Part 12 (1/2)

Science coverage is further crippled, of course, by the fact that the subject can be quite difficult to understand. This in itself can seem like an insult to intelligent people, like journalists, who fancy themselves as able to understand most things, but there has also been an acceleration in complexity in recent times. Fifty years ago you could sketch out a full explanation of how an AM radio worked on the back of a napkin, using basic school-level knowledge of science, and build a crystal set in a cla.s.sroom which was essentially the same as the one in your car. When your parents were young they could fix their own car, and understand the science behind most of the everyday technology they encountered, but this is no longer the case. Even a geek today would struggle to give an explanation of how his mobile phone works, because technology has become more difficult to understand and explain, and everyday gadgets have taken on a 'black box' complexity that can feel sinister, as well as intellectually undermining. The seeds were sown.

But we should return to the point. If there was little science, then what did did appear in all these long stories on MMR? Going back to the 2002 data from the ESRC, only a quarter mentioned Andrew Wakefield, which seems odd, considering he was the cornerstone of the story. This created the erroneous impression that there was a large body of medical opinion which was suspicious of MMR, rather than just one 'maverick'. Less than a third of broadsheet reports referred to the overwhelming evidence that MMR is safe, and only 11 per cent mentioned that it is regarded as safe in the ninety other countries in which it is used. appear in all these long stories on MMR? Going back to the 2002 data from the ESRC, only a quarter mentioned Andrew Wakefield, which seems odd, considering he was the cornerstone of the story. This created the erroneous impression that there was a large body of medical opinion which was suspicious of MMR, rather than just one 'maverick'. Less than a third of broadsheet reports referred to the overwhelming evidence that MMR is safe, and only 11 per cent mentioned that it is regarded as safe in the ninety other countries in which it is used.

It was rare to find much discussion of the evidence at all, as it was considered too complicated, and when doctors tried to explain it they were frequently shouted down, or worse still, their explanations were condensed into bland statements that 'science had shown' there was nothing to worry about. This uninformative dismissal was pitted against the emotive concerns of distressed parents.

As 2002 wore on, things got really strange. Some newspapers, such as the Daily Mail Daily Mail and the and the Daily Telegraph Daily Telegraph, made MMR the focus of a ma.s.sive political campaign, and the beatification of Wakefield reached a kind of fever pitch. Lorraine Fraser had an exclusive interview with him in the Telegraph Telegraph in which he was described as 'a champion of patients who feel their fears have been ignored'. She wrote a dozen similar articles over the next year (and her reward came when she was named British Press Awards Health Writer of the Year 2002, a gong I do not myself expect to receive). in which he was described as 'a champion of patients who feel their fears have been ignored'. She wrote a dozen similar articles over the next year (and her reward came when she was named British Press Awards Health Writer of the Year 2002, a gong I do not myself expect to receive).

Justine Picardie did a lavish photo feature on Wakefield, his house and his family for the Telegraph Telegraph Sat.u.r.day magazine. Andy is, she tells us, 'a handsome, glossy-haired hero to families of autistic children'. How are the family? 'A likeable, lively family, the kind you would be happy to have as friends, pitted against mysterious forces who have planted bugging devices and have stolen patients' records in 'apparently inexplicable' burglaries.' She fantasises-and I absolutely promise you I'm not making this up-about a Hollywood depiction of Wakefield's heroic struggle, with Russell Crowe playing the lead 'opposite Julia Roberts as a feisty single mother fighting for justice for her child'. Sat.u.r.day magazine. Andy is, she tells us, 'a handsome, glossy-haired hero to families of autistic children'. How are the family? 'A likeable, lively family, the kind you would be happy to have as friends, pitted against mysterious forces who have planted bugging devices and have stolen patients' records in 'apparently inexplicable' burglaries.' She fantasises-and I absolutely promise you I'm not making this up-about a Hollywood depiction of Wakefield's heroic struggle, with Russell Crowe playing the lead 'opposite Julia Roberts as a feisty single mother fighting for justice for her child'.

