Jan Helge Solbakk
Professor - Centre for Medical Ethics at University of Oslo
“This project aims at developing a test for a serious medical condition, endometriosis, affecting around 180 million women worldwide.
This is a chronic disease seriously affecting women’s sexual and reproductive health, and with a high potential for stigmatization. Early diagnosis and treatment is of key importance.
The project description is very carefully designed, and contains, as well pertinent reflections about the ethical questions and cultural questions that need to be addressed before developing such a test and during its implementation in different cultural settings”
Rein Aasland
Professor - Genetics and Evolutionary Biology at the University of Oslo
“The choice of detection of endometriosis as theme is excellent, given that this is a dreadful disease affecting many women and for which a fast and efficient diagnostic test is in great demand”
“The iGEM-UiO team has also selected a potent and promising technology base for their project”
Anne-Marie Lingaas
Former department head nurse at the Women's Clinic at Akershus University Hospital of Oslo
"Menstruation should not have to be a painful burden for todays young women.
More women should be given the opportunity to get tested for diseases such as endometriosis, as an earlier diagnosis has the potential to give said women the resources and interventions needed to be able to lead a normal life”
MD Jolanta Sąlygienė
Gynecologist and Obstetrician who has worked in hospitals in Lithuania for over 30 years and owner of a gynecology clinic.
“If successful, such a test would give way for early endometriosis diagnosis, which would in turn contribute to increasing the patients’ quality of life by enabling them to take action to prevent disease progression, the opportunity to better manage symptoms and prevent infertility.”
Human Practises
Endometriosis is a disease affecting 5-10% of the population ranging from a mild illness to severe forms that with the need for surgical treatment or lengthy medical leaves due to severe pain.
The disease has not gotten a lot of focus from doctors resulting in difficulties getting a diagnosis and the appropriate treatments.
Multiple doctors and gynecologists are required to perform several diagnostic procedure ranging from pelvic exam to invasive surgeries and with symptoms overlapping with disease it is difficult getting a diagnosis.
The average diagnostic delay from the onset of the disease is 7 years resulting in development of severe endometriosis that could be stopped if the road to diagnosis was not so complex.
There are three common categories of endometriosis: Ovarian Endometriosis (OE) also called endometriomas, superfical endometriosis (SE) and deep endometriosis (DE), whereas deep endometriosis is endometric lesions that has penetrated more than 5 mm [1], [2].
This variation in pathology results in difficulties development for one specific test for all the types of endometriosis.
- Limitations of pelvic exams for endometriosis diagnosis: Pelvic examinations are often the initial step in diagnosing endometriosis. However, recent studies indicate that while a pelvic exam may suggest the presence of endometriosis, it does not necessarily exclude the condition if no evidence is found [3]. This is largely due to the fact that the areas most commonly affected by endometriosis are not easily accessible for examination during a pelvic exam. Therefore, an overreliance on this method could potentially result in patients with endometriosis being overlooked [4].
- Limitations of ultrasounds for endometriosis diagnosis: Ultrasound is a technique used where a probe is either held above the abdominal region or inserted into either the rectum or into the vagina. Transvaginal ultrasound (TVS) and transrectal ultrasound (TRS), are used in the examination of endometriosis while abdominal ultrasounds are typically not used for diagnosing endometriosis due to their inability to provide sufficient detail of the pelvic organs. According to a 2022 study by [2], TVS can detect with high accuracy both DE and OE, however SE remains a problem and with higher rates of false positives. TRS may be used in situations where TVS are not practical, to detect with high accuracy intestinal and rectovaginal endometriosis often associated with severe endometriosis [5]–[7]. However, accurate endometriosis diagnostics with ultrasound is a skill with a steep learning curve [8], [9], resulting in high costs and a long time to estabilsh centers with the required competence to perform these techniques. Patients with endometriosis often have pain related to vaginal penetration, therefore TVS may not be suitable for all paitents. TRS may be used in that circumstance but due to percived invasiveness and potential negative experience of the procedure clinicians may be uncomfortable performing the procedure resulting in non-performance [2]. These methods may re-traumatize patients who have experienced trauma such as adverse childhood experiences, intimate partner violence, obsetric violence, birth trauma or religious restrictions [10], [11].
- Limitations of MRI for endometriosis diagnosis: Magnetic resonance imaging (MRI) is a medical technique where strong magnetic fields, magnetic field gradients and radio waves to visualize the organs, as it does not require X rays nor ionizing radiation it is safe to use for examinations of the genital areas. MRI use two different contrast images where T1 weighted enhances signals of fatty tissue and supressed water while T2 weighted enhances the signal of water [12]. In a meta analysis performed by [13], MRI did not achieve high enough accuracy to replace diagnostic laprascopic surgery (LS) for diagnosing DE, nor SE pelvic endometriosis. However, the examined studies showed high enough accuracy for diagnosis OE to replace LS, but due to small sample size further research need to be conducted. MRI may also be performed prior to LS for increased accuracy of the procedure[13].
