Harnessing AI and Patient-Centered Research to Advance Female Pelvic Floor Health

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Daniel Simon, MD: Hello everyone, this is your Science@UH host Dr. Dan Simon. Today, I'm happy to be joined by Dr. David Sheyn. He is the Associate Professor of Urology and Reproductive Biology at Case Western Reserve University School of Medicine. He is also the Division Director of Female Pelvic Medicine and Reconstructive Surgery at University Hospitals. Welcome Dr. Sheyn.

David Sheyn, MD: Thank you. It's a pleasure to be here.

Daniel Simon, MD: So David, you know it's very interesting. I was reading a little bit about you and saw that you originally wanted to be a radiologist. In fact, maybe a pediatric interventional radiologist. But you switched your specialty to obstetrics and gynecology and have obviously soared in this area after your training in female pelvic reconstruction in the Department of Urology at UH. Tell me a little bit about how you completely changed your focus, from going into radiology to pelvic floor disorders in women focusing on urinary incontinence and prolapse, it's quite a change.

David Sheyn, MD: Yeah, I'm actually at the American Urogynecologist Society meeting now, and I every time I meet someone new, they're like, oh, you used to be a radiologist, so it's, I'm very rehearsed in answering this question. I was really fortunate to go to medical school at the University of Cincinnati, which has one of the best children's hospitals in the world, and just by accident I did a summer internship became my first and second year in pediatric interventional radiology.  On the very first day, these two little girls walked in with their parents and the baby was named after the neuro interventionist who saved the older child’s life by embolizing the vein of Galen aneurysm. And every day after that for the entire summer, it was like that, like kids coming from Brazil, Puerto Rico, for angioplasties of their renal artery for anti-hypertensive. It was just an amazing experience. And I was like, I want to be an interventional radiologist, and I wanted to do peds and adult. And the main driver was I really wanted to make a massive difference in people's lives and be the person you get called to fix a problem that no one else can. And I also wanted to innovate. IR is like really at the forefront of innovation.

And I had this amazing patient experience. A lot of people may want less patient interaction, and I wanted to do radiology for like the most patient interaction. And the reason I decided to switch, I had a great experience, I did my radiology residency at UH, there was a patient coming in for a biopsy of their bone for an osteosarcoma, and I spent an hour with him trying to describe the biopsy, that procedure, what comes next. And he sent me this very beautiful letter. And that was my first interaction like that as a radiologist. And I was like, I this is what I want every day to be like.   And the other rotation that I really enjoyed in medical school was OBGYN and actually GYN oncology. So, I decided to do obstetrics to become a GYN oncologist and that was the main reason for switching.

Throughout my residency though, I got exposed to urogynecology and this was another field with a ton of innovation, ton of like for a really motivated person to develop novel treatments, novel understanding of things. I always joke about our boards like we don't know what am I gonna get asked on my boards? Everything we do is just based on how we're trained. So that's what drew me to urogyn.

I'm an engineer by training. And there's a lot of engineering involved in your gynecology, just like in radiology. So I'm superficially, it doesn't look like there's a lot of similarity between interventional radiology and urogynecology, but the things that drew me to both fields are the same. This innovative ability to make a big change, really change someone's life for the better and be the person that gets called in when everything else has failed.

Daniel Simon, MD: What's really amazing because as you point out, it is a little bit of swimming upstream, right? You have a lot of people now who are focused, as you pointed out, on not necessarily limiting interactions but having non longitudinal focused interactions that remove them a little bit from that kind of patient care and put it more technically based. And so it's great to hear that it's your drive for that human connection and compassion that led you into your gynecology. It's just, it's just amazing.

So, during your fellowship, you developed an artificial intelligence model to predict therapeutic response to medications for overactive bladder. This model is currently undergoing some clinical verification. Tell us a little bit about this project and how has it informed your current work. I think maybe before you even get there, you might want to tell just some of our lay listeners what's the difference between urinary incontinence and overactive bladder and how do you look at it and how does AI help?

David Sheyn, MD: Overactive bladder is an umbrella term that the definition is anyone that has urgency that they can't defer. They just have to stop. And drop what they're doing. Pull over on the side of the road and go to the bathroom. That's the broad term and urgency incontinence is within that umbrella. It's somebody that has an urge that's associated with involuntary leakage of urine. There are multiple kinds of incontinence. The other big type of stress incontinence, which people might be more familiar with that's leaking with coughs, sneeze, laugh, usually related to childbirth but can be associated with any sort of anatomic disruption.

