Like many of us, I love animals, and am crazy about both dogs and cats. It is almost hard to describe how much I love them. But is this all very good for me? I mean, dogs can bite, cats scratch, and all animals can transmit infections. On the other hand, they are psychotropic; cuddly, warm and attentive. Some evidence suggests that people who keep pets are healthier than those without.
However, a rather dismal paper in the BMJ puts paid to all of that. According to an analysis of a large cohort study of aging individuals, those who own pets do no better than those who do not. They are no stronger, happier or otherwise healthier than people without pets. Still, I would like to live with a cat or dog.
— Richard Lilford, CLAHRC WM Director
- Batty GD, Zaninotto P, Watt RG, Bell S. Associations of pet ownership with biomarkers of ageing: population based cohort study. BMJ. 2017; 359: j5558.
In observational studies, adding a third or fourth anti-hypertensive medication leads to rapidly diminishing marginal improvements in blood pressure and an increase in side effects. However, this finding could originate from a type of selection bias called bias by indication; the harder cases get more treatments. To get around this problem an Instrumental Variable (IV) analysis was carried out on a dataset generated by a randomised trial of intensive versus standard blood pressure target.
In the IV analysis, where randomised group was the instrument, the incremental effect of adding a further anti-hypertensive was maintained across all orders of increment. Not only was there an improvement in blood pressure, but also a reduction in cardiovascular events. There was only a small increase in adverse events. This proves that there is a bias by indication in observational studies, which reduces the apparent marginal benefit and increases marginal harms. This is a neat study and a fine example of IV analysis.
— Richard Lilford, CLAHRC WM Director
- Markovitz AA, Mack JA, Nallamothu BK, Ayanian JZ, Ryan AM. Incremental effects of antihypertensive drugs: instrumental variable analysis. BMJ. 2017; 359: j5542.
I thank Julian Bion for drawing my attention to an interesting paper by Joanna Westbrook and colleagues in BMJ Quality and Safety. In this meticulous study, 36 emergency physicians were shadowed for over 120 hours. When physicians experienced interruptions or were tired they made many more prescription errors than when they were not interrupted or were refreshed. This study corroborates the existing psychological literature and supports efforts to try to create a calm and ordered environment in which physicians can do complex tasks.
— Richard Lilford CBE, CLAHRC WM Director
- Westbrook JI, Raban MZ, Walter SR, Douglas H. Task errors by emergency physicians are associated with interruptions, multitasking, fatigue and working memory capacity: a prospective, direct observation study. BMJ Qual Saf. 2018.
In a previous news blog we drew attention to the psychological consequences of insinuating a computer into the clinician-patient consultation. The deleterious effect of computers on the clinician-patient interaction was published by the CLAHRC WM Director over three decades ago. This concern has been corroborated in Robert Wachter’s recent book.
In this news blog we will focus on another disadvantage of the current generation of electronic clinical notes. This is the threat to patient safety that results from the inchoate nature of electronic clinical record systems. In short, they do not reflect the heuristic patterns that determine appropriate clinical care. This failure to follow medical logic is most dangerous in the context of diagnosis.
While clinical diagnosis may sometimes be clear from a single episode of care, the correct diagnosis frequently depends on the pattern of data as it emerges over time. Just as an understanding of politics requires an understanding of history, so a clinical diagnosis frequently requires an understanding, not just of the current symptoms and signs, but also of their provenance.
Building on this safe premise, one has to conclude that the way clinical record systems are organised can either facilitate or hinder accurate diagnosis. Diagnostic errors are the single largest threat to patient safety ; it is all very well to promote evidence-based care and safe prescribing, but if the patient is on the wrong pathway, then they are heading for a big disaster. Diagnosis lies at the heart of clinical medicine and a system that impedes accurate diagnosis is likely to do more harm than good. A recent study of electronic notes carried out by Aziz Sheikh, in collaboration with CLAHRC WM, showed that big reductions in medication error could be achieved by means of electronic prescribing and decision support [in press]. However, careful qualitative research showed that the electronic prescribing systems disrupted the normal flow of knowledge, and that doctors had to implement numerous ‘work-arounds’. This way be dragons!
The problems of disorganised clinical information have been the subject of investigation for over half a century; Professor Laurence Weed’s system of problem-orientated notes inspired the CLAHRC WM Director when he was a young doctor (a long time ago)! The most urgent requirement in modern computing is not to saturate the health service with electronic records, but to develop them in a way that preserves the logic of medical practice. In the meantime we should rely on structured paper-based notes, such as those recommended by Rupert Fawdry, and confine the use of computers to things that they really are good at, such as electronic prescribing and disseminating medical images.
