Bob Underwood, MD (Host): Welcome to pediatric Front Lines from Shriner's Children's. Where we explore the best in pediatric care. I'm your host, Dr. Bob Underwood. Joining us today is Dr. Michelle Welborn, chief of Spine Surgery and president of the medical staff at Shriners Children's Portland. Together we will explore groundbreaking research into the collagen X biomarkers role in predicting skeletal growth for scoliosis treatment.

Dr. Welborn, welcome to pediatric front lines.

Michelle C. Welborn, MD: Thank you so much for having me, Dr. Underwood. It's a pleasure to be here.

Bob Underwood, MD (Host): This is really exciting stuff. So can you explain, This is gonna kind of a complex question 'cause it's multiple parts, but can you explain what the collagen X biomarker or CXM is, how it is produced, does it represent and why is that relevant as a marker for skeletal maturity or growth?

Michelle C. Welborn, MD: Perfect. So what I'm gonna do is I'm gonna flip the order of your questions. 'cause if we start with the reason, then I can explain the why. That's okay.

Bob Underwood, MD (Host): You bet.

Michelle C. Welborn, MD: Perfect. So first of all, as a pediatric orthopedic surgeon, we often deal with patient's that have deformity, And that deformity can be in the limbs, it can be in the spine, it can be in lots of different places, and. Oftentimes those deformities get worse when we're growing. This is especially true for scoliosis because when we're growing, our bones grow in response to the stresses on them.

So if there's more pressure, the curve grows faster, and if there's less pressure, it grows slower. So when we go through big growth spurts, what we find is that deformity accelerates. So predicting the timeframe at which kids are growing. Matters a lot. It matters because there are some surgeries that we do that are very risky, but really only need to be done in kids with dramatic growth left.

Then there's some surgeries that we do that are not so risky, but maybe more than average, and they need to be done when people have some growth left, And the safest surgeries are the ones that are done when people have only a small amount of growth left Now. The same applies for bracing.

And bracing is the primary conservative treatment that we have for this. And so if somebody's growing a lot, we've actually seen that their curve can get better in a brace. without a brace, it definitely gets worse. And if we take that brace off before they're done growing, then it definitely get worse.

So we use growth to time the treatment of scoliosis, both operative and non-operative. Okay, so that's our why. So then the next thing is how are we measuring growth right now? Well, so we're measuring growth right now, either with X-rays or actually how much people grow. Well, because we all stand taller or shorter or all over the place, it can take us six months to a year to figure out if somebody's grown at all, which means it takes me six months to a year to figure out if I need to do something to change treatment.

Six months to a year ago, that's not as helpful. And if we use x-rays, well what X-rays do is x-rays tell us about the amount of time that somebody's gonna grow. But somebody who's got like skeletal dysplasia and is gonna be three feet tall, may have the same amount of time left as somebody who's say on the New York Knicks, or gonna be on the New York Knicks and has a massive amount of growth left, but they may grow for the same amount of time.

except the problem is, is that that difference actually matters. So we need to know now how much you're gonna grow in the future and not Well, we probably also need to know for how long. Okay. So now your question about the collagen. 10. So Collagen 10 is produced in the growth plate.

Okay, so the growth plate is how our bones get longer. our bones actually get wider in a different way, than they get longer, so it's kind of cool. Collagen 10 is something that's specific to bones getting longer, but not bones getting wider. So This is really cool 'cause it helps us to predict how much growth is going on right now.

why is that? Well, when we grow, I think nobody's surprised by this. We need to make a lot of bone fast. And when we make bone fast, the way we do it is we make soft bone And then the soft bone is turned into hard bone. And I kind of think about it like cotton candy or something like that.

Like you make a whole lot that's soft and fluffy, And then that kind of then gets converted over time into something more solid. so that's kind of how Collagen 10 Works, is it's a cartilaginous for our medical people, a cartilaginous model of growth or a soft model that then gets remodeled.

