Referee report. For: Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care [version 1; peer review: 1 not approved]

Endometriosis, diagnosis, prediction, diagnostic laparoscopy, primary care, pelvic pain, dysmenorrhoea ALL Metrics - Views Downloads How to cite this article Bainton T, Jeyapala S, Zamora J et al. Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:453 (https://doi.org/10.12688/f1000research.131729.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente Select a format first ▬ ✚ Systematic Review [version 1; peer review: 1 approved with reservations, 1 not approved] PUBLISHED 28 Apr 2023 Author details Author details 1 Metabolism Digestion and Reproduction, Imperial College London, London, UK 2 Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital NHS Foundation Trust, London, SW10 9NH, UK 3 Institute of Metabolism and Systems Research, University of Birmingham, UK, Birmingham, UK 4 Clinical Biostatistics Unit, Hospital Ramon y Cajal (IRYCIS), Madrid, 28034, Spain 5 Department of Preventative Medicine and Public Health, University of Granada, Grenada, Spain 6 Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain 2 Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital NHS Foundation Trust, London, SW10 9NH, UK 3 Institute of Metabolism and Systems Research, University of Birmingham, UK, Birmingham, UK 4 Clinical Biostatistics Unit, Hospital Ramon y Cajal (IRYCIS), Madrid, 28034, Spain 5 Department of Preventative Medicine and Public Health, University of Granada, Grenada, Spain 6 Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain Thomas Bainton Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Sobanakumari Jeyapala Roles: Investigation, Methodology, Writing – Review & Editing Roles: Investigation, Methodology, Writing – Review & Editing Javier Zamora Roles: Formal Analysis, Resources, Software, Writing – Review & Editing Roles: Formal Analysis, Resources, Software, Writing – Review & Editing Khalid S Khan Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Amer Raza Roles: Conceptualization, Methodology, Project Administration, Supervision, Writing – Review & Editing Roles: Conceptualization, Methodology, Project Administration, Supervision, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS This article is included in the Health Services gateway. This article is included in the Endometriosis collection.

Endometriosis is a chronic, often debilitating condition with a current significant delay from symptom onset to diagnosis with much of this in primary care.

A systematic review and meta-analysis of the primary literature was conducted to investigate the accuracy of symptoms, clinical history and first-line non-invasive tests to predict pelvic endometriosis (PROSPERO: CRD42020187543). We searched Medline, Embase, Web of Science and Scopus from conception (1966; 1972; 1997; 2004 respectively) to September 2022 for primary test accuracy studies assessing non-invasive tests against reference standard diagnosis for endometriosis. Two authors independently conducted data extraction and quality assessment. Grading of evidence was performed using a novel visual pentagon model. Meta-analyses of test accuracy was estimated using bivariate random effects models.

The 125 included studies (250,574 participants) showed mixed quality. Studies applying non-surgical (database/self-reporting) reference standard had a greater risk of bias. In 98 studies applying surgical reference standard, summary diagnostic odds ratios for endometriosis were: dysmenorrhoea 2.56 (95% confidence interval 1.99-3.29); pelvic pain 2.56 (1.73-3.74); dyschezia 2.05 (1.36-3.10); dyspareunia 2.45 (1.71-3.52); family history of endometriosis 6.79 (4.08-11.3); nulligravidity of 2.01 (1.62-2.50); body mass index (BMI) ≥30kg/m2 0.37 (0.19-0.68); trans-vaginal ultrasound scan (TVUSS) endometrioma 91.2 (44.0-189); TVUSS invasive endometriosis 26.1 (9.28-73.5); and cancer antigen-125 (CA-125) >35U/mL 16.0 (8.09-31.7). Sensitivity analysis excluding all high-risk studies found concordant results.

This meta-analysis collated the performance of non-invasive tests for endometriosis across a comprehensive and geographically varied population. Study quality was mixed, however results were consistent with high-risk studies excluded. These findings will inform future prediction models for triage in primary care.

A systematic review and meta-analysis of the primary literature was conducted to investigate the accuracy of symptoms, clinical history and first-line non-invasive tests to predict pelvic endometriosis (PROSPERO: CRD42020187543). We searched Medline, Embase, Web of Science and Scopus from conception (1966; 1972; 1997; 2004 respectively) to September 2022 for primary test accuracy studies assessing non-invasive tests against reference standard diagnosis for endometriosis. Two authors independently conducted data extraction and quality assessment. Grading of evidence was performed using a novel visual pentagon model. Meta-analyses of test accuracy was estimated using bivariate random effects models.

The 125 included studies (250,574 participants) showed mixed quality. Studies applying non-surgical (database/self-reporting) reference standard had a greater risk of bias. In 98 studies applying surgical reference standard, summary diagnostic odds ratios for endometriosis were: dysmenorrhoea 2.56 (95% confidence interval 1.99-3.29); pelvic pain 2.56 (1.73-3.74); dyschezia 2.05 (1.36-3.10); dyspareunia 2.45 (1.71-3.52); family history of endometriosis 6.79 (4.08-11.3); nulligravidity of 2.01 (1.62-2.50); body mass index (BMI) ≥30kg/m2 0.37 (0.19-0.68); trans-vaginal ultrasound scan (TVUSS) endometrioma 91.2 (44.0-189); TVUSS invasive endometriosis 26.1 (9.28-73.5); and cancer antigen-125 (CA-125) >35U/mL 16.0 (8.09-31.7). Sensitivity analysis excluding all high-risk studies found concordant results.

