Periodic Reporting for period 1 - Endosolve (She Sense: an accurate and non-invasive test that enables simpler, earlier and more cost-effective diagnosis of patients with endometriosis)
Reporting period: 2023-01-01 to 2023-12-31
Background
Endometriosis is a chronic inflammatory disease defined as the presence of endometrium-like tissue outside the uterus(1). Establishment and growth of such endometriotic tissue is estrogen-dependent(2), thus it is mostly found in women of reproductive age. It is estimated that currently at least 190 million women and adolescent girls worldwide are affected by the disease during reproductive age although some women may suffer beyond menopause(3).
The Problem
Despite years of chronic pelvic pain, discomfort, and other incapacitating symptoms, some women receive their first diagnosis of endometriosis when attempting, and failing, to conceive. This is associated with several pain-points in the system: (i) The gold standard for diagnosis of endometriosis is laparoscopy, which requires an operative procedure under general anaesthesia to visualise the lesions which is expensive and not without risks. However, the presence of lesions does not preclude other pathologies for the patient’s symptoms such as irritable bowel syndrome; (ii) This is exacerbated by the fact that women who visit their GP with pain, which can be described as ‘intense’ and ‘overwhelming’, can be overlooked due to trivialization/normalisation of symptoms or misdiagnosis. The correct diagnosis is made as late as 7 – 12 years from the onset of pain symptoms to a surgical diagnosis (4). More worryingly, the longest delays are experienced by adolescents; (iii) Compounding matters is the fact that the disease is highly individual. The extent of endometriotic lesions does not correlate with disease stage or symptom severity. Therefore, there are likely to be many subsets of patients, all presenting with various symptoms at various disease stages who require different treatment approaches. Now is the time to change this paradigm by increasing access to timely diagnosis and early treatment. That is precisely what is proposed with our novel digital biomarker.
The Technology
The technology is an accurate non-invasive test that enables simpler, earlier, and more cost-effective diagnosis of patients with endometriosis. The test should enable physicians to make informed medical decisions to prevent disease progression and potentially safeguard fertility. Core to technology development is the investigation and validation of a novel digital biomarker. The electrical activity of the uterus recorded by uterine electromyogram (EMG), also known as electro-hysterogram (EHG), is known to be representative of uterine contractility/motility. While numerous studies have demonstrated the feasibility of using EHG to predict preterm birth, as well as external monitoring of uterine contractions in pregnant women, limited studies have been performed to understand the uterine electrical activity in non-pregnant women. This is the focus of the EndoSolve project where we seek to understand this bio-signal and develop a novel digital biomarker with clinically acceptable sensitivity and specificity to perform as a non-invasive, adjunct diagnostic test which can be used at home for women with suspected endometriosis.
1 ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod 2005;20: 2698-2704.
2 Kitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H. Endometriosis: the pathophysiology as an estrogendependent disease. J Steroid Biochem Mol Biol 2002;83: 149-155.
3 Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382: 1244-1256.
4 As-Sanie, Sawsan, et al. Assessing research gaps and unmet needs in endometriosis. American Journal of Obstetrics and Gynecology, 2019, 221.2: 86-94
Endometriosis is a chronic inflammatory disease defined as the presence of endometrium-like tissue outside the uterus(1). Establishment and growth of such endometriotic tissue is estrogen-dependent(2), thus it is mostly found in women of reproductive age. It is estimated that currently at least 190 million women and adolescent girls worldwide are affected by the disease during reproductive age although some women may suffer beyond menopause(3).
The Problem
Despite years of chronic pelvic pain, discomfort, and other incapacitating symptoms, some women receive their first diagnosis of endometriosis when attempting, and failing, to conceive. This is associated with several pain-points in the system: (i) The gold standard for diagnosis of endometriosis is laparoscopy, which requires an operative procedure under general anaesthesia to visualise the lesions which is expensive and not without risks. However, the presence of lesions does not preclude other pathologies for the patient’s symptoms such as irritable bowel syndrome; (ii) This is exacerbated by the fact that women who visit their GP with pain, which can be described as ‘intense’ and ‘overwhelming’, can be overlooked due to trivialization/normalisation of symptoms or misdiagnosis. The correct diagnosis is made as late as 7 – 12 years from the onset of pain symptoms to a surgical diagnosis (4). More worryingly, the longest delays are experienced by adolescents; (iii) Compounding matters is the fact that the disease is highly individual. The extent of endometriotic lesions does not correlate with disease stage or symptom severity. Therefore, there are likely to be many subsets of patients, all presenting with various symptoms at various disease stages who require different treatment approaches. Now is the time to change this paradigm by increasing access to timely diagnosis and early treatment. That is precisely what is proposed with our novel digital biomarker.
