Abstract
STUDY QUESTION
Can cartilage oligomeric matrix protein (COMP) and transforming growth factor-β-induced protein ig-h3 (TGFBI) alone or in combination with cancer antigen 125 (CA-125) be ...considered as potential blood biomarkers of endometriosis?
SUMMARY ANSWER
The results of this study indicate that COMP has no diagnostic value. TGFBI has potential as a non-invasive biomarker of the early stages of endometriosis, while TGFBI together with CA-125 has similar diagnostic characteristics as CA-125 alone for all stages of endometriosis.
WHAT IS KNOWN ALREADY
Endometriosis is a common, chronic gynecological disease that significantly affects patient quality of life by causing pain and infertility. The gold standard for diagnosis is visual inspection of pelvic organs by laparoscopy, therefore there is an urgent need for discovery of non-invasive biomarkers for endometriosis to reduce diagnostic delays and allow earlier treatment of patients. The potential biomarkers for endometriosis evaluated in this study (COMP and TGFBI) were previously identified by our proteomic analysis of peritoneal fluid samples.
STUDY DESIGN, SIZE, DURATION
This is a case–control study divided into a discovery (n = 56 patients) and a validation phase (n = 237 patients). All patients were treated between 2008 and 2019 in a tertiary medical center.
PARTICIPANTS/MATERIALS, SETTING, METHOD
Patients were stratified based on the laparoscopic findings. The discovery phase included 32 endometriosis patients (cases) and 24 patients with confirmed absence of endometriosis (controls). The validation phase included 166 endometriosis and 71 control patients. Concentrations of COMP and TGFBI were measured by ELISA in plasma samples, whereas concentration of CA-125 was measured using a clinically validated assay for serum samples. Statistical and receiver operating characteristic (ROC) curve analyses were performed. The classification models were built using the linear support vector machine (SVM) method with the SVM built-in feature ranking method.
MAIN RESULTS AND THE ROLE OF CHANCE
The discovery phase revealed significantly increased concentration of TGFBI, but not COMP, in plasma samples of patients with endometriosis compared to controls. In this smaller cohort, univariate ROC analysis showed fair diagnostic potential of TGFBI, with an AUC value of 0.77, sensitivity of 58%, and specificity of 84%. The classification model built using linear SVM and combining TGFBI and CA-125 showed an AUC value of 0.91, sensitivity of 88% and specificity of 75% in distinguishing patients with endometriosis from controls. The validation phase results revealed similar diagnostic characteristics of the SVM model combining TGFBI and CA-125, with an AUC value of 0.83, sensitivity of 83% and specificity of 67% and CA-125 alone with AUC value of 0.83, sensitivity of 73% and specificity of 80%. TGFBI exhibited good diagnostic potential for early-stage endometriosis (revised American Society for Reproductive Medicine stage I–II), with an AUC value of 0.74, sensitivity of 61% and specificity of 83% compared to CA-125, which had an AUC value of 0.63, sensitivity of 60% and specificity of 67%. An SVM model combining TGFBI and CA-125 showed a high AUC value of 0.94 and sensitivity of 95% for diagnosing moderate-to-severe endometriosis.
LIMITATIONS, REASONS FOR CAUTION
The diagnostic models were built and validated from a single endometriosis center, and thus further validation and technical verification in a multicenter study with a larger cohort is needed. Additional limitation was lack of histological confirmation of disease for some patients in the validation phase.
WIDER IMPLICATIONS OF THE FINDINGS
This study revealed for the first time increased concentration of TGFBI in plasma samples of patients with endometriosis, particularly those with minimal-to-mild endometriosis, compared to controls. This is the first step in considering TGFBI as a potential non-invasive biomarker for the early stages of endometriosis. It also opens a path for new basic research to investigate the importance of TGFBI in the pathophysiology of endometriosis. Further studies are needed to confirm the diagnostic potential of a model based on TGFBI and CA-125 for the non-invasive diagnosis of endometriosis.
STUDY FUNDING/COMPETING INTEREST(S)
The preparation of this manuscript was supported by grant J3-1755 from the Slovenian Research Agency to T.L.R and EU H2020-MSCA-RISE project TRENDO (grant 101008193). All authors declare that they have no conflicts of interest.
TRIAL REGISTRATION NUMBER
NCT0459154.
Endometriosis is a common gynaecological disease that is characterized by endometrium-like tissue outside the uterine cavity. Endometriosis significantly compromises the quality of life of women and ...is a major cause of infertility. The gold standard for diagnosis of endometriosis is visual inspection by laparoscopy, which significantly prolongs the time to final diagnosis. This lack of non-invasive diagnostic approaches is why the discovery of biomarkers for endometriosis has been defined as a research priority. In this report, we describe hypothesis-driven and hypothesis-generating approaches for biomarker discovery, along with some important potential biomarkers of endometriosis and their diagnostic characteristics, sensitivities, and specificities. Finally, we present our perspective on the discovery of biomarkers for endometriosis, and discuss some results from our previous and more recent studies. Future studies must focus on improving patient quality of life rather than on discovering significant differences, and therefore close collaboration between clinicians and pre-clinical researchers is essential.
OBJECTIVESEndometriosis is a common benign gynaecological disease that significantly compromises the quality of life of patients. To date, invasive surgery is the method of choice to visually and ...histologically confirm endometriosis. Thus, there is a major interest to develop noninvasive diagnostic tools. Oxidative stress is one of the proposed mechanisms of pathogenesis and may be involved in pelvic pain, dysmenorrhea, dyspareunia, and infertility in endometriosis patients. Thus, markers of oxidative stress may serve as diagnostic biomarkers for endometriosis. DESIGNThis prospective case-control study assessed erythrocyte superoxide dismutase (SOD), erythrocyte glutathione peroxidase (GPX), serum hexanoyl lysine (HEL) and peritoneal fluid HEL. PARTICIPANTS/MATERIALS, SETTING, AND METHODSWe enrolled 86 women with primary infertility; the case group included 57 women with endometriosis, and the control group included 29 women with unexplained primary infertility. All the patients underwent laparoscopy, and the diagnosis was confirmed histologically. RANDOX and RANSEL reagents were used to determine the levels of SOD and GPX, respectively, and ELISA was used to determine the levels of HEL. RESULTSWe found no statistically significant differences in the erythrocyte levels of GPX (p value 0.623) or SOD (p value 0.122) or the serum or peritoneal fluid levels of HEL (p value 0.562 and 0.329 accordingly). CONCLUSIONSSOD, GPX, and HEL levels most likely do not differ between patients with unexplained infertility and patients with endometriosis.
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