- Limitations of Laparoscopy for endometriosis diagnosis: As the final diagnostic method, laparoscopy is the golden standard for endometriosis diagnosis and a patient cannot get a diagnosis without undergoing this procedure [14], [15]. The procedure entials an incision in the abdomen followed by filling the abdominal cavity with CO2. Afterwards a canula with a camera is used to visualize the exterior of the uterus, furthermore a small scalpel can be inserted into the incision which allows excision of endometrial growths. In combination with MRI and histological analysis laparoscopy gives high accuracy for endometriosis diagnosis [14], [16]. Even though it is a highly effective procedure, a significant precentage of women undergoing the procedure do not have endometrial lesions [17], [18]. Therefore women without endometriosis are unnecessarily exposed to surgical complications related to gynecological laparoscopy [19]. Furthermore, laparoscopy is a procedure that require specialized surgeons for optimal results, untrained surgeons may be unable to identify endometrial lesions [2]. This procedure may not be accesiable to everyone as only urban areas may have the talent required for the procedure and the expensive infrastructure required for surgery [20].
These current diagnostic methods has several limitations as discussed above.
It is a clear need for tests that do not rely on the training of the medical practitioner for a diagnosis, as it may result in the misdiagnosis of the disease and leads to a long the diagnostic delay until the patient yet again contacts the medical practitioners for another check.
Our test will therefore be a test that do not rely on the skill of the doctors for a diagnosis, which can calm the patient and allows quick adoption of preventative measures such as birth control earlier than the current average of 7 years.
As this disease affects an estimated 10 % of the female population a rapid accessible test is required to test all those at risk for the disease.
Furthermore current diagnostic methods require advanced medical infrastructure so an alternative test that can be used at point of care diagnostic centers is sought after.
We hope our project can help resolve this problem, below we describe limitations of alternative solutions.
Limitations of miRNA amplification with qPCR:
qPCR machines are complex temperature cyclers that allow measurment of fluroscense inside of it.
This can be used to measure the exponential growth of a PCR reaction, and by looking at this growth a researcher can find out how much RNA/DNA was at the start of the reaction.
qPCR machines is commonly used for measuring miRNA as it gives accurate and quantative information. However, there are multiple limitations of a qPCR machine that makes it unsuitable for point of care usage.
The qPCR machines are more advanced than regular PCR machines as it requires the ability to measure real time changes in fluorescence and therefore it is also more expensive witch prices ranging from $15,000 to over $90,000 [21], [22].
Furthermore, it requires the knowledge on the principles of PCR, how to properly analyse the data, and sample preparation. Trained personell is thus required to operate the machine, increasing the costs further.
Our optimal diagnostic plan introduces a one-step RPA amplification of crude blood miRNA to pure target DNA [23], [24], this removed the need for the sensitive RNA isolation step.
The studies of Kubo et al showed it was possible to amplify mRNA from crude blood samples and as s it was based on RPA that has been shown the be able to be performed for miRNA [25].
With our dCAS dual complex we also remove the need for expensive fluorometers needed for RT-RPA. RPA reagents also be transported in ambient temperatures removing the need for expensive cooled transports [26], [27].
Furthermore, we tested that our protein would not lead to any allergic reactions to the untrained personell that will operate the test as outlined the parts registry.
With these factors our test to be performed outside of professional laberatories at places such as point of care diagnostics centers and get a diagnosis faster than the traditional methods allowing the patients to start preventative measuress such as birth control.
In response to a affirmative endometriosis diagnosis birth control is usually administered. However there are many types of birth control which need further dicussion to show that our detecting the disease earlier is beneficial for the patient. We could not find any definitive guides from the investigated nations on which birth controls should be used however [28]discuss a wide range of birth controls which will be dicuseed below.
Combined Hormonal Contraceptives (CHCs) are contraceptives using a combination of estrogen and progestin. Some examples of CHC are Combined Oral Contraceptives (COCs), vaginal rings and transdermal paches. COCs is orally administered and contain Estrogen in the form of ethinylestradiol (EE) or estradiol (E2) combined with three different generations of progestins. Vaginal rings and transdermal patches work with the same components as COC but gradually release the components which can increase compliance as the patient do not need to remember to take oral pills everyday.
Progestin-Only Contraceptives (POCs) are contraceptives that only use progestin that come in the form of Progestin-Only Pills (POPs) that are orally administered, furthermore subdermal implants and intrauterine devices can also be inserted for slow release of the progestin.
As described in [28] there was no significant difference in efficiency between CHCs and POCs. However there are some differences between them like reduced risk of harm to the patient due to the absence of thrombosis risk, those suffering from migraine or breastfeeding.
