Who, me?? Why did I clog my 'widow maker'? [on medical cause and effect...and how we know, if we know]

So, having just returned from and now recuperating from coronary bypass surgery, I have to ask the 'complexity' question--a very personal one in this case: Why me? I've lived a physically and physiologically vigorous life.  My diet may not have always been the very best for cardio health (though, for reasons we've discussed here many times over the years, it's not completely clear what that diet should actually be), but it wasn't particularly bad, given what's thought these days to be a "healthy" diet.  

The surgeon who remodeled me at Penn State's fine medical complex in Hershey, said he knows the risk factors in a population but couldn't know why any given individual developed clogged coronary arteries, nor which artery would be affected.  His job was to replace, not explain them, one might say.  So, he didn't even attempt to tell me why I was now in need of bypass surgery.  

As he said, there are five known major risk factors: obesity, unhealthy diet, high cholesterol, genetic predisposition, and smoking. Yes, having diabetes and high blood pressure are risk factors as well, but correlated enough with obesity that perhaps he considers these two conditions to be side effects of obesity.  In any case, these risk factors have been determined by looking at associations between possible causal variables and heart disease in populations.  Resulting statistics describe the population, not identifying specific high-risk individuals within it.  Indeed, some people with heart disease have all the risk factors, some have a combination of a few, and some have none.  And even then, it's not possible to say which was the cause of the disease in most individual cases.   

I have none of these risk factors -- though, I could make up a story.  I smoked when I was young, my father had a pacemaker when he was old, but he lived to 99.  Still, I have done vigorous exercise my whole life, thinking that was my "get cancer program" since it meant, I thought, that I would go not out with a coronary.  What caused my artery to clog?  Indeed, why in my case was the clog in an unstentable artery location, and hence required major surgery? 

This brings up, again, the question of whether one's individual risk can even be known with any sort of 'precision'. Or is that an illusion? Is it a culpably false promise made by the calculating Dr Collins at NIH, to get NIH funding, rather than to give the public a realistic understanding of what we know and what we can hope to know based on research investment of the type he favors?

How, based on current methods of science, can it really be individual? What kind of information would that require, just considering actual, i.e., past effects, assuming they could really be ascertained to any reasonable measurement standard?  What would you need to consider?  Diet, exercise, personality (temperament, for example).  Climate?  Profession? The effects of war, drought, epidemic?  Genes, even?

Of course, the gross and inexcusable BS of promising 'precision genomic medicine' based on very costly, open-ended genomic (and other 'omic) data collection enterprises is culpable.  It is an often openly acknowledged way of getting, and keeping, mega-funding without having any real ideas (and understandable since medical schools culpably don't pay faculty salaries or basic research costs as part of their jobs).  Focused science has chances of finding things out; blind data enumeration, far less so--and what we've done of that so far shows this quite clearly.

We often say 'family history', and clinically this may be the most useful piece of predictive information, but what does that actually explain?  Did Dad or Uncle Jane have the same trait because of genes, or because of their shared family habits and lifestyles?  How could you really tell?  A surgeon need not care, as their job is to fix the clogged pipes, and if heart disease runs in a family the physician will treat his or her patient as high risk.  Still, to prevent this sort of thing, we need to know what causes it. 

This is a central biomedical question!  It is hard enough to know, much less accurately measure, all factors in life that might in this or that way be a 'risk' factor for a given disease, like clogged coronary plumbing.  Is it a delusion to think we could identify, much less measure all the factors?  If, as seems obvious, there isn't just a single factor, and probably everyone's exposure set is different (and their effects need not be 'additive'), how on earth can we even know how well we are measuring, or ascertaining, such factors?

And, if we can do this, it only applies directly to current cases and their past lifestyle exposures.  But what we would like to do, for individuals and for public health, is to predict the future to lower risks.  However, there is no way, not even in principle, no reasonable chance of knowing what future exposures will be, not even for populations.  Diets and lifestyles change in ways we cannot predict, nor can we predict major future events--climate, war, pestilence, food types and availability, etc., that would be highly relevant.

So what should we do with our understanding of these unpredictable factors?  Perhaps just level with patients and the public, and stop using the public to endow a particular, and particularly costly, part of the university research empire.  Maybe a return to focused, hypothesis--based research--actual science--in my view.

Real Truth in Labeling for the new statin replacement

The FDA is about to or just has approve a new cholesterol-fighting drug to supplement or replace statins.  But is it taking all the 'side effects' into account?  Should it?  The new substances (several pharmaceutical outfits apparently have them near to market) inhibit a different genetic pathway from what statins do and can be used to treat high cholesterol in those who can't handle statins, or for whom statins aren't lowering their LDL cholesterol, and may also actually be much more effective even for the current millions who take statins.