This meta-analysis collated the performance of non-invasive tests for endometriosis across a comprehensive and geographically varied population. Study quality was mixed, however results were consistent with high-risk studies excluded. These findings will inform future prediction models for triage in primary care. Endometriosis, diagnosis, prediction, diagnostic laparoscopy, primary care, pelvic pain, dysmenorrhoea Corresponding Author(s) Thomas Bainton ([email protected]) Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2023 Bainton T et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Bainton T, Jeyapala S, Zamora J et al. Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:453 (https://doi.org/10.12688/f1000research.131729.1) First published: 28 Apr 2023, 12:453 (https://doi.org/10.12688/f1000research.131729.1) Latest published: 28 Apr 2023, 12:453 (https://doi.org/10.12688/f1000research.131729.1) Endometriosis is a chronic condition affecting women of reproductive age characterised by extra-uterine deposits of endometrial tissue with a prevalence of up to 10%.1–3 It can be found in peritoneal deposits, ovarian endometriomata, and invasive disease, with sufferers experiencing pain and sub-fertility.2,4–6 There is currently a 7-12 years delay between symptom onset and definitive diagnosis, by laparoscopy and biopsy.7–9 Reducing this has long a research priority.10,11 Up to 58% of sufferers present to primary care 10 or more times before diagnosis, demonstrated across a variety of healthcare systems and geographies.4,7,12–14 A better understanding of the accuracy with which symptoms, clinical history and non-invasive tests diagnose pelvic endometriosis would aid triage and referral. Many studies have attempted to find replacement tests for diagnostic laparoscopy.15–17 These are often invasive or otherwise not applicable to primary care.16,18 Previous meta-analyses have been restricted by a narrow inclusion criteria yielding a small number of eligible studies, limiting findings.19 Meta-analyses assessing imaging and biomarkers showed that no individual test met their criteria as a replacement or triage test alone, but findings on trans-vaginal ultrasound and serum CA-125 showed a high specificity for disease.20,21 These studies did not include assessment of other clinical factors. A 2019 narrative review demonstrated the importance of clinical factors in prediction of disease, but primary studies were not assessed for quality and absence of meta-analysis limited quantitative assessment of test performance.22 A 2021 case-control study reporting on the accuracy of a simple patient-completed questionnaire identified those at high or low risk of disease with good accuracy reflecting the utility of assessment of patient reported symptoms at a primary care level.23 Research related to endometriosis is increasing in volume, with 75% of primary studies published in the last decade.24,25 Given this, and due to the limitations of previous reviews a new comprehensive systematic review and meta-analysis is required. We performed such an evidence synthesis and determined the accuracy of symptoms, clinical history, a simple low-cost biomarker and first line ultrasound for the diagnosis of pelvic endometriosis by means of a comprehensive systematic review and accuracy meta-analysis. The protocol was designed and registered with PROSPERO (Registration number: CRD42020187543).26 Reporting followed the PRISMA guidelines.27,59 A virtual patient and public involvement meeting involving endometriosis sufferers at Chelsea and Westminster Hospital, London was held following an open invitation on social media to inform them of plans for this study. The aim was to better understand non-invasive predictors of endometriosis and reduce the diagnostic delay, which was well supported and resonated with their personal experience. No specific ethical approval was required for the patient and public involvement, in accordance with Health Research Authority (HRA) guidelines. No specific ethical approval was required as this study retrieved and synthesised data from already published studies. No individual participant data was collected and no participant consent was required. Medline, Embase, Web of Science and Scopus were searched from conception (1966; 1972; 1997; 2004 respectively) to September 2022 Search strategies are shown in Table 1 (see Extended data).53 Review article references were also screened. Titles and abstracts were screened independently by two authors (TB; SJ) using EndNote-X9 and duplicate or irrelevant studies removed. Full texts were screened and justification for inclusion or exclusion recorded, differences were resolved by discussion with the senior author (AR).28 We included published peer reviewed studies reporting accuracy estimates to predict pelvic endometriosis (peritoneal; ovarian; disease >5mm retroperitoneal invasion) for one or more index tests in participants with reported presence/absence of endometriosis. Included tests were dysmenorrhoea; pelvic pain; dyschezia; dyspareunia; nulligravidity; BMI ≥30kg/m2; family history of endometriosis; transvaginal ultrasound finding (TVUSS) of endometrioma; TVUSS finding of invasive disease; serum CA-125 >35U/mL. Target population was reproductive age women excluding pregnancy or systemic co-morbidities. Studies with reporting non-reproductive age participants were included only where their data could be excluded from meta-analysis. Studies were included where a 2x2 contingency table for index test(s) could be constructed. We imposed no limits to language of publication, setting, or number of participants. All non-English studies were translated by a medically trained native speaker. Studies reporting laboratory and ultrasound tests were included only when performed prior to reference standard and using only standard 2D protocols. Definitions for each test for the purposes of study selection are shown in Table 2 (see Extended data).54 We excluded reviews; case reports; studies where information on recruitment or study population was unavailable; letters; and abstracts. Studies reporting non-pelvic endometriosis were included only where pelvic endometriosis was reported separately. Authors were contacted to obtain full texts only. Failing this, they were obtained through the British Library. Studies with incomplete data preventing determination of inclusion, exclusion or test accuracy were excluded. For each included study, two authors (TB; SJ) independently recorded information on study characteristics and data was extracted to form 2x2 tables. Where there was unreliability in data extraction from some non-English language studies, these were excluded. Risk of bias was assessed independently by two authors (TB; SJ) using the Quality Assessment of Diagnostic Test Accuracy Studies (QUADAS 2) tool.29 For studies regarding serum CA-125 or TVUSS we included the additional questions: ‘was the index test performed by a single operator?’ to assess inter-observer bias; and ‘was timing in the participants’ menstrual cycle controlled for?’. We adjusted the original question ‘if a threshold was used, was it pre-specified?’ to ‘was there a clear definition of what was considered a positive test?’