So where Collagen 10 comes in is that when we're growing, we're turning soft bone, which is cartilaginous into hard bone. And in that process, collagen 10 is used. So we actually break it down as we convert it, And we can measure that in the blood. So how fast you're converting that bone can be measured.

Bob Underwood, MD (Host): So it's really part of the ossification process of the cartilage into the bone. That's fascinating. So why is there a need to have a biomarker like that rather than relying on traditional methods such as radiographic methods, RISKER score, Sanders staging, in order to assess that growth or growth potential in scoliosis patient's?

Michelle C. Welborn, MD: yeah, So, it goes back to amount of growth, right? So standard score, risker score, they're great and they're actually really predictive of a lot of things. But they're predictive of a timeframe and timeframes are helpful, but timeframe is not amount. And the other thing is that there's standard error.

With these. And so when you look at Risker score or Sandra score in girls, the standard error is six months. Okay? And in boys it's actually a year, and that's not even taken into account people with bone growth differences. So all of a sudden, if I'm, for example, saying, when do we stop bracing?

if you are a teenager and you are wearing a brace for scoliosis. While as a orthopedic surgeon who loves taking care of kids, I think to myself, I'm not torturing you, I'm helping you. That same teenager probably thinks that I'm torturing them, and their parents probably do too. Maybe they don't.

maybe they don't mind. But the number of people that truly don't mind or truly like their braces relatively small. I know. Gasp, surprise. so now. If I say to you, okay, you've got a 35 degree curve, and if I use ER score to determine when to take your brace off, historically we use risser four.

We use Risser four, which is almost done, but not totally. Again, 50% of people will have progression of their curve, five zero, and that's more than five degrees. And so if you've got a 35 degree curve. And now you've got a 40 degree curve, all of a sudden you're at potential risk of that getting worse throughout your life.

In contrast, if I use Sanders score, so Sanders score is a little bit better. For a long time we were using Sanders seven, And then we realized that seven was not specific enough, so we broke seven down into seven A and seven B. Well, the problem is, is that seven A, we see that again, if we use that.

Roughly 50% of people still progress if we use seven A and you haven't grown more than a centimeter in the past six months, a third will progress if we use seven B and you haven't grown a centimeter in the past year. Then 22% will progress. So. So basically, I'm gonna have to see you not grow for a full year to say, oh, I could have stopped racing you a year ago.

Bob Underwood, MD (Host): It is completely reactive at this point.

Michelle C. Welborn, MD: right? So This is something where what we've also seen is that when your collagen 10 biomarker drops below a certain number, that at that point you actually fall into that 22% range. So about half of the number of people having some sort of progression of their curve. Okay, instead of say waiting and looking back in time, what we can do is use that to look forward, if that makes sense.

Okay.

Bob Underwood, MD (Host): Absolutely. So with your research in pediatric scoliosis patient's, how well does the CXM correlate with growth velocity, skeletal maturity compared to the standard anthropometric and other radiographic measures then?

Michelle C. Welborn, MD: Yeah, So, It shows the best correlation out of all of them. Now, arguably, that and standard score are very close. They're very, very close in terms of their correlation, which is fantastic because Sanders score is a very good measure, and Risker score is actually a good measure as well.

However, again, the challenges that time sensitivity, right? So with, even though Sanders score and RISKER score are great. For those, you have to wait again that period of time. And it's looking back in time as opposed to looking forward. Where the eye marker is pretty cool, is that actually, it's a heat stable test.

We've got these excellent reagents, so that's how we process the samples. so. I've processed samples that are a decade old and from other countries, And so they're all dried up and it's still really accurate. This is something that's a finger prick. So I could literally have somebody in Mongolia send me a drop of dried blood and I could tell them if they are still growing or if they're not growing.

I could also tell them if they're going through a massive growth spurt or if they're not.

Bob Underwood, MD (Host): so that kind of comes into the next question. How do C XM levels change during the different phases of skeletal growth? And what do those changes actually signify when it comes to scoliosis management?