These drugs inhibit the action of a gene called PCSK9 and interfere with the liver's detection and response to LDL levels in the body; see the NYT story here from last week for more details about the drugs.  The excited news reports, at least, describe what are truly remarkable reductions in LDL levels without untoward side effects. If these facts stand up to larger or longer term trials and experience, it will be a major pharmaceutical success....in more ways than one.

One immediate issue is the 'usage creep' that almost inevitably seems to follow the appearance of a new drug, and in this case one with fewer side effects and higher efficacy with regard to lowering the most dangerous type of circulating cholesterol (the 'bad', or LDL form). Recommended approval is for use in three groups of patients: those whose high LDL cholesterol can't be lowered sufficiently with statins, those at particularly high risk because of previous heart attack or diabetes and high LDL, and those with high levels of LDL who can't tolerate statins.

But if these agents are as effective as reports suggest, and with less or even no serious side effects, then even if they are initially approved or recommended for just these specific groups, usage will surely expand as the definition of who is 'at risk' expands. Perhaps people whose cholesterol is responding to statins but who don't like the side effects, or someone whose close relative has had heart disease but whose current LDL levels are not high will ask for this treatment as a preventive, or doctors will think 'off label' usage is absolutely proper, assuming no serious side effects. Hell, if the makers are extremely lucky, maybe it will turn out it even treats erectile dysfunction or male-pattern baldness! And then, what about extending to, say, younger ages or even simply to everyone, like putting vitamins in milk or iodine in salt?  This is what we mean by usage creep.

One might reasonably say that this is just what should be done.  Precedent might suggest that eventually we'll find that the agents are less effective than current tests suggest or have some serious long-term but as yet undiscovered downsides.  However, things that can't be known until the drug is used by millions of people for numbers of years.  Making decisions about usage is harder than one might think.

One reason for concern about usage creep is already being mentioned in the blaring news stories about the apparently genuinely major advantages of these compounds.  That is, the obvious issue of the financial mega-bonanza to be reaped by the pharmaceutical firms.  These drugs are going to be very expensive.  The money to be made is certain to encourage usage creep.  Could we expect otherwise?

But worse than just profiteering is that, even with Obamacare available so that presumably even the poor could have access to these beneficial drugs, putting the whole population, so to speak, on these pills for their whole lives, could bankrupt the health-care funding system that is already a heavy burden on society.  It's being suggested that these new pharmaceuticals could simply by themselves eat up any reasonable premium level for health care plans.

But there is another issue, and that relates to truth in advertising and the issue of side effects--and here we don't refer to incomplete data that may be leading to premature approval or anything like that.  Instead, it's more of a philosophical issue:  What does a list of side effects mean, in this case, and what would the whole truth actually be? What should the manufacturer or the FDA tell you so you would be truly better informed when you take the new drugs for the rest of your life, as so many are likely to do, across the developed world?

From the Sanofi website; Sanofi is one of the makers of these statin replacements

What the FDA and medical community doesn't list on the label
The FDA requires that known side effects of drugs be clearly stated on packaging or labeling material, and surely physicians will know about them.  Isn't that right?  It should be, but there is a sleeping tiger here, that apparently nobody has thought about or, if they have, that they've buried so deep you never will realize it.  In fact, there will be huge unstated negative side effects of these new drugs.  Indeed, shouldn't a proper labeling for these new medications include something like the following?:

"WARNING: Use of this product will greatly increase your risk of Alzheimer's Disease and other dementias, arthritis and other muscle and joint diseases, some forms of cancer, diminished vision and hearing, other degenerative disorders, and accidental death."

Of course such truth in labeling won't happen, and the reasons are subtle and if taken seriously would lead us, as a society, to think more deeply about the role of medicine in health, and of the meaning of health, in a real world in which life is finite.  There is no one who can provide 'the' answers to the problems that are raised, and indeed each person would, in principle, provide his/her own answers.

But at least, there should be a societal discussion.  The reason has to do with the concept of 'causation' and the demographic realities in a world of competing causes.  If these drugs lower LDL cholesterol anywhere nearly as much as they seem on present evidence to do, and if the association between LDL cholesterol and heart disease is as linear as is hoped, then that by itself will eliminate or greatly forestall the occurrence of fatal heart disease in those who take them.  But then what?