What I find the most interesting about overactive bladder and urgency incontinence is in 70% of people, it's a really limiting condition and we have no idea why. So that's where a lot of my research has gone is to try to understand why this is happening, and then to have a precision-based approach to each individual patient. At the end of my career, I want people to be able to walk into an office and have some algorithms say, we're gonna do medicine, we're gonna do Botox, we're gonna do neuromodulation. So that's where the idea for this project came from is right now the order of therapy is based on order of invasiveness, not the order of effectiveness. And certain insurances require us to try multiple medications and we're just basically trying whatever's under hand. So I wanted to make that a little more effective and efficient. And we developed this algorithm to predict who will respond to specific medication using up to 40 different parameters I just pulled in everything that I thought could influence treatment outcomes. And what was interesting when I was working with the Department of Computer Science, we built the model and it worked fairly well, but it also detected things that we weren't expecting.

So, one of the things I pulled in was CAT scans of the head and it picked up that as a very important variable for medication failure. So, we went back and looked at the CTs, like, we actually went with radiology and looked at the CTs and the distribution of white matter lesions was associated with treatment failure, so if you had more white matter lesions in the frontal cortex, you had a higher chance of failing medication therapy. And then we went even further and reviewed people's MRI's if they had them and did volumetric analysis and we found that people that didn't respond to medication also had volume loss of areas of the brain that control the bladder. And now there's this whole thing about brain OAB. And when I talk about OAB, I talk about it as a neurologic condition rather than a urologic, which a lot of our treatments are neurology based.

Daniel Simon, MD: Well, that's terrific. I think that obviously it's the focus of medicine right now and your comments that you ordered therapy based on the order of sort of less invasive to invasive but not necessarily based on effectiveness is really quite sobering. And so obviously your work is very important and we look forward to having you come back. So we can hear those outcomes.

So, we're sitting here today, you're kind of a rock star around the institution this week because we had a major announcement of your $9.2 million grant award from the Patient Centered Outcome Research Institute. This grant is comparing Bulking versus Sling for treating stress urinary incontinence at the time of a vaginal prolapse repair. Can you explain to us again, I'm just a simple cardiologist, so what is bulking and what is sling? And what led you to this comparative effectiveness project?

David Sheyn, MD: This is meant to address the other kind of incontinence I mentioned, which is stress urinary incontinence, and it often occurs with pelvic organ prolapse, which is the descent of the bladder, the uterus or the rectum through the vagina. The biggest risk factor for that being pregnancy. So, we often treat these at the same time, and urethral bulking involves injecting a hydrogel, so it's 98% water, 2% polyacrylamide into the urethral lining to basically bulk the urethra. Sort of like people will get lip fillers with collagen. And a sling is a synthetic material made out of mesh, that creates a hammock for the urethra. They're both meant to treat this kind of incontinence.

The sling is considered the most effective treatment. It's a very short procedure. It's generally very, very safe, and it's meant to last your entire life. Bulking is not as effective, but we think it's close enough. It has no complications, but it may not last as long as a sling.  Versus a sling has the word mesh associated with it and some people are really reluctant to have that. And the non-mesh alternatives that we have for urinary incontinence right now are very invasive. These require a big abdominal incision. They tend to fail over time and they're just not worth the risk associated with them compared to the sling. So bulking came on the scene. It's been around for a long time, but it was never as effective because it was using particulate material. And this gel is more homogeneous, so it doesn't leak out of the injection sites and a lot of people have compared sling to bulking alone for incontinence, which is great if you want to avoid therapy. A big surgery then you have bulking fine, but if you already having major surgery, how willing are you to trade a lower outcome for more quote unquote safety. Like is it really safer to do bulking in this setting? And there is absolutely no data to guide this. People want this. People ask about it, and I counsel them, I’m like, it's probably fine. I don't know how long it lasts. Do you want to risk having a second procedure later on if you already having major surgeries?  And this was really patient centered. This came out of talking to patients.

So before we even applied and submitted our letter of intent to PCORI we asked numerous patients if they wanted us to do this study and they all uniformly said yes, and as a precursor to that, we published a retrospective study with a medical student. She was actually the first author that actually showed that bulking has more complications, so it further reinforced our need to do something for these patients.

