Hello, everyone. It is a pleasure that you could join us today. And on behalf of the TCA, I want to thank you for being here. Today's webinar is titled Biomarkers for Traumatic Brain Injury and Application in Pediatrics. And joining us today to share her expertise is Dr. Grace Lai. Dr. Lai is a pediatric neurosurgeon at Children's Nebraska. She is originally from the East Coast, where she completed her undergraduate and PhD in child development and developmental neuroscience at Cornell and Columbia Universities. She went to medical school at the University of California, San Diego, residency in neurosurgery at Northwestern University, and fellowship in pediatric neurosurgery at the University of California, San Francisco. So based on these credentials, I am sure that Dr. Lai will add a rich content to this webinar series. And with that, I am going to pass it off to Dr. Lai. All right. Thank you very much. And thank you for joining me here today. As Kim had mentioned, I'm going to be talking about biomarkers for traumatic brain injury. I have no disclosures. And the objective is really review the available and potential biomarkers for traumatic brain injury in general, review pivotal studies leading to a recent FDA approval for the use of two of these biomarkers for mild TBI in adults, and review past and ongoing and future studies for use of biomarkers for TBI in the pediatric population. So quick summary on TBI in pediatrics. In 2022, the CDC did a survey of children under 17, and about 3.2% of them have reported a diagnosis of a concussion or a brain injury in their lifetime. In 2013 alone, of children under 15 years, there were 1500 deaths in the US, 18,000 hospitalizations, 640,000 ED visits, 75% of which were mild, minor concussions. So how do we grade concussions or grade traumatic brain injury in general? There's mild, moderate, severe. Most typically, people use the Glasgow Coma Scale, so a score of 13 to 15, you know, awake, alert, answering questions, oriented, that would be mild injury, moderate and severe are lower GCS scores. You can also supplement this with clinical loss of consciousness, the duration of that, did they have an alteration of consciousness, did they have post-traumatic amnesia? So these are also things to assess when you are assessing for concussion. And in addition, structural imaging, right, so you can most typically CT scan. More, I think, you know, more recent definitions have actually included, you know, like mild positive findings on a structural MRI can still be considered a mild TBI. So the CDC guidelines as of 2019 do not recommend routinely imaging patients to diagnose a mild TBI, so GCS 13 to 15. The PCARN has developed, and there are various decision rules on when to obtain a CT scan in a child. The PCARN is most typically used in pediatric EDs, and this separates between children under two years old and those greater than two years old. It's a little harder to get a GCS for under two years old, so there's a modified GCS for pediatrics. So first of all, is there an altered mental status, you know, is there a palpable skull fracture? If not, I mean, was there a loss of consciousness, is there a palpable hematoma, are they acting normally, and was it a severe mechanism? And if all of those things are negative, there should not be a CT scan ordered. This was based on a large study that enrolled 40,000 children, so I think it's important to actually go over the numbers to see how few of the kids who have, who presented with a GCS 14 to 15 actually had a positive CT scan. So of this 42,000 patients, 35% of them actually got a CT scan, but only 5% of those scans were positive, so that could include a skull fracture, that can include a small traumatic subarachnoid. Only 0.9% of these patients had a clinically significant TBI, which means either death, needed neurosurgery, needed to be intubated, needed to be admitted for over two nights. So even a positive CT scan, not all of them are operative, not all of them are clinically significant, and only 0.1% actually underwent neurosurgery. So I think the concern with these findings is that we are scanning kids a lot more than is necessary, and you know, with kids, there's a concern with increased radiation exposure with scans. So since PCARN has been introduced, you know, what is the compliance of this? So this was National Hospital Ambulatory Medical Care Survey, but of about 30,000 annual visits from randomly selected USEDs, this is between 2000, and they looked at the data between 2007 to 2015. So PCARN was introduced, those rules were introduced in 2010, and this is the percentage of patients receiving CT scans with mild TBI. So they did find that there were certain factors that were associated, increased number of CT scans, you know, I think this is actually supposed to be younger age, white race, higher acuity, a non-teaching or a non-pediatric hospital. They did find that despite the rules being published, the incidence of getting CT scans has not significantly decreased. Here's another study that showed for younger kids, it's between 2015 to 2019, so that's after PCARN has been introduced. They're looking at only children under two years, so these are the kids who are getting the most CT scans, and 40% of these kids under two years old are, 40% of kids under three months old are getting CT scans. And if you, you know, this