Wednesday, 23 December 2009

Don't blame the system for winter travel chaos. Stay put

Simon Jenkins says:
Hypermobility is now the opium of the people, an obsession that wrecks communities and planet. There are no free trips.

My solution to winter travel chaos? Don't travel. Stay indoors. Build a fire. Live and shop within walking distance of civilisation. Associate with neighbours. See distant relatives some other time of the year. Above all, do not complain if you insist on laying siege to motorways, stations and airports and the weather or the labour force let you down, as they do every year. It is not their fault, it is yours for being there.
I really don't know why people insist on not being London based journalists telecommuting from home.
If a hospital visit requires a drive of 50 rather than five miles, the NHS does not pay but someone does; indeed everyone does.
On the plus side, when you get to the 50 miles away hospital the economies of scale that entails mean that there might actually be some doctors and services there to provide you with at least a minimally effective service...that's if the doctors are allowed to get to work despite the fear of offending metropolitan pseudo-intellectuals.

Don't get sick this Christmas Dr Jenkins...and if you do don't you dare come to my hospital and screw up my already crappy Christmas day.

Sunday, 22 November 2009

Newtongate

Brilliant:
If you own any shares in companies that produce reflecting telescopes, use differential and integral calculus, or rely on the laws of motion, I should start dumping them NOW. The conspiracy behind the calculus myth has been suddenly, brutally and quite deliciously exposed after volumes of Newton’s private correspondence were compiled and published.

Saturday, 14 November 2009

Are glutamatergic drugs the future for the treatment of schizophrenia?

Just found this on my PC, I wrote it some time ago, before the latest news on the failure of the LY2140023 trial was known (I altered it a little around the time to reflect this). I started it with the intention of doing an updated meta-analysis of glutamatergic drugs in schizophrenia but it became apparent that the quality of the data was so low that I wasn't going to be able to carry out any sensible analysis. I wrote the following as a summary of what I'd wasted my time doing, it isn't really publishable quality but I thought people might be interested if psychiatry is their area (I could have put it on a pre-print server like Nature Precedings but they don't like clinical treatment data).

Abstract

There is growing evidence for the role of glutamate in the aetiology of schizophrenia and a number of glutamatergic drugs are being developed and trialled. This systematic review finds that there is evidence for beneficial effects on symptoms in schizophrenia for both adjuvant NMDA glycine binding-site agonists and monotherapy with a type II metabotropic glutamate receptor agonist (LY2140023). LY2140023 represents the first successful placebo controlled clinical trial of non-dopamine based antipsychotic therapy for schizophrenia but the evidence for its greater efficacy over glycine binding-site agonists is tentative at best. It is unclear why the apparently antagonistic effects of post-synaptic NMDA co-agonism and reduced glutamate release via pre-synaptic inhibition from type II metabotropic agonism both appear to have beneficial effects on schizophrenic symptoms, nor why the latter is so much more successful than direct NMDA antagonism. Ongoing trials should help to clarify the promising results found to date.

Introduction

All existing antipsychotics work via the dopamine D2 receptor (1) but this class of medication has several important limitations. Although effective at treating ‘positive’ symptoms of schizophrenia (such as hallucinations and delusions) antipsychotics have limited impact on ‘negative’ symptoms (such as emotional blunting) or cognitive deficits, and it is these that are thought to have most relevance for prognosis (2). Side-effects are significant and range from considerable weight gain and hyperprolactinaemia to movement disorders such as extra-pyramidal effects and tardive dyskinesia. Although clozapine, and the atypical antipsychotics have been considered superior to typical antipsychotics any advantages appear to be fairly marginal (3).

While pathophysiological investigations of schizophrenia have traditionally concentrated on the dopaminergic system (4, 5) there is increasing evidence from gene association and neuropathological studies for an involvement of the glutamatergic system (6). For some time there have been hopes that medications which interact with the glutamatergic system may be able to ameliorate some of the negative and cognitive deficits of schizophrenia. In this review I appraise the current clinical evidence in a narrative systematic review of double blind randomised controlled clinical trials of adjuvant or monotherapy with glutamatergic drugs in schizophrenia.

Methods

Glutamatergic drugs were defined as those primarily acting via glutamate receptors or the glutamatergic system (e.g. re-uptake inhibition). Medline was searched via PubMed using the ‘broad’ and ‘therapy’ clinical study filters and the Cochrane Central Register of Controlled Trials (CENTRAL) was also searched up to January 2009. Search terms were ‘schizophrenia’ AND either ‘glutamate*’ or the names of specific glutamatergic compounds discussed below (glycine, d-cycloserine etc.). Unpublished trials from the CENTRAL database were not included in the results because no data was available, this may produce a degree of publication bias in the studies considered. Following from previous reviews I concentrate on overall symptoms as determined by the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS), negative symptoms as determined by the PANSS negative subscale or the Scale for the Assessment of Negative Symptoms (SANS), and positive, cognitive, and general symptoms from the relevant PANSS subscales.

Results

Searches produced 522 records from Medline and 102 records from CENTRAL with 18 trials previously covered by a Cochrane review and a further 18 new studies identified. Trials were generally of good quality although small in size and of short duration. Reporting of blinding methods was poor, and outcome measures and statistical methodology were well validated but varied between trials making comparisons difficult. The initial goal to perform a meta-analysis using the additional data from newly identified studies was abandoned due to the difficulty in extracting usable data. All trials mentioned in this review are placebo controlled unless stated otherwise.

Glutamatergic stimulation

One model for pathology in schizophrenia is a hypoglutamatergic state or N-methyl-d-aspartate (NMDA) receptor dysfunction. Consistent with this proposal blockade of the NMDA receptor with phencyclidine or ketamine produces a psychotic syndrome similar to schizophrenia, including negative and cognitive symptoms. In pre-clinical trials, the use of co-agonists at the glycine binding-site of the NMDA receptor has been shown to modify some of the effects of NMDA antagonism (7).

The genes G72 and d-amino acid oxidase (DAAO) have been implicated in the genetics of schizophrenia (8) and are involved directly in neurotransmission at the NMDA receptor glycine binding-site, with DAAO metabolising the endogenous agonist d-serine.

These findings suggest that glycine binding-site agonists may potentially act to facilitate NMDA neurotransmission and correct underlying glutamate hypofunction in schizophrenia.

