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    Senior Member Benson's Avatar
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    Default Cholesterol, Correlation & Causation

    A really excellent article on why we cannot assume that because we have found a correlation, we have also determined causation...

    http://www.wired.com/magazine/2011/1...ausation/all/1
    Remember, believe none of what you hear and half of what you see...





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    Senior Member The450Man's Avatar
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    I read and skimmed sections so i may have missed something

    Im curious as why the drug had such a negative effect on all cause mortality. Maybe the enzyme that was inhibited had some beneficial effect?

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    Senior Member Benson's Avatar
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    That is precisely the point.

    Despite the fact that this is a very well-studied pathway, messing with it caused exactly the opposite effect from what was expected even though the participants lipids changed in a way that should be beneficial...should be if we have the cause and effect straight which we probably do not.
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    CETP is implicated in vitamin E transport - and if you inhibit the pathway that packs vitamin E into lipoproteins, well...

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    Senior Member FunkOdyssey's Avatar
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    Wow that is such a good article, I love it.
    "Also, can I rig some sort of enema out of household items?" -Tussman

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    Quote Originally Posted by Niflheim View Post
    CETP is implicated in vitamin E transport - and if you inhibit the pathway that packs vitamin E into lipoproteins, well...
    on a related note, I remember having read that only Gamma, but not alpha tocopherol protects LDL (in particular) from oxidation...unfortunately I obviously did not archive the study... I have on the other hand found another related study, which could be of interest
    J Nutr Biochem. 2011 Jun 27. [Epub ahead of print]
    The two faces of α- and γ-tocopherols: an in vitro and ex vivo investigation into VLDL, LDL and HDL oxidation.
    Nadeem N, Woodside JV, Kelly S, Allister R, Young IS, McEneny J.
    Abstract
    BACKGROUND:

    Vitamin E and its derivatives, namely, the tocopherols, are known antioxidants, and numerous clinical trials have investigated their role in preventing cardiovascular disease; however, evidence to date remains inconclusive. Much of the in vitro research has focused on tocopherol's effects during low-density lipoprotein (LDL) oxidation, with little attention being paid to very LDL (VLDL) and high-density lipoprotein (HDL). Also, it is now becoming apparent that γ-tocopherol may potentially be more beneficial in relation to cardiovascular health.
    OBJECTIVES:

    Do α- and γ-tocopherols become incorporated into VLDL, LDL and HDL and influence their oxidation potential in an in vitro and ex vivo situation?
    DESIGN:

    Following (i) an in vitro investigation, where plasma was preincubated with increasing concentrations of either α- or γ-tocopherol and (ii) an in vivo 4-week placebo-controlled intervention with α- or γ-tocopherol. Tocopherol incorporation into VLDL, LDL and HDL was measured via high-pressure liquid chromatography, followed by an assessment of their oxidation potential by monitoring conjugated diene formation.
    RESULTS:

    In vitro: Both tocopherols became incorporated into VLDL, LDL and HDL, which protected VLDL and LDL against oxidation. However and surprisingly, the incorporation into HDL demonstrated pro-oxidant properties. Ex vivo: Both tocopherols were incorporated into all three lipoproteins, protecting VLDL and LDL against oxidation; however, they enhanced the oxidation of HDL.

    CONCLUSIONS:

    These results suggest that α- and γ-tocopherols display conflicting oxidant activities dependent on the lipoprotein being oxidized. Their pro-oxidant activity toward HDL may go some way to explain why supplementation studies with vitamin E have not been able to display cardioprotective effects.

    Copyright © 2011 Elsevier Inc. All rights reserved.
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    Senior Member John Barleycorn's Avatar
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    Quote Originally Posted by Benson View Post
    A really excellent article on why we cannot assume that because we have found a correlation, we have also determined causation...
    It's an interesting, provocative read, and serves its purpose well. However, it glosses over a couple of significant technicalities. Consider, for example, this paragraph:

    The good news is that, in the centuries since Hume, scientists have mostly
    managed to work around this mismatch as they’ve continued to discover new
    cause-and-effect relationships at a blistering pace. This success is largely a
    tribute to the power of statistical correlation, which has allowed researchers
    to pirouette around the problem of causation. Though scientists constantly
    remind themselves that mere correlation is not causation, if a
    correlation is clear and consistent, then they typically assume a cause has been
    found—that there really is some invisible association between the measurements.
    There is a fundamental difference between a controlled experiment (which, technically, is capable of disproving some hypothesis), and a correlational study. I like the article, but it seems unaware of that basic distinction. Modus Ponens, Modus Tollens, and all that reductionist stuff. Now, if they had wanted to advance an argument that classic experimentation is inadequate in the face of complex systems possessing feedback loops, then that would have also been quite interesting, but unfortunately they didn't really advance that argument. Reading the article did, however, give me a warm glow.