Michelle C. Welborn, MD: Yeah, so This is something we actually just won an award for this past year. It's really cool stuff. and This is an area where we're actually changing dogma. So everybody, hold on. 'cause This is gonna shake things up. So first of all, we used to only think that scoliosis got worse And that with a brace you could prevent it from getting worse.

But we never thought that it could get better. And what's so cool is that there was kind of this dogma that said if you're eight years old and you have a 30 degree curve, you were gonna progress to surgery pretty much no matter what. And so there were people that were operating on eight-year-olds.

'cause they're like, I wanna make sure this curve never gets bad, that it never impacts them. And we realized that that was, bad And so most people have kind of moved away from that. However, what we found in this study, and we've been doing this for about eight years now, and we've been following these kids longitudinally, is actually that during rapid phases of growth, you're just as likely to get better as you are to get worse.

So equal numbers of people get better, ask, get worse, the people that get better are wearing a good brace. And the people that get worse, for the most part, are not wearing a good brace or they're not wearing it a lot. And so the quality of the brace, the timing of the brace matter, and there's certainly a genetic component to it as well.

There's some people that are more relentlessly progressive And that even though they're fall into the idiopathic or I don't know why you have it, there's definitely genetic correlations. so to answer your question, one. What we're finding is that those kids, when their biomarker goes through the roof, which indicates really rapid growth velocity, that's the time to double down on bracing.

So what's super cool is that if my patient is doing this and they're in a brace, I can be like. I know you, you've been wearing your brace 16 hours a day. Bob, I'm so proud of you. You're doing awesome, but you're growing really fast And for the next few months I need you to go 20.

Okay, you can do it. And I can give them a pep talk and I can give them a shorter timeframe. Because right now what I do is, you know what, you've got two more years of growth. I want you to wear it 20 hours a day for two years.

That's so much harder than me to say, Hey, You know what, 16 hours a day is fine, but in the next four months I need you to go 20. That's more tangible, So I, that's really our next step with the study is figuring out how do we quantify the timing of all of this.

But right now, what I can tell you is that when those biomarker levels are going through the roof, that that's the time when the biggest changes are happening for the better or for the worse. And then it's also telling me when you're done. And so that's telling me when I can stop the brace and not waiting to see that you haven't grown in a year.

Bob Underwood, MD (Host): Right. Yeah. And then that would be huge for an adolescent. Wow.

Michelle C. Welborn, MD: Especially our adolescent boy population. People used to think that you couldn't brace boys because they were tended to be less compliant and arguably most boys are developing scoliosis later, so they're in high school. It's a very different thing to wear a brace to high school than it is in junior high or elementary school.

I don't find that my male patient's are less compliant. I just find that socially there's more challenges. So really, if I have to tell a 16-year-old boy, Hey, You know what? I don't think you're gonna to grow anymore, but I really want you to wear this brace for another year, just in case.

That's probably pretty different than like an 11-year-old girl,

Bob Underwood, MD (Host): Speaking of the differences, is there a difference in collagen, 10 expression between. Male and female adolescents. And how might that affect scoliosis monitoring protocols between girls and boys?

Michelle C. Welborn, MD: So we don't see that there's sex-based differences. Okay. So yeah. So, basically there's a delusional component to your overall volume of blood, but it's much more consistent with rapidity of growth. And what the principle differences that we see between boys and girls, and that's Not so much boys and girls though it's more commonly so is that in general girls are more likely to have kind of peak quickly And then taper off and boys are more likely to grow more gradually, and not quite have that same concentrated burst of growth.

Now, that's not always the case. There's girls that do it and boys that are the reverse, but they're, that's just a more common growth pattern for them, if that makes sense.

Bob Underwood, MD (Host): Absolutely. Okay. The big topic right now in healthcare, everybody wants to know how AI is gonna affect it. So what role would artificial intelligence or machine learning play in analyzing CXM, alongside imaging, clinical findings, other personalized scoliosis care? What, where do you see that playing into this, this whole scenario?

