Isaac Newton was one of the founders of modern science. He helped promulgate the idea of formal Laws of Nature, that Nature was law-like in that everywhere and every time the same fixed principles were at work, like the totally deterministic Law of Universal Gravitation. Because the Law worked everywhere and was deterministic, it worked at the smallest possible level, such as in time or space. That's why Newton could formulate natural law in terms of the calculus or, rather, that's why Newton developed what we call calculus. And this worked in part because space and time were absolutes. In that sense, causation was absolute as well.
Charles Darwin was clearly a product of the Newtonian age. He repeatedly wrote about natural selection as if it were at Law of Nature -- one Nature, indivisible, with Liberty and Justice for all. Justice here, would be the realization of your inherent fitness.
But life is not necessarily like that. Einstein spoiled Newton's party by showing, so to speak, that things were not absolute but only had meaning in terms relative to each other.
In evolution, we usually frame natural selection in relative terms -- this variant at a gene does better than that one does in this particular population and time. We could also view evolution in more absolute terms: this species or population, as a whole, does better today than it did yesterday. Usually this would refer to population expansion which would come at the expense of some other species, so would be relative in that sense.
In genetics, we tend to want to be Newtonian/Darwinians. We want genes to cause things in a rigorously predictable, law-like way. Thus we think of genetic variants as having inherent fitness value. And the important area of biomedical genetics is GWASh in such deterministic thinking.
But life's not like that! There is, for starters, a substantial number of 'known' disastrous disease-associated variants in humans that are normal in other vertebrates (one estimate is that 10% of our 'disease' mutations are like that). In fact, it's true even within our own species: in every individual whose whole genome sequence has been published to date, there are many 'disease' alleles, though the person is unaffected as of his current age.
And then there's the environment, which geneticists pray to Newton will go away! Genes have their effect in context, a point so obvious that it's easy to ignore if it's bad for business.
An area of Finland had the world's highest recorded risk of heart disease. But over a 20 year period, change of diet was the major factor in reducing heart disease mortality in Finland by something like 65% (that's no typo!).
And a new paper in The Lancet on diabetes, comparing outcomes in progression to diabetes in at-risk adults reports that "intensive lifestyle intervention" was significantly more effective in preventing diabetes than medication or placebo.
We've talked of Newton and Einstein, and how causation is relative. But even Einstein hungered for Newtonian lawlike deterministic Nature. And along came quantum mechanics.....
Wednesday, December 2, 2009
Tuesday, December 1, 2009
The Feminine Mystique?
Ok, here's a story that was the second most emailed article at the New York Times website for most of Monday. Oddly, a story about hiking the Grand Canyon had even more appeal than this one, and this morning, a story about kindergartners in forests is number one. But, in keeping with Holly's racy tendencies, we could hardly pass up this also-ran (its place in the queue suggesting that New Yorkers crave nature more than they crave sex?). Called "Women Who Want to Want", the story is about curing an affliction that is apparently common among women, to judge by interest in this article -- lack of sexual desire. It's also about whether that's a disease or not -- pharmaceutical companies seem to be training us to think it is in case they come up with a female form of Viagra, so we'll all get in line to buy it when they do, but that's not news (in fact, the Times also ran a story saying that there's already a product that will do the trick, but that's beyond our scope today, and anyway, no brand names here).
All that is interesting enough, sociologically and so on, but here's what really interests us about the article, given all our posts on how to determine cause-and-effect, and evidence-based medicine etc. Bear with us as we quote at length, just so you get the full effect.
All that is interesting enough, sociologically and so on, but here's what really interests us about the article, given all our posts on how to determine cause-and-effect, and evidence-based medicine etc. Bear with us as we quote at length, just so you get the full effect.
Various pharmaceutical companies, at various times, have pursued testosterone as a remedy for women’s lack of desire, and some doctors prescribe it for the condition — Laura Berman, Oprah's anointed sex expert, avidly promotes this method — though the Food and Drug Administration hasn’t approved this use. Brotto and Basson [sexologists] are about to publish research demonstrating that low levels of testosterone in women do not correspond with low libido. Yet there is a paradox. Brotto explained that giving extra testosterone to women with desire problems can, it appears, spike sexual interest. For reasons unknown, the administered hormone has a unique effect. But there’s a further complication. In studies, women given a placebo report a similar result, not quite as marked but definitely not insignificant either. To add to the intrigue, the women using a placebo often report testosterone’s unwanted side effects: facial hair; acne. Speaking about all this, Brotto smiled in bewilderment — and in something close to awe at the inscrutability of the human mind, the organ that is the locus of desire.Did you get that??! Giving women a placebo instead of testosterone can cause the same unwanted side effects, facial hair and acne, as giving them the hormone itself! That is so beautiful, and says more in one sentence than anything we've come up with yet about the difficulty of determining causation.
Monday, November 30, 2009
Water, water everywhere, ... for Astronauts to drink
Once upon a time science was about understanding our world. Alas, now it's another marketing ploy. We see this in genetics, and we are not the only ones who have noticed the phenomenon. Any finding is immediately turned into a genetic-counseling-for-sale event, or a plea for more grant money.