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    Senior Member kassem23's Avatar
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    I agree with John here. Here's some of my thoughts:

    1. It describes a very well known phenomenon of the limitations of the reductionistic approach in biology. It should be said, however, that there have now been created a new branch in biomedical research called Systems Biology, which is now trying to delineate these complex systems, devising ways that allow us to study them and test them in silico, before conducting the actual experiments.

    2. It is true that causation is a mental construct, but the achievements acquired by the reductionistic medicine and science are plenty and amazing. And every once in a while, even when we think that complex systems cannot be fully understood, we discover primary movers (central players) that influence the whole system, e.g. strong attractors in chaos theory.

    3. One should also be very careful about drawing the line between the limitations of the scientific method and discarding the scientific method entirely.

    That said, it's an excellent article which probes a lot of interesting discussion(s).

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    Senior Member Benson's Avatar
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    What is particularly interesting about the cholesterol hypothesis is that we lept from correlation to causation so rapidly and with so little evidence...that we took what is likely a symptom of a condition and made it into the causative factor will, I suspect, eventually turn out to be one of the most costly mistakes ever in medicine both in terms of dollars spent and in terms of lives lost.

    How many millions of people have we put on statins as a means of primary prevention when we know that for many patients, there is no evidence at all that the changes in cholesterol that the statins produce provide any improvements in CVD mortality or morbidity...I find it particularly amusing/troubling when I hear about older people (>65) spending their money on regular statin therapy that will likely do nothing at all to protect them from a cardiac event.
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    Quote Originally Posted by Benson View Post
    What is particularly interesting about the cholesterol hypothesis is that we lept from correlation to causation so rapidly and with so little evidence...that we took what is likely a symptom of a condition and made it into the causative factor will, I suspect, eventually turn out to be one of the most costly mistakes ever in medicine both in terms of dollars spent and in terms of lives lost.

    How many millions of people have we put on statins as a means of primary prevention when we know that for many patients, there is no evidence at all that the changes in cholesterol that the statins produce provide any improvements in CVD mortality or morbidity...I find it particularly amusing/troubling when I hear about older people (>65) spending their money on regular statin therapy that will likely do nothing at all to protect them from a cardiac event.
    while I agree with (almost) all that has been said, I think that there is another "down-the-line" problem we are completely overlooking here... with the paradigm being "cholesterol = bad"; ALL studies are based on a false assumption. In essence that would be like still believing that the earth is flat. If that was the case all our theories and studies that are based on this assumption would be false... and worst of all - chances are that for centuries we would not even notice... (I know the example is not a particularly good one, but I guess you will be getting my point)
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    Senior Member The450Man's Avatar
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    Now lets start hypothesizing some of the probably causes of CVD..

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    Senior Member Benson's Avatar
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    Quote Originally Posted by The450Man View Post
    Now lets start hypothesizing some of the probably causes of CVD..
    Inflammation.
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    Senior Member FunkOdyssey's Avatar
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    This is a must-read blog for anyone interested in cardiovascular health: http://www.trackyourplaque.com/blog/
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

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    Great article! It reminds me of all the bold claims that were made back in the 90's that after we had fully mapped out the human genome we would be able to cure a wide range of diseases. That hasn't panned out, and in fact we are finding the opposite appears to be happening where many diseases are influencing a wide number of genes in different ways. Or what is now known as epigenetics.

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    Senior Member John Barleycorn's Avatar
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    Quote Originally Posted by Benson View Post
    What is particularly interesting about the cholesterol hypothesis is that we lept from correlation to causation so rapidly and with so little evidence...that we took what is likely a symptom of a condition and made it into the causative factor will, I suspect, eventually turn out to be one of the most costly mistakes ever in medicine both in terms of dollars spent and in terms of lives lost.
    That is in fact a good illustration of the problems of complex systems research. If there is a feedback loop between cause(s) and effect, then it becomes somewhat arbitrary which is labelled as which. I guess I'm probably being too much of a science geek here, but the article alluded to this problem in a roundabout way without really explaining it.

