Is Functional Medicine Stool Testing Validated?

Important updates on stool testing for gut health and what test I’m using with Dr. David Brady and Tony Hoffman.

Functional medicine stool testing can be a helpful tool when it comes to uncovering gut health issues or imbalances in bacteria that might be contributing to bloating, constipation, diarrhea, fatigue, brain fog, and everything in between. But are functional medicine stool tests validated, and how do they compare to traditional stool tests?

Dr. David Brady and Tony Hoffman from Diagnostic Solutions Laboratory, which is the lab that provides the popular GI-MAP stool test, help to answer these questions and clear up some of the confusion surrounding functional medicine stool test methodology.

We also talk about the importance of contextualizing test results, and how clinicians can combine the information they get from a functional medicine stool test with an individual’s symptoms, history, and other test results to make better decisions about treatment.

In This Episode

Intro … 00:00:45
PCR-based Stool Testing vs. Traditional Methods … 00:06:09
False Positives in PCR Testing … 00:18:52
Overtreating Based on Test Results … 00:23:35
Testing and H. Pylori … 00:27:50
Ranges Used for Detection … 00:33:26
Lab-Based Research … 00:40:46
Differences in PCR Technology … 00:45:02
Proper Utilization of Tests … 00:49:27
The Dysbiosis Index … 00:57:15

Is Functional Medicine Stool Testing Validated? - Podcast306b DavidBrady

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Hey everyone. Today I spoke with Dr. David Brady and Tony Hoffman from Diagnostic Solutions Laboratories. We were doing a follow-up on a podcast that you may have noticed aired only recently and then we actually took the podcast down because there were a few things that I had wrong, and of course I care about being truthful and honest. So once some of the errors in our analysis and fact checking of stool testing validation, or potentially lack thereof, came to my attention, I wanted to re-analyze everything and set the record straight. So there’s a few key things that we cover in this podcast. Have PCR-based stool tests been validated? Do PCR-based stool tests outperform traditional tests? The answer on both of these is yes. Have functional medicine PCR-based tests been validated? Essentially, yes. There’s a little bit of nuance here, and there’s an important delineation between when we say validated. Most of the PCR technology has been validated in the setting of acute gastroenteritis or overt disease states. The functional medicine labs are mostly using validated technology, but different ranges that may be better for more of these chronic subacute, if you will, populations.

We go into more detail about what’s considered positive, let’s say via a test that would be done at a hospital, versus how some of the functional medicine labs are reporting. We get into dysbiosis markers rather than, and as compared to, strict pathogens, and how to look at those. That’s maybe perhaps the lion’s share. We also close with some thoughts on our center collaborating with the lab in a neutral way, but in order to try to develop a better scoring, reporting, treatment system, and recommendation for clinicians. So this is the update on stool testing. Is functional medicine stool testing and PCR or DNA-based stool testing valid, and how do we best use it and also avoid some of the pitfalls with it?

I hope you will enjoy this podcast. If you’re enjoying the podcast in general, please leave us a review on iTunes. And also remember that if you need help with navigating and improving your gut health, there is the resource Healthy Gut, Healthy You. Okay, and with that, we will go to the show.

➕ Full Podcast Transcript

Intro:

Welcome to Dr. Ruscio radio, providing practical and science-based solutions to feeling your best. To stay up to date on the latest topics, as well as all of our prior episodes, make sure to subscribe in your podcast player. For weekly updates, visit DrRuscio.com. That’s D R R U S C I O dot com. The following discussion is for educational purposes only and is not intended to diagnose or treat any disease. Please do not apply any of this information without first speaking with your doctor. Now let’s head to the show.

DrMichaelRuscio:

Hey everyone. Today I spoke with Dr. David Brady and Tony Hoffman from Diagnostic Solutions Laboratories. We were doing a follow-up on a podcast that you may have noticed aired only recently and then we actually took the podcast down because there were a few things that I had wrong, and of course I care about being truthful and honest. So once some of the errors in our analysis and fact checking of stool testing validation, or potentially lack thereof, came to my attention, I wanted to re-analyze everything and set the record straight. So there’s a few key things that we cover in this podcast. Have PCR-based stool tests been validated? Do PCR-based stool tests outperform traditional tests? The answer on both of these is yes. Have functional medicine PCR-based tests been validated? Essentially, yes. There’s a little bit of nuance here, and there’s an important delineation between when we say validated. Most of the PCR technology has been validated in the setting of acute gastroenteritis or overt disease states. The functional medicine labs are mostly using validated technology, but different ranges that may be better for more of these chronic subacute, if you will, populations.

DrMR:

We go into more detail about what’s considered positive, let’s say via a test that would be done at a hospital, versus how some of the functional medicine labs are reporting. We get into dysbiosis markers rather than, and as compared to, strict pathogens, and how to look at those. That’s maybe perhaps the lion’s share. We also close with some thoughts on our center collaborating with the lab in a neutral way, but in order to try to develop a better scoring, reporting, treatment system, and recommendation for clinicians. So this is the update on stool testing. Is functional medicine stool testing and PCR or DNA-based stool testing valid, and how do we best use it and also avoid some of the pitfalls with it?

DrMR:

I hope you will enjoy this podcast. If you’re enjoying the podcast in general, please leave us a review on iTunes. And also remember that if you need help with navigating and improving your gut health, there is the resource Healthy Gut, Healthy You. Okay, and with that, we will go to the show.

DrMR:

Hey everyone, welcome back to another episode of Dr. Ruscio radio. This is Dr. Ruscio, and today I’m here with Dr. David Brady and Tony Hoffman from Diagnostic Solutions Laboratory. We’re going to be having this follow-up on a podcast that appeared briefly, and then we actually took the podcast down because some of my initial conclusions were incorrect. This was predominantly due to the fact that we were trying to perform research in an independent fashion, however, as we’ll outline throughout the body of the discussion here today, there was other information that one could not obtain essentially through an independent PubMed query that came to my understanding after the podcast.

DrMR:

As I hope our audience is accustomed to, I care mostly about the truth, and if I make a mistake, I’m more than happy to correct that mistake. So that’s what we’re here to do today, which is essentially unpack some criticism that’s been levied against PCR testing, and perhaps more specifically, certain functional medicine iterations of PCR stool testing. That’s why we have David and Tony here today, to try to help us better understand some of the goings on behind these tests, how to use them, and their validity. So David and Tony, welcome to the show.

DrDavidBrady:

Thanks, Michael. Appreciate you having us on, and looking forward to it.

TonyHoffman:

Yes, thank you.

DrMR:

It’s great to have you guys both here, because I think this is an important issue, especially for our audience, the patients and the clinicians who are using stool testing to try to figure out, “Are my gut problems, my food reactive brain fog, my fatigue, my insomnia, my joint pain, my skin issues, my bloating, my constipation, my diarrhea, my abdominal pain, my reflux, is that coming from some thing in the gut that can be remedied?” So obviously, stool testing has an important place in that process. Perhaps we can start high-level, and we’re going to try to keep the discussion today as simple as possible. I’m reminded of having lunch with one of my colleagues, and we were banding back and forth different rationales and defenses of stool testing, and he said, “When, you guys at the labs and on your podcast start talking about these different methodologies and pathways, it’s all so over my head. I don’t really know who to believe.”

