Tag Archives: slighty ranty

David Goldstein Proves Himself Wrong

A recent paper in PLoS Biology by David Goldstein’s group is being seen as another ‘death of GWAS’ moment (again?). I have a lot of issues with this paper, but I will be brief and stick to my main objection; the authors attempt to demonstrate that common associations can be caused by sets of rare variants, and in doing so inadvertantly show they most of them are not.

The Paper and the Press

This is another example of a scientific paper being careful to make no solid, controversial claims, but being surrounded by a media story that is not justified by the paper itself. The only real solid claim in the paper is that, if you do not include rare SNPs in your genome-wide association study, and rare SNPs of large effect are contributing to disease, then you will sometimes pick up more common SNPs as associated, because they are in Linkage Disequilibrium with the rare SNPs. Pretty uncontroversial, in so far as it goes. The paper makes no attempt to say whether this IS happening, just says that it CAN happen, and that we should be AWARE of it.

However, in the various articles around the internet, this paper is being received as if it makes some fundamental claim about complex disease genetics; that this somehow undermines Genome-Wide Association Studies, or shows their results to be spurious. David Goldstein is quoted on Nature News:

…many of the associations made so far don’t seem to have an explanation. Synthetic associations could be one factor at play. Goldstein speculates that, “a lot, and possibly the majority [of these unexplained associations], are due to, or at least contributed to, by this effect”.

Another author is quoted here as saying

We believe our analysis will encourage genetics researchers to reinterpret findings from genome-wide association studies

Much of the coverage conflates this paper with the claim that rare variants may explain ‘missing heritability’, which is an entirely different question; Nature News opens with the headline “Hiding place for missing heritability uncovered”. Other coverage can be found on Science Daily, Gene Expression and GenomeWeb.

Does this actually happen?

Is all this fuss justified? How common is this ‘synthetic hit’ effect; are a lot of GWAS hits caused by it, or hardly any? There are many ways that you could test this; for instance, you could make some predictions about what distribution of risk you’d expect to see in the many fine mapping experiments that have been done as follow ups to Genome-Wide Association Studies (this would be trivially easy to do using the paper’s simulations).

However, there is an even easier way to test the prevalence of the effect. If most GWAS hits are tagging relatively common variants, then you would expect to see most disease associated SNPs with a frequency in the 10% to 90% range (the range for which GWAS are best powered). However, a SNP with a frequency of 50% is less likely than one with a frequency of 10% to tag a SNP with frequency 0.5%, so if most GWAS hits are tagging rare variants, then you would expect to see most associated SNPs with a frequency skewed towards the very rare or the very common.

In fact, the paper makes an explicit calculation of the expected frequency distribution of GWAS hits, under their synthetic model. In-double-fact, the paper plots this distribution against the distribution of know GWAS hits. And here is that plot, taken directly from the paper (Figure 5):

The green line is the expected frequency distribution of ‘synthetic’ associations; the red line is the actual distribution. We can see that the GWAS hits we do see fail to follow the distribution for synthetic associations; in fact, they follow pretty much exactly the distribution we’d expect if most common associations are tagging common causal SNPs.

The paper manages to pretty conclusively show both that demonstrate that synthetic SNPs can occur, but they rarely do.

Dickson, S., Wang, K., Krantz, I., Hakonarson, H., & Goldstein, D. (2010). Rare Variants Create Synthetic Genome-Wide Associations PLoS Biology, 8 (1) DOI: 10.1371/journal.pbio.1000294

Cargo Cult Science and NT Factor®

A recent blog post on Chronic Fatigue Syndrome linked in passing to a ‘treatment’ called Mitochondria Ignite™ with NT Factor®. This product caught my attention as an example of what Richard Feynman called ‘Cargo Cult Science’; a company dressing up like scientists, using chemical names and precise sounding figures, without actually having any science underlying it.

However, the product is not arguably not exactly pure Cargo Cult Science; there is a small amount of science content present. The product page contains a number of references, some of which point to peer review journals, and some of which are actually studies of the effect of some of the contents of the drug on humans. Of cours,e taking apart the studies shows that the product is still unproven, despite the thin glaze of real science; I can’t help but feel that this sort of thing has slightly grim implications for the future of accurate consumer information.

