The Omega-3 Index and Stroke Risk

OmegaMatters: Episode 31

Hosts: Drs. Bill Harris & Kristina Harris Jackson

Guest: Dr. James O’Keefe

Background and Key Takeaways:

Dr. James O’Keefe is a preventative cardiologist at St. Luke’s Hospital in Kansas City. He’s also the director of the Duboc Cardio Health and Wellness Center and director of Preventative Cardiology at St. Luke’s in Kansas City and the Mid America Heart Institute. Dr. O’Keefe has also joined the Fatty Acid Research Institute (FARI) to dig deeper into some of the questions he encounters in the clinic. In addition to that, he’s an excellent communicator, a regular on Dr. Radio, has been on The Drive, which is  Peter Attia’s podcast and has given several TED talks and written numerous books. So today we’re going to talk about some of the research In this episode, Drs. Harris and Jackson speak with Dr. O’Keeffe about research he did with FARI around Omega-3s/Omega-3 Index and stroke. For more information on OmegaMatters, visit: https://omegaquant.com/omegamatters-broadcasts/

 

 

SHOW TRANSCRIPT

Dr. Kristina Harris Jackson: Welcome to Omega Matters, where we talk about all things Omegas. I’m Kristina Jackson. This is Bill Harris, and today we’re welcoming back Dr. James O’Keefe. He’s a preventative cardiologist at St. Luke’s Hospital in Kansas City. He’s also the director of the Duboc Cardio Health and Wellness Center and director of Preventative Cardiology at St. Luke’s in Kansas City and the Mid America Heart Institute. Dr. O’Keefe has also joined the Fatty Acid Research Institute to dig deeper into some of the questions he encounters in the clinic. In addition to that, he’s an excellent communicator, regular on Dr. Radio, has been on the Drive Peter Attia’s podcast and has given several TED talks and written books. So today we’re going to talk about some of the research Dr. O’Keeffe did with FARI around Omega-3s and stroke. So welcome back and thanks for coming on to talk about this paper.

Dr. James O’Keefe: Thanks, Kristina. [00:02:00] It’s fun to be discussing this topic with you and your father, Bill, the “codfather”.

Dr. Kristina Harris Jackson: I think, well, the last time I saw you, we were at a conference in France, and I believe you did do a presentation about this topic, but the paper wasn’t quite published yet. Is that-

Dr. James O’Keefe: Right.

Dr. Kristina Harris Jackson: Yeah, it was great to have that conference in person again. I think that was the first time since Covid, so [00:02:30] that helps.

Dr. James O’Keefe: Delightful spot.

Dr. Kristina Harris Jackson: So this paper we’re going to talk about is about stroke and omega-3s, and I’m going to let you guys take off on why you decided to do this study.

Dr. Bill Harris: Well, yeah, what do you think? Why do we care about Omega-3 and stroke?

Dr. James O’Keefe: Well, stroke like dementia, these things that incapacitate us mentally are understandably among our biggest fears for most people along up there with cancer and heart disease, it’s still the number one killer, but people aren’t that afraid of it, maybe because it’s manageable and whatnot, but you start talking about stroke and ending up in a wheelchair, in a diaper, can’t talk, that gets their attention. And stroke still is among the leading causes of death and disability worldwide, in the top two or three causes it because it can be so catastrophic. And the thing is that we’ve made a lot of progress. It’s controlling blood pressure and diabetes and not smoking and reducing LDL cholesterol in people that have atherosclerotic cardiovascular disease, we like to abbreviate ASCVD, but there’s a lot of biologic plausibility that you and I know about and have been writing about and talking about and doing papers on for decades of why Omega-3 might reduce risk of stroke. Bill, you probably could touch on those, right, the effects.

Dr. Bill Harris: You mentioned an interesting thing there. Are the risk factors for stroke the same as they are for heart attacks?

Dr. James O’Keefe: Not exactly, because there’s a subset of strokes that’s hemorrhagic stroke and that is not due to atherosclerotic cardiovascular disease. Number one, the lion’s share of strokes are due to ASCVD, but then there’s also another substantial part of strokes, ischemic strokes that are due to embolic phenomenon like atrial fibrillation, a really important and growing cause of stroke. So they overlap substantially. Hypertension, dyslipidemia, smoking, obesity, sleep apnea, family history, these kinds of things that we really focus on a lot in the general field of preventive cardiology. But there’s a saying that goes something like what’s good for the heart is good for the brain. There’s huge overlap here, and it’s certainly true with Omega-3 as it turns out. This study is a case in point on that.