But heck, let's change tunes (and sciences) for at least a moment. NASA recently announced that their Moon bomb discovered 'copious' amounts of water, a whopping dozen 2-gallon buckets (i.e., about a small bathtub's worth), and one ebullient project scientist said "We practically tasted it with the impact." Unfortunately, even in the first stories about this, what the taste was, was the taste of money.
The stories basically focused quickly around the importance of this frozen-mircotub as the salvation of future Lunarnauts, NASA's next Gimme project, not on the legitimately scientifically interesting reasons for the water, the actual amounts, how it got to where it is, etc.
We're in a bottom-line society, where lobbying and advertising are indistinguishable from real work, and the scientists involved know this very well. Much about the events, and the excitement, is staged lobbying.
In genetics and, perhaps especially in biomedical research, the same is true: a prevailing ethic is that of lobbying. "Grantsmanship" is taught early on in graduate students' academic careers. That means how to strategize. It is routinely said, often glowingly or even gloatingly, by senior investigators that they apply for grants to do what they've already done (but not yet published), so they know they can later claim success.
This is lying! It is but the tip of the iceberg of questionable science ethics. Dissembling and over-stating is par for the course. But so what? As anthropologists we can say, truthfully, that this is simply how our particular culture manages its dispensing of research funds (public through government grants, or privately through investment decisions). Whether anyone likes it or not, all cultures have their ways, almost always not entirely in synch with their supposed rules and ethics, and if the system functions, then as long as its nature generally understood among the practitioners, which in this case it is, well, that's life!
But it is legitimate to ask, if scientists are trained from the graduate school crib to mislead, where does one draw the line? Even if the line of actual data forgery is very rarely crossed, how much waste in the system is due to these practices, that are at best dissembling? Under competitive pressure, and when a project addresses the vested interests of a funder (e.g., a drug company or biotech equipment maker, or a faculty member seeking grants, salary, or tenure), how much are we misled? It's a fair question: even if this is our 'system', it is always in order to try to make it live up to its nominal claims (in this case, that science is ruthlessly objective honesty).
People always complain about the state of society, and a century from now we (well, somebody then) will look back and say, almost certainly, that recent decades have been the most scientifically productive of knowledge of any time in history, human foibles and personal vanities notwithstanding. We'll know who won the lobbying tournaments, and we'll know the science that resulted. We'll know how many entrepreneurs left little footprint, and how many were truly major contributors. But that's no excuse to look the other way. And it doesn't mean resources and thinking can't be put to better uses for society at large.
But lest we be accused simply of undue cynicism, failing simply to recognize that culture is as culture does, we note that while the Moon landings of the distant past brought us major societal advances (as NASA repeatedly tells us), they mainly consisted of Teflon and Tang. Personally, while we do occasionally cook with Teflon pans, we prefer actual orange juice to robotic orange juice (probably, that makes us some kind of food weirdos).
But we can at least, and without reservation, rejoice in the fact that future astronauts will not have to take their Tang dry. Now there's progress!
But heck, let's change tunes (and sciences) for at least a moment. NASA recently announced that their Moon bomb discovered 'copious' amounts of water, a whopping dozen 2-gallon buckets (i.e., about a small bathtub's worth), and one ebullient project scientist said "We practically tasted it with the impact." Unfortunately, even in the first stories about this, what the taste was, was the taste of money.
The stories basically focused quickly around the importance of this frozen-mircotub as the salvation of future Lunarnauts, NASA's next Gimme project, not on the legitimately scientifically interesting reasons for the water, the actual amounts, how it got to where it is, etc.
We're in a bottom-line society, where lobbying and advertising are indistinguishable from real work, and the scientists involved know this very well. Much about the events, and the excitement, is staged lobbying.
In genetics and, perhaps especially in biomedical research, the same is true: a prevailing ethic is that of lobbying. "Grantsmanship" is taught early on in graduate students' academic careers. That means how to strategize. It is routinely said, often glowingly or even gloatingly, by senior investigators that they apply for grants to do what they've already done (but not yet published), so they know they can later claim success.
This is lying! It is but the tip of the iceberg of questionable science ethics. Dissembling and over-stating is par for the course. But so what? As anthropologists we can say, truthfully, that this is simply how our particular culture manages its dispensing of research funds (public through government grants, or privately through investment decisions). Whether anyone likes it or not, all cultures have their ways, almost always not entirely in synch with their supposed rules and ethics, and if the system functions, then as long as its nature generally understood among the practitioners, which in this case it is, well, that's life!
But it is legitimate to ask, if scientists are trained from the graduate school crib to mislead, where does one draw the line? Even if the line of actual data forgery is very rarely crossed, how much waste in the system is due to these practices, that are at best dissembling? Under competitive pressure, and when a project addresses the vested interests of a funder (e.g., a drug company or biotech equipment maker, or a faculty member seeking grants, salary, or tenure), how much are we misled? It's a fair question: even if this is our 'system', it is always in order to try to make it live up to its nominal claims (in this case, that science is ruthlessly objective honesty).