Michelle C. Welborn, MD: Great question. So we've actually been collaborating with Georgia Tech for the past few years utilizing ai, and now This is where it gets really technical. So basically, and This is the simplified version for me as an orthopedic surgeon, as opposed to our wonderful engineers. But basically, what AI is helping us do is to analyze the individual contributions of these different things.

So for example, if you say that your hair is light and color, it's hard to say, is it light because it's blonde? Is it light because it's white? Is it light because it's gray? Okay. All three of those things make hair lighter in color. so what our traditional statistics would be able to measure is the lightness.

Does that make sense? As an example, what. AI can do is it can say, well, this percentage of lightness is from blonde, this percentage of lightness is from white And this percentage of lightness is from gray. I'm totally drawing this analogy 'cause I'm looking at my hair right now.

So.

Bob Underwood, MD (Host): Fair enough.

Michelle C. Welborn, MD: But what AI does is it increases the granularity of our data so we can see the individual contributions, whereas traditional statistics, because they overlap the contributions harder to separate those out. The other thing is that, for example, when people come in to visit us. Everybody's not coming at exactly six month intervals.

Some are coming at three, some are coming at eight. And so if you want to calculate velocity of height, then you have to normalize that spread. And so what AI does is it'll normalize it for us so that way we've got, we're truly comparing the height, velocity over a six month period.

As opposed to all these varying height velocities, because if I'm only looking at, say how much somebody grew in three months, but the other person it was how much they grew in eight months, that might look different if I didn't take into account the fact that the timeframes were different.

Bob Underwood, MD (Host): Right, right.

Michelle C. Welborn, MD: So basically it makes my data much more granular, which allows me to look at the individual components better.

Bob Underwood, MD (Host): that's phenomenal in, in terms of the, the capability that it's bringing to the, really making the data a lot more reliable overall. So lots of research going on. are the limitations or challenges that you're encountering when it comes to CXM and using it?

Michelle C. Welborn, MD: Totally. Well, so we've been doing this study for a while. So the biggest challenge that we had, first, COVID-19. So during the pandemic, people weren't coming in. when people were coming in, one of the things is that in order to protect our basic science researchers and our research team, they weren't allowed to see patient's.

You know, at the time. We weren't sure if the world was ending or not, and thankfully we can see now that wasn't, And that, a lot of wonderful things have changed, but, we really wanted to be careful and protect them, And so we limited their exposure. So we lost out on a significant amount of data over that period of time.

the other thing is that because This is a study that's based on growth, and I mentioned earlier that it can take us six months to a year to figure out if somebody's grown, then it just. Takes time and it takes a lot of time. So really the goal is to follow.

Each kid through their whole growth spurt. And so we try to enroll 'em as young as we can. Starting at age seven. I even had somebody come in on their seventh birthday, their dad was a science teacher. They were super nerdy. It was so awesome. But I wanna follow that kid.

And I have continued to follow that kid until they're done growing And that kid like 17. Right? So, you know. Each kid, I'm following in them anywhere from one to 10 years, depending upon kind of when they enroll in this study. And so. if you can imagine that's for each kid.

And I wanna follow a ton of kids this research to do it really well, to make sure I'm incorporating people of different ethnic backgrounds, different sex, all these different factors. It means that I need to follow these kids, for a long time. So this study is gonna take me my whole career.

It's probably a 15, 20 plus year study.

Bob Underwood, MD (Host): Right. Absolutely. Because you've gotta know the longitudinal data,

Michelle C. Welborn, MD: yeah. exactly.

Bob Underwood, MD (Host): so what do you and other researchers foresee as kind of the next breakthrough in biomarker led scoliosis management? How central could CXM be in the future?

Michelle C. Welborn, MD: well cool things are is that we are getting our lab CLIA certified. And for those that aren't familiar, what that means, it basically means that we can do testing here. So we can actually start opening this up, for, diagnostic testing. And really, I think the first step for that, where it will become applicable to kiddos is when do we stop racing?

