Richard Lehman’s journal review—25 January 2016

richard_lehmanNEJM 21 Jan 2016 Vol 374
Share data or be damned
OL The most important article this week also appears on the websites of JAMA, The BMJ, Annals of Internal Medicine, and The Lancet. It’s a proposal from the International Committee of Medical Journal Editors to move towards a requirement that all published research should be accompanied, within six months of publication, by a full dataset of de-identified participant level data. I’m writing this during a brief stay at the home of the Yale Open Data Access project, which began in 2011 when this would have seemed the stuff of fantasy. We didn’t actually open champagne, though we did talk of it. One reason is that it we now will have even more work to do; another is that this is still just a proposal. If you support it, write to

If you share data you’ll be damned
276 Having signed the remarkably radical ICMJE proposal, Jeff Drazen, editor of NEJM, co-authors an editorial simply titled “Data Sharing.” It begins by mocking a delusive biscuit-tin landscape of everybody happily sharing data, moves on to grave warnings about “research parasites” feeding off other people’s hard work, and ends up advocating “research symbiosis,” by which the original researchers collaborate with others in moving beyond the data already gathered. I think they are trying to be witty, and I don’t want to discourage that, but they make it clear that they regard re-analysis and meta-analysis as little better than what a tapeworm gets up to in the bowel, as illustrated on p.234.

Personally, I think we need all the data parasites we can get, as well as symbionts and all sorts of other creatures which this ill-chosen metaphor can’t encompass. What this piece really shows, in my opinion, is how far the authors are from understanding and supporting the true opportunities of clinical data sharing.

208 A beautiful piece describes the gifts of a helpless person, and her dying. Take five minutes to read it (open access) and five to lie down and think about it.

Colon cancer genes – a good fit?
211 It may be something to do with my age, but I find that the genomics of cancer risk interest me less and less, while the genomics of cancer lines interest me more and more. Knowledge of personal risk for the most part just brings helplessness and anxiety. Knowledge of cancer gene expression, on the other hand, can predict progression and response to treatment. But it is still an immature science, dependent in part on serendipity and in part on data trawling. At least that’s the way it looks to me as I’ve tried to follow developments over 18 years. In this paper we’re told that “Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy.” This took a colossal effort of detective work and I’m not sure I am entirely convinced. “In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006).” Why that irrelevant P value instead of some confidence intervals? How can you base clinical decisions on such a tiny sample? The editorial is pretty clear on this: you can’t.

New opioid for IBS?
242 What can you do if you have irritable bowel syndrome with diarrhoea? I can tell you: live with it, mostly, and take loperamide sometimes if you’re going out or having a bad day. Loperamide is a very safe essential medicine which acts as a local µ-opioid receptor agonist, and it costs almost nothing. Eluxadoline is a new oral agent with mixed opioid effects (μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist), made by Furiex Pharmaceuticals and tested against placebo in 2427 adults who had IBS with diarrhoea. They took it twice a day, and it seems to do much the same thing as loperamide: reduce stool frequency at the risk of constipation and occasionally nausea. Ah, and it also seems to cause occasional pancreatitis. So shared decision making about this drug should include the offer of loperamide and a warning about pancreatitis.

JAMA 19 Jan 2016 Vol 315
A disappointing issue about end-of-life care. The pieces for and against helping dying people to end their lives when and where they choose are of a really low standard, with little attempt to clarify the issues. Waffle and rhetoric abound, on both sides. Some editing would have been welcome.

Place of cancer death in 7 countries
In one sense the USA comes top in this international comparison: it has the lowest percentage of cancer patients dying in acute hospitals. England, birthplace of the hospice movement, has the highest. But our costs lie at the bottom. And our ICU usage for dying cancer patients is a small fraction of America’s. I suspect there are no real winners here. You can access this article free, and it’s worth a look. When I first got interested in “terminal care,” as it was known 40 years ago, I hoped we would be further on than this by 2016. And this is just for cancer, which is privileged. Most people die from other things.

JAMA Intern Med Jan 2016
PPIs and CKD
OL This study examining a possible association between the use of proton pump inhibitors and the development of chronic kidney disease used two cohorts. I like that; but even so I’m not quite convinced. The first was from 10 482 participants in the Atherosclerosis Risk in Communities study followed up for over ten years. This depended on self-reported PPI consumption, and showed a 20-50% added risk of incident CKD after adjusting for various variables. A confirmation cohort (with lower estimates) was provided by 248 751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m2 from the Geisinger Health System. Given the looseness of the term CKD, the added risk may not be clinically significant, and I think this hypothesis needs testing with yet another, really large cohort. I’d like to see particular attention to concomitant drug treatment such as non-steroidal anti-inflammatories, both prescribed and over-the-counter.

Fat inactive youngsters get high BP
OL I hope I don’t have such a thing in me as an inner Sally Davies, but I still don’t like to see fat young people spending most of their time doing nothing. We all have to die of something, but you can see these youngsters wooing a premature death from cardiovascular disease, as all the epidemiology predicts. Here is a study showing that some of this is mediated by high blood pressure, which is three times more likely to develop in adolescents who have a high BMI and low levels of cardiorespiratory fitness.

