Insights into the global TSIX study program: An interview with Prof. Lori Daniels

Guest speaker: Prof. Lori Daniels - Principal Investigator, TSIX Study Program, University of California, San Diego (UCSD)

Interviewer: Konstantin Schmidt - Scientific Communications Manager, Roche Diagnostics

Konstantin Schmidt: Could you tell me a high-level summary of the TSIX study program, what it entails, and maybe also talk about the scale and what makes it unique?

Lori Daniels: The TSIX study program is a unique study because it is global in nature, which is new in and of itself, and it comprises four regions around the world: the EU, the United States, Japan, and China. And it's a study program designed to evaluate the new hs Troponin T Gen 6 assay. And it's one of the largest studies of its kind evaluating cardiac troponin. As we said, it's global and it's designed, number one, to establish reference ranges.

So, we have the REF-TSIX reference study, and it's using a healthy global population to figure out the 99th percentile, Upper Reference Limit or URL. And it's also comprised of the PERFORM-TSIX Performance Study, which is designed to evaluate the clinical performance of the Gen 6 assay among individuals, patients presenting to the emergency department with symptoms of acute coronary syndrome.

Because of its size and because it is global in nature, we expect that these results will be generalizable to a real-world population, and it will give a trove of data for future studies and understanding of troponin in general. So a very exciting program to be involved with. 

Konstantin Schmidt: That’s amazing and a great summary. You touched upon this: the program is comprised of two studies: the reference range, mentioned, and PERFORM. So for the reference range, could you maybe give us an overview? What does it mean to have a truly healthy reference range population? Why does it matter? Why would you define this and how should it be done? 

Lori Daniels: Yeah. Great question. So I did mention the reference range studies of healthy individuals. And one of the unique aspects of the TSIX reference study is that we really aim to get to a truly healthy population. Why is that important? There's a lot of hidden subclinical disease, and the definition of healthy depends on how hard you look. Do you just exclude high blood pressure and known cardiac problems? Or do you go a little bit deeper and try to exclude subclinical disease as well?

If we have somewhat unhealthy individuals in a healthy reference study, what happens is the troponin levels will be higher. Our reference value, our 99th percentile reference value will be higher, and we'll set the upper reference limit for the assay too high. If the assay is set too high, then when individuals present to the emergency department with chest discomfort, they may be having a heart attack, but their troponin level will have to get to a higher level before it registers so we can miss diagnoses. And that's especially a concern in younger patients, and especially in women who tend to have lower troponin levels.

So it's really important to get a truly healthy population. The International Federation of Clinical Chemists, IFCC, has put out new guidelines to try to harmonize how to do reference studies like this. And in the REF-TSIX study, we follow those guidelines to exclude patients with subclinical disease to the best that we can, using all the latest standards aiming at getting a truly healthy population. 

Konstantin Schmidt: And that's probably also maybe one of the first to follow is because these recommendations are not too old. Let’s say, they're not brand new. 

Lori Daniels: These recommendations came out in the last year or two. And so for sure, this is the largest and probably first study to look at a healthy reference population using these stringent IFCC criteria. The intent of the criteria was to harmonize the establishment of troponin URLs, because up until now, up until these guidelines came out, pretty much every study was creating their own definition of what's healthy. So you can imagine that has led to a lot of different URLs that really are not equivalent. So hopefully now that there's this harmonization, you know, we're trying to lead the way and really get to a healthy population and a true URL of a healthy population. 

Konstantin Schmidt: That is the goal and the results, soon to come. What do you also think are the aspects that would help with global harmonization? I mean, you touched upon as a global cohort, what else do you see there are the potentials to foster real harmonization across the globe? 

Lori Daniels: I think it's helpful to have one cut point that we can all point to. My care when I'm having chest pain and whether I am diagnosed as having a heart attack shouldn’t depend upon whether I go to an emergency department in the U.S. or in Asia or anywhere else. There should be one universal truth. “Am I having a heart attack or not?” And so the purpose of this study is to try to harmonize that and get one global cut point. Now we'll have enough data regionally that we can, of course, look for regional differences and try to understand that, should they exist. But having this harmonization can make us all speak the same language, so that we are all following the same rules and diagnosis. 

Konstantin Schmidt: And as you said, it's a beautiful, big study. Both of them are, of course. So you can look at subgroups, not only regions, but there's out of that for sure of interest that will follow. 

Lori Daniels: Yeah, that's exactly right. One of the benefits of having such a large global study is that we can slice this and evaluate it however we want, and we will. You know, I'm very curious to learn more about how age differences, sex differences, race and ethnic differences all play into the establishment of reference ranges and how troponin levels vary in these seemingly healthy populations. It will help us learn a lot more about how troponin works. 