The evidence on MMR So what is the evidence on the safety of MMR?

There are a number of ways to approach the evidence on the safety of a given intervention, depending on how much attention you have to give. The simplest approach is to pick an arbitrary authority figure: a doctor, perhaps, although this seems not to be appealing (in surveys people say they trust doctors the most, and journalists the least: this shows the flaw in that kind of survey).

You could take another, larger authority at face value, if there is one that suits you. The Inst.i.tute of Medicine, the Royal Colleges, the NHS, and more, all came out in support of MMR, but this was apparently not sufficient to convince. You could offer information: an NHS website at mmrthefacts.nhs.uk mmrthefacts.nhs.uk started with the phrase 'MMR is safe' (literally), and allowed the reader to drill down to the detail of individual studies.* started with the phrase 'MMR is safe' (literally), and allowed the reader to drill down to the detail of individual studies.*

- Whether you buy the DoH phrase 'MMR is safe' depends on what you decide you mean by 'safe'. Is flying safe? Is your was.h.i.+ng machine safe? What are you sitting on? Is that safe? You can obsess over the idea that philosophically nothing can ever be shown to be 100 per cent safe-and many will-but you would be arguing about a fairly meaningless and uncommon definition of the word. - Whether you buy the DoH phrase 'MMR is safe' depends on what you decide you mean by 'safe'. Is flying safe? Is your was.h.i.+ng machine safe? What are you sitting on? Is that safe? You can obsess over the idea that philosophically nothing can ever be shown to be 100 per cent safe-and many will-but you would be arguing about a fairly meaningless and uncommon definition of the word.

But that too did little to stem the tide. Once a scare is running, perhaps every refutation can seem like an admission of guilt, drawing attention to the scare.

The Cochrane Collaboration is as blemishless as they come, and it has done a systematic review of the literature on MMR, concluding that there was no evidence that it is unsafe (although it didn't appear until 2005). This reviewed the data the media had systematically ignored: what was in it?

If we are to maintain the moral high ground, there are a few things we need to understand about evidence. Firstly, there is no single golden study which proves that MMR is safe (although the evidence to say it is dangerous was exceptionally poor). There is, for example, no randomised controlled trial. We are presented instead with a huge mora.s.s of data, from a number of different studies, all of which are flawed in their own idiosyncratic ways for reasons of cost, competence and so on. A common problem with applying old data to new questions is that these papers and datasets might have a lot of useful information, which was collected very competently to answer the questions which the researchers were interested in at the time, but which isn't perfect for your needs. It's just, perhaps, pretty good.

Smeeth et al et al., for example, did something called a 'case-control' study, using the GP Research Database. This is a common type of study, where you take a bunch of people with the condition you're looking at ('autism'), and a bunch of people without it, then look to see if there is any difference in how much each group was exposed to the thing you think might be causing the condition ('MMR').

If you care who paid for the study-and I hope you've become a bit more sophisticated than that by now-it was funded by the Medical Research Council. They found around 1,300 people with autism, and then got some 'controls': random people who did not have autism, but with the same age, s.e.x, and general practice. Then they looked to see if vaccination was any more common in the people with autism, or the controls, and found no difference between the two groups. The same researchers also did a systematic review of similar studies in the United States and Scandinavia, and again, pooling the data, found no link between MMR and autism.

There is a practical problem with this kind of research, of course, which I would hope you might spot: most people do do get the MMR vaccine, so the individuals you're measuring who get the MMR vaccine, so the individuals you're measuring who didn't didn't get the vaccine might be unusual in other ways-perhaps their parents have refused the vaccine for ideological or cultural reasons, or the child has a pre-existing physical health problem-and those factors might themselves be related to autism. There's little you can do in terms of study design about this potential 'confounding variable', because as we said, you're not likely to do a randomised controlled trial in which you randomly don't give children vaccines: you just throw the result into the pot with the rest of the information, in order to reach your verdict. As it happens, Smeeth get the vaccine might be unusual in other ways-perhaps their parents have refused the vaccine for ideological or cultural reasons, or the child has a pre-existing physical health problem-and those factors might themselves be related to autism. There's little you can do in terms of study design about this potential 'confounding variable', because as we said, you're not likely to do a randomised controlled trial in which you randomly don't give children vaccines: you just throw the result into the pot with the rest of the information, in order to reach your verdict. As it happens, Smeeth et al et al. went to great lengths to make sure their controls were representative. If you like, you can read the paper and decide if you agree.

