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Monthly Archives: November 2013

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One of my scientific heroes is Bernard Katz. The closing words of his inaugural lecture, as professor of biophysics at UCL, hang on the wall of my office as a salutory reminder to refrain from talking about ‘how the brain works’. After speaking about his discoveries about synaptic transmission, he ended thus.

"My time is up and very glad I am, because I have been leading myself right up to a domain on which I should not dare to trespass, not even in an Inaugural Lecture. This domain contains the awkward problems of mind and matter about which so much has been talked and so little can be said, and having told you of my pedestrian disposition, I hope you will give me leave to stop at this point and not to hazard any further guesses."

BK
Drawing ©Jenny Hersson-Ringskog

The question of what to eat for good health is truly a topic about "which so much has been talked and so little can be said"

That was emphasized yet again by an editorial in the British Medical Journal written by my favourite epidemiologist. John Ioannidis. He has been at the forefront of debunking hype. Its title is “Implausible results in human nutrition research” (BMJ, 2013;347:f6698.
Get pdf
).

The gist is given by the memorable statement

"Almost every single nutrient imaginable has peer reviewed publications associating it with almost any outcome."

and the subtitle

Definitive solutions won’t come from another million observational papers or small randomized trials“.

Being a bit obsessive about causality, this paper is music to my ears. The problem of causality was understood perfectly by Samuel Johnson, in 1756, and he was a lexicographer, not a scientist. Yet it’s widely ignored by epidemiologists.

sj

The problem of causality is often mentioned in the introduction to papers that describe survey data, yet by the end of the paper, it’s usually forgotten, and public health advice is issued.

Ioannidis’ editorial vindicates my own views, as an amateur epidemiologist, on the results of the endless surveys of diet and health.

There is nothing new about the problem. It’s been written about many times. Young & Karr (Significance, 8, 116 – 120, 2011: get pdf) said "Any claim coming from an observational study is most likely to be wrong". Out of 52 claims made in 12 observational studies, not a single one was confirmed when tested by randomised controlled trials.

Another article cited by Ioannidis, "Myths, Presumptions, and Facts about Obesity" (Casazza et al , NEJM, 2013), debunks many myths, but the list of conflicts of interests declared by the authors is truly horrendous (and at least one of their conclusions has been challenged, albeit by people with funding from Kellogg’s). The frequent conflicts of interest in nutrition research make a bad situation even worse.

The quotation in bold type continues thus.

"On 25 October 2013, PubMed listed 291 papers with the keywords “coffee OR caffeine” and 741 with “soy,” many of which referred to associations. In this literature of epidemic proportions, how many results are correct? Many findings are entirely implausible. Relative risks that suggest we can halve the burden of cancer with just a couple of servings a day of a single nutrient still circulate widely in peer reviewed journals.

However, on the basis of dozens of randomized trials, single nutrients are unlikely to have relative risks less than 0.90 for major clinical outcomes when extreme tertiles of population intake are compared—most are greater than 0.95. For overall mortality, relative risks are typically greater than 0.995, if not entirely null. The respective absolute risk differences would be trivial. Observational studies and even randomized trials of single nutrients seem hopeless, with rare exceptions. Even minimal confounding or other biases create noise that exceeds any genuine effect. Big datasets just confer spurious precision status to noise."

And, later,

"According to the latest burden of disease study, 26% of deaths and 14% of disability adjusted life years in the United States are attributed to dietary risk factors, even without counting the impact of obesity. No other risk factor comes anywhere close to diet in these calculations (not even tobacco and physical inactivity). I suspect this is yet another implausible result. It builds on risk estimates from the same data of largely implausible nutritional studies discussed above. Moreover, socioeconomic factors are not considered at all, although they may be at the root of health problems. Poor diet may partly be a correlate or one of several paths through which social factors operate on health."

Another field that is notorious for producing false positives, wirh false attribution of causality, is the detection of biomarkers. A critical discussion can be found in the paper by Broadhurst & Kell (2006), "False discoveries in metabolomics and related experiments".

