Friday, December 5, 2014

Epidemiology behind a rack of eight-balls?

With some diseases and disorders it's very clear when incidence is rising -- asthma in the 1980's and 90's, obesity since World War II, type 2 diabetes, heart disease.  Which is not to say that it's always clear why (other than what's obviously true, that infectious diseases aren't killing us when we're young, so we age into some chronic disease), but at least it's fairly clear that the number of new cases per population-at-risk (incidence) has risen in a given time period.

With other diseases and disorders, it's not necessarily so clear.  Autism spectrum disorders, attention deficit disorder and attention deficit hyperactivity disorder (ADD and ADHD), anxiety, depression; yes, incidence rates have risen, and sharply, but this may reflect increased knowledge or changing definition of the disorder and thus increased diagnosis rather than a true increase in cases.

Incidence of yet other conditions, like schizophrenia, continues apace, and prevalence (the proportion of the population with the condition) doesn't change much over decades.

Ken and I were talking about this. How do we know if a condition has truly become more common, or if apparent increased incidence reflects other things?  Depression, for example.  The following map indicates that prevalence of depression in the US ranged between 4.8% and 15% in 2006 and 2008.    

Data Source: CDC. Current Depression Among Adults --- United States, 2006 and 2008. MMWR 2010;59(38);1229-1235. (this map includes revised state estimates)
And a 2006 paper in The American Journal of Psychiatry reports an increase in prevalence from 3.3% in 1991-1992 to 7.1% in 2001-2002.  But are we more depressed, or just more frequently diagnosed as depressed?

Incidence of diagnosed ADHD has increased significantly, from "7.8% in 2003 to 9.5% in 2007 and to 11.0% in 2011".  Again, whether this is 'real' or an artifact of changing diagnostics isn't clear.  Incidence of autism increased more than ten-fold in the last 40 years.  Certainly some of this is due to increased ascertainment, and some due to broadening of the definition of the trait.  But, probably not all.

Let's say it's real?
But, let's assume these increased incidence rates for behavioral disorders in fact represent something real. We can dismiss genetic causation per se out of hand, because genes don't change this quickly.  (That is, we, as in Ken and I, since hundreds of millions of dollars have been spent on the genetics of susceptibility to all of these conditions by people hoping to find a simple genetic explanation.)

And perhaps there is a simple explanation, though not a genetic one.  If incidence of a disease changes quickly, that may be an indication that there's a single environmental risk factor that explains the change.  Increased lung cancer rates pinpointed smoking, it has been suggested that decreasing stomach cancer rates may indicate year round availability of fresh fruits and vegetables, lead paint exposure can lead to cognitive disorders in children, of course infectious agents are responsible for many diseases, and so forth.  Just as with single-gene disorders, single environmental factors can have major effects, and environmental epidemiologists spend lots of time looking for them.  They can be very elusive.

If the cause is not genetic per se (it's true that genes are involved in everything, but they aren't the interesting or changeable aspect of these diseases with quickly rising incidence rates), it means that something environmental has changed, and is responsible.  It can mean that a subset of the population has more of a genetic susceptibility to that change than others, and sometimes knowing the genetic risk factor can be useful in prevention.

But this isn't likely to be the rule with most complex chronic conditions, and generally it's a very small subset of the population.  And generally, one might expect that with rapidly rising incidence of a disease that's due to an environmental risk factor, only some genes would be responding to the factor whose prevalence has increased -- that is, that the factor was a substrate for a particular gene or something like that.  That is basically the only seriously justifiable rationale for the very extensive mapping that so many insist on doing, to find the genetic basis of traits that are, by and large, clearly not 'genetic' in the usual sense.

And, for both traits that have had stable incidence patterns and those with very major rapid change, the patterns of complexity of genomic contributors is about the same.  There are individually very rare clear genetic causes, for most traits, that aren't really due to environmental change (e.g., they're present at birth or very early in life), but again, this is not the rule.

So yes, of course, since genes are involved in everything, even clearly environmentally-induced diseases are due to gene environment interaction of a sort, but the evidence even in rapidly increasing disorder shows that focusing on the gene part of that isn't going to help prevent these disorders and diseases.  So let's stick with environment, which is presumably something that can be changed.