So 'Smeeth' was a 'case-control study', where you compare groups which had the outcome or not, and look at how common the exposure was in each group. In Denmark, Madsen et al et al. did the opposite kind of study, called a 'cohort study': you compare groups which had the exposure or not, in order to see whether there is any variation in the outcome. In this specific case, then, you take two groups of people, who either had MMR or didn't, and then check later to see if the rate of autism is any different between the two groups.

This study was big-very big-and included all the children born in Denmark between January 1991 and December 1998. In Denmark there is a system of unique personal identification numbers, linked to vaccination registers and information about the diagnosis of autism, which made it possible to chase up almost all the children in the study. This was a pretty impressive achievement, since there were 440,655 children who were vaccinated, and 96,648 who were unvaccinated. No difference was found between vaccinated and unvaccinated children, in the rates of autism or autistic spectrum disorders, and no a.s.sociation between development of autism and age at vaccination.

Anti-MMR campaigners have responded to this work by saying that only a small number of children are harmed by the vaccine, which seems to be inconsistent with their claims that MMR is responsible for a ma.s.sive upswing in diagnoses of autism. In any case, if a vaccine caused an adverse reaction in a very small number of people, that would be no surprise-it would be no different from any other medical intervention (or, arguably, any human activity), and there would be, surely, no story.

As with all studies, there are problems with this huge study. The follow-up of diagnostic records ends one year (31 December 1999) after the last day of admission to the cohort: so, because autism comes on after the age of one year, the children born later in the cohort would be unlikely to have shown up with autism by the end of the follow-up period. But this is nagged up in the study, and you can decide whether you think it undermines its overall findings. I don't think it's much of a problem. That's my verdict, and I think you might agree that it's not a particularly foolish one. It did run from January 1991, after all.

This is the kind of evidence you will find in the Cochrane review, which found, very simply, that 'existing evidence on the safety and effectiveness of MMR vaccine supports current policies of ma.s.s immunisation aimed at global measles eradication in order to reduce morbidity and mortality a.s.sociated with mumps and rubella'.

It also contained multiple criticisms of the evidence it reviewed, which, bizarrely, has been seized upon by various commentators to claim that there was some kind of st.i.tch-up. The review was heading towards a conclusion that MMR was risky, they say, if you read the content, but then, out of nowhere, it produced a rea.s.suring conclusion, doubtless because of hidden political pressure.

The Daily Mail's Daily Mail's Melanie Phillips, a leading light of the anti-vaccination movement, was outraged by what she thought she had found: 'It said that no fewer than nine of the most celebrated studies that have been used against [Andrew Wakefield] were unreliable in the way they were constructed.' Of course it did. I'm amazed it wasn't more. Cochrane reviews are Melanie Phillips, a leading light of the anti-vaccination movement, was outraged by what she thought she had found: 'It said that no fewer than nine of the most celebrated studies that have been used against [Andrew Wakefield] were unreliable in the way they were constructed.' Of course it did. I'm amazed it wasn't more. Cochrane reviews are intended intended to criticise papers. to criticise papers.

Scientific 'evidence' in the media But the newspapers in 2002 had more than just worried parents. There was a smattering of science to keep things going: you will remember computer-generated imagery of viruses and gut walls, perhaps, and stories about laboratory findings. Why have I not mentioned those?

For one thing, these important scientific findings were being reported in newspapers and magazines, and at meetings, in fact anywhere except proper academic journals where they could be read and carefully appraised. In May, for example, Wakefield 'exclusively revealed' that 'more than 95 per cent of those who had the virus in their gut had MMR as their only doc.u.mented exposure to measles'. He doesn't appear to have revealed this in a peer-reviewed academic journal, but in a weekend colour supplement.