. Due to differences in design, studies were divided into groups according to application of the reference standard: ‘Complete verification’, all participants received visual inspection of the pelvis at surgery; ‘Partial verification’, all cases received surgical confirmation but controls did not; and ‘Database/self-reporting’, cases confirmed by healthcare coding or self-reporting and controls from healthy populations not known to have endometriosis. Statistical analysis was conducted using Stata software (version 15)30 to allow exploration of heterogeneity and statistical pooling using a bivariate random effects model and produced summary accuracy measures and summary receiver operative characteristic curves for each index test. A bivariate random effects model was applied for index tests with ≥5 contributing studies, and a univariate fixed effects model for index test with ≤4. Index tests were assessed for performance as a ‘rule-in’ or ‘rule-out’ tool with pre-specified threshold summary accuracy of 95% sensitivity/50% specificity or 95% specificity/50% sensitivity respectively. Of 22,016 studies identified 125 met the inclusion criteria involving 250,574 participants (Figure 1). Details of included studies by number of participants and index test(s) are shown Table 2 (see Extended data54). Characteristics of included and excluded studies are shown in Tables 3 and 4 (see Extended data).55,56 Mean number of index tests per study was 2 (range 1-6). A total of 241 were assessed across all studies. Included studies were geographically varied: 45 Europe, 34 North America, 19 Asia/Oceania, 13 the Middle East/Africa, 12 South America, and 2 transcontinental. Publication date ranged from 1986 and 2022 with 57% since 2010: 4 before 1989; 22, 1990-1999; 18, 2000-2009; and 71, 2010-2022. Most studies (75) were ‘single-gate’ design with 50 of ‘two-gate’ design, including all studies in the partial verification and database/self-reporting groups. The mean prevalence of endometriosis in studies of a ‘single-gate’ design was 52% (range 9-93%), due to the selection of matched controls, prevalence in ‘two-gate’ studies was not relevant. There was heterogeneity in population selection, with participants having surgery for a broad range of indications such uterine fibroids or adnexal cysts as well as pelvic pain or sub-fertility. In the 61 studies assessing symptom-based tests 20 did so by self-administered questionnaire; 14 by structured interview; 12 by clinical history taking, and 15 were undefined (Table 5 - see Extended data).57 Risk of bias The assessment of study quality by QUADAS-2 is presented in Figures 2-6. Overall methodological quality was mixed, with 5 studies presenting a low risk of bias across all domains31–35 and 64 presenting a high risk of bias or applicability in at least one domain. In patient selection, 22 studies presented a low risk of bias, with 73 and 30 presenting an unclear or high risk respectively. Non-consecutive or non-random selection, two-gate selection for cases and controls, and having a highly selected group of participants (infertility cohort, surgery for a narrow indication etc.) were the main reasons for a high risk of bias. Symptom based index tests presented an unclear or high risk of bias due to a lack of definition of a positive test and of blinding. Just 9 studies presented a low risk in symptom-based tests across all groups. Index tests applicable to clinical history or investigations performed better, with 66 studies presenting a low risk. Reasons for an unclear or high risk of bias were a lack of pre-specified criteria for a positive test; no blinding to results of the reference standard; and inter-observer variability regarding imaging. Studies in the partial verification group assessed a proportionally higher number of index tests nulligravidity and BMI ≥30kg/m2, which, less subjective to interpretation presented a lower risk of bias. The risk of bias regarding the reference standard performed best in the complete and partial verification groups where 74 studies were at low risk of bias. Those with an unclear or high risk lacked information on how likely the surgery was to correctly classify the target condition or operators not blinded to the result of index test(s). In the database/self-reporting group, 5 studies assessed for probable surgical confirmation by means of additional codes at the time of recording and therefore presented a lower risk, all other studies were high risk. In flow and timing, the complete verification group presented the lowest risk. An unclear or high risk of bias was attributable to a long (>12 months) or unclear time interval, and a high or unclear withdrawal of participants from analysis. All other studies presented a high risk as not all participants received the same reference standard. In patient selection, 40 studies gave low concern, with 63 and 22 giving unclear or high risk respectively. An unclear or high risk was attributable to the two-gate selection of controls, or the study likely to only classify a limited spectrum of disease (tertiary centres or infertility clinics). In regard the reference standard, 97 studies showed a low concern. Studies in the database/self-reporting group were deemed high/unclear depending on whether additional coding input for surgery was recorded. Due to heterogeneity in methodology and study quality, meta-analysis was performed on studies from each group separately. The accuracy of index tests to predicting endometriosis was variable, although results across groups were consistent. Each index test gave a positive likelihood for the presence of pelvic endometriosis, apart from a BMI ≥30kg/m2, which decreased the likelihood of disease. The positive likelihood ratio (LR+) for disease was highest in investigation tests and there was a trend towards a greater specificity than sensitivity. The summary results of bi/univariate meta-analysis are shown in Figure 7. An assessment of confidence in individual sensitivity and specificity of each test is displayed by a visual pentagon model, the methodology for this assessment is described in the discussion and legend shown in Figure 8. Investigation category tests were the best performing overall and TVUSS finding of endometrioma gave the highest summary LR+ at 21.6, at sensitivity and specificity of 77.2% and 96.4% respectively. Serum CA-125 >35U/mL showed sensitivity and specificity of 55.8% and 92.7% respectively, with LR+ of 7.63. TVUSS finding of DIE had showed sensitivity and specificity of 86.5% and 80.2% with LR+ of 4.39. Symptom based tests showed LR+ within a similar range: 1.47 (dysmenorrhoea) to 1.93 (dyspareunia). Symptoms showed a generally higher specificity than sensitivity. Dyspareunia showed the highest LR+ at 1.93 with a sensitivity and specificity of 36.3% and 81.1% respectively. Family history of endometriosis showed a LR+ of 6.25 with a high specificity (98.5%) but low sensitivity (9.25%). The finding of BMI ≥30kg/m2 showed a decreased likelihood of diagnosis of endometriosis (LR+ 0.44). Hierarchical Summary Receiver Operating Characteristics (HSROC) curves for index tests in each group are shown in Figures 9-11. The HSROC curves show the greatest area under the curve (AUC) for investigation category tests. In the partial verification group, symptom index tests showed a greater LR+ than the complete verification group, range 2.47 (dysmenorrhoea) to 7.13 (dyschezia). Specificity was also higher, range 69% (dysmenorrhoea) to 92% (dyschezia). In the database/self-reporting group symptom-based index tests performed similarly to other groups. In partial verification and database/self-reporting groups BMI ≥30 kg/m2 showed no correlation with disease and had 95% CI crossing 1.0. In all other index tests across all groups the 95% CI was >1.0. The greatest inter-study variability in confidence intervals was shown in Forest plots for the symptom-based tests, notably pelvic pain. The inter study variance for specificity was generally lower than that for sensitivity, as was the overall width of confidence intervals. Forest plots for each index test in each group are shown in Figures 12-18. Sensitivity analysis performed for studies without any high-risk features is shown in Table 6 (see Extended data58). All studies included are from the complete verification group. Summary accuracy measures are consistent with those in this group for the majority of index tests, although sensitivity for TVUSS finding of endometrioma and DIE reduced to 69.8% and 73.4% respectively. This meta-analysis presents an up-to-date, large, and geographically varied data set identifying predictive factors for diagnosis of pelvic endometriosis with a high degree of confidence. Index tests showed a positive association with endometriosis and trended towards a greater specificity than sensitivity, excluding elevated BMI, which demonstrated an inverse correlation. TVUSS finding of endometrioma reached a desired threshold for use as a ‘rule-in’ test and none achieved a summary sensitivity of >95%. A family history of endometriosis, dyschezia and serum CA-125 >35U/mL showed summary specificity of >90% although low sensitivity. Sensitivity was poor for symptom and clinical history tests, where the best performing was dysmenorrhoea. We undertook a thorough