-and-after comparison of diagnostic certainty for having diagnosed the cause of CPP

2. before-and-after comparison of diagnostic certainty for the leading diagnosis

3. before-and-after comparison of the number of differential diagnoses considered per patient

4. retrospective survey of the test’s perceived usefulness.

On the basis of clinical history, examination and ultrasound findings only, treating gynaecologists were asked to state whether or not a pathological cause for CPP was identified, and to express their certainty regarding this decision. They were also asked to list their differential diagnoses, to state whether each was thought to be a cause of CPP and to express their certainty regarding these opinions. After the laparoscopy was performed, clinicians were asked for a revised differential diagnosis and associated certainty using identical questions. A comparison between pre- and post-laparoscopy diagnostic certainty was made, primarily to determine the utility of laparoscopy for identifying a pathological cause of CPP, and secondarily to compare changes in the certainty surrounding the leading differential diagnosis. The number of differential diagnoses considered before laparoscopy was also compared directly with the number considered after the test results were known.

An identical process was followed with independent non-treating gynaecologists (who were blind to the laparoscopic findings) who used MRI to arrive at a diagnosis. Pre-MRI diagnoses and associated certainty based on the same clinical history, examination and ultrasound findings were compared with post-MRI revised diagnoses and certainties. Independent gynaecologists were also asked whether or not they believed that the patient required a laparoscopy.

The gynaecologist’s subjective assessment of the usefulness of MRI or laparoscopy was evaluated after disclosure of the relevant test results, by asking clinicians to select one of four statements that best reflected their perception of the contribution of the test to each case. These statements were initially drafted with reference to those used in published before-and-after diagnostic confidence studies,71–73 and modified for their relevance to a CPP diagnosis following consultation with eight practising gynaecologists.

Aim and objectives

Introduction

We conducted a test-accuracy study in a prospective cohort of women with CPP symptoms, subjected them to thorough investigations, including our index tests (MRI scan and laparoscopy), and sought expert panel consensus to establish a reference diagnosis. We performed a comparative test-accuracy study with panel consensus for determining the reference standard.

Oversight

The study was conducted in accordance with the protocol, which received a favourable ethics opinion from East Midlands (Nottingham 1) Research Ethics Committee (reference number 11/EM/0281). NHS trust research governance approval was obtained from 26 recruiting hospitals in the UK. The study sponsor was the Queen Mary University of London. Independent oversight for the MEDAL study was requested by the funding body; however, how this oversight should be arranged or what it should entail were unclear, as the study was not considered to be distinct from that of randomised controlled trials. For the MEDAL study, the Data Monitoring Committee was defined as a subgroup of the Study Steering Committee (SSC). All members were independent of the MEDAL study management group. The chairperson of the SSC (along with the lay member) was not included in the Data Monitoring Committee.

Study oversight was provided by an independent steering committee and an independent data monitoring committee (see Acknowledgements for membership).

Study participants and setting

Any woman aged ≥ 16 years, who had been referred to a gynaecologist with CPP of at least 6 months’ duration, was potentially eligible. Women were assessed by a gynaecologist, which involved a standardised assessment and a clinical examination. If clinically indicated, women were referred for an ultrasound scan. If a laparoscopy was indicated and the patient wished to proceed with the laparoscopy, and was prepared to have a MRI scan, eligibility to participate in the study was confirmed. Women were excluded if they had had a hysterectomy, were pregnant or were unable to give written informed consent, or if they definitely had a clinical indication for a MRI scan, based on examination, history or ultrasound. Women were also excluded if they had an identifiable cause of CPP for which treatment could be initiated without a laparoscopy. Eligible women who provided written informed consent were committed to the study by telephone registration service at Birmingham Clinical Trials Unit (University of Birmingham, Birmingham, UK).

Pre-index tests

Index tests

Assigning the cause of pain

At several stages in the study path for each patient, the treating gynaecologist and the independent gynaecologist reviewed the diagnostic evidence available. To establish a possible diagnosis for each target condition (including idiopathic CPP), they indicated their level of certainty that the condition was causing the pelvic pain on a numerical rating scale, ranking from 10 being certain (expressed as a 99 in 100 chance), through 5 being a fairly good possibility (a 5 in 10 chance) to 0, considered to be no chance or less than a 1 in 100 chance.

The first condition was the absence of structural cause, defined as idiopathic or unknown. There then followed seven structural gynaecological causes (superficial peritoneal endometriosis, deep-infiltrating endometriosis, endometrioma of the ovary, adhesions, ovarian cysts, adenomyosis, fibroids), together with the option to specify another gynaecological cause. The non-gynaecological causes offered were psychological or psychosexual, gastrointestinal, urinary, musculoskeletal, neurological or another pathological cause, with the requirement to specify the diagnosis further. Definitions for idiopathic CPP, superficial peritoneal and deep-infiltrating endometriosis, adhesions and pelvic congestion syndrome were provided.

Determining the role of magnetic resonance imaging by independent assessment

The treating gynaecologists were kept blind to the MRI scan report so that they could make an unbiased assessment of the laparoscopic findings. If MRI was found to be useful in the MEDAL study, an MRI scan would precede laparoscopy in the investigative pathway in the future. In order to model the impact of using the MRI scan report, an independent gynaecologist reviewed each case. This gynaecologist was randomly selected from another hospital recruiting to the MEDAL study, so was familiar with the study aims, processes and data collection. The independent gynaecologist was provided with all the data collection forms for the pre-index tests and clinical history, together with the laparoscopy report. The information was anonymised. The independent gynaecologists were asked to complete the certainty scales for each condition, which constituted the pre-MRI independent diagnosis and should be highly correlated with the recruiting gynaecologists’ diagnoses post laparoscopy, being derived from the same information. The independent gynaecologists were then asked to read the MRI scan report and repeat the process, completing the certainty scales. There were three extra hypothetical questions at this second post-MRI stage: if the gynaecologist was treating that particular patient, would they have scheduled a laparoscopy (having reviewed the MRI scan report), if they would have scheduled a therapeutic laparoscopy and, if so, would they anticipate that the diagnostic and therapeutic elements would be performed as part of a single procedure?

Reference standard

The analysis considers two sets of reference standard. The first identified was to assess the accuracy of the MRI scan for observing a condition, and the second was to assess the accuracy of the MRI scan for identifying the condition(s) causing pelvic pain. The first set used findings from laparoscopy for the reference standard, and the second used consensus from an EIP. It was expected that not all women who were observed to have each condition would have it categorised as being the source of pelvic pain.

Sample size

A sample size of 250 women was chosen a priori to address the primary research question of determining the proportion of women for whom MRI is sufficiently accurate to replace laparoscopy in the investigation of CPP, following evaluation of the presenting characteristics. With this sample size, the study was anticipated to have > 90% power (at p = 0.05) to detect a reduction of 10% in the number of laparoscopies needed (i.e. from 100% down to 90%). This difference would be cost-effective if laparoscopy was at least 10 times more expensive than MRI. Estimates used at the start of the study placed laparoscopy at being 7.4 times more expensive than MRI (£1274 vs. £173); however, these NHS tariffs may not necessarily reflect the true cost of the total investigative pathway, which will be estimated through primary data collection as part of this study.

Having 250 women as the sample size was also expected to provide a reasonable number of cases of each of the more common target conditions from which to estimate the sensitivity of MRI for diagnosis. We anticipated a high sensitivity of MRI for detecting common pathological causes of CPP; therefore, we based our calculations on an anticipated sensitivity of 80% for any particular condition (a sensitivity of 90% has also been provided for comparison; Table 4). We then computed the 95% confidence intervals (CIs) for these sensitivities for a range of prevalences of any particular condition (see Table 4). These figures could equally apply to specificity. For a target condition with a prevalence of 30% or more, we expected to be able to reliably rule out a sensitivity or specificity of < 70% if the ‘true’ sensitivity or specificity was > 80%.

In May 2013, when the target sample size had already been slightly exceeded (269 women), the trial team, together with the input of the independent oversight committees, decided to extend recruitment until the end of September 2013, with a revised target of 340 women, and the protocol was amended accordingly. At this stage, the study was recruiting faster than was originally planned. The aim of extending recruitment was to improve the statistical precision of the accuracy estimates for the less prevalent gynaecological causes, and this revised plan was ratified by the external Trial Steering Committee. For example, a sensitivity of 90% would have a lower 95% CI boundary of 80% for conditions occurring in 30% of women in a sample size of 250, and in conditions occurring in 20% of women in a sample size of 340. However, between May 2013 and September 2013, recruitment to the study unexpectedly started to slow and this revised target was not met, with a final sample size of 291 participants at the start of the diagnostic study.

Data analysis

Recruitment

The recruitment of participants started in December 2011 and closed in September 2013. A total of 1667 women were screened. A total of 435 women, who consented to participate, were recruited into the study from 26 centres (see Appendix 1, Table 29). Ultimately, 287 women contributed to the analysis (Figure 3).

FIGURE 3.

