The Horror, The Horror

You're watching a horror movie.

The characters are going about their lives, blissfully unaware that something horrifying is about to happen. You the viewer know that things are going to end badly, though, because you know it's a horror movie.

Someone opens a closet - a bloody corpse could fall out! Or they're drinking a glass of water - which could be infected with a virus! Or they're talking to some guy - who's probably a serial killer! And so on.

The effect of this - and a good director can get a lot of mileage from it - is that scenes which would otherwise be entirely mundane, are experienced as scary, purely because you know that something scary is going to happen, so you see potential horror in every innocent little thing. An expectation as to what's going to happen, leads to you interpreting events in a certain way, and this creates certain emotions.

In a medical context, that would be called a placebo effect. Or a nocebo effect when expectations make people feel worse rather than better.

The horror movie analogy is useful, because it shows that placebo effects don't just happen to other people. We all like to think that if we were given a placebo treatment, we wouldn't be fooled. Unlike all those silly, suggestible, placebo responders, we'd stay as sick as ever until we got a proper cure.

I wouldn't be so sure. We're always interpreting the world around us, and interpreting our own thoughts and feelings, on the basis of our expectations and beliefs about what's going on. We don't suddenly stop doing this when it comes to health.

Suppose you have the flu. You feel terrible, and you're out of aspirin. You don't think you'll be able to make that meeting this afternoon, so you phone in sick.

Now, clearly, flu is a real disease, and it really does make you feel ill. But how do you know that you wouldn't be able to handle the meeting? Unless you have an extensive history of getting the flu in all its various forms, this is an interpretation, a best guess as to what you'll feel in the future, and it might be too pessimistic.

Maybe, if you tried, you'd get on OK. Maybe if you had some aspirin that would reassure you enough to give it a go. And just maybe it would still have worked even if those "aspirins" were just sugar pills...

Link: See my previous posts I Feel X, Therefore Y and How Blind is Double Blind?

A PCR Primer

The latest episode in the nail-biting scientific drama of "Does The XMRV Virus Cause Chronic Fatigue Syndrome?" has arrived, in the form of a paper in PNAS. A team of virologists led by the renowned Harvey Alter reported finding various XMRV-like viruses, but not XMRV itself, in chronic fatigue patients.

There's been plenty of excellent coverage of this new study, but most of it has come from specialists and has assumed a certain degree of technical knowledge. So here's my attempt to provide a summary for the non-expert, writing as someone who last got his hands dirty in a molecular lab 5 years ago...

The key to the controversy is PCR, a very useful technique invented by a guy on acid (kind of). PCR means Polymerase Chain Reaction. Polymerase is an enzyme which copies DNA. If you ask it nicely, it also copies the copies, then copies the copies of the copies, and so on. Thanks to this chain reaction, you can start with a tiny bit of DNA and end up with loads.

Using PCR, you can detect certain DNA sequences, for example, the DNA sequence of XMRV. (XMRV itself has RNA, rather than DNA, but as a retrovirus, it's able to insert itself into the DNA of infected cells.)

Here's how. DNA is a chain, or strand, of simple molecules called nucleotide bases. There are four: A, C, T, and G. Most of the time, DNA molecules are double-stranded, containing two chains of bases paired up (bound) together. Whenever one strand has A, the other has C, and vice versa. T and G pair up in the same way. They can only pair up in that particular way. T can't pair with C, or G, or with another T.
PCR takes double-stranded DNA and makes more of it. It does this by taking each strand and adding a second strand which is the "opposite" (complementary) sequence of the original, with T and A swapped, and C and G swapped.

That's nothing more than a replica of the original double-stranded DNA.

However, there's a catch. Polymerase can't start a strand of DNA out of nothing, it can only make an existing strand longer. So it needs a primer which can bind to the original DNA and provide "something to work with".

No primer, no duplication. The primer has to be specific: it has to be able to pair up with the DNA. This fact allows us to use PCR to detect specific DNA sequences. Suppose you want to know whether a sample of DNA contains a certain gene, and you know that this gene starts with AAAAA, and ends with CCCCC.

