we have this idea that science is about precision and certainty. that we can run a scientific
experiment and prove something beyond all doubt. but in reality, the opposite is true. most if not
all sciences deal in uncertainty. in biomedical science (biology, medicine, public health) we're never
100% sure. instead, the scientific process is about approximation. a gradual reduction of uncertainty
this is very jarring for a lot of people because it clashes with our expectations. i'll
give you a real world example: red meat. totally non-controversial topic, right? forget for a second
whether you love or hate red meat, push all of that to the side, pretend we're a team of scientists
trying to objectively figure out this question, what is the health impact of consuming red meat? to
make it more specific let's say on cardiovascular disease. now, we're starting from square one so we
know nothing and we have zero certainty. so we start by studying a group of people, let's
say the population of a city. for example this study found that higher consumption of red meat
was associated with increased risk of coronary heart disease and this one found increased risk
of death due to different causes, including heart disease, was associated with red meat intake
so just with that information, what's our level of certainty regarding the effect of red meat
on cardiovascular disease? it's very low. we're slightly better off than we were a minute ago
by learning all of this but not by much, because there's just too many loose ends
for example red meat includes bacon, salami, beef jerky and steaks, and those are very different
beasts. so maybe processed meat is a problem but steaks are totally fine? so we want to look at
those things separately. so the first study we saw a minute ago found higher intake of total red meat
or red meat excluding processed meat both were significantly associated with higher risk of
coronary heart disease, and the second study also found both processed and unprocessed red meat
were associated with higher risk of death of multiple causes including heart disease. okay, so
that adds some information. the associations seem to hold up with unprocessed red meat specifically
but we still have a lot of loose ends. for example, these two studies we've been looking at, are they
just a fluke? maybe they're just outliers? so we want to run this type of analysis on multiple
populations and average everything, that's called a meta-analysis. here's a recent one
from last year, they included 13 studies and they found higher consumption of unprocessed red meat
was associated with 9% higher risk of ischemic heart disease. now, these estimates are
always for a specific amount, in this case it's for each 50 grams eaten daily, and 50 grams is about
1.7 ounce, so about a quarter of a full-size eight-ounce steak. so averaging out a bunch of
studies confirms the general direction of association which increases our confidence
slightly, but it's far from a slam dunk. for example the overall effect, although significant,
is modest, at least for a relatively small amount of meat. i told you this video is about uncertainty
so we always want to ask ourselves, am i being shown a pixel or the big picture? if i zoom out
does the picture change? it's the same with these videos, you want to continuously ask yourself,
is somebody else showing an even broader picture with even more nuance?
okay, we still have tons of confounders in the mix, for example, people who eat more red meat
also tend to exercise less, smoke more, drink more, be more overweight, etc. so maybe those factors are
the real problem and red meat is just an innocent bystander. so in order to address this question,
studies adjust for those factors. for example, that second study we looked at, with mortality.
their results were adjusted for sex, age, ethnicity, education, health at baseline, history of heart
disease, stroke, diabetes and cancer, smoking, BMI, physical activity, alcohol and total calories
among other factors. interestingly, they found the associations with red meat were actually stronger
after other risk factors were removed from the equation. the mortality associated with red meat
was stronger in non-smokers or former smokers, in people with normal bmi and in non or mild alcohol
drinkers. so this is the opposite of what we would expect if red meat was an innocent bystander
the effect is stronger in a clean background, in healthy, lean people who don't smoke or drink much
the authors explain: the effects were more pronounced in the absence of other important risk
factors, for example, the risk associated with red meat was weaker among current smokers. these people
already have higher risk to begin with, from smoking, so the relative contribution of red
meat to this already higher risk will seem smaller. so these results argue against the idea that red
meat is just an innocent bystander and that the links to disease are just due to smoking more
or exercising less, the data is pointing in the opposite direction. okay, so maybe tobacco and booze
don't explain it but what about junk food? maybe the problem is the soda and the bun, and the patty
is just getting a bad rep by association? how do we untangle those factors? for example, this study
asked if ultra processed food and animal foods, including red meat, have independent health effects
they found that ultra-processed foods, aka junk food, were associated with more total death, even
when all animal foods were taken out of the equation. adjusted statistically. so the harm
associated with junk food can't simply be pinned on animal foods. ultra-processed foods seem to