And So, it may be that, we are trying to figure that out and, I'm hopeful that maybe in the next few years we might be able to make a commercially available test that says, have you dropped below this number? And if you have, then. It should be okay in conjunction with your physician's decision-making to, take that brace off.

Now, obviously you never wanna do that without your physician because, it's not just the amount of growth, it's your curve pattern. It's a whole lot of things, but, it would just increase the granularity, increase the data for them to make that decision. So I think that's one. the next is just simply changing dogma around this and helping to show people that actually rapid growth is a great thing And that, if we do a really good job with a brace, that This is, an incredible opportunity to reshape bones, to make curves straighter, And that we can do that non-surgically in some kids.

And so I think that's really, really awesome. 'cause if we can avoid surgery, that's always great. And then, maybe by the time I'm grayer or retired, we'll be able to say, Hey, you know what? You're growing super fast right now and I want you to wear your brace more.

And that, would be, I think, really cool. because maybe that means that, you can wear your brace at night for a year And then when you start to go through that growth spurt. You wear it more and you wear it more for a period of time And then you can back off again.

because I think that would ultimately be maybe less psychologically impactful for some. I also worry about people's muscles getting weak when they're in a brace for a long time. So even though there's a lot of great things about it, I'm totally aware that there's some not so great things about it.

Bob Underwood, MD (Host): Sure. So Anything else you wanna add before we kind of close this episode down? This has been really, really exciting stuff.

Michelle C. Welborn, MD: No, just, it's been really fun sharing it with you. I love seeing how excited you get, because I mean, if you can imagine that's like. A small bit of how excited I am. I think This is something where I'm never imagined that my ability to impact people would be so great.

And I'm eternally grateful for a hallway conversation that led to this. And I'm eternally grateful to my partners who laid the foundation for this work, that really allowed me to kind of carry it forward. But, I would just encourage everybody out there, to give these ideas a chance, and we've certainly grown and adapted with it over time, but I'm really hopeful that, someday, you'll see this coming to you.

And if it doesn't, at the very least, so many of the other things that we've learned will make that impact and make our care of scoliosis patient's better.

Bob Underwood, MD (Host): Yeah, no, and, and that's exactly why I get excited. I think about the kids that I've taken care of with scoliosis and thinking how much it's gonna benefit them, and that's what makes it really exciting.

Michelle C. Welborn, MD: it's just so cool these kids coming in and they're like so excited to share stuff with me And then I'm so excited to share stuff with them. And they're not doing it for themselves. 'cause they know that they're not gonna get any change in their care. They're doing it because they think they're gonna help somebody else down the road and.

This is something where they do a little finger prick and can you imagine a lot of 7, 8, 10 year olds doing a little finger prick? They're doing it and they're excited about it because they're like, happy to take care of the rest of the world. And that just also brightens my outlook, that there's so many wonderful people, right, that are willing to do something that's maybe not always comfortable to help other people.

So yeah, they keep me going.

Bob Underwood, MD (Host): absolutely. Dr. Wellborn. Thank you.

Michelle C. Welborn, MD: Thank you so much Dr. Underwood. It was lovely meeting you.

Bob Underwood, MD (Host): likewise. Pediatric front lines is brought to you by Shriners Children's, which is changing lives every day by providing innovative pediatric specialty care, conducting research to improve the quality of lives and of care, and offering outstanding educational programs for medical professionals. It offers pediatric and patient-centered care in several areas, including Burns, C craniofacial conditions, orthopedic spine care.

And sports medicine, all care and services are provided regardless of the family's ability to pay. Shriners Children's is a 5 0 1 C3 nonprofit organization and relies on the generosity of donors. All donations are tax deductible to the fullest extent permitted by law. And for more information, including the full range of care disciplines, please visit shriners childrens.org to hear more pediatric frontlines episodes.

Please subscribe wherever you listen to podcasts.