Dr. Bill Harris: Well, you mentioned Afib. There’s been some noise about Afib in the Omega world lately. Did this paper play into that at all?

Dr. James O’Keefe: Yeah, it sure does. It was one of the reasons you and I decided to really do this study is because there’s [00:06:00] this very complex and nuanced issue about the effect of Omega-3 on atrial fibrillation, and probably at high doses like pharmacologic doses, two, three, four grams a day of EPA plus DHA, we see an increased risk of atrial fibrillation probably because in part due to augmented vagal tone and bradycardia and susceptible people like folks who have sick sinus syndrome and slow heart rates [00:06:30] or untreated sleep apnea or athletes who are doing very large volumes of endurance exercise.

But the thing is with atrial fibrillation, low dose Omega-3 probably reduces risk of atrial fibrillation, which is just really complex and most people don’t know what to make of Omega-3 anyway. And then you put this nuanced thing, but [00:07:00] we have a paper in press right now looking at that and explaining it. It’s probably low dose vagal stimulation is antiarrhythmic. It prevents sudden death, it reduces risk of atrial fibrillation and it improves health and wellbeing. And I mean, it’s good to have high vagal tone, but really high vagal tone can cause trouble, especially in susceptible people. And that’s why you probably see this biphasic, bidirectional dose dependent risk of atrial fibrillation.

[00:07:30] But in any event, the dreaded side effect consequence of atrial fibrillation is stroke, and these are big strokes. The left atrial appendage is about the size of your little finger. And so when you go into atrial fibrillation and the atrial become, they’re basically just sitting and quivering and not contracting, you get stagnant blood in this nook and crannies of the atria like the left atrial appendage and these [00:08:00] clots can form that are a centimeter big, and when they flip out of there, about 20 or 25% of the blood goes to the brain and this clot gets filtered out in the brain and it’s like a really, really catastrophic stroke.

So atrial fibrillation for a good reason is, and we’ve seen it more and more all the time with an aging demographic and more obesity and diabetes and sleep apnea, I mean atrial fibrillation, our hospital service is full of it. [00:08:30] So you’d guess that if you might surmise that if high dose of Omega-3 increases risk of atrial fibrillation, then it would increase risk of stroke too. But that’s not what we found. We found the opposite. When you see paradoxes in nature, lots of times that’s like a key to unlocking important knowledge [00:09:00] that we hadn’t appreciated before. And I think this is an unfolding story that I think is really important.

Dr. Kristina Harris Jackson: Yeah. And I need to jump in and say the name of the paper so people know where to go find this and what we’re talking about as we get into the nitty-gritty. So the paper was published in the journal Stroke and it’s entitled Omega-3 Blood Levels and Stroke Risk, A Pooled and Harmonized analysis of 183,291 [00:09:30] participants from 29 perspective studies. So we’ve already covered stroke and the severity of it and the risk factors and why you guys really wanted to look at the relationship between Omega-3 blood levels and actual stroke, the outcome that is even more severe than Afib. So how did you go about answering this question, finding out if there is a relationship between higher [00:10:00] blood levels and risk for stroke?

Dr. James O’Keefe: Yeah, the blood levels of Omega-3, particularly EPA and DHA, which are marine Omega-3s that you really can only get by swallowing them, these are not… I mean, we can make small quantities of them from the ALA, alpha-linolenic acid, but for the most part, this is a function of dietary intake [00:10:30] and/or a supplement, or there’s the drug versions of Omega-3 too. There’s two or three branded Omega-3 products for real high dose usually used for triglyceride lowering. But the point is that the levels of these correlate really strongly with outcomes. And Bill and I were just talking about this the other day. Lots of times [00:11:00] you can give two different people the same dose of Omega-3, and it’ll have very different effects on their levels of Omega-3. And we’re finding that it’s the levels that really correlate with the improved outcomes and the changes in biology.