Adjuvant therapy

There have been a number of reports that augmentation of antipsychotics with agonists at the glycine binding-site preferentially improve negative and cognitive symptoms (7). A Cochrane Review has looked at the endogenous agonists glycine and d-serine and the partial agonist d-cycloserine as adjuvant therapy in schizophrenia (9). From data published up to 2003 they found 18 double blind randomised controlled trials, all short (≤12 weeks) with small numbers (358 subjects randomised in total).

d-cycloserine appeared to be ineffective on all measures, with trends towards harm compared to placebo. Glycine and d-serine were effective on some global measures and symptom scores. These comparisons all involved few patients (<150)>

Three further adjuvant studies of daily d-cycloserine have since been published and none of these found a beneficial effect on symptoms confirming the negative findings from the Cochrane review (10-12). However, an 8-week study of once weekly d-cycloserine adjuvant therapy in 38 patients found a statistically significant effect on mean negative scores but not 20% improvement rates or mean positive or cognitive scores (13).

Several studies of full glycine binding-site agonists have also been published since the Cochrane review. A 16-week trial, with 104 patients in the glycine and placebo groups combined, looking at adjunctive glycine found no difference from placebo for mean difference or 20% improvement in negative symptom scores, or for mean differences in cognitive or positive symptom scores (12). Conversely, a cross-over study of 17 patients using high dose glycine added to atypical antipsychotics resulted in a significant decrease in mean negative, cognitive, and positive symptom scores at 6-weeks. There was not a significant increase in 20% improvement rates for overall symptoms but there was for negative symptoms (14).

Similarly, in a cross-over study of 39 patients with adjuvant d-serine and atypical antipsychotics there was a significant decrease in mean negative, cognitive, and positive symptom scores, and also extra-pyramidal side-effects at 6-weeks, with 20% improvement rates significant for overall symptoms and negative symptoms (15). However, in a trial of d-serine added to risperidone, with 44 patients with acute exacerbations of schizophrenia in the d-serine and placebo groups combined, there was no statistically significant mean difference in overall or negative symptom scores at 6-weeks (16). Another small cross-over trial of 12 patients on clozapine also found no difference in mean overall, negative, positive, or general scores at 12-weeks (17).

Finally, d-alanine, another glycine binding-site agonist, has been tested as a adjuvant therapy in a 6-week study of 32 patients which found a significant benefit in mean scores on overall, negative, positive, and cognitive symptom scales (18).

The Cochrane review and later studies suggests that the partial agonist d-cycloserine is ineffective as adjuvant treatment in schizophrenia but the balance of evidence is still equivocal for the full glycine binding-site agonists. A reasonable estimate of the NNT for a 20% improvement in symptoms would be of the order of five patients but there is an obvious need for better and more consistent reporting to facilitate comparisons between trials and meta-analysis, particularly for cross-over trials. From the evidence these drugs appear to be well tolerated but they are not very practical to use, requiring fairly high doses diluted in liquid. Most trials have been fairly short, except for one 6 month trial of d-cycloserine, so estimates of long-term efficacy and tolerability are needed.

An alternative method of promoting agonist activity at the glycine binding site is the use of glycine re-uptake inhibitors. The glycine transporter-1 inhibitor N-methyl-glycine (sarcosine) has been examined in three studies. A 6-week trial of sarcosine with 38 patients showed benefits on mean differences in overall, negative, positive, cognitive, and general symptoms. These results were dependent on the analysis method, but mean differences at 6 weeks appear robust for overall and general symptoms (19).

Another 6-week study of sarcosine added to risperidone in acute exacerbations of schizophrenia, with 44 patients in the sarcosine and placebo arms combined, found significant changes in mean overall, negative, cognitive, and general symptom scales (although these depended on the analysis method used), with a significant difference in the rates of clinical response (defined as a 30% reduction in overall symptoms) (16). However, in a 6-week study of sarcosine added to clozapine with 20 patients there was no significant effect on mean difference in overall, negative, positive, cognitive, or general symptom scales (20). Pooling 6-week mean differences from all three studies will not result in significant effects because the statistical differences in the original studies largely depends on using regression to control for baseline imbalance in severity.

There has been some suggestion that use of glycine agonists with clozapine results in lower efficacy, perhaps because clozapine already has some glutamatergic activity. The Cochrane review found no evidence of differential efficacy of these drugs when used with typical or atypical antipsychotics, or with clozapine, and later studies have not provided any strong evidence to contradict this finding.

The compound CX516 is an ‘AMPAkine’ and allosterically binds to the ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor prolonging channel opening. It has been studied as an adjuvant therapy in schizophrenia with no significant benefit found in mean overall, negative, positive, cognitive, or general symptom scales (21, 22). A tiny trial of eight patients also failed to find evidence of benefit for CX516 as monotherapy (23).

Monotherapy

Recently a small trial of 20 patients was published looking at 6-weeks of sarcosine monotherapy for acute exacerbation of schizophrenia. This was not placebo controlled but rather compared high and low doses of sarcosine. There were no significant benefits of a higher dose on mean overall, negative, positive, or general symptom scales, but on the dichotomous outcome of 20% improvement in overall symptom score there was a significant benefit over the lower dose, and this was found in those subjects who were antipsychotic naïve (24). Although the dichotomous data suggests a NNT under three patients, in the absence of a change in mean symptom scores it seems unlikely that this finding reflects a true clinical benefit.

Glutamatergic inhibition

In contrast to the above proposition that glutamate hypofunction contributes to the symptomatology of schizophrenia, there has been some suggestion that glutamate hyperfunction may also play a role. Although superficially contradictory there is evidence that NMDA receptor hypofunction preferentially affects inhibitory interneurons causing disinhibition of pyramidal cells and increased glutamate release in prefrontal cortex (25).

Adjuvant therapy

Given the known effects of NMDA receptor antagonists such as phencyclidine in producing psychotic symptoms there has been little focus on these drugs as therapy. However, memantine is an NMDA antagonist used for the treatment of the cognitive symptoms of Alzheimer’s disease and has been investigated in an 8-week clinical trial of 138 patients as an adjunct to atypical antipsychotics. This study found no significant effect of memantine on global scores, or on overall, positive, negative, or cognitive symptom scales (26). There was also no significant difference in response rates (10% reduction in overall symptom score) but an increased rate of adverse events, including 6% of patients experiencing auditory hallucinations. Another study published only in abstract form has also found no effect of adjunctive memantine on cognitive measures (27).

