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Thursday, May 21, 2009

Genes, Brains and the Perils of Publication

Much of science, and especially neuroscience, consists of the search for "positive results". A positive result is simply a correlation or a causal relationship between one thing and another. It could be an association between a genetic variant and some personality trait. It could be a brain area which gets activated when you think about something.


It's only natural that "positive results" are especially interesting. But "negative" results are still results. If you find that one thing is not correlated with another, you've found a correlation. It just happens to have a value of zero.

For every gene which causes bipolar disorder, say, there will be a hundred which have nothing to do with it. So, if you find a gene that doesn't cause bipolar, that's a finding. It deserves to be treated just as seriously as finding that a gene does cause it. In particular, it deserves to be published.

Sadly, negative results tend not to get published. There are lots of reasons for this and much has been written about it, both on this blog and in the literature, most notably by John Ionnidis (see this and this, for starters). A paper just published in Science offers a perfect example of the problem: Neural Mechanisms of a Genome-Wide Supported Psychosis Variant.

The authors, a German group, report on a genetic variant, rs1344706, which was recently found to be associated with a slightly raised risk of psychotic illness in a genome-wide association study. (Genome-wide studies can and do throw up false positives so rs1344706 might have nothing to do with psychosis - but let's assume that it does.)

They decided to see whether the variant had an effect on the brains of people who have never suffered from psychosis. That's an extremely reasonable idea, because if a certain gene causes an illness, it could well also cause subtle effects in people who don't have the full-blown disease.

So, they took 115 healthy people and used fMRI to measure neural activity while they were doing some simple cognitive tasks, such as the n-back task, a fairly tricky memory test. People with schizophrenia and other psychotic disorders often have difficulties on this test. They also used a test which involves recognizing people's emotions from pictures of their faces.
They found that -
Regional brain activation was not significantly related to genotype...Rs1344706 genotype had no impact on performance.
In other words, the gene didn't do anything. The sample size was large - with 115 people, they had an excellent chance to detect any effect, if there was one, and they didn't. That's a perfectly good finding, a useful contribution to the scientific record. It was reasonable to think that rs1344706 might affect cognitive performance or brain activation in healthy people, and it didn't.
But that's not what the paper is about. These perfectly good negative findings were relegated to just a couple of sentences - I've just quoted almost every word they say about them - and the rest of the article concerns a positive result.The positive result is that the variant was associated with differences in functional connectivity. Functional connectivity is the correlation between activity in different parts of the brain; if one part of the brain tends to light up at the same time as another part they are said to be functionally connected.
In risk-allele carriers, connectivity both within DLPFC (same side) and to contralateral DLPFC was reduced. Conversely, the hippocampal formation was uncoupled from DLPFC in non–risk-allele homozygotes but showed dose-dependent increased connectivity in risk-allele carriers. Lastly, the risk allele predicted extensive increases of connectivity from amygdala including to hippocampus, orbitofrontal cortex, and medial prefrontal cortex.
And they conclude, optimistically:
...our findings establish dysconnectivity as a core neurogenetic mechanism, where reduced DLPFC connectivity could contribute to disturbed executive function and increased coupling with HF to deficient interactions between prefrontal and limbic structures ... Lastly, our findings validate the intermediate phenotype strategy in psychiatry by showing that mechanisms underlying genetic findings supported by genome-wide association are highly penetrant in brain, agree with the pathophysiology of overt disease, and mirror candidate gene effects. Confirming a century-old conjecture by combining genetics with imaging, we find that altered connectivity emerges as part of the core neurogenetic architecture of schizophrenia and possibly bipolar disorder, identifying novel potential therapeutic targets.
I have no wish to criticize these findings as such. But the way in which this paper is written is striking. The negative results are passed over as quickly as possible. This despite the fact that they are very clear and easy to interpret - the rs1344706 variant has no effect on cognitive task performance or neural activation. It is not a cognition gene, at least not in healthy volunteers.

By contrast, the genetic association with connectivity is modest (see the graphs above - there is a lot of overlap), and very difficult to interpret, since it is clearly not associated with any kind of actual differences in behaviour.

And yet this positive result got the experiment published in no less a journal than Science! The negative results alone would have struggled to get accepted anywhere, and would probably have ended up either unpublished, or published in some rubbish minor journal and never read. It's no wonder the authors decided to write their paper in the way they did. They were just doing the smart thing. And they are perfectly respectable scientists - Andreas Meyer-Lindenberg, the senior author, has done some excellent work in this and other fields.

The fault here is with a system which all but forces researchers to search for "positive results" at all costs.

[BPSDB]

ResearchBlogging.orgEsslinger, C., Walter, H., Kirsch, P., Erk, S., Schnell, K., Arnold, C., Haddad, L., Mier, D., Opitz von Boberfeld, C., Raab, K., Witt, S., Rietschel, M., Cichon, S., & Meyer-Lindenberg, A. (2009). Neural Mechanisms of a Genome-Wide Supported Psychosis Variant Science, 324 (5927), 605-605 DOI: 10.1126/science.1167768

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