PCR-based Stool Testing vs. Traditional Methods

DrMR:

That was a good piece of feedback for me to make sure that we don’t go too deep so as to only allow people who are really privy to the nuances of this conversation to be able to follow us. So if you zoom out high-level, one of the first questions I ask is, has PCR stool testing been validated, and do PCR-based stool tests outperform traditional stool testing, whether it be antigen recognition or culture? And the answers are yes, and yes. We’ll put some notes in the show notes here, but there’s a 2020 systematic review with meta-analysis finding a higher positivity rate when using PCRs compared to using stool. And there’s a really impactful, in my opinion, albeit observational study from 2019 that found a higher degree of pathogen positivity when using PCR as compared to other methodologies.

DrMR:

Most importantly, this reduced the use of follow-up invasive procedures, testing, and reduced the use of antibiotics. So yes, PCR has been validated to really help clinicians be more precise and not just indiscriminately blast people with antibiotics or refer them for more invasive testing like endoscopies or biopsies. There’s an important hook here I want to plant, which is, this is usually in the setting of acute gastroenteritis, acute, somewhat severe symptoms. And that’s an important facet to keep in mind that we’re going to get to later as it pertains to reference ranges. But I guess keeping things high-level and starting there, David, Tony, anything that you want to add regarding the utility of PCR and how it’s been validated to outperform the more traditional stool testing?

DrDB:

I’ll go first, and Tony and I will try not to step on each other the whole interview, because we’re not in the same place. I’ll speak with the clinician’s hat, and Tony is far more of the laboratory scientist than I. So I think between two of us, we should be able to give a little bit of different perspectives, but well-rounded perspectives on this. I agree with you, Mike. It’s an interesting topic. It’s a confusing topic for clinicians because they’re not laboratory scientists. They’re not lab wonks; they don’t spend a lot of their time looking into all of the nuances here because they’re too busy seeing patients and trying to get people better. And it’s complex, right? Even in stool testing, we didn’t even mention the things that make it even more complex still. We have older stool tests that old guys like me grew up with that are non-molecular. They’re culture sensitivity-based stuff.

DrDB:

At this point, I almost don’t even want to waste my time talking about them because it’s like arguing how we’re now in electric cars, and I’ll argue those against a really good, top-notch, latest engineering combustion engine car. We can have that argument, but I’m not going to argue a Tesla versus a horse with a wagon. I’m not doing that anymore. So we’re not even going to talk about those tests. That’s old school; I think there’s been enough said and shown that that’s not the way to go. But even in molecular, there’s various different ways to do it. I published an article in the Townsend Letter, I think in January. It was like, “Methodology Matters in Stool Testing.” I looked at the different even molecular methodologies out there and talked about how they all have their place. They’re all good for certain things, but none of them are good at everything.

DrDB:

You even look at sequencing, like 16S sequencing tests that people were used to with uBiome before it went away, or these direct-to-consumer microbiome tests. Everyone’s had patients put those on their desk, where there’s 400 organisms and you don’t know what 90% of them are. You’ve never even heard of them. We don’t know what clinical utility they have, if any, and it’s totally non quantitative. It’s just the percentage of the total DNA caught. Now those actually somewhat clinically useless. They were never meant for clinicians to make clinical decisions on. They were meant for researchers to look at large populations and try to figure out what is a normal total composition of the GI microbiota.

DrDB:

Or what’s the composition of the GI microbiota in people with rheumatoid arthritis versus people without. Or people with diabetes versus without. Or people in Los Angeles versus people in Tokyo, or vegetarians versus meat-eaters. They’re perfect for that, but they require Big Data analysis, and the throughputs slow and it’s expensive to do it right. The ones that are direct-to-consumer are very cheap because they don’t have enough reads, and I don’t even want to get into that. But those tests are just not the kind of stool tests that you do on Mary Jones in your office to find out if she has an infection and if you need to treat it. Or does she have dysbiosis, or is there some other kind of metabolic issue going on in the gut?

DrDB:

And as we know, those tests have no stool chemistries. They’re not going to give you inflammation markers, immunological markers, permeability markers, digestive markers. None of that’s on there. So people are often confused. Do I do a next-gen sequencing or meta-transcriptomics test, or do I do one of these things that we’re more used to in the functional integrative medicine space? Like our GI-MAP is really meant for doctors to make decisions with on patients. So it’s quantitative; it uses quantitative PCR.

DrDB:

But I will admit, it’s been a bit of a learning curve for practitioners. A great analogy is how with new technology, with better technology, with a better methodology, there comes with it better sensitivity. It’s almost like looking at high-definition television versus old analog televisions. The resolution is entirely different, and there’s some disadvantages to that. Ask newscasters, you can see every blemish on their face. They had to get used to that. They had to come up with ways around it, but the answer isn’t going back to analog TV and into worse resolution.

DrDB:

We’ve had that adjustment period in stool analysis. We see pathogens more than you used to see them on culture and sensitivity. We can look very precisely and get quantitative information on organisms we never were able to do before because they were anaerobic and we just couldn’t deal with them in the lab with a culture and a sensitivity. So everything has changed, and it’s been hard for clinicians who have been around for a while to get used to the change. Sometimes there’s misperceptions created because of that learning curve. So I hope we can address some of those today, and Tony I’ll let you have any comments to open.

TH:

Yeah, absolutely. I agree 100% with David’s comments of evolution of testing and not trying to go backwards and discuss those much older. Dave made a good point that we use qPCR. We actually started with PCR, and there’s a nuance there as far as what we’re doing, with qPCR being even more sensitive. And just from the laboratory standpoint, I just want to make it clear that when we set reference ranges, we understand this change in resolution to the point where we flag things as being high when they’re much more likely to be contributory to symptoms. But just the presence of an organism doesn’t necessarily mean it’s causing symptoms or disease. It literally is reference range-based. So as we discuss things, keeping in mind that we may see a fairly high amount of H. Pylori, for example, but a lot of that we see it in is trace amounts or below reference range.

TH:

And it’s noted there because we are doing a method that is quite capable of looking at very, very trace amounts of organisms. So we do our best to educate around that, but also have reasonable reference ranges. We’re not going to flag an H. Pylori high at equivalent of 150 cells per gram. We flag it high at 1000 cells per gram, e³ or 10^3. Does it mean that somebody is 5% below that cutoff, and they’re not totally symptomatic? No, they very well could be. No reference range is absolute, but that goes into why we even switched from our previous PCR platform using a Luminex technology and their kit for pathogens. Specifically, I just wanted to mention that we would see patients whose particular assays, whether it’d be the BioFire or Luminex, were set up to be predictive of disease.

