5 ms·

1. The best evidence that there is no safe amount of alcohol consumption is the Mendelian randomization (MR) by Holmes et al from 2014 [1]. I believe that the m

1. The best evidence that there is no safe amount of alcohol consumption is the Mendelian randomization (MR) by Holmes et al from 2014 [1]. I believe that the more recent paper making such claims is no better than the usual observational studies. But the MR paper is convincing to me. The risks for mild drinking appear to be low enough that I don't abstain, and I am happy to tell my patients about my thought process. 2. While we like to claim that a study randomizing people to alcohol wouldn't be ethical, pre-2014 I don't think that would have been true. I think there was enough equipoise. Post-2014, I would need to see some strong counter-evidence to make me think there is equipoise once again. 3. The environment changes. A trial came out last week showing that ASA may be harmful for older healthy people [2]. This probably reflects that our bloodstream is no longer nicotine-filled, etc., so the heart attack risk is low enough that the bleeding risk may outweigh it. There may be something about alcohol that was helpful in the 1950s that is no longer so today, due to these environmental changes. 1 = (Free full link): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091648/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091648/ 2 = https://www.nejm.org/doi/full/10.1056/NEJMoa1800722?query=featured_home https://www.nejm.org/doi/full/10.1056/NEJMoa1800722?query=fe...

beefman 8y ago
The first paper is about blood lipids and CHD and doesn't seem to mention alcohol. Did you post the wrong link?
- carbocation 8y ago
  Whoops, yes. Correcting it now. Thank you. Also updated 2015 to 2014.
deleted 8y ago
[deleted]
sjbase 8y ago
Edit: disregard, seeing the updated link you posted. ---- If I'm reading correctly, that 2015 MR paper establishes that LDL and triglycerides play a role in heart disease by filtering populations used in prior studies for genetic blood lipid factors. But it doesn't make any claims about alcohol. Is there already a well established link between alcohol and LDL / triglycerides? My impression is that the relationship between LDL, HDL, and triglycerides and what we eat/drink is not well understood. But I'm not involved in biology or medicine, so maybe you can help me understand this better?
- carbocation 8y ago
  Yes, this is my fault. Sorry about that. Thanks to 'beefman for catching the wrong link, as well.
FLUX-YOU 8y ago
>There may be something about alcohol that was helpful in the 1950s that is no longer so today, due to these environmental changes. Maybe an interaction with the prevalence of leaded gasoline?
alexlikeits1999 8y ago
Thank you very much for that first link. It seems to be severely under-publicised considering the huge amount of exposure that the topic gets. Do you happen to know if rs1229984 is linked to any particular group that could make this result problematic? I noticed that the paper mentions that "There was also some evidence for a difference in years of education, and, while the size of the effect was small, this requires further investigation." That sounds like a decent-sized red flag.
- bhk 8y ago
  > Do you happen to know if rs1229984 is linked to any particular group that could make this result problematic? It seems to me that we would not have to know about the link in order for the conclusions to be unfounded. These MR analyses rest on the assumption that the instrument is not linked to any potential confounders. This seems like a bold and unwarranted assumption when we are talking about an instrument linked to behavior, given the complexity of the chain of events (chemical, biological, and psychological) between gene expression and observable human behavior. That education red flag involves just one possible confounder out of many that were never considered.
- carbocation 8y ago
  Yes, there is almost always stratification across populations for any chosen marker. You can check out gnomAD for this SNP: http://gnomad.broadinstitute.org/variant/4-100239319-T-C http://gnomad.broadinstitute.org/variant/4-100239319-T-C Take a look at the population frequencies on the right. While the minor allele is infrequent in Europeans, it is extremely common in East Asians, for example.
nealabq 8y ago
Does ASA stand for Alcohol Septal Ablation?
- rpeden 8y ago
  In this case, ASA is Aspirin.
  - nealabq 8y ago
    I am surprised that taking a baby aspirin every day may turn out to be harmful. It's been common wisdom for years, and now it may (or may not) be wrong. Like the advice that chocolate and red wine is good for you.
    - justtopost 8y ago
      Why would taking a drug everyday not seem like it could have some obvious concequences?
    - copperx 8y ago
      I remember reading a paper some time ago claiming a relationship between NSAID use and kidney cancer. And then one about Aspirin use and lower risk of colon cancer. The side effects of Aspirin are not just the risk of stomach bleeding as stated on the package.
    - jakobegger 8y ago
      If some drug was unconditionally good for us, why haven't our bodies evolved to secrete that drug on their own?
quotemstr 8y ago
> 2. While we like to claim that a study randomizing people to alcohol wouldn't be ethical, pre-2014 I don't think that would have been true. I think there was enough equipoise. Post-2014, I would need to see some strong counter-evidence to make me think there is equipoise once again. That's a very convenient way to socially forbid replication attempts. I don't buy it. The argument basically amounts to a claim that we answered the question definitively in 2014 and anyone questioning that result now is unethical. Today's scientific research, especially in any area pertaining to people, is too unreliable to blindly trust this way.
- joshgel 8y ago
  What's the line? If we found that some intervention group had 90% mortality with the control group having 10% mortality in some experiment, I think you would agree we shouldn't repeat that experiment with a lot of people as you would be randomizing to something likely to kill them. What about 20% mortality to 10%? What about 11% to 10%? What degree of certainty about the results do you need? Obviously there is a line somewhere. But, its not easy, so I wouldn't recommend dismissing such concerns glibly. Is that the same as claiming we answered the question definitively, or is that just ethical research?
  - quotemstr 8y ago
    We're not talking about administering arsenic to people just in case we're wrong about thousands of years of experience. We're talking about randomizing exposure to an activity that billions of people choose voluntarily, an activity that at worst has an effect of a few parts per 100,000. That's on the same order of risk as being struck by lightning. Unnecessary x-rays are likely worse. Why the outrage over this risk in particular? Declaring this level of risk to be outside the bounds of permissible research is an attitude incompatible with scientific progress. It's elevating short-term harm prevention to an unjustifiable extreme that makes it impossible to determine whether we have an accurate model of the world.
- carbocation 8y ago
  Sure, you could run an alcohol intervention by an IRB and see what they say. If they think there is equipoise they might go for it. Just because I don't agree doesn't mean I feel strongly about it or would throw down some gauntlet.