Perhaps the most important part when choosing the birth control is the compliance, to mitigate the need for surgical procedures in reproductive years of a womans life. Where possible contraceptives such as vaginal rings, transdermal patches, subdermal patches and intra uterine devices which allow long term adherence as there contraceptives do not require daily compliance to uphold.
Lastly an important part for the usage of contraceptives is that it may require multiple rounds of testing before a patient may see an effect of the treatment as upto one third of patients do not respond to the contraceptive therapy [28].
Due to these reasons good routines to increase compliance and early testing for the optimal birth control is required for an optimal preventative measure. Both of these aspects require a test as quick as possible from the onset of the disease and therefore could lead to a better outcome.
Interview with Endometriose foreningen 23.03.23
Endometrioseforeningen or the Norwegian Endometriosis Association, is a key player in the fight against endometriosis and adenomyosis. These conditions, which are among the most prevalent diseases in women, affect nearly 500,000 individuals in Norway. They arrange lectures, courses, and workshops, in places such as schools, hospitals, and gynecological units, they hope to increase awareness about the disease and educate stakeholders in the form of present or future healthcare professionals and women affected by the disease.
Throughout the interview with Ane we got a good introduction into the societal impact of endometriosis and how the disease affects the patients. This became clear in four sections of the interview:
Treatment time:
At the start of our project, we knew that it took a long time to get diagnosed with endometriosis but the consequences was not that apparent. If you can diagnose the disease earlier, then it is a larger likelihood that the more severe forms never develop. According to her 4/5 endometriosis patients do not get the diagnosis before they develop reduced life quality. Infertility is an especially detrimental issue for women as it comes with social stigma, martial instability and increase in domestic abuse. Aswell as developing psychological distress by continually being doubted and questioned by medical professionals who do not trust their story nor their symptom picture attributing it to just being regular menstrual cramps or psychological issues instead of helping the women by giving them an affirmative diagnosis and getting professional help to cope with the chronic disease.
Resources and follow up:
Navigating the aftermath of a diagnosis presents a many challenge. These range from the financial burden of treatment and the struggle with pain management, to disparities in regional accessibility and the absence of official government treatment guidelines. In Norway, a ‘blue marked’ medicine system partially covers treatments and medications. However, this system does not extend to birth control, the only non-surgical medication for the disease, leaving women to shoulder the full cost. Interestingly, legal loopholes exist: if an IUD is inserted by a doctor or gynecologist during an examination, patients pay the full price. However, if the procedure is performed by a nurse at a health clinic, it is subsidized.
As birth control merely slows the disease’s progression, patients are still left grappling with pain management. With no official guidelines available, patients are often left to their own devices in figuring out how to alleviate their pain. The Endometriosis Association offers some guidance, suggesting potential strategies such as endometrial tissue removal, pelvic region physical therapy, heat treatment, and painkillers (both ‘blue marked’ and regular over-the-counter (OTC)). They also recommend consulting with a medical professional to determine the best solution, as well as seeking help from a sexologist and psychiatrist. However, these are not official guidelines and thus accessing these treatments can prove challenging for patients.
To further exacerbate the treatment there are large regional difference in female health availability in Norway due to a dispersed rural population where a patient have to travel hours to get treatment in the north while in large cities the patients only have to travel a couple of minutes before they reach a their closest healthcare provider.
Facilitation:
From an community perspective it is also important to get help to these women earlies as the severe stages forces the patient out of the job market and onto social safety nets as well as reduce the cost from the patients having to contact multiple doctors and get multiple examinations before meeting a doctor with the correct experience to diagnose her. Different countries have different approaches but here are some examples of health initiatives that will make it easier for patients with endometriosis to participate in the job market.
Recently Spain made sick leave days for menstrual pain which make it easier women who suffer from debilitating pain to participate in the job market as they are not forced to work days where they are unable to. This is an example where increased facilitation for female reproductive health will allow more women to participate in the job market, however sceptics argue that this may also lead to employers being more hesitant to employ women at the job in contrast to men who do not require it.
France is well on its way to create an endometriosis protocol for the public healthcare which would allow women to easier get a diagnosis and the associated medical support they need.
Denmark has health clinics that are specialized for endometriosis and female health.
Education:
From an community perspective it is also important to get help to these women earlies as the severe stages forces the patient out of the job market and onto social safety nets as well as reduce the cost from the patients having to contact multiple doctors and get multiple examinations before meeting a doctor with the correct experience to diagnose her. Different countries have different approaches but here are some examples of health initiatives that will make it easier for patients with endometriosis to participate in the job market.
