Development of a biomarker panel for minimally-invasive screening and diagnosis of gynecological disease

PROJECT SUMMARY One-third of all women of reproductive age will experience nonmenstrual pelvic pain at some point in their lives and one-third of outpatient visits to gynecologists in the U.S. are for evaluation of abnormal uterine bleeding. For many women, these symptoms accompany infertility which is reported in ~10% of all US women and even higher percentages worldwide. For almost all of these women, these conditions result in a diagnostic odyssey wherein women struggle through multiple physicians over many years for a definitive diagnosis, frequently culminating in invasive laparoscopy or hysteroscopy with dilation and curettage (Dandamp;C) for definitive diagnosis. To reduce the burden of diagnosis and enable early treatment, MDDx, Inc. is developing the first biomarker- based diagnostic test to enable minimally invasive simultaneous diagnosis of four of the most common causes which together result in chronic pain, uterine bleeding and infertility: adenomyosis, endometrial polyps, leiomyoma, and endometriosis. MDDx, Inc. has been leveraging access to andgt;12 years of longitudinally collected and deeply annotated biobanked uterine lavage samples from the Gynecologic Cancer Translational Research Program (Icahn School of Medicine at Mount Sinai; New York, NY and Nuvance Health; Danbury, CT) to identify diagnostic autoantibodies (AAb) that could serve as diagnostic biomarkers for these benign gynecological diseases. By performing AAb profiling against the entire human proteome and applying our novel machine-learning based method for classification of molecular profiles we have determined that there is a common set of ~200 biomarkers that could be used to diagnose women with adenomyosis, endometrial polyps, leiomyoma, or endometriosis. The goal of Phase I is to finalize and validate the optimized set of ~200 diagnostic AAbs, while Phase II will focus on validation of the commercial diagnostic assay. In Aim 1 we will expand our proprietary database of uterine lavage autoantibody profiles to ensure that we have a sample size (~935) that will enable us to confidently apply our machine learning approaches to identifying the minimal panel of AAbs for the diagnostic. We will use this enhanced database to identify a prototype panel of ~200 AAbs for construction of classification scoring functions to distinguish between adenomyosis, endometrial polyps, leiomyoma, and endometriosis. In Aim 2 we will perform a blinded validation and performance study using an independent set of 300 uterine lavage samples to provide proof-of- concept for clinically useful sensitivity and specificity prior to large scale prospective validation in Phase II. Successful completion of this Phase I program will identify the optimized panel of AAbs for an affordable, laboratory-based diagnostic test that will significantly reduce the number of women who will need to undergo laparoscopy or hysteroscopy with Dandamp;C for definitive diagnosis, enabling early treatment of disease and reducing the significant psychological and financial burden of diagnoses that otherwise can take years.PROJECTIVE NARRATIVE Nearly half of all women of reproductive age will experience some combination of nonmenstrual pelvic pain, abnormal uterine bleeding, and infertility in their lifetimes, yet there are no non-invasive methods to definitively diagnose the primary causes of these symptoms. MDDx, Inc. is developing the first laboratory diagnostic test to enable minimally invasive simultaneous diagnosis of four common causes of these often debilitating symptoms and infertility: adenomyosis, endometrial polyps, leiomyoma, and endometriosis. This test will enable early detection, early treatment, and reduce the physical, emotional, and financial burden of obtaining a diagnosis for women suffering from these common yet disruptive symptoms.