Other people started popping up all over the place, claiming to have made some great finding, but never publis.h.i.+ng their research in proper, peer-reviewed academic journals. A pharmacist in Sunderland called Mr Paul Shattock was reported on the Today Today programme, and in several national newspapers, to have identified a distinct subgroup of children with autism resulting from MMR. Mr Shattock is very active on anti-immunisation websites, but he still doesn't seem to have got round to publis.h.i.+ng this important work years later, even though the Medical Research Council suggested in 2002 that he should 'publish his research and come forward to the MRC with positive proposals'. programme, and in several national newspapers, to have identified a distinct subgroup of children with autism resulting from MMR. Mr Shattock is very active on anti-immunisation websites, but he still doesn't seem to have got round to publis.h.i.+ng this important work years later, even though the Medical Research Council suggested in 2002 that he should 'publish his research and come forward to the MRC with positive proposals'.

Meanwhile Dr Arthur Krigsman, paediatric gastrointestinal consultant working in the New York area, was telling hearings in Was.h.i.+ngton that he had made all kinds of interesting findings in the bowels of autistic children, using endoscopes. This was lavishly reported in the media. Here is the Daily Telegraph Daily Telegraph: Scientists in America have reported the first independent corroboration of the research findings of Dr Andrew Wakefield. Dr Krigsman's discovery is significant because it independently supports Dr Wakefield's conclusion that a previously unidentified and devastating combination of bowel and brain disease is afflicting young children-a claim that the Department of Health has dismissed as 'bad science'. Scientists in America have reported the first independent corroboration of the research findings of Dr Andrew Wakefield. Dr Krigsman's discovery is significant because it independently supports Dr Wakefield's conclusion that a previously unidentified and devastating combination of bowel and brain disease is afflicting young children-a claim that the Department of Health has dismissed as 'bad science'.

To the best of my knowledge-and I'm pretty good at searching for this stuff- Krigsman's new scientific research findings which corroborate Andrew Wakefield's have never been published in an academic journal: certainly there is no trace of them on Pubmed, the index of nearly all medical academic articles.

In case the reason why this is important has not sunk in, let me explain again. If you visit the premises of the Royal Society in London, you'll see its motto proudly on display: 'Nullius in verba '-'On the word of no one'. What I like to imagine this refers to, in my geeky way, is the importance of publis.h.i.+ng proper scientific papers if you want people to pay attention to your work. Dr Arthur Krigsman has been claiming for years now that he has found evidence linking MMR to autism and bowel disease. Since he hasn't published his findings, he can claim them until he's blue in the face, because until we can see exactly what he did, we can't see what flaws there may be in his methods. Maybe he didn't select the subjects properly. Maybe he measured the wrong things. If he doesn't write it up formally, we can never know, because that is what scientists do: write papers, and pull them apart to see if their findings are robust. '-'On the word of no one'. What I like to imagine this refers to, in my geeky way, is the importance of publis.h.i.+ng proper scientific papers if you want people to pay attention to your work. Dr Arthur Krigsman has been claiming for years now that he has found evidence linking MMR to autism and bowel disease. Since he hasn't published his findings, he can claim them until he's blue in the face, because until we can see exactly what he did, we can't see what flaws there may be in his methods. Maybe he didn't select the subjects properly. Maybe he measured the wrong things. If he doesn't write it up formally, we can never know, because that is what scientists do: write papers, and pull them apart to see if their findings are robust.

Krigsman and others' failures to publish in peer-reviewed academic journals weren't isolated incidents. In fact it's still going on, years later. In 2006, exactly the same thing was happening again. 'US Scientists Back Autism Link to MMR', squealed the Telegraph Telegraph. 'Scientists Fear MMR Link to Autism', roared the Mail Mail. 'US Study Supports Claims of MMR Link to Autism', croaked The Times The Times a day later. a day later.