Daniel Simon, MD: So how many sites are involved in this study, David?

David Sheyn, MD: We have 11 sites. I was able to submit this grant because of a lot of help from my CO-PI Cecile Ferrando, who's at UCSD. So we have 5 sites on the West Coast and we have 6 sites on the East Coast. She'll manage the west side, I’ll manage the east, and together we need 450 patients.

Daniel Simon, MD: Wow. So that's a pretty big study. So obviously sufficiently powered to answer this question.

So, after the PCORI is completed, what's next for you in pelvic floor health? I guess what's hot, what is the technologies? What are you doing right now for the future?

David Sheyn, MD: One of the hot things right now is biologic implants. So, my partner and mentor Adonis Hijaz, has developed a collagen-based sling and we're doing a clinical trial of that. I think our field has been a little stagnant on reconstruction. We have mesh and we have native tissue, but we don't have anything in between. And I think these collagen-based implants will potentially replace all of mesh eventually, but we need to do a lot more work.

We were recently awarded a $3,000,000 grant to do a pilot first in human pilot in 2025. The other really hot thing is what I alluded to earlier, which is understanding the basic mechanism of overactive bladder and actually how it influences dementia. So, we submitted one R01 already and we're working on two basic science R01s and one clinical R01’s that are all going to go in June, all looking at the relationship between overactive bladder, the medications used to treat this condition as well as developing dementia later in life. Because our belief is that sort of the bladder is the window to the rest of the body's health. There's even that correlation with ischemia and coronary and peripheral artery disease and urgent incontinence. It may be an early sign of that. So we're looking at all of these areas like how the bladder can inform the whole health and how especially it's related to cognition.

Daniel Simon, MD: That is really very, very interesting. Is there any evidence of, for instance, amyloid angiopathy in the bladder that would track with amyloid deposition in the brain or is it completely unrelated?

David Sheyn, MD: We're actually looking at that. There's a huge Alzheimer's study at RUSH and we're partnering with them. We're going to look at amyloid deposition, but in the bladder. But I think it's actually coming from the brain. [12:45] I think a lot of people that have urgent continence when they're older actually have a frontal cortex dysfunction.

And there is this big debate in our field about whether anticholinergic medications cause dementia. And it's significantly confounded by the fact that overactive bladder can be a symptom of dementia that occurs before people are even diagnosed with it. So it's this protopathic bias. So I really believe that a lot of overactive bladder is due to brain and spinal cord and nerve dysfunction. There are some people that will respond amazing to medication and other treatments, and some people that won't, and I think the ones that won't have a nervous system problem and that's what we're going to try to tease out as well. [13:28]

Daniel Simon, MD: Well, this is really very, very exciting. My final question for you is that you deal with a very difficult population, which is pelvic floor disorders and cancer survivors. So on the one hand, these individuals go through some combination of chemo, radiation and surgery and then they're left with significant post survivor issues. Tell us a little bit about that. It's obviously got to be a very difficult situation for many of these patients.

David Sheyn, MD: I think this is actually one of the most rewarding parts of my job. A lot of people come in with significant quality of life issues. We're really, really great at treating cancer. We need to get better at helping people deal with the fallout of cancer therapy and the great thing is it's very easy to do. A lot of these people I only put on medication, or I send to physical therapy, I don't have to do invasive things to them. We have the survivorship clinic that's in the brain Health Center. So I just tell them just bring these people over if they're here and they're bothered, bring them over. I'll see them that day, and there's a lot of research going on right now. I'm even working in a PCORI as a Co-PI on managing cancer survivorship and people undergoing endometrial cancer and pelvic floor disorders. And I think what we're failing to tell people is that they're going to experience this. And I think if we did and they saw urogynecologist at the same time as they're going through cancer therapy, we could shave these side effects off. We can even intervene during therapy.

Daniel Simon, MD: Yeah, it's really great and it's so nice to talk to a physician who is technically advanced and on the leading edge of research but has this deep connection to patients and for understanding this whole idea that patient reported outcomes are really, really important and I'm so glad that we have you on faculty here. So thank you very much for joining us today to learn more about research at University Hospitals. Please visit. Uhhospitals.org/UHresearch, thanks so much, David.

David Sheyn, MD: Thank you very much.