Flow chart of participants, showing the numbers who provided data at each stage.

The original sample size of 250 participants was reached ahead of schedule, so the sample size was revised to 340 participants. The sample size was increased to improve the precision of estimates for all target conditions, but most notably for the less common target conditions.

Characteristics of participants

The mean age of the women in our sample was 31.6 years [standard deviation (SD) 8.3 years]. Of these, 197 women (68.5%) were in employment and 96 (33.5%) had received a university-level education. There were 216 white women (74.5%). The duration of pain was, on average, 4.2 years (SD 4.8 years); pain was present on at least 1 day every week in 226 women (79.5%), with a mean pain score of 7.1 points (SD 2.8 points) during menstrual periods and 6.4 points (SD 2.6 points) before menstrual periods. The average age at menarche was 12.8 years (SD 1.7 years). Heavy periods were a feature in 147 women (58.6%). Around three-quarters of women (n = 212; 73.4%) were sexually active, with pain during intercourse featuring over the last 20.3 months (SD 20.7 months). Contraceptive hormones had been prescribed for pain to 162 women (55.7%). Chlamydia testing was undertaken in 202 women (70.4%), of whom 176 (89.3%) had received negative results. Laparoscopy and MRI had been used for diagnosis in the past in 80 (27.5%) and 30 women (10.3%), respectively. Infertility was not a complaint in 206 women (85.1%). Further details of participant characteristics are shown in Table 5 and Appendix 1, Tables 30 and 31.

The median duration between the MRI scan and the diagnostic laparoscopy was 26 days (interquartile range of 9–54 days).

Reliability of the expert independent panel diagnoses

We investigated the reliability of the EIP reference diagnoses by looking first at the consensus ratings made with and without access to the MRI report and, second, at the agreement between individual raters in the independent expert group.

Table 6 reports the prevalence of each condition as defined by the EIP with and without access to the MRI report. We considered the primary reference standard to be the EIP consensus statement without the MRI report, as this would reduce the risk of incorporation bias in assessing the accuracy of the MRI report. However, we were interested in noting when the reference standard consensus diagnoses differed, as it was known that an MRI scan may be the only test to identify several of the conditions in some women.

Table 6 shows that the difference in the number of cases detected was between zero and two for all conditions other than adenomyosis (difference of five cases detected), and cases with psychological and psychosexual causes (difference of three cases detected). Although there are clinical reasons why adenomyosis can only be detected by a MRI scan, which are likely to explain the difference, there are no reasons to explain the difference for cases with psychological and psychosexual causes. We therefore report comparisons with the second-stage MRI scan-informed EIP consensus reference diagnosis for analysis of adenomyosis, but not for any other conditions.

To assess the reliability of the EIP diagnoses, we considered the agreement between the three individual ratings made by the panel members prior to any group discussion. We computed the kappa statistic across the three raters to describe the agreement beyond that explained by chance. Kappa values above 0.80 were considered to indicate excellent agreement, whereas those between 0.60 and 0.79 indicate good agreement and those below 0.60 indicate poor or moderate agreement.

The panel were in excellent agreement in identifying deep-infiltrating endometriosis and endometrioma of the ovary as causes of pelvic pain, and in good agreement in identifying superficial peritoneal endometriosis and adenomyosis when the MRI reports were used in the reference standard. Lower levels of agreement were noted for deciding that adhesions, fibroids and PID were the cause of pelvic pain. The expert panel failed to demonstrate adequate reliability in determining whether any of the non-gynaecological causes were the cause of pelvic pain for further detailed examination of these causes.

Prevalence of conditions being the cause of pelvic pain or observed on magnetic resonance imaging scans or through laparoscopy

Table 7 reports the prevalence of the causes of pelvic pain as judged by the EIP and observed through laparoscopy and MRI scans. For many conditions (superficial peritoneal endometriosis, endometrioma of the ovary, adhesions, ovarian cysts, adenomyosis and fibroids), the prevalence of observing the condition through MRI scans and/or laparoscopy was higher than the prevalence according to the judgements of the EIP, reflecting that, in many women, the conditions may be observed but not judged to be the cause of pelvic pain.

TABLE 7 - Prevalence of conditions being the cause of pelvic pain or observed through MRI scans or laparoscopy

See Table 2 for definitions used for MRI findings.

Values when MRI Table 2 definition 1 of adenomyosis is applied.

Values when MRI Table 2 definition 2 of adenomyosis is applied.

Cause of pelvic pain	Judged as being the cause of pelvic pain, n (%)		Observation by technique, n (%)
	Reference diagnosis without MRI	Reference diagnosis with MRI	Laparoscopy (N = 287)	MRIa (N = 287)
Idiopathic (no structural gynaecological cause)	156 (54.4)	153 (53.3)	75 (26.1)	49 (17.1)b 148 (51.6)c
Superficial peritoneal endometriosis	71 (24.7)	71 (24.7)	120 (41.8)	No criteria
Deep-infiltrating endometriosis	40 (13.9)	42 (14.6)	37 (12.9)	3 (1.0)
Endometrioma of the ovary	11 (3.8)	13 (4.5)	68 (23.7)	31 (10.8)
Adhesions	24 (8.4)	25 (8.7)	109 (39.6)	37 (12.9)
Ovarian cysts	1 (0.3)	0 (0)	56 (19.7)	27 (9.4)
Adenomyosis	11 (3.8)	16 (5.6)	21 (7.3)	193 (67.2)b 34 (11.8)c
Fibroids	4 (1.4)	5 (1.7)	24 (8.4)	56 (19.5)
PID	10 (3.5)	10 (3.5)	10 (3.5)	15 (5.2)
Urinary causes	18 (6.3)	16 (5.6)	Not assessed	No criteria
Musculoskeletal causes	48 (16.7)	47 (16.4)	Not assessed	No criteria
Gastrointestinal causes	24 (8.4)	23 (8.0)	Not assessed	No criteria
Psychological/psychosexual causes	78 (27.2)	75 (26.1)	Not assessed	No criteria

Superficial peritoneal endometriosis was identified as the most common gynaecological cause of pelvic pain in 25% of women, followed by deep-infiltrating endometriosis in 14%, adhesions in 8%, endometrioma of the ovary, adenomyosis and PID each in 4% and fibroids and ovarian cysts in ≤ 1%. Of the non-gynaecological causes, psychological/psychosexual causes were the most common in 27% of women, musculoskeletal causes in 17%, gastrointestinal causes in 8% and urinary causes in 6%. Fifty-four per cent of women were judged to have idiopathic pelvic pain with no structural gynaecological cause identified.

The three endometriosis conditions (superficial peritoneal, deep-infiltrating and endometrioma of the ovary) and ovarian cysts were observed twice as often with laparoscopy, and adhesions three times as often, as with MRI scans. Adenomyosis, fibroids and PID were noted more often through MRI than through laparoscopy. No MRI diagnostic criteria were available for the non-gynaecological conditions.

Figure 4 shows the relationships between the causes of pelvic pain based on the EIP diagnoses without the MRI report for structural gynaecological causes. Superficial peritoneal endometriosis, deep-infiltrating endometriosis and endometrioma of the ovary often occurred together: 17 out of 40 women with deep-infiltrating endometriosis also had superficial peritoneal endometriosis, 7 out of 11 women with endometrioma of the ovary also had deep-infiltrating endometriosis and 7 out of 11 women with endometrioma of the ovary also had superficial peritoneal endometriosis. Adhesions also appeared in combination with the three types of endometriosis.

FIGURE 4.

Relationships between the structural gynaecological causes.

Connecting lines indicate the number of women with both diagnoses. A total of 131 women (46%) had structural gynaecological causes and are included in Figure 4.

The impact of magnetic resonance imaging on confidence and accuracy in making diagnoses

The independent gynaecologist rated the likelihood of each cause of CPP first when provided with all baseline data (including ultrasound reports) and, second, when additionally provided with the report from the MRI scan. This allows an assessment to be made of the degree to which the MRI scan provided additional diagnostic information over and above that available from the baseline assessments. The independent gynaecologist was not provided with the MRI criteria stated in Table 2, but was provided wih only the measurements made on MRI and the textual report. Each independent gynaecologist rated their certainty that each condition was causing pelvic pain on a scale of 0 (no chance) to 10 (certain). We deduced the certainty that the diagnosis was idiopathic by subtracting the highest score for the gynaecological structural causes from 10. The results for scores of 0–3, 4–6 and 7–10 are presented in Table 9, along with the likelihood ratios computed to indicate the degree to which high (or low) scores rule each condition in (or out). We measured the diagnostic accuracy across all scores by plotting ROC curves for each condition (Figure 5) and summarised the accuracy as the AUROC value. The likelihood ratio and AUROC values were computed for assessments made on baseline evidence alone, and then made with the additional provision of the MRI report; the incremental diagnostic value of the MRI scan is summarised using the change in the AUROC value and by comparing the likelihood ratio values.

FIGURE 5.