search of the current literature, undergoing analysis by two independent reviewers with strict quality assessment. Attempts were made to mitigate inter-study heterogeneity by division of studies into groups. All index tests are relevant to primary care, are immediately available without novel techniques or additional training and can assist in the triage of those with symptoms that could be attributable to endometriosis. There were, however, limitations. Due to difficulties in data extraction from some non-English journals, 15 studies were excluded from the analysis. Some studies, such as Chapron et al 2005, which was seminal in providing a clinical prediction model for moderate/severe endometriosis, were not able to be included due to the inability for construct 2x2 tables.36 We did not contact authors to obtain individual data that was not available in the published text. Overall, there was significant methodological variance and population heterogeneity in age; presentation; and stage of disease. Variation in selection of cases and controls may not reflect a clinically representative population. Prevalence of disease was higher than seen in the general female population, which may reflect a high degree of surgical accuracy, but also indicates the selective nature of study populations. There is the possibility of inappropriate assignment of cases and controls, occurring in both directions due to uneven application of the reference standard, although we attempted to account for this by assigning groups. We included studies that diagnosed endometriosis by visual inspection and there is debate regarding this in the absence of histological confirmation.37–39 There was variation in the definition of positive symptom index tests. This is common across many reviews and although there is guidance on symptom reporting, it was not clearly followed in all studies.40–42 Assessment of symptoms varied, with most studies using a self-administered questionnaire. Although the use of standardised validated tools would better allow for comparison across studies, the nuance and detail acquired through clinical history taking is likely to better grasp the nature and significance of a symptom and its implications. It is likely that imaging and surgical techniques have developed over time. A trend towards recent studies may mitigate this. Imaging modalities such as MRI and advanced sonographic techniques were not assessed due to their lack of universal availability in a primary care setting. Considering the balances of strengths and weaknesses, however, we believe that our data synthesis presents an objective summary of the current evidence. An understanding of the degree of likelihood associated with various symptoms and features in the clinical history can help assessment of patients with possible endometriosis in primary care. The negative association between elevated BMI and endometriosis shown in the complete verification group is consistent with that demonstrated previously.43 This was not replicated across other groups. This may reflect a greater negative correlation between elevated BMI in higher risk populations in all surgical cohorts who may have more severe disease. This possibility is consistent with previous studies, demonstrating a significantly lower BMI in those with severe compared to mild disease and a 12-14% decrease in the likelihood of endometriosis being diagnosed for each unit increase in BMI (kg/m2).31,44 The interplay between BMI and endometriosis pathogenesis, however, remains poorly understood. The trend of data from the partial verification and database/self-reporting groups to demonstrate better performing accuracy measures was likely a reflection of the selection of controls. This effect seems to outweigh the possibility of an undiagnosed disease burden in controls not exposed to a surgical reference standard. The accuracy of self-reported diagnosis of endometriosis has been assessed and performs well,45 false attribution of disease in the self-reporting group may therefore only present a small source of bias. A greater specificity than sensitivity of tests may be associated with their correlation to disease severity. Dyschezia and dyspareunia have been linked to severe disease due to the involvement of a precise anatomical location in cases of invasive disease.46,47 Tests showing a greater sensitivity such as dysmenorrhea were also less specific. Previous systematic reviews have similarly highlighted the heterogeneity and poor methodological quality of primary studies, limiting interpretation of findings.17,48 As our methodology allowed a wide inclusion criteria, we applied a novel grading protocol in order to more quantitively assess limitations. Grading of evidence for index tests was performed for sensitivity and specificity by application of a visual pentagon model for grading of test accuracy studies described by Rogozinska and Khan.49 This methodology is described in detail elsewhere but briefly, studies were given a score of 0 to -2 in each of 5 domains: design (study design type); risk of bias (QUADAS 2 risk of bias); indirectness (QUADAS 2 applicability); inconsistency (visual assessment of inter-study variance in confidence intervals); and imprecision (width of confidence intervals). The complete verification group shows the fewest limitations, whist the database/self-reporting studies showed very serious limitations. There was greater limitation in the investigation category tests due to more highly selective populations and a generally higher inter-study inconsistency and imprecision. The need for high-quality studies of predictive factors for endometriosis remains, particularly assessing populations attending primary care. Further multivariate analysis in powerful primary observational studies assessing factors that can be immediately and readily assessed in primary care would be of great value, as we anticipate the index tests assessed in this study to provide a greater degree of accuracy when applied in combination.4,36,50 We examined serum CA-125 at a cut off >35 U/mL, considered the upper limit of normal range, meta-analysis from 2016 found a cut off of 30 U/mL gave a sensitivity and specificity of 52% and 93% respectively, but sensitivity dropped to just 24% for detection of minimal disease.51 Further research assessing the accuracy of CA-125 at different thresholds and in combination with other tests could help improve accuracy. Two recent studies (Fauconnier et al 2021 and Chapron et al 2022) assessed the accuracy of a patient-completed questionnaire and epidemiological data for the early identification of endometriosis and found it could do so with high diagnostic accuracy.23,52 Although these studies were conducted in a high-risk population undergoing surgery, the model maintained accuracy in population with a lower endometriosis prevalence of 10%. We do not anticipate a clinical score replacing laparoscopy due to its added therapeutic advantages and requirement to exclude other pathologies. If, however, disease can be predicted with a high degree of accuracy early on, medical therapy may be instigated and referral made for definitive diagnosis and counselling regarding treatment, prognosis and fertility in a timely manner with the aim of reducing the current extraordinary delay. All data underlying the results are available as part of the article and no additional source data are required. Figshare: Table 1.xlsx. https://doi.org/10.6084/m9.figshare.22419178.v1. 53 This project contains the following extended data: - Table 1. xlsx (key word search strategy for all databases to identify primary studies for inclusion). Figshare: Table 2.xlsx. https://doi.org/10.6084/m9.figshare.22419184.v1. 54 This project contains the following extended data: - Table 2. xlsx (index tests and definitions for the purposes of study selection and data extraction and number of included studies and participants reporting on each index test by group according to confirmation of diagnosis of endometriosis. BMI, body mass index; TVUSS, trans-vaginal ultrasound scan; DIE, deep invasive endometriosis; CA-125, cancer antigen-125). Figshare: Table 3.xlsx. https://doi.org/10.6084/m9.figshare.22419187.v1. 