If people live much longer as a result, they will inevitably get the sorts of diseases that could be included in an empirically correct labeling!  If you don't get heart disease, it is simply obvious that you will get something else, and it is likely to be slower and more progressive than the quick end to life that heart attacks can be.  Note that our warning list did not include some causes, like kidney failure, diabetes, and the like that could be stalled or avoided by lowering LDL cholesterol--so we are being quite conservative here.

The problem is that of what are known as competing causes, and we've written about it before.  It is inevitable that you will die of something.  If not heart disease, something else.  One might say, well, OK, but at least I'll have more years of life before that something-else gets me. This is likely to be true to some extent, but there are two cautions.

First, people with heart disease often have other health issues because by and large heart diseases gets people at older age, and they are more likely to have less healthy lifestyles.  That includes more risky conditions than high cholesterol.  So, these other causes may be lurking just around the corner, so the removal of heart disease may mean that the gain in years might not be very much!

Secondly, other disorders that those saved from heart attacks will eventually get, if they don't have them already, are ones with gradual onset: you become more and more affected over time.  Mental deficiencies, joint and mobility problems, vision and hearing, are clear examples.  And the nature of accelerating risk is that if you slow it down you defer the onset of serious-level symptoms but you also stretch out the decay process at the end: you have more years with more and more serious symptoms before your body finally conks out.

What is 'cause'?
Are we just playing word games here?  Is it accurate to suggest that the new drugs will 'cause' dementia?  Surely the chemical doesn't mess with neurons!  Let's assume that's true and that no such direct molecular effect is ever found. Then the effect of the medication is related to the occurrence of these other traits, but not in a directly causal way.

This raises questions about causation.  It is more than simply saying that correlation is not the same as causation, because while the active mechanisms responsible for, say, Alzheimer's or joint disease, are not affected by the LDL-reducing drugs, they open the way for the former to act because the person lives longer.  Correlations such as the brand of car you drive being associated with some forms of disease arise because both may be the result of income levels and associated dietary habits. The dietary habits, not the type of car, are causes of interest.

But in the case of competing causes of disease, reduction of one is a sort of mechanistic effect, not just a spurious cause.  If a mechanism is changed in a way that allows a different mechanism to proceed for longer times, this is part of the overall mechanism of the related traits.  The chronic late-onset diseases most of us in the rich world die of now are directly the result of so successfully controlling infectious diseases, our previous killers. One definition of cause is that if you remove it, the effect changes, in this case the protective effect, relative to cancer, of dying of a heart attack.

And what if widespread use of these new drugs puts serious pressure on the health care system, so that some treatments will have to be deferred or denied to more people than presently?  Is that so unlikely?  And is that then not a cause of deteriorating health?

And what if it worked miracles and the relative fraction of our population (and the world's population) of wearing-out old people substantially increased?  That puts all sorts of pressures and pinches on everyone else, indeed, even on the normal living needs of the increased elderly segment.

Causation is not so simple and straightforward a notion.

So, what is 'health care'?
The new LDL reducers raise many deep, and deeply important questions.  The point here is to be realistic about disease in our society and have an open consideration of how to deal with the kinds of game-changing environmental or behavioral aspects of our society, and their long shadow of implications.

In a very serious sense, even if indirectly, the new LDL-lowering agents might have disastrous effects for countless numbers of people.  It's a discussion we should be having.  The news media should be leading the way, to force that on the scientists and health system.

Indeed, these issues should force us to consider what, exactly, we even mean by 'medical care' and 'health care'.  How do they relate to each other, and to the idea of 'public health'?

We think these are real, complex, disturbing, serious truths that have no one answer, and that affect individuals as well as society.  This is not a matter of complaining about science, policy or even drug company profits.  It is about profound issues in human life, that should be discussed openly and fully, because they affect everyone's future.

When good cholesterol isn't

First we were told to lower our cholesterol.  This was back in the 1960's, when the first results of the then major new epidemiological project, the Framingham Heart Study, were released.  If the Framingham Heart Study taught us anything, it was that high cholesterol was a major risk factor for heart disease.  So we all started eating oat bran and granola and eschewing beef.

And then,  in the 80's we were told that it's not all cholesterol we need to be concerned about, that there's a good and a bad cholesterol, and we should be raising one and lowering the other.  How?  Eat healthy -- no eggs, no butter, no red meat.