is a busy slide, so of the kids who are under three months, you have, you know, 50% of these kids had imaging, and of the, and you know, and only, let's see, so 50% of the kids had imaging, only 5% had clinically important TBI. And then if you look at the hospital admissions, only 5% of them even needed to be admitted to the ICU. So clearly we're imaging a lot more kids than are necessary. So there have been studies that looked at implementing a particular protocol to apply for, sorry, so there have been studies looking at the effect of of implementing a protocol that includes a monthly site visit, individual physician feedback, a graphic alert every time you order a CT that has shown that, you know, with these additional reminders, people can be more compliant with the PCARN rules. But however, I think, you know, especially in smaller hospitals, the preference is to be more conservative, which is to scan more often, even if the clinical concern does not meet criteria. So biomarkers, why is a biomarker important? Why are people looking for biomarkers? So a biomarker, you know, we know for heart attacks, for example, CK, you know, that is a protein that you can measure that's in the blood that's indicative of there being injury to the heart. So is there something like that for the brain? And there are many biomarkers that have been studied. One of the ones that we're going to talk about today is UCHL1. This is an enzyme that's specific to neurons. So when you have damage to the neurons and damage to the brain barrier, this can spill into the blood. The other one we're going to be talking about is GFAP. And this is a component of astrocytes, which is a support cells in the brain, and they surround the neurons. They support the blood-brain barrier and the neurons. And this is also released during astrocytic cell death. Other…you'll probably hear of other proteins that have been studied, like S100B, also an astrocyte protein has been studied in Europe a lot, and there have been clinical trials on that. But we're not going to talk about that today, just letting you know that this is something that's under active investigation. The reason I do want to talk more about UCHL1 and GFAP is because there has been a recent FDA-approved test for adults that uses these two proteins to predict positive CT findings in adults presenting with mild TBI. So each of the biomarkers actually have a different time course in terms of when they peak in the bloodstream. The ones that we're talking about, UCH and GFAP, do peak within the first 24 hours. And this thus makes it a good test for acute diagnosis of TBI. Okay. So the Abbott test, so this is actually…was first approved in 2018. That was a serum test. And just last year, they've introduced a whole blood test. So this is something that you can get a drop of the blood from an EGTA tube that's obtained and get a result on this portable device within 15 minutes. So that's very useful, kind of a point of care test. So I'm going to first go over some of the studies that were published that led to the initial FDA approval, and these are all in adult patients. So this ALERT-TBI is a multicenter observational study that was part of the TRACK-TBI group. There were 22 sites, both in the US and the EU. Of course, all these patients were older adults. They had a GCS of 9 to 15, a head CT within 12 hours of injury, and blood within 12 hours of injury. They did determine the cutoff values from an independent group of 334 subjects, and they're testing these cutoff values for the prediction of a positive head CT in these patients. So this is just how they ended up…you know, there were about 2,000 patients with a biomarker test, and then they looked at the positive and whether you had a positive test, negative test, and whether the head CT corresponded to the test or not. Based on this, they did find a very high sensitivity at a negative predictive value. So if you had a positive test, the likelihood of having a positive head CT is almost 100%, and if you had a negative test, the likelihood of not having a positive head CT is also 100%. However, the specificity and the positive predictive value is a little bit lower. So even if you get a positive test, there is a likelihood that you'll have a negative head CT. They did GFAP alone and UCH alone, as well as together, and they found that, you know, even GFAP alone actually had a very high sensitivity. And it probably depends on the timing, too, because the GFAP peaks a little bit sooner than the UCH, but, you know, given the variability in when people present, I think it is nice to have both of those tests available. So they also did another large study in Europe for 65 sites, and they wanted to look at a number of biomarkers, a lot of these that we talked about. Overall, there was 60% positive head CT, and they found that of all of these biomarkers, GFAP was the best predictor for a positive head CT. They also looked at association with outcomes. This is a little less strong than for the prediction of a positive head CT. In this tracked TBI cohort, they looked at patients with a higher GCS, so mild TBI versus moderate to severe TBI, and six-month follow-up. They had blood within the first 24 hours. The primary outcome was death or unfavorable outcome. And then the secondary is an incomplete recovery. They did find that there was, for both GFAP and