"Since the early days of transcriptome analysis (Golub et al., 1999), many workers have looked to detect different gene expression in cancerous versus normal tissues. Partly because of the expense of transcriptomics (and the inherent noise in such data (Schena, 2000; Tu et al., 2002; Cui and Churchill, 2003; Liang and Kelemen, 2006)), the numbers of samples and their replicates is often small while the number of candidate genes is typically in the thousands. Given the above, there is clearly a great danger that most of these will not in practice withstand scrutiny on deeper analysis (despite the ease with which one can create beautiful heat maps and any number of ‘just-so’ stories to explain the biological relevance of anything that is found in preliminary studies!). This turns out to be the case, and we review a recent analysis (Ein-Dor et al., 2006) of a variety of such studies."

The fields of metabolomics, proteomics and transcriptomics are plagued by statistical problems (as well as being saddled with ghastly pretentious names).

What’s to be done?

Barker Bausell, in his demolition of research on acupuncture, said:

[Page39] “But why should nonscientists care one iota about something as esoteric as causal inference? I believe that the answer to this question is because the making of causal inferences is part of our job description as Homo Sapiens.”

The problem, of course, is that humans are very good at attributing causality when it does not exist. That has led to confusion between correlation and cause on an industrial scale, not least in attempts to work out the effects of diet on health.

More than in any other field it is hard to do the RCTs that could, in principle, sort out the problem. It’s hard to allocate people at random to different diets, and even harder to make people stick to those diets for the many years that are needed.

We can probably say by now that no individual food carries a large risk, or affords very much protection. The fact that we are looking for quite small effects means that even when RCTs are possible huge samples will be needed to get clear answers. Most RCTs are too short, and too small (under-powered) and that leads to overestimation of the size of effects.

That’s a problem that plagues experimental pyschology too, and has led to a much-discussed crisis in reproducibility.

"Supplements" of one sort and another are ubiquitous in sports. Nobody knows whether they work, and the margin between winning and losing is so tiny that it’s very doubtful whether we ever will know. We can expect irresponsible claims to continue unabated.

The best thing that can be done in the short term is to stop doing large observational studies altogether. It’s now clear that inferences made from them are likely to be wrong. And, sad to say, we need to view with great skepticism anything that is funded by the food industry. And make a start on large RCTs whenever that is possible. Perhaps the hardest goal of all is to end the "publish or perish" culture which does so much to prevent the sort of long term experiments which would give the information we want.

Ioannidis’ article ends with the statement

"I am co-investigator in a randomized trial of a low carbohydrate versus low fat diet that is funded by the US National Institutes of Health and the non-profit Nutrition Science Initiative."

It seems he is putting his money where his mouth is.

Until we have the results, we shall continue to be bombarded with conflicting claims made by people who are doing their best with flawed methods, as well as by those trying to sell fad diets. Don’t believe them. The famous "5-a-day" advice that we are constantly bombarded with does no harm, but it has no sound basis.

As far as I can guess, the only sound advice about healthy eating for most people is

  • don’t eat too much
  • don’t eat all the same thing

You can’t make much money out of that advice.

No doubt that is why you don’t hear it very often.

Follow-up

Two relevant papers that show the unreliability of observational studies,

"Nearly 80,000 observational studies were published in the decade 1990–2000 (Naik 2012). In the following decade, the number of studies grew to more than 260,000". Madigan et al. (2014)

“. . . the majority of observational studies would declare statistical significance when no effect is present” Schuemie et al., (2012)

20 March 2014

On 20 March 2014, I gave a talk on this topic at the Cambridge Science Festival (more here). After the event my host, Yvonne Noblis, sent me some (doubtless cherry-picked) feedback she’d had about the talk.

tweets

Jump to follow-up

gphc

The General Pharmaceutical Council (GPhC) has been the statutory body responsible for the regulation of pharmacy since 2010. It’s status is similar to that of the GMC and. heaven help us, the GCC. Before that the regulator was the same as the professional body, the Royal Pharmaceutical Society of Great Britain (RPS). The RPS proved to be as useless as most other regulators, as documented in detail in my 2008 post, At around the time it stopped being a regulator, the RPS started to condemn quackery more effectively, but by then it had lost the power to do much about it (I hope the latter wasn’t the cause of the former). The body that could do something, the GPhC has done essentially nothing. as described in this post.

I did a 2 year apprenticeship in Timothy White’s and Taylor’s Homeopathic (yes, really) Chemists in the 1950s.
My first degree was in pharmacy. I got my interest in pharmacology from reading Martindale’s Extra Pharmacopoeia in the shop. I soon decided that I didn’t really want to spend the rest of my life selling lipstick and Durex. The latter was quite a big seller because the Boots across the road didn’t sell contraceptives (they changed their minds in the 1960s).