Recently Spain made sick leave days for menstrual pain which make it easier women who suffer from debilitating pain to participate in the job market as they are not forced to work days where they are unable to. This is an example where increased facilitation for female reproductive health will allow more women to participate in the job market, however sceptics argue that this may also lead to employers being more hesitant to employ women at the job in contrast to men who do not require it.
France is well on its way to create an endometriosis protocol for the public healthcare which would allow women to easier get a diagnosis and the associated medical support they need.
Denmark has health clinics that are specialized for endometriosis and female health.
Research:
Blood Tests: Markers are used, primarily for treatment purposes. However, these markers are not typically used for non-hormonal treatments. There’s optimism in the research community about new treatments for endometriosis, but it’s important to note that such studies and research are not always conducted on the right basis. The distinction between endometrial tissue and endometriosis tissue is often overlooked, which can lead to uncertainty about the effectiveness of treatments on endometriosis.
Hormonal Treatment
This type of treatment primarily addresses symptoms rather than the root cause of the disease.
Laparoscopic Surgery::
This method addresses both the disease and its symptoms. However, it doesn’t guarantee a complete cure. The procedure involves removing visible tissue either by burning or cutting (the latter is preferred as it removes the tissue at its roots). However, certain areas like the intestines cannot be cut. This presents a challenging choice for surgeons, and there are few who possess the necessary expertise. Some foreign practitioners guarantee complete removal, but this is often seen as impossible to guarantee and is likely tied to marketing efforts in private practice abroad.
Cause and Cure
The root cause of endometriosis has not yet been identified, which means a definitive cure is still out of reach.
As endometriosis is a disease that has been understudied and is not well known to the general public nor the general medical practitioners. Therefore a large goal of our iGEM project was to educate those who are most likely to be affected by the disease which are young women. Specifically we held multiple presentations across multiple departments, in these presentations we focused on what the disease is, how it develops, what the symptoms are, who it affects and most importantly what the current process for diagnosis is and treatments. This way we hope to spread awareness within academic circles and potentially inspire them to take interest in female reproductive health that often goes unnoticed.
Bioscience master introduction week:
The 16th of august we were able to present our project for the new master students at our insitute of bioscience. This was quite successful with many showing interest through questions and discussions after the presentations. There were also some who shared their own stories of endometriosis with us afterwards that help us get a better understanding of those who are directly affected by the disease.
Presentation for the bachelor students from the Faculty of Mathematics and Natural Sciences:
At 17th of august we had another presentations, this one was for an even broader audience as there was a intro week for the bachelor students at the faculty of mathematics and natural sciences. There we were able to show the potential research opportunities in female reproductive health that they can choose to participate in during their higher education.
Presentation for the pharmacy deparment:
We wanted to have a better talk with the people who work directly with developing the medicines. Therefore we contacted the pharmacy department and presented our project to the master students at the 30th of august. Hopefully this presentation also helped sparked healthy conversations between the students regarding female health.
Integrated Human Practices
Discussion about how we started our project etc. before talking to experts. Our initial project plan aimed to make the test to be as easily applicable, quick and cheap. It included a diagnostic workflow that would enable a person to self-test themselves anywhere in the world and with 100% efficacy. We therefore sat out to make sure our project was useful, responsible and reasonable. To improve this, we spoke with experts, communities, and stakeholders in the field
Discussing our project ideas with Rein Aasland (11.05.23)
At this point in our project, we needed advice on the rules in regarding medical research in Norway and ways to make our project less complex. We therefore contacted Professor Rein Aasland due to his expertise with proteins and familiarity with Norwegian governmental regulatory bodies. Rein gave us valuable insights. We include here the most important takeaways from the meeting and how we have integrated the feedback into our project.
In Norway, the main regulatory body of academic research is the Norwegian research council (Forskningsrådet). They are responsible for making rules and guidelines for all government-sponsored research. These guidelines can be confusing for those who have not worked with them before, but with help we found the guidelines which were most relevant for our project: the “Generelle forskningsetiske retningslinjer” or “General research-ethical guidelines”. These guidelines consist of four pillars: Respect, Good consequences, Equitably designed, and Integrity. Based on these pillars, several topics are described for researchers to consider when conducting research in Norway.
Working with proteins can be challenging if the proteins are not designed for purification, furthermore, the design of antibodies that target specific epitopes on a protein is also a complex and expensive process. Both these problems may be resolved by the introduction of tag sites. If tags are added to our target protein it may bind to a tag specific resin, and when we introduce this tag specific resin during protein purification, we get a really easy way to extract our protein from the rest of the cellular content. These tags can be divided into two classes, the peptide tags, and the protein tags. These two classes have their own benefits and limitations to consider when choosing them. The tags have an additional benefit as they are well characterized. They are also popular targets for antibody binding, granting ease of access to commercial antibodies for our test.
