Tag Archives: Director’s Choice – From the Journals

Effects of Vitamin D Supplements

Bolland and colleagues have written a lovely summary of the evidence on the effects of vitamin D supplements, with or without calcium, on health.[1] Their careful and comprehensive systematic overview based on a large sample, and providing narrow confidence limits, finds that there is no evidence that vitamin D, with or without calcium, reduces the risk of fractures in elderly people with no known bone disease. It is, as expected, efficacious in people with established osteomalacia. Systematic reviews of lower quality or based on per protocol analyses, tend to find the more optimistic results, but the data, taken in the round, yield a null result. The reviewers find that additional research is unlikely to further clarify the issue, as an effect of more than a 10% reduction in fracture has been ‘excluded’ by the existing studies. From a Bayesian perspective, further data are unlikely to have much effect on credible limits. The studies do not find any evidence that calcium plus vitamin D have either harmful or beneficial effects on the other (non-skeletal) outcomes, such as cancer or heart disease. Perhaps this is an example of the horizon of science; science cannot prove a null result, merely exclude a positive or negative effect beyond certain limits. We will never know everything, but let’s just forget about the use of vitamin D and calcium as prophylaxis in healthy people as any benefit must be nugatory – less than 10% relative risk reduction, which equates to a very small absolute reduction.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Bolland MJ, Leung W, Tai V, et al. Calcium intake and risk of fracture: systematic review. BMJ. 2015; 350: h4580.

 

On Foetal Growth Charts – the WHO May Have Adopted the Correct Policy for the Wrong Reason

The journal ‘Science’ reports a controversy over two studies of foetal growth across countries [1] – the first study showed very similar growth rates across eight countries (Brazil, Italy, Oman, UK, USA, China, India, Kenya).[2] They conclude that a common threshold should be used in countries to identify slow-growing foetuses. The second study looks only at the socio-economically advantaged populations across ten countries, ranging from Norway and Denmark to India and Egypt.[3] It finds markedly different rates across countries among socio-economically advantaged segments of the population. So that would suggest the use of country-specific thresholds.
I am not so sure – I question the assumption that the search for the growth-retarded foetus should be based on a fixed proportion of the foetal population – say the slowest growing 5%. The risk of stillbirth is higher in the countries with slower foetal growth (e.g. India and Egypt), than in those with higher growth rates (e.g. Norway and Denmark). So the cut-off threshold for foetal growth as a screening test should, logically, be set at a higher point in high-risk countries than in lower-risk countries. If it is set to identify the ‘bottom’ 5% in low-risk countries it should be set at, say, 10% in high-risk countries. This suggests that the WHO (which recommends a universal chart on the basis of the first study above) has the correct solution for the wrong reason. The universal chart will identify a higher proportion of still-births in the high-risk countries – just what one would want.

— Richard Lilford, CLAHRC WM Director

References:

  1. de Vrieze J. Big studies clash over fetal growth rates. Science. 2017; 355(6323): 336.
  2. Papageorghiou AT, Ohuma EO, Altman DG, et al. International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21stProject. Lancet. 2014; 384: 869-79.
  3. Kiserud T, Piaggio G, Carroli G, et al. The World Health Organization Fetal Growth Charts: A Multinational Longitudinal Study of Ultrasound Biometric Measurements and Estimated Fetal Weight. PLoS Medicine. 2017.

Fine Dining and Fine Hygiene are Negatively Correlated

A recent study shows that restaurants rated highly in food guides are associated with a greater overall risk of foodborne gastrointestinal diseases outbreaks than your run-of-the-mill restaurant.[1] However, the ‘high-end’ restaurants also score more highly on the Food Agency Inspection visits. So why do the posh restaurants generate more GI diseases than their more mundane peers despite better hygiene in the restaurants with the best food? The high disease risk in highly rated restaurants probably comes from the nature of the food served (e.g. oysters) and cooking methods (e.g. low temperatures to produce chicken liver parfait). So the risk is real, but worth running!