In those days, we spent quite a lot of time making up (almost entirely ineffective) ‘tonics’ and ‘cough mixtures’. Now the job consists largely of counting pills. This has exacerbated the ‘chip on the shoulder’ attitude that was present even in the 1950s. For a long time now, pharmacists have wanted to become the a ‘third tier’ in the NHS, alongside GP practices and hospitals., after hospitals and doctors". . Here are a few comments on this proposition.

First let me say that I’ve met some very good and ethical pharmacists. I did a vacation job in a hospital pharmacy where the boss had an encyclopaedic knowledge of the effects and side effects of drugs, and of their dosage. His advice was often sought by doctors, and rightly so. He had no way of knowing at the time that his advice to replace barbiturates with thalidomide would lead to such a tragedy, because the evidence had been concealed by the manufacturer. Some of the problems alluded to here have already been highlighted by two excellent pharmacists, Anthony Cox and @SparkleWildfire, neither of whom work in pharmacists shops. They are absolutely spot on but they seem to be in a minority among pharmacists.

The problems seem to lie mostly in retail shops. Their shelves are laden with ineffective pills and potions. And the pharmacist has every incentive to sell them. His/her income depends on it directly if it’s a privately owned pharmacy. And his/her standing with head office depends on it in chain store pharmacies. This conflict of financial interest is the prime reason why pharmacists are not qualified to form a third tier of healthcare. The avoidance of conflicts of interest among doctors was one of the great accomplishments of the NHS. In the USA there are huge scandals when, as happens repeatedly, doctors order expensive and unnecessary treatments from which they profit. It’s no consolation that such problems are creeping back in the UK as a result of the government’s vigorous efforts to sell it off.

Here are few examples of things that have gone wrong, and who is to blame. Then I’ll consider what can be done.

Ineffective medicines

In any pharmacy you can see ineffective ‘tonics’ and ‘cough medicines’, unnecessary supplements with dishonest claims and even, heaven help us, the ultimate scam, homeopathic pills.

What’s worse, if you ask a pharmacist for advice, it’s quite likely that they’ll recommend you to buy them.

I was amazed to discover that a number of old-fashioned ‘tonics’ and ‘cough medicines’ still have full marketing authorisation. That’s the fault of the Medicines and Healthcare Regulatory Auhority (MHRA) who are supposed to assess efficacy and totally failed to do so, Read about that in “Some medicines that don’t work. Why doesn’t the MHRA tell us honestly?” . It’s hard to blame a pharmacist for the bad advice given by the MHRA, but a good one would tell patients to save their money.

benylin

Big corporate pharmacies

Companies like Boots seem to have no interest whatsoever in ethical behaviour. All that matters is sales. They provide “(mis)educational” materials that promote nonsense They advertise ridiculous made-up claims in the newspapers, which get shot down regularly by the Advertising Standards Authority, but by that time the promotion is over so they don’t give a damn. See for example, CoQ10 scam and the ASA verdict on it. And "Lactium: more rubbish from Boots the Chemists. And a more serious problem". And "The Vitamin B scam. Don’t trust Boots"

Recently the consumer magazine Which? checked 122 High Street pharmacies. They got unsatisfactory advice from 43% of them, a disastrously bad performance for people who want to be the third tier of healthcare.

Even that’s probably better than my own experience. Recently, when I asked a Sainsbury’s pharmacist about a herbal treatment for prostate problems, he pointed to the MHRA’s kite mark and said it must work because the MHRA approved it -he was quite unaware that you get the THR kite mark without having to present any evidence at all about efficacy.

mhra

Of course that is partly the fault of the MHRA for allowing misleading labels, but nevertheless, he should have known. See “Why does the MHRA refuse to label herbal products honestly? Kent Woods and Richard Woodfield tell me” for more on how the MHRA has betrayed its own standards.

When I’ve asked Boots’ pharmacists advice about persistent diarrhoea in an infant, saying I wanted a natural remedy, I’ve usually been guided to the homeopathic display. Only once was I told firmly that I should use rehydration not homeopathy (something every good parent knows) and when I asked that good pharmacist where she’d been educated, she said in Germany (mildly surprising given the amount of junk available in German pharmacies)

Regulators

Anthony Cox, a pharmacist who has been consistently on the side of right, says

"This is something that needs to be dealt with at a regulatory and professional body by the whole profession, and I am certain we have the majority of the UK pharmacy profession on side."