UCH1, it does predict whether the patient will survive or not. A little less strong in terms of predicting unfavorable outcome or incomplete recovery, but there is a correlation. In terms of six-month outcomes here, so this is about whether they return to work or not. In a single-center study in the Netherlands, they did find that GFAP did predict whether the patient will end up returning to work at six months. So there's some positive studies here, and this is still an ongoing area of investigation in terms of how these tests will predict future outcomes. Okay, so evidence in children. There have been numerous studies actually already that have started looking at these biomarkers in children. There were actually quite a few, I think like four or five studies that looked at whether these biomarkers can separate children who had a TBI versus those who haven't had a TBI, whether they had TBI in trauma patients as well as TBI in patients who didn't have trauma. So a lot of these findings have showed high sensitivity as well. In terms of prognosis, there still hasn't been too much in terms of evidence of whether these can predict how patients do in the long run. There have been actually a large group in Canada that's been looking at using these biomarkers to diagnose whether a patient had a concussion or not. So this is not for CT scans, this is just do you have the symptoms of concussions? And so they excluded all the patients with positive head CTs, and they did find that both, that GFAP did predict whether a patient will have, sorry, they found that these tests were higher in patients who had a concussion versus those who didn't. The GFAP was the most, sorry, GFAP had the highest area under the curve for differentiate between patients with concussion versus just the trauma to the body. In terms of, yeah, so there, I'm just, this is just a few more studies that looked at whether you can use these biomarkers to differentiate between patients with mild to moderate TBI versus severe TBI, and there was a difference. And this particular study, the first one over here, there weren't that many patients, but they did find that GFAP can differentiate favorable versus unfavorable outcome at 12 months. Oh, this is actually the large Canadian study that looked at patients who were all athletes, and they got samples at multiple time points after a concussion, and they did find that patients with concussions had a higher GFAP and UCHL1 at all time points, regardless of sex, although they didn't look at age differences. And then most recently in January 2025, actually just this month, the European group published a study using the Alinity device, so the serum biomarker for GFAP and UCHL1. They did establish a reference range with 700 controls, and they did find that these biomarkers were able to differentiate patients who had a clinically significant TBI, which is defined as admission greater than two days, positive head CT, need for admission to the ICU, needing neurosurgery or death. So where are we now? I think all of these studies are interesting, and they're important in terms of finding correlations and differences in the average range of these biomarkers in the serum for different groups, but in order to use it clinically, there are other things that need to be done. So in terms of replicating what we did on the adult side, trying to determine whether these biomarkers would be predictive of a positive CT scan, there is a large multicenter study that's ongoing in Europe that plans to test that hypothesis. In the U.S., there's also kind of a parallel study that is sponsored by BARDA and Abbott. It's currently involving five sites, and they're also looking at this question in addition to determining whether these biomarkers will have a predictive value for future functioning. So these two are ongoing. At Children's Nebraska, we're actually doing our own small study before joining the larger Abbott group. We do have quite a few TBIs. Within three years, we had over a thousand presentations to the ED with a diagnosis of head injury or concussion and up to 350 positive CT scans. So given that, we did purchase the Alinity iSTAT TBI device, the first children's hospital in the world to get it. We're going to use it clinically for the patients who are 18 or older and then use it for research purposes for patients who are under 18. So the first aim is to kind of to use the Abbott device to kind of replicate some of the previous studies. I've used Serum, which has been analyzed separately in their labs. So we're going to use the Abbott device for all kids who present with a trauma and TBI to see if the device, if we can find differences between moderate and severe and mild TBI. The second aim, which is I think the most important one, is actually to see if this test for patients with mild TBI can predict an abnormal CT scan. And of course, in order to do this, we have to use our population to determine what the cutoff would be. So this might be different than the cutoff for adults. So we do need to optimize that. And then there may be more studies that need to validate whether this test is correct or not, is accurate or not. And then the third aim, we are going to follow our patients at three and six months after to see if there is a predictive value of the initial serum levels. So the design, as I mentioned, would be presentation