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Kanagarajah S, Mook P, Crook P, Awofisayo-Okuyelu A, McCarthy N. Taste and Safety: Is the Exceptional Cuisine Offered by High End Restaurants Paralleled by High Standards of Food Safety? PLoS Curr Outbreaks. 2016.

Exercise and Energy Expenditure: Not What You Think?

Each week I burn up to 1,500 kcals in my two hours of intense ‘spinning’. So you might have thought (like me) that I could indulge in 1,500 kcals worth of extra puddings. Well you (like me) would have thought wrong, at least according to careful animal and human studies described by Pontzer in this month’s Scientific American.[1] Apparently, short of being an absolute coach potato or an extreme sportsman like Mark Spitz, the rest of us burn the same number of Calories per day, adjusted for mass, irrespective of how much we exercise. Apparently the body compensates for activity by consuming less Calories at rest. Says Pontzer, “exercise to stay healthy, but restrict Calories to control weight

Richard Lilford, CLAHRC WM Director

Reference:

  1. Pontzer H. The Exercise Paradox. Scientific American. February 2017.

 

An Epidemic of Meta-Analyses – a Veritable Plague?

So says the great John Ioannidis, the world’s leading clinical epidemiologist.[1] He has a point – CLAHRC WM associates Sarah Damery, Sarah Flanagan and Gill Coombes recently published an overview of systematic reviews of ‘Integrated Care’.[2] They over-viewed – wait for it – over 70 individual systematic reviews. But even that number is dwarfed by the 185 systematic reviews of anti-depressants. This might not be a problem (save for waste) if the quality was universally high. Sadly quality is often poor – many (most) reviews are junk. Some are used as a marketing tool and appear to have been manipulated in the service of shareholders rather than patients. Chinese meta-analyses of associations between candidate genes and outcomes are particularly unreliable; they are castles built on sand because the original association studies are so poor. Associations detailed in ‘first generation’ studies were found to be valid in a staggeringly low proportion of less than 2% when compared to multi-centre studies with built-in procedures to preclude selective reporting of data.

The systematic review ‘industry’ seems to be in some disarray. Clearly primary studies need to be improved, although big steps are being made in this regard. Systematic reviews should be done by people without commercial ties to companies whose product is being evaluated. Other ideas are welcome.

— Richard Lilford, CLAHRC WM Director

References:

  1. Ioannidis JPA. The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses. Milbank Quart. 2016; 94(3): 485-514.
  2. Damery S, Flanagan S, Combes G. Does integrated care reduce hospital activity for patients with chronic diseases? An umbrella review of systematic reviews. BMJ Open. 2016; 6: e011952.

Thyroid Cancer: Another Indolent Tumour Prone to Massive Over Diagnosis

Park and colleagues, writing in the BMJ, document a massive (80 times) rise in the incidence of thyroid cancer in South Korea over the past two decades.[1] What is going on here? An epidemic of thyroid cancer in South Korea? No, the mortality from cancer of the thyroid has remained absolutely flat over the study period. The rise in the incidence of cancer is due entirely to screening uncovering cancers that would have otherwise remained occult. It turns out that the great majority of thyroid cancers are entirely innocent. As with prostate cancer and intraductal breast cancer, thyroid cancer tends to have a very long lead time, such that the patient is most likely to die with, rather than from, the disease.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Park S, Oh C-M, Cho H, et al. Association between screening and the thyroid cancer “epidemic” in South Korea: evidence from a nationwide study. BMJ. 2016; 355: i5745.

An Argument with Michael Marmot

About two decades ago I went head-to-head in an argument with the great Michael Marmot at the Medical Research Council. The topic of conversation was information that should be routinely collected in randomised trials. Marmot was arguing that social class and economic information should be collected. He made a valid point that these things are correlated with outcomes. I pointed out that although they may be correlated with outcomes, they were not necessarily correlated with treatment effects. Then came Marmot’s killer argument. Marmot asked whether I thought that sex and ethnic group should be collected. When I admitted that they should be, he rounded on me, saying that this proves his point. We met only recently and he remembered the argument and stood by his point. However, it turns out that it is not really important to collect information on the sex after all. Wallach and colleagues, writing in the BMJ,[1] cite evidence from meta-analyses of RCTs to show that sex makes no difference to treatment effects when averaged across all studies. So there we have it, a parsimonious data set is optimal for trial purposes, since it increases the likelihood of collecting essential information to measure the parameter of interest.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Wallach JD, Sullivan PG, Trepanowski JF, Steyerberg EW, Ioannidis JPA. Sex based subgroup differences in randomized controlled trials: empirical evidence from Cochrane meta-analyses. BMJ. 2016; 355: i5826.