Egg in a spiral eggcup; Wikimedia

And then it turned out that the people living on the Mediterranean had known all along what eating healthy is -- everything in moderation, except for olive oil and red wine, two foods that we should all be consuming more of.  From the Mayo Clinic:

Key components of the Mediterranean diet

The Mediterranean diet emphasizes:

• Eating primarily plant-based foods, such as fruits and vegetables, whole grains, legumes and nuts
• Replacing butter with healthy fats, such as olive oil
• Using herbs and spices instead of salt to flavor foods
• Limiting red meat to no more than a few times a month
• Eating fish and poultry at least twice a week
• Drinking red wine in moderation (optional) [not clear which is optional here, the red wine or the moderation]

So, follow these new rules and live as long as the Italians do.  Somewhere along the line, though, eggs were taken off the list of forbidden foods, and the usual American replacement for butter, margarine, turned out to have transfats which are bad for you, and anyway, saturated fats -- the stuff that's hard at room temperature, like margarine -- aren't good for you in any form.

And it turns out it's hard to lower your bad cholesterol with diet.  So, maybe try doing it with drugs.  Statins are good.  Indeed, the more people taking statins the merrier.  But whether statins are lowering all the risky components of LDL is still open to question (e.g., this paper).  Statins are designed to control circulating lipids (fats), which confer heart-disease risk. They inhibit an enzyme called 'HMG-CoA reductase' which is expressed in liver cells as they produce cholesterol from raw ingredients and secrete it into the blood stream. Lower enzyme activity, lower circulating lipids. Whether this is what they are doing is still not entirely clear, however.  There is evidence that statins may be reducing inflammation in irritated arteries and veins, which may be what reduces risk of heart disease rather than any effect on cholesterol.  Perhaps heart disease is an inflammatory process more than one affected by cholesterol levels, after all.

Oh, but then a rather confusing study was published last year, showing that Australian men who switched polyunsaturated fat for the saturated fats in their diet did in fact lower their LDL, but they also were more likely to die of a heart attack than those who hadn't changed their diets.  Indeed, most people who have heart attacks don't have high LDL.

But ok, assuming the cholesterol model of heart disease, along with lowering LDL, it would make sense to also raise your HDL, the good cholesterol.  But now it turns out that it's possible to have too much of a good thing.  A new paper in Nature Medicine (paywall) reports that while HDL normally should keep arteries clear and protect against heart disease, in arterial walls, HDL acts quite differently from circulating HDL, and can lead to arterial blockage and heart attack.

The BBC reports that the authors say people should still "eat healthily".  But, what this means, when the definition of a healthy diet keeps changing, and today's healthy diet can be the cause of ill health, is not at all clear.

Everything in moderation seems good to go with.

Universal statins: scam....or just honest good luck for Pharma...or what?

The American Heart Association and American College of Cardiology issued new guidelines on Tuesday for reducing risk of heart disease and stroke (the first of five explanations of these new recommendations is offered here).  If you've got a 7.5% risk of heart disease or higher, as measured by their risk calculator (downloadable here), they recommend you go on statins.  This means, according to the panel, that 70 million Americans should now be considering taking these drugs.  This is perhaps 70% more than the number who now take them, and would put at least one third of all adults in the US on this drug.  For life. 

These recommendations have caused quite a ruckus, but perhaps for the wrong reasons. Before Tuesday, people were put on these drugs to lower their LDL cholesterol levels beyond a given threshold, but, confusingly to many, that threshold which we had supposed was a well-established rock-solid risk factor, has now been eliminated!  Before Tuesday, the indication for going on statins was high LDL, but the indications have now been broadened to include other risk factors such as diabetes and obesity.  So, people now taking statins wonder if they should continue, and others wonder if they need to start.  Some doctors commenting on these changes hasten to add that the most important protection against heart disease is a healthy lifestyle -- don't smoke, exercise, lose weight -- but if these can't be accomplished, statins are recommended (see Dr Harlan Krumholz on "The Newshour" on PBS, e.g.).

Wikipedia

But the new recommendation seems strange. First, a word about statins, drugs designed to control circulating lipids (fats), which confer heart-disease risks. They inhibit an enzyme called 'HMG-CoA reductase' which is expressed in liver cells as they produce cholesterol from raw ingredients and secret it into the blood stream.  Lower enzyme activity, lower circulating lipids.  But in fact, there is evidence that for some reason statins target inflammation in irritated arteries and veins, which may be what reduces risk of heart disease rather than any effect on cholesterol, so there is mystery even in the supposed reason for their supposed effectiveness.


Now, according to John Abramson and Rita Redberg in an editorial in the Thursday New York Times, statins aren't actually effective at preventing heart disease.

Statins are effective for people with known heart disease. But for people who have less than a 20 percent risk of getting heart disease in the next 10 years, statins not only fail to reduce the risk of death, but also fail even to reduce the risk of serious illness — as shown in a recent BMJ article co-written by one of us. That article shows that, based on the same data the new guidelines rely on, 140 people in this risk group would need to be treated with statins in order to prevent a single heart attack or stroke, without any overall reduction in death or serious illness.