have an independent effect. similarly, they found that red meat was also associated with more total
death after ultra-processed food was taken out of the equation, suggesting the association between
red meat and disease can't simply be pinned on junk food. so that's one approach to this question
another approach is to look at overall dietary patterns. similar to the logic we saw before. if
red meat is an innocent bystander and if the real culprit is junk food, then we might expect
red meat to look less harmful in the context of a healthy diet, with more fruits and vegetables,
less soda, less trans fats and less added salt. but this study found the exact opposite
the association between unprocessed red meat intake and cardiovascular disease was stronger
in participants consuming a higher quality diet with those characteristics we just listed, so
this makes it less likely that's all just due to junk food, because the red meat without the junk
food if anything is showing stronger associations. okay, but everything so far is just correlations
just association, just epidemiology. so what other types of evidence do we have? well, analyses have
shown the increased risks associated with red meat may be partly accounted for by heme iron
which is very concentrated in red meat. so that's a candidate mechanism for the effect of red meat. now,
we want to be very careful with mechanisms because they get used and abused
mechanisms never replace outcome evidence, actual evidence of cardiovascular disease in humans, but
if they align with the outcome evidence then they can be ancillary, they can increase our confidence
a little bit. okay, what about randomized controlled trials, RCTs? aren't those the big dogs when it
comes to data? well, most of the large randomized controlled trials in nutrition that lasted for
several years changed entire dietary patterns, not a single food. for example, Lyon and PREDIMED looked
at mediterranean diets, which are typically low in red meat, while the women's health initiative
lowered dietary fat in general, including lowering red meat by about one and a half servings per week
predimed reported 30% lower cardiovascular risk, lyon reported 50 to 70% lower
and the women's health initiative reported no significant effect, although when they followed
the volunteers past the trial for a total of 18 years observationally, there was a significant
association between higher intake of unprocessed red meat and risk of dying from cardiovascular
disease. the bottom line for me, these large trials looking at entire dietary patterns
are pretty inconclusive when it comes to red meat specifically, because they change a thousand things
so how can we know what is or isn't caused by red meat among all the other factors? okay, what if we
ran an RCT that swapped only red meat? that would nail it, right? well, studies have done that, this one
for example. for three days every week they swapped red meat with legumes like lentils, beans and
chickpeas while leaving overall calories constant, and the legume-based diet decreased blood glucose,
insulin, triglycerides and ldl-cholesterol. okay, that raises our confidence a little bit. is it 100%
yet? nope. why not? it's a randomized controlled trial. number one, it only looked at serum markers, not
actual disease outcomes. so do these short term improvements result in actual lower risk of
disease long term? maybe, but this trial can't prove it. also, the population they looked at
was overweight diabetics. would we see the same thing in healthy fit 25 year olds?
this study can't prove that. also, maybe it's not the red meat that's harmful, maybe it's
the beans that are really healthful. did i mention uncertainty? okay, do we have any more data that
can raise our certainty? most foods that are rich in saturated fat, like fatty meats and butter,
raise ApoB. ApoB is a measure of the lipoprotein particles in our blood that cause plaque,
heart disease. okay, so that points in the same general direction and gives us a little bit more
confidence. why doesn't that nail it though? if red meat, at least red meat with any fat, raises ApoB,
and ApoB causes heart disease, how is that not 100%? well, red meat could raise ApoB,
and ApoB could raise risk, but red meat could do something else physiologically that offsets risk
and the net effect of the food could be neutral or even positive theoretically. you see where we're
going with all of this? there's no such thing as a perfect experiment, if we look at things
objectively, every piece of evidence has blind spots, regardless of how rigorous it is. it's not
a flaw, it's a feature of scientific experiments. so looking at a study and pointing out the blind
spots is trivial, it doesn't even require any specific insight. don't get me wrong, study quality
matters, there are more and less rigorous RCTs and the same for epidemiology. so we go through each
study carefully and the most rigorous ones rank higher, but the idea that any limitation or blind
spot makes a study useless is a misunderstanding. because they all have them, without exception. now,
sometimes people say nutrition science is weak because it's all epidemiology
nothing could be farther from the truth. there are thousands of randomized controlled trials in
nutrition, i just showed you several. the real epiphany is that RCTs, although they're abundant,
are also imperfect. this does not mean that we can't ever know anything so we just give up and
wait for the perfect experiment to come along. it's the exact opposite of that, the perfect experiment
will never come. confidence around a scientific question is built not by finding the perfect pixel
but by stepping back and looking at the big picture. preponderance of evidence.
