The band aid analogy doesn’t make sense when we consider the MR studies showing the lower your genetically determined LDL-c, the lower your risk of CVD. If everything was randomised except the number of band aids, why would having fewer band aids result in lower CVD risk?
> This is one of the reasons statins reduce the number of heart attacks, but don't always seem to reduce all-cause mortality.
That’s one potential explanation, but I don’t think it’s the most likely one. We tend to see non significant ACM in smaller, less powered trials, or those with lower LDL-c lowering. ACM is simply a less sensitive endpoint - if you have a treatment that reduces CVD incidence, then the “CVD incidence” endpoint will give you significant results with fewer CVD event differences between study arms compared to ACM since your power to detect differences is diluted by other fatal events that aren’t affected by statins (cancer, motor accidents etc).
Across different genetic variants, lower lifetime LDL -> lower risk of death. Check out figure 3.
The causality of LDL -> plaque buildup -> 55-60% [1] of heart disease related deaths is also well understood, so it seems clear to me that preventing plaque buildup in the first place prevents over half of heart disease related deaths.
Would like to know if you disagree, "Minimize LDL at all costs" goes current mainstream medical guidance, so I'd like to disconfirm my beliefs if possible.
Graboy has provided the citation I would have given, as well as an excellent explanation. I’m not sure what you mean by “heart disease is clearly not Mendelian”.
Mendelian is characterized by effects having strong influence from a single gene. Heart disease is clearly more complex than gene -> heart disease. I thought that was basic enough that I didn't need to explain it. But here goes...
A clinical score changing with treatment is not unconfounded by mendelian randomization. When the genetics are clearly more complex than what you are mathematically randomizing for, the control doesn't solve the confounding. eg you haven't suddenly "proven" the effects are non-genetic. We already knew heart disease is non-mendelian. But showing something is non-mendelian doesn't mean you've shown it's not genetic. I hope that clarifies, because I'm not sure I can explain it to you in simpler terms.
> I thought that was basic enough that I didn't need to explain it. But here goes...
This is quite the tone to take when the actual point being made has demonstrably sailed over your head, considering the reference provided to you explains it very clearly.
Which is more likely - nigh on every lipidologist, cardiologist and nutrition researcher is wrong, or you might have made a mistake yourself?
> Mendelian is characterized by effects having strong influence from a single gene. Heart disease is clearly more complex than gene -> heart disease
This seems like a misunderstanding. A single SNP clearly can affect CVD risk, that’s precisely what the paper shows. The assumptions required for an MR study to be valid do not include “the outcome must only be affected by a single gene and no other gene”. It’s required that there’s no pleiotropy present in the exposure (I.e. the SNPs). The exposure here isn’t heart disease, it’s SNPs that affect LDL-c levels, and the outcome being measured is CVD. So your point doesn’t pose an issue for the study and the inferences it makes.
But honestly - just read the paper. I think both that paper and the EAS consensus paper are very approachable.
I think maybe you are saying that there may be some way that the genes affect heart disease not through LDL, and therefore MR does not apply because the "exclusion restriction" [1] fails here? Or are you talking about a different assumption?
The cited study addresses this, which is why I pointed to figure 3. They argue that if genes were causing heart disease not through LDL in any meaningful way, you wouldn't expect such a clean dose-response consistency across different genetic variants - it would be more jagged.
It seems you are confusing mendelian randomization for specific alleles associated with LDL-C production and conflating that with mendelian randomization somehow controlling genetic confounding of heart disease. The control is for the LDL production, not heart disease.
Please review the key principles and assumptions section. Using MR to control for genetic confounding of heart disease fails all assumptions. Thats why it quite directly does not follow.
This is why the paper presented does not support the claim that LDL is the sole source of heart disease. I'd be interested to hear what the authors of that paper (which is legitimate) think about it being used to support the OP's claim because "mendelian randomization".
> This is why the paper presented does not support the claim that LDL is the sole source of heart disease
Is that what we were arguing about? I guess it was. At some point in thinking about this my frame must have shifted into agreement with you. Of course there are other causes of heart disease besides LDL, like blood pressure, duh. The smooth dose response is about the particular gene not being linked to heart disease through something other than LDL, roughly.
What do you think of Dr. Schooling's response that the Mendellian effects might be inflated? I think they had a good defense but was not entirely convinced they hadn't sidestepped the issue that Schooling was getting at, wasn't sure either way.
I wasn’t aware of that critique, thanks for sharing. Before I read the response my first thought was “why such consistency across different SNPs, then?”, so I would certainly agree with that aspect of the defence.
In general, Ference’s explanation just seems more parsimonious than Schooling’s. It’s possible that they’re right, but I think they would need to show that the specific genes in Ference’s study are affected by age in this way.