If the recommendation is not based on evidence that everyone can agree is reliable then, where is it coming from? Partly, we think, it's a reflection of our belief that we're immortal, partly a general belief in the benefits of drug intervention.... and partly it's a reflection of the fact that some of the recommendation-makers have a vested interest in statins.

The first reason, our belief in immortality, is cultural, and of course very natural.  Few of us, even apparently those with strong religious belief in life hereafter, want to test out that belief.  Heart disease is the number 1 killer in the US and most of us don't want to die of it.

The second reason is more problematic. The most reliable way to lower heart disease risk is through diet, exercise and not smoking.  Indeed, lean, fit, non-smoking individuals whose only risk factor is high LDL are generally at low risk of heart disease.  Until this week, the purpose of statins was to lower LDL cholesterol, but that doesn't reliably lower risk of heart disease. So, are statins a good replacement for life-style?  The answer is No.

But what about the vested interest issues?  As Abramson and Redberg say:

The process by which these latest guidelines were developed gives rise to further skepticism. The group that wrote the recommendations was not sufficiently free of conflicts of interest; several of the experts on the panel have recent or current financial ties to drug makers. In addition, both the American Heart Association and the American College of Cardiology, while nonprofit entities, are heavily supported by drug companies. 

This kind of conflict of interest means that one must be highly suspicious.  One might argue that industry reps are the most knowledgeable about the benefits of their product.  If you want to know how to cure a toothache, ask a dentist, after all.  But how are we to judge the motive behind the recommendations?  Corporate-sponsored research is notoriously biased toward findings favoring their sponsor.  This doesn't mean the bias is intentional, but the evidence suggests that often it is.  At least, the corporate-sponsored research the corporate sponsors tell us about is that which favors their product, since they aren't in fact required to report all their results, and often don't.  (This is why Ben Goldacre, physician, writer and epidemiologist, started the AllTrials campaign to require that all clinical trials be registered, and all results be reported, positive and negative.)  So, when the science isn't convincing, and vested interests are involved in decision-making, it's not unreasonable to be suspicious.

Contingency and context
In addition, the related roles of context and contingency are fundamental and important to understand here.  Risk of heart disease is based on the context--genomic and environmental exposures affect the levels of statins and their consequences.  The risk in an individual is contingent on his/her situation at present, and that can change.  This seems so hard for the established system to understand!

Statins have side effects.  Risk of statin-related disease is estimated in the context of current culture.  If that culture changes, then the risks will change and by all that we know, they'll change dramatically.  If the major contexts change--better diets and so on, things we know a lot about--then the overall risk of heart disease will change.  Models can only do so well at estimating the interaction among the various factors (as the above quote suggests).  If people live healthier lives and if physicians actually pay attention to risk calculations, many may be able to go off their statins, or not start on them, as a result.

But how many will actually risk going off?  Will they keep taking, or their physicians not dare to recommend stopping, for various subjective, inertial, or even emotional reasons?  Will drug companies recommend cessation if, say, body weight goes below some value?  Will they fully advertise the fact that if other factors are favorable, to stop buying their product?  What does history--including their history--suggest to you?

And 10 years from now, how accurate will the predictions have been on which lifelong medications are now being recommended?  Will results be contingent, for example, on the current recommendations themselves?   For example, if you're on statins, will you be more likely to take that second helping of fries, feeling protected by the drug?  The Times Op-Ed puts it this way:

Perhaps more dangerous, statins provide false reassurances that may discourage patients from taking the steps that actually reduce cardiovascular disease. According to the World Health Organization, 80 percent of cardiovascular disease is caused by smoking, lack of exercise, an unhealthy diet, and other lifestyle factors. Statins give the illusion of protection to many people, who would be much better served, for example, by simply walking an extra 10 minutes per day.

These are not secret or new issues by any means, but they tend to be overlooked or minimized by a system that tries to be 'objective' based on current data.  The Op-Ed is written by respectable authors, but they are also known skeptics of the over-medicating problem, with its built-in conflicts of interest as we noted above.  So is their skepticism itself a disqualifying issue--does it mean they bias their views in a similar way to having Pharma-supported people on the panel that made the new recommendations?

Clearly, the issues are complex as so many issues related to late-onset disease are.  After all, you don't get a heart attack even at a young age like 40, unless you live to be 40.