TH:

So when they go through their FDA-approval process, they’re only including patients who are clinically diagnosed with the disease from the organism they’re looking for. They take thousands of those patients who have disease, say C. difficile toxin A, and if they’re showing symptoms or diseases, the finding and the presence of, along with symptoms, one plus one equals two, and then they would set a reference range. So those tests that are positive or negative, it’s horrible terminology that it comes out as positive or negative, but because they’re FDA-approved, you have to use those terminologies. What it really is, is predictive that positive or negative predictive value of disease. So if it says positive, it’s above a level that correlates disease. If it says negative, it’s below a level that correlates to disease, but it’s not necessarily negative for an organism.

TH:

We saw things like Giardia just 5% below the cutoff level of 10^4-ish, and that patient absolutely had thousands of cells per gram of Giardia. That’s clinically significant, as far as I’m concerned from a laboratory standpoint, that we’d want to note that for a position. But on the Luminex assay, or conversely on the newer BioFire assay, that would actually say negative, but they may have thousands of cells per gram. And if there had been 500 more cells per gram, it would have said positive. So I think it’s real important, and maybe I got long-winded and we might want to clear that up if it didn’t come across correctly, but these are the reasons we use qPCR because we have a patient population and most of our clinicians that are more chronic. They have episodic diarrhea. And these are patients who might be just below threshold, have a total dysbiosis going on, and they keep having episodic diarrhea or something. They would most often show up negative on one of those assays.

DrMR:

Yes. All great points guys. A lot there to unpack, but just try to kind of touchstone on a few of these. David to your first point, I agree completely. It’s sad that using tests like uBiome or Viome is still being done clinically, even though we’ve been trying to sound that alarm bell on this podcast for a long time. Great for research, but taking that to your doctor tends to get treatment recommendations and is really misguided. So I’m glad you raised that point. To your other point, why I think it’s important to at least mention the PCR as being validated is we’ve discussed in the past some of the criticisms that PCR may, amongst other things, and this might be one of the chief criticisms, suffer from false positives. I mean, it’s a true statement, but when we look at it in the larger context, the overwhelming majority of the data suggests that’s not actually an issue given that you have the right test, use it at the right time, and it’s well-calibrated and it’s using good equipment, it’s not some cheap knockoff.

DrMR:

So I think it’s important for me to maybe clarify the record that as we have gone more into checking the literature on this, it’s pretty clear, to your point, David, that traditional stool tests are almost horse and buddy now, and the PCR, albeit whatever criticisms are levied against them, seem to be accurate.

False Positives in PCR Testing

DrDB:

Well, Mike, it’s even more complicated when you talk about an issue like what you mean by a false positive. Does that mean you’re identifying an organism as being present when actually that organism is not there? That’s truly a false positive, but what a lot of people are talking about is if you would get an indication on the test that some organism is present at whatever level, but that it’s not correlated clinically with symptoms or with overt pathology. That’s where you get into some level of subjectivity on what your definition of a meaningful positive is. Now, if you’re talking in very, very conventional standard gastroenterology, they’re looking at positive thresholds on pathogenic organisms that are correlated clearly with acute disease, like fulminant diarrhea or overt inflammatory bowel disease.

DrDB:

Now, our GI-MAP test, we understand those dynamics. We understand those pathologies, those cut points, what those organisms are, their mechanism of action and causing the pathology, et cetera, et cetera. We’re not trying to put out a diagnostic test that’s simply for conventional gastroenterologists because quite frankly, all the hospital pathology labs have these automated systems that do PCR-based pathogen profiles, but they’re confined to a very short, curated list of overt pathogenic organisms. And as Tony alluded to, they’re FDA-cleared to call positive or negative. Now negative doesn’t mean “no organisms.” Negative means the organism may be there or not be there, but it’s not risen to the amount of positivity that they correlate with acute disease, such as ulcerative colitis, Crohn’s disease, or whatever the disease may be.

DrDB:

Now, most of our patients coming to functional medicine — doctors, integrative physicians, even functional nutritionists and the like are not coming to us for the same type of tests, the same type of management, or the same thresholds on what is considered treatable as the conventional gastroenterologist, or why would they come to us? They’re not looking for the same thing. And clearly in functional medicine, we understand that a lot of people have gastrointestinal complaints. They know their gut’s not right, but they’ve been to five gastroenterologists who have run Luminex platforms or where they’ve run tests on BioFire or whatever, and they’ve all come back negative. Meanwhile, they have diarrhea four times a week, they bloat every time they eat something, they feel horrible, and they end up in your office.

DrDB:

They’re ending up there for a reason. They’re not getting what they need going the other way. So we’re not trying to replicate that, we’re trying to come up with a science-based, evidence-based tool that uses the absolute best technology to identify these organisms, but creates thresholds in reference ranges that are based in rationality, but are not necessarily at the same exact cut point that you would have in an FDA-cleared test for inflammatory bowel disease proper. It’s just not what we’re trying to do. So if you compare it to that, there’s going to be dissonance.

DrMR:

Sure, sure.

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Overtreating Based on Test Results

DrMR:

And that’s really the crux of this whole argument. And I think the main point for people to take away is that there are different conditions that we’re trying to optimize the test for. Conventional medicine is going to be looking for the more conventional, acute manifestation. But there’s this almost subclinical manifestation, if you will. Now, that being said, there’s a devil’s advocate argument to be made here, which is very important. Functional medicine sometimes thinks that the test that gives you the most positives is the best test. And there are clearly areas where this is severely misguided. I think subclinical hypothyroidism and hypothyroidism is one shining example of where the field is doing more harm than good. As a quick aside, there was just recently a Danish cohort study, I believe of 400 patients, who had subclinical hypothyroid, and they were assessed to see if they exhibited any additional symptoms as compared to how the controls. And they had no additional thyroid mediated symptoms then did healthy controls.

DrMR:

So whether or not you guys agree with it, it’s a different debate I don’t necessarily want to open, but just using this as an example of an area where in functional medicine, we’re oftentimes over-treating. And so we have to be careful about this on the one hand, but in this case, I think that the right call is to have these ranges that will give you something other than to your very well said, point, David, what they are already getting when they come to you. They say, “Well, my gastro already tested me for parasites.” Okay, good. So we’ve ruled that out, but there could be this middle ground here that’s still evading diagnosis.

TH:

So I wanted to comment a little further on that. Outside of the acute pathogens, the first page of our report is those acute pathogens, most of the other opportunistic organisms are those that are truly that, just opportunistic. We do our level best; we have high call ranges that say, “Hey, this is above what your average patient would be. It may be contributing to something.” And some of these like Pseudomonas are actually toxin producers, and are close to being a true pathogen themselves. But in most cases, when you’re talking about the GI, the microbiome, all these organisms that we’re measuring may be in super trace amounts all the time. Trace amounts being, one to two cells per gram, or maybe 50 cells in a pound of poop.