You would make some corresponding primers: a forward primer AAAAA and a reverse primer GGGGG. If the gene is present, these primers will bind to the corresponding target sequences bookending the gene of interest. The PCR will work, and you'll end with loads of copies of that gene. Hooray. If not, nothing much happens. Note that the forward primer is the "opposite" of what you might expect, because it has to bind to the complementary strand. The two primers bookend the region to be amplified - see this pic for an explanation of why.

Once you've run the PCR it's relatively easy to tell whether it amplified the gene or not. But remember that PCR doesn't detect genes, it detects primer targets. The DNA in between the target regions could be anything, as long as the primers fit. In fact, you can tell the length of the amplified DNA, which does provide some information. You can also resequence the amplified DNA to see exactly what it is, but that's expensive.

On the other hand, the match has to be exact. If you're testing for a gene starting with AAAAA, and that gene is present except that it starts with AAAAC instead, you won't find it: a single base difference in the primer sequence throws the whole thing off.

So if someone "used PCR to detect dog DNA", what they mean is that they used primers which they think are specific to dog DNA. This relies on two things being true: that the primers do in fact match the DNA of all dogs (not just some breeds of dog) and that they only match dog DNA (not cats, or mice.)

There are also technical considerations. PCR is vulnerable to contamination by unwanted DNA, because it's so sensitive: even a tiny bit of contamination will cause a false positive. Rogue DNA could come from anywhere: from the researcher running the experiment, from other samples in the lab... So, every PCR experiment needs a negative control, a sample known not to contain the gene of interest. A drop of water is the simplest example. If you "detect" the gene in the negative control, you have to try again (after cleaning all your equipment and washing your hands.)

PCR also doesn't always work. It's like cooking: you have to have the right mix of ingredients, the right temperature, the right timing. If not, you'll end up with a mess. This is why every PCR experiment needs a positive control, i.e. a sample in which you know the gene of interest is present. If you fail to detect the gene in the positive control, you have to check the recipe and try again.

How does this relate to the XMRV story? That's another post...

Normal? You're Weird - Psychiatrists

Almost everyone is pretty screwed up. That's not my opinion, that's official - according to a new paper in the latest British Journal of Psychiatry.

Make sure you're sitting down for this. No less than 48% of the population have "personality difficulties", and on top of that 21% have a full blown "personality disorder", and another 7% have it even worse with "complex" or "severe" personality disorders.

That's quite a lot of people. Indeed it only leaves an elite 22.5% with no personality disturbances whatsoever. You're as likely to have a "simple PD" as you are to have a normal personality, and fully half the population fall into the "difficulties" category.

I have difficulties with this.

Where do these results come from? The Adult Psychiatric Morbidity Survey, which is a government study of the British population. They phoned up a random sample of several thousand people, and gave them the SCID interview, in other words they asked them questions. 116 questions in fact.

48% of people answered "yes" to enough questions such that, according to their criteria, they had "personality difficulties". They defined "personality difficulties", which is not a term in common use, as being "one criterion less than the threshold for personality disorder (PD)" according to DSM-IV criteria.

So what? Well, as far as I'm concerned, that means simply that "personality difficulties" is a crap category, which labels normality as pathological. I can tell that most of people with "difficulties" are in fact normal because they are the literally the norm. It's not rocket science.

So we can conclude that "personality difficulties" should either be scrapped or renamed "normal". In which case the weird minority of people without any such features should be relabelled. Maybe they are best known as "saints", or "Übermenschen", or perhaps "people who lie on questionnaires".

This, however, is not what the authors say. They defend their category of Personality Difficulties on the grounds that this group are slightly more likely to have a history of "issues" than the elite 22.5 percent, e.g. homelessness (3.0% vs. 1.6%), 'financial crisis' (10.1% vs. 6.8%), or having had treatment for mental illness (11% vs 6%).

They say:

The finding that 72% of the population has at least some degree of personality disturbance is counterintuitive, but the evidence that those with ‘personality difficulty’ covering two out of five of the population [it's actually closer to half], differs significantly from those with no personality disturbance in the prevalence of a history of running away from home, police contacts, homelessness... shows that this separation is useful from both clinical and societal viewpoints.

Well, yeah...but no. The vast majority (90+%) of people with Personality Difficulty had no history of these things. It's true that, as a group, they have higher average rates, but all this tells you is that some of them have problems. I suspect they're the ones right at the "top end" of this category, the people who are almost into the next category up.

