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.

Publishing Health Economic Models

It has increasingly become de rigueur – if not necessary – to publish the primary data collected as part of clinical trials and other research endeavours. In 2015 for example, the British Medical Journal stipulated that a pre-condition of publication of all clinical trials was the guarantee to make anonymised patient-level data available on reasonable request.[1] Data repositories, from which data can be requested such as the Yoda Project, and from which data can be directly downloaded such as Data Dryad provide a critical service for researchers wanting to make their data available and transparent. The UK Data Service also provides access to an extensive range of quantitative and, more recently, qualitative data from studies focusing on matters relating to society, economics and populations. Publishing data enables others to replicate and verify (or otherwise) original findings and, potentially, to answer additional research questions and add to knowledge in a particularly cost-effective manner.

At present, there is no requirement for health economic models to be published. The ISPOR-SMDM Good Research Practices Statement advocates publishing of sufficient information to meet their goals of transparency and validation.[2] In terms of transparency, the Statement notes that this should include sufficiently detailed documentation “to enable those with the necessary expertise and resources to reproduce the model”. The need to publish the model itself is specifically refuted, using the following justification: “Building a model can require a significant investment in time and money; if those who make such investments had to give their models away without restriction, the incentives and resources to build and maintain complex models could disappear”. This justification may be relatively hard to defend for “single-use” models that are not intended to be reused. Although the benefits of doing so are limited, publishing such models would still be useful if a decision-maker facing a different cost structure wanted to evaluate the cost-effectiveness of a specific intervention in their own context. The publication of any economic model would also allow for external validation which would likely be stronger than internal validation (which could be considered marking one’s own homework).

The most significant benefits of publication are most likely to arise from the publication of “general” or “multi-application” models because those seeking to adapt, expand or develop the original model would not have to build it from scratch, saving time and money (recognising this process would be facilitated by the publication of the technical documentation from the original model). Yet it is for these models that not publishing gives developers a competitive advantage in any further funding bids in which a similar model is required. This confers partial monopoly status in a world where winning grant income is becoming ever more critical. However, I like to believe most researchers also want to maximise the health and wellbeing of society: am aim rarely achieved by monopolies. The argument for publication gets stronger when society has paid (via taxation) for the development of the original model. It is also possible that the development team benefit from publication through increased citations and even the now much sought after impact. For example, the QRISK2 calculator used to predict cardiovascular risk is available online and its companion paper [3] has earned Julia Hippisley-Cox and colleagues almost 700 citations.

Some examples of published economic models exist, such as a costing model for selection processes for speciality training in the UK. While publication of more – if not all – economic models is not an unrealistic aim, it is also necessary to respect intellectual property rights. We welcome your views on whether existing good practice for transparency in health economic modelling should be extended to include the model itself.

— Celia Taylor, Associate Professor

References:

  1. Loder E, & Groves T. The BMJ requires data sharing on request for all trials. BMJ. 2015; 350: h2373.
  2. Eddy DM, Hollingworth W, Caro JJ, et al. Model transparency and validation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force–7. Med Decis Making. 2012; 32(5): 733-43.
  3. Hippisley-Cox J, Coupland C, Vinogradova Y, et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ. 2008; 336(7659): 1475-82.

Doctor-Patient Communication in the NHS

Andrew McDonald (former Chief Executive of Independent Parliamentary Standards Authority) was recently asked by the Marie Curie charity to examine the quality of doctor-patient communication in the NHS, as discussed on BBC Radio 4’s Today programme on 13 March 2017 (you can listen online). His report concluded that communication was woefully inadequate and that patients were not getting the clear and thorough counselling that they needed in order to understand their condition and make informed choices about options in their care. Patients need to understand what is likely to happen to them, and not all patients with the same condition will want to make the same choice(s). Indeed my own work [1] is part of a large body of research, which shows that better information leads to better knowledge, which in turn affects the choices that patients make. Evidence that the medical and caring professions do not communicate in an informative and compassionate way is therefore a matter of great concern.