Following the meeting with Rein we prioritized integrating his response in two ways. We were also able to lower the cost of our diagnostic workflow significantly as we integrated the tags into our project in the form of His-tag and Strep-tag. These tags allow easier purification making production time shorter and cheaper due to the usage of well-established commercial antibodies targeting these tags.
What did we learn?
How did we integrate this into our project?
Talking to gynecologists (people in the frontline working with endometreosis): (27.06.23)
Jolanta Sąlygienė - gynecologist and obstetrician who has worked in hospitals in Lithuania for over 30 years and owner of a gynecology clinic.
We reached out to M.D. J. Sąlygiene as a specialist to gain knowledge about the endometriosis cases and treatment in Lithuania. This we felt was important to expand our knowledge outside of Norway’s context.
In Lithuania, the general approach to diagnosing endometriosis starts with mapping out the patients’ symptoms. These questions include whether there is irregular staining throughout the menstrual cycle, pain in the pelvic area, family history of endometriosis.
This is followed by a pelvic exam and ultrasound, where a trained eye can occasionally see endometriosis like tissue formation on the ovaries. This image might also be mistaken for the corpus luteum cycle – ovary release stage. If histological testing rejects the latter – laparoscopy is highly recommended to perform in order to diagnose and catch endometriosis in its earliest stage possible.
As mentioned by Ane from Endometrioseforeningen in the march interview, expertise is needed when examining and diagnosing a patient.
J. Sąlygiene also specified the need for early detection of endometriosis. She stated that in her experience, patients that are diagnosed with endometriosis in its earliest stages (stage 1 or 2) have the posibility to stall the development of endometriosis which would prevent pain, infertility and allow women to live a more healthy and productive life.
In Lithuania, doctors usually use a diagnostic protocol of the American Society of Reproductive Health1. This protocol includes images that are very helpful not only for doctors' investigation but also while communicating with the patient.
At this point in time, our project was aimed at making a test available to patients themselves, that they could then present to their general practitioners to interpret the results.
M.D. J.S said that even our test should be conducted in a hospital or clinic where the results should only be interpreted by a specialist – a gynecologist. This will not only ensure clear information and communication with the patient but also planning of disease treatment and management.
M.D. J.S also said that better therapeutics should be established for endometriosis, current medication prescribed for patients have debilitating side effects such as unwanted menopausal-like symptoms and even potential reduction in bone density2.
What did we learn?
How did we integrate this into our project?
Sources
- https://www.asrm.org/practice-guidance/coding/coding-art-clinical-care/endometriosis-and-infertility/
- Nothnick W, Alali Z. Recent advances in the understanding of endometriosis: the role of inflammatory mediators in disease pathogenesis and treatment. F1000Res. 2016 Feb 17;5:F1000 Faculty Rev-186. doi: 10.12688/f1000research.7504.1. PMID: 26949527; PMCID: PMC4760268.
- Wang WT, Zhao YN, Han BW, Hong SJ, Chen YQ. Circulating microRNAs identified in a genome-wide serum microRNA expression analysis as noninvasive biomarkers for endometriosis. J Clin Endocrinol Metab. 2013 Jan;98(1):281-9. doi: 10.1210/jc.2012-2415. Epub 2012 Nov 1. PMID: 23118427.
Discussion with Anne-Marie Lingaas – Former head- nurse and midwife of the women’s clinic at Akershus University Hospital of Oslo (16.07.23)
- Nurse and midwife
- Former Chief academic officer in the Norwegian Midwife Association
- Former assisting head-of-department at the Women’s Clinic at Akershus University Hospital of Oslo
- Former department head-nurse at the Women’s Clinic at Akershus University Hospital of Oslo
Anne-Marie has seen the damage endometriosis can cause up close. She specifies that endometriosis is a disease that progresses in stages, and that there is a need for fast and efficient detection of the beginning lesions in the early stages of disease progression.
Anne-Marie also commented on how some patients are hesitant to undergo pelvic examinations and consequent ultrasound. In her experience, many patients that have been victims of sexual assault often do not wish to undergo pelvic exams. The same is true for women who for religious or cultural reasons are hesitant to undergo pelvic examinations do to issues regarding being a virgin and protecting the hymen.
We communicated that, while depending on the efficacy of the test, our goal was that patients could be able to forego examinations with perceived invasiveness and be allowed to get further tests such as MRI and exploratory surgery if needed. All in all, she thinks that even an indication that a woman is suffering from endometriosis could mean that it will be possible to skip such examinations, which could potentially make it easier for the patients to seek medical advice.
When asked about who she thought should be offered the test, she rapidly stated that all women with painful and heavy periods – and especially those who report other symptoms associated with the disease – should not be met with indifference and placating comments at the doctor’s office. She adds that this is unfortunately often the case, and that the consequences can be dire for these young women who should have been seen and heard in the early stages of disease progression.