People always complain about the state of society, and a century from now we (well, somebody then) will look back and say, almost certainly, that recent decades have been the most scientifically productive of knowledge of any time in history, human foibles and personal vanities notwithstanding. We'll know who won the lobbying tournaments, and we'll know the science that resulted. We'll know how many entrepreneurs left little footprint, and how many were truly major contributors. But that's no excuse to look the other way. And it doesn't mean resources and thinking can't be put to better uses for society at large.
But lest we be accused simply of undue cynicism, failing simply to recognize that culture is as culture does, we note that while the Moon landings of the distant past brought us major societal advances (as NASA repeatedly tells us), they mainly consisted of Teflon and Tang. Personally, while we do occasionally cook with Teflon pans, we prefer actual orange juice to robotic orange juice (probably, that makes us some kind of food weirdos).
But we can at least, and without reservation, rejoice in the fact that future astronauts will not have to take their Tang dry. Now there's progress!
Thursday, November 26, 2009
Keeping your cool with global warming
Well, we just had to write, even over this holiday break (in the US), rather than just leave any hungry or un-turkeyed readers with just our Oulipo challenge to keep them occupied.
The story about the hacked emails from the University of East Anglia's program on climate change is making the rounds. A hacker discovered correspondence, including from faculty here at our own Penn State group on climate change, that appeared to indicate cover-up and cooking of the data about whether global warming is a true, anthropogenic (human-produced) fact.
As expected, the anti group, who want to keep on truckin' (with the exhaust emissions that go with it), are reveling in what they claim is a "Gotcha!" moment, showing the faking of evidence, with the earth-huggers responding in outrage that their innocent statements have been taken out of context.
Neither party seems to be against science in this case, so we're not into religion vs science conflicts here. But who's right? Clearly each side is coloring the evidence to support its pre-existing perspective. Here is yet another instance where tribalism, bullying, and ideology reflect the realities of the real world of human beings. So we offer another installment in the "What is 'evidence-based?' " series of posts.
We are scientists ourselves, so we know how language used as shorthand can be twisted, and how data can also be ambiguous. One of the hacked emails referred to a 'trick' referred to in a Nature article, which the smoke-spewers say shows that data were fudged if not faked. But 'trick' clearly meant analytic method of blending different kinds of data into a single unified analysis, done completely in the open, and not fraud in any sense. To get a continuous climate record from 1400AD to now, the authors had to blend indirect data such as from tree-ring patterns with direct instrumental measurements which were not available in the past. Was this legitimate? Yes, it seems to have been an entirely routine and appropriate.
There was other intercepted email correspondence about 'hiding' some tree-ring data set because of a change in responsiveness to climate. So says the news story. The Penn State correspondent is quoted as replying that nothing bad was done and the dirt-digging was just a way to undermine the 'strong consensus' that global warming is real.
But that is no kind of defense! Science is not a democracy and a 'consensus' is in itself no indicator of truth (or else we'd still be practicing Galenic four-humors medicine, and who knows what else). Comparably illegitimate would be the argument that we should excuse hiding data because, overall, the 'consensus' must be right. But the underpublication of negative results is well known and is a problem of that sort.
We don't know the details in this particular instance, but science always works from a theory or hypothesis. We are only human, and we like our own ideas, so we try to defend them against the evidence. It is routine to find ways to fit new data into our preferred theory, even when the data on the surface seem to conflict. There is a subjective element to this, in that we try to show how our theory really is true. Eventually, if enough 'bad' data are found, some other theory is needed, as the pretzel of contorted explanations is replaced by something more plausible. But no scientist gives up easily!
Scientists certainly color evidence and the way they present it. Negative results are under-reported, if reported at all, and weak positive evidence is highly touted. Of course this will happen, when careers, prestige, money, research resources, and publications are at stake! It's not just science -- after all, shell-games are how bankers picked your pockets and got away with it, no?
In the same way, those opposed to a given view will stress the problematic data and minimize the oomph of positive findings. We write about this all the time. It's a perfectly natural part of our culture. If you think it is not part of genetics and evolutionary biology and biomedical research, you are being naive (and have negligently not been reading our recent posts!)
In a way it's a kind of built-in dishonesty in what is supposed to be a bluntly honest area of life. Part of the problem here, as in other aspects of human social life is that most of us who pass judgment don't have the facts at hand, but have to base our judgment on what we read (even in science articles, since we, after all, didn't do the actual work ourselves). Yet, it's right and important to question and criticize the system, to keep it as straight as possible.
But criticism of a theory, as in the gloating embers of the coal-huggers over these hacked emails, can also be pure opportunism of those with something to gain that has zero to do with the real issues--such as profiting by clear-cutting a forest whether or not it damages our climate. In this case, from what we know, the emails were the usual kind of informal chat, perhaps even about coloring the data to present the best case of a theory in which the correspondents believed. So we think there was no fraud here, and no scandal.
But, of course, we're tree-huggers!
