Medical Check-up RCTs: 250,000 and Counting

The number of people in trials of routine check-ups is now over a quarter of a million according to the most recent systematic review of randomised trials from Cochrane.[1] Still, the result remains null. If early diagnosis is so important, then the question is why? The argument often given is that these trials in high-income countries take place against a backdrop of well-developed primary care services. Any marginal gains are therefore very small and could be outweighed by marginal losses due to over investigation.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Krogsbøll LT, Jørgensen K, Gøtzsche PC. General health checks for reducing morbidity and mortality from disease. Cochrane Data Syst Rev. 2019; CD009009.

Improvement Science: Tackling Integration and the Causes of Integration!

A recent paper in JAMA discusses the issue of collaboration across institutions.[1] I single this paper out because our forthcoming ARC West Midlands will place an emphasis on such cross-institution collaboration. For example, our ‘Mental Health’ theme, led by Professor Swaran Singh, seeks to improve mental health services for young people across the educational and healthcare divide; while our ‘Acute Transitions in Care’ theme, led by Professor Daniel Lasserson, focuses on people with acute illness who might be cared for at home rather than in the hospital. Our ‘Chronic Conditions’ theme, led by Professor Christian Mallen and Dr Gill Combes, focuses on improving integration across sectors through multi-disciplinary teams. All of these themes will include social care and its interface with health, working with the Department of Social Work and Social Care, led by Professor Robin Miller.

The above JAMA article gives a nice example of the need for collaboration in the management of childhood asthma. Primary care is positioned to ensure that the appropriate medicines are prescribed, provide health education to schools, and detect early signs of deterioration, while social services can visit homes to identify mould. There is evidence that service delivery interventions that bring these services together can reduce hospitalisation by 50%.[2] But how to achieve inter-sectoral working – that is the question!

Our ARC will draw on evidence regarding how to achieve inter-sectoral working:

First, we are inspired by the brilliant work on factors that facilitate or impede cross-institutional collaboration by the Nobel Prize winner Elinor Ostrom. Her work, carried out in the context of fisheries, farms and industry,[3] is described in a previous News Blog.[4]

Second, our ‘Organisational Sciences’ cross-cutting theme has done ground-breaking work on how Ostrom’s principles play out among the various health care ‘tribes’ and what can be done to forestall problems when designing integrated services. Again, examples were given in a recent News Blog.[5]

Third, our CLAHRC West Midlands has carried out an overview of systematic reviews on the topic.[6]

We have established a mechanism to integrate our work programme with that of Sustainability and Transferability Partnerships (STPs) and with our Academic Health Sciences Network (AHSN), and to form collaborations with other organisations pursuing this topic, including other ARCs. We wish to integrate the study of integration! Our ARC seeks a leadership role in the critical over-arching theme of ‘collaboration and investigation of care between organisations whose individual short-term interests are not necessarily served by such integration.’

— Richard Lilford, CLAHRC WM Director

References:

1. Stout SS, Simpson LA, Singh P. Trust Between Health Care and Community Organizations. JAMA. 2019.
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(11): e011952.
3. Ostrom E. Beyond Markets and States: Polycentric Governance of Complex Economic Systems. Am Econ Rev. 2010; 100(3): 641-72.
4. Lilford RJ. Sustainability and Transformation Partnerships: Why They Are So Very Interesting. NIHR CLAHRC West Midlands News Blog. 27 July 2018.
5. Lilford RJ. How Theories Inform Out Work in Service Delivery Practice and Research. NIHR CLAHRC West Midlands News Blog. 21 September 2018.
6. Watson SI & Lilford RJ. Essay 1: Integrating Multiple Sources of Evidence: a Bayesian Perspective. In: Challenges, solutions and future directions in the evaluation of service innovations in health care and public health. Southampton (UK): NIHR Journals Library, 2016.

Does Having an Older Sibling Hinder Your Development?

Previous research has shown that birth order can affect a child in a number of ways, including verbal skills where there is a negative association between the number of older siblings a child has and their language skills. It has been hypothesised that this is due to parents having less time for one-to-one interactions with the younger child. A recent study looked at the language skills of a cohort of French children (n=1,154) at ages 2, 3, and 5-6 years.[1] Analysis showed that children with an older sibling scored significantly worse than children with no older siblings, but when separated by sex, children with an older sister had better language skills than children with an older brother, and were comparable to children with no older sibling. There was no significant impact associated with the age difference between children.