Monotherapy

In 2007 a glutamate agonist trial was published that caused some considerable interest. This was a 4-week trial of 196 patients with poorly controlled chronic schizophrenia given the compound LY2140023 (versus olanzapine or placebo) (28). LY2140023 is metabolised to LY404039, a selective agonist at metabotropic mGluR2/3 glutamate receptors. The gene for mGluR3 has previously been associated with schizophrenia (6). As an agonist at type II metabotropic autoreceptors LY2140023 would be expected to antagonise rather than potentiate glutamate transmission, a mechanism that contrasts with the NMDA glycine binding-site agonists. However, LY2140023 has been shown to ameliorate the effects of NMDA antagonists in pre-clinical studies. Significant reductions were seen in mean overall, negative, and positive symptom scores for both LY2140023 and olanzapine, but LY2140023 did not show the weight gain associated with olanzapine. The reduction in symptom scores was greater for olanzapine than LY2140023, particularly with positive symptoms, but this difference was not statistically significant. With the dichotomous outcome of improvement (25% reduction) in overall symptoms there was a significant benefit to both LY2140023 and olanzapine compared to placebo suggesting a NNT of less than three patients for olanzapine and around 3.5 for LY2140023.

It is worth noting that while commentators have been quick to hail the advent of a new antipsychotic agent without the extra-pyramidal side-effects of dopamine blockade this study did not find any evidence for a difference using a variety of rating scales for these side-effects, although there was a significant difference in prolactin levels between the two drug groups. A substantial number of patients dropped out of the study (40%, primarily due to lack of efficacy), significantly more in the placebo group although the LY2140023 group also had more dropouts than the olanzapine group.

Discussion

The study of LY2140023 represents the first successful placebo controlled clinical trial of non-dopamine based antipsychotic therapy for schizophrenia* and the results suggest that this and similar compounds represent a promising avenue for developing antipsychotics with a different side-effect profile to that of current medication and the potential for efficacy in patients resistant to current treatments. This study does not establish that LY2140023 is better than olanzapine for negative symptoms, an early hope for these compounds, nor that it has a lower incidence of extra-pyramidal symptoms (since there were few of these in this short study) although prolactin levels were lower and weight gain less. There is an outstanding issue regarding the optimum dosing regime with LY2140023 and it is possible that higher doses could result in a greater antipsychotic effect and more marked effect on negative symptoms. A dosing study has just been completed but the manufacturers have recently announced that this failed to show a benefit of LY2140023 over placebo with no dose response effect – this failure has been ascribed to the large placebo response in the trial and further studies are awaited with interest.

It is worth comparing the NNT in the 2007 LY2140023 study with the evidence from glycine binding-site agonists as adjuvant treatment. The Cochrane review found a NNT for 20% reduction in symptoms of three patients (including evidence from later studies a more reasonable estimate would be five) and high dose sarcosine monotherapy produced a NNT of less than three patients (compared to a low dose of sarcosine). These effects are not markedly dissimilar to the results of LY2140023 and mean differences in negative symptom scales (the main outcome used in the adjuvant studies) for glycine binding-site agonists are of a similar magnitude to LY2140023. However, the difference in mean overall symptom scores is much larger for LY2140023 than the glycine binding-site agonists, and the sarcosine monotherapy trial produced no significant differences in mean symptom scores at all.

These comparisons suggest that, while LY2140023 has evidence for somewhat greater efficacy than glycine binding-site agonists this is a tentative conclusion at best, and may prove to be premature when the results of the latest trial of LY2140023 are published. We are still awaiting the outcome of placebo controlled trials of glycine binding-site agonists as monotherapy, but it is conceivable that use as adjuvant therapy may have underestimated the full antipsychotic effect of these compounds. Similarly, trials of LY2140023 as an adjuvant therapy may show an additive therapeutic benefit over-and-above the effect of conventional antipsychotics, which may be similar to or greater than that of the glycine binding-site agonists.

It is not entirely clear why both NMDA glycine binding-site agonism and reduced glutamate release (via type II metabotropic receptor agonism) appear to have beneficial effects on schizophrenic symptoms, nor why the latter is so much more successful than direct NMDA antagonism. Presumably differential and complex effects on neural circuits underlie this apparent paradox but it highlights how poor our understanding of the glutamatergic pathology of schizophrenia still is. Glutamatergic drugs may still not prove to be the future of schizophrenia treatment, but they are currently offering some hope.

References

* Although the original study found no evidence that LY2140023 or LY404039 interact with dopamine receptors it has been proposed that there may be some action at high-affinity state dopamine D2 receptors (29), and there are considerable interactions between the glutamatergic and dopaminergic systems (6).

1. Seeman P, Chau-Wong M, Tedesco J, Wong K. Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci U S A 1975;72(11):4376-80.

2. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996;153(3):321-30.

3. Tandon R, Belmaker RH, Gattaz WF, Lopez-Ibor JJ, Jr., Okasha A, Singh B, et al. World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res 2008;100(1-3):20-38.

4. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44(7):660-9.

5. Matthysse S. Antipsychotic drug actions: a clue to the neuropathology of schizophrenia? Fed Proc 1973;32(2):200-5.

6. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10(1):40-68.

7. Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004;9(11):984-97, 979.

8. Li D, He L. G72/G30 genes and schizophrenia: a systematic meta-analysis of association studies. Genetics 2007;175(2):917-22.

9. Tuominen HJ, Tiihonen J, Wahlbeck K. Glutamatergic drugs for schizophrenia. Cochrane Database Syst Rev 2006(2):CD003730.

10. Duncan EJ, Szilagyi S, Schwartz MP, Bugarski-Kirola D, Kunzova A, Negi S, et al. Effects of D-cycloserine on negative symptoms in schizophrenia. Schizophr Res 2004;71(2-3):239-48.

11. Goff DC, Herz L, Posever T, Shih V, Tsai G, Henderson DC, et al. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berl) 2005;179(1):144-50.

12. Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry 2007;164(10):1593-602.

13. Goff DC, Cather C, Gottlieb JD, Evins AE, Walsh J, Raeke L, et al. Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study. Schizophr Res 2008;106(2-3):320-7.

14. Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry 2004;55(2):165-71.

15. Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 2005;57(6):577-85.

16. Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry 2005;62(11):1196-204.

17. Diaz P, Bhaskara S, Dursun SM, Deakin B. Double-blind, placebo-controlled, crossover trial of clozapine plus glycine in refractory schizophrenia negative results. J Clin Psychopharmacol 2005;25(3):277-8.

18. Tsai GE, Yang P, Chang YC, Chong MY. D-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2006;59(3):230-4.

19. Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2004;55(5):452-6.

20. Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 2006;60(6):645-9.

21. Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, et al. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 2001;21(5):484-7.

22. Goff DC, Lamberti JS, Leon AC, Green MF, Miller AL, Patel J, et al. A placebo-controlled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 2008;33(3):465-72.

23. Marenco S, Egan MF, Goldberg TE, Knable MB, McClure RK, Winterer G, et al. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res 2002;57(2-3):221-6.

24. Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH, et al. Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study. Biol Psychiatry 2008;63(1):9-12.

25. Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007;27(43):11496-500.

26. Lieberman JA, Papadakis K, Csernansky J, Litman R, Volavka J, Jia XD, et al. A Randomized, Placebo-Controlled Study of Memantine as Adjunctive Treatment in Patients with Schizophrenia. Neuropsychopharmacology 2008.

27. Lee JG, Kim Y-H, Lee SW. Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: A 12-week, double-blind, placebo-controlled trial (abstract). International Journal of Neuropsychopharmacology 2008;11(Suppl 1):141-2.

28. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 2007;13(9):1102-7.

29. Seeman P. Glutamate agonists for schizophrenia stimulate dopamine D2High receptors. Schizophr Res 2008;99(1-3):373-4.

Call of Duty: Modern Warfare 2

Off to get the new Call of Duty today (because at heart I'm just a little boy). I was watching the review of it last night on Newsnight Review - it was rather bizarre, while I haven't seen the controversial level that's got so much coverage, most* of the reviewers (who also appeared to be unfamiliar with computer games in general) seemed to object to the overall violence (in a first person modern warfare shooter!) because, as far as I could tell, killing people 'is like bad, m'kay?'

Now I totally agree that killing people is bad, but I'm pretty unclear how computer simulated violence has quite the same moral ramifications as actually killing someone**, particularly when our reviewers didn't extend their objection to all those films about killing people, or films with other morally dubious things like rape, or infidelity***, or just being mean.

I suppose you could make a more specific objection that in computer games you are taking on an active role rather than being a passive observer - this seems to have been behind some of the objections to the controversial level in Modern Warfare 2 - but the reviewers didn't actually seem to make that point. But if that was the direction you were going, arguing that taking part in simulated violence has some negative impact on an individuals moral integrity (does that include paintball, laser quest, archery even?) then why should we not extrapolate that out to other immoral acts as I've intimated above? And why are actors not faced with such opprobium for playing roles in films about, for example, incest - roles where they are getting a whole lot more involved that someone bashing the plastic controller on their games console?

At one point Paul Morley bemoans that there has been this divide between gamers and non-gamers with the latter dismissing the condemnation of the former because they 'just don't get it' - sadly I think the latter are correct, non-gamers seem to be condemning something they don't understand and fear because of that - Morley seems to be making a pretty penny watching and writing about X-Factor at the moment, I wonder does he feel morally degraded through his complicity in that nasty piece of voyeurism?

ETA: This is hilarious:
Video games depicting war have come under fire for flouting laws governing armed conflicts.

Human rights groups played various games to see if any broke humanitarian laws that govern what is a war crime.

The study condemned the games for violating laws by letting players kill civilians, torture captives and wantonly destroy homes and buildings.

Hmm, perhaps the authors ought to concentrate on having real life violations of humanitarin law prosecuted first, before defending out pixelated friends.


* Admittedly one of them thought it was great

** You also have to wonder whether the thousands of people being blown to bits in wars around the world might be worthier of our defence before we start helping out the little pixelated pretend people from being killed by by teenage boys

Sunday, 8 November 2009

Dowsing for IEDs

So unbelievably fucking disgusting it makes my skin crawl. The Halliburton of woo. Not entirely unlike the use of pointless lie detectors by the British government only this time it leads to lots of people dying - arrogant and ignorant morons in power will never cease to piss away millions of pounds on magic beans because they sound cool.

Tuesday, 1 September 2009

Tedious psychological turf wars

Richard Bentall has a new book out so it was only a matter of time before he made his way into the British press. I don't have time for an indepth critique but here's a few selected highlights:
"Many studies have also reported an association between trauma in early life and psychosis. These effects are large: one recent study estimated that individuals who had been sexually abused in childhood were 12 times more likely than others to suffer from serious mental illness, and another calculated that the population-attributable risk of a diagnosis of schizophrenia associated with an inner-city childhood was 15% (that is, there would be 15% fewer cases if we all grew up in the countryside). The risk associated with having a parent with the diagnosis is 7% (ie, there would be 7% fewer cases if patients stopped having children)."(my emphasis)
Note that what this segment subtly doesn't point out is that the evidence suggests that schizophrenia in particular isn't actually associated with childhood abuse (unlike, say, depression).

The whole piece is a depressing blow in a pointless academic turf war where psychologists seek to undermine 'biological' psychiatric research (which, is to some extent justified) only to posit even weaker little barely-theories to replace it:
These effects are understandable in the light of psychological research. For example, early trauma seems to disrupt the process by which we distinguish between our own thoughts and our perceptions, leading to a specific risk of hallucinations. Disruption of early relationships with caregivers, coupled with victimisation, create a tendency to mistrust others and to anticipate threats, leading to paranoid delusions.(my emphasis)
I mean, seriously, what is the highlighted sentence even supposed to be telling us? That there is an association between trauma and hallucination? But he's just told us that, what does 'psychological research' tell us on top of that? What are the useful therapeutic insights that this research igives us?
To date, about 30 trials of cognitive therapy for psychosis have been completed; by comparison, in the period 2001-3, nearly 400 drug trials were published in the five leading American psychiatric journals. There is therefore an urgent need to develop a less drug-based, more person-centred approach to understanding and treating mental illness, which builds on the recent scientific findings and which takes the experiences of patients seriously.
CBT is similarly effective to antidepressants (but of little use in psychosis compared to anti-psychotics) but if psychologists think the recent success of psychological therapies supports their approach then they are going to have to look very hard at why their therapies are little better (and often worse) than the 'biological' therapies they seek to undermine.

The problem wth Bentall (and I've read Madness Explained) is that he makes valid but somewhat overstated arguments against things like psychiatric labels or the efficacy of psychoactive drugs but then thinks that he has somehow completely demolished existing medical understanding of mental illness and its treatment (rather than having slightly deflated its claims) and then goes on to make 'psychological' theories that are often much worse supported that the 'biological' theories he has just tried to undermine and also to present them as radically opposed to existing understanding rather than being complementary (which is what they are).