beefman 8y ago

The first paper is about blood lipids and CHD and doesn't seem to mention alcohol. Did you post the wrong link?

carbocation 8y ago
Whoops, yes. Correcting it now. Thank you. Also updated 2015 to 2014.

deleted 8y ago

[deleted]

sjbase 8y ago

Edit: disregard, seeing the updated link you posted. ---- If I'm reading correctly, that 2015 MR paper establishes that LDL and triglycerides play a role in heart disease by filtering populations used in prior studies for genetic blood lipid factors. But it doesn't make any claims about alcohol. Is there already a well established link between alcohol and LDL / triglycerides? My impression is that the relationship between LDL, HDL, and triglycerides and what we eat/drink is not well understood. But I'm not involved in biology or medicine, so maybe you can help me understand this better?

carbocation 8y ago
Yes, this is my fault. Sorry about that. Thanks to 'beefman for catching the wrong link, as well.

FLUX-YOU 8y ago

>There may be something about alcohol that was helpful in the 1950s that is no longer so today, due to these environmental changes. Maybe an interaction with the prevalence of leaded gasoline?

alexlikeits1999 8y ago

Thank you very much for that first link. It seems to be severely under-publicised considering the huge amount of exposure that the topic gets. Do you happen to know if rs1229984 is linked to any particular group that could make this result problematic? I noticed that the paper mentions that "There was also some evidence for a difference in years of education, and, while the size of the effect was small, this requires further investigation." That sounds like a decent-sized red flag.

bhk 8y ago
> Do you happen to know if rs1229984 is linked to any particular group that could make this result problematic? It seems to me that we would not have to know about the link in order for the conclusions to be unfounded. These MR analyses rest on the assumption that the instrument is not linked to any potential confounders. This seems like a bold and unwarranted assumption when we are talking about an instrument linked to behavior, given the complexity of the chain of events (chemical, biological, and psychological) between gene expression and observable human behavior. That education red flag involves just one possible confounder out of many that were never considered.
carbocation 8y ago
Yes, there is almost always stratification across populations for any chosen marker. You can check out gnomAD for this SNP: http://gnomad.broadinstitute.org/variant/4-100239319-T-C http://gnomad.broadinstitute.org/variant/4-100239319-T-C Take a look at the population frequencies on the right. While the minor allele is infrequent in Europeans, it is extremely common in East Asians, for example.

nealabq 8y ago

Does ASA stand for Alcohol Septal Ablation?

rpeden 8y ago
In this case, ASA is Aspirin.
- nealabq 8y ago
  I am surprised that taking a baby aspirin every day may turn out to be harmful. It's been common wisdom for years, and now it may (or may not) be wrong. Like the advice that chocolate and red wine is good for you.
  - justtopost 8y ago
    Why would taking a drug everyday not seem like it could have some obvious concequences?
  - copperx 8y ago
    I remember reading a paper some time ago claiming a relationship between NSAID use and kidney cancer. And then one about Aspirin use and lower risk of colon cancer. The side effects of Aspirin are not just the risk of stomach bleeding as stated on the package.
  - jakobegger 8y ago
    If some drug was unconditionally good for us, why haven't our bodies evolved to secrete that drug on their own?

quotemstr 8y ago

> 2. While we like to claim that a study randomizing people to alcohol wouldn't be ethical, pre-2014 I don't think that would have been true. I think there was enough equipoise. Post-2014, I would need to see some strong counter-evidence to make me think there is equipoise once again. That's a very convenient way to socially forbid replication attempts. I don't buy it. The argument basically amounts to a claim that we answered the question definitively in 2014 and anyone questioning that result now is unethical. Today's scientific research, especially in any area pertaining to people, is too unreliable to blindly trust this way.

joshgel 8y ago
What's the line? If we found that some intervention group had 90% mortality with the control group having 10% mortality in some experiment, I think you would agree we shouldn't repeat that experiment with a lot of people as you would be randomizing to something likely to kill them. What about 20% mortality to 10%? What about 11% to 10%? What degree of certainty about the results do you need? Obviously there is a line somewhere. But, its not easy, so I wouldn't recommend dismissing such concerns glibly. Is that the same as claiming we answered the question definitively, or is that just ethical research?
- quotemstr 8y ago
  We're not talking about administering arsenic to people just in case we're wrong about thousands of years of experience. We're talking about randomizing exposure to an activity that billions of people choose voluntarily, an activity that at worst has an effect of a few parts per 100,000. That's on the same order of risk as being struck by lightning. Unnecessary x-rays are likely worse. Why the outrage over this risk in particular? Declaring this level of risk to be outside the bounds of permissible research is an attitude incompatible with scientific progress. It's elevating short-term harm prevention to an unjustifiable extreme that makes it impossible to determine whether we have an accurate model of the world.
carbocation 8y ago
Sure, you could run an alcohol intervention by an IRB and see what they say. If they think there is equipoise they might go for it. Just because I don't agree doesn't mean I feel strongly about it or would throw down some gauntlet.