I wouldn’t claim to be a great expert in MR, though. I can just about keep up with surface level understanding of them but once you get into the nitty gritty stats, pleitropy testing etc it’s a bit over my head tbh.
We have some case studies and pilot studies without any kind of control. Perhaps keto/low carb could be helpful (it certainly is with epilepsy!), but I certainly haven’t seen any evidence that it’s superior to other diets that achieve the same things (I.e. weight loss, or higher clinician contact time - a lot of these pilot studies end up losing a bunch of weight and getting several extra hours per week of contact with their clinician - who knows if much/all of the benefit comes from this?).
Having had quite a lot of experience with the keto/low carb crowd, I think we’d see a lot more adoption/interest in their ideas if they approached things in a less ideological/dogmatic way. It’s hard for responsible clinicians to get involved with, say, Metabolic Mind when people like Bret Scher hand wave around the CVD risks from high SFA intakes, or big up low quality work like the godawful Keto-CTA paper.
There _are_ responsible keto advocates out there like Ethan Weiss, and I suspect that if the keto/low carb community were to promote _their_ work rather than that of people like Nick Norwitz and Dave Feldman then their diet of choice would be taken more seriously.
Unfortunately much of the low carb movement is quack town at the moment. I hope they get their act together, there are benefits in there for people in need, but they need to get serious first.
I've never heard of any other diet or non-keto nutritionist being able to reverse such mental illness. Do you have any links?
>> but I certainly haven’t seen any evidence that it’s superior to other diets that achieve the same things
You can find many N=1 examples for this on the linked youtube channel and then you have hundreds of testemonials here (click load more) on the carnivore diet healing autoimmune issues:
https://www.revero.com/blog/success-stories
No other non-keto diet comes even close to this.
I've only ever come across the keto diet as the one that can do this to such an extent. I've only heard of some T2 diabetics reversing it by losing weight in the context of "any diet that causes weight loss".
They don't wave around CVD risks: they show you that all the pro "SFA is bad because of CVD" crowd is also full of biases and very bad science and pharma sponsored studies that shill statins etc...
I agree that the Keto-CTA paper was trash. Horwitz isn't the best when it comes to this.
Though when you say that most are quaks: the entire "SFA is bad" field can also be marked like this when you see that most of those studies are trash, how eg "lasagna" is designated as "meat" in studies and similar trash.
There is no clear signal about SFAs being bad since you can find counter-studies for each viewpoint.
If “highest number of n=1 studies wins” is your yardstick for causal inference then you’re part of the reason the keto crowd isn’t taken seriously. Wish I could sugar coat it more but that’s the reality, and I think some people on that side of the fence could do with some home truths.
> They don't wave around CVD risks: they show you that all the pro "SFA is bad because of CVD" crowd is also full of biases and very bad science and pharma sponsored studies that shill statins etc...
That is hand waving. The implicit claim being made by your statement is that because researchers have biases (true of all researchers) or they’re sponsored by interested parties (also true of keto studies, and not necessarily an indication of an issue with any given study) or also push medications or supplements (again, also true of keto studies) then we should treat all hypotheses tested in ways that contain these “flaws” as identical in validity.
However, that’s absurd. The evidence in favour of the claim that substituting PUFA in place of SFA reduces CVD incidence is absolutely mountainous in comparison to the evidence base supporting the claim that ketogenic diets cure mental health disorders.
In both cases, there exist sponsored studies, biased researchers and medication peddlers that support the hypothesis. Yet it sounds like you are willing to believe one but not the other. So what explains the difference in your attitude towards the two? Why do you believe it’s likely that keto cures these mental health issues but not that SFA consumption increases CVD incidence?
> A lot of the COVID pseudo-science was specifically designed to manipulate people's emotions (e.g. journals rejecting correct papers because fewer people might take vaccines as a result [1]).
1. What Covid pseudo science are you referring to?
2. How does the x thread you referenced show “journals rejecting correct papers because fewer people might take vaccines as a result”? As I read it, the rejection was because the journal had a higher bar for evidence on claims around herd immunity than the researchers were able to meet. That is, they’d happily publish papers suggesting lower levels of herd immunity, but the papers would require more rigour than that which was provided.
It’s not clear to me that this bar existed just to increase vaccine uptake, but to generally avoid moves towards relaxing interventions based on insufficiently strong evidence (social distancing, mask wearing, etc).
It’s not clear to me what objection one would have to having a high threshold for evidence when publishing research with such high potential to impact public health. That seems like a good thing to me.
It's damning for academia that on HN of all places, a forum filled with academics, this stuff has to be spelled out by outsiders. Once more unto the breach?