This is really just a slightly more sophisticated vesion of Oliver James - if mental illness doesn't have a genetic component then drugs don't work, if mental illness is associated with childhood abuse then we need psychological therapies. That mental illness is probably both partly genetic and partly associated with envronmental factors including childhood abuse (a) tells us nothing about whether drugs or therapy work, and (b) that the evidence tells us that both drugs and therapy work (depending on the diagnosis) is just too complex and nuanced for this pathetic dick-swinging Sunday supplement debate.

Wednesday, 22 July 2009

Dr Simon Jenkins

Dr Jenkins shares his well informed views of how trivial swine 'flu is:
...a condition correctly diagnosed by a Dulwich 12-year-old during the initial outburst of hysteria in May as "like a cold"

...the one thing not to take is Tamiflu...People should take an aspirin.
After all, who are you going to trust, doctors and scientists who have dedicated their lives to studying and treating disease, trying their best to plan and advise based on incomplete information, or some bloke in the pub?

If swine 'flu turns out to kill a lot of people this Autumn* then Jenkins should really be forced to confront his words***. Of course, it probably won't, further inflating his dick swinging braggadocio, until we finally do get a pandemic viral illness (which we will eventually) - when he'll be clamouring to know why more wasn't done**. Ah, the privilege of consequence free comment pieces, the life of a journalist is so easy - you get to feel so important while doing fuck all. Reminds me a little of the greatest intellectual struggle of our time.

EDIT: Heh, Gimpy got there first, pointing out that aspirin shouldn't be used in children, although there are plenty of other errors tackled in the comments to Jenkins's article. Also jonnyhead covers it and the Times's Mark Henderson.


* I really hope it doesn't, not least because it'll mean I have to deal with the consequences at work as everyone in the NHS goes off sick or to look after their children, leaving me with a massive workload and lots of really sick patients trying their hardest to infect me.

** And, I'd be willing to bet, making demands that health workers and/or other people (e.g. patients or healthy people depending on whether he's caught it) risk their own health to preserve his.

*** According to Gimpy, it would appear he's already been wrong about another viral epidemic - so it looks like it probably wouldn't bother him. Here's Jenkins on AIDS/HIV:
"Aids has been confined largely to homosexuals and drug abusers, whose activities put them at risk of blood contamination and leave them vulnerable to lethal disease. There are some Aids cases outside the “high-risk” groups, but numbers are tiny: 60 at most in Britain. As far as Britain is concerned, the plague appears to be passing."

Wednesday, 17 June 2009

'New Vegetarianism'

I was all ready to make the above joke after reading this article:
The worst thing about not eating meat isn't the limp salads - it's the other vegetarians
But I was beaten to it by the second comment:
"New Vegetarianists" are so shrill.

Friday, 5 June 2009

NICE infiltrated by Berties

As they say on teh interwebs, quoted for truth:
First the MHRA lets down the public by allowing deceptive labelling of sugar pills (see here, and this this blog). Now it is the turn of NICE to betray its own principles.
...
If NICE does not reconsider this guidance, it is hard to see how it can be taken seriously in the future...
David Colquhoun on NICE, low back pain, and the Woo-sters here, here, and here.

I think D^2 has an interesting, but ultimately flawed take on it:
Similarly, in the early days of the evidence-based medicine movement, when they were the Young Turks or punk rockers, shaking up a complacent medical establishment that had got out of touch with the cutting edge of medical research, they had the potential to do a lot of good. But now they are the establishment, and as a result of that, the very evidence that they rely on, is shaped by the fact that it needs to appeal to them. The fact that a movement which begun by trying to bring science back into medicine, has now ended up putting its imprimateur on some obvious pseudoscience, ought to worry us more than it does, because this is only the most obvious manifestation of the general problem.
I think he is wrong here, in fact I'm not even sure exactly what he's trying to say is the institutional weakness of Evidence Based Medicine - the strength of EBM is that it has relatively objective and impartial methods to decide questions like this - which is why this failure to adhere to those standards has caused such outrage.

Also, see the guy in the comments lamenting that these EBM enthusiasts have no way to combine data from multiple trials and other misapprehensions.

Simon Singh

Simon Singh is to appeal and fight on against the ridiculous libel action brought by the British Chiropractic Association for his article accusing them of promoting 'bogus' treatments. I urge you to sign the petition about this abuse of the overly harsh libel laws of England & Wales:

We the undersigned believe that it is inappropriate to use the English libel laws to silence critical discussion of medical practice and scientific evidence.

The British Chiropractic Association has sued Simon Singh for libel. The scientific community would have preferred that it had defended its position about chiropractic for various children's ailments through an open discussion of the peer reviewed medical literature or through debate in the mainstream media.

Singh holds that chiropractic treatments for asthma, ear infections and other infant conditions are not evidence-based. Where medical claims to cure or treat do not appear to be supported by evidence, we should be able to criticise assertions robustly and the public should have access to these views.

English libel law, though, can serve to punish this kind of scrutiny and can severely curtail the right to free speech on a matter of public interest. It is already widely recognised that the law is weighted heavily against writers: among other things, the costs are so high that few defendants can afford to make their case. The ease and success of bringing cases under the English law, including against overseas writers, has led to London being viewed as the "libel capital" of the world.

Freedom to criticise and question in strong terms and without malice is the cornerstone of scientific argument and debate, whether in peer-reviewed journals, on websites or in newspapers, which have a right of reply for complainants. However, the libel laws and cases such as BCA v Singh have a chilling effect, which deters scientists, journalists and science writers from engaging in important disputes about the evidential base supporting products and practices. The libel laws discourage argument and debate and merely encourage the use of the courts to silence critics.

The English law of libel has no place in scientific disputes about evidence; the BCA should discuss the evidence outside of a courtroom. Moreover, the BCA v Singh case shows a wider problem: we urgently need a full review of the way that English libel law affects discussions about scientific and medical evidence.

Putting any reservations I might have about SaS to one side, this is an important fight - libel law should not be used to shut down scientific disagreements.

free debate

Saturday, 30 May 2009

Atheists: No God, just whining

This is amusing reading:
"I can't stand atheists – but it's not because they don't believe in God. It's because they're crashing bores...and their fixation with the fine points of Christianity.

The problem with atheists – and what makes them such excruciating snoozes – is that few of them are interested in making serious metaphysical or epistemological arguments...