55 This project contains the following extended data: - Table 3. xlsx (characteristics of all included studies in the systematic review and meta-analysis). Figshare: Table 4.xlsx. https://doi.org/10.6084/m9.figshare.22419967.v1. 56 This project contains the following extended data: - Table 4. xlsx (excluded studies and reason for exclusion of all screened full texts in the systematic review and meta-analysis). Figshare: Table 5.xlsx. https://doi.org/10.6084/m9.figshare.22419973.v1. 57 This project contains the following extended data: - Table 5. xlsx (method of assessment for all included studies assessing participants for a symptom-based index test (61) in the systematic review and meta-analysis Diagnosis of pelvic endometriosis: a systematic review and accuracy meta-analysis of non-invasive tests available in primary care). Figshare: Table 6.xlsx. https://doi.org/10.6084/m9.figshare.22419976.v1. 58 This project contains the following extended data: - Table 6. xlsx (sensitivity analysis - summary diagnostic results of bivariate meta-analysis of index tests for included studies excluding those with any high-risk feature for bias or applicability. BMI, body mass index. TVUSS, transvaginal ultrasound scan. DIE, deep invasive endometriosis. CA-125, cancer antigen-125. DOR, diagnostic odds ratio. LR, likelihood ratio). Figshare: PRISMA checklist for ‘Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care’. https://doi.org/10.6084/m9.figshare.22420591.v1. 59 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). KSK is Distinguished Investigator at University of Granada funded by the Beatriz Galindo (senior modality) program of the Spanish Ministry of Education. - 1. Eskenazi B, Warner ML: Epidemiology of endometriosis. Obstet. Gynecol. Clin. N. Am. 1997; 24(2): 235–258. Publisher Full Text - 2. Farquhar C: Endometriosis. BMJ. 2007; 334(7587): 249–253. PubMed Abstract | Publisher Full Text | Free Full Text - 3. Giudice LC: Clinical practice. Endometriosis. N. Engl. J. Med. 2010; 362(25): 2389–2398. Publisher Full Text - 4. Ballard KD, Seaman HE, de Vries CS , et al.: Can symptomatology help in the diagnosis of endometriosis? Findings from a national case-control study--Part 1. BJOG. 2008; 115(11): 1382–1391. Publisher Full Text - 5. Prescott J, Farland LV, Tobias DK, et al.: A prospective cohort study of endometriosis and subsequent risk of infertility. Hum. Reprod. 2016; 31(7): 1475–1482. Publisher Full Text - 6. Fuldeore MJ, Soliman AM: Prevalence and Symptomatic Burden of Diagnosed Endometriosis in the United States: National Estimates from a Cross-Sectional Survey of 59,411 Women. Gynecol. Obstet. Investig. 2017; 82(5): 453–461. Publisher Full Text - 7. Nnoaham KE, Hummelshoj L, Webster P, et al.: Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil. Steril. 2011; 96(2): 366–373.e8. Publisher Full Text - 8. Kuznetsov L, Dworzynski K, Davies M, et al.: Diagnosis and management of endometriosis: summary of NICE guidance. BMJ. 2017; 358: j3935. Publisher Full Text - 9. Zondervan KT, Becker CM, Koga K, et al.: Endometriosis. Nat. Rev. Dis. Primers. 2018; 4(1): 9. Publisher Full Text - 10. Rogers PAW, D'Hooghe TM, Fazleabas A, et al.: Priorities for endometriosis research: Recommendations from an international consensus workshop. Reprod. Sci. 2009; 16(4): 335–346. Publisher Full Text - 11. Rogers PA, Adamson GD, Al-Jefout M, et al.: Research Priorities for Endometriosis. Reprod. Sci. 2017; 24(2): 202–226. - 12. Arruda MS, Petta CA, Abrão MS, et al.: Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of Brazilian women. Hum. Reprod. 2003; 18(4): 756–759. Publisher Full Text - 13. Surrey E, Soliman AM, Trenz H, et al.: Impact of Endometriosis Diagnostic Delays on Healthcare Resource Utilization and Costs. Adv. Ther. 2020; 37(3): 1087–1099. PubMed Abstract | Publisher Full Text | Free Full Text - 14. UK All Party Parliamentary Group on Endometriosis Inquiry Report. Endometriosis in the UK: time for change (October 2020). UK All Party Parliamentary Group on Endometriosis.2020. - 15. Liu E, Nisenblat V, Farquhar C, et al.: Urinary biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst. Rev. 2015; 2015(12). PubMed Abstract | Publisher Full Text | Free Full Text - 16. Gupta D, Hull ML, Fraser I, et al.: Endometrial biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst. Rev. 2016; 2016(4): Cd012165. Publisher Full Text - 17. Nisenblat V, Prentice L, Bossuyt PM, et al.: Combination of the non-invasive tests for the diagnosis of endometriosis. Cochrane Database Syst. Rev. 2016; 2016(7): Cd012281. Publisher Full Text - 18. May KE, Conduit-Hulbert SA, Villar J, et al.: Peripheral biomarkers of endometriosis: A systematic review. Hum. Reprod. Update. 2010; 16(6): 651–674. PubMed Abstract | Publisher Full Text | Free Full Text - 19. Nisenblat V, Prentice L, Bossuyt PMM, et al.: Combination of the non-invasive tests for the diagnosis of endometriosis. Cochrane Database Syst. Rev. 2016; 2016(7). Publisher Full Text - 20. Nisenblat V, Bossuyt PMM, Shaikh R, et al.: Blood biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst. Rev. 2016; 2016(5). - 21. Nisenblat V, Bossuyt PM, Farquhar C, et al.: Imaging modalities for the non-invasive diagnosis of endometriosis. Cochrane Database Syst. Rev. 2016; 2(2): Cd009591. PubMed Abstract | Publisher Full Text - 22. Agarwal SK, Chapron C, Giudice LC, et al.: Clinical diagnosis of endometriosis: a call to action. Am. J. Obstet. Gynecol. 2019; 220(4): 354.e1–354.e12. Publisher Full Text - 23. Fauconnier A, Drioueche H, Huchon C, et al.: Early identification of women with endometriosis by means of a simple patient-completed questionnaire screening tool: a diagnostic study. Fertil. Steril. 2021; 116(6): 1580–1589. Publisher Full Text - 24. Bruggmann D, Elizabeth-Martinez A, Klingelhofer D, et al.: Endometriosis and its global research architecture: an in-depth density-equalizing mapping analysis. Bmc Womens Health. 2016; 16. Publisher Full Text - 25. Malvezzi H, Marengo EB, Podgaec S, et al.: Endometriosis: current challenges in modeling a multifactorial disease of unknown etiology. J. Transl. Med. 2020; 18(1): 311. Publisher Full Text - 26. Bainton TJS, Raza A: A systematic review of the literature to determine the accuracy measures of various predictors of endometriosis. Published 2020. Accessed. Reference Source - 27. Page MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71. Publisher Full Text - 28. EndNote [computer program]. Version EndNote X9. Philadelphia, PA: Clarivate.2013. - 29. Whiting PF, Rutjes AW, Westwood ME, et al.: QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann. Intern. Med. 2011; 155(8): 529–536. Publisher Full Text - 30. StataCorp: Stata Statistical Software: Release 15. College Station TSL.2017. - 31. Hediger ML, Hartnett HJ, Louis GM: Association of endometriosis with body size and figure. Fertil. Steril. 2005; 84(5): 1366–1374. Publisher Full Text - 32. Paiva P, Lappas M, Barker G, et al.: Using symptom scores, lifestyle measures and biochemical markers to create a test for endometriosis. Journal of Endometriosis and Pelvic Pain Disorders. 2014; 6(3): 135–143. Publisher Full Text - 33. Backonja U, Hediger ML, Chen Z, et al.: Beyond Body Mass Index: Using Anthropometric Measures and Body Composition Indicators to Assess Odds of an Endometriosis Diagnosis. J. Womens Health (Larchmt). 2017; 26(9): 941–950. Publisher Full Text - 34. Tanmahasamut P, Preukthanathorn R, Dangrat C: Serum interleukin 6 and cancer antigen 125 in the non-invasive diagnosis of endometriosis. Journal of Endometriosis and Pelvic Pain Disorders. 2018; 10(2): 116–122. Publisher Full Text - 35. Kim H, Choi YS, Kim JS, et al.: Identification of Serum Biomarkers for Diagnosis of Endometriosis Using Multiplex Immunoassays. Reprod. Sci. 2020; 27(5): 1139–1147. Publisher Full Text - 36. Chapron C, Barakat H, Fritel X, et al.: Presurgical diagnosis of posterior deep infiltrating endometriosis based on a standardized questionnaire. Hum. Reprod. 2005; 20(2): 507–513. Publisher Full Text - 37. Kazanegra R, Zaritsky E, Lathi RB, et al.: Diagnosis of stage I endometriosis: comparing visual inspection to histologic biopsy specimen. J. Minim. Invasive Gynecol. 2008; 15(2): 176–180. Publisher Full Text - 38. Dunselman GA, Vermeulen N, Becker C, et al.: ESHRE guideline: management of women with endometriosis. Hum. Reprod. 