So we looked at, and this is a consortium, the FORCE Consortium that Bill put together along with Dariush Mozaffarian, and it’s about 60 different centers that have [00:11:30] prospective ongoing observational studies where they have baseline levels of Omega-3. And then in this instance, 29 of the centers had data that was available and pertinent to this study. And then we had 14 years of follow-up. So it’s really, really powerful data. I mean, you got 183,000 people followed for 14 years, and you look back on their baseline Omega-3 level [00:12:00] and correlated with things like the risk of stroke, ischemic stroke where a vessel is blocked off or hemorrhagic stroke, which is about, as I mentioned earlier, about 10% of strokes are caused by bleeding into the brain where a blood vessel ruptures that goes along with other things like uncontrolled hypertension or bleeding abnormalities or inherent aneurysms in the brain.

But in any event, we looked at this and because there’s many [00:12:30] different ways to measure Omega-3 levels, we basically standardized these 29 trials by breaking the EPA and DHA and total Omega-3, EPA plus DHA into Quintiles. So the people in the top Quintile had the highest Omega-3 levels and the bottom Quintile had the lowest. And then we correlated outcomes based on the Quintiles. And I don’t know if we [00:13:00] can show the figures from the study, but they are pretty striking. The Quintiles show a dose dependent reduction in risk of stroke, ischemic stroke, in particular with about a 17 to 18% reduction in ischemic stroke in the top Quintile compared to the lowest Quintile and the hemorrhagic stroke really showed no effect. The highest Quintile versus the lowest Quintile, there was [00:13:30] no statistically significant change in risk of hemorrhagic stroke. So yeah, so we think that it’s like… Well, it’s without question, the largest, most comprehensive observational epidemiological study looking at the question of Omega-3 levels in stroke. And it came up with pretty darned unequivocal results suggesting that a higher level of Omega-3 is associated with a lower risk [00:14:00] of stroke.

Dr. Kristina Harris Jackson: And was the highest Quintile, I guess, at least for the red blood cell, maybe you’re going to be showing some things. What Omega-3 index was that about? Was that about 8%?

Dr. James O’Keefe: Bill, do you want to chime in on that?

Dr. Kristina Harris Jackson: Yeah.

Dr. Bill Harris: Yeah, and I think we’re not sure we did it in this study, but I know we did it on the total mortality study, which is the same general idea, the same group of studies and [00:14:30] I believe the top quintile was roughly 7.8% Omega-3 index.

Dr. Kristina Harris Jackson: That’s average?

Dr. Bill Harris: Yeah, it was the average of the median one of the two.

Dr. Kristina Harris Jackson: Yeah. Okay.

Dr. James O’Keefe: And the lowest quintile would be about 3% or three and a half percent.

Dr. Bill Harris: Yeah, three and a half, below four and around eight. So it’s as we proposed 20 years ago, those markers seem to be the extremes.

Dr. James O’Keefe: And the average adult in America, [00:15:00] I believe has an omega index of about 5.3 or 5.2.

Dr. Bill Harris: Yeah, 5.5, between five and six, somewhere in that area.

Dr. James O’Keefe: And so you can see there’s a lot of room for improvement here. I think 90% of people in America are not in that top Quintile. I mean, I guess, based on this study you’d say 80% aren’t in that top Quintile because by definition these are the highest 20% of people. But yeah, if we use 8%, I mean it does [00:15:30] seem like a really solid number that keeps coming up. And it’s about the average omega index for Japanese population, for example, which has a very high intake of fish and seafood and also a very low incidence of ASCVD events. They do have a higher stroke risk traditionally, but it was because of high smoking rates and uncontrolled hypertension from too much salt in the diet. But their stroke risk has been coming [00:16:00] down in the last few decades substantially as they cut back on smoking and control their blood pressure.

Dr. Bill Harris: Are you all seeing this figure from the paper?

Dr. Kristina Harris Jackson: Yeah.

Dr. Bill Harris: Okay. Can you explain this to the viewer, James?

Dr. James O’Keefe: Well, it just shows that this is the FORCE plot where a neutral risk would be right in that vertical line in the middle, and so that’d be the reference list and that would be the Quintile one, and [00:16:30] then going to the left, that’s a reduction in risk and you can see that the reduced risk is for total stroke down to Q4 and Q5 are about the same there, the same reduction. And then ischemic stroke is where you see that even a little bit more because that’s where the action is. That’s what the Omega-3 does. It reduces ischemic stroke and it doesn’t reduce the [00:17:00] hemorrhagic stroke, but it doesn’t increase it either. But you can just see again that you’d want to be in the fourth or fifth Quintile to get the full benefit there on that.