TH:

So it’s important to understand that outside of the true pathogens and H. pylori, which is what I want to get to for just a second, to see 10^0 or 10^1 level of an opportunistic type pathogen doesn’t mean it’s become a communal presence in your GI. When you’re under 100 cells per gram, it may just be that you’ve ingested a bunch, or you have a certain amount coming through from your oral cavity. Usually ingesting, or just blips, ups and downs. Again, they’re almost all there in trace amounts all the time. The more biosis you have, the more likely they are to start to take hold, multiply, and get into higher levels that become a resident population of your GI. And those tend to be greater than 10^2, and in most cases, greater than 10^3.

TH:

And they get to 1,000 cells per gram, that’s not some you ingested. Keep in mind, you’re diluting everything in somewhere between 2,000 and 2,500 grams of fecal matter. So it’d be hard pressed to ingest that much organism that you would then see hundreds of cells per gram, or certainly not thousands of cells per gram. That would have to be a resident population. Those are the organisms we want to worry about. Are they there for a short period and going away? It is very difficult to understand exactly how and when to treat. I think running tests for a while, you get a handle on that, definitely calling in and talking with our staff.

Testing and H. Pylori

TH:

But I say all that to get us to H. pylori. That’s the one that we probably get the most questions on. It’s the one that differentiates us from most other laboratories. It also presents a little bit of a different interpretation because we’re not talking about the colon or the small intestine. We’re talking about an organism that predominantly populates the stomach, the duodenum. And comparing that to a lot of labs that do the stool antigen test, which again, you’re taking organism that’s leaving the stomach and coming out in stool. It takes a fairly high amount to make one of those stool antigen test positive. Quite a bit, actually, in which case you should have a very, very large infection and are almost always symptomatic from H. pylori by the time you get a positive on the stool antigen. Not everybody. Just because H. pylori is present in a high amount, or even if one of the pathogens we have on page one is present in high amount, doesn’t mean you have pathology from it.

TH:

These are toxin-producing organisms. If they’re not actively producing toxin, you could be asymptomatic even with a high amount. E. coli is notorious. It’s just E. coli; it just happens to be a coli, for lack of a better way to say it, similar to a snip in the human genome. They have a snip for the ability to produce a particular toxin. We’re not doing the outcome of that, say that gene is turned on, and actively producing toxin. Especially in chronic patients, it may not be, but we measure that gene for that ability to produce toxin, and that’s what we target in those E. coli. But other than that, it’s just E. coli. It grows really, really well. So if you get E. coli, in your GI, and it happens to be the right setup to grow E. coli, you could have a fairly high amount and be asymptomatic.

TH:

That’s the nuances of what we know today using PCR testing and research. Not us, but as a whole, for the last 20 plus years. We definitely understand the microbiome and these organisms much, much better. So there is that learning curve we talked about, but H. pylori becomes a different problem because of where it’s located. How much H. pylori does it take to cause an ulcer? Well, 5,000 or 10,000 cells in the stomach if it has the right virulence factor, or if it’s located in the right area of the stomach. You definitely can have an ulcer of 5,000 cells in your stomach. However, again, you don’t pass all 5,000 cells all day, every day, you pass a certain percentage of those into the GI tract. And by the time you dilute it in a couple of thousand grams of fecal matter, how many cells per gram is that? Two or three.

TH:

So even on our assay where we don’t call high until 1000 cells per gram, 10^3, a patient could absolutely have an ulcer from H. pylori, but the sample type is limiting. We can pick up trace amounts of that, but it’s not our job as a laboratory. We’re giving the information. We give the best information we can, paying attention to reference ranges, but it is information to be used for the clinician, with the patient with symptoms in front of them. We have no idea of any of that as a laboratory, nor do we want to. We’re not practicing medicine; we’re just trying to give the best information we can. Certainly a patient could have disease from H. pylori, and it wouldn’t even show up as a positive. It’s present on our assay, but not a flagged high. So there are definitely some nuances.

DrDB:

And Tony, that’s a good point. This goes for any kind of laboratory test, but all of the information can’t be looked at in a vacuum. There are exceptions to what I’m about to say, but generally one marker can’t be looked at in isolation, in a vacuum and it needs to be clinically contextualized. So that’s a big part of what our education team and our technical services team do when clinicians call and want a consultation on their test. They learn a lot when they do that because we’ve seen so many of these things, and we understand pattern analysis. We understand which, for instance, opportunistic organisms tend to group together in dysbiotic states, in hypoacidity states, with pancreatic exocrine inefficiency. We see certain types of groupings of opportunistic organisms that go high.

DrDB:

When Tony was talking about H. pylori based on the level of H. pylori and the symptoms, you can make some conclusions, but we also look at the various virulence factors. We’re looking under the hood at the H. pylori, not just is there H. pylori present and how much, but what about that H. pylori? Is it benign H. pylori, or is it the H. pylori with the genomics to be able to produce various virulence factors? We know it can tear up the gastric mucosa or the duodenal mucosa and can cause ulcers and even higher incidence of gastric cancer. So we’re looking at a myriad of virulence factors to combine that information with the level of the actual H. pylori by genus and species, and then you have to contextualize it within the clinical symptoms and history of the patient. So, there’s a lot of things I’ve got to roll into it to make a clinical decision, and the laboratory report is not the sole determinant of that in the vast majority of cases.

Ranges Used for Detection

DrMR:

Using H. pylori just as one example, just to make sure I’m clear in my understanding, you will report any detectable H. pylori, or any pathogen, but when you get to the flagged, the report essentially turns red, that’s not the FDA cutoff range. This is a range that you guys are establishing as what you feel to be, termed loosely, the subclinical cutoff range. Am I correct in that understanding?

TH:

So to be clear, for the true pathogens, excluding H. pylori at this moment, so things like the C. diff and the pathogenic strains of E. coli, vibrio cholerae, et cetera, those reference ranges were determined side by side with the Luminex Pathogen Panel, because we used to run it. We still have it in house. We still have the Luminex equipment. Those reference ranges are a close fit to the FDA cutoffs for positive, negative, and predictive value. H. pylori is a little different. There is no clinical way to determine a level of H. pylori in stool to correlate back to disease. Again, that comes from the fact that the stool is a sample for something in the stomach; it is not the best way to diagnose disease. And that being peptic ulcer disease. Let me be clear, disease, not presence.

TH:

So we use a combination of things to determine a flag for high call. What does literature suggest? What do some of the other kits that flag high, the EIA type kits, the stool antigens, what do they flag high at, and standard laboratory practice for determining reference ranges? So H. pylori is a little different, and that’s why I bring this particular one up, because it is not the same as trying to diagnose a level of an organism in the colon, because it does not reside there in the colon. So again, the clinical significance of H pylori goes back to if you have hundreds of cells per gram, or in this case, we flag high a 1,000 cells per gram, you have to have a heck of a lot H. pylori in the stomach to excrete detectable amounts in the stool. So is it clinically significant? Well, you can have H. pylori with no virulence factors at say, 5.0 e². That’s 500 cells per gram of stool. You can have an argument out there, I know that people do all the time.

DrMR:

Let me just interrupt, because that nuance is fine. Heard, that H. pylori may have been the worst example for me to pose, but with the pathogens, did you say that you’re using the cutoffs for the FDA, or you’re close to, but solely underneath?