2014; 29(3): 400–412. Publisher Full Text - 39. Lier MCI, Vlek SL, Ankersmit M, et al.: Comparison of enhanced laparoscopic imaging techniques in endometriosis surgery: a diagnostic accuracy study. Surg. Endosc. 2020; 34(1): 96–104. Publisher Full Text - 40. Chen CX, Kwekkeboom KL, Ward SE: Self-report pain and symptom measures for primary dysmenorrhoea: a critical review. Eur. J. Pain. 2015; 19(3): 377–391. Publisher Full Text - 41. Doggweiler R, Whitmore KE, Meijlink JM, et al.: A standard for terminology in chronic pelvic pain syndromes: A report from the chronic pelvic pain working group of the international continence society. Neurourol. Urodyn. 2017; 36(4): 984–1008. Publisher Full Text - 42. Steingrímsdóttir ÓA, Landmark T, Macfarlane GJ, et al.: Defining chronic pain in epidemiological studies: a systematic review and meta-analysis. Pain. 2017; 158(11): 2092–2107. Publisher Full Text - 43. Liu Y, Zhang W: Association between body mass index and endometriosis risk: a meta-analysis. Oncotarget. 2017; 8(29): 46928–46936. Publisher Full Text - 44. Yi KW, Shin JH, Park MS, et al.: Association of body mass index with severity of endometriosis in Korean women. Int. J. Gynaecol. Obstet. 2009; 105(1): 39–42. Publisher Full Text - 45. Shafrir AL, Wise LA, Palmer JR, et al.: Validity of self-reported endometriosis: a comparison across four cohorts. Hum. Reprod. 2021; 36(5): 1268–1278. Publisher Full Text - 46. Seracchioli R, Mabrouk M, Guerrini M, et al.: Dyschezia and posterior deep infiltrating endometriosis: analysis of 360 cases. J. Minim. Invasive Gynecol. 2008; 15(6): 695–699. Publisher Full Text - 47. Fauconnier A, Chapron C: Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum. Reprod. Update. 2005; 11(6): 595–606. Publisher Full Text - 48. May KE, Villar J, Kirtley S, et al.: Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum. Reprod. Update. 2011; 17(5): 637–653. Publisher Full Text - 49. Rogozińska E, Khan K: Grading evidence from test accuracy studies: what makes it challenging compared with the grading of effectiveness studies? Evid. Based Med. 2017; 22(3): 81–84. Publisher Full Text - 50. Eskenazi B, Warner M, Bonsignore L, et al.: Validation study of nonsurgical diagnosis of endometriosis. Fertil. Steril. 2001; 76(5): 929–935. Publisher Full Text - 51. Hirsch M, Duffy JMN, Davis CJ, et al.: Diagnostic accuracy of cancer antigen 125 for endometriosis: a systematic review and meta-analysis. BJOG Int. J. Obstet. Gynaecol. 2016; 123(11): 1761–1768. Publisher Full Text - 52. Chapron C, Lafay-Pillet MC, Santulli P, et al.: A new validated screening method for endometriosis diagnosis based on patient questionnaires. EClinicalMedicine. 2022; 44: 101263. Publisher Full Text - 53. Bainton T, Jeyapala S, Zamora J, et al.: Table 1.xlsx. figshare. Figure. 2023. Publisher Full Text - 54. Bainton T: Table 2.xlsx. figshare. Figure. 2023. Publisher Full Text - 55. Bainton T: Table 3.xlsx. figshare. Figure. 2023. Publisher Full Text - 56. Bainton T: Table 4.xlsx. figshare. Figure. 2023. Publisher Full Text - 57. Bainton T: Table 5.xlsx. figshare. Figure. 2023. Publisher Full Text - 58. Bainton T: Table 6.xlsx. figshare. Figure. 2023. Publisher Full Text - 59. Bainton T: PRISMA checklist. Diagnosis of pelvic endometriosis- A systematic review and accuracy meta-analysis of non-invasive tests available in primary care.docx. [Dataset]. figshare. 2023. Publisher Full Text Author details Author details 1 Metabolism Digestion and Reproduction, Imperial College London, London, UK 2 Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital NHS Foundation Trust, London, SW10 9NH, UK 3 Institute of Metabolism and Systems Research, University of Birmingham, UK, Birmingham, UK 4 Clinical Biostatistics Unit, Hospital Ramon y Cajal (IRYCIS), Madrid, 28034, Spain 5 Department of Preventative Medicine and Public Health, University of Granada, Grenada, Spain 6 Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain 2 Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital NHS Foundation Trust, London, SW10 9NH, UK 3 Institute of Metabolism and Systems Research, University of Birmingham, UK, Birmingham, UK 4 Clinical Biostatistics Unit, Hospital Ramon y Cajal (IRYCIS), Madrid, 28034, Spain 5 Department of Preventative Medicine and Public Health, University of Granada, Grenada, Spain 6 Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain Thomas Bainton Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Sobanakumari Jeyapala Roles: Investigation, Methodology, Writing – Review & Editing Roles: Investigation, Methodology, Writing – Review & Editing Javier Zamora Roles: Formal Analysis, Resources, Software, Writing – Review & Editing Roles: Formal Analysis, Resources, Software, Writing – Review & Editing Khalid S Khan Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Amer Raza Roles: Conceptualization, Methodology, Project Administration, Supervision, Writing – Review & Editing Roles: Conceptualization, Methodology, Project Administration, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Copyright © 2023 Bainton T et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. metrics | Views | Downloads | | |---|---|---| | F1000Research | - | - | | PubMed Central Data from PMC are received and updated monthly. | - | - | Citations CITE how to cite this article Bainton T, Jeyapala S, Zamora J et al. Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:453 (https://doi.org/10.12688/f1000research.131729.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. track receive updates on this article Track an article to receive email alerts on any updates to this article. Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 28 Apr 2023 Views 0 How to cite this report: Hendarto H. Reviewer Report For: Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:453 (https://doi.org/10.5256/f1000research.144598.r216511) The direct URL for this report is: https://f1000research.com/articles/12-453/v1#referee-response-216511 https://f1000research.com/articles/12-453/v1#referee-response-216511 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 30 Nov 2023 Approved with Reservations VIEWS 0 - The title of the study should be changed to better match the content of the manuscript and be useful for clinicians for application in the field. Proposed title: “Clinical diagnosis of endometriosis: A systematic review and accuracy - The title of the study should be changed to better match the content of the manuscript and be useful for clinicians for application in the field. Proposed title: “Clinical diagnosis of endometriosis: A systematic review and accuracy of meta-analysis of non-invasive tests to prevent diagnosis delay”. - The study objectives stated in the abstract and introduction should be answered specifically in the conclusion. In the conclusion, authors do not describe it, but instead write suggestions for future research. - The author made extraordinary efforts in creating research methods and statistical analysis at several levels, which are described in the written results section in detail and excellence. This should be followed by providing useful recommendations for clinicians to establish a clinical diagnosis of endometriosis. - Endometriosis is a complex disease and involves various factors. Is it sufficient to use bivariate analysis, or is it possible to carry out analysis on more than two variables? - This study provides an excellent systematic review and meta-analysis, but is less conclusive and should be supplemented with specific recommendations for clinicians. - Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes - Are sufficient details of the methods and analysis provided to allow replication by others? Yes - Is the statistical analysis and its interpretation appropriate? Yes - Are the conclusions drawn adequately supported by the results presented in the review? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Reproductive endocrinology, endometriosis and Infertility CITE HOW TO CITE THIS REPORT Hendarto H. Reviewer Report For: Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:453 (https://doi.org/10.5256/f1000research.144598.r216511) The direct URL for this report is: https://f1000research.com/articles/12-453/v1#referee-response-216511 https://f1000research.com/articles/12-453/v1#referee-response-216511 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Martin DC. Reviewer Report For: Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:453 (https://doi.org/10.5256/f1000research.144598.r216534) The direct URL for this report is: https://f1000research.com/articles/12-453/v1#referee-response-216534 https://f1000research.com/articles/12-453/v1#referee-response-216534 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 27 Oct 2023 Not Approved VIEWS 0 Update 31/10/2023: On the request of the reviewer, a minor language edit has been made to point 5 for clarity. No other edits have been made. 2. Likes CE, Cooper LJ, Efird J, Forstein DA, et al.: Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression.J Assist Reprod Genet. 2019; 36 (3): 483-490 PubMed Abstract | Publisher Full Text 3. McGuinness B, Nezhat F, Ursillo L, Akerman M, et al.: Fallopian tube endometriosis in women undergoing operative video laparoscopy and its clinical implications.Fertil Steril. 2020; 114 (5): 1040-1048 PubMed Abstract | Publisher Full Text 4. Roman H, Merlot B, Forestier D, Noailles M, et al.: Nonvisualized palpable bowel endometriotic satellites.Hum Reprod. 2021; 36 (3): 656-665 PubMed Abstract | Publisher Full Text 5. Perry CP, Mena MV: Occult retrocervical endometriosis. A case report.J Reprod Med. 1995; 40 (9): 652-4 PubMed Abstract 6. Koninckx PR, Meuleman C, Oosterlynck D, Cornillie FJ: Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration.Fertil Steril. 1996; 65 (2): 280-7 PubMed Abstract 7. Possover M: Laparoscopic morphological aspects and tentative explanation of the aetiopathogenesis of isolated endometriosis of the sciatic nerve: a review based on 267 patients.Facts Views Vis Obgyn. 2021; 13 (4): 369-375 PubMed Abstract | Publisher Full Text 8. Longo LD: Classic pages in obstetrics and gynecology. Aberrant portions of the müllerian duct found in an ovary: William Wood Russell Johns Hopkins Hospital Bulletin, vol. 10, pp. 8--10, 1899.Am J Obstet Gynecol. 1979; 134 (2): 225-6 PubMed Abstract I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close - The authors perform high-level statistical analysis of many poor-quality papers in Update 31/10/2023: On the request of the reviewer, a minor language edit has been made to point 5 for clarity. No other edits have been made. - The authors perform high-level statistical analysis of many poor-quality papers in complex heterogenous populations and do not anticipate a clinical score replacing laparoscopy due to its added therapeutic advantages and the requirement to exclude other pathologies. The useful clinical conclusion is that this is a “watch this space” story. - Regarding if “disease can be predicted with a high degree of accuracy early on, medical therapy may be instigated, and referral made for definitive diagnosis and counseling regarding treatment, prognosis, and fertility in a timely manner with the aim of reducing the current extraordinary delay.” It would be simpler to avoid normalizing pain and treat all pain adequately. The initial treatment of dysmenorrhea and pelvic pain is the same as endometriosis. Good pain treatment is needed; if that also limits endometriosis, that would be a bonus. We spend too much time on statistics and not enough listening to patients. - Discuss the limitation of endometriosis to minimal and mild stages only with 10.2 years of follow-up of proactive care in Knox B, Ong YC, Bakar MA, Grover SR. A longitudinal study of adolescent dysmenorrhoea into adulthood. Eur J Pediatr. 2019, Sep;178(9):1325-1332. doi: 10.1007/s00431-019-03419-3. PMID: 312927291. - Scientists do like statistics more than clinicians, and I will review this, anticipating that the journal will find a statistician who understands the analysis. Although the authors do not need to agree with my comments, they do need to discuss the controversy. - The title “Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care” is misleading. No studies are reviewed of testing validated in primary care ObGyn or family practice. As stated in the conclusions, “studies were conducted in a high-risk population undergoing surgery.” There are no studies quoted that were validated in either type of primary care. That is compatible with my reviews. The title is more accurate as, “Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in tertiary care for recognized endometriosis. Are they useful in tertiary care? Will they be useful in primary care?” - Discussions are needed for both primary care ObGyn and Family practice where the prevalence of 10% may be an incidence of 0.1% to 0.7% with a mean in diagnosed cases of less than 5 cases yearly in primary care ObGyn and one yearly in family practice. About half of those have pain with or without infertility and need pain and surgical specialists. The half with infertility only needs primary infertility triage and REI referral as needed. - In the concluding paragraph, Fauconnier et al. 2021 and Chapron et al. 2022 are almost misquoted. “The model maintained accuracy in population with a lower endometriosis prevalence of 10%” suggests this was in a live population, not a computer-generated population. Please clarify that the model was statistical people, not real people. Statisticians may know that, but I had to read the papers to understand your meaning. - Those models are primarily for pain and do not appear to be useful in determining which infertility patients might benefit from GnRH or surgery. Discuss concepts like Likes CE, Cooper LJ, Efird J, Forstein DA, Miller PB, Savaris R, Lessey BA. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression. J Assist Reprod Genet. 2019 Mar;36(3):483-490. doi: 10.1007/s10815-018-1388-x. Epub 2019 Jan 4. PMID: 30610661; PMCID: PMC64390152. - The sensitivities, etc., do not consider non-recognized endometriosis. Discuss the effect of non-recognized endometriosis on the sensitivity, specificity, PPV, PNV, and accuracy of studies. - Discuss non-visualized tubal endometriosis and conclusion about salpingectomy in McGuinness B, Nezhat F, Ursillo L, Akerman M, Vintzileos W, White M. Fallopian tube endometriosis in women undergoing operative video laparoscopy and its clinical implications. Fertil Steril. 2020 Nov3. - Discuss non-visualized bowel endometriosis in Roman H, Merlot B, Forestier D, Noailles M, Magne E, Carteret T, Tuech JT, Martin DC. Nonvisualized palpable bowel endometriotic satellites. Hum Reprod. 2021, 36(3):656-665. doi: 10.1093/humrep/deaa340. PMID: 33432338; PMCID: PMC7891810. Open access: https://academic.oup.com/humrep/article/36/3/656/60858324. - Discuss non-visualized retrocervical endometriosis in Perry CP, Mena MV. Occult retrocervical endometriosis. A case report. J Reprod Med. 1995 Sep;40(9):652-4. PMID: 85768835. - Discuss the patients with a normal pelvis at laparoscopy in Koninckx PR, Meuleman C, Oosterlynck D, Cornillie FJ. Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration. Fertil Steril. 1996 Feb;65(2):280-7. PMID: 8566249. Open Access: https://www.sciencedirect.com/science/article/pii/S0015028216580868?via%3Dihub6. - Discuss non-visualized sacral endometriosis in Possover M. Laparoscopic morphological aspects and tentative explanation of the aetiopathogenesis of isolated endometriosis of the sciatic nerve: a review based on 267 patients. Facts Views Vis Obgyn. 2021 Dec;13(4):369-375. doi: 10.52054/FVVO.13.4.047. PMID: 35026098. Open Access: https://fvvo.eu/archive/volume-13/number-4/original-articles/laparoscopic-morphological-aspects-and-tentative-explanation-of-aetiopathogenesis-of-isolated-endome/7. - Discuss the non-visualized ovarian endometriosis in Russell WW. Aberrant portions of the Müllerian duct found in an ovary: Johns Hopkins Hospital Bulletin, 1899, 10(Nos 94-95-96)(Jan-Feb-Mar)):8-10, plates I-III. HathiTrust.org https://babel.hathitrust.org/cgi/pt?id=uva.3470085735&view=1up&seq=20. Google Books Vol 10 Bulletin of the Johns Hopkins Hospital https://www.google.com/books/edition/Bulletin_of_the_Johns_Hopkins_Hospital/nzFHAAAAYAAJ?hl=en&gbpv=0. An easier review to find is Longo LD. Aberrant portions of the müllerian duct found in an ovary: William Wood Russell Johns Hopkins Hospital Bulletin, vol. 10, pp. 8--10, 1899. Am J Obstet Gynecol. 1979, 134:225-6. PMID 3779668. - Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes - Are sufficient details of the methods and analysis provided to allow replication by others? Yes - Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. - Are the conclusions drawn adequately supported by the results presented in the review? No