However, there is a paradox – feedback from patients, that communication should lie at the heart of their care, has not gone unheard. For instance, current medical training is replete with “communication skills” instruction. Why then do patients still feel dissatisfied; why have matters not improved radically? My diagnosis is that good communication is not mainly a technical matter. Contrary to what many people think, the essence of good communication does not lie in avoiding jargon or following a set of techniques – a point often emphasised by my University of Birmingham colleague John Skelton. These technical matters should not be ignored – but they are not the nub of the problem.

In my view good communication requires effort, and poor communication reflects an unwillingness to make that effort; it is mostly a question of attitude. Good communication is like good teaching. A good communicator has to take time to listen and to tailor their responses to the needs of the individual patient. These needs may be expressed verbally or non-verbally, but either way a good communicator needs to be alive to them, and to respond in the appropriate way. Sometimes this will involve rephrasing an explanation, but in other cases the good communicator will respond to emotional cues. For example a sensitive doctor will notice if, in the course of a technical explanation, a patient looks upset – the good doctor will not ignore this cue, but will acknowledge the emotion, invite the patient to discuss his or her feelings, and be ready to deal with the flood of emotion that may result. The good doctor has to do emotional work, for example showing sympathy, not just in what is said, but also in how it is said. I am afraid to say that sometimes the busyness of the doctor is simply used as an excuse to avoid interactive engagements at a deeper emotional level. Yes, bringing feelings to the surface can be uncomfortable, but enduring the discomfort is part of professional life. In fact, recent research carried out by Gill Combes in CLAHRC WM showed that doctors are reticent in bringing psychological issues into the open.[2] Deliberately ignoring emotional clues and keeping things at a superficial level is deeply unsatisfying to patients. Glossing over feelings also impedes communication regarding more technical issues, as it is very hard for a person to assimilate medical information when they are feeling emotional, or nursing bruised feelings. In the long run such a technical approach to communication impoverishes a doctors professional life.

Doctors sometimes say that they should stick to the technical and that the often lengthy business of counselling should be carried out by other health professions, such as nurses. I have argued before that this is a blatant and unforgivable abrogation of responsibility; it vitiates values that lie (and always will lie) at the heart of good medical practice.[3] The huge responsibilities that doctors carry to make the right diagnosis and prescribe the correct treatment entail a psychological intimacy, which is almost unique to medical practice and which cannot easily be delegated. The purchase that a doctor has on a patient’s psyche should not be squandered. It is a kind of power, and like all power it may be wasted, misused or used to excellent effect.

The concept I have tried to explicate is that good communication is a function of ethical practice, professional behaviour and the medical ethos. It lies at the heart of the craft of medicine. If this point is accepted, it has an important corollary – the onus for teaching communication skills lies with medical practitioners rather than with psychologists or educationalists. Doctors must be the role models for other doctors. I was fortunate in my medical school in Johannesburg to be taught by professors of Oslerian ability who inspired me in the art of practice and the synthesis of technical skill and human compassion. Some people have a particular gift for communication with patients, but the rest of us must learn and copy, be honest with ourselves when we have fallen short, and always try to do better. The most important thing a medical school must do is to nourish and reinforce the attitudes that brought the students into medicine in the first place.

— Richard Lilford, CLAHRC WM Director

References:

  1. Wragg JA, Robinson EJ, Lilford RJ. Information presentation and decisions to enter clinical trials: a hypothetical trial of hormone replacement therapy. Soc Sci Med. 2000; 51(3): 453-62.
  2. Combes G, Allen K, Sein K, Girling A, Lilford R. Taking hospital treatments home: a mixed methods case study looking at the barriers and success factors for home dialysis treatment and the influence of a target on uptake rates. Implement Sci. 2015; 10: 148.
  3. Lilford RJ. Two Ideas of What It Is to be a Doctor. NIHR CLAHRC West Midlands News Blog. August 14, 2015.

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.