DrDB:

Analogous cutoffs, Michael, because the methodology or the instrumentation is different, but we can run them in parallel. We went away from Luminex into our own quantitative real-time PCR for the advantages of the full quantitation. In other words, we’re not limited with just calling a pathogen positive or negative. We can report the levels quantitatively, even when they’re below, what would be the flagged positive on a Luminex platform, if that makes sense.

TH:

Our high flag does correlate very, very close to the Luminex.

DrMR:

Gotcha. I’m just trying to help clinicians understand.

DrDB:

But we can show that the organism is present, and what the quantitative level is, and not flag it high. See that’s where people get confused. Just because a pathogen is present at some level, we don’t necessarily flag it as high, because it’s not correlated with either the amount of organism necessary for a true ongoing infection to be present. It may be a transient and it’s not correlated with any disease.

DrDB:

And even in H. pylori, 50% of the population is believed to be infected with H. pylori. Only about 2% go on to develop gastric cancer. The independent data, this is not our internal data, we have that too, but with independent data we have over 4,000 tests, and the positivity rate for H. pylori presence is about 35%. But then when you look further into virulence factors, many of those are at 3%, 1%, 2%. So you need to put the whole picture together, but ideally if you get a H. pylori that’s positive, and the quantitation seems rather high, and you have multiple virulence factor genes present, and the patient has GERD, reflux, or some ulcer symptoms, that’s really concerning. But ultimately still, the gold standard is endoscopy, visualizing the gastric mucosa, biopsies of the gastric and duodenal mucosa, and then usually a direct reagent test like a CLO test for the presence of H. pylori.

DrMR:

Right. Just to make sure we don’t bury the point here, with the pathogens, when you report positive, it’s similar to what a conventional gastroenterologists hospital-based test would use, but you’ll also be able to see detectable level. Ok, same page there. Now with the opportunists, I don’t believe that there’s the same normative data established in that flagging positive is more something that you guys have crafted over time.

DrDB:

Correct, and that’s where Tony had mentioned the absolute amount or the exponent amount of organisms that would be consistent with it being a communal, like an actual situation that remains or that’s static. With the opportunists, hence the name, when they’re given the opportunity, they can overgrow and cause symptoms that might be diagnosed as IBS or more functional gut issues, whatever it may be, but rarely are they in isolation. So that’s when you get into the pattern analysis, and there are many more opportunistic organisms in the human intestine than are on our report. We’re curating a rather long list of them, but it’s certainly not exhaustive. If you want that, you’ve got to go to one of these 16S sequencing tests, and then you’re into a million organisms you’ve never heard of.

DrDB:

But we’re looking at the ones that we know clinically matter. They are the ones that can cause problems when they overgrow and are more commonly present in states of dysbiosis, particularly if there’s overabundance, overgrowth, maybe low pancreatic exocrine output, low stomach acidity, and dysbiosis for various other reasons. And then we’re curating out a sub-component of those opportunistic organisms that the literature has identified either to be in association with, or even some of them causally related to various pathologies, mainly auto-immune conditions. So everything from auto-immune arthritities, rheumatoid arthritis, and ankylosing spondylitis, to Hashimoto’s, Graves’, and other things.

Lab-Based Research

DrMR:

Okay. I think that helps our audience clarify some of this, because there’s another question behind this which is what tripped me up in trying to validate various stool studies. When you go into PubMed or wherever, you don’t really see the functional medicine labs pop up by name. Part of that could have just been my oversight, but I think it’s important for people to understand that there’s this evolution of, in your case, the Luminex platform. In other platforms, like Doctor’s Data, they’re using the BioFire, and they’re using that, to my understanding, as is without the modification of the levels. That has swayed me away from using Doctor’s Data given the fact that, as we’re discussing here, it may not be the best practice for a functional provider to be using the same sort of analysis that they’ve probably already gotten from their gastro, given they’ve seen their gastro.

DrDB:

And Mike, it’s a good point, but let me point out that BioFire and Luminex are not clinical laboratories. They’re developing kits or technologies or platforms for clinical laboratories to use and buy. So they’re going through validation procedures, that involves research, to get the FDA to say, “Yes, these cut points align with a certain clinical state, so this is a valid platform.” Clinical laboratories don’t do that. Clinical laboratories do clinical testing for diagnosticians or either for healthcare providers or in many cases, contract research organizations, CROs. They’re doing laboratories for drug development and things like that for research, but the laboratories themselves don’t do the clinical research. Academic researchers, clinicians, and institutions do research on clinical disease states or clinical scenarios using specific types of diagnostic tests. But the laboratories themselves do not do research that you’re finding in PubMed and all that. That’s just not what we do; it’s not our business.

DrDB:

We do our internal research and have to look at our data all the time to maintain validity of our assays and to maintain CLIA certification. We get audited by the state, we get audited by CLIA. We have to be able to show all of that validation data. So the fact that it’s not in a public PubMed study does not mean that the data doesn’t exist. Clinical commercial laboratories are intentionally not going to publish the under-the-hood, down-and-dirty intricacies of their methodology and their validated data for the world to see. It would be like Coca-Cola publishing their recipe so Pepsi can see it.

DrMR:

Right, which makes it harder for someone like me to fact-check. But this is why I’m trying to explain this to the audience, because fact-checking is something that in this case involves a little bit more nuance, looking into some of the backstory, the technology, and having conversations with the labs.

TH:

You’re absolutely correct.

DrDB:

The other challenge you’re looking at, Mike, is if you’re looking at PubMed for data published in very conventional journals and so forth, they’re usually doing that research against a certain agreed upon formal disease state, a disease pathological diagnosis. So you’re looking at very different types of testing and end points that are related to overt pathology. When we’re dealing in functional and integrative medicine, it’s hard to get functional integrative medicine doctors, clinicians, or researchers to agree what it is that we’re treating, because by nature, it’s fuzzy around the edges. It’s not a formal, discrete diagnosis many times. And that’s why they’re sitting in that doctor’s office, because none of the specialists have helped them. So it can be a bit challenging, I agree.

Differences in PCR Technology

TH:

So just in general, though, when you’re looking at stool testing in functional medicine and integrative medicine laboratories, laboratories that work in our niche, ultimately what you’re looking at there is just comparing technologies. Those technologies are purchased. So in fact, what we do is no longer the Luminex platform. We used to use the Luminex platform, including their pathogens, but also our own developed assays. But we moved from that to what’s called qPCR or real-time PCR. If you just look at comparing real-time PCR, or qPCR, quantitative PCR, to say, regular PCR versus culture, versus microscopy, versus any other methods, that’s really where you get into the comparison of methods. Our lab versus another lab, if we’re both running qPCR, we still may be way, way better than them because we’re really good at this technology. So those nuances may exist between one lab and another on the same platforms, but that’s not even what we’re looking at here.