1. Knox B, Ong YC, Bakar MA, Grover SR: A longitudinal study of adolescent dysmenorrhoea into adulthood.Eur J Pediatr. 2019; 178 (9): 1325-1332 PubMed Abstract | Publisher Full Text2. Likes CE, Cooper LJ, Efird J, Forstein DA, et al.: Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression.J Assist Reprod Genet. 2019; 36 (3): 483-490 PubMed Abstract | Publisher Full Text 3. McGuinness B, Nezhat F, Ursillo L, Akerman M, et al.: Fallopian tube endometriosis in women undergoing operative video laparoscopy and its clinical implications.Fertil Steril. 2020; 114 (5): 1040-1048 PubMed Abstract | Publisher Full Text 4. Roman H, Merlot B, Forestier D, Noailles M, et al.: Nonvisualized palpable bowel endometriotic satellites.Hum Reprod. 2021; 36 (3): 656-665 PubMed Abstract | Publisher Full Text 5. Perry CP, Mena MV: Occult retrocervical endometriosis. A case report.J Reprod Med. 1995; 40 (9): 652-4 PubMed Abstract 6. Koninckx PR, Meuleman C, Oosterlynck D, Cornillie FJ: Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration.Fertil Steril. 1996; 65 (2): 280-7 PubMed Abstract 7. Possover M: Laparoscopic morphological aspects and tentative explanation of the aetiopathogenesis of isolated endometriosis of the sciatic nerve: a review based on 267 patients.Facts Views Vis Obgyn. 2021; 13 (4): 369-375 PubMed Abstract | Publisher Full Text 8. Longo LD: Classic pages in obstetrics and gynecology. Aberrant portions of the müllerian duct found in an ovary: William Wood Russell Johns Hopkins Hospital Bulletin, vol. 10, pp. 8--10, 1899.Am J Obstet Gynecol. 1979; 134 (2): 225-6 PubMed Abstract Competing Interests: Dan Martin Financial and Non-Financial COI Disclosure October 22, 2023 Daniel Clyde Martin, MD, Richmond, Virginia. CV and other summaries are at https://www.danmartinmd.com/dcm.html Associations with Authors Are you a current collaborator with any of the authors of the paper in question, or have you been in the past 3 years? No. Have you co-authored a paper with any of the authors of the paper in question in the past 3 years? No. Employment: Virginia Commonwealth University Institutional Review Board Grant received/Grants pending: None Consulting fees or honorarium: Distinguished Surgeon Award, American Society of Reproductive Medicine, Oct 20, 2021; Support for travel to meetings for the study, content preparation, or other purposes Endometriosis Foundation of America, reimbursement of expenses, 2023 Endometriosis Foundation of America Annual Meeting, 2023. American College of Ob-Gyn Annual Meeting, 2023. American Society of Reproductive Medicine, Annual Meeting, 2023 American Society of Reproductive Medicine, Annual Meeting, 2021; Reimbursed travel, meal, and room expenses Honorarium for presentation of endometriosis. Myovant Pharmaceuticals Attended a dinner presentation on ‘Shared Decision-Making’ in endometriosis at the American College of Ob-Gyn Annual Meeting, May 19, 2023, sponsored by Myovant Pharmaceuticals. Honorary President, 6th European Endometriosis Congress, June 16, 2022; Room and meals were paid, and travel expenses were reimbursed. University of Tennessee Health Science Center; Travel and lodging for Grand Rounds Oct 10, 2023 Access to digital library, Virginia Commonwealth University Access to digital library, Baptist Memorial Health Care Corporation Access to library through librarian; Fees for participation in review activities such as data monitoring boards, etc Reproductive Health Investors Alliance Inc. interview on endometriosis for an anonymous principal. 9/22/2022 Payment for writing or reviewing the content: None Provision of writing assistance, medicines, equipment, or administrative support: Administrative support by the Endometriosis Foundation of America as the volunteer Scientific and Medical Director including an Administrative Assistant. Received educational and marketing material from multiple companies. Multiple meetings with medical and surgical industry representatives, developers of diagnostic tests, and investors, including solicitation for funding of Endometriosis Foundation of America educational and research activities. Advisory Board Positions: Genome Profiling, LLC, 650 Swedesford Rd, Suite 190, Wayne, PA 19087, volunteer, non-paid Senior Clinical Advisor, Nov 18, 2021 - Sept 1, 2023, for diagnostic test development. SLBST Pharma Inc., Tampa, FL, Advisory Board, 11/9/2021, volunteer, non-paid position supporting the repurposing of an arthritic medicine for endometriosis-associated pain. Payment for lectures, including service on speaker’s bureaus: Distinguished Surgeon Award, American Society of Reproductive Medicine, 2021 IntegritasGrp.com/ Paid to help produce an endometriosis CME Activity, Aug 25, 2023Investments/Stocks/Stock options Passive income from investments made during 44 years of practicing medicine and surgery. Most is from surgery, and much is from before the 1992 initiation of the Omnibus Reconciliation Act of 1989, RBRVS, DRGs, managed care, and provider panels. I am 77 with financial accounts coordinated or run by Edward Jones Financial Advisors, TIAA, Methodist Hospital, and the University of Tennessee. My decisions at Edward Jones are for general allocations only. I have no control at TIAA, Methodist Hospital, or UT. There were 36 pages sent to the IRS for 2022 taxable income in five accounts at Edward Jones. There are also four tax-deferred accounts. Expert testimony: Dennis M. Abrams, Esq. of Lowenthal & Abrams, P.C., Bala Cynwyd, PA 19004 Patents (planned, pending, or issued): None Royalties: None Other: Licensed to practice medicine in the State of Tennessee Volunteer Scientific and Medical Director of the Endometriosis Foundation of America. Time donated to several medical journals as a reviewer and academic editor. Member of AMA, ACOG, AAGL, ISGE ACOG free Life Fellowship AMA discounted senior membership. AAGL discounted senior membership Academic editor of 5 medical journals, Author or Co-Author on multiple scientific reviews Editor: Endometriosis Concepts and Theories Co-author, Roman et al. Nonvisualized palpable bowel endometriotic satellites. PMID: 33432338. Author. Regarding "Intraoperative Detection of Rectosigmoid Endometriosis." PMID: 37031856 Co-author, Mackenzie et al. Effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women (ESPriT2): protocol for a multi-centre randomised controlled trial. PMID: 37349849. Co-author, Noar et al. Non-invasive endometriosis detection: Electroviscerography and artificial intelligence threshold scoring. Submitted. Donor to the Endometriosis Association, Donor to Endometriosis.org, Webmaster Dan Martin (https://www.danmartinmd.com/), Webmaster Endo Concepts (http://www.endometriosisconcepts.com), Donor to three universities, Donor to one high school, Donor to several charities, Gifts and support of wife, children, grandchildren, relatives, friends, and strangers Reviewer Expertise: Endometriosis, operative laparoscopy, laparotomy for palpation, patient advocacy CITE HOW TO CITE THIS REPORT Martin DC. Reviewer Report For: Diagnosis of pelvic endometriosis: A systematic review and accuracy meta-analysis of non-invasive tests available in primary care [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:453 (https://doi.org/10.5256/f1000research.144598.r216534) The direct URL for this report is: https://f1000research.com/articles/12-453/v1#referee-response-216534 https://f1000research.com/articles/12-453/v1#referee-response-216534 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Alongside their report, reviewers assign a status to the article: - Approved - Approved with reservations - Not approved | Invited Reviewers | || |---|---|---| | 1 | 2 | | | Version 1 28 Apr 23 | read | read | Sign up for content alerts You are now signed up to receive this alert Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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