 

Living on Less Than One Dollar per Day

Sam Watson recently drew my attention to this fascinating article by my heroes – Adhijit Banerjee and Esther Duflo.[1] How do people in the “bottom billion” spend an income of around $1 per day? The authors turn to household surveys covering 13 countries in Asia, Africa and Central America (one assembled by the World Bank, and the others by the RAND Corporation). Even though it is hard to get a full stomach on $1 per day and many are hungry, not all money is spent on food – the proportion varies from a half to three-quarters of income spent on food. Nor are the cheapest foods always selected – taste crowds out Calories, even if that leaves you hungry. The second largest source of expenditure is festivals, such as weddings and funerals. Radios are a priority and show elastic demand on income. There is an inverse relationship across countries between spending on radios and on festivals. Asset ownership is very low – even in rural areas bicycle ownership is low – at a third of households or less. Education attracts a very low proportion of expenditure; 2-3% of the household budget in Pakistan, for example. People often feel hungry, many are anaemic, and energy levels are low. Illness rates are high and anxiety common when compared to high income countries. I guess many are in a poverty trap and need a little help to get them out of it, but the results resonate with the Gospel of Matthew, ‘Man shall not live by bread alone’.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Banerjee AV & Duflo E. The Economic Lives of the Poor. J Econ Perspect. 2007; 21(1): 141-67.

Physiotherapy – No Use in Ankle Sprain Injury

As touched upon in the main Director’s Blog, Robert Brison and colleagues recently conducted a randomised controlled trial of physiotherapy for ankle sprain injury.[1] The result is entirely null. The paper concentrates only on the ankle, not mentioning potential implications beyond this single joint. This broader picture is also ignored in the accompanying editorial.[2] So solipsistic is the attention on the ankle that the broader question about the role of physiotherapy in sprains is not discussed. The interesting question now is to evaluate the role of physiotherapy across a wide range of joint injuries – this is an excellent opportunity for a multiple indication review.[3] I am looking for collaborators who might want to take on such a task.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Brison RJ, Day AG, Pelland L, et al. Effect of early supervised physiotherapy on recovery from acute ankle sprain: randomised controlled trial. BMJ. 2016; 355: i5650.
  2. Bleakley C. Supervised physiotherapy for mild or moderate ankle sprain. BMJ. 2016; 355: i5984.
  3. Chen Y-F, Hemming K, Chilton PJ, Gupta KK, Altman DG, Lilford RJ. Scientific hypotheses can be tested by comparing the effects of one treatment over many diseases in a systematic review. J Clin Epidemiol. 2014; 67: 1309-19.

Worm Wars Continued

We have discussed results of deworming before and argued that it is important to treat at cluster level because of rapid re-infection from reservoirs in soil. A recent important meta-analysis compares deworming targeted at children versus a community-wide intervention.[1] It finds that community-wide approaches are more effective than treatment targeted at children for roundworms (Ascaris) and hookworms (Ancylostoma), but not whipworms (Trichuris). This finding is consistent with the much greater efficiency of the medicine in the former two worm types. The relative effect was greater in roundworms (odds ratio >16) than the more dangerous hookworms (OR >4), consistent with the shorter life-span of hookworm eggs than of roundworm eggs. These are important findings, but there is a worry that resistance may emerge with mass treatment. It would be interesting to see whether any studies have been done in slum populations specifically.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Clarke NE, Clements ACA, Doi SA, et al. Differential effect of mass deworming and targeted deworming for soil-transmitted helminth control in children: a systematic review and meta-analysis. Lancet. 2017; 389: 287-97.