#627

While this all may be true about MRs, when the RCTs are also in the same direction (negative), hard to ignore the preponderance of evidence here.

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#628

Thanks. Really good point. I asked to ChatGPT 4.5: ChatGPT - MR Studies on EPA DHA

Most interesting bit:

  1. Direction of bias
    When SNPs explain little variance, there’s a greater risk of Type II error (missing a real effect), not Type I (finding a false effect). So if a strong signal does appear despite low variance explained, it’s often more impressive — though still needs caution.

And the conclusion:

Yes — a significant MR finding can be strong even with SNPs that explain only a small fraction of variance, but only if the instruments are valid and the assumptions are met. In fact, finding significance despite limited variance can indicate a real and potentially important biological effect. Still, MR is best interpreted as part of a triangulation approach with RCTs, biology, and observational data.

So when MR studies find that DHA is a risk factor for colorectal cancer, lung cancer and cardiovascular disease while EPA is protective against depression, coronary heart disease and myocardial infarction: these are HUGE findings, as they were found despite a low variance.

On the other hand, for MR that find no associations (for examples EPA and DHA with dementia) one has to look at the details (F-statistics, effect size, confidence intervals, consistency across methods, etc.) and whether this aligns with RCTs. That’s the case.

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How much omega-3 do you need?
Omega-3 fatty acids are a risk factor for colorectal cancer
#629

Sure, and I must admit that @adssx arguments against DHA look more and more convincing.

I was just making a point about MR in general because a lot of people think they are even better than RCTs while they are clearly not. It’s just another tool with its pro and cons like RCTs, epidemiological studies, etc.

There is a specific issue with MR though. Any grad student (anybody even) can use the MR tools and generate a “study” about anything in a few hours and at no cost. Most of them are meaningless and should be ignored but it takes time and effort to rule them out.

That said there are also truly insightful MR studies. It’s just that being an MR study should not be perceived as the highest level of evidence. Same for RCTs and the rest obviously.

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#630

That’s helpful re variance being small.

—

There was another big type of issue with Omega 3 MR instruments though:

Pleiotropy Risk : Variants in FADS1/FADS2 influence both omega-3 and omega-6 pathways, complicating causal inference.

What are your and your AIs thoughts on that?

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How much omega-3 do you need?
Omega-3 fatty acids are a risk factor for colorectal cancer
#631

I do think you want to throw out the baby with the bathwater

For something things where the instruments are clean, clear and explain a lot of the variance they can be hugely important and perhaps more valuable or as valuable as short term RCT in sick people only when you are trying to understand the long term effect and in a population that is healthy or not like that specific clinical trial.

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#632

My thoughts: I don’t know enough.

ChatGPT 4.5: ChatGPT - MR Studies on EPA DHA

tl;dr: “Cautious conclusions: The presence of pleiotropy means MR results based solely on FADS variants require careful interpretation and additional verification (e.g., using sensitivity methods or other SNPs).”

So did the MR only used FADS variants or other variants as well? I don’t know, for instance this paper does not even mention “FADS”: Medicine

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Omega-3 fatty acids are a risk factor for colorectal cancer
How much omega-3 do you need?
#633

Unfortunately, the more I dig, the more I’m convinced that DHA is detrimental. I emailed or tweeted my questions to Yassine Hussein (PI behind PreventE4, here), Matt Kaerberlein, Brad Stanfield, Kellyann Niotis, Thomas Dayspring, Rhonda Patrick, and OmegaQuant. Let’s see if one of them gets back to me… Hopefully, someone will prove me wrong but so far it doesn’t look really good for DHA supplementation…

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#634

No. I did wrote:

But not all of them.

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#635

This looks like horizontal pleiotropy according to this paper (SNP’s can affect Omega-3 and Omega-6 to a specific outcome, or maybe one SNP to two factors before the outcome), here it’s education, intelligence, and schizophrenia:

So would need to in that case do Multivariable MR on a possible confounding factor and account for it (in this case Omega-6 if it seems relevant). Is this correct do you think? If so you would check (1) what factor you believe is relevant in horizontal pleiotropy (2) if the study authors did a multivariable MR analysis with that factor, if not, why.

A multivariable Mendelian randomization to appraise the pleiotropy between intelligence, education, and bipolar disorder in relation to schizophrenia 2020

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#636

Although we only used 1–3 SNPs as instrumental variables for each PUFA, the SNPs explained a relatively large variation in PUFA levels and they fulfilled the criterion as not being weak instrumental variables (F statistic > 10)

Study: Polyunsaturated fatty acids and risk of Alzheimer’s disease: a Mendelian randomization study 2019

Regarding instrument relevance, we have selected independent SNPs strongly associated with circulating PUFA concentration, which explained from 4.8 to 7.9% of phenotypic variance (mean F statistics 109–201) among the UK Biobank participants (discovery sample). In addition, we replicated these associations in an independent dataset [12] using the same NMR metabolomics platform as the one used in the UK Biobank participants (median sample size 13,516), where SNPs explained 3.1 to 6.9% of phenotypic variance in circulating PUFA. This indicates that bias due to weak instruments is unlikely to be substantial in our analyses, even though bias due to winner’s curse (due to using the UK Biobank to select SNPs and estimate their effect on PUFA) could affect the magnitude of effect estimates.