Like second-hand smoke?  The real beneficiaries
Smokers get all sorts of diseases, because of the direct effects of the ugly weed.  But those who live in the same house also get diseases, indirectly, courtesy of their smoking cohabitant.  We have just the opposite story here.  The vendors of statins will get filthy rich as a direct result of their recommendations, whether or not they actually prevent heart disease.  And if they do, some other people--maybe the same people--will get even richer as an indirect result of the same recommendations!

If we don't die of heart disease or its associated diseases, we may live longer but that means more of us will get the slower, nastier, very expensive lingering ailments of old age.  The surgeons, retirement homes, cancer and dementia drug-makers will rake it in big-time!

We've written a few times about the subtle, surreptitious problem of competing causes, and this is another manifestation of the problem.  It's largely unavoidable that if you survive the quick-hitting earlier causes of death, you'll last and linger in service to the slower causes.  They're even more expensive.

We would not credit (nor blame) the statin-promoters for the diabolical scheming that would be involved in salivating over the indirect benefits of statin use.  That takes more perception and a longer view than most people, even scientists, usually have.  It is clear that most drug companies, not to mention the scientific research community itself, as we often write, are in for the quick kill, so to speak.

Is "more research" really needed?

The epidemiology roller-coaster
In our recent post "Wait! Wait! Don't tell me!" we discussed the roller-coaster nature of epidemiological studies of heart disease.  The attempt to identify factors that raise or lower risk has been largely farcical--tea, coffee, antioxidants, vitamin C, cholesterol, meat, processed meat, red wine, cruciferous vegetables, olive oil.....  and a host of other poisons or coronary salves that have been in and then out of favor when it comes to diet and heart disease.  Is the 'Mediterranean Diet' (the subject of another recent post) good for you or not??  (But, if it turns out you ate the wrong diet after all, here's some advice from The Onion: "Aspirin Taken daily with Bottle Of Bourbon Reduces Awareness Of Heart Attacks"--H/T Dan Parker.)

This, despite countless large, long studies.**  And going along with that, a similar story in regard to the genetics of heart disease. Genes found to be 'causal' in some studies are ruled out in others.  This has become a largely typical scene.  Yet investigators keep demanding more funding for larger, longer studies.  In our previous post, we said that when investigators or news media reporting such studies conclude with "more research is needed", you should beware that your pocket is about to be picked.  Here's why.
 
Let's here make little reference to the selfish motives of the investigators who want to leverage inconclusive results as a rationale for doing more, more, even much more of the same. We regularly carp on the opportunism, rather than careful cogent thinking, by which epidemiologists and geneticists demand ever more funding.  In fact, there are a host of more scientifically legitimate reasons to say that the plea for more studies should be ignored and is misplaced.  Clinicians have a very hard time knowing what to tell their patients, even though we know enough about diet to know--as Hippocrates explicitly did 2500 years ago!--that moderation is the key.  

Cochrane Reviews sets the whole dilemma, and the solution, to "Somebody That I Used To Know":



(Confused as a practitioner?  Bottom line - tell your patients "Don't eat like a pig and go get some activity.")

If we just do larger studies, we'll be able to get off the roller coaster... Really?
Indeed, there are many real health problems to be solved.  So let's take the issues from a scientific point of view: The rationale for more is based on the assumption that our uncertainties are due to the inadequate sizes of our samples, not to the nature of complex causation that underlies traits like heart disease--if 'heart disease' is indeed a biologically meaningful trait in the context of finding causes for 'it'.
 
The underlying assumption is basically a statistical one, that these are true, more or less independent causes and that other factors will 'even out' if we have large enough samples.  That is another way of saying that the 'signal to noise ratio' will be favorable so that the bigger the sample the clearer the signal (the measured purportedly causal factor), because it will be more easily detectable against the background of measurement errors and other unaccounted complications.  Yet another way of saying this is that these factors really are causes in the scientific sense.

The premise for the "more research is needed" claim is that by such enlarged studies we can slice and dice these putative causal factors to find out what in our diet, or, say, in the proverbial Mediterranean diet, are really responsible. Is it the skin or the meat of the almond?  Is it the tomato or some element of olive oil?  Reservatrol in red wine?  (And a lot of people with a lot invested in reservatrol certainly hope it's that.)

From philosophy of science and practical points of view alike, we can be pure empiricists:  it doesn't matter what aspect of a sensible diet, and we all have a general idea what that means, is specifically responsible! There is a time in science to accept a kind of ignorance once we know the main facts: even Isaac Newton didn't see a need to know what gravity 'is', once he knew how to understand its effects.