We also wanted to include a discussion on women who for various reasons are reserved or skeptical of using hormonal birth control as a way to stall or halt the progression of the disease – either due to general skepticism, or as a part of a religious or cultural choice. In some cases, the choice does not belong to the woman at all. There are many women with minority-backgrounds where the woman has little or no control over the use of medications and whether or not certain medical procedures are allowed. Anne-Marie said that she suggests shifting the focus from the use of hormonal birth control as a form of contraception over to its use as a way to manage the symptoms of a severe disease. In her experience, properly educating the woman and her family on the detrimental effects endometriosis can have on future and current fertility can be a way to shift this focus onto viewing hormonal birth control as a medicine – and as a part of a treatment plan.
After talking to Ane from Endometrioseforeningen, we had started to discuss internally in our group about whether or not we should continue the project model of making an at-home test. We therefore wanted Anne-Maries opinion on how she felt it would be responsible for the test to be administered. She made it clear that patient follow-up and care both before and after the test would be performed is definitely an important discussion. Symptoms such as severe pain can induce things such as serious anxiety and depression – especially when the patient has to live with said pain and other symptoms. It is therefore important that the patient receives the appropriate guidance on what a diagnosis means, how the symptoms can be managed, options for further medical examinations or medications, etc.
We then presented our previous discussion with J. Sąlygiene (MD) regarding how the test should be administered. While Anne-Marie agreed with the fact that an at-home test would be irresponsible due to the points discussed above, she did not agree that only a gynecologist or specialist should be able to administer such a test. She believes that while it should certainly be a certified healthcare-worker, that it could potentially act as a bottleneck to get a diagnosis – which is exactly what we set out to solve. She suggested that personnel could instead recieve specific training on how to communicate what potential results mean, how this can affect the patients’ life, and to be equipped to guide the patient to the next logical step.
Our discussion with Ane in March had made us aware that some people have previously been negatively inclined to increasing awareness for female health and disease, due to concerns that companies and others could potentially use this as a reason for not wanting to hire younger women.
Anne-Marie suggested looking at this problem from a different perspective: by increasing awareness for endometriosis so that patients and doctors recognize the symptoms at earlier stages, we have the opportunity to lower the number of sick-days. Earlier and better testing of endometriosis should thus still work in the favor of women.
What did we learn?
How did we integrate this into our project?
Follow-up discussion with the endometriosis foundation 09.10.23
As Endometrioseforeningen were the first stakeholders we spoke to regarding our project, we wanted to have a final meeting to update them on our project progress and also how we have changed our project during the summer. Ane Løvereide agreed to meet with us again.
We presented our thoughts and concerns towards developing an at-home test for endometriosis, based on the feedback we had received by J. Sąlygiene (MD) and Anne-Marie Lingaas. Although she did agree that there would be several benefits to ensuring a test such as this is only administered by a trained health-care professional, she also added a new angle to the discussion: She had some thoughts on how an at-home test could be beneficial: It could prove to be a valuable tool to bring to the doctors’ office to inquire if this is a path worth looking into - as many women experience being turned down when they first reach out to their general practitioner.
She also mentioned that the potential benefits of a diagnosis, as discussed before, should weigh heavily when discussing when, who, where and how a patient should be offered a potential test.
What did we learn?
How did we integrate this into our project?
Discussion regarding the medical ethics of our project and how it can be applied to future patient testing - Jan Helge Solbakk from the Medical Ethics Centre at the University of Oslo (15.09.23-11.10.23)
Integrated human practices, specifically the review of medical ethics, societal impacts, and patient care: authored by Anna Lislerud.
The feedback we received from the experts and stakeholders made us want to conduct a thorough exploration of the ethics surrounding medical testing of patients.
We therefore reached out to the Center for Medical Ethics at the University of Oslo.
After presenting our project and our thoughts/worries/considerations, we scheduled a meeting with Jan Helge Solbakk – Medical Doctor (MD) and Professor in medical ethics at the University of Oslo since 1996, with a Master of Theology and PhD in ancient Greek philosophy.
After first briefly explaining our project design, we then gave a more detailed description of the rationale behind how we chose our project, how it is intended to work, how the patient was thought to interact with the test, and our questions regarding the ethics that applies to such questions.
To prepare for the discussion with Prof. Solbakk, we systematically explored the questions and stakes raised in the previous interviews with experts and stakeholders.
We were thus able to have valuable discussion with Prof. Solbakk, where he kindly gave us feedback on our thoughts on the issues being investigated.
The following test is the result of our previous discussions, thoughts within the team, and Prof. Solbakks’ input.
The discussion has been implemented as a part of our final review and conclusion on how we believe that our project is responsible and good for the world, and how we have incorporated the feedback of experts and stakeholders into our project design.
