# What if the problem is not as we thought it was

Posted by Francesco Gadaleta on August 26, 2014

At the end of GAW19, a very interesting workshop about Genetic Analysis, held in Vienna last week, I find it necessary to take a big breath and draw some conclusion. Or maybe start a new way of thinking about The problem. Genetic analysis is not an easy task to solve. We all know that. When we try to put it in mathematical terms, the problem is likely to be ill-posed, being the number of unknowns larger than the known variables. When we do it in statistical terms, there is too much uncertainty. Are we doomed to leave such problems unsolved, acknowledging that we spent billions and we actually lost that money? Not so fast. Research works like that.

No substantial discovery is made on day-to-day basis. But when it happens it is big (ignoring the micro steps of the $k_{t}$ paper that improves on the $k_{t-1}$, that in turns improves on the $k_{t-2}$, and so forth in a pretty indefinitely long sequence of publications that nobody read but that is cool to refer to).

The observation of a researcher I know, What if the genome does not explain enough? was raised only four years ago. I believe it is still a good one that made me think deeply about the subject and realise that, maybe, the common feeling about research in genetics has not changed much. This is just a feeling of course, which I hope could be disproved. Let me refer to the problem of inferring gene regulatory networks. So much science has been called to the rescue and so many researchers (mainly statisticians) have been hired to take care of such a challenge. The most common tools that researchers (I ashamedly include myself here) are considering since ages are regression (in all its flavours, linear, non-linear, penalised, etc.), Principal Component Analysis or PCA (in all its flavours, independent, randomised, kernel, etc.), statistical correlation which usually leads to clustering highly correlated genetic compounds within the same group.

Is this solving the issue? Not really. As Gordon Webster summarises in a beautiful and diplomatic way on his blog, the digital biologist,

Looking back over almost a decade since the first working draft of the human genome was completed […] I think it is fair to say that the impact has not been on anything like the scale that was initially anticipated, largely as a result of having underestimated how difficult it is to translate such a large and complex body of data into real knowledge.”

What statistics is certainly doing is giving researchers a grip on the problem. Interpreting the regression coefficients of some genes as handlers to manipulate a limited number of genetic compounds (statistically) associated to the trait under investigation is a relief indeed. However, considering such a result an oracle that should be undeniably used for subsequent analyses is equivalent to accepting the idea that dipping one foot into fire and the head into ice leads, on average, to a comfortable temperature.

Speaking to a medical doctor I met at GAW, who is genuinely interested in exploring the new insights of computational biologists, we agreed on what we both see as a trend in our community: when a model works 3 times out of 100, improving on that other model working only 0.2 times out of 3000 (and this is rather optimistic), we tend to claim that we’re done. The best model is almost considered a gold standard, it gets a bunch of citations and becomes The Way of solving things in the future. What exactly is happening is that by doing so we are accepting the average of the average of the average result and we are pretty much happy with that.

### Statistics is not biology

How could such an abstraction be interpreted as a real thing? Going back to the question of “What if the genome does not explain enough?” I do agree that indeed it might not. Actually I am pretty sure it doesn’t. But, once the majority will figure out that this might be the case, the real question will be “What if statistics does not explain it at all?”

My conclusion wants to be provocative, of course. But is there anybody out there who truly believes that complex genetic traits are merely a statistical problem in which a t-test or anova would provide a solution? Statistics, as I see it, is just a wonderful abstraction that gives us a comfortable point of view on complexity. If we do not accept the fact that it is just a starting point, not an oracle, then yes!, we are doomed to leave our problems unsolved.

Happy research!

(oo) Piggy

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