An article in the New York Times describes research that supposedly linked a rare gene mutation to autism:
Dr. Matthew W. State, a professor of genetics and child psychiatry at Yale, led a team that looked for de novo mutations [= mutations that are not in the parents] in 200 people who had been given an autism diagnosis, as well as in parents and siblings who showed no signs of the disorder. The team found that two unrelated children with autism in the study had de novo mutations in the same gene — and nothing similar in those without a diagnosis.
“That is like throwing a dart at a dart board with 21,000 spots and hitting the same one twice,” Dr. State said. “The chances that this gene is related to autism risk is something like 99.9999 percent.”
It is like throwing 200 darts at a dart board with 21,000 spots (the number of genes) and hitting the same one twice. (Each person has about 1 de novo mutation.) What are the odds of that? If all spots are equally likely to be hit, then the probability is about 0.6. More likely than not. (Dr. State seems to think it is extremely unlikely.) This is a variation on the birthday paradox. If there are 23 people in a room, it is 50/50 that two of them will share a birthday.
When Dr. State says, “The chances that this gene is related to autism risk is something like 99.9999 percent,” he is making an elementary mistake. He has taken a very low p value (maybe 0.000001) from a statistical test to indicate the likelihood that the null hypothesis (no association with autism) is true. P values indicate strength of evidence, not probability of truth.
One way to look at the evidence is that there is a group of 200 people (with an autism diagnosis) among whom two have a certain mutation and another group of about 600 people (their parents and siblings) none of whom have that mutation. If two instances of the mutation were randomly distributed among 800 people what are the odds that both instances would be in any pre-defined group of 200 of the 800 people (defined, say, by the letters in their first name)? The chance of this happening is 1/16. Not strong evidence of an association between the mutation and the actual pre-defined group (autism diagnosis).
Another study published at the same time found an link between autism and a mutation in the same gene identified by Dr. State’s group but again the association was weak. It may be a more subtle example of the birthday paradox: If twenty groups of genetics researchers are looking for a gene linked to autism, what are the odds that two of them will happen upon the same gene by chance?
If the gene with the de novo mutations is actually linked to autism, then we will have insight into the cause of 1% of the 200 autism cases Dr. Smart’s group studied. When genetics researchers try so hard and come up with so little, it increases my belief that the main causes of autism are environmental.
Thanks to Bryan Castañeda.
for some reason scientist keep banging their heads against the same genetic door. why do they want this to be genetic so badly? There’s no such thing as a genetic epidemic! as a parent with a child who has autism, I find this a frustrating waste of energy, time, and funds. its environmental folks. time to come out of denial. its epigenetics. the toxins/pollutants in the environment are changing the way genes are expressing the cells of the brain during gestation and altering the structure and developmental trajectory of the brain. the timing, duration, and intensity of exposure during specific critical windows of development dictate the level of damage done and where that individual will fall on the autism ” spectrum” and its in us. these toxins are already in us. so this will be only be getting worse. time to take all those funds and work on trying to isolate the worse toxic offenders and clean up the environment if its not already too late… I’m not hopeful though.
This is a fabulous post, and I whole heartedly support your analysis. [nitpicking] Never the less, I wouldn’t be in the sciences if I didn’t love nit-picking and correct people. While your number of 1 de novo mutation is doubtlessly the right number to use for your analysis, there are about 175 de novo substitutions per diploid genome, and you can’t forget that there are many other classes of mutations. Whole gene duplications and deletions are quite common and likely occur at per base rates comparable to substitutions. Since, of course, the authors were only sequencing the exome, which entails roughly 1% of the human genome, they were only able to identify ~1
substitution mutation per individual. [/nitpicking]
I would call their results somewhat suggestive (after all, they did only have 15 nonsense mutations), but certainly the press release and the paper itself oversell their results. I’m not really sure why people are looking for genetic factors when it seems so obvious that an environmental change must be associated with the rise in rates of incidents, since genes simply do not change in frequency that fast without strong selection. Oh well, yet another case of marginal science getting too much press attention.