The story about the hacked emails from the University of East Anglia's program on climate change is making the rounds. A hacker discovered correspondence, including from faculty here at our own Penn State group on climate change, that appeared to indicate cover-up and cooking of the data about whether global warming is a true, anthropogenic (human-produced) fact.
As expected, the anti group, who want to keep on truckin' (with the exhaust emissions that go with it), are reveling in what they claim is a "Gotcha!" moment, showing the faking of evidence, with the earth-huggers responding in outrage that their innocent statements have been taken out of context.
Neither party seems to be against science in this case, so we're not into religion vs science conflicts here. But who's right? Clearly each side is coloring the evidence to support its pre-existing perspective. Here is yet another instance where tribalism, bullying, and ideology reflect the realities of the real world of human beings. So we offer another installment in the "What is 'evidence-based?' " series of posts.
We are scientists ourselves, so we know how language used as shorthand can be twisted, and how data can also be ambiguous. One of the hacked emails referred to a 'trick' referred to in a Nature article, which the smoke-spewers say shows that data were fudged if not faked. But 'trick' clearly meant analytic method of blending different kinds of data into a single unified analysis, done completely in the open, and not fraud in any sense. To get a continuous climate record from 1400AD to now, the authors had to blend indirect data such as from tree-ring patterns with direct instrumental measurements which were not available in the past. Was this legitimate? Yes, it seems to have been an entirely routine and appropriate.
There was other intercepted email correspondence about 'hiding' some tree-ring data set because of a change in responsiveness to climate. So says the news story. The Penn State correspondent is quoted as replying that nothing bad was done and the dirt-digging was just a way to undermine the 'strong consensus' that global warming is real.
But that is no kind of defense! Science is not a democracy and a 'consensus' is in itself no indicator of truth (or else we'd still be practicing Galenic four-humors medicine, and who knows what else). Comparably illegitimate would be the argument that we should excuse hiding data because, overall, the 'consensus' must be right. But the underpublication of negative results is well known and is a problem of that sort.
We don't know the details in this particular instance, but science always works from a theory or hypothesis. We are only human, and we like our own ideas, so we try to defend them against the evidence. It is routine to find ways to fit new data into our preferred theory, even when the data on the surface seem to conflict. There is a subjective element to this, in that we try to show how our theory really is true. Eventually, if enough 'bad' data are found, some other theory is needed, as the pretzel of contorted explanations is replaced by something more plausible. But no scientist gives up easily!
Scientists certainly color evidence and the way they present it. Negative results are under-reported, if reported at all, and weak positive evidence is highly touted. Of course this will happen, when careers, prestige, money, research resources, and publications are at stake! It's not just science -- after all, shell-games are how bankers picked your pockets and got away with it, no?
In the same way, those opposed to a given view will stress the problematic data and minimize the oomph of positive findings. We write about this all the time. It's a perfectly natural part of our culture. If you think it is not part of genetics and evolutionary biology and biomedical research, you are being naive (and have negligently not been reading our recent posts!)
In a way it's a kind of built-in dishonesty in what is supposed to be a bluntly honest area of life. Part of the problem here, as in other aspects of human social life is that most of us who pass judgment don't have the facts at hand, but have to base our judgment on what we read (even in science articles, since we, after all, didn't do the actual work ourselves). Yet, it's right and important to question and criticize the system, to keep it as straight as possible.
But criticism of a theory, as in the gloating embers of the coal-huggers over these hacked emails, can also be pure opportunism of those with something to gain that has zero to do with the real issues--such as profiting by clear-cutting a forest whether or not it damages our climate. In this case, from what we know, the emails were the usual kind of informal chat, perhaps even about coloring the data to present the best case of a theory in which the correspondents believed. So we think there was no fraud here, and no scandal.
But, of course, we're tree-huggers!
Wednesday, November 25, 2009
An Oulipo challenge!
Here's a change of pace for a drizzly holiday week (here in Pennsylvania, at least), a game challenge for any readers brave enough to take it! You've heard of Googlelwhacking? It's the old internet challenge to find two words that, together, bring up only a single hit on Google. Think it's easy? Try it! It was a lot easier when there weren't so many websites!
Now here's another entry into the intellectual game-world: the Oulipics. Oulipo is a 50-year old French elite organization that tries to find potential in literature--ways of doing art that follows very strict rules or structures, rather than conventional constraints (or freedoms). The name is a contraction of the French for Workshop of Potential Literature. I learned about this from a BBC podcast (my only source of real news!).
One classic Oulipo formulaic is called "N+7": Take a piece of writing and substitute every noun with the noun that appears seven nouns later in the dictionary (agreement such as pluralization is OK, and for our purposes to make it easy, we'll accept an English dictionary--sorry, no French on this post! And to make this even a tad more practicable, we'll allow adding or subtracting articles like 'a' or 'the')
Here's an example. The original, from Longfellow's poem Evangeline, is:
For starters, here's the most obvious example:
"There is grandiflora in this view of life-giving...."
Que les jeux commencents!