Accuracy of assessments of the cause of pelvic pain pre and post MRI and laparoscopy: ROC curves for comparison. (a) Idiopathic; (b) superficial peritoneal endometriosis; (c) deep-infiltrating endometriosis; (d) endometrioma of the ovary; (e) adhesions; and (f) adenomyosis (reference standard with MRI).

An AUROC value of 0.5 would be obtained if diagnoses were made by chance, whereas a test with perfect discrimination would have a value of 1.0. The baseline values of the AUROC were not significantly different from 0.5 for all conditions except adhesions (AUROC value of 0.64), indicating that the independent gynaecologist was not significantly better than chance in producing a diagnosis that agreed with that of the EIP, and only had a weak relationship for adhesions. Provision of the MRI report improved the accuracy of all diagnoses, but the increase in AUROC value was only statistically significant for deep-infiltrating endometriosis (p = 0.006) and endometrioma of the ovary (p = 0.02). Likelihood ratios for scores in the 4–6 and 7–10 categories deep-infiltrating endometriosis and endometrioma of the ovary were around 4–7, which are not high enough to convincingly rule in these diagnoses. Although scores of 7–10 for adhesions had the highest likelihood ratio, at 7.3, they were made in only 15 women, and detected in only 30% of those with adhesions as a cause of pelvic pain (Table 10).

TABLE 10 - Impact of MRI on confidence in, and accuracy of, diagnoses made

Cause of pelvic pain	Diagnostic confidence score	Rating								Change in AUROC (95% CI; p-value)
		Before MRI results revealed				After MRI results revealed
		Expert panel consensus, n		Likelihood ratio (95% CI)	AUROC (95% CI)	Expert panel consensus, n		Likelihood ratio (95% CI)	AUROC (95% CI)
		Yes	No			Yes	No
Idiopathic	7–10	53	43	1.0 (0.7 to 1.4)	0.53 (0.46 to 0.60)	77	44	1.5 (1.1 to 2.0)	0.60 (0.53 to 0.67)	+0.07 (–0.01 to 0.15; p = 0.06)
	4–6	86	69	1.0 (0.8 to 1.3)		49	47	0.9 (0.6 to 1.2)
	0–3	17	19	0.8 (0.4 to 1.4)		30	40	0.6 (0.4 to 1.0)
Superficial peritoneal endometriosis	7–10	9	13	2.1 (0.9 to 4.7)	0.54 (0.46 to 0.61)	5	10	1.5 (0.5 to 4.3)	0.56 (0.49 to 0.64)	+0.02 (–0.05 to 0.10; p = 0.5)
	4–6	28	92	0.9 (0.7 to 1.3)		19	54	1.1 (0.7 to 1.7)
	0–3	34	111	0.9 (0.7 to 1.2)		47	152	0.9 (0.8 to 1.1)
Deep-infiltrating endometriosis	7–10	1	2	3.1 (0.3 to 33.3)	0.53 (0.43 to 0.62)	5	6	5.1 (1.7 to 9.4)	0.66 (0.57 to 0.76)	+0.13 (0.04 to 0.23; p = 0.006)
	4–6	9	42	1.3 (0.7 to 2.5)		8	12	4.1 (1.8 to 9.4)
	0–3	30	203	0.9 (0.8 to 1.1)		27	229	0.7 (0.6 to 0.9)
Endometrioma of the ovary	7–10	0	2	0	0.58 (0.44 to 0.71)	2	8	6.3 (1.5 to 26.1)	0.78 (0.62 to 0.95)	+0.20 (0.02 to 0.39; p = 0.02)
	4–6	0	24	0		4	14	7.2 (2.8 to 18.2)
	0–3	11	250	1.1 (1.0 to 1.2)		5	254	0.5 (0.3 to 0.9)
Adhesions	7–10	1	5	2.2 (0.3 to 18.0)	0.64 (0.53 to 0.75)	6	9	7.3 (2.8 to 18.8)	0.72 (0.60 to 0.83)	+0.08 (–0.03 to 0.18; p = 0.2)
	4–6	5	39	1.4 (0.6 to 3.2)		6	37	1.8 (0.8 to 3.8)
	0–3	18	219	0.9 (0.7 to 1.1)		12	217	0.6 (0.4 to 0.9)
Adenomyosis (post-MRI EIP consensus)	7–10	2	7	4.8 (1.1 to 21.4)	0.53 (0.36 to 0.71)	6	22	4.6 (2.2 to 9.8)	0.68 (0.50 to 0.85)	+0.15 (–0.03 to 0.32; p = 0.1)
	4–6	3	80	0.6 (0.2 to 1.8)		4	41	1.7 (0.7 to 4.0)
	0–3	11	184	1.0 (0.7 to 1.4)		6	208	0.5 (0.3 to 0.9)

Introduction

One of the factors that contributes to the lack of speedy diagnosis of CPP among women is that laparoscopy is perceived to be an invasive, expensive and potentially risky procedure, and that it is used far too frequently in the NHS, as a significant proportion of women have no pathology identified. 73 MRI represents a less invasive and, potentially, less expensive procedure than laparoscopy, and as such may be the preferred option for the woman or for the health-care provider. However, as shown in previous chapters of this report, the test accuracy of diagnostic laparoscopy in detecting the structural causes of CPP is greater than that for MRI, meaning that women are more likely to be properly diagnosed and then access the appropriate treatment following a diagnostic laparoscopy than with a MRI scan. In this chapter, all of these factors are considered as part of a wider cost-effectiveness analysis, the objective of which is to examine the cost-effectiveness of MRI compared with diagnostic laparoscopy in women with undiagnosed CPP. However, the study design used in the research meant that all women received all tests, and from the data collected, ROC curves were obtained for both MRI and laparoscopy which could then inform their sensitivity and specificity values based on alternative cut-off points. This meant that the actual sensitivity and specificity values for laparoscopy, as used in usual practice, could not be informed by this study, and so consequently it was not possible to parameterise a usual-practice scenario in this economic analysis. Therefore, we consider MRI and laparoscopy with alternative sensitivity and specificity pairs (as informed by the ROC curves) as separate strategies and examine which test and sensitivity and specificity values is the most cost-effective for women with CPP. For completeness, we also compare these strategies with a no-testing scenario, in which a patient receives neither MRI nor laparoscopy.

Methods

Developing the model structure

The comparison of the pathways undertaken by women in this study is best represented in a modelling framework, in which the alternative pathways that women can follow are compared in order to diagnose the cause of their CPP. As all women in the MEDAL study were tested with MRI scans and diagnostic laparoscopy, a model was required to simulate the outcomes of each of the patient pathways when only one test was administered. A model allows explicit representation of the impact of the accuracy of the tests, the costs to the health service and the impact on the health-related QoL experienced by the women undergoing a particular pathway.

A model was developed via consultation with the research team, drawing on key clinical and modelling expertise. A decision tree was applied using TreeAge Pro 2001 software (TreeAge Software, Inc., Williamstown, MA, USA). A 6-month time horizon was adopted, as this was the period of data collection, and, given that there was very little chance of events recurring on the patient pathways (such as a patient receiving multiple laparoscopies), it was felt that this approach was the most appropriate.

Women entered the model having been identified as having CPP and being eligible for diagnostic laparoscopy. Two different patient pathways were compared, which describe alternative approaches to the diagnosis and treatment of the causes of CPP, a summary of which can be found in Figure 6. Figures 7–10 show the patient pathways considered in this analysis, which together form the model structure for the decision tree used in the cost-effectiveness analysis. For both pathways, a baseline examination was conducted, which comprised a patient history followed by a physical examination, and an ultrasound scan when clinically indicated. The remainder of the pathway followed either the laparoscopy pathway or the MRI pathway.

FIGURE 6.

Women with CPP who were eligible for laparoscopy, who received either MRI or laparoscopy.

FIGURE 7.

Model structure for the laparoscopy treatment arm for women who tested positive for a structural cause of CPP. LNG-IUS, levonorgestrel-releasing intrauterine system.

FIGURE 8.

Model structure for the MRI treatment arm for women who tested positive for a structural cause of CPP. LNG-IUS, levonorgestrel-releasing intrauterine system.

FIGURE 9.

Model structure for the laparoscopy treatment arm for women who tested negative for a structural cause of CPP. LNG-IUS, levonorgestrel-releasing intrauterine system.

FIGURE 10.

Model structure for the MRI treatment arm for women who tested negative for a structural cause of CPP. LNG-IUS, levonorgestrel-releasing intrauterine system.

Laparoscopy pathway

Women were offered a diagnostic laparoscopy, which may or may not have been accepted. For those women who received the diagnostic laparoscopy, this would give either a positive or a negative result for the presence of a structural cause of CPP. For those who tested positive for a cause that required a therapeutic laparoscopy, this would be given during the same or a subsequent procedure. For women who tested positive for a structural cause that required other treatment, in this case fibroids or adenomyosis, this treatment would be subsequently administered. For those women who tested negative, no further tests or treatment would be administered, and if this was a false-negative test result, then the patient would remain in a decreased state of health (see Figures 7 and 9).