Study: Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk: analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants 2022

Mean F-statistics were 120- 8572 for UKBB fatty acid exposures and 15–6315 for FADS analyses, suggesting these analyses were unlikely to be substantially biased by weak instruments (Table S4). Mean F statistics for EPA analyses were 9, leading to possible weak instrument bias.

Study: Omega-3 fatty acids and major depression: a Mendelian randomization study 2024

–
I checked three MR papers and they seemed good with regards to weak instruments based on what they said.

Do people even publicize if they don’t have a good F-statistic (statistical power)/weak instrument? Might not pass peer review?

As a general rule, an F-statistic >10 indicates that the level of weak instrument bias is likely to be small. F-statistics should not be used to select IVs to avoid overfitting the estimation model. For example, an F-statistic of <10 does not indicate that an IV should not be used but, instead, it should be noted in the analysis that weak instrument bias should be a considered limitation.

https://mr-dictionary.mrcieu.ac.uk/term/f-statistic/

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How much omega-3 do you need?
#637

add Nicolas Verhoeven, PhD - Physionic - he’s a pure science guy, he doesn’t preach just dissects studies

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#638

https://www.physionic.org

His contact page says that he’s only interested in business enquiries! :man_shrugging:

#639

maybe there is a subscriber here on this forum that can comment about it, he responds to his subscribers

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#640
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#641

It depends on what you are most worried about (based on evidence) … for me I’m not worried about vascular disease as I both monitor for that, and optimize my ApoB and everything else. I appreciate the mouse data on phospholipid DHA, however, I would point out that ApoE4 carriers probably respond clinically and have protection with eating fish, but not taking standard DHA supplements. The only thing that is different is that #1 You are having all the other things in fish - not just the oil, #2 It is in phospholipid form.
So I’m more worried about my brain as I have no vascular disease and can monitor for developing it - so have more fish and I’m going with the phospholipid forms of DHA, but in a mix that still has plenty of EPA.

This is simply individualized risk/benefit. Obviously, my opinion would be different for someone with heart disease and no ApoE4.

I’ll wait for more data on the phospholipid forms … and it might prove useless in the end.

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#642

I agree that eating fish is the best way.

But what about the CVD and cancer risk in Mendelian randomization studies? Vitamin O (Omega 3) for athletes - #4 by adssx

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#643

I’ve not seen any data linking Omega 3’s to increased all cause mortality - and my personal concern is AD - and the absolute magnitude (not RR) are numbers that don’t concern me.

It does look like EPA transport into the brain is less affected in ApoE4 carriers as compared to the more significant loss of DHA transport. It also looks as though EPA does have at least come conversion to DHA in the brain.

I’ve then come across this article which is fascinating … I think the best situation is cutting the DHA amount significantly down and finding a good source of lysophosphatidylcholine-EPA as this looks to enhance brain DHA more than taking DHA directly according to the article. Now finding a good source of LPC-EPA will take some research.

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#644

Very interesting and aligns with this paper: "Together these findings suggest that an EPA-dominant formula may provide some benefit in APOEE4 carriers with no dementia and WMLs, and DHA-dominant formulas may benefit noncarriers of APOEE4 with mild-to-moderate AD.” (ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults A Randomized Clinical Trial 2024)

Commercially available here: Accentrate® Omega – Fenix Health Science

“Accentrate® Omega with LYSOVETA® LPC is specifically formulated with the omega-3s, LPC-EPA and LPC-DHA.”

image
image1184×848 167 KB

See also: LYSOVETA | LPC bound EPA & DHA by Aker BioMarine

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#645

Aker Biomarine gets NDI nod from FDA for brain health ingredient 2023

The Norwegian fishing and biotech company has successfully achieved New Dietary Ingredient (NDI) status from the US Food and Drug Administration for its Lysoveta. Under the NDI, Aker BioMarine can market Lysoveta at 1.5 grams/day for the general adult population.
Aker Bio has spent the last several years developing and building the clinical substantiation for Lysoveta, a novel dietary supplement for targeted delivery of lysophosphatidylcholine (LPC-EPA/DHA) derived from krill.
“I mean we started this project back in 2014, so it’s been several years of development, probably some $50 million of investment in developing a production process and then doing all the safety studies and now preparing for the commercialization of the product, so it’s quite exciting,” commented Matts Johansen, CEO, Aker BioMarine ASA.
The company, which develops krill-based ingredients for nutraceutical, aquaculture, and animal feed applications, has a supply chain that stretches from krill harvesting in Antarctic waters through its logistics hub in Montevideo, Uruguay, to its krill oil manufacturing facility in Houston, Texas.
Blood brain barrier
Aker Bio plans for supplement firms to use its EPA/DHA innovation bound by lysophosphatidylcholine to allow…

#646

I’ve looked at it and the only issue I have is how little EPA or DHA it has in it - and also, if we really want just LPC-EPA … probably want 500-1000 mg/day - and this is well below AND it has DHA. I’ve been unable to find a pure LPC-EPA product. Anyway, these options look to be sensible as compared to what I’m doing right now possibly. However the issue is if the LPC is better than phospholipids? If not - the NatureBell product I mentioned would be a better move if phospholipids work as well as LPC.

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