to ED with trauma, patients who are getting a head CT and blood work within the 24 hours of injury. And we're going to exclude patients with neurosurgical or known neurosurgical neurologic conditions or history of TBI. And then this is actually how the test looks on the machine. So it's one drop of blood from the EDTA tube that's collected for, say, a CBC, goes into this cartridge, and then you plug it into the machine within 15 minutes. This is the result that comes back. Of course, for the research patients, we're going to ignore the elevated versus not elevated value because we don't know what the cutoff is, but it does give you a quantitative value. So we're going to be looking at that to determine our own cutoffs. So we'll have the mild TBI group, the moderate to severe TBI group versus the trauma group, and then we're also going to run non-trauma controls in order to establish normal range. The outcomes would be whether you had a positive CT scan or not, what group, mild, moderate, or severe TBI, and then the functional outcomes at three and six months, which are going to be done via a phone interview. The power analysis that was done for alert TBI, that study showed that you need a minimum sample of 107 positive CT scans for a sensitivity of greater than 0.95 with 80% power. I think we should be able to obtain this within the time, within like a couple of years. So that's what we're working on. I think, you know, ultimately there's still outstanding questions for all, and all of these studies are ongoing, are going to address this. The most important thing is age stratification. We don't know, you know, a baby versus a 15-year-old. We're probably going to have different values. So we're going to be looking at ages and age groups, probably the under two versus two, you know, two to six, six to 12, and then 12 to 16. We also need to compare the sensitivity and specificity of the test to these clinical decision-making tools that we have for determining whether a child needs a head CT. So is it, does this do as well as PCARN or better? There are also the brain injury guidelines for repeat imaging, for neurosurgical evaluation, for transfer. So it may be useful not only for the initial, for determination of getting the initial CT scan, but for additional CT scans or whether you need to transfer the patient or not. So those are outstanding questions that we have not addressed thus far. And I think, you know, the concussion diagnosis and return to play, that is kind of the big question that is going to be very important in the pediatric population and, you know, particularly since we have so many athletes. And, you know, in high school, maybe different than in NFL. So hopefully we can prevent a lot of kids from returning to play when they don't need to, or when they don't, when they have evidence of a concussion. And then, and this is maybe a little reaching far at this point, screening for non-accidental trauma. So that's something that's very clear to my heart. And, you know, we see these kids many times, you know, they come in multiple times actually before they come in with that, you know, devastating head injury. So is there some way to have a blood test that can screen for, you know, potential concussion in these babies that are presenting with very like nonspecific symptoms that may not necessarily require a CT scan, but if there's any suspicion for non-accidental trauma, whether we can use this as a test. So that's my goal eventually, you know, but I think we need, we obviously need to get through the first couple of hurdles first, you know, for using for trauma patients. So yeah, so that's kind of the summary of everything, of some of just actually probably a small portion of things that have been studied so far. And I think there's a lot of potential for future research and for actual use in the clinical setting. Okay. That's it. Fantastic. Dr. Lai, thank you so much. I do have a couple of questions, but just, I'm going to tell, dovetail off of what you just said. And there is a lot of significant research that you presented here. So thank you, but how would you like to bring this into the clinical setting for tangible patient benefits? What do you envision this doing? Yes. I think the first thing would be, would be actually using this test to help with our decision-making for the CT scans. That's what it was FDA approved for so far. And I think that's kind of the low-hanging fruit. Right now that, you know, these, you're working at a more, in a more rural state. We do get a lot of calls from other hospitals, like, do we image this child? Do we transfer this child? And, you know, they, we all know the PECARN criteria, but, you know, when you're in a small hospital, kind of in the middle of nowhere, the stakes are high, right. And sometimes you don't want to, you know, you don't want your clinical judgment to be wrong. And a lot of these doctors and PAs that are in the EDs of these smaller hospitals, they might not have as much experience with TBI and especially in children. So having a test, a blood test that they can actually just run and it'll tell you, is the risk high or low? I think that would be very, very helpful in making those decisions. So I see that as a first step. And then, you know, before we get into things like, you know, concussions and, you know, doing a test on the field and things