Magnetic resonance imaging pathway

Women were offered a MRI scan that may or may not have been accepted; women who rejected or were ineligible for a MRI scan would then follow the laparoscopy pathway (see Figures 8 and 9). Women who received a MRI scan and a positive test result were given a therapeutic laparoscopy or other treatment, as appropriate. For women who tested negative, no further tests or treatments were administered and, again, if the test result was false negative, these women would remain in a decreased state of health (see Figure 10).

No testing (neither magnetic resonance imaging nor laparoscopy)

A no-testing scenario was incorporated into this analysis, which was assumed to consist of a baseline examination (see Model assumptions). Although we acknowledge that this strategy would not be considered in practice for this patient group, the inclusion of no testing is important for comparative purposes, and can show whether or not a testing strategy is more harmful than no testing.

Test accuracy

The test accuracy of diagnostic laparoscopy and MRI was based on the sensitivity and specificity for the detection of structural causes that required either a therapeutic laparoscopy or other treatment, and were informed by data collected during the MEDAL study.

The test accuracy of MRI and diagnostic laparoscopy, respectively, was explored through the use of ROC curves for structural causes that required a therapeutic laparoscopy, and for those that required other treatment (Figure 11). The ROC curve was created by plotting the true-positive rate (true-positive rate or sensitivity) against the false-positive rate (false-positive rate or 1 – specificity) at various threshold settings.

FIGURE 11.

Receiver operating characteristic curves for laparoscopic and MRI diagnoses. (a) Diagnostic laparoscopy for structural causes of CPP that required treatment using a therapeutic laparoscopy; (b) diagnostic laparoscopy for structural causes of CPP that required other treatment (not therapeutic laparoscopy); (c) MRI scan for structural causes of CPP that required treatment using a therapeutic laparoscopy; and (d) MRI scan for structural causes of CPP that required other treatment (not therapeutic laparoscopy).

In our analysis, we refer to a low cut-off point as one that sets a high sensitivity and low specificity (more positive tests), and a high cut-off point as one that sets a low sensitivity and high specificity (more negative tests).

Results

This section starts by examining the cost-effectiveness of MRI, laparoscopy, and no testing, whereby the different cut-off values to inform the sensitivity and specificity for each test was treated as a separate strategy. At baseline, a 6-month time horizon was utilised.

Quality-adjusted life-year outcome

Using the outcome of the QALYs, the cost-effectiveness of MRI and laparoscopy across varying cut-off points is shown in Table 19.

TABLE 19 - Baseline deterministic cost-effectiveness results for MRI and laparoscopy at various cut-off points using the QALY outcome and a 6-month time horizon

Cut-off points are based on the data points in Figure 11, which were obtained from questionnaires. There are 12 data points in these graphs, which matches the number of cut-off points.

Strategy and cut-off pointa	Cost (£)	QALY gain
MRI – 2	1856	0.3077
MRI – 1	1908	0.3082
MRI – 0	2097	0.3083
Laparoscopy – 0	2231	0.3084
MRI – 10	538	0.3094
No testing	166	0.3095
MRI – 11	497	0.3095
Laparoscopy – 11	1387	0.3095
MRI – 3	1691	0.3097
MRI – 4	1397	0.3100
MRI – 9	623	0.3103
MRI – 8	729	0.3109
MRI – 5	1171	0.3121
Laparoscopy – 1	2017	0.3134
MRI – 7	862	0.3137
MRI – 6	1002	0.3140
Laparoscopy – 10	1481	0.3140
Laparoscopy – 2	1973	0.3166
Laparoscopy – 9	1593	0.3176
Laparoscopy – 3	1904	0.3188
Laparoscopy – 8	1664	0.3200
Laparoscopy – 4	1873	0.3212
Laparoscopy – 5	1839	0.3215
Laparoscopy – 7	1747	0.3227
Laparoscopy – 6	1793	0.3235

As shown in Table 20, the baseline results for strategies on the cost-effectiveness frontier, using the outcome of the QALY for most scenarios and excluding the scenarios for the more extreme cut-off points, shows that laparoscopy is more effective than MRI in terms of QALYs gained. For both MRI and laparoscopy, for some of the highest and lowest cut-off values that appear at the extreme ends on the ROC curve, in terms of QALYs gained, these are no better than no testing, and, in some cases, are even worse than no testing. This can be explained, as, for some of these strategies, women are given expensive unnecessary treatment as a result of false-negative test results. Finally, it is noted that for most scenarios, excluding the scenarios for the more extreme cut-off points, laparoscopy is more effective than MRI in terms of QALYs gained. The cost-effectiveness frontier for the results in Table 20 is shown in Figure 12.

TABLE 20 - Baseline deterministic results for strategies on the cost-effectiveness frontier using the QALY outcome

Strategy	Cost (£)	Incremental cost (£)	QALYs gained	Incremental effectiveness	ICER (cost/QALY), £
No testing	166		0.3095
Laparoscopy (cut-off value of 6)	1793	1627	0.3235	0.014	116,618

FIGURE 12.

Cost-effectiveness frontier for the baseline strategies, using the QALY outcome and the 6-month time horizon.

As can be seen in Figure 12, all the strategies were either dominated (less effective and more costly) or subject to extended dominance (another strategy provides more units of benefit at a lower cost per unit of benefit), except for no testing and laparoscopy, at a cut-off value of 6, which therefore lies on the cost-effectiveness frontier.

As shown in Table 20, for a 6-month time horizon, using the outcome of the QALY, laparoscopy (with a cut-off value of 6) is more expensive (£1793 vs. £166) and more effective (0.3235 vs. 0.3095) than no testing. In addition, the ICER for laparoscopy (with a cut-off value of 6) compared with no testing is £116,618, which means that one extra QALY gained from laparoscopy (with a cut-off value of 6) will cost £116,618 compared with no testing.

Correctly diagnosed outcome

Using the outcome measure of a correct diagnosis, the cost-effectiveness results for MRI and laparoscopy at various cut-off points, for a 6-month time horizon, are shown in Table 21.

TABLE 21 - Baseline deterministic cost-effectiveness results for MRI and laparoscopy at various cut-off points, using the correctly diagnosed outcome and a 6-month time horizon

Cut-off points are based on the data points in Figure 11, which were obtained from questionnaires. There are 12 data points in these graphs, which matches the number of cut-off points.

Strategy and cut-off pointa	Cost (£)	Correctly diagnosed
No testing	166	0.0000
Laparoscopy – 0	2231	0.3994
MRI – 0	2097	0.4286
MRI – 2	1856	0.4303
MRI – 1	1908	0.4310
MRI – 3	1691	0.4770
Laparoscopy – 1	2017	0.4897
MRI – 4	1397	0.5051
Laparoscopy – 11	1387	0.5326
Laparoscopy – 2	1973	0.5447
MRI – 5	1171	0.5547
MRI – 10	541	0.5654
MRI – 8	729	0.5709
MRI – 11	497	0.5714
MRI – 9	623	0.5717
Laparoscopy – 10	1498	0.5801
Laparoscopy – 3	1904	0.5838
MRI – 6	1002	0.5956
MRI – 7	862	0.6022
Laparoscopy – 9	1593	0.6195
Laparoscopy – 4	1873	0.6255
Laparoscopy – 5	1839	0.6369
Laparoscopy – 8	1664	0.6421
Laparoscopy – 7	1747	0.6679
Laparoscopy – 6	1793	0.6733

As shown in Table 21, for the outcome of correctly diagnosed, the strategies at the extreme ends of the ROC curve were the least effective, with a few exceptions. The most effective strategies were the laparoscopy strategies around the mid-point of the ROC curve, that is, the cut-off values 4–9. The cost-effectiveness frontier for the results in Table 21 is shown in Figure 13.

FIGURE 13.

Cost-effectiveness frontier for baseline strategies, using the correctly diagnosed outcome and a 6-month time horizon.

As can be seen in Figure 13, all the strategies were either dominated or subject to extended dominance, except for the four strategies on the cost-effectiveness frontier, these being no testing, MRI (cut-off value of 11), MRI (cut-off value of 6) and laparoscopy (cut-off value of 6).

As shown in Table 22, for a 6-month time horizon and using the outcome of correctly diagnosed, MRI (cut-off value of 11) was more expensive and more effective than no testing. MRI (cut-off value of 7) was more expensive and more effective than MRI (cut-off value of 11), and laparoscopy (cut-off value of 6) was more expensive and more effective than MRI (cut-off value of 7). In the case of the comparison between laparoscopy (cut-off value of 6) and MRI (cut-off value of 7), the ICER was £13,092, which means that it would cost £13,092 for one extra correct diagnosis for laparoscopy (cut-off value of 6) compared with MRI (cut-off value of 7).

