Tag Archives: Richard Lilford

An Intriguing Suggestion to Link Trial Data to Routine Data

When extrapolating from trial data to a particular context, it is important to compare the trial population to the target population. Given sufficient data, it is possible to examine treatment effect across important subgroups of patients. Then the trial results can be related to a specific sub-group, say with less severe disease than the average in the trial. One problem is that trial data are collected with greater diligence than routine data. Hence a suggestion to link trial data to routine data collected on the same patients. That way one can compare subgroups of trial and non-trial patients recorded in a broadly similar (i.e. routine) way.[1] This strikes me as a half-way house to the day when (most) trial data are collected by routine systems, and trials are essentially nested within routine data-collection systems.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Najafzadeh M, Schneeweiss S. From Trial to Target Populations – Calibrating Real-World Data. N Engl J Med. 2017; 376: 1203-4.

Crying Infants – the Epidemiology of ‘Colic’

The period following childbirth is stressful for parents and uncontrollable crying is an important cause of this stress. Wolke and colleagues [1] have consolidated the results of studies across the world in a meta-analysis and show that:

  1. Crying peaks at around six weeks of age, and then declines sharply over the next three months.
  2. Bottle or mixed-fed babies cry less than those that are purely breastfed.
  3. Crying is much more common in some countries (Canada and UK) than others (Denmark and Japan), and this is a robust finding (i.e. replicated across many studies). I don’t suppose that this is the result of lower breastfeeding rates in Denmark and Japan than in Canada or the UK?

What the study does not show is how crying varies within families or by birth order. Nor does there seem to be an effective remedy for the problem. Pilgrim was right, it is not easy being a human, not at the beginning, not in the middle, and certainly not at the end.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Wolke D, Bilgin A, Samara M. Systematic Review and Meta-Analysis: Fussing and Crying Durations and Prevalence of Colic in Infants. J Pediatr. 2017.

 

More on Medical School Admission

I thank Celia Taylor for drawing my attention to an important paper on the relationship between personality test results, and cognitive and non-cognitive outcomes at medical school.[1] Everyone accepts that being a good doctor is about much more than cognitive excellence. That isn’t the question. The question is how to select for salient non-cognitive attributes? The paper is a hard read because one must first learn the acronyms for all the explanatory and outcome tests. So let the News Blog take the strain!

The study uses a database containing entry level personality scores, which were not used in selection, and outcomes following medical training. To cut a long story short “none of the non-cognitive tests evaluated in this study has been shown to have sufficient utility to be used in medical student selection.” And, of course, even if a better test is found in the future, it may perform differently when used as part of a selection process than when used for scientific purposes. I stick by the conclusions that Celia and I published in the BMJ many years ago [2]; until a test is devised that predicts non-cognitive medical skills, and assuming that cognitive ability is not negatively associated with non-cognitive attributes, we should select purely on academic ability. I await your vituperative comments! In the meantime can I suggest a research idea – correlate cognitive performance with the desirable compassionate skills we would like to see in our doctor. Maybe the correlation is positive, such that the more intelligent the person, the more likely they are to demonstrate compassion and patience in their dealings with patients.

— Richard Lilford, CLAHRC WM Director

References:

  1. MacKenzie RK, Dowell J, Ayansina D, Cleland JA. Do personality traits assessed on medical school admission predict exit performance? A UK-wide longitudinal cohort study. Adv Health Sci Educ Theory Pract. 2017; 22(2): 365-85.
  2. Brown CA, & Lilford RJ. Selecting medical students. BMJ. 2008; 336: 786.

Biological Underpinnings of Chronic Fatigue?

A recent synopsis in Nature describes a study showing that immune cells in patients with chronic fatigue behave differently in vitro to those in healthy controls.[1] This suggests that the disease is not psychosomatic, argues the synopsis. That is not just out of date thinking, it is long out of date – the inter-relationship between mind and body has been known for over a century. The article suggests that gut bacteria may differ in chronic fatigue syndrome. If this hypothesis is confirmed then maybe the condition originates somatically and affects the brain, not the other way around. We develop this idea further in the next exciting instalment of your news blog.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Maxmen A. Biological underpinnings of chronic fatigue emerge. Nature. 2017; 543: 602.