TH:

We’re really the only ones using qPCR, which if you look at research studies going back 20 years now, PCR, and more so now qPCR, is how all the studies are done. If you want to look and see how any organisms are being measured for any true research, around the world, it’s done by qPCR. If you don’t know how much of an organism is present, what good is knowing its presence, unless as Dave mentioned, you’re doing those other types where you’re just trying to characterize a large swath of organisms or something. But if you want to measure one organism, no matter what sample type it is, in research, academic research, and CRO research around the world, it is done by qPCR. So we’re using the best technology, and we have to then adopt that to unknown reference ranges because in the past we only had culture to go by for Morganella or pseudomonas, for example.

TH:

So we’re leading the way on this, but we do take research papers that suggest in diseases they see this much pseudomonas, or they might be measuring five or six different organisms and certain pathology. So we gather that information, but ultimately as the levels of an organism get high and get flagged high, they may be contributing to disease, and may be contributing to symptoms. Certainly our presence of dysbiosis patients who do not have dysbiosis or are otherwise healthy tend to have much lower numbers of overall opportunistic organisms and lower levels of those that are present. Almost everybody has a couple of these present all the time. It’s when you start to see eight or 10 of them present, and four, five, or six of them flagged high that you probably have a significant dysbiosis and a very stable pattern in the GI. So technology is qPCR versus culture versus microscopy versus, even PCR. That’s really how you can look at our laboratory rather than organism by organism. What’s our technology platform. It’s qPCR; it’s very well understood to be the best method for measuring microorganisms.

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Proper Utilization of Tests

DrDB:

As you alluded to Michael, you can go find discreet cutoffs using different specific platforms with various PCR technologies related to overt disease states. But when you start trying to extend this technology like we are for the functional integrative market, we’re using this best technology, this quantitative PCR technology, beyond just overt pathogens. We’re using them to actually quantitate the commensal organisms, the “good guys,” the keystone organisms, the probiotics, and the opportunistic organisms as well, along with stool chemistries and everything to paint as complete a picture as we can for the clinician to make good decisions. But the good decisions still have to involve the clinical contextualization that only the clinician would have dealing with that actual live human being in front of them, what their symptom profile is, what their story is, what their history is, and what their other lab tests may be that we don’t see.

DrDB:

We don’t necessarily know in the laboratory if they had a colonoscopy. Did they have endoscopy? Did they have a biopsy? Did they have a CLO test for H. pylori? Did they have breath tests? We don’t know any of that. That’s for the clinician to put all those pieces of the puzzle together, and we really encourage that they do so along with not relying on one organism or one number, but looking at pattern analysis and trying to make the best decision possible. Because we don’t want them over-treating; we don’t want them undertreating. We want them to try to get right in that pocket and try to get as many people better as possible. With the kind of sandbox we all play in in functional and integrative medicine, it’s not the easiest thing.

DrMR:

Sure, agreed. And I think aiming for that “Goldilocks zone,” so to speak, is really key, and it can be a double-edged sword. I think I’ve told the story on the podcast in the past where I don’t recall offhand the exact organism, but a patient came in and the prior provider got a GI-MAP on this individual, and it was fairly unremarked other than one, or maybe two dysbiotic organisms. And then she did a heavy-handed treatment with antibiotics, re-tested, and was still positive. And the provider said, “Well, you’re in really rough straits. You should probably just pray.”

DrDB:

Yeah, well see that’s just misapplying a test. Some practitioners actually complain, but us and maybe one other competitor are the most particular about who can even order our tests because we want them used right. So if you don’t come in with enough understanding and training to try to properly contextualize a lab test like this, you can go down rabbit holes like you’re talking about. But if you do have the right training and you understand them, I actually think in the right clinician’s hands with reasonable knowledge, it results in less treatment, because let’s talk about pathogens. Probably our highest positivity rate on pathogens is probably like C. difficile toxin A and B. They’re probably somewhere around 3% of samples. Enterohemorrhagic E. coli is probably somewhere hovering in that same area. The rest of them are often less than 1% and things like that. So we’re looking over lots and lots of data.

DrDB:

If you compare people who are treating, let’s just say based on a pathogen being flagged high, it would be the extreme minority of cases. We know there’s a lot of providers out there that don’t have a lot of in-depth training and don’t have a very sophisticated understanding of GI disease management, testing and so forth. The minute a patient says, “Oh, I have postprandial bloating,” or, “I have diarrhea every once in a while. I have alternating diarrhea and constipation,” or, “I have some bloating and distension,” whatever it may be. Boom, they’re off to a 4R program, because they took a functional medicine class or something. And that includes anti-microbial therapy with botanicals, volatile oils, whatever it may be.

DrDB:

Now, most of them are treating on symptoms alone. If you have the testing to go with it, you’re less likely to actually treat with the anti-microbial component. If you come back and there’s no pathogens and there’s maybe, one or two opportunists down at barely in the same exponent as the normal range, just a little bit over, and everything else looks good, the digestion absorption markers are good, and there’s nothing inflammatory, no zonulin, no calprotectin, everything else looks good, you’re probably not going to treat her. You’re going to treat maybe with a pro or a prebiotic or a dietary change or what have you. So I think the door swings both ways. You can take results, and if your aim is just to treat everybody, you’ll find a reason to treat everybody, but you’ll do that without the tests too, in my experience. And if you really read the tests right and can contextualize them, I think you’ll actually probably treat less.

TH:

Or make a better decision.

DrMR:

I just wish training was a little bit better in the field.

TH:

Absolutely. We try to put out, there are a number of webinars. Take H. pylori, we’ve barely scratched the surface on that organism. It happens to be my favorite organism because it’s more capable of doing a lot of different things. For example, Dave was saying that or making a better treatment choice, which, people say, “Well, I just could’ve sworn the patient had candida.” Well, no, they had pseudomonas. It may have very similar symptoms, pseudomonas in the mid gut. It may have a lot of the same symptoms. So it’s a different treatment protocol. Pseudomonas is probably a lot easier to treat than candida overgrowth. It is very significant to get and interpret the results for that patient in front of you. That’s our biggest takeaway or point that we make with new clinicians.

TH:

There is an understanding of our tests. You’re going to see positives or presence of organisms more routinely than if you were doing a culture test, because that culture test is only if it grows in the laboratory. Well, some things grow really well in the laboratory and some things don’t. So talk about grading scales, if you really want to talk about a difference in test. I’ve got a piece that I’ve done that says what’s a 4+ pseudomonas? What does that really mean? What is a 4+ growth? That’s a growth. Quadrants are on a plate, and if you get some growth into the fourth quadrant and you call it a 4+. Well, did the patient have 20,000 cells per gram, or did the patient have 96 cells per gram and just happen to have a colony grow up into the fourth quadrant so they call it a 4+?

TH:

Well, that’d be e^0, less than e^1. Is that clinically significant if you did a comparison? Probably not. We can’t say for sure, but we would suggest that it’s not. You know, 9.6 e^0 versus four plus. Now, the same organism, same amount, same stool, that’s how it could come out. And in a culture with a 4+, you’d be treating pseudomonas all day long and that might not be the problem. So those are the reasons why we do what we do, and why we use qPCR. It’s to give you an absolute amount of an organism so that you can better make decisions on where to go with a particular patient.