But the regulator has done nothing, and it isn’t even clear that there is a majority on his side.

At a 2009 meeting of Branch Representatives of the RPS a motion was proposed:

“…registration as a pharmacist and practice as a homeopath are not compatible, and that premises registered with the Society should not be used for the promotion of homeopathy”

Although that is obviously sensible to most people, the proposal was followed by a speaker from Leicester who thought it right to keep an open mind about Avogadro’s number and the motion was defeated. So much for the "scientists on the High Street" aspiration.

There have been two major scandals surrounding homeopathy recently. Both were revealed first by bloggers, and both came to wide notice through television programs. None were noticed by the regulators, and when they were brought to the attention of the regulator, nothing effective was done.

The malaria scandal

A lot has been wriitten about this here and on other blogs e.g. here and here. The idea that sugar pills can prevent or cure malaria is so mind-bogglingly dangerous that it was condemned by the Queen’s Homeopathic Physician, Peter Fisher. It was exposed on a BBC Newsnight programme in 2006. Watch the video.

The Gentle Art of Homeopathic Killing was an article that originally appeared on the excellent Quackometer blog produced by Andy Lewis. "The Society of Homeopaths were so outraged about one of their members flouting the code of ethics so blatantly that they took immediate action. That action was, as expected, not to do anything about the ethics breach but to threaten Andy and his hosting ISP with legal action for defamation. The article is reproduced here as a public service".

Some of the people involved in this bad advice were pharmacists, Very properly they were referred to the RPS in 2006 qnd 2009, the regulator at that time. They sat on the complaint so long that eventually the RPS was replaced by the GPhC as regulator. Nothing much has happened.

The GPhC did precisely nothing. Read their pathetic response.

Homeopathy for meningitis

An equally murderous fraud, "homeopathic vaccines" by Ainsworth’s has long been targeted by bloggers. In January 2013, Samantha Smith made an excellent BBC South West programme about it. Watch it and get angry.

Anthony Pinkus, pharmacist at Ainsworths, has been referred to the then regulator, the RPS, in 2006 and 2009. It’s said that he took "remedial action", though there is little obvious change judged by the video above. No doubt some of the most incriminating stuff has been removed from his web site to hide it from the ASA. It’s safer to mislead people by word of mouth. Since the last video more complaints have been made to the GPhC. So far, nothing but silence.

Why doesn’t the regulator regulate?

This pamphlet is reproduced from the July 2011 Quackometer post, “Ainsworths Pharmacy: Casual Disregard for the Law

ainsworth

It’s almost as though those royal warrants, enlarged on right, acted as a talisman that puts this dangerous company outside the grasp of regulators. I hope that the GPhC Council , and Duncan Rudkin (its chief executive and registrar), are not so worried about their knighthoods that they won’t risk upsetting the royal family, just to save patients from malaria and meningitis. Their CEO, Robert Nicholls is only a CBE so far.

warrants

Another reason for their inaction might be that the GPhC Council members, and Duncan Rudkin (its chief executive and registrar), lack critical faculties. Perhaps they have not been very well educated? Many of them aren’t even pharmacists, but that curious breed of professional administrators who inhabit the vast number of quangos, tick their boxes and do harm. Or perhaps they are just more interested in protecting the income of pharmacists than in protecting their customers?

Education

The solution to most problems is education. But there is no real knowledge of how many pharmacists in the UK are educated in the critical assessment of evidence. A recent paper from the USA did not give cause for optimism. It’s discussed by the excellent US pharmacist, Scott Gavura, at Science-based medicine. The results are truly horrifying.

“Few students disagreed with any CAM therapy. There was the greatest support for vitamins and minerals (94%, mean 4.29) which could include the science-based use these products. But there was strong support for demonstrably ineffective treatments like acupuncture, with 64% agreeing it was acceptable. Even homeopathy, which any pharmacy student with basic medicinal chemistry skills ought to know is absurd, was supported by over 40% of students.”

If the numbers are similar in the UK, the results of the Which? magazine survey are not so surprising. And if they are held by the GPhC Council. their inaction is to be expected. We just don’t know, and perhaps someone should find out.

