Rationality Case Study - Ad-36

EDIT: I have retracted the conclusion of this comment.

Figuring this out is basically a matter of doing a literature survey, judging a few of the studies for basic sanity, and reporting the results. Being able to do this is a very important skill, and everyone should practice it at least once so that if they suddenly develop a medical condition, they know how to double check their doctor's work. So here's what I found in the literature:

• Literature survey of multiple pathogens indicated to cause obesity
• Injecting AD-36 into rats makes them gain weight
• Injecting AD-36 into monkeys makes them gain weight
• Observational study showing AD-36 antibodies are correlated with obesity
• AD-36 correlated with greater BMI and body fat mass, but not with greater insulin resistance and again by the same department
• AD-36 makes cultured human adipose tissue accumulate more fat
• AD-36 correlated with obesity in children
• AD-36 increases glucose uptake by fat cells
• Chemical mechanism by which AD-36 induces adipogenesis

So that's correlation in both controlled animal tests and observational human tests, correlation in cultured human tissue, and observed mechanisms. A few names show up in a bunch of the studies, but there are also replications by unrelated research groups. There were even more studies to sort through, but I stopped there, because that's more than enough: being infected with AD-36 makes you fatter, proven beyond a reasonable doubt. Any commenters nitpicking the statistics and sample sizes of individual studies are missing the point, because the evidence is the sum of all the studies, and they are not all flawed, or at least not flawed badly enough to seriously undermine the conclusion.

That said, there are conclusions which it is tempting to leap to, but which I could not find support for. First, it is tempting to conclude that AD-36 infection is responsible for a large fraction of the rise in obesity in the United States. However, I could not find any data on the overall prevalence of AD-36 in the US or world population, nor on factors affecting AD-36's transmissibility; the studies I found seem to involve participants drawn from narrower geographic regions, whose exposure would be correlated and therefore not representative of the US as a whole. I also couldn't find any sort of historical data to indicate that AD-36 prevalence has risen, rather than remain constant. Not that I would expect to find historical data in any case, since that's very difficult to collect for recently discovered pathogens - but there are several inferential steps still not covered. The most likely conclusion, therefore, is that AD-36 accounts for some of the rise in obesity in the US, but an unknown amount, and not all. I also saw references to several other pathogens indicated to cause obesity in humans and animals, but did not research them in depth.

Rationality as the measure of all things.

I would like to suggest a more specific title, such as "Rationality Case Study: Adenovirus strain #36" or something similar.

That way, not only do you satisfy the general principle that titles should be informative as possible, but you also avoid giving the impression that this post is purely rhetorical (with an implied thesis that you supplied earlier).

There is a widespread belief here that we pretty much have epistemic rationality nailed here.

Really? I don't have that sense. Take a look at A Request for Open Problems and note that the top 4 suggestions (by comment rating) are all about epistemic rationality.

Nikhil V Dhurandhar and Richard L Atkinson, two researchers behind much of the research on Ad-36 and obesity, filed for a patent on using AD-36 antibody presence as a predictor of obesity. The initial filing was on Sep 9, 2005, after all the research I can find by those two was published, so it does not appear to constitute a conflict of interest.

(Edit: Actually they published more after that, but the conclusion was well proven before the filing and they seem to have moved on to details and mechanisms)

The blog "Junkfood Science" had a posting a little over a year ago that was highly critical of the Ad-36 obesity hypothesis. Based on this, I'm going to shift from a neutral stance to strong skepticism.

I just don't think there is any credible evidence that this virus is a cause of human obesity.

ETA: Ca-ching!

Criticisms of the recent Gabbert et al AD36<->obesity paper:

The data indicated that for the AD36 Negative group, the ages were 8-11 yrs (18%), 12-15 yrs (65%), and 15-18 yrs (17%). For the AD36 Positive group, the ages were 8-11 yrs (5%), 12-15 yrs (32%), and 15-18 yrs (63%). This is as we surmised above: more older kids are in the AD36 group. The weight average for the AD36 Negative group was 69 kg (+/- 24 kg SD); for the AD36 Positive group is was 93 kg (+/- 24 kg SD).

Thus, one sure finding is that older kids are heavier: in fact, they were about 24 kg heavier, which translated to about 50 lbs. It is at least good to see that the press release got this figure correct.

Another finding is that older kids are more likely to have been previously infected by AD36, also as we surmised (in two years, you have have plenty of colds).

There is no modeling of the expected distribution of biometric properties of the two populations (AD36-negative and -positive) given the other statistics (age,sex,race) reported. This is extremely surprising to me.

However, it's not just that older kids (adults, really) weigh more - the size-relative metrics BMI, and waist/height ratio were also higher in the AD36 antibody group. But still, those should be adjusted for age as well; their distribution (and mean) will surely change with age, and definitely will change for the worse with age in the destined-to-be-obese (it takes time to blossom into full adult obesity). The fact that no such adjustment was made means that the study contributes almost no additional evidence, but this could be corrected with a proper analysis. And, supposing the raw data is available, this can happen.