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    Quote Originally Posted by Benson View Post
    Inflammation.
    I agree and would add. Inability of the immune system to repair the damage... plus, I would venture the guess that a LACK OF CHOLESTEROL could also play an important role. After all, the ruptures start, when the immune cells are unable to incorporate enough cholesterol into the cell wall to keep it smooth and flexible. What would support this hypothesis is that WHENEVER YOUR BODY IS IN NEED OF REPAIR you will see him trying to pump out more cholesterol.
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    Senior Member Sanction's Avatar
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    Quote Originally Posted by John Barleycorn View Post
    That is in fact a good illustration of the problems of complex systems research. If there is a feedback loop between cause(s) and effect, then it becomes somewhat arbitrary which is labelled as which. I guess I'm probably being too much of a science geek here, but the article alluded to this problem in a roundabout way without really explaining it.
    This is a good point.
    It was, and is, normal to assume that phenomenon are causally related in a linear or hierarchical way. So, observation A is associated with precursor XYZ, and these have precursors of x1, x2, x3, y1, y1, z1, z2, z3. In any particular case where this is true, it is cost-effective to construct experiments that isolate the precursors and their linear/hierarchical pathways.

    Human cognition seems to be predisposed assume causality in this way.

    The nice thing about science is that eventually, and ideally, when the hypotheses are tested and found to be wanting that someone says "hey, this is all bullshit".
    But at that moment you have few choices. Perhaps there is some other factor that is linearly causative. It could be inflammation, or hyperventilation, or a virus.
    If it's not a linear thing though, then you are facing a complex system, possibly chaotic or a version of the "n-body problem".

    So, when the medical establishment comes to realize that many ideas that were optimistically proclaimed years ago (e.g. cholesterol and CVD, gene-sequencing leading quickly to cures, the war on cancer) do not work well, then it takes a new mindset to step back. That is a scientific mindset, not that of a practitioner in a profession.

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    Quote Originally Posted by Benson View Post
    for many patients, there is no evidence at all that the changes in cholesterol that the statins produce provide any improvements in CVD mortality or morbidity
    I am not fully up with the latest on statin research but I thought that there was a reduction in CVD mortality/mordbidity, particularly in high risk groups, but that there wasr ma no reduction in all-cause mortality?

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    Senior Member Benson's Avatar
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    Statins provide very limited primary prevention, particularly in women or men over 65. They appear to provide some protection against second CVD events in men who have had one already...

    http://summaries.cochrane.org/CD0048...scular-disease
    Remember, believe none of what you hear and half of what you see...





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    Quote Originally Posted by Benson View Post
    What is particularly interesting about the cholesterol hypothesis is that we lept from correlation to causation so rapidly and with so little evidence...that we took what is likely a symptom of a condition and made it into the causative factor will, I suspect, eventually turn out to be one of the most costly mistakes ever in medicine both in terms of dollars spent and in terms of lives lost.

    How many millions of people have we put on statins as a means of primary prevention when we know that for most patients, there is no evidence at all that the changes in cholesterol that the statins produce provide any improvements in CVD mortality or morbidity...I find it particularly amusing/troubling when I hear about older people (>65) spending their money on regular statin therapy that will do nothing at all to protect them from a cardiac event.
    Unfortunately, I think you may be misinformed. I know you are a well respected member here, and I have read your posts over years of lurking intermittently, but you are incorrect in you statement that "changes in cholesterol that the statins produce provide any improvements in CVD mortality or morbidity."
    I won't waste you time with a spam war trading study links, but review of medical literature clearly shows a morbidity and mortality benefit with statin therapy in appropriate patient populations. Certain statins are proven to cause stabilization of vulnerable plaque, plaque reduction / regression, increased arterial luminal diameter via reduction in intra-luminal plaque, decreased post-op, post stent and post MI morbidity and mortality among others. In general I refer to Lipitor, as it is the most studied statin available. Note - all statins are NOT equal. Many statins have inferior results compared to Lipitor (ie simvastatin, pravastatin etc.). Some statins have "favorable" changes in CRP / HS-CRP, while others do not. The "changes in cholesterol" statement you casually make implies that you are not familiar with the concept of plaque modification / composition in response or relation to statin therapy. Target LDL is only one small part of the M&M reduction.....alterations in plaque composition and plaque stabilization are key components you are not appreciating.....and where many of the lesser statins have not been proven to have benefit (neither has red yeast rice / your "natural" statin).

    Spend some time reviewing literature at circulation aha org
    You can read a majority of it for free.


    *I do not own stock or have a vested interest in any statin.
    FWIW I am a practicing physician - one of the hated, feared, and misinformed medical professionals

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