TABLE 22 - Baseline deterministic results for strategies on the cost-effectiveness frontier, using the correctly diagnosed outcome

Strategy	Cost (£)	Incremental cost (£)	Correctly diagnosed	Incremental effectiveness	ICER (cost/correctly diagnosed), £
No testing	166		0
MRI (cut-off value of 11)	497	331	0.5714	0.5714	579
MRI (cut-off value of 7)	862	365	0.6022	0.0308	11,864
Laparoscopy (cut-off value of 6)	1793	1627	0.6733	0.0711	13,092

Correctly treated outcome

Using the outcome measure of a patient being positive for a structural cause of CPP and receiving the correct treatment, the model results for MRI and laparoscopy at various cut-off points, for a 6-month time horizon, are shown in Table 23.

TABLE 23 - Baseline deterministic cost-effectiveness results for MRI and laparoscopy at various cut-off points, using the correctly treated outcome and a 6-month time horizon

Cut-off points are based on the data points in Figure 11, which were obtained from questionnaires. There are 12 data points in these graphs, which matches the number of cut-off points.

Strategy and cut-off valuea	Cost (£)	Correctly treated
No testing	166	0.0000
MRI – 0	2097	0.4286
MRI – 2	1856	0.4303
MRI – 1	1908	0.4310
Laparoscopy – 0	2231	0.4383
MRI – 3	1691	0.4770
MRI – 4	1397	0.5051
Laparoscopy – 1	2017	0.5285
MRI – 5	1171	0.5547
MRI – 10	541	0.5654
MRI – 8	729	0.5709
MRI – 11	497	0.5714
Laparoscopy – 11	1387	0.5714
MRI – 9	623	0.5717
Laparoscopy – 2	1973	0.5835
MRI – 6	1002	0.5956
MRI – 7	862	0.6022
Laparoscopy – 10	1498	0.6189
Laparoscopy – 3	1904	0.6226
Laparoscopy – 9	1593	0.6583
Laparoscopy – 4	1873	0.6643
Laparoscopy – 5	1839	0.6757
Laparoscopy – 8	1664	0.6810
Laparoscopy – 7	1747	0.7068
Laparoscopy – 6	1793	0.7121

Table 23 shows that the least effective scenarios were the MRI strategies with low cut-off points, that is, those with high sensitivity and low specificity. The most effective scenarios were the laparoscopy scenarios for the cut-off values 3–10. The cost-effectiveness frontier for the results in Table 23 is shown in Figure 14.

FIGURE 14.

Cost-effectiveness frontier for baseline strategies, using the correctly treated outcome with a 6-month time horizon.

As can be seen in Figure 14, all the strategies were either dominated or subject to extended dominance, except for the three strategies on the cost-effectiveness frontier, which were no testing, MRI (cut-off value of 11), and laparoscopy (cut-off value of 6).

As shown in Table 24, for a 6-month time horizon, using the outcome of a women being correctly treated with MRI (cut-off value of 11) was more expensive (£497 vs. £166) and more effective (0.5714 vs. 0) than no testing, and the ICER for MRI (cut-off value of 11) compared with no testing was £579, which means that one extra patient correctly treated with MRI (cut-off value of 11) would cost £579 compared with no testing. Likewise, laparoscopy (cut-off value of 6) was more expensive (£1793 vs £497) and more effective (0.7121 vs. 0.5714) than MRI (cut-off value of 11) with an ICER of £9211, meaning that one extra woman correctly treated with laparoscopy (cut-off value of 6) will cost £9211 compared with MRI (cut-off value of 11).

TABLE 24 - Baseline deterministic results for strategies on the cost-effectiveness frontier, using the correctly treated strategy outcome

Strategy	Cost (£)	Incremental cost (£)	Correctly diagnosed	Incremental effectiveness	ICER (cost/correctly treated), £
No testing	166		0
MRI (cut-off value of 11)	497	331	0.5714	0.5714	579
Laparoscopy (cut-off value of 6)	1793	1296	0.7121	0.1407	9211

Sensitivity analysis

Time horizon

The baseline analysis has a time horizon of 6 months. The impact of extending the time horizon up to 3 years for the outcome of the QALY on model results is shown in Table 25.

TABLE 25 - Model results for the QALY outcome with variations in the time horizon of the analysis strategy

Time horizon and strategy	Cost (£)	Incremental cost (£)	QALYs gained	Incremental effectiveness	ICER (cost/QALY), £
6-month time horizon
No testing	166		0.3095
Laparoscopy (cut-off value of 6)	1793	1627	0.3235	0.0140	116,618
1-year time horizon
No testing	166		0.6267
Laparoscopy (cut-off value of 6)	1793	1627	0.6574	0.0307	53,000
2-year time horizon
No testing	166		1.2610
Laparoscopy (cut-off value of 6)	1793	1627	1.3251	0.0641	25,384
3-year time horizon
No testing	166		1.8952
Laparoscopy (cut-off value of 6)	1793	1627	1.9929	0.0977	16,654

The results when varying the time horizon are shown in Table 25. In each case, only the strategies that lie on the cost-effectiveness plane are shown (dominated and subject to extended dominance scenarios not shown). It can be seen that, as the time horizon of the analysis is increased, laparoscopy (cut-off value of 6) becomes more cost-effective than no testing. However, it is noted that, although the effectiveness of the interventions increases over time, as a result of the model assumptions, the costs remain the same.

Prevalence

The impact of varying the overall prevalence of structural causes among women with CPP was examined, with the results shown in Table 26. Note that only the results for the scenarios that lie on the cost-effectiveness frontier are described.

TABLE 26 - Model results using variations in the prevalence of a structural cause of CPP

Prevalence	Strategy (with cut-off value)	Cost (£)	Incremental cost (£)	QALY gain	Incremental QALY	ICER (cost/QALY), £
0%	No testing	166		0.3317		Dominates
10%	No testing	166		0.3264		Dominates
20%	No testing	166		0.3214		Dominates
30%	No testing	166		0.3162
30%	Laparoscopy – 7	1730	1564	0.3198	0.0036	430,292
40%	No testing	166		0.3110
40%	Laparoscopy – 6	1788	1622	0.3227	0.0117	138,407
Baseline (42.86%)	No testing	166		0.3095
Baseline (42.86%)	Laparoscopy – 6	1793	1627	0.3235	0.0140	116,618
50%	No testing	166		0.3058
50%	Laparoscopy – 6	1805	1639	0.3256	0.0197	83,032
60%	No testing	166		0.3007
60%	Laparoscopy – 6	1820	1654	0.3285	0.0278	59,389
70%	No testing	166		0.2955
70%	Laparoscopy – 6	1836	1670	0.3315	0.0360	46,398
70%	Laparoscopy – 4	1896	60	0.3327	0.0012	48,842
80%	No testing	166		0.2903
80%	Laparoscopy – 4	1905	1739	0.3369	0.0467	37,255
80%	MRI – 0	2061	156	0.3388	0.0018	85,124
90%	No testing	166		0.2852
90%	MRI – 1	1959	1793	0.3445	0.0593	30,248
90%	MRI – 0	2051	91	0.3467	0.0022	40,899
100%	No testing	166		0.2800
100%	MRI – 1	1970	1804	0.3523	0.0723	24,966
100%	MRI – 0	2042	72	0.3550	0.0027	26,169

Table 26 shows the model results with variations in the prevalence of a structural cause of CPP. At low prevalence rates (0–20%), no testing is cheaper and more effective than all other strategies. As the prevalence increases, laparoscopy (cut-off value of 6) becomes increasingly cost-effective up to 60%, and then laparoscopy (cut-off value of 4) is preferred for prevalences of 70–80%. At the highest prevalence rates, MRI with a low cut-off value becomes the preferred option. This can be explained through the fact that, with a high prevalence rate, it is better to offer a cheap test that has a high sensitivity and low specificity, as there will be few false-positive test results.

Deep-infiltrating endometriosis

It was assumed that at baseline 50% of women with deep-infiltrating endometriosis required a second therapeutic laparoscopy. The results in Table 27 show the impact of varying this assumption from 0% to 100%.

TABLE 27 - Model results with a variation in the proportion of women with deep-infiltrating endometriosis who required a second therapeutic laparoscopy

Proportion of women with deep-infiltrating endometriosis who required two therapeutic laparoscopies	Cost (£)	Incremental cost (£)	QALY gain	Incremental QALY	ICER (cost/QALY), £
0%
No testing	166		0.3095
Laparoscopy – 6	1730	1564	0.3235	0.014	112,109
Baseline
No testing	166		0.3095
Laparoscopy – 6	1793	1627	0.3235	0.014	116,618
100%
No testing	166		0.3095
Laparoscopy – 6	1856	1690	0.3235	0.014	121,126

As shown in Table 26, varying the parameter describing the percentage of women with deep-infiltrating endometriosis who required two therapeutic laparoscopies had very little impact on the ICER values, and did not impact on the conclusions drawn from the model. All the ICER values lie close to the baseline ICER of £116,618 and remain above the £20,000–30,000 acceptance threshold for the cost/QALYs, as recommended by the National Institute for Health and Care Excellence (NICE). 90

Hysterectomy for adenomyosis

It was assumed at baseline that 50% of women with adenomyosis are treated with a hysterectomy. The results in Table 28 show the impact of varying this assumption from 0% to 100%.