The rejection reason: "it is appropriate to hold claims around the herd immunity threshold to a very high evidence bar, as these would be interpreted to justify relaxation of interventions, potentially placing people at risk."
What should scientific institutions do? Answer questions about the natural world honestly.
What should politicians do? Make policy tradeoffs informed by those answers and the preferences of the public.
What were the institutions actually doing? Hiding correct answers due to an ideological and pathologically strong preference for risk avoidance without any regard for cost.
> they’d happily publish papers suggesting lower levels of herd immunity, but the papers would require more rigour than that which was provided.
A "very high evidence bar" that isn't described anywhere is one that doesn't actually exist. They never showed anything wrong with the science, they rejected it out of hand because they didn't like that it would support a libertarian conclusion. Even if they had invented such a bar, requiring weak evidence for policies you like and strong evidence for policies you dislike is exactly the kind of pseudo-scientific intellectual fraud being criticized in the article.
COVID was full of this stuff. That event wasn't surprising, it was typical behavior of most "scientists".
You have to realize, that when the universities get disestablished, it'll be because of decades of discussions like this one. The correct response to that Twitter thread is to demand the journal be immediately shut down and that heads roll at the publisher. The wrong response is to say "of course we should block research that supports policies we dislike, why would anyone be against that?"
> A "very high evidence bar" that isn't described anywhere is one that doesn't actually exist
If your claim is: “if a standard isn’t explicitly written down somewhere such that one can utilise it to ascertain whether something meets it without ambiguity then it doesn’t exist” then the entailments are absurd. The world is full of standards that do not meet such a bar (“reasonable doubt”, for example) yet obviously this is a real standard.
> COVID was full of this stuff
Yet when I asked you for to give examples of “this stuff” you failed to do so. How come?
> when the universities get disestablished
Lmao. Not going to happen, I see we’re off in cloud cuckoo land now.
> The EU has already defined dairy items milk, butter, cream, yoghurt and cheese as "products secreted by mammary glands"
I think they should just label things more explicitly like this - accelerate veganism 100x when people in the supermarkets have to choose between “pressed soybeans” and “mammary gland secretions”.
Two different things. If you don’t want to eat animal products for ethical reasons but you want something high protein and/or similar in taste/texture to a beef burger, eating a vegetable stir fry isn’t going to cut it. That’s what these products are for.
Not only is the study itself very interesting, but it does a great job going over the evidence landscape on UPFs and food at the current point in time.
Dr Dicken is very clear that at the moment, in his view, they have insufficient evidence to make policy decisions like this, a view that has been echoed by pretty much all academic institutions when they’ve helped inform recent dietary guidelines.
Making big sweeping moves based on flimsy evidence is a good way to make people wary of following dietary guidance at all. After all, what’s the point of listening to “the science” if they turn around in 5 years and say “whoops, turns out we were wrong”?
Be aware that the science on this is evolving pretty quickly.
A study came out recently that showed when folks ate a designed diet, one with and one without UPFs, they found the UPF diets resulted in a few additional lbs of weight gain.
The study accounted for a ton of variables. It showed that UPF calories lead to weight gain when consuming the same number of unprocessed calories.
I think, at the current moment, there is enough evidence to support guidelines to avoid UPFs for the most part. Idk about banning but I do think it'll eventually get there, at least in schools. But who knows? American lunches are garbage in the first place
I’m not an absolutist on this myself, if convincing evidence comes out then I’m happy to change my mind. I have no horse in this race besides wanting people to stay healthy. I’m just not currently convinced the UPF category adds much to our existing dietary guidelines.
Avoiding UPFs can serve as a reasonable heuristic as it can help you avoid HFSS foods, but you could also easily make some adverse switches following such advice.
I’m not sure that study really supports the inference you’re making re: calories and weight gain. The UPF diet had ~15g fibre/1000kcal less than the MP diet, so for an individual consuming 2500kcal/day there’s a 150kcal difference of energy per day that doesn’t seem to be accounted for by the studies methods (could be missing this in their calcs though?).
So yeah, if we don’t equate things like this, things look bad for UPFs. But what is the “UPF” category adding here. We don’t need it to know that if more calories are consumed as fibre in an otherwise calorie-equated diet, you’ll lose weight relative to the low fibre diet.
> and yet when Americans set foot on European soil the first thought they have is 'everyone is so thin'.
I’m not sure how this interacts with the point I’m making.
> if there's any misstep here, it's not focused enough on sugar (which is a hard drug for kids) .
Sure, free sugars are associated with risk (which is reflected in dietary guidelines). Plenty of UPFs are not (which is why they generally aren’t flagged as a concern in dietary guidelines).
reply