Now here's another entry into the intellectual game-world: the Oulipics. Oulipo is a 50-year old French elite organization that tries to find potential in literature--ways of doing art that follows very strict rules or structures, rather than conventional constraints (or freedoms). The name is a contraction of the French for Workshop of Potential Literature. I learned about this from a BBC podcast (my only source of real news!).
One classic Oulipo formulaic is called "N+7": Take a piece of writing and substitute every noun with the noun that appears seven nouns later in the dictionary (agreement such as pluralization is OK, and for our purposes to make it easy, we'll accept an English dictionary--sorry, no French on this post! And to make this even a tad more practicable, we'll allow adding or subtracting articles like 'a' or 'the')
Here's an example. The original, from Longfellow's poem Evangeline, is:
THIS is the forest primeval. The murmuring pines and the hemlocks, bearded with moss, and in garments green, indistinct in the twilight, Stand like Druids of eld...
- Oulipoing this, we get:
THIS is forgiveness primeval. The murmuring pinks and the henroosts, bearded with moths, and in garrets green, indistinct in the twirl, stand like drumsticks of the electorate...
- Now that may be highly adventurous as literature, but it's right in the spirit of Oulipo to break the bounds of conventionality--and it's easy, no? (Actually, the original was written in the 1800s so for my N+7's I used Samuel Johnson's Dictionary, the definitive source at the time).
For starters, here's the most obvious example:
"There is grandiflora in this view of life-giving...."
Que les jeux commencents!
Tuesday, November 24, 2009
Drinking your way to....health? oblivion? cancer? More on 'evidence based' medicine
Perhaps the main concern of our blog is to understand biological causation. Our interests are general, but the issue comes up disproportionately in understanding the findings of medical research, because that is naturally what a large fraction of funding supports.
Well, last week the BBC reported a study in Spain that says that men's health is substantially improved by moderate daily drinking (sorry, women, maybe your turn will come with the next discovery). That is, 3 or so drinks a day reduces heart disease risk by 35 to even 50 percent-- a very substantial difference indeed!
But why did this story make the news? How many times does alcohol consumption have to be studied in regard to health risks? It is included in many, perhaps the vast majority of epidemiological studies, and it has been so for many decades. How could such an effect have been missed? Indeed, how could it possibly be that we don't have solid, irrefutable knowledge by this time? Why would even a Euro cent have to be spent to study its effects any further?
This is highly relevant to the notion of 'evidence based' medicine, because the recommendation about alcohol use bounces around like silly putty. The only thing that is uniformly agreed on is that too much is, well, too much (but the greatest heart disease risk reduction includes those Spanish guys downing 11+ drinks a day).
Here is a case in which culture is part of the nature of 'evidence'. In prudish America, alcohol is considered something so pleasurable as to be necessarily a sin and is studied intensely. It has been controversial whether hospitals should offer patients a dinner glass of wine. Officials dread to recommend drinking at all. So the 'evidence' required to make a recommendation depends on subjective value judgments. But even if one were to be a hard-nosed empiricist, we again ask how we could possibly not know the answers with indisputable rigor.
If this is the nature of evidence, then what evidence do we accept? Is it always the latest study? Why do we think that is any better than the next latest study to come down the pike tomorrow? And if so, why don't we ignore today's study? Why do we think former studies were wrong (some may be identifiably so, but most aren't obviously flawed). Is some aggregate set of studies to be believed? Is it the study that let's business as usual be carried on, for whatever reason?
Our answer is that in addition to the cultural side-issues, there are so many complex factors at play, both causal in regard to what alcohol does in the body and what the body does to it, and in regard to confounding factors, that there is no simple 'truth' and hence it is unclear what counts as 'evidence.' Confounders are factors that may not be known or measured but that are highly correlated with the measured variable of interest (daily alcohol consumption) so that cause itself is hard to identify.Confounders may be causal on their own, or may causally interact with the factor under study.
For example, if the more you drink the more you smoke or the less sleep you get, or the more sex you enjoy (which, since pleasurable, is a sin and must be harmful) these other factors, rather than the alcohol, could be what affect your heart disease risk directly.
Confounders are confoundedly difficult to identify or tease out. Their exposure patterns and even their identity can change with lifestyle changes. And then there are many potentially directly relevant variables, too. When do you drink? What do you drink? With or without olives or a twist of lemon (or salt on the rim)? How uniform is your daily consumption whose average is measured on a survey? Even if these things were known, the future exposure patterns cannot be known, so that today's evidence is really about yesterday's exposures and so the accuracy of future risks based on this evidence is inherently unknowable.
Finally, if drinking is encouraged and heart disease is reduced, will this be good for public health? Or will it increase the number of, say, fatal accidents or violent crimes? Or is it -- well, it is -- a kind of Get-Cancer program? Why? Because if you don't get heart disease you'll live longer and that by itself increases your cancer risk. Not to mention the risk of Alzheimer's, hearing and vision problems, and a host of other older-age problems.