Dr. Bill Harris: And so that last set, the hemorrhagic stroke, the estimates are for benefit actually down there, 0.9 roughly. It’s just that there’s so few of them, like you said, like 10% of strokes are hemorrhagic. In this study, the number of people [00:17:30] was small so we have a wide confidence band and we have to say non-significant, but certainly the trend is for improvement in risk, which is why is that comforting particularly? I mean, was there something?

Dr. James O’Keefe: Well, as you know, the first hints that Omega-3 are good for your heart came from the Greenland Eskimos with Bang and Dyerberg publishing that article in the New England [00:18:00] Journal of Medicine probably 50 years ago or more. And they noted that there was these Eskimos which had the high levels of these unusual fatty acids, the EPA and DHA, they weren’t really household names, but at that point that they had a markedly reduced risk of myocardial infarction. They just didn’t really see coronary disease in this population. But they did see strokes actually. Now these Eskimos, you can correct [00:18:30] me Bill, but I believe they were consuming upwards of 15 or 20 grams of EPA plus DHA per day.

Dr. Bill Harris: Well, no, wasn’t quite that bad or that much. I think it was like seven or eight in one of Dyerberg / Bangs paper, but still that’s-

Dr. James O’Keefe: The average American consumes a hundred milligrams, so.

Dr. Bill Harris: Milligrams, right?

Dr. James O’Keefe: Yeah, hundred milligrams, so-

Dr. Bill Harris: And of course, the Eskimo lifestyle, it ain’t all about Omega-3. I mean, smoking, [00:19:00] exercise, not good, a lot of things, infections and anyway, so.

Dr. James O’Keefe: Yeah. But they had some increased-

Dr. Bill Harris: Bleeding.

Dr. James O’Keefe: Risk of death from hemorrhagic stroke, and so we were worried about that. And Omega-3 does have some anticlotting mechanisms and reduces platelet aggregability and it can increase risk of bleeding, especially, I mean especially even at modest doses at one or 2000 [00:19:30] milligrams a day of EPA plus DHA, especially if you’re taking it with aspirin, it can increase bruising after say, getting your blood drawn or bumping into something. But yeah, we don’t really at doses, I mean, I think, Bill, you did a paper that said that you don’t really see pathologic bleeding with Omega-3 until you get into the 7,000 milligrams a day. Is that about right?

Dr. Bill Harris: Something like that. I think that’s where they… Right, and even the package insert for Lovaza and Vascepa [00:20:00] say there’s no increased risk for clinically significant bleeding for Omega-3, even when you’re taking blood thinners.

Dr. James O’Keefe: Yeah. And there’s that OPERA study, which is a randomized trial of Omega-3 for trying to prevent Afib around the time of open heart surgery. It was neutral with respect to that. They used about 2000 milligrams of EPA plus DHA, and it was a sizable study, I think it was like 700 people, and they saw a substantial [00:20:30] reduction in need for transfusion and real serious bleeding in the people that got the Omega-3 around the time of surgery. It’s very counterintuitive and full disclosure, we don’t recommend high dose Omega-3 preoperatively. In fact, most surgeons insist on holding the Omega-3 for a week or two before surgery, but I think that’s probably not really warranted, but-

Dr. Bill Harris: Yeah, I agree.

Dr. James O’Keefe: Kind of a superstition.

Dr. Bill Harris: Yeah. Well, as we wrap [00:21:00] this up, do you think this new paper on stroke is going to move the needle in the cardiology community?

Dr. James O’Keefe: I think it’s probably the most compelling data out there. It’s an observational study, so you can’t really draw firm conclusions on causation. But on the other hand, as you know, the REDUCE-IT study, which used four grams of EPA, about four grams, in people [00:21:30] with high risk for ASCVD, it reduced overall MI stroke and cardiovascular death by about 26%. And if you look specifically at the stroke, it reduced at about 29% or so. And strangely, it also in that study, increased risk of atrial fibrillation, the four grams of EPA, increased the risk of atrial fibrillation by 30% or 35%. [00:22:00] And the meta-analysis shows that it does too at high doses. At one gram of EPA plus DHA, there might be a marginal increase or probably a neutral effect.