If we follow common sense, the problem will be eased.  We can turn out attention elsewhere.  Indeed, the cases of a disease, like heart disease, that remain, even after we do that, may be those that really are genetic or due to some specific, strong risk factor.

Why not?  Why not.
But there are many other reasons to say it doesn't matter and we don't need to chase the rainbows of this kind of hyper-reductionism.  And these reasons apply widely to biological causation, and to many other common diseases for which similar "more research is needed" demands are made. These reasons are both practical and reflect an understanding of how evolution works and how genes affect traits:

1.  Traits like heart disease arise after decades of normal life that is in fact made possible by our plentiful life style.

2.  For complex diseases, a cause whose effects don't appear for decades is a very weak one with small biological effects, so naturally will be hard to find.

3.  The effects can largely be avoided: environmental exposures, rather than genes, contribute the bulk of risk, but individual environmental components usually have very weak causal effects.

4.  Environmental (even more than genomic) components are notoriously hard and very expensive to identify, or to measure in an accurate way in practice.

5. Most environmental effects seem to be beneficial in some contexts and harmful in others (lower risk of some disease but raise it for others).

6.  Environmental effects are estimated retrospectively by studies like case-control comparisons.  But what we want to do with exposures is predict their effects, yet we don't know what the mix of future exposures will be.  Changes in other factors will affect the risk associated with a test factor--environment or gene--by so much that the factor's specific risk may be wildly different.  Yet future environments cannot be predicted in principle.

7.  Genotypic risk (the target of 'personalized genomic medicine' and GWAS research) is based on many different genes.  Common variants in those genes will stay around, but many or most causal risk factors are (a) so weak they depend thoroughly on the context of the rest of the person's genome, (b) rare so that they will not even be in the future population.  (c) New variants arise by mutation all the time, so that yesterday's genomic complexes are not tomorrow's.  Furthermore, because of sexual reproduction, segregation, and recombination (Mendel's principles), the same genotypes at the many contributing loci will not arise in new samples.  

8.  As a result, especially if rare variants are a major part of the story as they seem to be, we can't assume that the background genotypes of a given test gene will not 'even out' in large samples.

9. Genetic as well as environmental risk factors are pleiotropic--they affect many different traits.  That is why they won't necessarily have an overall good or bad effect, but will have differing effects on different traits.

10.  Even large relative risks are typically very small absolute risks.  A 30% increase in risk (quite a large increase as these things go) will only change a typical disease risk of 1% to 1.3%.  The rest of the uncertainties and inaccuracies mentioned in this list mean that such risk effects aren't stable and aren't worth the cost of identifying them, if we can get even better results with general lifestyle changes, requiring no technical or clinical costs, as we know very well.

11.  Small risks are very difficult to estimate accurately even if the estimates were stable, raising the question whether they are worth estimating, given the above issues that cloud the picture.

12.  If as we are repeatedly told, translation of research to public health improvement is the objective, we should take the overall lifestyle rather than  nit-picking approach. We don't need to identify each sub-sub-sub-element of, say, the Mediterranean or a moderation-diet, if we know that such a diet can have major effects.

13.  Elimination of one disease just leads to the increase in others, sometimes of later onset perhaps but often with longer, more miserable morbidity, higher treatment costs to the health care system and so on.

14.  And the corollary, elimination of a dietary component identified as a risk factor for one disease (alcohol and breast cancer, e.g.) might mean elimination of a factor identified as protective for another (red wine and heart disease).

So let's fund real problems, ones we can actually solve
There are many really important problems, like antibiotic resistance, the need for vaccines, other infectious disease and truly genetic disease problems that would be very suitable for focused (not 'omic') research and where the resources would be well spent, rather than throwing them in the expensive chase to estimate micro-risks.  Of course, it is the lobbying of the university research system that keeps funds pouring into the latter.

Many studies that have been going on for decades are long past their shelf-date.  The first wave of them were valuable because we didn't know better, but now we know that their findings are not stable or even correct (which doesn't mean the studies were badly done in any way---quite the contrary--it's that they were basically done well that makes the point!).  But now we have to face what we know and why these studies didn't generate definitive or clear answers.  Even the Framingham heart study, which is certainly one of the most prominent of them, shows this.  That study's primary findings, about factors as cholesterol, are now coming under various types of question to a surprising extent. Whether or to what extent we have been mistaken in our LDL/HDL/etc obsessions about cholesterol, the study that decades ago set us onto the problem long ago stopped yielding sufficient new important information.   

This is only one of the most prominent among a number of other such studies.  The new onslaught of biobanks is the next generation of such studies.  They either long ago found their main result, or they never found a cogent, durable result, or even if they just showed that definitive results are elusive, they have reached the point of costly diminishing returns.