Here's what I think is going on:

The "difficulties" group and the "none" group are essentially the same in terms of the levels of crap stuff happening to them - because they are the same, normal, everyday people - except that a small % of the "difficulties" group do have some moderate degree of problems, because they are close to being "PD".

This does not mean that the "difficulties" category is good. Quite the reverse, it means it's rubbish, because it spans so many diverse people and lumps them all together. What you should do, if you insist on drawing lines in the sand, would be this:

Now I don't know that that's how things work, but it seems plausible. Bearing in mind that the categories they used are entirely arbitrary, it would be very odd if they did correspond to reality.

To be fair to the authors, this is not the only argument in their paper. Their basic point is that personality disturbance is a spectrum: rather than it being a black-and-white question of "normal" vs."PD", there are degrees, ranging from "simple PD" which is associated with a moderate degree of life crap, up to "complex PD" which has much more and "severe PD" which is worst of all.

They suggest that in the upcoming DSM-V revision of psychiatric diagnosis, it would be useful to formally incorporate the severity spectrum in some way - unlike the current DSM-IV, there everything is either/or. They also argue that with more severe cases of PD, it is not very useful to assign individual PD diagnoses (DSM-IV has no less than 10 different PDs) - severe PD is just severe PD.

That's all fine, as long as it doesn't lead to pathologizing 78% of the population - but this is exactly what it might do. The authors do admit that "the SCID screen for personality disorder, like almost all screening instruments, overdiagnoses personality pathology", but provide little assurance that a "spectrum" approach won't do the same thing.

Yang M, Coid J, & Tyrer P (2010). Personality pathology recorded by severity: national survey. The British Journal of Psychiatry 197, 193-9 PMID: 20807963

Are "Antipsychotics" Antipsychotics?

This is the question asked by Tilman Steinert & Martin Jandl in a letter to the journal Psychopharmacology.

They point out that in the past 20 years, the word "antipsychotic" has exploded in popularity. Less than 100 academic papers were published with that word in the title in 1990, but now it's over 600 per year.

The older term for the same drugs was "neuroleptics". This terminology, however, has slowly but surely fallen into disuse over the same time period.

To illustrate this they have a nice graph of PubMed hits. Neuroskeptic readers will be familiar with these as I have often posted my own and I recently wrote a bash script to harvest this data automatically. Now you too can be a historian of medicine from the comfort of your own home...

Why does it matter what we call them? A name is just a name, right? No, that's the problem. Actually, neuroleptic is just a name, because it doesn't mean anything. The term derives from the Greek "neuron", meaning... neuron, and "lambanō" meaning "to take hold of". However, no-one knows that unless they look it up on Wikipedia because it's just a name.

Antipsychotic, on the other hand, means something: it means they treat psychosis. But whether or not this is an accurate description of what "antipsychotics" actually do, is controversial. For one thing, these drugs are also used to treat many non-psychotic illnesses, like depression, and PTSD.

More fundamentally, it's not universally accepted that they have a direct anti-psychotic effect. All antipsychotics are powerful sedatives. There's a school of thought that says that this is in fact all they are, and rather than treating psychosis, they just sedate people until they stop being obviously psychotic.

Personally, I don't believe that, but that's not really the point: the point is that it's controversial, and calling them antipsychotics makes it hard to think about that controversy in a sensible way. To say that antipsychotics aren't actually antipsychotic is a contradiction in terms. To say they are antipsychotic is a tautology. Names shouldn't dictate the terms of a debate in that way. A name should just be a name.

The same point applies to more than just antipsychotics - I mean neuroleptics - of course. Perhaps the worst example is "antidepressants". Prozac, for example, is called an antidepressant. Implying that it treats depression.

But according to clinical trials, Prozac and other SSRIs are a lot more effective, relative to placebo, in obsessive-compulsive disorders (OCD) than they are in depression (though this is not necessarily true of all "antidepressants", yet more evidence that the word is unhelpful.)

So, as I asked in a previous post: "Are SSRIs actually antiobsessives that happen to be helpful in some cases of depression?" Personally, I think the only name for them which doesn't make any questionable assumptions, is simply 'SSRIs'.