Our meta-analysis of observational study pulled analysis, and the four showed that 600 milligrams a day, 6 or 700 milligrams a day, there was actually a small reduction in risk of atrial fibrillation. I think it was about 15% or so. But in other words general, [00:22:30] there’s prospective randomized controlled data showing that it looks like it reduces risk of stroke as well. There’s a lot of other reasons to take Omega-3. Getting back to the brain benefits, I mean, I think, Bill, you did an observational study on the Framingham cohort showing that high DHA intake being in the top Quintile or so was correlated with a 49% reduction in Alzheimer’s disease.

Dr. Bill Harris: [00:23:00] Yeah, you’re right.

Dr. James O’Keefe: And again, the biological plausibility is good. I mean, they have anti-inflammatory effects, which is good for the arteries and good for the brain. We talked about the antiplatelet effects, they reduce triglycerides. They also are a really important component of the cell membranes and the cells that are electrically based, like the neurons and [00:23:30] the myocardial cells would be especially the ones that you’d expect to benefit from, like getting those DHA levels, especially to a lesser extent, EPA levels, up to replete, good high levels to just improve membrane performance and communications between cell to cell and pliability and resilience. I mean, [00:24:00] there are good studies showing that Omega-3 levels correlate quite strongly, inversely with brain shrinkage with age, that if you want a nice plump, healthy, youthful brain, you want to keep your Omega-3 levels high. People with Alzheimer’s and other causes of dementia, like multi-infarct dementia tend to have shriveled up brains, which is definitely not ideal.

Dr. Bill Harris: Yeah, hopefully we can get into that one of these days. Anything else, [00:24:30] Tina, we wanted to talk about?

Dr. Kristina Harris Jackson: I guess to finish up, we aren’t doing medical advice here. We’re talking research, but it’s still a complicated story. So how do you talk to your patients about Omega-3s generally? 

Dr. James O’Keefe: Well, I mean, one of the things that Bill and I were just talking about this week is that this study does emphasize the importance of knowing your level. This is a simple test, and Omega quant [00:25:00] is, in my opinion, the gold standard for knowing that whether you’re a young woman who’s thinking about getting pregnant or are pregnant or you’re somebody with heart disease or high triglycerides or somebody who wants to avoid a stroke, know what your levels are and if you are like your average American, you need to be taking probably a thousand milligrams a day of EPA plus DHA, or if you’re in the lowest quintile, more like 1600 milligrams of EPA plus DHA per day. I think there’s a lot of good [00:25:30] reasons for that. And my wife Joan, is a smart dietitian and one of her missions in life is to improve mental health by just getting the Omega-3 levels up to normal. She argues that you don’t even know what… There’s all sorts of people who are depressed or angry or forgetful or all sorts of things.

And the mental health in America has almost never been worse since the pandemic and all this rhetoric and [00:26:00] confrontational, all this antagonism. There’s really good studies showing that things like mood, and we’re doing a study right now correlating Omega-3 levels inversely with suicide and suicidal ideation. So you don’t even know if a brain works well until you get the Omega-3 levels up there. And that’s good for mental function. It’s good for reducing cardiovascular risk, reducing stroke risk. It probably is associated [00:26:30] with lower Alzheimer’s. And yeah, and it’s inexpensive. But interestingly, in the randomized trials, actually the levels attained are more predictive of good outcomes than the therapy assigned. Some people don’t take it, some people don’t absorb it. I mean, whatever else, it’s like blood pressure. You don’t just give somebody a blood pressure med and say, “Okay, you’re good now.” You need to know that the level you’re shooting for is where you’re [00:27:00] at.

And that’s why I think with the Omega quant, know what your level is, get it up to 8%, and I take Omega-3, I eat fish most days, and in recent years I’ve been increasingly eating a Mediterranean diet that’s real high in healthy fat, like extra virgin olive oil, Italian polyphenols, and lots of nuts and lots of avocados and fatty fish. And my omega level, omega index was like [00:27:30] 11% or something. But then it started dropping and I realized I had to increase my Omega-3 intake just because I think it’s because, and I don’t know Bill if you’ve seen this before, but I think it’s because I eat such a diet that’s high in fat. I mean, it’s good fat. I don’t eat a lot of saturated fat, but I think it’s just a matter of balancing off all that other fat. It’s not Omega-3. And so in any event, I’m taking more Omega-3 now than I was before. I take about 2000 milligrams a day.