Infection Sensitisation

A previous News Blog [1] discussed the finding that a previous infection with one strain of Dengue fever can sensitise a person so that infection with a second strain will be more severe than would otherwise have been the case. There is new evidence that such Antibody Dependent Enhancement (ADE) may cross species barriers, such that a person sensitised with one type of flavivirus, say Dengue, is more likely to have a severe illness if inflected with another flavivirus, such as the Zika virus.[2] Such cross species ADE has obvious implications for vaccination programmes. In previous News Blogs [3] we have drawn attention to cross-resistance such that vaccines protect against non-target organisms (e.g. small pox vaccines provide protection against HIV). The above paper shows that the reverse can also occur. This is not the first time that vaccination has been shown to have adverse consequences.[4]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Three hits hypothesis. NIHR CLAHRC West Midlands News Blog. 7 April 2017.
  2. Cohen J. Dengue may bring out the worst in Zika. Science. 2017; 355(6332): 1362.
  3. Lilford RJ. Two papers try to answer the question – do vaccinations for one communicable disease offer protection against others? NIHR CLAHRC West Midlands News Blog. 27 January 2017.
  4. Guzman MG, Alvarez M, Halstead SB. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Arch Virol. 2013; 158(7): 1445-59.

Measuring Quality of Care

Measuring quality of care is not a straightforward business:

  1. Routinely collected outcome data tend to be misleading because of very poor ratios of signal to noise.[1]
  2. Clinical process (criterion based) measures require case note review and miss important errors of omission, such as diagnostic errors.
  3. Adverse events also require case note review and are prone to measurement error.[2]

Adverse event review is widely practiced, usually involving a two-stage process:

  1. A screening process (sometimes to look for warning features [triggers]).
  2. A definitive phase to drill down in more detail and refute or confirm (and classify) the event.

A recent HS&DR report [3] is important for two particular reasons:

  1. It shows that a one-stage process is as sensitive as the two-stage process. So triggers are not needed; just as many adverse events can be identified if notes are sampled at random.
  2. In contrast to (other) triggers, deaths really are associated with a high rate of adverse events (apart, of course, from the death itself). In fact not only are adverse events more common among patients who have died than among patients sampled at random (nearly 30% vs. 10%), but the preventability rates (probability that a detected adverse event was preventable) also appeared slightly higher (about 60% vs. 50%).

This paper has clear implications for policy and practice, because if we want a population ‘enriched’ for high adverse event rates (on the ‘canary in the mineshaft’ principle), then deaths provide that enrichment. The widely used trigger tool, however, serves no useful purpose – it does not identify a higher than average risk population, and it is more resource intensive. It should be consigned to history.

Lastly, England and Wales have mandated a process of death review, and the adverse event rate among such cases is clearly of interest. A word of caution is in order here. The reliability (inter-observer agreement) in this study was quite high (Kappa 0.5), but not high enough for comparisons across institutions to be valid. If cross-institutional comparisons are required, then:

  1. A set of reviewers must review case notes across hospitals.
  2. At least three reviewers should examine each case note.
  3. Adjustment must be made for reviewer effects, as well as prognostic factors.

The statistical basis for these requirements are laid out in detail elsewhere.[4] It is clear that reviewers should not review notes from their own hospitals, if any kind of comparison across institutions is required – the results will reflect the reviewers rather than the hospitals.

Richard Lilford, CLAHRC WM Director

References:

  1. Girling AJ, Hofer TP, Wu J, et al. Case-mix adjusted hospital mortality is a poor proxy for preventable mortality: a modelling studyBMJ Qual Saf. 2012; 21(12): 1052-6.
  2. Lilford R, Mohammed M, Braunholtz D, Hofer T. The measurement of active errors: methodological issues. Qual Saf Health Care. 2003; 12(s2): ii8-12.
  3. Mayor S, Baines E, Vincent C, et al. Measuring harm and informing quality improvement in the Welsh NHS: the longitudinal Welsh national adverse events study. Health Serv Deliv Res. 2017; 5(9).
  4. Manaseki-Holland S, Lilford RJ, Bishop JR, Girling AJ, Chen YF, Chilton PJ, Hofer TP; UK Case Note Review Group. Reviewing deaths in British and US hospitals: a study of two scales for assessing preventability. BMJ Qual Saf. 2016. [ePub].