What was this frightening new data? These scare stories were based on a poster presentation, at a conference yet to occur, on research not yet completed, by a man with a track record of announcing research that never subsequently appears in an academic journal. In fact, astonis.h.i.+ngly, four years later, it was Dr Arthur Krigsman again. The story this time was different: he had found genetic material (RNA) from vaccine-strain measles virus in some gut samples from children with autism and bowel problems. If true, this would fit with Wakefield's theory, which by 2006 was lying in tatters. We might also mention that Wakefield and Krigsman are doctors together at Thoughtful House, a private autism clinic in the USA offering eccentric treatments for developmental disorders.

The Telegraph Telegraph went on to explain that Krigsman's most recent unpublished claim was replicating similar work from 1998 by Dr Andrew Wakefield, and from 2002 by Professor John O'Leary. This was, to say the least, a mis-statement. There is no work from 1998 by Wakefield which fits the went on to explain that Krigsman's most recent unpublished claim was replicating similar work from 1998 by Dr Andrew Wakefield, and from 2002 by Professor John O'Leary. This was, to say the least, a mis-statement. There is no work from 1998 by Wakefield which fits the Telegraph's Telegraph's claim-at least not in PubMed that I can find. I suspect the newspaper was confused about the infamous claim-at least not in PubMed that I can find. I suspect the newspaper was confused about the infamous Lancet Lancet paper on MMR, which by 2004 had already been partially retracted. paper on MMR, which by 2004 had already been partially retracted.

There are, however, two papers suggesting that traces of genetic material from the measles virus have been found in children. They have received a mountain of media coverage over half a decade, and yet the media have remained studiously silent on the published evidence suggesting that they were false positives, as we will now see.

One is from Kawas.h.i.+ma et al et al. in 2002, also featuring Wakefield as an author, in which it is claimed that genetic material from measles vaccine was found in blood cells. Doubt is cast on this both by attempts to replicate it, showing where the false positives probably appeared, and by the testimony of Nick Chadwick, the PhD student whose work we described above. Even Andrew Wakefield himself no longer relies on this paper.

The other is O'Leary's paper from 2002, also featuring Wakefield as an author, which produced evidence of measles RNA in tissue samples from children. Futher experiments, again, have ill.u.s.trated where the false positives seem to have arisen, and in 2004, when Professor Stephen Bustin was examining the evidence for the legal aid case, he explained how he established to his satisfaction-during a visit to the O'Leary lab-that these were false positives due to contamination and inadequate experimental methods. He has shown, firstly, that there were no 'controls' to check for false positives (contamination is a huge risk when you are looking for minuscule traces of genetic material, so you generally run 'blank' samples to make sure they do come out blank); he found calibration problems with the machines; problems with log books; and worse. He expanded on this at enormous length in a US court case on autism and vaccines in 2006. You can read his detailed explanation in full online. To my astonishment not one journalist in the UK has ever bothered to report it.

Both of these papers claiming to show a link received blanket media coverage at the time, as did Krigsman's claims.

What they didn't tell you In the May 2006 issue of the Journal of Medical Virology Journal of Medical Virology there was a very similar study to the one described by Krigsman, only this one had actually been published, by Afzal there was a very similar study to the one described by Krigsman, only this one had actually been published, by Afzal et al et al. It looked for measles RNA in children with regressive autism after MMR vaccination, much like the unpublished Krigsman study, and it used tools so powerful they could detect measles RNA down to single-figure copy numbers. It found no evidence of the magic vaccine-strain measles RNA to implicate MMR. Perhaps because of that unfrightening result, the study was loudly ignored by the press.

Because it has been published in full, I can read it, and pick holes in it, and I am more than happy to do so: because science is about critiquing openly published data and methodologies, rather than press-released chimeras, and in the real world all studies have some flaws, to a greater or lesser extent. Often they are practical ones: here, for example, the researchers couldn't get hold of the tissue they ideally would have used, because they could not get ethics committee approval for intrusive procedures like lumbar punctures and gut biopsies on children (Wakefield did manage to obtain such samples, but he is, we should remember, currently going through a GMC professional conduct hearing over the issue).