What primarily seems to motivate atheists isn't rationalism but anger – anger...So, atheists, how about losing the tired sarcasm and boring self-pity and engaging believers seriously?"

Wednesday, 29 April 2009

Eight out of ten cats prefer...Boots

Via badscience forums I see that there has been a placebo controlled randomised clinical trial of an anti-ageing creme that found a positive effect of the product - expect to hear about it:

Scientists say they have clinical proof that a face cream available on the high street does reduce wrinkles.

Five months' worth of stock of the leading brand sold in a day after Professor Chris Griffiths announced in 2007 it appeared to combat sun damage.

Two years on from the BBC Horizon programme showcasing his work, his team has shown the cream visibly smoothes out the skin.

Boots predicts boom sales of its No 7 Protect & Perfect Intense Beauty Serum.

Now it is certainly good that Boots has conducted a clinical trial, published in the British Journal of Dermatology no less, but it is, I'm afraid, bollocks.

I'm going to ignore everything in the paper other than the clinical trial as they are, to be blunt, irrelevant. So what did they do? Well they randomised 60 adults to placebo or the face cream in question to apply to their hands and face for 6m -and they looked at four measures, clinical scales for fine lines and wrinkles, dyspigmentation, and the overall clinical grade of photoageing and tactile roughness at baseline, 1m, 3m, and 6m.

So what did they find? Well they report that at 6m there was no statistically significant difference on any of the measures - including improvement in facial wrinkles (compared to baseline) where 43% who had used the product improved and 22% of the placebo group (that's a relative improvement of 1.89 times, 95% CI .86-4.0, with a p-value of .11*). As the paper says:

"the test product did lead to a noticeable clinical improvement in facial wrinkles...in 43% of treated individuals after 6 months, compared with only 22% of those treated with the vehicle...In a comparison between groups, this improvement was not statistically significant" (my emphasis)
Huh? Yes, that's right, no differences. So why is this supposed to be a positive study? Well that's because they were rather sneaky, after 6m - at which point their were no significant differences remember - they stopped doing a blinded placebo controlled trial and put all the subjects on the face cream. They then extrapolated (using linear regression, and presumably the 1m, 3m, and 6m response rates) the placebo response to 'guess' what the 12m response rate might be. They found that 70% of the 60 people now getting cream had improved facial wrinkles (not improved hand wrinkles, or improved dyspigmentation, photoageing, or tactile roughness of the hands or face**) while they estimated that only 33% of the extrapolated placebo group would have improved.

Now we don't know anything about this regression because they don't tell us any data from baseline***, 1m, or 3m, but you might argue that 33% seems a rather low rate, and, since we might want any regression to go through 0,0 (since at baseline there can have been no improvement) and only have data from 6m presented we could suggest that 44% would be just as reasonable a 12m response rate for the placebo group.

This is an inherently dodgy way to go about analysing the data (and it gives free additional sample size artificially inflating the power of the study) which is now not even from a blinded randomised trial but instead a open label trial (everyone now knows they're on the cream, not placebo) but if we look at what the results give we might find that, assuming the placebo group is 30 (and, of course, that group doesn't really exist) and the cream group has 60 people we get a response rate of 70% for cream and 33% placebo (2.10 times relative improvement 95% CI: 1.23-3.58, p=.006****) - if we assume my 44% placebo response it is 1.62 times 95% CI: 1.04-2.51, p=.03).

However, we've also forgotten that they made a lot of statistical comparisons, we'll let them off the comparisons at 1m, 3m, and 6m (they're not independent anyway, if this had been a pain relief trial, say, they might have tried to make something of them if they had proven to be signficant early in the trial and then became non-significant later on - but that is unlikely here) but they did do 4 measures on each of the hands and face - that's 8 sets of statistical tests - so our error rate of p=.05 will get inflated with all those tests (which each have a 5% error rate) so we need to correct for that - a simple Bonferroni correction implies that we need to multiply the p-values by 8, which makes the 70%-33% comparison barely significant (p=.048) and the 70%-44% comparison non-significant (p=.24).

It is worth noting that although only 13/30 showed an improvement with 6m treatment when the placebo arm was added in and another 6m of treatment given, assuming the original 13 sustained their improvement, a whacking great 29 further people showed an improvement (i.e. we might think that a second 6m had the same response rate as in the first 6m, doubling the response rate for that first 30, plus an extra 30 people have that same 6m response rate). I find that pharmacologically unlikely*****.

Take home message - they did a randomised blinded clinical trial for 6m and found no statistically significant effects of the Boots cream (or even remotely nearly significant given the necessary multiple testing correction). They then did a non-trial where they essentially made-up placebo control group results and gave the cream to all the real patients in a non-blinded fashion. And then, maybe, they have a borderline statistically significant result.

The data is sufficiently badly presented, and given that the clinical trial is what, ultimately, they'll use to sell it, that I'd say they have deliberately done dodgy stats to hide the negative nature of the data. God knows what the Manchester researchers were thinking, and I despair of the British Journal of Dermatology and its peer review.

I wonder what the following were thinking when they said:

"Nina Goad of the British Association of Dermatologists said: "Approximately one in five people using the cream will get something extra for their money over plain moisturisers. "It is an interesting step forward in research although the long term benefits are unknown. "The main preventable causes of skin ageing are sun exposure and smoking, so if you're worried about wrinkles, limiting these factors is sensible."

Dr Nick Lowe, clinical professor of dermatology at UCLA School of Medicine, said: "The previous rapid study reported from this group measured fibrillin a substance that predicts the formulation of collagen. More collagen should result in skin rejuvenation. "This latest longer study over six months appears to confirm skin rejuvenation as measured by dermatology examination."

Dr Richard Weller, senior lecturer in dermatology at the University of Edinburgh, said: "This is, as far as I am aware, the first properly conducted placebo controlled, double blind trial of an over the counter cosmetic product. Boots are to be congratulated for doing this."

I wonder if they actually read it (it was published on the 28th - the same day as the BBC article - the media have a habit of asking for quotes before anyone gets to read the article).


NHS Behind the Headlines has also covered this story.


Acknowledgements to the observations of willowtree and BenFranklin in the thread.


UPDATE
We can see here from the press release from Manchester that there was specific misrepresentation:
"The study, published online in the British Journal of Dermatology today (Tuesday, April 28), showed that 70% of individuals using the beauty product had significantly fewer wrinkles after 12 months of daily use compared to volunteers using a placebo." (my emphasis)

* Maentel-Haenszel assuming 30 in each group - we can only assume because they give no details of numbers in each group or if any dropped out - looking at the 22% placebo response rate I think that either the two groups were not of equal sizes or there were dropouts because that figure does not give a whole number for number of responses if you assume a sample size of 30 - in the actual study they report p-values derived from Wilcoxon rank tests which doesn't make any sense given the data they present.