The time has come for resources to go elsewhere.  

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**A brief digression on epidemiology's failings: first, see this nice discussion by a statistician of the idea that "90% of epidemiology is wrong." Then, consider that there are many reasons that studies can be 'wrong.'  In part it depends on the definition of 'wrong'--methodology can be inapt or misapplied, or statistical analysis can be in technical error or wrongly applied or interpreted, so that the results don't in fact accurately answer the question posed by the study. 

Or, methodology and statistics are first-rate but the study isn't replicable, which, by definition, means 'wrong', even if the results accurately reflect the study population--that is, they're 'correct', but it's a weird sample and for that reason can't be replicated.  This is often true of genetic studies, because families or isolated populations or populations with a history of isolation might have their own causal mutation/s.  Or, samples can simply be different, with no errors involved.

Or, because so many complex diseases are due to environmental factors, or genetic interaction with environmental factors, the environment will change, and what was once causal no longer is, or vice versa--type two diabetes is endemic in Native American populations, but was unknown before WWII, e.g.  So, 'wrong' need not imply culpable failings by the investigators, but just that the subject matter is challenging--and that preconceptions or theoretical assumptions can subtly affect the chosen design or implementation, etc.

Who's at risk and why?

The problem of determining causation is one of our ongoing themes here on MT, so, with that in mind, given what is known about the causes of heart disease, why is this man at risk of heart disease?  The article on the CNN website begins:

If you're not overweight, eat pretty well and exercise now and then, you might think you're in good heart health. But doctors say you don't have to look like a heart attack waiting to happen to be one.

Tom Bare, 54, is a case in point. The high school science teacher was thin, active and ate well, but still needed open-heart surgery this spring to bypass blocked coronary arteries.

The risk factors for heart disease are well-known -- obesity, smoking, high cholesterol, inactivity, diabetes, family history.  It's primarily a lifestyle disease. But Tom Bare was doing everything right, was even taking statins to lower his cholesterol (which they did, from 300 to 125), but because of his family history (probably a mix of genetic background and decades of environmental exposures), he was worried.  And it turned out he had good reason to be, given the plaque on his arteries.  So he underwent bypass surgery, and is now hoping he can avoid the heart attack that once seemed to be inevitable.

Bill Clinton has gone even further.  If heart disease is a lifestyle disease, it's clear why he had it.  He loved junk food and was overweight.  After surgery for heart disease, he has now drastically changed his diet.  He calls himself a vegan, and eats no meat, dairy, eggs or added oil.  He has lost 20 pounds and says he is healthier than he has ever been.  And is hoping he has dramatically reduced his risk of dying of heart disease. Indeed, Clinton is now following the "heart attack-proof" diet, if you believe the man selling it. 

Two men, one with the classic risk factors, the other doing everything currently considered to be protective.  Why are they both at risk?

With most common chronic diseases, causation is worked out at the population level, and then applied to individuals who will look like the average at-risk person determined in aggregate not at all, spot-on, or somewhere in between (as both Bare and Clinton, neither of whom had all the major risk factors).  Someone -- epidemiologists, clinicians translating epidemiological data to clinical practice -- will have to make a judgement call as to when a patient looks enough like study subjects with the disease, that is, has enough risk factors, to warrant intervention.

These people could be at genetic risk, but not involving known genes.  But small effects at hundreds of genes could be contributing in ways we can specifically identify but that might be reflected in the family history.  Or not.  This is the problem with genetically based prediction, and the same applies to environmental exposures, surely not all of which are identified, measured, or even accurately measurable.

You can calculate your own risk of heart disease using one of many heart attack risk calculators on the web.  Here's one -- enter a few numbers and you'll get your probability of having a heart attack in the next 10 years.

But what if the calculator tells you your risk is 30%?  The site explains that this means that 30 of 100 people with your level of risk will have a heart attack in the next 10 years.  So, does that mean that all 100 of you share the same level of risk, and bad luck or unidentified factors will push 30 of you over the edge, or that 70 of you are not in fact at risk, while the unlucky 30 are at 100% risk?  And if 70 of you aren't at risk, why are you being treated as though you are?

It's understandable that clinicians will treat anyone with some risk as though they are at 100% risk, and suggest the patient do whatever it takes to bring down that risk, but it skirts the question of how to reliably predict who will in fact have a heart attack and who will not -- something that in fact can not be known, if people change their behavior when told they are at risk, and if luck or unidentified factors are in fact at play.  From a public health point of view, that's perfectly ok, but it does make understanding causation rather murky.