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The Economist Mangles Disease Genetics

The Economist has a rather distressingly bad article by the evolutionary psychologist Geoffrey Miller, about the supposed general failure in human disease genetics over the last 5 years. The thesis is that Genomes Wide Association Studies (GWAS) for common diseases have been a failure that geneticists are trying to keep hidden, and that the new techniques required to solve the problem of disease genetics will raise ‘politically awkward and morally perplexing facts’ about the different traits and evolutionary histories of races. The former claim is pretty much the same as Steve Jones Telegraph article earlier this year, and is just as specious. I will look at both claims separately.

A quick point of terminology: Miller uses ‘GWAS’ to refer to studies that look for disease association in common variants using a genotyping chip, and acts as if sequencing studies are not, in fact, GWAS. In fact, a sequencing association study is just another type of GWAS, just looking at a larger set of variants.
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ASHG: Chatting with the Sequencing People

While I am here, I though I’d take the chance to chat to the people at the booths for the three major Second Gen sequencing platforms (Illumina, SOLiD and 454). It was surprisingly fun, the guys I talked to all seemed enthusiastic, and it was nice to find out where the scientists in the companies think the technology is going.

In the interests of openness: the 454 booth gave me a cool T-shirt and poster, so this may well have biased my opinion of them
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Unbelief, Class and Bad Statistics

I like to read the Comment is free: Belief section of the Guardian website; it has comment pieces on a pretty large range of religious matters, which satisfies both my “reading about religious affairs” and “reading things that annoy me” urges (in particular, I find a bit of an odd pleasure in reading the regular posts by Andrew Brown, a man who has a wonderful habit of saying things I would probably agree with in such a smug, sneering style that I can’t help but disagree).

Today there is a post up called Religion And Learning: what do we know, by Nick Spencer of the religious thinktank Theos. It feeds on from a somewhat substance-light Andrew Brown post claiming that atheism (or ‘new atheism’, or some ill-defined form of non-belief) is becoming a way of the upper middle class setting themselves apart from the Daily Mail-reading working class.

Nick Spencer’s article attempts to shed some light on the relationship between class and religious belief by looking at the relationship between NRS social classes and belief in God, based on some Theos data from their recent Darwin report. The report, unfortunately, doesn’t tell us very much; it says that Atheists tend to come from higher social grades (AB), and theists tend to come from lower social grades (DE); this was already well know.

Spencer goes on to look at the social classes of converts; he finds that converts to theism tended to come from the roughly the same classes as atheists (ABC), and that converts to atheism tended to come from the same classes as theists (DE). This is unsurprising, it basically says that there is no real social indication of conversion; it is more or less a random process, with atheists going to theists and vice versa more or less independent of social class. It would be interesting to follow up these converts over larger periods of time, or to break it down into recent and older conversions, to see whether converting to a religion causes a change in class, but so far we have no evidence for this. So, in conclusion, the data doesn’t tell us anything interesting about how religion and class or education beyond what we already knew; if anything, it tells us that class or education aren’t really playing much of a factor in conversion.

Or, that is the conclusion that any non-reaching person would draw. What is odd is that Nick Spencer uses this essentially Null result to argue that some sort of revolutionary change on the nature of atheism:

On a less grand scale, the data suggest that the effect of vocal atheism over the last decade has been to reach successfully into previously uncharted demographic territory (witness The God Delusion’s sales figures) but at the cost of losing some of its intellectual credibility (the critical review of The God Delusion in the London Review of Books, for example).

If this is happening, we might expect to see atheism become increasingly “religious” in its composition if not in its size.

So, according to Nick Spencer, the expected class distribution of converts if there is no relationship between class and conversion is an indicator of a grand, sweeping change in the nature of atheism, and we should all be prepared for atheism to become a ‘religion-like’ mass movement of unthinking godlessness. This is completely the opposite conclusion that I have made from the same data; that non-belief is going on the same as it always has (as far as I can see, the current bunch of non-believers are no more outspoken or populist than Carl Sagan, Richard Feynman, Bertrand Russell and Thomas Huxley), and there is no particular evidence that anything new is going on in unbelief.