The authors conclude that the negative older sibling effect should be more accurately thought of as an older brother effect. A number of hypotheses are put forward for this difference, including that girls are more talkative or more willing to play with their younger siblings, and so can better contribute to language development, making up any lost parental interactions; or that girls require less parental attention, so parents can focus more on the younger child.

— Peter Chilton, Research Fellow

Reference:

1. Havron N, Ramus F, Heude B, et al. The Effect of Older Siblings on Language Development as a Function of Age Difference and Sex. Psychol Sci. 2019.

Mandatory Measles Vaccination

Different American states have taken a very different approaches to measles outbreaks in the USA. While most have tried to reassure the public, produce scientific evidence, and elicit the support of trusted influential people, some have been more heavy-handed.

Rockland County (New York) banned unvaccinated students from schools, sequentially lifting the threshold vaccination rates as more people accepted vaccination for the children. New York City went further and actually fined the parents if their child was not vaccinated.

I agree with Dr Julie Cantor’s opinion that this is going too far.[1] The state should preserve individual liberty over invasion of citizens’ bodies. State coercion might exacerbate the mistrust that led to suspicion of vaccinations in the first place. The thought of physically removing children from their parents in order to vaccinate them is abhorrent. In my opinion the argument to overrule parents’ liberty in the interest of the child or of the population is excessively utilitarian, unless there is a clear and immediate danger.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Cantor JD. Mandatory Measles Vaccination in New York City — Reflections on a Bold Experiment. N Engl J Med. 2019; 381: 101-3.

Another Null Result With Respect to Water and Sanitation Interventions

In my recent blog posts [1] [2] on water quality, sanitation and hygiene (WASH) interventions I missed this important cluster randomised trial of community health clubs in Rwanda.[3] The study evaluates a facilitator-based intervention in communities in Rwanda, using a trial with 50 control, 50 low-intensity and 50-high intensity intervention sites. The intervention encouraged safe behaviours and the construction of sanitary facilities. However, there was no effect on diarrhoea or stunting. There was not even an effect on the intermediate outcome of faecal contamination of drinking water. The authors do not provide a convincing explanation for their disappointing findings, which contrast with the more positive findings from women’s groups to deal with maternity care and outcomes.[4] Participants did attend the community health club sessions, however, even a per-protocol analysis did not show a difference in growth or diarrhoea rates.

I posit that interventions targeted on people of lower status in local hierarchies will only be effective if also targeted across the hierarchy more generally, in most cases.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. WASH 1: Explaining the Results of Clinical Trials: A Superb Study of Mediating Variables. NIHR CLAHRC West Midlands News Blog. 16 August 2019.
2. Lilford RJ. WASH 2: Thoughtful Analysis of the Three Great Recent WASH Trials. NIHR CLAHRC West Midlands News Blog. 16 August 2019.
3. Sinharoy SS, Schmidt W-P, Wendt R, Mfura L, Crossett E, Grépin KA, et al. Effect of community health clubs on child diarrhoea in western Rwanda: cluster-randomised controlled trial. Lancet Glob Health. 2017; 5(7): e699-709.
4. Prost A, Colbourn T, Seward N, et al. Women’s groups practising participatory learning and action to improve maternal and newborn health in resource-limited settings: systematic review and meta-analysis. Lancet. 2013; 381(9879): 1736-46.

Chlamydia Vaccine

Chlamydia, is the most common bacterial sexually transmitted infection (STI), with around 218,000 new cases in the UK in 2018, accounting for 49% of all new STI diagnoses.[1] Worldwide it is estimated that there are 131 million new cases each year. Although it can be treated with antibiotics, around 75% of people with chlamydia do not show any signs of infection, and left untreated it can lead to infertility. Therefore there is a need for a preventive measure. The first ever clinical trial looking at a vaccine for genital chlamydia was recently published in Lancet Infectious Diseases.[2]