Dr. Bill Harris: So your index is up around 10 or 11%?

Dr. James O’Keefe: [00:28:00] Yeah, it’s traditionally been between nine and 11%, and the last one was more like 8%. Yeah.

Dr. Bill Harris: Yeah.

Dr. Kristina Harris Jackson: Yeah. I mean that’s all [inaudible 00:28:14]-

Dr. James O’Keefe: Where do you keep you guys’ levels?

Dr. Kristina Harris Jackson: Mine bounces, [inaudible 00:28:20]-

Dr. Bill Harris: I’m around 10, but I hope. I just did another test today. I’ll find out. It’s been a while.

Dr. Kristina Harris Jackson: Yeah, I haven’t tested in a bit, but I’ll be at eight, between six and eight, depending on if I’ve [00:28:30] forgotten my supplements, like if I run out of them. That’s what happens and then I drop and I remember to get them and then it gets back up.

Dr. James O’Keefe: Well, I was getting, being a cardiologist, I’m like a cardiac neurotic and I can feel my heart beating. And so I was noticing some premature atrial contractions, which [inaudible 00:28:50] bleeds from the top of the heart. And so I got all checked out from one of my colleagues and stuff. My heart’s fine, but I do exercise a lot and I’m like one of those poster boy for [00:29:00] somebody who could get the atrial fibrillation for too much exercise. And so I was thinking the real high dose Omega-3 would be aggravating that potentially. And so then I stopped taking my Omega-3 for a while and went down too, despite eating fish like a Japanese person, I mean, my Omega-3 level went down to 6.6 or something else, so I got back on Omega-3 and now it’s back above eight. But it’s a good example of how to use the [00:29:30] Omega index. It’s like blood pressure. It’s not a one-time check. It’s like you need to follow it. It can change.

Dr. Kristina Harris Jackson: Yeah, it changes.

Dr. Bill Harris: Great example.

Dr. Kristina Harris Jackson: You say it’s moves slowly, but it still does move. And I think also just what we’re talking about today is you can potentially be too high or there are some consequences of supplementing without knowing what you’re at, and you want to get enough to get to a good level, but you don’t need to go way beyond that basically. Like with all nutrients.

Dr. James O’Keefe: Yeah, there’s [00:30:00] a popular female podcaster, which we don’t want to name by name, but I think she was bragging about an omega index of 16 or something like that, 15 or 16, and I’m just thinking, in biology, most things in biology, you want to be in the middle of the normal range. Well, when you define normal as healthy, fully functional, healthy people, the problem with most labs in America is they take an average of [00:30:30] generally unhealthy people. But if you get an average of healthy people on a paleolithic diet, like our ancestors would’ve eaten for hundreds of thousands of years, I think you’d have an Omega index of eight or nine or something like that. So I think that’s a good target. It’s like there’s not much in biology where if a little is good, a lot is best. Almost anything, it’s not a straight line [00:31:00] monotonic relationship.

Dr. Bill Harris: [inaudible 00:31:05]. Great.

Dr. Kristina Harris Jackson: That’s it. Well, great. Thank you so much for coming on and talk about this paper and for working with FARI to do research and also practice. It’s a really great partnership, so thank you so much for coming on again.

Dr. James O’Keefe: Yeah, well thanks Kristina and Bill. It’s like a personal passion besides a professional passion. I’m just totally honored and thrilled to be working with you guys. It’s just a real joy.

Dr. Bill Harris: It’s great to have you.

Dr. Kristina Harris Jackson: [00:31:30] All right.

Dr. Bill Harris: We started together 30 years ago or something. Let’s keep it going.

Dr. James O’Keefe: That’s right. Yeah, we’ve been collaborating for a long time and I mean, honestly, this is the best ever. The stuff we’re doing right now is in my opinion, so important. And surprisingly, it’s still a controversial topic out there.

Dr. Bill Harris: No controversy, there’s nothing to do.

Dr. James O’Keefe: That’s true.

Dr. Bill Harris: All right, James, thanks a lot.

Dr. James O’Keefe: Yeah, my [00:32:00] pleasure.

Dr. Kristina Harris Jackson: Thanks.

Dr. James O’Keefe: Thanks.

Dr. Bill Harris: Okay, bye-bye.

Dr. James O’Keefe: Bye-bye.

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