Biomarkers for Endometriosis: State of the Art and Going Digital

The current standard for diagnosing endometriosis is to perform laparoscopic surgery. Surgery is not an ideal diagnostic tool given it is invasive, recovery time must be taken, and complications may occur. Moreover, diagnostic endo surgery can be expensive — particularly if the patient does not have insurance or is underinsured. This diagnostic approach is unlike most other diseases, which can be identified in non-invasive ways. The laboratory test HbA1C, for example, can be used to diagnose diabetes and monitor patients’ status; renal diseases can be diagnosed and monitored using laboratory tests like serum creatinine; and similarly for many other diseases. In fact, research efforts for a particular disease area are often actively focused on devising or identifying biomarkers that can help identify both the presence of a disease and severity as well as monitor its progression.

Looking for biomarkers to non-invasively diagnose endometriosis

The holy grail for endo is a non invasive biomarker to diagnose the disease. Biomarkers are biological signals that allow us to measure the severity and/or presence of a disease non-invasively or less invasively. Identifying a biomarker for endo could drastically increase the number of women screened for the disease by offering them a simple blood or urine test instead of surgery, for instance. Biomarkers can also help identify high-risk individuals. For example, a well-known biomarker is blood cholesterol, which signals risk of coronary heart disease. For endo there is currently no such evidence-based biomarker.

Dr. Neil Johnson and colleagues including Devashana Gupta, Vicki Nisenblat, and Emily Liu, have published several Cochrane systematic reviews to understand the current literature on biomarkers for endometriosis. For those of you outside the biomedical domain — Cochrane reviews are essentially very methodical, rigorous systematic reviews about a topic (think collecting and summarizing all the scientific literature to answer a specific question). Cochrane reviews are regarded as the standard for evidence in medicine and healthcare. The reviews focused on five types of potential biomarkers: urine, blood, the endometrial lining, imaging, and combination of non-invasive tests. In urine, there are several biomarkers, specifically proteins, that may be indicative of the disease. Blood based biomarkers have more narrowly focused on primarily Cancer antigen-125 (CA-125). Cancer antigens are essentially markers on a cell that distinguish the diseased cell from healthy cells. Given endometriosis is associated with unregulated cell growth — a characteristic similar to cancer cells — this makes sense. For endometrial biomarkers, only one called a neural fibre marker seems promising so far. Neural fibre markers are similar to cancer antigens in that they distinguish a particular cell from other cells, but fibre markers do not indicate cancer. No combination of non-invasive tests or imaging studies have had encouraging results. Overall, no biomarker studies had been found to be significant (i.e., have a clear signal that a good biomarker may exist) and there are clear issues methodologically in terms of small study populations and non-standard research approaches. There is another potential issue, which is that we do not know the actual composition of the populations tested — if there are distinct subgroups of disease (which most likely exist given the heterogeneity of symptoms reported) and women are lumped together, then the analysis might miss a signal related to a biomarker for a specific subgroup, for example. In summary, evidence thus far is not telling us that there are no biomarkers for endo. Rather, evidence is pointing out that there has not been enough high-quality evidence produced yet to to identify good biomarkers for the disease. And there is still the chicken-and-egg problem: without good stratification of women with endo, we might miss good biomarkers.

Towards better stratification

If better stratification of women with endo might lead us toward better biomarker identification, why not use the way patients experience the disease as a way to group patients? This type of distinction based on patient experience is the basic hypothesis of Phendo. Phendo aims to collect the experiences of women with endo in real-time via self-tracking of signs and symptoms of the disease as the occur. Such tracking is novel compared to more traditional methods like surveys or retrospective clinical chart review. Given that the disease is highly dynamic and can vary greatly over the course of an hour, day, week, or year, it is important to capture these fluctuations as they happen and when it is easy for individuals with the disease to report what is going on with their bodies.

What about other types of biomarkers?

Beyond real-time disease tracking from the patients’ reports, what if there were other cues we could harness about a women’s every day behavior that would hint at her health status? There may be other types of disease “markers” beyond the biological and physiological ones investigated so far. The idea of such markers is not a crazy idea. For example, frequent trips to the emergency room for abdominal pain could signal presence of endometriosis. Alternatively, many days spent at home while a person is on their period could signal they have endometriosis. There exists an unprecedented opportunity to leverage new information as these events are now electronically recorded and available to researchers: electronic health records contain logs of our visits to the emergency departments; mobile apps store all the data we produce actively (e.g., self-tracking in an app) or passively (e.g., the steps you took today that your phone has inferred from your movements). This digital revolution allows us to sense disease via alternative means. The data we implicitly generate as we go about our daily lives online and via smartphone can act as a “digital pulse”, according to Dr. Deborah Estrin, Professor of Computer Science at Cornell Tech and Citizen Endo collaborator. Combining all of our “digital breadcrumbs” can help to create health-related insights about our individual selves as well as groups of patients. For example, an arthritis patient might be able to see if a supplement is working better for them if they are getting up and out of the door earlier in the day through the data they generate on their phone or fitness tracker.

Our work through Phendo can provide a different way to think about disease markers. Cochrane reviews recommend confirming or replicating the aforementioned studies in larger, higher quality investigations. On average, previous studies had at most a few hundred patients. The Phendo community, now comprising over 2000 patients (and we hope many more as the project continues to get disseminated), represents an exciting opportunity to study the disease on a larger scale. We hope that you will spread the word or participate in our study by downloading Phendo and using the app if you are eligible!

Patients and data science for an endometriosis cure: We bridge the gap between patient experience and clinical characterization of endometriosis.

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