The Dysbiosis Index

DrMR:

That begs the question about arming clinicians with a better way to interpret this gray area section of dysbiosis. This is one of the things I find appealing about the dysbiosis index by the GA-MAP out of Norway. I know you guys are not incorporating that, but you have your own thoughts about how your dysbiosis profile operates, but high-level, what’s appealing again about the dysbiosis index is it gives me a “5/5 danger zone,” or, “1/5, things look pretty good,” and it takes some of the pressure of interpreting the different organisms, the number of, the elevation of, and the pattern. And at least that has appeal for the clinicians who especially might be newer into practice, and still haven’t had six months to years of seeing test after test and developing some of this pattern recognition. So what do you guys think about how to interpret it and any high-level remarks in juxtaposition to the GI-MAP from Norway’s dysbiosis index?

DrDB:

I understand the appeal. People want an easy, binary answer from a test. Yes, they have it. No, they don’t. Yes, I treat. No, I don’t. GI just doesn’t work like that. It’s such a complicated environment, and these things like that index, it’s done on a small number of organisms on a very technological methodology-specific platform. It’s only specific to a variant of IBD, of specific inflammatory bowel disease of a certain subset or variant. It’s certainly not an index of general dysbiosis or every single thing.

DrMR:

Well, they did validate distinction between an IBS cohort and an IBD cohort in one paper. Albeit in only one paper, which is really important to state.

DrDB:

I took IBD out of it because that’s an overt pathological diagnostic.

TH:

What do you weight the most? Do you say, “Oh, there’s an overt pathogen present. Now that’s a nine.” Well with that overt pathogen, you may asymptomatic, or you got food poisoning and it goes away on its own. And so is it really part of the index? Do we weight candida higher than we weight pseudomonas than we would weight citrobacter? You really can’t go that way because you really need to take into account, “Are there imbalances in normal flora? Yes. Are there overgrowths in opportunistics and yeast or something like that? Yes. What do the health markers look like? Hey, we’ve got a low elastase and positive H. pylori.” Well then to me, that one would be a 10 right off the bat, because now you have hyperchlorhydria, either caused by or allowing H. pylori to grow, which is then going to lead over time to other things.

TH:

So it is way too subjective. We thought about it; we worked in a lab before where we did an index. It’s just, you can’t include enough of the patient population appropriately in that index where you either leave some people out or you pull other people in who don’t belong based on the fact that there are multiple different factors playing into each patient in front of you. So do you see imbalanced to normal flora highs and lows there? Yep. And opportunistic overgrowth? Yep. Symptoms? Yes. Then score ’em high, right?

DrMR:

Well, one thing I’d like to just plant the seed on now here quickly, and this would definitely be something we’d want to have a follow-up call regarding, now at the Center that we have five clinicians all treating in the same model, it seems that we would at least theoretically have a high enough end to try to assign some sort of scoring system that could be applied to the data here. One of the things I think can add the most value in any system is taking the thought processes in your head and mapping them out into a mathematical process, so to speak, because then that process can be assisted with machine learning or computer learning. And so that’s something I’d like to plant the seed here. I think if we really put our heads together, we could come up with a scoring system. And it might even be algorithmic, to your point, where when you have dysbiosis and pathogens and inflammatory markers, some of those are weighted differently depending on what you see. There might even be an order of operations that is given in that. Maybe it’s not just a score, but it’s a score plus an order of operations.

DrMR:

So anyway, I’ll plant that seed here, but that’s something I would like for us to try to work together regarding, because if we can take the thought algorithm from a few really good clinicians and map that into technology, now average clinicians can perform above average. I think that’s really an aim.

TH:

It is; I agree with that.

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TH:

One thing we’re doing, by the way, Michael, is we are building a database just for help with interpretation that will include some of those things. But we’ll probably base it a lot off of the different types of dysbiosis. Do you have inflammatory dysbiosis? Do you have insufficiency dysbiosis? Those are actually fairly well-characterized in literature, and on our website we already have a really good webinar on it, and a compendium piece to help say, as Dave alluded to earlier, these organisms are more associated with inflammatory dysbiosis. So we may go and score it that way. And then within each of those categories you could increase, or be normal, or increasing in that level to at least point the path towards what to recognize, what to look for, what to weight the most within this particular patient.

TH:

But again, as much as we can do that, we would still then have to highlight things that are outside of that characterization in another way. And we will do that. I think our conversation here was just about how having a single index score is not really appropriate.

DrMR:

Too simplistic, probably.

DrDB:

It’s just myopic when it comes down to what we’re trying to deal with, but it could be helpful if done. I agree, Michael, one of the challenges we’ve discussed offline a little bit in doing the kind of research you’re talking about is when it’s multi-center, there’s lack of agreement on what is IBS to functional medicine doctors and integrative medicine, and even conventional doctors. It’s a very fuzzy, around-the-edges diagnostic construct.

DrDB:

And then we get into a million other things that may not be IBS, but are some functional bowel issue or a constellation of bowel complaints or other types of complaints. It’s hard to get agreement that we’re all looking at the same thing. So if we don’t know we’re looking at the same entity in different individuals, how do we compare the data on the diagnostics and/or treatment interventions? That’s the real challenging part. So having a contained center, like you’re talking about, where you have all the providers there, where they can meet regularly and they can agree on what are the rules of the game very tightly, and have a study administrator that’s making sure everything is conformed to, that’s exactly what we need to do. But as a laboratory, we need the partners who bring that, who can offer that, who have the clinicians, who have the investigators who want to do it. We’re very eager.

DrMR:

It’s a lot to ask you guys to do that.

DrDB:

We’ll do the testing; we’ll be involved with it.

TH:

Legally, we can’t. We’d have to hire somebody to do it because even with MDs on staff, we cannot. As a laboratory, they have to wear the laboratorian hat. They can’t then go do the studies from collecting patients. That’s not allowed. So yeah, there’s some questions there.

DrDB:

And Michael, we had a study on SIBO and lower dysbiosis, kind of what you’re aiming at ready to roll at Johns Hopkins with Gerry Mullin, and it was tabled by COVID because they were all called into bedside service.

DrMR:

Frustrating, I’m sure. Well, that’s something I’m excited about. And also because one of the things that I see more being published regarding, but they’re still very far to go, in my opinion, is looking at non-GI indexes, like overall well-being, fatigue, perhaps cognitive measures, just so we can quantify, as I was, someone who had a GI pathogen, E. histo, but had no GI symptoms, and it solely manifested as brain fog, fatigue, insomnia, and depression. And that’s where I think we can really start to enhance the level of importance in the gut, when we start documenting that these people came in maybe with only some mild bowel irregularity, but their fatigue score and their depression score markedly improved via a peer-reviewed symptom survey index pre/post treatment, and that also correlated with this objective pamphlet.

DrDB:

Yeah, but that takes big data crunching Michael, because you’ve got to power it to the point where you’d even pick up those correlations. Because for instance, Entamoeba histolytica, that’s what you you said?