The authors conducted a phase 1 RCT in 35 women, randomly assigning them to receive one of two versions of a new chlamydia vaccine (CTH522:CAF01 or CTH522:AH) (N=15 in each arm) or a saline placebo (N=5). Thirty-two women completed the study, being given an injection at the start of the study and then again 1 and 4 months later. This was followed by intranasal administrations at 4.5 and 5 months. No serious adverse events were reported, and there was no significant differences in the incidence of reactions at the injection-site (P=0.0526), or in reactions to intranasal administration (P=1.000) when comparing either vaccine to placebo. Analyses showed that both versions of the vaccine induced an immune response in all participants, compared to none in the placebo group. When comparing the two vaccines, one (CTH522:CAF01) showed more promising results including antibodies detected earlier, higher levels of IgG antibodies, an enhanced mucosal antibody profile, and a more consistent cell-mediated immune response profile. With both vaccines appearing to be safe and tolerable, further clinical trials will hopefully be forthcoming.

— Peter Chilton, Research Fellow

References:

1. Public Health England. Sexually transmitted infections and screening for chlamydia in England, 2018. Health Protection Report. 2019; 13(19).
2. Abraham S, Juel HB, Bang P, et al. Safety and immunogenicity of the chlamydia vaccine candidate CTH522 adjuvanted with CAF01 liposomes or aluminium hydroxide: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Infect Dis. 2019.

Ban the Term Animal ‘Model’

I have always been somewhat bemused by the term ‘animal model’ in research. As an animal lover and admirer, I have always bridled at the harsh denigration of animals to mere ‘models’ for our species.

Recently I read about the Arizona Cancer Evolution center, which compares and contrasts findings across the animal kingdom as a whole to learn generalisable lessons.[1] One interesting example concerns Peto’s paradox. This paradox turns on the observation that larger animals do not have higher cancer rates than humans, despite having many more cells. The resolution to the paradox comes from the finding that very large animals have a higher proportion of DNA repair and apoptosis genes. These genes help reduce somatic mutations or their effects, and compensate for the greater a priori risk.

Using animals as mere ‘models’ for humans is not only speciesist, but non-scientific. I hope we can get rid of this patronising and scientifically limiting term once and for all.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Tollis M, Boddy AM, Maley CC. Peto’s Paradox: how has evolution solved the problem of cancer prevention? BMC Biol. 2017; 15: 60.

WASH 2: Thoughtful Analysis of the Three Great Recent WASH Trials

We have reported previously on two of the above three trials, conducted in Kenya and Bangladesh.[1] A third similar trial has now been reported from Zimbabwe.[2] All three trials show that nutritional interventions reduce stunting. However, other trials have shown that nutritional interventions, while reducing stunting, do not improve cognitive outcomes.[3]

The water quality, sanitation and handwashing (WASH) interventions have no consistent beneficial effect on childhood diarrhoea, as mentioned in the previous article. Similarly, behavioural interventions are only helpful when they are very intense and even then the effects are not sustained. The WASH interventions do not reduce stunting. This is in contrast to observational studies that consistently show a correlation between WASH interventions and reduced stunting. When the investigators analysed the control group they reproduced the findings from the observational studies; WASH conditions were strong independent risk factors for poor linear growth in children. Inconsistency between the experimental and observational studies supports the conclusion that the observational studies are likely confounded by unmeasured factors in households that correlate with WASH conditions.

A number of studies have examined environmental faecal contamination and intestinal colonisation. These show that the WASH interventions did not significantly or sufficiently decontaminate the environment (see previous report). This means that more thorough interventions are required; presumably proper indoor lavatories and clean water piped into households. We simply have not yet found the tipping point when it comes to the intensity and coverage required to provide sanitary living conditions for poor people in poor countries. This is bad news. Many of the large gains in infant mortality have been achieved through relatively inexpensive interventions, such as a vaccination and impregnated mosquito nets. We seem to have run up against a more intractable problems when it comes to the eradication of childhood diarrhoea.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. Important New Data on WASH and Nutritional Interventions from Kenya and Bangladesh. NIHR CLAHRC West Midlands News Blog. 18 May 2018.
2. Pickering AJ, Null C, Winch PJ, et al. The WASH Benefits and SHINE trials: interpretation of WASH intervention effects on linear growth and diarrhoea. Lancet Glob Health. 2019; 7(8):e1139-46.
3. Lilford RJ. Nutritional Interventions for Childhood Stunting in Slums. NIHR CLAHRC West Midlands News Blog. 21 June 2019.