On Lamarck and Trees

Over at Genetic Future, Daniel MacArthur quotes Joel Parker berating as ‘embarrassing’ biologists who claim that it was Darwin, and not Lamarck, who came up with the idea of an evolutionary tree:

I have noticed many evolutionary biologists making an embarrassing mistake of falsely attributing the first use of the tree analogy to Darwin. This has occurred in numerous documentaries and on websites which I will pass on naming here. Ironically, the earliest use of the tree analogy diagram to depict evolution was published in the year of Darwin’s birth (1809) by Lamarck in his book Philosophie Zoologique (see pg 463, http://tinyurl.com/knt7vr). Lamarck even uses botanical terms (branches and rameaux) to describe the origin of animals with respect to this figure. The figure that is usually cited from Darwin’s notebook is from 1837 (http://tinyurl.com/6hs5uv), a full 8 years after Lamarck’s death. Even with our high admiration for Darwin, we should at least give credit where credit is due, and not forget that much of evolution was becoming understood before Darwin. Explaining the mechanism of natural selection was Darwin’s great contribution.

This is actually largely correct; Lamarck did have a view of evolution that involved what we would now call evolutionary branching, though it was very different from what we now know to be the case. Lamarck deserves to be read and understood as one of the first people to put together a coherent view of evolution.

However, the statement is very wrong in a number of ways. It is far from a mistake to refer to Darwin as the originator of the evolutionary tree, and those of us who do so do so not out of ignorance.
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The (Lack Of) Genetics of Rape

There has been a flurrylet of blog posts recently to do with, in various forms, genetic determinism and adaptationism; two ideas that together form a general philosophy that the traits that make up human biology are largely determined by human genetics, and that these traits (and the genes that underlie them) have come about as the direct result of natural selection. In particular, people have been talking about evolutionary psychology, which involves explaining human behaviour in terms of adaptations. I felt like commenting, which I guess you have already infered by the existence of this post.

Jerry Coyne pointed out two articles in the popular press about genetic determinism, the first by the journalist David Brooks, and the second by the journalist Sharon Begley. Jerry Coyne himself wrote a detailed takedown of evolutionary psychology as early as 2000. There is a lot to say about Sharon Begley’s piece in particular.
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The Genome Campus is a Mac?

Catching up on my RSS feeds, I came across a post at PolITiGenomics, about the European Bioinformatics Institute’s Paul Flicek taking part in one of those ‘I am a person of significance, I use a Mac’ videos:

First the most important bits. At 0:06, THAT’S MY COLLEGE! And at 0:25, THAT’S THE BUILDING I WORK IN! And at 2:24, I EAT THERE! How exciting.
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On GSK’s Announcement

Hello again, reader; we have been seeing a lot of each other this week. This is my promised post on GSK’s recent announcement of a set of initiatives to help fight disease in the 50 poorest developing countries. I’ll go through some background about GSK’s business model and what has been happening to them recently, and then we’ll take a look through what the responses to the initiatives have been, and what my take on it is.
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On Michele Hanson and Game Theory

I read the Guardian newspaper on a semi-regular basis, and I find their coverage to range from Pretty Good to Good Lord No, with a peak around Not Bad (the quality is somewhat moot, since the ever-delightful Ben Goldacre, among other loved columnists, guarantee that I will always return).

However, there is the occasional distressing piece from an individual notably unaware of the complexity, and often the substance, of what they are talking about. One source that provides such tidbits with unfortunate frequency is in the G2 columnist Michele Hanson. Now, her column usually just offers Humorous Anecdotes and Gripes, which is fine for a supplement, but she also spends plenty of time commenting on science subjects from a platform of ignorance and, more worrying, derisive scorn. From yesterday’s column:

A bumper crop of bad science plopped out of our universities and hospitals this week. Three lots at once, and all about relationships. The first gang, from UCL, LSE and Warwick Medical School, have “developed a mathematical model of the mating game to help explain why courtship is often protracted”. Or as every girl’s mother has probably told her, “Don’t do it on the first date. If he can’t wait, he’s not worth it.” [...]

I would like to tear my hair out. I ought to be used to professors churning out this sort of old-hat, inapplicable drek, time after time, but for me the shock never fades. How do they get away with it? Has Professor Robert Seymour, of UCL, been shut away in the groves of academe since birth, and does he really think that we don’t know that “longer courtship is a way for the female to acquire information about the male”. Has he ever met a female person? Or a male from the outside world? Did he not know already that we know that you can’t get to know someone all that well in the course of a quick bang?

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