We hope that this can be a valuable contribution to other iGEMers striving to do ethically responsible diagnostics of medical conditions and diseases. Whether a diagnostic test should be developed or not must not simply be based on whether it is possible to develop or not alone. There are several considerations that should be made while designing the type of test, such as who should be offered the test, how the patient will interact with the test, who should interact with the patient and at what capacity, ensuring that the patient is able to give informed consent and how widely the test should be offered.
Although potentially distressing, receiving a diagnosis can be seen as a relief to many patients. In some instances, such as when the patient has been trying to understand what is affecting their physical health, relationships, or mental health negatively, finally knowing the reason for the problems can open the door to taking charge of one’s own health. Referring to the above interviews in our human practices and integrated human practices, as well as the literature reviewed and presented in our project description, we conclude that endometriosis is widely regarded as a debilitating and serious disease.
Many patients often try for years to finally get a formal diagnosis, with the average diagnostic delay in Norway being 7 years. As discussed with Ane, there are several measures the patient and their doctor can take once the patient is taken seriously and the evaluation of diagnostically relevant symptoms has been properly conducted. As mentioned above, there are options for managing symptoms such as pain, gastrointestinal problems, etc. This gives the patient the opportunity to take back control over their life, while also understanding the cause behind the symptoms they are experiencing.
Prof. Solbakk pointed out that if an earlier diagnosis/less diagnostic delay also has consequences for the quality of treatment or quality of life for the patient, then this is a strong argument as to why a test should be offered. As Ane pointed out, an earlier diagnosis and treatment can have potentially life-saving effects. There is also the option of starting treatment in the form of hormonal birth control, which can give symptom relief and even stall or halt disease progression in many cases.
In addition to primary symptoms of a given disease, there will likely be several resulting ways in which diseases such as endometriosis can affect the patient – and those around them. Issues with sexual intimacy is a common problem described by patients with endometriosis. Prof. Solbakk added that this can have great consequences for romantic relationships. Ane also specified that something as simple as understanding why the sexual intimacy might be lacking, difficult, or even be non-existing in the relationship could be helpful to the relationship, as it can help the couple understand the underlaying causes behind the experienced difficulties. This allows the couple to seek help to improve their relationship, such as by seeing a couple’s therapist, sexologist, physiotherapist, or gynecologist that can give proper advice and assistance.
There are thus clear benefits to receiving a formal diagnosis of endometriosis, and the experts interviewed and literature reviewed seem to agree that these outweigh the potential distress the diagnosis can cause.
However, we need to acknowledge that this is line of thought and argumentation is valid for countries such as Norway, and areas the treatment and other responses are actually possible to both access and afford – meaning the patient has the opportunity to respond to the diagnosis by treating symptoms, potentially stalling, or even stopping the disease progression, as well as potentially benefitting the patient in other areas of their life that may be affected by the disease.
In response to this, Prof. Solbakk introduced us to the important concept of cultural context. We will discuss the notion of cultural context later in the text.
The issue of potential false positive and false negative test results had already come up in several discussions and interviews. Prof. Solbakk expressed that the specificity (the occurrence of false positives and false negatives) of a given test will greatly impact whether or not such a test should be offered.
From what we have learned from these previous conversations, we feel it is important to specify that a negative test result should not lead to the patient being dismissed. As Ane (for Endometrioseforeningen), Anne-Marie Lingaas (nurse/midwife and previous assistant manager and head nurse for the clinic for female health at Ahus regional hospital in Oslo), and M.D. J. Sąlygienė (gynecologist and specialist) have all previously stated: a negative test-result should be seen as an indication that the symptoms experienced by the patient could be symptoms of a different disease than what the patient was being tested for. This is especially true for diseases such as endometriosis, where the symptoms can vary and are sometimes diffuse – often dependent on the stage of disease progression. Thus, it should be noted that patient follow-up should be considered just as important when given a negative test-result – but it might entail further investigating the symptoms experienced by the patient by doing further examinations and analyses.
This should also clearly be communicated to the patient by the person administering the test and should thus be reflected in the level of competency of the medical professional.
It is also important that a positive test result does not immediately lead to a patient being diagnosed with the disease in question, and that all symptoms and dialogues with the patient should be considered before a final diagnosis is decided upon. Further examinations and follow-up should always be included in the patient care.
Prof. Solbakk also gave us feedback on how widely medical tests should be offered, and what should influence this type of a discussion. Lower levels of required competency will strengthen the argument that the test could be offered widely. If only people with a high level of competency on the disease are able to communicate the results and do patient follow-up in a responsible and accurate way, this does indeed make the test more difficult to distribute widely.
The advantages and disadvantages of such levels of competency, and thus resources needed to deploy the test, versus the availability of the tests, should thus be elucidated carefully. The matter of who should be considered to possess sufficient knowledge and expertise will likely vary based on the type of disease. The consequences of formally setting a diagnosis should also be considered.