Konstantin Schmidt: So, as a clinician, in your cardiology experience, you get troponin values all the time and patients with chest discomfort, you get called to look at, what do you think from a clinical perspective is the key benefits, the clinical benefits you see for this new assay? 

Lori Daniels: So, the Gen 6 assay has several improvements over the Gen 5 assay. The most notable one is the analytical characteristics. It's much more sensitive and it's more precise at lower levels.

So what does that mean? It means that we will be able to measure troponin down to a much lower level with good accuracy. So in the past, because of the FDA, at least in the US, labs haven't been able to report as low down as the assay can measure because of poor precision at that level. Now, with the Gen 6 assay, even at the very low limits of detection, the precision is very good. And so labs can report these lower levels. That means we can use these assays. We can use hs Troponin T Gen 6, at lower detection limits and lower reference limits for earlier rule out of patients.

There are other improvements as well. Gen 6 assay is much less prone to interference from things like hemolysis. So even if a sample is very hemolyzed, the level should be reliable and trustable. So that's very helpful from a clinical perspective. And then there are other things that the lab folks care about a lot. As a cardiologist, I may not see it as much, but things like lot-to-lot variability, platform-to-platform variability, and different sample measures are very similar; so, plasma versus serum, there are a lot of similarities there that are improvements in Gen 6. And so, a lot of good improvements in the assay. 

Konstantin Schmidt: What would you say, beyond diagnosis of acute myocardial infarction, what future applications do you see to leverage this capability, this increased sensitivity? 

Lori Daniels: In my view, having the ability to accurately measure troponin at very low levels opens the playbook to a lot of future potential for risk prediction. Now that we can measure troponin in most healthy individuals, we'll be able to see what happens when supposedly healthy individuals have elevated levels. And we know from decades of study that the higher your troponin, the higher your risk of future adverse events, especially heart failure, but to some degree, acute coronary syndrome, and all-cause death. So, now that we can measure it, you know, I think we can really look at risk prediction in an outpatient setting.

There are already some guidelines to that effect in patients with diabetes, but hopefully we can expand the evidence pipeline and improve our knowledge on how troponin can be used for risk prediction in other populations and other disease conditions. 

Konstantin Schmidt: Yes. With such a rich data set as it is, that there are many things to learn and many things to grow in the future and to look into it. 

Lori Daniels: Right, we have the data set already with the PERFORM data. I already mentioned how with the Reference data we can look at it in a lot of different ways, but with the PERFORM data we can too. We'll have a great trove of data to look at patients in the emergency department and how diagnosis and use of troponin varies based upon comorbidities, renal function, age, all of that, to leverage troponin, but also future markers, potentially, point of care opportunities, digital algorithms, all of that. This data set can be used well into the future for that. 

Konstantin Schmidt: Yeah. And one important group we didn't touch upon is the patients. I mean, they come to, if they come with chest discomfort to the emergency department, they will say: “What's going on? Do I have a heart attack? Do I not?” So, they want to know, very quickly usually, what is going on. But what would you say from the patient’s perspective? What is their potential to gain with this new assay generation? And maybe also, you know, thinking about faster responses in the emergency room or long-term health management? What is the potential you see there? 

Lori Daniels: So one of the most important groups, right? The patient. From a patient perspective, you know, the hope is that now that we have much more accurate, precise, sensitive troponin measures, this can facilitate early rule-out algorithms in the emergency department with a higher efficiency, higher yield.

What does that mean? It means we may be able to get a higher percentage of patients out of that emergency department more quickly. So, patients won't be having to sit around in the emergency department as long. So that helps that patient. But it also helps the next patient who's waiting for a bed or who's maybe not getting the care from the doctor they need because the doctor has been, you know, taking care of all these other patients. So, decongesting emergency departments, getting patients out sooner, and getting patients more and quicker care, I think, are all very important goals for this assay. 

Konstantin Schmidt: And that's a win-win-win situation, right? Like the patient gets help earlier, staff is overwhelmed, and there's hopefully decongestion as you mentioned. And for the hospital, it's overall efficiency gains. So that is, of course, the ideal scenario that we hope to strive for. 

Lori Daniels: Right, that helps everyone if we can move everyone through quicker and safer, of course. And that's the hope with a faster but also more accurate algorithm. 

Konstantin Schmidt: Thank you so much for sharing all your insights. 

Lori Daniels: My pleasure. Thank you.