Tilman Steinert and Martin Jandl (2010). Are antipsychotics antipsychotics? Psychopharmacology DOI: 10.1007/s00213-010-1927-3

Marc Hauser's Scapegoat?

The dust is starting to settle after the Hauser-gate scandal which rocked psychology a couple of weeks back.

Harvard Professor Marc Hauser has been investigated by a faculty committee and the verdict was released on the 20th August: Hauser was "found solely responsible... for eight instances of scientific misconduct." He's taking a year's "leave", his future uncertain.

Unfortunately, there has been no official news on what exactly the misconduct was, and how much of Hauser's work is suspect. According to Harvard, only three publications were affected: a 2002 paper in Cognition, which has been retracted; a 2007 paper which has been "corrected" (see below), and another 2007 Science paper, which is still under discussion.

But what happened? Cognition editor Gerry Altmann writes that he was given access to some of the Harvard internal investigation. He concludes that Hauser simply invented some of the crucial data in the retracted 2002 paper.

Essentially, some monkeys were supposed to have been tested on two conditions, X and Y, and their responses were videotaped. The difference in the monkey's behaviour between the two conditions was the scientifically interesting outcome.

In fact, the videos of the experiment showed them being tested only on condition X. There was no video evidence that condition Y was even tested. The "data" from condition Y, and by extension the differences, were, apparently, simply made up.

If this is true, it is, in Altmann's words, "the worst form of academic misconduct." As he says, it's not quite a smoking gun: maybe tapes of Y did exist, but they got lost somehow. However, this seems implausible. If so, Hauser would presumably have told Harvard so in his defence. Yet they found him guilty - and Hauser retracted the paper.

So it seems that either Hauser never tested the monkeys on condition B at all, and just made up the data, or he did test them, saw that they weren't behaving the "right" way, deleted the videos... and just made up the data. Either way it's fraud.

Was this a one-off? The Cognition paper is the only one that's been retracted. But another 2007 paper was "replicated", with Hauser & a colleague recently writing:

In the original [2007] study by Hauser et al., we reported videotaped experiments on action perception with free ranging rhesus macaques living on the island of Cayo Santiago, Puerto Rico. It has been discovered that the video records and field notes collected by the researcher who performed the experiments (D. Glynn) are incomplete for two of the conditions.

Luckily, Hauser said, when he and a colleague went back to Puerto Rico and repeated the experiment, they found "the exact same pattern of results" as originally reported. Phew.

This note, however, was sent to the journal in July, several weeks before the scandal broke - back when Hauser's reputation was intact. Was this an attempt by Hauser to pin the blame on someone else - David Glynn, who worked as a research assistant in Hauser's lab for three years, and has since left academia?

As I wrote in my previous post:

Glynn was not an author on the only paper which has actually been retracted [the Cognition 2002 paper that Altmann refers to]... according to his resume, he didn't arrive in Hauser's lab until 2005.

Glynn cannot possibly have been involved in the retracted 2002 paper. And Harvard's investigation concluded that Hauser was "solely responsible", remember. So we're to believe that Hauser, guilty of misconduct, was himself an innocent victim of some entirely unrelated mischief in 2007 - but that it was all OK in the end, because when Hauser checked the data, it was fine.

Maybe that's what happened. I am not convinced.

Personally, if I were David Glynn, I would want to clear my name. He's left science, but still, a letter to a peer reviewed journal accuses him of having produced "incomplete video records and field notes", which is not a nice thing to say about someone.

Hmm. On August 19th, the Chronicle of Higher Education ran an article about the case, based on a leaked Harvard document. They say that "A copy of the document was provided to The Chronicle by a former research assistant in the lab who has since left psychology."

Hmm. Who could blame them for leaking it? It's worth remembering that it was a research assistant in Hauser's lab who originally blew the whistle on the whole deal, according to the Chronicle.

Apparently, what originally rang alarm bells was that Hauser appeared to be reporting monkey behaviours which had never happened, according to the video evidence. So at least in that case, there were videos, and it was the inconsistency between Hauser's data and the videos that drew attention. This is what makes me suspect that maybe there were videos and field notes in every case, and the "inconvenient" ones were deleted to try to hide the smoking gun. But that's just speculation.

What's clear is that science owes the whistle-blowing research assistant, whoever it is, a huge debt.