Mortality Associated with Proton Pump Inhibitors

Proton pump inhibitors (PPI) are very widely used in society. Moreover, their use is often prolonged, lasting years if not decades. These agents have an important effect upon a fundamental biological mechanism: the transport of positively-charged ions across cell membranes. It is therefore a matter of great importance to investigate the potential risks of widespread and prolonged use of an agent with such a profound effect on the body’s metabolism.

It is already known, or at least frequent investigations have found, that, in addition to an increased risk of diarrhoea, there is an association between PPI use and all-cause mortality. A recent paper in the BMJ has investigated this matter further.[1] The study was based on a cohort of US Veterans. The investigators compared all-cause and specific-cause mortality in patients taking PPIs with those who were not, and also examined the strength of any association by duration of use. They also examined for possible reverse causality by looking at outcomes only after a considerable duration from the start of therapy. They examined for selection bias by comparing outcomes among people taking PPIs with those taking other medicines for upper abdominal symptoms.

The study replicated the findings of previous studies, confirming an association between PPI use and all-cause mortality. In fact there was an extra 45 deaths per thousand people taking PPIs (95% confidence interval 28.20–61.40). Kidney disease and cancer of the upper gastrointestinal tract were significantly increased. Risks increased in proportion to duration of use.

Of course, such an observational study cannot prove causality beyond all reasonable doubt. However, the finding that the results were not consistent with reverse causality and that they were unlikely to be due to selection bias, makes a causal explanation highly plausible. The increasing association of deaths with duration of use is of particular practical importance. Since the burden of evidence favours a causal explanation between increasing duration of use and risk of premature death, people taking these medicines should be weaned off them as soon as possible.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019; 365: l1580.

WASH 1: Explaining the Results of Clinical Trials: A Superb Study of Mediating Variables

The disappointing results of water quality, sanitation and handwashing (WASH) interventions in low-income countries have been reported previously in this News Blog.[1][2] We suggested that the intensity of the interventions and their coverage, had not been sufficient, to decontaminate the environment in these trials. We posited a type of herd effect, whereby a tipping point would be reached if the interventions were sufficiently intensive and their coverage sufficiently wide.[3]

I can now report on a lovely study that was nested into one of the randomised trials. In this study water, hands, food, soil and flies were examined in both the intervention and control clusters in the trial.[4] What the study does is explain why the trials showed null results. While the water delivered did improve in terms of faecal contamination, the hands, food, soil and flies remained equally contaminated across both the control and intervention groups. It is becoming increasingly clear that interventions to reduce childhood diarrhoea are simply going to have to be more intensive and hence, unfortunately, more expensive than those deployed hitherto. We also need a better index of contamination. Diarrhoea is a very nonspecific measure of risk. Dysentery is too rare to use as an outcome in clinical trials, though it is much more specific. Measuring contamination along the causal chain, as in this brilliant study, is time intensive and expensive. In collaboration with our partners at the icddr,b in Bangladesh, we are working on a possible alternative measure, based on the profile of gastrointestinal tract bacteria in the early childhood population.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. Important New Data on WASH and Nutritional Interventions from Kenya and Bangladesh. NIHR CLAHRC West Midlands News Blog. 18 May 2018.
2. Lilford RJ. Childhood Diarrhoeal Diseases – Update of the Famous Wolf Review. NIHR CLAHRC West Midlands News Blog. 19 October 2018.
3. Lilford RJ, Oyebode O, Satterthwaite D, Melendez-Torres GJ, Chen Y-F, Mberu B, et al. Improving the Health and Welfare of People Who Live in Slums. Lancet. 2017; 389: 559-70.
4. Ercumen A, Pickering AJ, Kwong LH, et al. Do Sanitation Improvements Reduce Fecal Contamination of Water, Hands, Food, Soil, and Flies? Evidence from a Cluster-Randomized Controlled Trial in Rural Bangladesh. Environ Sci Technol. 2018; 52(21): 12089-97.