** I'll get back to these in a bit

*** IT would certainly be nice to know baseline scores because, since they report improvement over baseline, differences between the two groups in baseline scores (these happen by chance often in trials, particularly small ones like this) could lead to differences in improvement (say, because those who start out less severe have less opportunity to improve because their skin was pretty good already).

**** Obviously these are make believe stats since this would really be a cross-over design and I'm assuming independence, and because, obviously, you just can't make up placebo responses like this
.

***** Would have been nice to be able to judge that by showing the 1m, 3m etc data.

Sunday, 26 April 2009

The test of liberalism

Via butterfliesandwheels and the comments at aaronovitch watch - Terry Eagleton on CiF tells us:
"There is no quarrel about how to treat those whose scorn for liberal values takes the form of blowing the legs off small children. They need to be locked up. But socialists as well as Islamists reject the liberal state, so what is to be done about them? Are they to be indulged only until they successfully challenge the state...?

"Liberalism holds that the state should tolerate any opinion that does not seek to undermine that very tolerance. It is an ironic kind of politics.

"If the test of liberalism is how it confronts its illiberal adversaries, some of the liberal intelligentsia seem to have fallen at the first hurdle. Writers such as Martin Amis and Hitchens do not just want to lock terrorists away. They also tout a brand of western cultural supremacism. Dawkins strongly opposed the invasion of Iraq, but preaches a self-satisfied, old-fashioned Whiggish rationalism that can be wielded against a benighted Islam. The philosopher AC Grayling has an equally starry-eyed view of the stately march of Western Progress. The novelist Ian McEwan is a freshly recruited champion of this militant rationalism. Both Hitchens and Salman Rushdie have defended Amis's slurs on Muslims. Whether they like it or not, Dawkins and his ilk have become weapons in the war on terror. Western supremacism has gravitated from the Bible to atheism.

"There is also an honorable legacy of qualifying too-absolute judgments with an awareness of context: the genuine liberal is appalled by Islamist terrorism, but conscious of the national injury and humiliation that underlie it. None of the writers I have mentioned is remarkable for such balance.

"For the liberal state to accommodate a diversity of beliefs while having few positive convictions is one of the more admirable achievements of civilization. But such neutrality, once under pressure, can easily slide into superiority, as sitting loose to other people's faith comes to look like rising disdainfully above it. It is then only a short step from superiority to supremacism."
I think this is a rather confused piece. I don't buy the claim that liberals are necessarily obliged to not tolerate opinions that seek to undermine the liberal state - but if that is, in fact the case, then how is intolerance of Islam to fail 'the test of liberalism'?

Note that Eagleton rather sneakily slides from the dodgy views of Amis to claiming that Dawkins's rationalism can be wielded against Islam and that he is a 'weapon' in the 'war on terror' - I mean, so what? I'm sure the findings of academic psychology can be wielded in the 'war on terror' - should we abandon the practice of psychology?

But what intrigues me is how the socialist is supposed to fit in. After all, as Eagleton points out:
The left objects to the liberal case not because it believes in crushing those who differ, or dislikes the idea of a partisan state, but because this case rules out the kind of partisan state that ­socialism requires. It rules out, for example, a state that would not be neutral on whether cooperation or individualism should reign supreme in social and economic life.
Socialism is no friend to Islam, sure it seeks to defend the oppressed, and Eagleton is right that Muslims have been the target of some unpleasant demonisation, but fundamentally socialists reject most religious belief. In fact, I'm not entirely clear how the SWP and Richard Dawkins differ in this regard.

Martin In The Margins
notes that:
Eagleton is a master of the classic pseudo-leftish 'guilt by association' move. If you can get your audience to see your opponents as part of a wider, sinister movement - the war on terror, neoconservatism, late capitalism, imperialism - this relieves you of the necessity of engaging with their arguments.

El Gordo

It seems I may be one of the few people in the UK who thinks Gordon Brown's performance was a perfectly creditable piece of public speaking. I guess my ability to detect mental illness through hand gestures just isn't up to the standards of the rest of the population - I must be in the wrong job.

Saturday, 7 March 2009

Are the new antidepressants any better?

You may recall that the Kirsch et al study showed a trend (that was not statistically significant) for venlafaxine to be superior to other antidepressants. But there are a number of newer antidepressants, how do they compare to the vanilla SSRIs?

A new meta-analysis in the Lancet tried to find out:
"Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1·39, 1·33, 1·30 and 1·27, respectively), fluoxetine (1·37, 1·32, 1·28, and 1·25, respectively), fluvoxamine (1·41, 1·35, 1·30, and 1·27, respectively), paroxetine (1·35, 1·30, 1·27, and 1·22, respectively), and reboxetine (2·03, 1·95, 1·89, and 1·85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine."
I haven't read it yet, so I can't speak for its veracity.

Friday, 6 March 2009

Someone else on anti-depressants and placebo

Nice post on Neuroskeptic looking at a recent meta-analysis of anti-depressants:
After fifty years of research, and untold millions of research dollars, there are hundreds of published clinical trials of antidepressants. It's when you try to make sense of the results of this great mass of trials that the problems become apparent. The latest attempt to do that is a paper from a German-American collaboration, Rief et. al.'s Meta-analysis of the placebo response in antidepressant trials. The authors set out to
Determine overall effect sizes of placebo and drug effects in antidepressant trials
In other words, they wanted to find out how much people improve when given antidepressants, and how much of that improvement is due to the placebo effect.
Read it all.

Friday, 27 February 2009

Grow your own drugs

No, not the good kind, there is a new TV series being heavily trailed, by that title:

...James Wong, a 27-year-old ethnobotanist (a scientist who studies how people use plants), wants to change our minds. He passionately believes that safe, natural remedies can be made from the everyday plants you find in hedgerows, the back garden or local garden centres.

...In Malaysia, where Wong grew up, everyone treated themselves with natural remedies. Food, too, was used as medicine...

The problem, Wong believes, is that there's a big cultural dividing line between conventional medicine, which is thought of as effective, proven and serious, and herbal medicine, which has the reputation of being a bit flaky.