Perhaps the oldest advice in western medical history is from Hippocrates, about 400 BCE. That was "moderation in all things." In today's world, with our romantic notions about the powers of science, such advice is so non-specific and non-technical, that it is considered a cop-out that is not 'evidence-based'. Maybe so, but it's still the best advice. That's because it implicitly includes the unmeasured and unpredictable risk-factor regimes to which people are exposed--and that is evidence.
"Just the facts" sounds like raw empiricism, the kind of rational empiricism our society values. But the 'facts' weave a tangled web.
Well, last week the BBC reported a study in Spain that says that men's health is substantially improved by moderate daily drinking (sorry, women, maybe your turn will come with the next discovery). That is, 3 or so drinks a day reduces heart disease risk by 35 to even 50 percent-- a very substantial difference indeed!
But why did this story make the news? How many times does alcohol consumption have to be studied in regard to health risks? It is included in many, perhaps the vast majority of epidemiological studies, and it has been so for many decades. How could such an effect have been missed? Indeed, how could it possibly be that we don't have solid, irrefutable knowledge by this time? Why would even a Euro cent have to be spent to study its effects any further?
This is highly relevant to the notion of 'evidence based' medicine, because the recommendation about alcohol use bounces around like silly putty. The only thing that is uniformly agreed on is that too much is, well, too much (but the greatest heart disease risk reduction includes those Spanish guys downing 11+ drinks a day).
Here is a case in which culture is part of the nature of 'evidence'. In prudish America, alcohol is considered something so pleasurable as to be necessarily a sin and is studied intensely. It has been controversial whether hospitals should offer patients a dinner glass of wine. Officials dread to recommend drinking at all. So the 'evidence' required to make a recommendation depends on subjective value judgments. But even if one were to be a hard-nosed empiricist, we again ask how we could possibly not know the answers with indisputable rigor.
If this is the nature of evidence, then what evidence do we accept? Is it always the latest study? Why do we think that is any better than the next latest study to come down the pike tomorrow? And if so, why don't we ignore today's study? Why do we think former studies were wrong (some may be identifiably so, but most aren't obviously flawed). Is some aggregate set of studies to be believed? Is it the study that let's business as usual be carried on, for whatever reason?
Our answer is that in addition to the cultural side-issues, there are so many complex factors at play, both causal in regard to what alcohol does in the body and what the body does to it, and in regard to confounding factors, that there is no simple 'truth' and hence it is unclear what counts as 'evidence.' Confounders are factors that may not be known or measured but that are highly correlated with the measured variable of interest (daily alcohol consumption) so that cause itself is hard to identify.Confounders may be causal on their own, or may causally interact with the factor under study.
For example, if the more you drink the more you smoke or the less sleep you get, or the more sex you enjoy (which, since pleasurable, is a sin and must be harmful) these other factors, rather than the alcohol, could be what affect your heart disease risk directly.
Confounders are confoundedly difficult to identify or tease out. Their exposure patterns and even their identity can change with lifestyle changes. And then there are many potentially directly relevant variables, too. When do you drink? What do you drink? With or without olives or a twist of lemon (or salt on the rim)? How uniform is your daily consumption whose average is measured on a survey? Even if these things were known, the future exposure patterns cannot be known, so that today's evidence is really about yesterday's exposures and so the accuracy of future risks based on this evidence is inherently unknowable.
Finally, if drinking is encouraged and heart disease is reduced, will this be good for public health? Or will it increase the number of, say, fatal accidents or violent crimes? Or is it -- well, it is -- a kind of Get-Cancer program? Why? Because if you don't get heart disease you'll live longer and that by itself increases your cancer risk. Not to mention the risk of Alzheimer's, hearing and vision problems, and a host of other older-age problems.
Perhaps the oldest advice in western medical history is from Hippocrates, about 400 BCE. That was "moderation in all things." In today's world, with our romantic notions about the powers of science, such advice is so non-specific and non-technical, that it is considered a cop-out that is not 'evidence-based'. Maybe so, but it's still the best advice. That's because it implicitly includes the unmeasured and unpredictable risk-factor regimes to which people are exposed--and that is evidence.
"Just the facts" sounds like raw empiricism, the kind of rational empiricism our society values. But the 'facts' weave a tangled web.
Monday, November 23, 2009
De-code me
Well, we return to real science after our soap opera of the last post!
We referred the other day to the story that deCode Genetics, the Icelandic genomics company, has gone into Chapter 11 bankruptcy. It's been coming for some time. As a story in the Times put it,
But the story is not over. deCode will be taken over by someone, and their founder says their activities will continue. Apparently also, another genetic testing company, 23andMe, has just raised its prices, which has been speculated as indicating financial trouble in Silicon City, too. Whether financial recovery will occur remains to be seen, and these entities may morph to other kinds of analysis or testing to stay in business. But it's not the first time; Celera Genomics, which co-sequenced the human genome, folded some years ago on much the same grounds, that genotypes don't effectively predict disease.