I suspect that sympathy for quackery may sometimes creep in through that old-fashioned discipline known as pharmacognosy. It is about the botany of medicinal plants, and it’s still taught, despite the fact that very few drugs are now extracted from plants. At times, it gets dangerously close to herbalism. For example, at the School of Pharmacy (now part of UCL) a book is used Fundamentals of Pharmacognosy and Phytotherapy  by Michael Heinrich, Joanne Barnes, Simon Gibbons and Elizabeth M. Williamson, ot the Centre for Pharmacognosy and Phytotherapy at the School of Pharmacy. The introductory chapter says.

“TRADITIONAL CHINESE MEDICINE (TCM) The study of TCM is a mixture of myth and fact, stretching back well over 5000 years. At the time, none of the knowledge was written down, apart from primitive inscriptions of prayers for the sick on pieces of tortoise carapace and animal bones, so a mixture of superstition, symbolism and fact was passed down by word of mouth for centuries. TCM still contains very many remedies, which were selected by their symbolic significance rather than proven effects; however, this does not necessarily mean that they are all ‘quack’ remedies!”

Well, not necessarily. But as in most such books, there are good descriptions of the botany, more or less good accounts of the chemical constituents followed by uncritical lists of things that the herb might (or might not) do. The fact that even the US National Institutes of Health quackery branch, NCCAM, doesn’t claim that a single herbal treatment is useful tells you all you need to know.

Joanna Barnes is Associate Professor in Herbal Medicines, School of Pharmacy, University of Auckland, New Zealand. She has written a book, Herbal Medicines (“A useful book for learning holistic medicine”) that is desperately uncritical about the alleged theraputic effectiveness of plants. ("Simon Gibbons is on the editorial board of The Chinese Journal of Natural Medicine. Elizabeth Williamson is editor of the Journal of Phytotherapy Research, a journal that has a strong flavour of herbalism (take the infamous snoring remedy). These people aren’t quacks but they are dangerously tolerant of quacks.

The warning is in the title. "Phytotherapy" is the current euphemism for herbalism. It’s one of those red light words that tells you that what follows is unlikely to be critical. Exeter’s fantasy herbalist, Simon Mills, now describes himself as a phytotherapist. What more warning could you need?

Perhaps this explains why so many pharmacists are unworried by selling things that don’t work. Pharmacy education seems not to include much about the critical assessment of evidence. It should do.

Chemist and Druggist magazine certainly doesn’t help. It continually reinforces the idea that there is a debate about homepathy. There isn’t. And in one of its CPD modules Katherine Gascoigne says

"Homeopathic remedies are available, but are best prescribed by a homeopath"

Ms Gascoigne must be living on another planet.

Conclusions

The main conclusion from all of this is that the General Pharmaceutical Council is almost criminally negligent. It continues to allow pharmacists, Anthony Pinkus among them, to endanger lives. It fails to apply its own declared principles. The members of its Council, and Duncan Rudkin (its chief executive and registrar), are not doing their job.

Individual pharmacists vary a lot, from the superb to those who believe in quackery. Some, perhaps many, are embarrassed by the fact that their employer compels them to sell rubbish. It’s too much to expect that they’ll endanger their mortgage payments by speaking out about it, but the best ones will take you aside and explain that they can’t recommend it.

The GPhC itself is regulated by the Professional Standards Authority, the subject of my last post. We can’t expect anything sensible from them.

In the USA there is a shocking number of pharmacists who seem to believe in quackery. In the UK. nobody knows, though judging by their failure to vote against the daftest of all scams, homeopathy, there is no cause for complacency here.

It seems that there will have to be big improvements in pharmacy education before you can have much confidence in the quality of the advice that you get in a pharmacy.

Follow-up

Yesterday a talk was given at the School of Pharmacy, organised by the “The Centre for Homeopathic Education” (an oxymoron if there ever was one). The flyer had all the usual nonsense. Its mention of “Remedies & Tonics for Cancer Recovery” might well have breached the Cancer Act (1939). When I asked whether the amount received in room rental was sufficient to offest the damage to the reputation of the School of Pharmacy resulting from hosting a nutty (and possible illegal) event, I had the greatest difficulty in extracting any sort of response from the school’s director, Duncan Craig. I’m told that he considers “the policy on space rental to be a UCL management issue, rather than a matter of discussion on scientific ethics with a colleague”. Oh dear.