Lancet 23 Jan 2016 Vol 387
Increasing overdiagnosis with ultrasound
341 Screening for breast cancer is a bad topic to get me started on when I am a bit jet-lagged. Or indeed when I am not. Just abolish it: it does more harm than good. The epidemiology of breast cancer in Japan is different from that in Europe or the USA. The peak risk period is between 40-49, and the breasts of Japanese women are denser, making X-ray mammography less sensitive. In the J-START trial they strove to improve the sensitivity of population breast screening in Japanese women aged 40-49 by adding ultrasonography, and they succeeded. But when you improve the sensitivity of a bad test, you create even more overdiagnosis. This is a terrible idea, but that doesn’t stop the editorialists hailing it as an advance. Let me get some more coffee, or go to bed.

Stents: eluting or deluding?
357 I am not one to rush to judgement, honestly. It has taken me 15 years of puzzled attention to the literature to come to the conclusion that drug-eluting stents may just be a massive con. Even now I am not sure, but the special pleading in an article like this tends to confirm my suspicions. It reports the results of a 5-year Spanish trial of everolimus-eluting stents versus bare metal stents for ST-elevation myocardial infarction. The conclusion of the abstract simply states: “Our findings should be taken as a point of reference for the assessment of new bioresorbable polymer-based metallic stents or bioresorbable scaffolds in patients with ST-segment elevation myocardial infarction.” This is crazy: the study has absolutely no relevance to the study of bioresorbable stents, which are a different thing altogether. More helpful is the following summary: “The superiority of the EES over BMS was slight overall (5% absolute reduction in the rate of the patient-oriented endpoint) and it was mainly attributable to reduced rate of all-cause death and revascularisation. The reduction in all-cause and non-cardiac mortality rates cannot be directly explained. According to the results of landmark analyses, there was no interaction between treatment effect and time.” Taken separately, the elements of the “patient-oriented endpoint” failed to reach any statistical (or clinical) significance, but the difference in all-cause mortality at 5 years was right at the borderline in favour of the EES: 9% v 12%, CI 0.52-1.00. If I were deciding the national budget of a state-run health system in a low-medium income country, I wouldn’t even look at buying drug-eluting stents, let alone bioresorbables.

BMJ 23 Jan 2016 Vol 352
AF is worse for women
Women, honestly. Not only are they bringing the NHS to its knees with their work-shy attitudes, but they also insist on having more complications when they develop atrial fibrillation, thus putting a further strain on resources. This—I mean the AF bit—is the conclusion of a systematic review and meta-analysis of the cohort studies. The data parasites who looked at 30 studies with 4 371 714 participants find that women who have AF are nearly twice as likely to have a stroke or die from cardiovascular causes than men with AF. This is important news for shared decision making. We need the data parasites to go back and look at sex differences in responses to anticoagulation too.

Sercular evidence
I remember when betahistine first appeared in the early 1980s under the trade name Serc. Taken every day, it was supposed to reduce the attack rate in people with Meniere’s disease. I use The BMJ spelling and refuse to be drawn on where any accents should fall. I also refuse to be drawn on how many patients with this label in primary care actually have the syndrome described by Prosper Menière (as he called himself) in 1861. And I blush to confess that in general practice there was widespread indication creep, so that betahistine became widely prescribed for all sorts of people with balance problems and/or tinnitus. Those whose symptoms got better could stay on it, just in case, while those whose symptoms did not get better often stayed on it, just in case. A German study confirms that 30% of patients with Meniere’s have fewer attacks while taking betahistine. This applies equally to 30% of patients taking placebo. So we were right all along. Betahistine is as good as placebo.

Parasite of the Week: Johannes Kepler

From the moment that the NEJM editorial on Data Sharing appeared, there was a Twitter storm about great scientists who had been “data parasites”. Among those mentioned was Johannes Kepler, the first and perhaps the greatest of them all.

Astronomical observations predate writing, and were one of the reasons for its invention. The Sumerians, who invented writing, drew up accurate predictive records of planetary movements (and also cube root tables) in the third millennium BCE. All this was done with the naked eye in perfect climatic conditions. Tycho Brahe was a Danish nobleman who attempted to go one better in the far from perfect climatic conditions of a Danish island in the 1580s and 90s, about 4,000 years later. He still had to work with the naked eye (Galileo’s telescopes came a decade or two later) but with carefully designed instruments and a much better system of mathematical notation to record planetary movements.

Brahe was an eccentric figure (to use an astronomical expression) whose only duty to the king of Denmark was to maintain a royal chapel in Roskilde cathedral in good condition. When he failed to do this after several reminders, the king expelled him from Denmark and he ended up fleeing to Bohemia with his retinue, his library, his instruments and his catalogue of planetary observations. He set up a new observatory near Prague, and in 1600 took on a brilliant young assistant, Johannes Kepler.

Kepler had already published a mathematical (and theological) description of the new Copernican astronomy in Mysterium Cosmographicum (The Cosmographic Mystery). But the mathematical modelling was not a perfect fit so he took a minute interest in Brahe’s data. He used the best software and hardware available – pieces of paper and his brain. When Brahe unexpectedly died in 1601, Kepler became a data parasite/necrophyte par excellence. After sucking up the dead man’s observations for several years, he deduced that the orbits of the planets were elliptical. Eventually in 1618 he came up with his third law, which is so remarkable that I put it down to his deep reading in musical theory, especially that of Michael Praetorius, a fellow mathematician-mystic:
“The square of the periodic times are to each other as the cubes of the mean distances.”

From this, Isaac Newton developed his theory of gravitation. When he said that he only saw further because he stood on the shoulders of giants, it is widely believed that he was referring to Kepler. But on that Twitter stream someone suggested that Newton should have said “because I stood on the shoulders of parasites”.