The proponents of the current GWAS (genome-wide association studies)-personalized medicine-and-biobank-laden ethos, that has been so good for the grant, equipment, and recreational genomics business, naturally want to keep the tap open on the promise of Heaven-to-come. Director Francis Collins has nominally staked NIH's future substantially on the basis of this belief. "Salvation's just around the corner" is always how faith-healers have justified passing the hat, and the same can be seen in the quote with which the Times story ends:
It is true, depending on your definition of 'success', that GWAS has found genes that contribute to disease. But there is no reason to expect, and every biological and evolutionary reason not to expect that major complex diseases will ever be generally predictable by individual genotypes--and that is what the GWAS main findings have actually shown. Commercial prediction (or, ethically more responsible, within-clinic genetic counseling) services will grow in their ability to predict certain kinds of disorder, like classical single-gene diseases. That will include a subset of common 'complex' diseases. But most risk variants cause only small statistical, environmentally affected, rather than certain risk.
The Times article was again incorrect, and rather naively so, in stating that
The Times was right, however, that the aggregate effects of large numbers of rare alleles seem to be the reason why family correlation of risk for many or even most traits is high, implicating genetic factors, but we can't find the genes. There is -- and has long been -- a plethora of evidence of many kinds, from many species, to suggest that this is the case.
The problem was the genome frenzy, driven largely by gold-rush mentality, but also genuine frustration at the difficult of understanding the cause of so many important diseases. That frenzy could not be stopped, and many GWAS and biobank studies are being launched or are committed to that will have similar bleak futures; unfortunately they entail commitments to long-term expense, because vested interests cannot easily be slowed. Country after country has sheepishly followed the wealthier countries, and they're now heavily invested in these costly but questionable studies. They could have known better!
The story is subtly deeper than meets the eye, too. deCode was founded on the idea that Iceland was an isolate founded by a small number of individuals and hence greatly reduced variation so that causal variants could more easily be detected. There were always problems with that logic, but it quickly turned out that the founding population wasn't all that small, relative to the questions at hand. Instead, Iceland did provide a great potential advantage: it was to have a whole-population genealogy, connecting everyone in families back for centuries, with comprehensive medical records in recent generations.
There were apparently lots of political and social problems involved, but the great advantage deCode had, at least in principle, was that a genealogy will generally carry fewer variants than a whole population, and linkage studies in families are more statistically able to detect things than comparisons between cases and controls. That loaded the dice in deCode's favor, and they did find a number of things. But the bottom line was that those findings did not reduce complex traits to simple traits. Just as experiments with crosses between just two inbred animals have shown, even very small populations carry enough variation for complex traits to remain complex.
deCode failed to do what its commercial hyperbole promised even with these advantages. From a scientific point of view, that may be a commercial failure but it's a positive scientific contribution to understanding. That understanding should be what is needed to show convincingly that over-geneticizing common diseases is a mug's game, for reasons that we've known for a long, long time. What else is science all about except to learn and adapt to the realities of Nature?
The best way to slow this train so we can get off and go to more creative approaches is to formally curb funding for these kinds of wholesale genetic studies, and thus force investigators to think and think again about other ways to approach these diseases--and not just by scaling up their demands for funds. As long as more of the same is fundable, that's what'll be proposed.
Other approaches, going under names like 'network' or 'systems' biology will likely make progress, and probably can stimulate the opening of the conceptual door, since molecular interactions are what life is all about (as we argue as a major theme of The Mermaid's Tale). However, the network studies to date mainly show just what GWAS finds and evolutionary biology predicts: things can be genetic in the sense that many interacting genes contribute, but are not easily targetable in terms of 'personalized' medicine related to individual genotypes.
So, if there's something clearly genetic in your family, see a legitimate genetic counselor. Otherwise, put away your wallets: Tea leaves and crystal balls are almost as effective as DNA sequence for predicting risk, and much, much cheaper. if you're in a truly high-risk family, see a real genetic counselor. Meanwhile, to stay healthy, eat right, exercise, and stop worrying: Drink your tea, but toss away the leaves!
We referred the other day to the story that deCode Genetics, the Icelandic genomics company, has gone into Chapter 11 bankruptcy. It's been coming for some time. As a story in the Times put it,
Whatever business errors deCode may have made, a principal reason for its downfall is scientific — the genetic nature of human disease has turned out to be far more complex than thought.We certainly have a vested interest in saying that this statement is far from the truth. "than thought" refers to those who believed, wished, or tried to quickly capitalize on the notion, never supported by the body of facts, that common diseases were genetic in the sense of being reliably predicted from individual genotypes. Those who hoped or hyped this tale know that today's state of affairs has been predicted and for correct reasons that have, among other things, to do with evolution, for at least a decade.
But the story is not over. deCode will be taken over by someone, and their founder says their activities will continue. Apparently also, another genetic testing company, 23andMe, has just raised its prices, which has been speculated as indicating financial trouble in Silicon City, too. Whether financial recovery will occur remains to be seen, and these entities may morph to other kinds of analysis or testing to stay in business. But it's not the first time; Celera Genomics, which co-sequenced the human genome, folded some years ago on much the same grounds, that genotypes don't effectively predict disease.