TABLE 28 - Model results with variation in the proportion of women with adenomyosis who were treated with a hysterectomy

Proportion of women with ademomysis who were treated with a hysterectomy	Cost (£)	Incremental cost (£)	QALY gain	Incremental QALY	ICER (cost/QALY), £
0%
No testing	166		0.3095
Laparoscopy – 6	1682	1516	0.3235	0.014	108,624
Baseline
No testing	166		0.3095
Laparoscopy – 6	1793	1627	0.3235	0.014	116,618
100%
No testing	166		0.3095
Laparoscopy – 6	1905	1739	0.3235	0.014	124,612

As shown in Table 28, varying the parameter describing the percentage of women with adenomyosis who are treated with hysterectomy had very little impact on the ICER values, and did not impact on the conclusions drawn from the model. All the ICER values lie close to the baseline ICER of £116,618, and remain above the £20,000–30,000 acceptance threshold for the cost/QALYs, as recommended by NICE.

Probabilistic sensitivity analysis

The results for the PSA for 10,000 model runs are shown in the cost-effectiveness acceptability curves in Figure 15, and those results for no testing and laparoscopy (cut-off value of 6) are shown in Figure 16. These two strategies were chosen because they appear on the cost-effectiveness frontier at baseline. From Figure 15, no testing is always the most likely strategy to be cost-effective across willingness-to pay-values for the QALY from £0 to £200,000. In Figure 16, it can be seen that no testing is more likely to be cost-effective up to a willingness to pay for a QALY of approximately £150,000, at which point laparoscopy (cut-off value of 6) is more likely to be cost-effective.

FIGURE 15.

Cost-effectiveness acceptability curve showing the results of the PSA for a 6-month time horizon, for the strategies likely to be cost-effective across a range of willingness-to-pay thresholds for the QALY.

FIGURE 16.

Cost-effectiveness acceptability curve showing the uncertainty in the difference between costs and effectiveness (QALYs gained) for no testing and laparoscopy (cut-off 6) for 10,000 model runs using a 6-month time horizon.

Principal findings

The diagnostic study demonstrated that, compared with the reference standard diagnosis verified at laparoscopy, MRI had high specificity but poor sensitivity for observing deep-infiltrating endometriosis (3%), endometrioma (33%), adhesions (19%) and ovarian cysts (20%). Sensitivity was higher for detecting these conditions as a cause of pelvic pain as categorised by the EIP, but not high enough to be useful. MRI correctly identified 56% of those women judged to have idiopathic CPP, but missed 46% of those women considered to have a gynaecological structural cause of CPP.

Laparoscopy was significantly more accurate than MRI in diagnosing idiopathic CPP (p < 0.0001), superficial peritoneal endometriosis (p < 0.0001), deep-infiltrating endometriosis (p < 0.0001) and endometrioma of the ovary (p = 0.02) as the cause of pelvic pain. The accuracy of laparoscopy appeared to be able to rule in these diagnoses. Laparoscopy was not able to make accurate diagnoses that adhesions were the cause of pelvic pain, nor was it able to diagnose adenomyosis.

Using MRI to identify those who require therapeutic laparoscopy would lead to 369 women in a cohort of 1000 receiving laparoscopy unnecessarily, and 136 women who required laparoscopy not receiving it. A strategy of all women receiving laparoscopy would lead to 557 women receiving unnecessary laparoscopic treatment.

Feeding these diagnostic performance data into a decision-analytic model, using a 6-month time horizon and taking the test cut-off value to inform the sensitivity and specificity values as a decision variable, it was found that diagnostic laparoscopy (with a cut-off value of 6) has an ICER value of £116,223 (cost/QALY) compared with a no-testing scenario, in which women only have a baseline examination and are then left untreated. This means that one extra QALY gained from the diagnostic laparoscopy will cost an average of £116,618 compared with no testing. This ICER is above the NICE acceptance threshold of £20,000–30,000 for the QALY. However, this value is based on a short time horizon (only 6 months) and strong assumptions, particularly regarding QALY gain in women treated with different strategies which were not actually observed in the study, which must be considered alongside these limitations, and does not provide strong enough evidence to inform clinical care.

Notably, all other scenarios, including all of the MRI scenarios across all cut-off values, were found to be either dominated (more costly and less effective) or subject to extended dominance (another strategy provides more units of benefit at a lower cost per unit of benefit). This means that MRI is not cost-effective in this setting.

As part of an extensive sensitivity analysis, the time horizon was extended to 3 years. Under these circumstances, the ICER for laparoscopy (with a cut-off value of 6) was £16,654 (cost/QALY) compared with the no-testing scenario, which would not be considered cost-effective. However, it is noted that extending the time horizon beyond the data collection period of 6 months does require further strong assumptions to be made. Nevertheless, this result does suggest that a time horizon of > 6 months should be adopted for data collection in this setting in future studies, in order for the impact of these interventions on patient QoL to be fully evaluated.

The ICER values for the outcome of cost per correct diagnosis were £579 for MRI (with a cut-off value of 11) versus no testing, £11,864 for MRI (with a cut-off value of 7) versus MRI (with a cut-off value of 11) and £13,092 for laparoscopy (with a cut-off value of 6) versus MRI (with a cut-off value of 7). In addition, the costs per patient correctly treated were £579 for MRI (with a cut-off value of 11) versus no testing, and £9211 for laparoscopy (with a cut-off value of 6) versus MRI (with a cut-off value of 11). Although it is difficult to draw conclusions as to which strategy should be preferred based on these outcomes, as there is no acceptable threshold for either outcome, it is notable that laparoscopy (with a cut-off value of 6) continues to be the most cost-effective strategy for each.

Strengths and weaknesses of the diagnostic study

The MEDAL study examined the diagnostic value and cost-effectiveness of MRI placed before laparoscopy in a care pathway for women presenting with CPP (incorporating several target conditions) in a gynaecology clinic. If found to be accurate and cost-effective, a strategy involving use of MRI triage to direct laparoscopy could lead to more selective use of the latter, an invasive, costly test requiring use of general anaesthesia in a day-case operating theatre. Construction of an appropriate study designed to produce valid, reliable and generalisable results to guide decision-making proved to be challenging from the outset. The challenges included, among others, variation in gynaecological practice; multiplicity of target conditions with respect to cause of CPP; incongruence between observed conditions and attribution of cause to CPP symptoms; a lack of consensus on radiology standards and reporting of pelvic MRI for benign gynaecological conditions; the need to blind MRI results to avoid bias in assessment of their value; and a lack of objective reference standards for the various target conditions.

The MEDAL study was a multicentre study with recruitment from 26 gynaecology outpatient clinics in the UK. The units represented the spectrum of settings, from busy district general hospitals to specialised tertiary centres, covering the whole range of existing women’s health referral networks, to hospitals with MRI facilities. These units served large, socioeconomically and ethnically diverse populations, which served to maximise the generalisability of the findings. The MEDAL study sought to approach all consecutive eligible women to obtain a suitably representative sample of women with CPP. The median interval between a MRI scan and a diagnostic laparoscopy was less than 1 month, making it unlikely that disease progression bias could influence the results, given the slow and chronic nature of the gynaecological conditions under consideration. The variation inherent in clinical and radiological practice in this mixture of settings also posed a challenge with respect to baseline data collection and MRI reporting. Establishing a standard operating procedure for MRI reporting was a key issue. We established a reporting template for CPP through a survey of an expert panel of radiologists specialising in gynaecological MRI from across the UK. 63 This format would facilitate the applicability of the findings of our study.

The use of laparoscopy for diagnostic evaluation in CPP was well established as the standard practice in these settings. Variations existed in the recording of history, gynaecological examination and pelvic ultrasound, before performing diagnostic laparoscopy. We standardised these during the course of the study using piloted data collections forms, which all had the input of consumers and experts to ensure sensitivity and relevance to women and their presenting complaint. These data were necessary for the care provided by the gynaecologist (who had to be kept blind to the MRI results), but their standardised collection was also necessary for replicable use by the independent gynaecologist assessing the information gained by MRI and the EIP, for establishing a reference diagnosis by consensus.

To determine the accuracy of MRI for each condition separately would require a large number of participants to accommodate the low prevalence of some conditions, such as ovarian cysts. Some pathologies are not independent of each other and could frequently be concurrently observed; for example, endometriosis can give rise to adhesions from fibrotic tissue. Furthermore, conditions observed are not always causes of the CPP symptoms. Therefore, our principal research question was developed to ascertain how MRI could be judiciously employed in a care pathway to minimise the use of laparoscopy, while maximising the correct identification of target conditions for treatments (diagnostic study) that improve QoL with the least investigative burden (decision-analytic cost-effectiveness analysis). Taking this approach, MRI test accuracy for each of the observed conditions served only as a secondary aim. Understanding the difference between diagnostic accuracy and diagnostic value in a care pathway is key to the interpretation of our findings.