It seems that it should be easy to figure out something relatively clear-cut and simple that has changed in the environment to cause our widespread disease of interest.  Another way to put this is to ask if rapid increases in prevalence suggest a single, or 'point' cause, rather than some smear of multiple causes.

Ten percent of smokers develop lung cancer, and we consider smoking to be a hugely damaging single sledgehammer of a causal factor.  And, ten percent of people exposed to Factor-X are developing ADHD or depression, so we should consider X to be hugely damaging, an environmental factor with a large effect.  And thus one might expect Factor-X to be easy to ascertain.  Another bird in the hand for environmental epidemiology.

Except that so often it's not.  We've got little clue about environmental factors associated with, or causing ADHD, or widespread depression, or autism.  Or asthma, or diabetes, or obesity.  In part, probably because many differing traits are subsumed in each of these categories, and there are many pathways to each one of them.  But, even if there's a single cause, it can be difficult to identify.  And perhaps requires making unlikely connections.

Speaking of which, Ken has an idea about ADD and ADHD. I'll let him explain:

One often hears about television and in particular rapidly flashing, constantly moving programming aimed at kids (indeed, at adults as well).  It once may have been ads that did this most intensely, to keep you tuned in and not off to get a bite before the actual program returned. But every program these days, from sports, to scoreboards, to ads, to programs, and also to video games, is a breathless race of succeeding images.

Now, I'll present this idea, and hope perhaps some reader will comment with an answer, or references.  First, video screens run on many cycles per second, depending on how its done and its electric AC frequency.  Some technologies, like old CRTs, refresh the screen by painting from a top corner down to a bottom opposite corner.  Digital screens--I think!--refresh by loading the whole screen basically at once.  I understand from some quick Google checking, that some systems, to make motion less herky-jerky, interleave other images, such as a flash of pure black.  I don't know how fast this happens or how accurate our understanding it.  At least, I cannot easily find the answer on the web. But it may be relevant.

Your retinal cells capture photons in their opsin proteins which are then insensitive for a brief instant (another thing I could not easily find, but which also must be well-known to relevant specialists), and then the opsin is back in business ready to capture another photon.  Nature sends streams of photons to our eyes continuously, and our eyes refresh at their natural rate, which is not (I think) like a whole-screen-at-once process.  How our brains interpret the changing images that reach it in this way is not well-known, as far as I an aware, but that isn't the question.

In our current world, besides the frenetic stream of images from screens like the one you are reading the one I am writing on, the images are synchronized, in one or another form of lock step.  This is not designed to be in lock step with retinal refresh patterns and is far more orchestrated than visions of natural nature.  In other words, I wonder if our brains, evolved to process images that come in an unsynchronized way (or in a way synchronized by the brain) are forced to process images that try to synchronize the brain's reception.  Could this be a kind of dissonant information phenomenon, a 'dys-synchrony', that causes stress or confusion of brain function, and that shows up symptomatically (after years of, or continuous dys-synchronous input) as what we now consider to be behavioral disorders?

Or put another way, it doesn't matter what kinds of images our brains were processing as they evolved; they evolved with the ability to process many kinds of images, and this in turn may affect how synapses are laid down, particularly in infancy, with whatever behavioral sequelae.  There may be environments in which the brain and behavioral sequelae of this cause and effect would be beneficial, but not our current educational one.

If by chance any reader of this post knows the answers to the points of types of synchrony, refresh patterns and refresh rates, we'd greatly appreciate hearing from you--with references to the literature, and any reactions about the plausibility of the idea as a subtle cause of many different behavioral problems.

And this leads to a larger point
Whether or not Ken is on to something, the larger point is to keep in mind that environmental exposures may have unintended, unconsidered, unmeasured or even unmeasureable consequences.  Surely there are causal factors, exposures, that haven't yet even been recognized.  Epidemiology is behind a rack of eight-balls here -- we don't know if many diseases and disorders are actually increasing, we don't really know the physiology of many of them, and we don't know which environmental exposures even to suspect, which factors might have unintended effects, nor, often, how to assess them.

Indeed, correlation doesn't imply causation... except when it does.  Helicobacter pylori and stomach ulcer?  But first, someone has to think of the correlation.

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