The proponents of the current GWAS (genome-wide association studies)-personalized medicine-and-biobank-laden ethos, that has been so good for the grant, equipment, and recreational genomics business, naturally want to keep the tap open on the promise of Heaven-to-come. Director Francis Collins has nominally staked NIH's future substantially on the basis of this belief. "Salvation's just around the corner" is always how faith-healers have justified passing the hat, and the same can be seen in the quote with which the Times story ends:
“DeCode has been very successful using genome-wide association studies, and among the first to publish many discoveries,” said Dr. David Altshuler, a medical geneticist at the Massachusetts General Hospital. But he expressed optimism that the human genome project would succeed despite deCode’s stumble.
“It would be a mistake to draw any connection between the medical promise of the human genome and the success of a specific company and business model,” he said.This is right to the extent that no sane person thinks that we'll learn nothing more from genetics! But if the quote accurately portrays what David, who is a first-rate scientist said, he might have been being cagey. Nobody is questioning whether the 'genome project' would 'succeed'. But we're not talking about the genome project here: instead, what's questioned is how usefully genotype data predicts disease.
It is true, depending on your definition of 'success', that GWAS has found genes that contribute to disease. But there is no reason to expect, and every biological and evolutionary reason not to expect that major complex diseases will ever be generally predictable by individual genotypes--and that is what the GWAS main findings have actually shown. Commercial prediction (or, ethically more responsible, within-clinic genetic counseling) services will grow in their ability to predict certain kinds of disorder, like classical single-gene diseases. That will include a subset of common 'complex' diseases. But most risk variants cause only small statistical, environmentally affected, rather than certain risk.
The Times article was again incorrect, and rather naively so, in stating that
Natural selection seems to be much more efficient than expected at ridding the population of dangerous genes, even of those that act well after the age of reproduction.To the contrary, it was always 'expected' that selection would purge very serious mutations, so that mainly the brand-new, or older but highly recessive (low penetrance) ones would be found at any given time. But selection has little way to purge mutants with long post-reproductive effects.
The Times was right, however, that the aggregate effects of large numbers of rare alleles seem to be the reason why family correlation of risk for many or even most traits is high, implicating genetic factors, but we can't find the genes. There is -- and has long been -- a plethora of evidence of many kinds, from many species, to suggest that this is the case.
The problem was the genome frenzy, driven largely by gold-rush mentality, but also genuine frustration at the difficult of understanding the cause of so many important diseases. That frenzy could not be stopped, and many GWAS and biobank studies are being launched or are committed to that will have similar bleak futures; unfortunately they entail commitments to long-term expense, because vested interests cannot easily be slowed. Country after country has sheepishly followed the wealthier countries, and they're now heavily invested in these costly but questionable studies. They could have known better!
The story is subtly deeper than meets the eye, too. deCode was founded on the idea that Iceland was an isolate founded by a small number of individuals and hence greatly reduced variation so that causal variants could more easily be detected. There were always problems with that logic, but it quickly turned out that the founding population wasn't all that small, relative to the questions at hand. Instead, Iceland did provide a great potential advantage: it was to have a whole-population genealogy, connecting everyone in families back for centuries, with comprehensive medical records in recent generations.
There were apparently lots of political and social problems involved, but the great advantage deCode had, at least in principle, was that a genealogy will generally carry fewer variants than a whole population, and linkage studies in families are more statistically able to detect things than comparisons between cases and controls. That loaded the dice in deCode's favor, and they did find a number of things. But the bottom line was that those findings did not reduce complex traits to simple traits. Just as experiments with crosses between just two inbred animals have shown, even very small populations carry enough variation for complex traits to remain complex.
deCode failed to do what its commercial hyperbole promised even with these advantages. From a scientific point of view, that may be a commercial failure but it's a positive scientific contribution to understanding. That understanding should be what is needed to show convincingly that over-geneticizing common diseases is a mug's game, for reasons that we've known for a long, long time. What else is science all about except to learn and adapt to the realities of Nature?
The best way to slow this train so we can get off and go to more creative approaches is to formally curb funding for these kinds of wholesale genetic studies, and thus force investigators to think and think again about other ways to approach these diseases--and not just by scaling up their demands for funds. As long as more of the same is fundable, that's what'll be proposed.
Other approaches, going under names like 'network' or 'systems' biology will likely make progress, and probably can stimulate the opening of the conceptual door, since molecular interactions are what life is all about (as we argue as a major theme of The Mermaid's Tale). However, the network studies to date mainly show just what GWAS finds and evolutionary biology predicts: things can be genetic in the sense that many interacting genes contribute, but are not easily targetable in terms of 'personalized' medicine related to individual genotypes.
So, if there's something clearly genetic in your family, see a legitimate genetic counselor. Otherwise, put away your wallets: Tea leaves and crystal balls are almost as effective as DNA sequence for predicting risk, and much, much cheaper. if you're in a truly high-risk family, see a real genetic counselor. Meanwhile, to stay healthy, eat right, exercise, and stop worrying: Drink your tea, but toss away the leaves!
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