Prof. Solbakk also added that more concrete examples of how and when it is likely that an earlier diagnosis could be beneficial to the patient, the stronger the argument will be for offering the test widely. A useful starting point to such a discussion could be to clarify the severity of the disease in question, and to then explore whether a test should be provided for a specific disease.
Depending then on the severity of the disease and thus what needs to be communicated to the patient if a positive diagnosis is decided upon, this should also influence who should be informing the patient. This should also apply before, during, and after the test is completed. As previously stated, endometriosis is widely considered på be a debilitating and severe disease.
Some diseases can be difficult for the patient to bring up in a discussion with healthcare professionals. Endometriosis in particular has several symptoms, such as pain during sexual intercourse, pain during bowel movements, and heavy bleeding during periods can be difficult for some patients to openly discuss. While this is certainly subjective and will be more difficult to overcome for some patients compared to others, it is still not a trivial matter if it hinders patients from seeking advice and medical attention.
As endometriosis is strongly linked to struggles with infertility and sexual intimacy, both in actuality and in the manner which the public discusses and views the disease, it can be a delicate topic and should be handled as such.
This illustrates that it could be necessary for the person(s) interacting with the patient, such as those...
- initially speaking to the patient,
- administering the test,
- conveying the results, or
- giving guidance on the road ahead, such as potential screenings and examinations, medications that can be utilized, etc.
For endometriosis in particular, a range of healthcare personnel has been mentioned to us as potential administrators of a test for endometriosis, from school nurses to primary practitioners to gynecologists and other experts. It also then follows that the test would be administered in the type of establishment these people work in – meaning everything from schools to the regular doctors’ office, to clinics and gynecologists’ offices, hospitals, and specialized clinics. This means that the price-tag of administering such a test would also vary greatly based on the level of competency concluded to be sufficient. This will again likely be reflected in who is offered a test for a certain disease; a school nurses’ office makes it easier to argue for offering the test to a wider range of people.
It also, however, means that the level of expertise will be lower, which again affects the patient’s care. Careful considerations of which factors should be taken into account, and to what extent they should be weighed in the final sum of factors, are needed. It is also worth mentioning that informed consent from the patient relies heavily on how the information about the test and the disease in question in handled and conveyed by the person administering the test.
This introduces the potential problem where the initially intended interaction between the test and the user (the patient) is lost. If the test is only to be offered at a specialists’ office, where a high level of expertise is likely, and at a clinic or a hospital, it is likely that only patients experiencing severe symptoms will be prioritized. This would mean that the initial aim of the test, which was to increase the availability of tests so that the patient can be in charge of managing their own health, is lost.
As discussed with Ane Undhjem Løvereide, Anne-Marie Lingaas, and M.D. J. Sąlygienė, our test specifically should be used to give an indication that further testing is needed, to give patients the opportunity to start preventative measures to manage symptoms, disease progression and other areas of life affected by the disease.
How the test is supposed to be considered as a diagnostic tool should play a large role in this discussion. If the test is meant to give an indication that the patient might have the disease in question, so the they have the opportunity to start preventative measures such as hormonal birth control etc., should not be treated the same as a test meant to give a definite diagnosis.
We will not be able to provide an answer to who should administer the test, only that we see that a though investigation is needed.
At this point in time, we do not have the capability and competency to answer all these questions and talking points, both as a general analysis and for endometriosis in particular. We do, however, add these reflections as we hope that they can be useful for future teams that also want to ensure they are operating within responsible ethical guidelines. Issues surrounding medical ethics are important and should always be addressed and thoroughly investigated when attempting to develop and market new technologies aimed at patients – even when there are no obvious right or wrong answers.
As the last part of our discussion with Prof. Solbakk, we discussed the potential consequences of being diagnosed with endometriosis in different parts of the world. As discussed previously with Ane Undhjem Løvereide, stigma surrounding female health differs around the world. In some regions and countries, being given a diagnosis for endometriosis goes beyond simply being stigmatizing for the woman in questions – it can be detrimental to their status in society and how they are regarded in a family setting.
This brings us to the point that cultural competency will likely play an important role when deploying a test for a disease such as endometriosis. The ethical discussion will always need to be adapted based on the context of where it is being deployed, and what potential cultural or religious views will likely play a role in how the test itself, and also the results, is received.
While female reproductive health has been gaining increasing momentum and space in the public discussions in the last few years some places in the world, there are still many areas and regions where female reproductive health, especially in regard to fertility and sexual relations of any kind, is a highly taboo subject. This has implications for how a test should be discussed with patients, both before and after said test is performed.
We have not yet had the time to follow up on this particular discussion about how we would solve issues of communication within different cultural contexts, but we choose to include it here as it can hopefully prove useful for others at a later point in time.
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