To establish whether or not MRI can minimise the use of laparoscopy in a diagnostic pathway, a paired design was employed whereby both tests were performed in the study cohort. During the conduct of the study, it was necessary to blind the MRI report so that clinicians providing care remained uninfluenced by its results in their decision-making, otherwise there was a risk that the assessment of the MRI test performance in the study may be biased. The MRI test preceded laparoscopy in the study, so its findings can be interpreted for development of a triage test that can be used to direct only women with specific conditions towards laparoscopic confirmation or an operative laparoscopic procedure. By providing a MRI test prior to laparoscopy, any conditions that MRI can identify as a cause of CPP with sufficient accuracy can be treated medically without laparoscopy, or a therapeutic laparoscopy can be planned without the need for an initial diagnostic laparoscopy after the findings of the study are known. As it was feasible to perform MRI and laparoscopy in the same women with CPP in a blinded fashion, so that MRI did not interfere with laparoscopy, the paired design offered statistical efficiency over a randomised trial comparing two diagnostic strategies.

The most challenging issue was establishment of a reference diagnosis that attributed cause to the CPP symptoms. For this, we employed a panel consensus method. The panel reflected the clinical reality in which several items of information are synthesised to make a treatment decision. In this assessment, the reference standard in the MEDAL study was kept independent of the MRI test to confirm or refute the presence or absence of disease beyond reasonable doubt. A judgement was made by the expert panel about whether or not the conditions observed were a cause of the CPP symptoms without the use of MRI results, avoiding incorporation bias (except in the evaluation of adenomyosis as a target condition, as other means for this diagnosis are inadequate).

There is little evidence on how panels should be convened, how information should be presented or what the best methods for consensus are. We used a standardised approach to minimise variation in delineation of the reference standard. We established an expert panel of consultant gynaecologists who were not involved in the care of women recruited in the study. Although non-gynaecological conditions were considered as potential diagnoses, we did not include experts from other specialities, which may have contributed to the poor consensus regarding the attribution of pain to non-gynaecological causes. Using an EIP comprised solely of gynaecologists does, however, produce a diagnosis reflecting the clinical decision point, as the decision as to whether or not to perform a laparoscopy is made by gynaecologists.

Given the large amount of information to be considered per case, a piloted structured report was produced for the panel’s consideration. Each panel meeting involved three experts who provided the reference diagnosis for each case presented based on the structured summary of all the data collected, with the various case report forms available in their entirety, if required. Each member individually recorded their reference diagnosis. The meeting chairperson documented the discussion that followed and how agreement was reached through consensus. Understanding the difference between the presence of a condition and a target condition being the cause of pain proved to be the main challenge. After running pilot panels, the procedures for the panel meetings were reviewed and finalised. During the course of the panel assessments, we undertook formal repeatability testing for inter-rater agreement. We employed the agreement statistics in determining the reliability of the reference standard for the interpretation of our findings. We found that agreement among experts for the assignment of gynaecological conditions as causes of CPP was either good or very good, although it was weak for non-gynaecological conditions.

The MEDAL study has been reported in accordance with the Standards for Reporting of Diagnostic Accuracy (STARD) statement. Not all items apply to the MEDAL study, as it is not a typical test-accuracy evaluation, but this statement provides for a minimum requirement to ensure completeness and transparency of reporting.

Strengths and weaknesses of the economic evaluation

The strength of this model-based analysis is that it has utilised contemporary data informing the test accuracy of diagnostic laparoscopy and MRI in their application to women with CPP. In addition, these data have provided information for the model on the impact of successfully testing and treating women with structural causes of CPP on their QoL. Moreover, as part of this analysis, the cut-off value on the ROC curve to inform the sensitivity and specificity of each test was treated as a decision variable, meaning that the most cost-effective test at its optimum cut-off value could be identified.

This analysis has a number of weaknesses that need to be acknowledged. QoL data were collected from women over a 6-month period only, meaning that a time horizon of only 6 months could be adopted in the model, unless strong assumptions were made about the QoL and costs incurred beyond 6 months. During the sensitivity analysis, the time horizon was extended up to 3 years, but this relied on the assumptions that QoL did not change beyond 6 months and no costs were incurred by either strategy beyond that time. It is acknowledged that CPP among women is a problem that can often take many medical consultations to resolve, and so it is likely that the positive benefits of properly diagnosing and treating a structural cause of CPP will be felt long after the 6-month time horizon considered here.

Given that this model utilised data from a test-accuracy study in which all women received both tests, it was difficult to tease out the impact of the different test results and the resulting treatment on patient QoL. This meant that assumptions had to be made regarding how negative test results might affect women. This is really an unavoidable issue with model-based analyses that examine medical tests, but is acknowledged here nonetheless.

This economic analysis has considered only the diagnosis and treatment of structural causes of CPP, and has not included other possible causes of CPP, such as PID. Including more possible causes of CPP would make the model more cumbersome, and would also require the different treatment and test characteristics for the new causes to be incorporated into the model. This means that the full patient benefit of laparoscopy and MRI has not been considered here. Nevertheless, varying the prevalence of structural causes of CPP was undertaken in the sensitivity analysis presented here, and slightly increasing the prevalence could be regarded as a proxy for the inclusion of other causes of CPP, and thus this does help to show how their inclusion might impact on the conclusions drawn from the model.

In this model-based economic evaluation, a decision tree was utilised rather than a Markov model. This was attributable to the short time horizon and the fact that women acquiring new cases of CPP over time were not considered in the study. However, it is acknowledged that an individual sampling model could have been used, whereby the different structural causes of CPP would be described for each patient. However, given that the testing and treatment pathways for many of the causes of CPP considered in this study are the same, this approach was considered unnecessary as these pathways could easily be described using a decision tree.

Public and patient involvement

We have been supported throughout the project by the Pelvic Pain Support Network (PPSN) and, in particular, its chairperson. Public and patient involvement was crucial in improving the acceptability of the MEDAL study and promoting recruitment. We engaged with the PPSN chairperson throughout, developing an appreciation of the apprehension and uncertainty surrounding MRI and laparoscopy among women, as well as the opinions of clinicians and barriers to accessing MRI that the chairperson had encountered. This prompted us to provide a study-specific MRI information leaflet to potential participants. We also believed that it was important to establish a thorough understanding of all aspects of CPP and the potential underlying conditions, and so we designed the initial patient questionnaire with input from the PPSN.

We will engage with the PPSN regarding the dissemination of our findings, providing a plain English summary of the findings and the uncertainties around the evidence we have discussed here. This will be distributed via the PPSN website and e-newsletter. Any future research groups taking forward the research recommendations from this project would benefit from engaging with the PPSN.

Interpretation of the findings

To our knowledge, this is the first study that has examined the diagnostic value and cost-effectiveness of MRI compared with diagnostic laparoscopy in women with CPP.

The risks of MRI revolve around changing radiofrequencies and magnetic fields, which can theoretically produce heat that is absorbed by the body tissue; this is not known to produce any side effects. Conversely, like any surgery, a laparoscopy is not without its risks. It involves day care admission and general aesthesia. Laparoscopy involves minimal invasion of body tissues, but its complications can include damage to organs inside the abdomen and wound infections. Therefore, if MRI could minimise the use of laparoscopy, it could be beneficial to women and health services. Our diagnostic study found that MRI tests were not accurate for detecting structural gynaecological conditions. Furthermore, it did not add value over and above baseline history, examination and pelvic ultrasound in verifying the absence of a cause of CPP symptoms (before performing diagnostic laparoscopy).

With respect to specific gynaecological conditions, MRI was most accurate for endometrioma, adhesions and fibroids when compared with observations at laparoscopy but, even so, its performance was too inadequate to be useful. Evaluation of non-gynaecological conditions suffered from poverty of agreement over verification of the diagnosis by an expert panel, and this limits the useful interpretation of these data.

The health economic analysis found that MRI was never more cost-effective than laparoscopy. Given the poor accuracy of MRI, this conclusion was expected. Our extended analysis comparing laparoscopy and MRI with a theoretical no-testing scenario revealed the interesting observation that, at the 6-month follow-up, a strategy of no laparoscopy or MRI would be the most cost-effective – this finding is likely to be strongly affected by the short follow-up period (the benefits of successful treatment of CPP are likely to last many years), and the assumptions made about QoL without treatment (which could not be directly observed in the study).

Implications for practice

Magnetic resonance imaging was dominated by laparoscopy in the differential diagnosis of women presenting to gynaecology clinics with CPP. It did not add value to the information, already gained from history, examination and ultrasound, about idiopathic CPP and various gynaecological conditions before considering a laparoscopy. The little value it did show for a few conditions, such as endometrioma, could be obtained only at the cost of undertaking large numbers of scans, and was not cost-effective, as the small diagnostic gain came tagged with additional costs.