The Technology
The technology is an accurate non-invasive test that enables simpler, earlier, and more cost-effective diagnosis of patients with endometriosis. The test should enable physicians to make informed medical decisions to prevent disease progression and potentially safeguard fertility. Core to technology development is the investigation and validation of a novel digital biomarker. The electrical activity of the uterus recorded by uterine electromyogram (EMG), also known as electro-hysterogram (EHG), is known to be representative of uterine contractility/motility. While numerous studies have demonstrated the feasibility of using EHG to predict preterm birth, as well as external monitoring of uterine contractions in pregnant women, limited studies have been performed to understand the uterine electrical activity in non-pregnant women. This is the focus of the EndoSolve project where we seek to understand this bio-signal and develop a novel digital biomarker with clinically acceptable sensitivity and specificity to perform as a non-invasive, adjunct diagnostic test which can be used at home for women with suspected endometriosis.
1 ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod 2005;20: 2698-2704.
2 Kitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H. Endometriosis: the pathophysiology as an estrogendependent disease. J Steroid Biochem Mol Biol 2002;83: 149-155.
3 Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382: 1244-1256.
4 As-Sanie, Sawsan, et al. Assessing research gaps and unmet needs in endometriosis. American Journal of Obstetrics and Gynecology, 2019, 221.2: 86-94
From a technical and scientific side, the main focus in P1 was on the signal refinement leading towards algorithm development. Data from the 2021-2022 human study was reanalyzed, and new signal features were identified and tested. The team carried out extensive testing to understand motion, acoustic, and saturation artifacts. A novel algorithm was developed to suppress saturation and motion artifacts and a new 3-lead electrode plan was designed to measure uterine signal.
During this data analysis it was identified that the original device intended to be used for trials had limitations in the signal range of interest. This device has a limited input voltage range (-0.25mv to 0.25mv) and since our signal is outside of this range, it saturates. Apart from the saturation events themselves, distortions in the signal due to the saturation affects the underlying uterine signal.
The device has a non-flat frequency response in the uterine signal frequency band from 0Hz to 0.05Hz. The device is mainly designed for electrogastrogram (EGG) applications whose frequency range is 0.015-0.15Hz. Therefore, the device does not measure the true uterine signal and attenuates the signal up to 10dB. The team identified that a device with an almost flat frequency response could help us to detect additional features of signal.
It was concluded during Period 1 that the limited input voltage range and non-flat frequency response of the intended device were critical limiting factors and that in order to progress successfully, the hardware would have to be optimized. This directed the team towards exploring the options which were quickly narrowed down to the option of developing a device.
The team explored the possibility of modifying the device in use to overcome the current limitations and also reached out to device manufacturers to understand cost and capabilities in the market for developing a device which met our requirements. However, due to time and cost, the team opted to work with a device designer and developer to look at the signal requirements and how a device like this could be designed to meet all user needs. Subsequent to this, the team embarked on device hardware and app software development.
During this data analysis it was identified that the original device intended to be used for trials had limitations in the signal range of interest. This device has a limited input voltage range (-0.25mv to 0.25mv) and since our signal is outside of this range, it saturates. Apart from the saturation events themselves, distortions in the signal due to the saturation affects the underlying uterine signal.
The device has a non-flat frequency response in the uterine signal frequency band from 0Hz to 0.05Hz. The device is mainly designed for electrogastrogram (EGG) applications whose frequency range is 0.015-0.15Hz. Therefore, the device does not measure the true uterine signal and attenuates the signal up to 10dB. The team identified that a device with an almost flat frequency response could help us to detect additional features of signal.
It was concluded during Period 1 that the limited input voltage range and non-flat frequency response of the intended device were critical limiting factors and that in order to progress successfully, the hardware would have to be optimized. This directed the team towards exploring the options which were quickly narrowed down to the option of developing a device.
The team explored the possibility of modifying the device in use to overcome the current limitations and also reached out to device manufacturers to understand cost and capabilities in the market for developing a device which met our requirements. However, due to time and cost, the team opted to work with a device designer and developer to look at the signal requirements and how a device like this could be designed to meet all user needs. Subsequent to this, the team embarked on device hardware and app software development.