Surely they could have borrowed some existing samples, from children said to be damaged by vaccines? You'd have thought so. They report in the paper that they tried to ask anti-MMR researchers-if that's not an unfair term-whether they could borrow some of their tissue samples to work on. They were ignored.*

- 'The groups of investigators that either had access to original autism specimens or investigated them later for measles virus detection were invited to take part in the study but failed to respond. Similarly, it was not possible to obtain clinical specimens of autism cases from these investigators for independent investigations.' - 'The groups of investigators that either had access to original autism specimens or investigated them later for measles virus detection were invited to take part in the study but failed to respond. Similarly, it was not possible to obtain clinical specimens of autism cases from these investigators for independent investigations.'

Afzal et al et al. was not reported in the media, anywhere at all, except by me, in my column.

This is not an isolated case. Another major paper was published in the leading academic journal Pediatrics Pediatrics a few months later-to complete media silence-again suggesting very strongly that the earlier results from Kawas.h.i.+ma and O'Leary were in error, and false positives. D'Souza a few months later-to complete media silence-again suggesting very strongly that the earlier results from Kawas.h.i.+ma and O'Leary were in error, and false positives. D'Souza et al et al. replicated the earlier experiments very closely, and in some respects more carefully: most importantly, it traced out the possible routes by which a false positive could have occurred, and made some astonis.h.i.+ng findings.

False positives are common in PCR, because it works by using enzymes to replicate RNA, so you start with a small amount in your sample, which is then 'amplified up', copied over and over again, until you have enough to measure and work with. Beginning with a single molecule of genetic material, PCR can generate 100 billion similar molecules in an afternoon. Because of this, the PCR process is exquisitely sensitive to contamination-as numerous innocent people languis.h.i.+ng in jail could tell you-so you have to be very careful, and clean up as you go.

As well as raising concerns about contamination, D'Souza also found that the O'Leary method might have accidentally amplified the wrong bits of RNA.

Let's be clear: this is absolutely not about criticising individual researchers. Techniques move on, results are sometimes not replicable, and not all double-checking is practical (although Bustin's testimony is that standards in the O'Leary lab were problematic). But what is striking is that the media rabidly picked up on the original frightening data, and then completely ignored the new rea.s.suring data. This study by D'Souza, like Afzal before it, was unanimously ignored by the media. It was covered, by my count, in: my column; one Reuters piece which was picked up by n.o.body; and one post on the lead researcher's boyfriend's blog (where he talked about how proud he was of his girlfriend). Nowhere else.*

- In 2008, just as this chapter was being put to bed, some journalists deigned-miraculously-to cover a PCR experiment with a negative finding. It was misreported as the definitive refutation of the entire MMR-autism hypothesis. This was a childish overstatement, and that doesn't help anyone either. I am not hard to please. - In 2008, just as this chapter was being put to bed, some journalists deigned-miraculously-to cover a PCR experiment with a negative finding. It was misreported as the definitive refutation of the entire MMR-autism hypothesis. This was a childish overstatement, and that doesn't help anyone either. I am not hard to please.

You could say, very reasonably, that this is all very much par for the course: newspapers report the news, and it's not very interesting if a piece of research comes out saying something is safe. But I would argue-perhaps sanctimoniously-that the media have a special responsibility in this case, because they themselves demanded 'more research', and moreover because at the very same time at the very same time that they were ignoring properly conducted and fully published negative findings, they were talking up scary findings from an unpublished study by Krigsman, a man with a track record of making scary claims which remain unpublished. that they were ignoring properly conducted and fully published negative findings, they were talking up scary findings from an unpublished study by Krigsman, a man with a track record of making scary claims which remain unpublished.

MMR is not an isolated case in this regard. You might remember the scare stories about mercury fillings from the past two decades: they come around every few years, usually accompanied by a personal anecdote in which fatigue, dizziness and headaches are all vanquished following the removal of the fillings by one visionary dentist. Traditionally these stories conclude with a suggestion that the dental establishment may well be covering up the truth about mercury, and a demand for more research into its safety.