when we see reproducibility, especially different experimental approaches pointing in the same
direction, that raises confidence. sometimes we confuse not knowing something with 100% certainty
with not knowing anything at all. but of course those are vastly different. uncertainty is normal,
it's integral to all life decisions. where we go to school, who we marry, what job we take. we
gather information to increase our confidence but it's never 100% guaranteed, it's always an educated
guess. in fact, here's some more uncertainty around red meat: dose matters. risk seems to get
larger above 100 grams per day average intake of unprocessed red meat. replacement matters,
cutting back on steaks to replace with bacon or ultra processed foods, refined grains, is not
a good move. and different cuts of meat can have very different effects, the bold trial showed it's
possible to add red meat to a diet while improving lipids as long as total saturated fat is reduced
which they achieved by using very lean cuts. so this might be useful information for people who
choose to include some red meat in their diet while still keeping their cardiovascular risk
factors under control. okay, what about grass-fed beef and wild game? the idea is that because those
animals live in more natural conditions, are leaner and aren't fed grains or stuffed with antibiotics
they might be more health promoting. some of those meats have also been shown to contain more
omega-3s. but at the end of the day what we want to know are the actual health effects in people
eating these products, and there is surprisingly little data on that. for example this study found
some undesirable changes to lipid profile when people ate grass-fed meat compared to grain-fed
for example, higher triglycerides. although the study wasn't quite isocaloric, people on
grass-fed ate a bit more calories overall so it's hard to interpret their results. and this trial
randomized volunteers to grass-fed or grain-fed meat and dairy and found no difference in lipids,
glucose metabolism or body composition between the two groups. if future data shows a lower
risk of disease long term on grass-fed or wild caught meat, great. until we have actual evidence,
the only rigorous thing we can say is we don't know. okay, more uncertainty: there are pros and
cons to red meat. for example this study found that unprocessed red meat was associated with
ischemic heart disease, diverticulosis and colon polyps, among other things, but less
iron deficiency anemia. so is red meat good or bad? depends on context. for a population in a
developing country, with an impoverished diet, low in amino acids, low in micronutrients, adding some
red meat is probably a good thing. for the typical overfed hypercholesterolemic western population,
replacing some of the red meat with some fish or plant protein would be a health-promoting move
for an elderly, frail population with low appetite, with nutrient insufficiencies
adding some red meat is probably a good thing. all about context. and there's always individual
variability, some people can handle more than others. one rule of thumb is, if your cholesterol
and your apoB are golden, you're probably doing alright, and family history can also give us
some hints. scientists have to bear all of these factors in mind, that's why food recommendations
by professional scientific organizations often sound vague. "favor a dietary pattern high in fruits
and vegetables and moderate or low in red meat". they all say essentially the same thing, notice that no
reputable organization says you have to have zero and nobody recommends eating piles of it
and of course this type of advice annoys everybody because usually half the people want meat to be
poison for humans and the other half want it to be completely risk-free no matter the amount
but the science doesn't support either of those scenarios which just ends up upsetting everyone
now wait a minute, what if we run the perfect randomized controlled trial? we take like a million
people, we randomly split them, we give half of them a pile of red meat every single day, the other half
no red meat, and we follow them for like 20 years. that would nail it, right? extremely difficult to
get volunteers to stick to the diets for that long, getting funding, getting an ethics committee to
approve a study like that, i doubt we'll ever see one, but even if it was done, how much difference
would it really make? it would raise our confidence a bit more, sure, but it still wouldn't be a hundred
percent? how do you know they stuck to the diet for that long? you can't trap people in a research
facility for decades so you have to let them go about their lives and then just ask them what
they ate. self-report. how do you know everything else stay the same? maybe the meatless group got
motivated by that change and decided to also smoke a little bit less and exercise a little bit more
so you gotta ask them. self-report again. these are the same caveats of epidemiology, which is
why some researchers say the longer your RCT the more it looks like epidemiology, the longer you go
the less control you have. if you study overweight pre-diabetics it doesn't apply to healthy people
if you look at super fit individuals it doesn't apply to most westerners. how is the meat cooked?
if it's grilled or fried then maybe the problem is not the meat, maybe it's the chemicals that get
formed at high temperature. if it's carefully boiled or steamed then it doesn't apply to
how most people eat it. what are the macros of the diet around the meat? if it's high fat it
doesn't apply to people on intermediate fat, if it's high carb it doesn't apply to low
carb, if you go low carb, let's say 10% carbs, it doesn't apply to people on very low carb or keto
if you go keto at five percent carbs, somebody will say, "ah the problem is not the meat it's the
five percent of carbs you left in there". and if you do zero carb then it doesn't apply to 99.99%
of the population. i think you get the point, there's no such thing as the perfect experiment
the perfect experiment is an abstract concept talked about by people who don't run experiments
and this gets us to another very common question, which is saying that the risk factor doesn't apply
to my specific characteristics. studies of tobacco usually look at populations that eat worse than me,
exercise less and have higher cholesterol so i'm just going to keep smoking like a chimney
until science can prove to me that tobacco is bad specifically for somebody with very
low cholesterol, who is 6'1'' and does yoga on mondays. i can discount every risk factor known
to man with this logic, but of course this misses the point. science is never going to
reflect my exact physiological characteristics and my exact diet and my exact circumstances
that's not the goal. tobacco is an accepted risk factor because it's been shown over and over in
different populations, different lines of evidence support it and it survived many adjustments. there's
never been a 20-year randomized controlled trial for tobacco or for trans fats or for diabetes or for
junk food and yet we accept all of them, we take them for granted and we assume they apply to us
until proven otherwise. as annoying as it is, science can never give us a hundred percent
certainty. what it's very good at doing though is giving us crucial pieces of information so
we can make educated decisions in a world packed with uncertainty. here's more details
on saturated fat and here's more on apob. let me know your thoughts below, be well, take care