like that. So I think, yeah. And, and actually using the, the device that is already approved. I think that's also a huge step. A lot of these studies are using blood samples that are analyzed in the lab. And eventually we are going to have to, you know, show that, you know, something that we have already is going to work. So that's why I was really pushing for doing this study, you know, outside of the, the larger multi-trial studies. How widely available are these biomarker tests for TBI? These, this test is available for purchase at this point to any institution that wants to, you know, invest in getting the Elanated device. So yeah, that is readily available. It is only FDA approved for adults. So, you know, it's harder for pediatric hospitals to obtain this and be able to bill for it. And, you know, the, the evidence isn't there yet to show how, how accurate it is for kids. But yeah, this, this particular test for these two biomarkers already is, is available anywhere. Yeah. Great. Great. So question for you. So the adolescent, that gray area between being a child and being an adult, especially for the non-pediatric centers, what would be your recommendations? Because for adults, we just pan scan and that's the end of it. But so what would you recommend for that adolescent group to manage that the best way? Yeah, I mean, I think that, well, the, the best thing we have so far are our criteria, our clinical criteria for scanning. I mean, there are clinical criteria for scanning for adults too. And I think not everybody, you know, abides to that. The test is like, we are using it for our 18 year olds. You know, I think that there's no concrete evidence for you shouldn't say like a 17 or a 15 year old just yet. So I can't say that, you know, you can use this test for that, but I think, you know, if it helps at all with your clinical decision-making I think if you have the device and you have an older kid, it might be reasonable to use that as a, as an adjunct. Okay. So just the blood testing aside when, and this is mostly for sort of the rural or the non-pediatric trauma centers, if they are considering imaging and they don't have the ability to, you know, phone a friend as it were, are CT scans better or MRIs better? CT scans are very sensitive to acute bleeding and they are also better for fractures than MRI scans. MRI scans also are much longer. My experience is, so in the pediatric hospital, we typically do have special sequences for a shorter MRI that's only, you know, a couple of minutes instead of an hour. I find that a lot of the adult hospitals, unless you have like a radiologist who can, you know, set up the sequence for you, they don't have that availability. So I feel like most of them will just default to a CT. And for trauma, we typically do default to a CT first. Okay. Okay. You know, children are considered that vulnerable population and do you have any sort of concepts or ideas or tips that might move research forward in the pediatric setting? Because this is, you know, the stuff that you presented is pretty significant and has potential to be very impactful. So, you know, what are your thoughts on moving pediatric research forward? Yeah. A lot of these studies require significant resources and time. I think it's, you know, getting people together to create consortia, you know, to apply for the funding. That's really what's going to be needed ultimately. I find that even in like tumors, for example, you know, a lot of funding goes to adults, but there's a lot less that's available for peds. So that might be something that we need to advocate for as well, you know, as a group for more research in kids. Fantastic. Well, I don't have any other questions for you today. I want to thank you for sharing this. This has been some great information and I appreciate the time and the expertise. Before we end this webinar, do you have any final comments, anything that you would like to have as a takeaway for our audience? I think, you know, I believe most of you guys are for clinicians are involved in the care of our patients. I think for me, it's, you know, we have that power to kind of push forward that research. So for me, a lot of what I do is inspired by the patients that I serve and the problems I see, you know, the barriers that I see. So I really want to empower everybody to, you know, speak up and to really motivate change. And I think the change is through research. That's really how we're going to be able to change management, change decision-making, change treatment of our patients. So I would say don't, I think big, you know, Children's of Nebraska is a small place relatively compared to some of the bigger hospitals. But, you know, we just, I don't think that you, I mean, I think that we need to not think about all the barriers that we have to overcome, but just continue to fight for what we think is right and to fight for our kids. Yeah. Well, that is a statement that you just can't argue with. And I think we will end on that note. Again, thank you very much for taking the time today to present for us. And on behalf of the TCAA, I want to thank everyone for joining us today, and I hope you have a lot of takeaways from this presentation and thank you again.

pediatric neurosurgery

traumatic brain injury

biomarkers

Glasgow Coma Scale

UCHL1 and GFAP

CT scan guidelines

pediatric concussion