The two populations also have a significant sex difference: the AD36-negative group is 58% male, and the AD36-positive is only 47%. However, it looks like adult men and women have similar recommended BMI and waist/height ratios (actually, women are recommended to have slightly lower) - I don't know what the actual averages are. Racially, there's a 13% shift from "non-hispanic white" to "hispanic" in the AD36-positive population. While I don't know how different those groups are re: AD36-positivity or BMI etc., this should be considered as well. The age mismatch is definitely the most severe problem.

The "discussion" section lists much other work which seems to provide better evidence of a AD36-obesity link (I assume the authors are leaving out any negative results that don't support their views). For example:

[In] a small substudy of adult twins with discordant AD36-specific antibody status, 13 Twins with antibodies to AD36 were noted to have higher BMI values and greater proportions of body fat then their respective antibody-negative twins.

(evidence of correlation, not causality - would be quite strong evidence if the number of twins and BMI/body fat mismatch were large enough)

infection of nonhuman primates, rodents, and chickens with AD36 increased total body fat independent of energy intake

(causality in animal models, although i would hope for exposure rather than infection as the trigger - perhaps p(infection|exposure) is high enough that it doesn't matter)

adipose-derived stem/stromal cells ... infected with AD36 showed increased differentiation and higher levels of lipid accumulation than noninfected control cells

(causal, but in vitro: doesn't guarantee net fattening in the context of a human body)

Cursory initial Internet searches identify Dr. Nikhil V. Dhurandhar as a prominent researcher associated with studies demonstrating weight gain associated with Ad-36. Two relevant papers: one showing correlation between Ad-36 infection and obesity in humans and one showing causal linkage between Ad-36 infection and weight gain in marmoset monkeys. Whether marmosets are a good human analogue for this purpose is an interesting question I am not qualified to discuss.

The study criticized by ERV in the "certain amount of skepticism" link does not appear to be associated with Dhurandhar. That said, I would like to see reliable studies not associated with Dhurandhar before I ascribe significant probability to the theory.

Some initial questions, before I even read into any of the controversy:

• Would there be an expected evolutionary benefit for Ad-36 to increase obesity?
• How can we distinguish correlation and causation in this case? One possible confounding variable - high vitamin D levels are positively correlated with viral resistance and negatively correlated with body fat.
• Have we or can we try this on experimental animal models? A controlled labortory test is the most effective tool for testing the biological effects of isolated factors (as in koch's postulates)

This is similar to the notion of polymath projects (apparently quite successful): http://polymathprojects.org/general-polymath-rules/

This paper is primarily a report on the results of infecting rats with Ad-36. Other people, jimrandomh in particular, have already mentioned it. I mention it here, not because of the results it reports, but rather because of this fascinating introduction:

Although obesity is associated with several health risks, not all obese individuals are adversely affected by it. To better utilize health care resources, it would help immensely to selectively target prevention and treatment efforts by identifying “at risk” individuals from those who are relatively protected from the adverse effects of obesity. Recent emerging evidence from animal models and human studies indicates that some forms of obesity may indeed carry relatively low health risk. We reported that human adenovirus Ad36 infection appears to be one such marker of “low risk” obesity. [snip summary of evidence] Thus, Ad36 induces obesity with metabolically favorable profile in animals and is associated with such obesity in humans.

I'm not sure whether this makes the Ad-36 hypothesis less important, or more important. If a sizable fraction of obese people can stop worrying about the long term health effects of their condition, isn't that a Good Thing?

Ceteris paribus AD-36 increasing obesity is a trivial information if true.

We have plenty of other means of making rats, monkeys, and humans fat - like feeding them vegetable oil and sugar. And if you haven't noticed this is exactly what we have been doing to ourselves - modern American diets are 36% vegetable oil and sugar, and everyone else is only a decade behind.

Epidemiologically AD-36 is entirely wrong, weight increase is broad process affecting most people, and viral origin would predict one subpopulation being strongly affected, while everyone else wasn't at all.

Broad increases in weight are what you'd expect from widespread environmental factors, like sugar, high trans-fat, and high-omega-6 vegetable oils being added to very wind range of food.

Lack of correlation with insulin resistance also seems to be rather damning.

Sum of all evidence clearly indicates that AD-36 is not the primary factor behind obesity epidemics. It might or might not be significant independent contributing factor, but remember that there might be plenty of other such independent factors each influencing weight in positive or negative direction, without them all necessarily resulting in any net effect. This requires little imagination, as a lot of pathogens are known for making people lose weight.

tl;dr If epidemiology doesn't fit, you must acquit.