DrMR:

Right. And that would be nice, you’re not going to see many of those, of course.

DrDB:

Well, I got data right in front of me. 4,080 tests on this sample, 0.98% positivity rate.

DrMR:

That’s very, very rare. So the E. histo, specifically, is a bad example, but in terms of the dysbiosis and some of these more common organisms, like H. pylori, that’s where I think we can start showing some correlation.

DrDB:

And we’re more than eager to do that whenever you’re ready to put it together, and we’ll help put it together. But we also want it to be very third-party where, we’re doing the analytics, but we don’t have any say over…

DrMR:

Sure. There should be a strong partition in between the two. Okay, well, I think that was a great overview to clear up some of the misconceptions. In closing, anything that you guys want to add?

TH:

Well, ultimately our website is diagnosticsolutionslab.com. Under “Tests” go to “GI-MAP,” and you can find a lot of additional information maybe surrounding H. pylori, like I brought up. There’s podcasts, writings, and webinars on it. Dysbiosis, where we were talking about an index, we have pieces specifically on the different types of dysbiosis. And I think it’s important just to overall learning is to understand there are patterns that emerge with different types of dysbiosis. And if you want to get down and dirty into the technical of what we do, there are pieces on that as well. So once you’re on our website, you can just go under “Tests” and just pick “GI-MAP,” and then you can go from there to get more information about some of the things I mentioned. But other than that it’s great.

DrDB:

Also under the “Clinicians” tab, you’ll see “Learning – Resource Library,” and you’ll have the whole history. We’ve just done countless, webinars, white papers, published papers, whatever it may be on these topics that we’re talking about, including responses on some of the controversies that we talked about on PCR, levels of positivity and differentiation between organisms and sensitivities and all of that. So you can sit there and dig through that for a couple of months, probably.

DrMR:

Alright, plenty of postdoc reading for people if they want it there. Awesome. Well guys, thank you so much. It was really reassuring to me that after that initial podcast, where I admittedly was a little bit upset in that I couldn’t find the validation data, there were a few things there I really needed to learn. So I wanted to right the record here. I’m glad that we had a chance to do it, and I’m grateful to you guys for taking the time and speaking with us, and also pioneering some of this how do we help test in that gap between healthy and overtly ill at a GI doc’s office with some of the testing that you’re doing. So I just really appreciate it. I’m looking forward to hopefully some future collaboration in the future.

TH:

Thanks for having us, appreciate it.

DrDB:

Love to. Thanks, Michael. Appreciate it.

Outro:

Thank you for listening to Dr. Ruscio radio today. Check us out on iTunes and leave a review. Visit DrRuscio.com to ask a question for an upcoming podcast, post comments for today’s show, and sign up to receive weekly updates. That’s D R R U S C I O dot com.

 

➕ Dr. Ruscio’s Notes

Have PCR-based stool tests been validated?

Do they outperform traditional stool testing? 

  • Yes & yes – mostly in a setting of acute GE/acute symptomatology and r/o IBD
  • BioFire, Luminex, Verigenen, etc… FDA ranges 

 

Evidence 

  1. MA/SR. https://pubmed.ncbi.nlm.nih.gov/33147077/.
    • BioFire Diagnostics vs. stool culture, 14 cohort studies : 
  • When considering only studies with control group (microbiological examination of the stools performed by other methods), FilmArray identified at least one pathogen in 48.2% of patients versus 16.7% when using comparative diagnostic methods. 
    • FilmArray GI panel was positive in 39.7% of patients suffering from gastroenteritis. This proportion has to be mitigated by the carriage rates of identified organisms. Ultimately, restricted ordering of molecular panels to those patients who might benefit from specific treatment could provide medical value by swift identification of the pathogen and more targeted therapy.

 

  1. Observational. https://pubmed.ncbi.nlm.nih.gov/33386740/.  
  • “In a retrospective cohort study of outpatients with IBD presenting to NYU Langone Health with flare from September 2015 to April 2019, we compared patients who underwent stool testing with GI PCR to age-, sex-, and IBD-subtype-matched patients who underwent culture and ova and parasite exam (conventional testing). … We identified 134 patients who underwent GI PCR matched to 134 patients who underwent conventional testing. Pathogens were more frequently identified on GI PCR (26 vs 5%; P < 0.01). We found that GI PCR was associated with less escalation in IBD therapy (16 vs 29%; P < 0.01) and fewer posttest endoscopies (10% vs 18%; P = 0.04), with no differences in IBD outcomes. On multivariate analysis, testing with GI PCR was associated with an odds ratio of 0.26 (95% confidence interval, 0.08-0.84; P = 0.02) for escalation of IBD therapies.”

 

  1. Observational. https://pubmed.ncbi.nlm.nih.gov/30651393/.
  • We performed a retrospective comparative analysis of 9,402 patients who underwent testing with the FilmArray GI panel from March 2015 through May 2017 and 5,986 patients who underwent conventional stool testing from December 2012 through February 2015. 
    • GI panel was positive in 2,746 exams (29.2%) compared with 246 exams (4.1%) with conventional testing. Within 30 days following stool testing, compared with patients who received a conventional stool test, patients who received a GI panel were less likely to undergo any endoscopic procedure (8.4% GI panel versus 9.6% stool culture, P = 0.008) or any abdominal radiology (29.4% GI panel versus 31.7%, P = 0.002)
    • Within 14 days following stool testing, patients who received a GI panel were less likely to be prescribed any antibiotic (36.2% GI panel versus 40.9%, P < 0.001). The implementation of multiplex PCR stool testing was associated with a reduction in the utilization of endoscopy, abdominal radiology, and antibiotic prescribing.”

 

Have FM PCR-based tests been validated? 

    • Seemingly no, but mostly yes. 
    • FM labs are/have
      • DD using other platforms which have been validated 
      • DSL is using their won platform which have been validated against previously validated platforms, and suited by CLIA.  
  • Clinical Laboratory Improvement Amendments (CLIA) regulate laboratory testing and require clinical laboratories to be certified by the Center for Medicare and Medicaid Services (CMS) before they can accept human samples for diagnostic testing.
    • DD is/was using BioFire
    • DS used Luminex now using their own version 
  • Why did DSL create own ranges?  
    • Wanted to modify cut-offs, may better apply to a setting outside acute GE.  
  • Opportunistic – How do we interpret? 
    • Some trace amount normal (Tony), high enough level 1,000 cells/g – could suggest colonization.  Is this where flag? 
    • We will attempt to provide scoring data, on our list of research agendas for the future

 

GI-MAP, detection vs positive

  • Detection is any detectable amount
  • FDA cutoff is higher than what DSL deems a positive; same for pathogens, no range data for dysbiotic markers

 

Do FM PCR-based stool tests miss the optimal balance between specificity and sensitivity, do they suffer from unacceptably high false positives? 

  • No official data? 
  • DrR: 
    • They could, and likely do for unbridled providers
    • They may also help provide rationale for further GI work, caveat a + does not = Habx/Abx exclusively.  
    • We are hoping to produce data 

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