An Interesting Report of Quality of Care Enhancement Strategies Across England, Germany, Sweden, the Netherlands, and the USA

An interesting paper from the Berlin University of Technology compares the quality enhancement systems across the above countries with respect to measuring, reporting and rewarding quality.[1] This paper is an excellent resource for policy and health service researchers. The US has the most developed system of quality-related payments (P4P) of the five countries. England wisely uses only process measures to reward performance, while the US and Germany include patient outcomes. The latter are unfair because of signal to noise issues,[2] and the risk-adjustment fallacy.[3] [4] Above all, remember Lilford’s axiom – never base rewards or sanctions on a measurement over which service providers do not feel they have control.[5] It is true, as the paper argues, that rates of adherence to a single process seldom correlate with outcome. But this is a signal to noise problem. ‘Proving’ that processes are valid takes huge RCTs, even when the process is applied to 0% (control arm) vs. approaching 100% (intervention arm) of patients. So how could an improvement from say 40% to 60% in adherence to clinical process show up in routinely collected data?[6] I have to keep on saying it – collect outcome data, but in rewarding or penalising institutions on the basis of comparative performance – process, process, process.

— Richard Lilford, CLAHRC WM Director

References:

  1. Pross C, Geissler A, Busse R. Measuring, Reporting, and Rewarding Quality of Care in 5 Nations: 5 Policy Levers to Enhance Hospital Quality Accountability. Milbank Quart. 2017; 95(1): 136-83.
  2. Girling AJ, Hofer TP, Wu J, et al. Case-mix adjusted hospital mortality is a poor proxy for preventable mortality: a modelling study. BMJ Qual Saf. 2012; 21: 1052-6.
  3. Mohammed MA, Deeks JJ, Girling A, et al. Evidence of methodological bias in hospital standardised mortality ratios: retrospective database study of English hospitals. BMJ. 2009; 338: b780.
  4. Lilford R, & Pronovost P. Using hospital mortality rates to judge hospital performance: a bad idea that just won’t go away. BMJ. 2010; 340: c2016.
  5. Lilford RJ. Important evidence on pay for performance. NIHR CLAHRC West Midlands News Blog. 20 November 2015.
  6. Lilford RJ, Chilton PJ, Hemming K, Girling AJ, Taylor CA, Barach P. Evaluating policy and service interventions: framework to guide selection and interpretation of study end points. BMJ. 2010; 341: c4413.

Computer Interpretation of Foetal Heart Rates Does Not Help Distinguishing Babies That Need a Caesarean from Those That Do Not

In an earlier life I was involved in obtaining treatment costs for a pilot trial of computerised foetal heart monitoring versus standard foetal heart monitoring (CTG). The full trial, funded by NIHR, has now been published in the Lancet,[1] featuring Sara Kenyon from our CLAHRC WM theme 1. With over 46,000 participants the trial found no difference in a composite measure of foetal outcome or intervention rates. Perinatal mortality was only 3 per 10,000 women across both arms and the incidence of hypoxic encephalopathy was less than 1 per 1,000. Of course, the possibility of an educational effect from the computer decision support (‘contamination’) may have reduced the observed effect, but this could only be tested by a cluster trial. However, such a design would create its own set of problems, such as loss of precision and bias through interaction between method used and baseline risk across interventions and control sites. Also, the control group was not care as usual, but the visual display IT system shorn of its decision support (artificial intelligence) module.[2] Some support for the idea that control condition affected care in a positive direction, making any marginal effect of decision support hard to detect, comes from the low event rate across both study arms. Meanwhile, the lower than expected baseline event rates mean that any improvement in outcome will be hard to detect in future studies. So here is another topic that, like vitamin D given routinely to elderly people,[3] now sits below the “horizon of science” – the combination of low event rates and low plausible effect sizes mean that we can move on from this subject – at least in a high-income context. If you want to use the computerised method, and its costs are immaterial, then there is no reason not to; economics aside there appear to be no trade-offs here, since both benefits and harms were null.