But, as Wong says, up to 50 per cent of over-the-counter medicines are based on chemicals that were first isolated from plants. "Aspirin, for example, is made from the same chemicals that were first isolated from willow, which has been used for thousands of years as a painkiller.

...Wong, who trained at the Royal Botanical Gardens at Kew, is quick to point out that the herbs and plants he recommends all have a long history of use and no record of toxicity.

So, presumably aspirin, which is derived from plants after all, has 'no record of toxicity'? This doesn't bode well.

Working women almost certainly caused the credit crunch

This is a brilliant article from the Irish Times:

Of course there will always be a place in the world of business for exceptional women. Women also have an important role to play in jobs that are too demeaning for men, like teaching. But the general employment of women is another matter. Indeed, working women almost certainly caused the credit crunch by bringing a second income into the average household, pushing property prices up to unsustainable levels.

Whether working women actually caused the credit crunch is now a moot point. The point is that removing women from the workforce would mitigate its effects.

...

It would be ludicrous to suggest that women should be sacked purely to give men their jobs. In many cases, their jobs should be abolished as well.

Wednesday, 25 February 2009

A Million Women Drinking

Some data from the Million Women Study (of women aged over 50) has caused some headlines today:

A glass of wine each evening is enough to increase your risk of developing cancer, women are being warned.
Consuming just one drink a day causes an extra 7,000 cancer cases - mostly breast cancer - in UK women each year, Cancer Research UK scientists say.
These reports are based on this study and press release. I've graphed some of their data (top right, 95% floated** CI). I think it is clear that the difference between a drink a day and less than 2 drinks a week (this was the reference group because non-drinkers often includes ex-alcoholics or those who have given up because they are already sick) is less than convincing (obviously it is difficult to interpret given that both the upper end of the 3-6u group and the lower end of the 7-14u group cover around 1u/day).

The claim that "each additional drink regularly consumed per day may account for approximately 15 excess cancers per 1000 women up to age 75" is actually based on a regression on the average amount of alcohol consumed in each category* - this data is represented in the middle right graph (as above but with mean alcohol, a regression line, excluding non-drinkers, and 95% CI). We can see that average consumption in neither group is conveniently near an average consumption of 1 drink (10g)/day.

It is clear that the regression is strongly driven by the heaviest alcohol consuming group, with a shallower regression being indicated if you exclude these subjects, and this highlights the limits of doing a regression analysis and then reporting the increased risks per unit of alcohol, since any non-linearity can make the linear regression coefficients misleading (such that while the regression line may describe a Y% risk for every X units, the data may still not support a statistically significant Y% increase for the first X units drunk).

It is always worth being circumspect when dealing with epidemiological data that produces very small risks, because we cannot know that every confounding variable has been accounted for in what is simply an observational study. Look at the zero alcohol consumption group (this would not actually be zero since 7% of these were actually drinking alcohol by the 3-year followup, but they don't provide the mean data), looks like there is something different between these individuals and those with minimal alcohol consumption - but this is not captured in the data (the relative risks have already been adjusted for available confounding variables).

I'm not sure why my estimates of additional risk per 10g/day are so much less than the study (obviously my regression is Mickey Mouse but it fits nicely, and it doesn't seem to be due to me not using log-linear regression either) - I get less than 1.05 relative risk (as you can see from the graph), their estimate of 15 additional deaths per 1000 women is around a 1.13 relative risk, although it appears that they are only include those cancers with an increased risk from alcohol associated with them, i.e. they don't include the lives saved by alcohol preventing lymphoma, thyroid, and kidney cancer!

If we look at the figures they report in the study, they say that there is an incidence of 118 cases of cancers that alcohol increases the risk for (oropharynx, oesophagus, larynx, rectum, liver, breast) per 1000 women up to age 75 years, and by drinking 10u/day this risk is up to 133 per 1000 women (which is where I got the 1.13 relative risk from)***. Since these cancers made up around half of those in this study we could estimate that the overall cancer risk for women up to 75 years is 236 per 1000, applying our approximate overall increase in cancer risk of 1.05 we get an extra 12 cancers per 1000 women, or an increase in absolute risk of cancer of 1.2% - that is, drinking 10u/day means that the chances of you getting cancer before you are 75, which is 24% anyway, goes up by another 1.2%.

Interestingly the data suggest that the increased risk in cancers of the upper aerodigestive tract (larynx, oropharynx, oesophagus), which are some of the cancers increased in incidence with alcohol consumption in this study (the others being liver, rectum and breast cancer), is due to a synergistic effect with smoking tobacco (see their figure 4 - bottom right) - and this may mean the study overstimates the risk of alcohol - or rather, it fails to highlight that some of the apparent additional risk of alcohol only applies if you also smoke (it would be possible to control for this using covariates if smokers and non-smokers were modelled seperately).


* A unit is 8g alcohol, nowadays many wines and beers a sufficiently strong that they contain 10g per serving (small glass, half a pint) and this study uses 'a drink' to mean 10g alcohol.

** These confidence intervals are based on a 'floating absolute risk' model which is controversial and results in narrower CIs than conventional techniques.

***This is dodgy, to multiply the 118 cases of cancer by the estimated relative risk at 10u/day of 1.13 (which is what they seem to be doing) would only be valid if the 118 cases was from women in the lowest risk group - those drinking <= 2u/week - but we know that many women do drink more than this (nearly half in this study), and the overall cancer rate therefore already includes this extra alcohol related risk. However, if I adjust my above figures to account for this it doesn't make much difference - giving an additional 11 cancer per 1000 women, and thus absolute increased risk of 1.1%.

Tuesday, 24 February 2009

Grandma

In these challenging times it is good to see unveiled a £2m state funded memorial to an unelected woman paid millions of pounds by the British taxpayer, and whose surviving family consists of further unelected state funded multimillionaires.

Her grandson said:
At long last my grandparents are reunited in this joint symbol, which in particular reminds us of all they stood for and meant to so many during the darkest days this country has ever faced

At long last indeed, perhaps he could have chipped in, got it speeded up, he could probably spare a few quid.

Monday, 16 February 2009

Friday, 13 February 2009

Bankrupt

I can't understand why this song has not got more airplay as background music for news reports given the current climate:



This is from "9 Red Songs" (from 2005, so prescient) by Chris T-T, I also recommend "The Huntsman Comes A-Marchin'" and "Preaching to the Converted".

Johann Hari on free speech

Writing in the Independent:

Last week, I wrote an article defending free speech for everyone – and in response there have been riots, death threats, and the arrest of an editor who published the article.
Read it all.