Unanswered questions and further research

The evaluation of subjective tests for differential diagnosis in care pathways targeting various conditions for treatment requires methodological development. Further data on the individual and joint distributions of the prevalence of causes of pain would be beneficial. In CPP, the development of diagnostic prediction models incorporating biomarkers into baseline data may improve the use of diagnostic laparoscopy; however, research will first be required to determine objective diagnostic criteria for the various target conditions and valid biomarkers for endometriosis.

The Magnetic resonance imaging for Establishing Diagnosis Against Laparoscopy study group

The MEDAL study collaborators (principal investigators/investigators/research nurses).

Expert independent panel (for establishing a consensus reference diagnosis)

Mr Christian Becker, John Radcliffe Hospital, Oxford; Mr Alfred Cutner, University College Hospital, London; Mr Patrick Chien (Expert Panel Chairperson), Ninewells Hospital, Dundee; Mr Justin Clark, Birmingham Women’s Hospital, Birmingham; Mr Yemi Coker, Queen’s Hospital, Romford; Mr Shane Duffy, Chelsea and Westminster Hospital, London; Mr Jed Hawe, Countess of Chester Hospital, Chester; Mr Kevin Phillips, Castle Hill Hospital, Cottingham; Dr Caroline Overton, University Hospitals Bristol NHS Foundation Trust, Bristol; Mr Adam Rosenthal, St Bartholomew’s Hospital, London; Mr Ertan Saridogan, University College Hospital, London; Mr Tom Smith Walker, Royal Cornwall Hospital, Truro; Mr Jim Thornton, Nottingham City Hospital, Nottingham; Mr Sanjay Vyas, Spire Bristol Hospital, Bristol; and Miss Ephia Yasmin, University College London Hospital, London.

Independent radiology review committee (for establishing a consensus diagnosis from the magnetic resonance imaging scan)

Dr Mark Blakeman, New Cross Hospital, Wolverhampton; Dr Claire Keaney, Sandwell General Hospital, West Bromwich/Birmingham City Hospital, Birmingham; and Dr Carolina Lopez, Bedford Hospital, Bedford.

The Study Steering and Data Monitoring Committees

The SSC provided independent supervision for the study, providing advice to the investigators and the sponsor on all aspects of the study and affording protection for women by ensuring that the study was conducted as applicable to the MRC guidelines for good clinical practice in clinical trials.

For the purposes of this study, the SSC nominated and convened a three-member independent Data Monitoring and Ethics Committee (DMEC) from within its membership, which did not include study researchers:

• Professor Ovrang Djahanbakhch (SSC Chairperson and Head of the Unit for Women’s Health, The Royal London Hospital, London)

• Professor Ben Willem Mol (DMEC Chairperson and Professor of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA, Australia)

• Professor Javier Zamora (until 2013, Senior Lecturer, Barts and The London School of Medicine and Dentistry, London)

• Dr Teresa Perez (replaced Dr Zamora in 2013; Complutense University of Madrid, Madrid, Spain)

• Dr George Harrison (Consultant in Pain, Queen Elizabeth Hospital Birmingham, Birmingham, UK)

• Ms Judy Birch (Chief Executive, Pelvic Pain Support Network, Poole, UK).

Study management group

The MEDAL study was co-ordinated by the Birmingham Clinical Trials Unit at the University of Birmingham and we acknowledge all of the hard work of all of the staff involved in the study, including Lee Priest (Trial Co-ordinator) and Julia Seeley (Data Manager). We thank Neil Winkles for designing and developing the study database. We thank Rita Champaneria and Bella Harris for the systematic review and reference support. We would also like to thank Christopher Webb for the organisation of the study meetings. The MEDAL study sponsor organisation was the Queen Mary University of London, and we acknowledge Kathline Mulligan (Senior Clinical Trials Manager until 2012), Julie Dodds (Senior Clinical Trials Manager from 2012), Tracy Holtham and Camille Paulsen for their support.

The study management group comprised Khalid Khan (Queen Mary University of London); Elizabeth Ball (The Royal London Hospital); Jon Deeks (University of Birmingham); Jane Daniels (University of Birmingham); Judy Birch (Pelvic Pain Support Network); Lee Middleton (University of Birmingham); Lee Priest (University of Birmingham); Julia Seeley (University of Birmingham); Seema Anushka Tirlapur (Queen Mary University of London); Julie Dodds (Queen Mary, University of London); and Teresita Beeston (Queen Mary University of London).

We are grateful to the British Society of Gynaecological Endoscopists.

Research governance

The study was conducted in accordance with the principles of MRC Guidelines for Good Clinical Practice in Clinical Trials (1998) and the appropriate NHS Research Governance Frameworks.

All centres will be required to sign an Investigator’s Agreement, detailing their commitment to accrual, compliance, good clinical practice, confidentiality and publication. Deviations from the agreement will be monitored and the SSC will decide if any action needs to be taken, such as withdrawal of funding or suspension of the centre. Proof of training in the principles of good clinical practice and informed consent may be required.

Study advisors

Dr Pallavi Latthe (Consultant Obstetrician and Gynaecologist, Birmingham Women’s Hospital) was a recruiting investigator and helped to develop the working diagnosis form.

Dr Susan Mallet (Senior Lecturer in Medical Statistics in the Test Evaluation Research Group, University of Birmingham) advised on the analysis of the study.

Dr Nigel Cowan (Consultant Clinical Radiologist, Nuffield Health Oxford Hospital) provided guidance on the criteria for the assessment of the target conditions investigated in the study.

Professor Charles Knowles (Clinical Professor of Surgical Research, Barts and the London School of Medicine and Dentistry Unit) provided guidance on bowel symptoms.

Professor Kasim Aziz (Professor of Neurogastroenterology, Queen Mary University of London) provided guidance on bowel symptoms.

Dr Jonathan Hill (Keele University) provided guidance on physiotherapy and musculoskeletal aspects.

Finally, we would like to thank all of the women who consented to participate in this study. The study would not have been possible without them.

Contributions of authors

Professor Khalid S Khan (Consultant Gynaecologist and lead applicant) conceived the idea for the study, contributed to the design, delivery, analysis and interpretation, recruited women, and, as the chief investigator, had overall responsibility for the MEDAL study.

Mr Konstantinos Tryposkiadis (Statistician) performed the analyses for the accuracy study and contributed to the interpretation and drafting of the report.

Dr Seema A Tirlapur (Clinical Research Fellow) recruited participants, developed the process for the EIP and contributed to the delivery of the accuracy study and the development of the economic model.

Mr Lee J Middleton (Senior Statistician) contributed to the design, analysis and interpretation of the accuracy study.

Dr Andrew J Sutton (Senior Economic Research Fellow) contributed to the design and interpretation of the economic evaluation, performed the analysis and drafted the economic study chapter (see Chapter 4).

Mr Lee Priest (Senior Trial Co-ordinator) was responsible for the day-to-day management and delivery of all study components, and developed the process for the EIP panel and edited the report.

Dr Elizabeth Ball (Consultant Gynaecologist and co-applicant) contributed to the design and delivery of the accuracy study and the development of the economic model, and recruited participants.

Dr Moji Balogun (Consultant Radiologist and co-applicant) contributed to the design of the accuracy study and the development of the MRI reporting standards.

Dr Anju Sahdev (Consultant Radiologist) contributed to the development of the MRI reporting standards.

Professor Tracy Roberts (Professor of Health Economics and co-applicant) contributed to the design, analysis and interpretation of the economic evaluation.

Mrs Judy Birch (Chairperson, Pelvic Pain Support Network and co-applicant) contributed to the design of the accuracy study and commented on the acceptability of participant-facing material.

Dr Jane P Daniels (Deputy Director of Birmingham Clinical Trials Unit and co-applicant) contributed to the design, delivery and interpretation of the MEDAL study, the first draft and overall editing of the final report.

Professor Jonathan J Deeks (Professor of Medical Statistics and co-applicant) defined the design and statistical analysis of the accuracy study and contributed to the interpretation of the accuracy study and economic model.

Publications

Tirlapur SA, Priest L, Daniels JP, Khan KS on behalf of the MEDAL study management group. How do we define the term idiopathic? Curr Opin Obstet Gynecol 2013;25:468–7.

Tirlapur SA, Priest L, Wojdyla D, Khan KS on behalf of the MEDAL Study. Bladder pain syndrome: validation of simple tests for diagnosis in women with chronic pelvic pain: BRaVADO study protocol. Reprod Health 2013;10:61.

Tirlapur SA, Daniels JP, Khan K on behalf of the MEDAL Study. Chronic pelvic pain: how does noninvasive imaging compare with diagnostic laparoscopy? Curr Opin Obstet Gynecol 2015;27:445–8.

Bharwani N, Tirlapur SA, Balogun M, Priest L, Khan KS, Zamora J, Sadhev A. MRI reporting standard for chronic pelvic pain: consensus development. Br J Radiol 2016;89:20140615.

Data sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to available anonymised data may be granted following review.

Patient data

This work uses data provided by women and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.