Amyotrophic Lateral Sclerosis and Environmental Toxins: A New Link?

An article appearing in JAMA Neurology links exposure to certain environmental toxins, like pesticides to Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s disease). While I could spend these 150 seconds talking about whether or not we should run home and clean all the Round-Up out of our garage, I’d like to take this chance to talk about 3 methodologic issues a study like this brings to the fore. For the video version of this post, click here.

But first, the details:

Researchers from the University of Michigan performed a case-control study of 156 individuals with ALS and 128 controls. They administered a survey, asking about all sorts of environmental exposure factors, and, importantly, they drew some blood to directly measure 122 environmental pollutants. The bottom line was that there did seem to be an association between some pollutants (like pentachlorobenzene – a now-banned pesticide) and ALS.

So – on to the three issues.

Number 1 – multiple comparisons. As I mentioned, the authors looked at over 100 pollutants in the blood of the participants. Given no effect of the pollutants, chance alone would leave you with several apparently statistically significant relationships.  In fact, a robust demonstration of the multiple comparisons problem is that lead exposure, in this study, was quite protective against ALS. This is not biologically plausible, but reflects that multiple comparisons can cut both ways – it can make measured factors seem to be positively, or negatively associated with the disease. Indeed, several pollutants seemed to protect against ALS.

The authors say they account for multiple comparisons, but I’m not sure this is true. In their statistics section, they write that they used a Bonferroni correction to lower the threshold p-value (from the standard 0.05 to 0.0018 to account for all the comparisons). But they never actually do this.  Rather, they report the odds ratios associated with the various pesticides and just don’t report the p-values at all, except in multivariable models where the Bonferroni correction isn’t used.

Number 2 – the perils of self-reported data. The survey exposure data – questions like “do you store pesticides in your garage?” and the measured blood data were hardly correlated at all. This should be read as a warning to anyone who wants to take self-reported exposure data seriously (I’m looking at you, diet studies). When in doubt, find something you can actually measure.

And Number 3 – the lack of variance explained. Studies like this one that look at risk factors for an outcome are building models to predict that outcome. The variables in the model are things like age, race, family history, and the level of pentachlorobenzene in the blood. It’s a simple matter of statistics to tell us how good that model fits – how much of the incidence of ALS can be explained by the model. We almost never get this number, and I suspect its because you can have a highly significant model that only explains, say, 1% of the variance in disease occurrence. It doesn’t make for impressive headlines.

So while we haven’t learned which, if any, organic pollutant causes ALS, hopefully we’ve learned something about the perils of risk factor research.

The diagnosis: Cancer. Should you blame your genes?

For the video version of this post, click here. The prevailing wisdom about almost all types of cancer is that the disease occurs due to a combination of genetic susceptibility and environmental exposures. For different types of cancers, the relative weight of each of these components may differ. But teasing out how much contribution to cancer incidence can be attributed to genetics versus environment is tricky. Unless, that is, you have access to a register of over 100,000 pairs of twins.

In an article appearing in the Journal of the American Medical Association, researchers from four Nordic countries combined national twin registries to create a very detailed database of cancer incidence. The idea here is that identical twins share 100% of the genetic risk factors for cancer (whatever those may be), while fraternal twins share only 50%. This knowledge in hand, you can deconstruct just how much genetics is to blame for cancer.

First some numbers.

32% of the cohort would develop at least one cancer in their lifetime - a number which pretty closely matches what we see in the US.

Now, if your fraternal twin developed cancer, your lifetime risk bumped from 32% to 37%. If your identical twin developed cancer, that lifetime risk went from 32% to 46%. Clearly, genetics are at play here. But how much, exactly? Well, overall, the researchers estimate that about 33% of the variance in cancer incidence is due to genetic factors, with 0% due to shared environmental factors.

Let's parse that a bit though.

First, the researchers are NOT saying that the environment has nothing to do with cancer. They are saying that shared environmental factors, those things that two siblings would experience together, don't account for much risk. Once you leave the nest, in other words, the environment can still play a role. In fact, just doing the math suggests that around 66% of the variance in cancer incidence is due to environmental factors – just factors that don't happen to be shared by two siblings in their youth.

But as I mentioned, these contributions vary by type of cancer. For lung cancer, the shared environmental exposures accounted for more of the variance than genetics – probably because twins tend to share smoking habits even at a young age.

The important thing about this study is to realize that the genetic factor percentage puts a cap on what we can hope to learn from genetic studies of cancer. In other words, even if we perfectly sequenced everyone's genome, we'd only explain a third of the reasons why people get cancer. The smart money remains on evaluating environmental exposures, with the exception of some types of cancer that appeared to have very high genetic risks such as leukemia.

I'd be remiss if I didn't mention that this study was done in four Nordic countries and so the results probably don't give a complete picture of the risks faced in a more multi-ethnic society. In addition, the study can't answer the intriguing question of whether certain environmental exposures interact with certain genes to promote cancer. For now, we simply know that some of your destiny lies in your genes, but more of it in your actions.