— Richard Lilford, CLAHRC WM Director

References:

  1. The INFANT Collaborative Group. Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. Lancet. 2017.
  2. Keith R. The INFANT study – a flawed design foreseen. Lancet. 2017.
  3. Lilford RJ. Effects of Vitamin D Supplements. NIHR CLAHRC West Midlands News Blog. 24 March 2017.

Small Pollution Particles May Pass Directly into the Brain through the Snout

Yes, they appear to be able to follow the pathway used by smell neurons and thus pass directly from the olfactory membrane into the brain, i.e. not going via the lung and bloodstream. Experiments in rodents using radio-labelled nano-particles show that very small particles really can penetrate directly through the roof of the nose and pass into the brain along olfactory neurons.[1] Here these particles set in motion an inflammatory process, which activates micro-glia (brain type macrophages), which attack neurons and lead to amyloid deposits – the hall mark of dementia. People who are exposed to particles have a high risk of dementia,[2] and animals randomised to be exposed (or not) to pollution particles acquire brain amyloid and manifest cognitive decline. So there you have it – there is growing and quite compelling evidence that pollution particles are bad news for humans and other animals. It is time to act – phase out diesel cars, incentivise car manufacturers to clean up emissions, gradually increase tax on cars/lorries/fuels, incentivise cycling in cities (and make it safer), and build rail lines. But none of this will happen without public support so proselytise and increase susceptibility to the message by increasing science teaching in schools. In the end, lots of things come back to the intellectual sophistication of the average citizen. In the meantime I suspect that an increasing proportion of people will adopt face masks, although I do not know how effective they are in trapping particles.

— Richard Lilford, CLAHRC WM Director

References:

  1. Underwood E. The Polluted Brain. Science. 2017; 355(6323): 342-5.
  2. Chen H, Kwong JC, Copes R, et al. Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: a population-based cohort study. Lancet. 2017; 389(10070): 718-26.

Three Hits Hypothesis

Quite a lot of diseases are brought about by the conflation of two factors. Mice infected with certain herpes viruses suffer no ill-effect unless a helminth infestation supervenes. Oral allergy syndrome arises when a certain pollen interacts with certain foods (usually raw fruits, vegetables and nuts). The hygiene hypothesis says that lack of exposure to certain gut bacteria sensitises the body to allergic reactions to a range of environmental allergens. The pathway for disease involves three hits:

Genetically predisposed person –> Exposure 1 –> Exposure 2 –> Disease.

An intriguing example of a three-hit condition is the severe disease of children – Burkitt’s lymphoma. This cancer arises in germinal centres of lymph nodes in the neck. It is known that Epstein-Barr (EB) virus infection is necessary for endemic Burkitt’s lymphoma to develop because it prevents apoptosis (cell death) when certain mutations occur in the cell. But endemic Burkitt’s lymphoma only occurs in the malaria belt, and why this is so has been a mystery until the last few years. Now we know that the malaria parasite Plasmodium falciparum ‘upregulates’ an enzyme that causes mutations in DNA in lymph cells. These mutations are a normal part of antibody production since rearrangements of chromosome segments is necessary for antibody specificity. But in people with falciparum malaria, the effect ‘spills over’ to cause mutations of cancer genes. The double hit of EB plus malaria sets the scene for carcinogenesis.[1] Why in the neck – perhaps because lymph cells in the necks of children work particularly hard eradicating throat and ear infections, in which case there is a ‘four hits’ hypothesis!

— Richard Lilford, CLAHRC WM Director

References:

  1. Thorley-Lawson D, Deitsch KW, Duca KA, Torgbor C. The Link between Plasmodium falciparum Malaria and Endemic Burkitt’s Lymphoma—New Insight into a 50-Year-Old Enigma. PLoS Pathog. 2016; 12(1): e1005331.