Tuesday, February 24, 2015

Causation revisited again

A paper* published recently in The Medical Journal of the Islamic Republic of Iran ("X-ray radiation and the risk of multiple sclerosis: Do the site and dose of exposure matter?" Motamed et al.) explores the possibility that X-rays are a risk factor for multiple sclerosis (MS).  (Do we routinely read this journal?  No.  Ken sent me a pdf of the paper, and when I asked him where he'd gotten it, he said he thought I'd sent it to him.  Which I had not.  On looking back at the email, he finds that it contained no actual message, just the pdf, and not even an identifiable sender.  Creepy spam? I guess we'll find out.  But until our computers are taken over by bots, despite its iffy provenience, the paper does bring up some interesting questions.)

From the paper abstract:
Methods: This case-control study was conducted on 150 individuals including 65 MS patients and 85 age- and sex-matched healthy controls enrolled using non-probability convenient sampling. Any history of previous Xray radiation consisted of job-related X-ray exposure, radiotherapy, radiographic evaluations including chest Xray, lumbosacral X-ray, skull X-ray, paranasal sinuses (PNS) X-ray, gastrointestinal (GI) series, foot X-ray and brain CT scanning were recorded and compared between two groups. Statistical analysis was performed using independent t test, Chi square and receiver operating characteristics (ROC) curve methods through SPSS software. 
Results: History of both diagnostic [OR=3.06 (95% CI: 1.32-7.06)] and therapeutic [OR=7.54 (95% CI: 1.59-35.76) X-ray radiations were significantly higher among MS group. Mean number of skull X-rays [0.4 (SD=0.6) vs. 0.1 (SD=0.3), p=0.004] and brain CT scanning [0.9 (SD=0.8) vs. 0.5 (SD=0.7), p=0.005] was higher in MS group as well as mean of the cumulative X-ray radiation dosage [1.84 (SD=1.70) mSv vs. 1.11 (SD=1.54) mSv; p=0.008].
So, it was a very small study, but the odds ratios were quite significant, particularly for therapeutic X-ray, for which dosage is likely to be higher than for diagnostic X-ray.

Chest x-ray; Wikipedia

And this isn't the only study, in fact, that has found an association between X-ray and MS.  Axelson et al. find a similar link in Sweden, described here, also in a very small study.  But, this about exhausts the reports of such a link.  The problem is that the risk of MS is small (the National Multiple Sclerosis Society estimates that there are 400,000 people in the US with MS, or about 1/1000) relative to the number of people getting X-ray, therapeutic or diagnostic.  This means that even if X-ray is causal, and the odds ratios (relative risk) in these small studies fairly large, the actual (absolute) risk is minuscule.

The cause of MS is unknown.  Many hypotheses have been considered -- it may be immune-related, or viral, or genetic, or perhaps environmental, and some believe lack of vitamin D is a prime candidate.  But as with other complex diseases, with the kind of varying and complex phenotype that is seen with MS, it's possible that there are numerous causes, and/or numerous triggers, rather than a single one.  So, if X-ray really is causal, perhaps it causes some tissue irritation that stimulates immune response, triggering some over-response that contributes to MS risk.  Thus, it's conceivably possible that X-ray is in fact contributory in some cases.  But one can imagine many such explanations.

But this again raises a larger question, one we've been blogging about off and on, well, forever, but recently, including last week, and again yesterday with respect to the new dietary recommendations, that no longer include cautions against eating foods high in cholesterol.  Why is it so hard to determine the cause of so many diseases?  Why don't we yet know the cause of MS, or heart disease, or obesity, or many other common diseases?  Essentially, it comes down to the fact that our methods for determining causation just aren't good enough when every case is different.

In the near future, we'll write about this issue in the context of how epidemiology is done these days.

*Here's the link, if you, too, want to chance it.  http://mjiri.iums.ac.ir/browse.php?a_code=A-10-1-758&slc_lang=en&sid=1&sw=sclerosis


Michael Finfer, Md said...

Without having read the paper, I suspect that it is more likely that people with a subclinical or a mild, but undiagnosed, case of MS, are more likely to have some sort of imaging study than the general population. Confusing correlation with causation is easy.

I also suspect that the data is presented in a way that it would be very difficult to determine if my first suspicion is true.

Ken Weiss said...

That's a very good point! I think there's almost no way of knowing in general. We tried to say clearly that we were circumspect about this particular paper (because of how we learned of it, among other things), but that it was an example that raised the sorts of questions about assessing risk and causation that we write (or rant) about regularly.

If your intuition is correct, then perhaps the MS 'phenotype' is also in need of revision?

Thanks for pointing these things out.

Anne Buchanan said...

Yes, and further, the data are retrospective, so depend on recall, and people with and without MS may have systematically better or worse recall about their history of X-ray exposure.

That brings up another point about studies like these. There can be many possible explanations for the findings, and it's often not possible to determine which is correct.

Michael Finfer, MD said...

Yes, studies that depend upon the patients' recall are treacherous at best.

As for MS, that's a fairly well defined entity, but can be difficult to diagnose early on. Beyond that, I am not a neurologist, so it might not be a good idea to say much more than that.

Also, plain X-Ray studies expose patients to very low doses of radiation, and it is odd that they would be associated with MS in any way, particularly those that do not expose the brain to radiation. MS may have an autoimmune component, but I usually think of radiation as suppressing the immune system, not activating it.

All in all, I think this finding sounds odd, and I would tend to ignore it unless it is supported in papers that do not appear magically in the in boxes of people in other fields.

Anne Buchanan said...

Indeed, magically appearing knowledge should always be suspect!

The paper did say that site of exposure was associated with risk, particularly for therapeutic radiation. Still, this doesn't change the caveats and problems with the study.

Perhaps the most unfortunate thing about a study like this is the undue fears it can cause. And not just about whether some bot has taken over my computer...

Ken Weiss said...

I think the value of such a study is mainly, or only, or possibly, that it shows the range of factors with no reason to suspect them that could be in the complex causal mix.

We speculated that radiation to any tissue could cause some local irritation that could arouse some response, even an inflammation one, even at a very low level, responding to cells in distress, and that could then trigger some autoimmune lymphocytes (or whatever) to proliferate.

But I wasn't suggesting that in any knowledgeable way! Just to suggest the idea that causation seems to come from all sorts of direction.

We hesitated to post about this paper and did so only for the above reasons.