— Richard Lilford, CLAHRC WM Director
- Brownbridge G, Lilford RJ, Tindale-Biscoe S. Use of a computer to take booking histories in a hospital antenatal clinic. Acceptability to midwives and patients and effects on the midwife-patient interaction. Med Care. 1988;26(5):474-87.
- Wachter R. The Digital Doctor: Hope, Hype, and Harm at the Dawn of Medicine’s Computer Age. New York, NY: McGraw-Hill Education. 2015.
- Singh H, Schiff GD, Graber ML, Onakpoya I, Thompson MJ. The global burden of diagnostic errors in primary care. BMJ Qual Saf. 2017; 26: 484-94.
- Lilford RJ. The WISDAM of Rupert Fawdry. NIHR CLAHRC West Midlands News Blog. 5 September 2014.
We recently carried the summary of an article showing that genes associated with higher educational attainment were also associated with a lower risk of coronary heart disease. The noble BMJ has published another interesting article on Mendelian randomisation. By Jupiter, they make the same finding; genes associated with high educational attainment are associated with a lower risk: this time of Alzheimer’s disease. These genes are also associated with a high level of intelligence, and both intelligence and educational attainment are associated with modifiable risk factors. Thus, it is not clear that modifying behaviour, for example through staying longer in education, would improve outcome in people who do not have these favourable genes. The paper does suggest that genes associated with alcohol consumption are also protective against Alzheimer’s disease, again reinforcing a recent news blog article. Interestingly, genes associated with favourable metabolic factors and normal blood pressure, are in no way protective against Alzheimer’s disease. Many public health people argue that avoiding cardiovascular risk will also reduce the risk of Alzheimer’s disease. I think it is high time to put a stop to this nonsense. It has been clear for some while that Alzheimer’s disease and cardiovascular disease are on different pathways. The well-known association between nicotine consumption and a reduced risk of Alzheimer’s disease was confirmed at the genetic level, but disturbingly for me, genes predisposing to high coffee intake were associated with an increased risk of Alzheimer’s disease.
I am a great fan of genetic randomisation and this is another extremely interesting and well-written paper. One thing that genetic randomisation completely gets around is of the problem of reverse causality. It is one of the most powerful techniques to have come into epidemiology in the last 50 years and the originators, Gray and Wheatley, deserve the Nobel prize.
— Richard Lilford, CLARHC WM Director
- Lilford RJ. A Very Interesting Paper Using Mendelian Randomisation to Determine the Effect of Extra Years of Education on Heart Disease. NIHR CLAHRC West Midlands News Blog. 10 November 2017.
- Larsson SC, Traylor M, Malik R, Dichgans M, Burgess S, Markus HS, for the CoSTREAM Consortium on behalf of the International Genomics of Alzheimer’s Project. Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis. BMJ. 2017; 359: j5375.
- Lilford RJ. So Where Are We Up to With Alcohol and Health? NIHR CLAHRC West Midlands News Blog. 12 January 2018.
- Oddo S, Caccamo A, Green KN, Liang K, Tran L, Chen Y, Leslie FM, LaFerla FM. Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2005; 102(8): 3046-51.
- Gray R & Wheatley K. How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant. 1991; 7(s3): 9-12.
Nearly every biology and medicine student will have learnt about the link between sickle cell anaemia (SCA) and protection from malaria. If a person inherits two faulty alleles of the haemoglobin gene then their red blood cells will be sickle shaped, which can result in pain, anaemia, swelling, infections and stroke. If they inherit only one faulty allele then the other, non-mutated allele, will ensure they are unlikely to have any symptoms of SCA – they will only be a carrier. If a SCA carrier is infected with the malaria parasite it is unable to reproduce in their red blood cells and so the person is less likely to develop malaria, or will suffer less severe symptoms.
Authors of a recent paper  in the American Journal of Human Genetics have traced the origin of the sickle allele through the use of whole-genome-sequence data from around 3,000 people. There are five main haplotypes of the sickle allele that cause varying severity of SCA, but it is unknown if these were caused by relatively recent independent occurrences of the same mutation, or a single mutation a longer time ago, from which they all originated. It turned out that there was a single mutation, which occurred 259 generations ago, or roughly 7,300 years ago, most likely in either the Sahara or west-central Africa. From this it spread to other areas in Africa, probably due to the protection it afforded against malaria, and then beyond. It is hoped that this finding will allow better medical care to be provided, and to predict the severity of a patient’s SCA.
— Peter Chilton, Research Fellow
- Shriner D & Rotimi CN. Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle Allele during the Holocene Wet Phase. AJHG. 2018.
A three way RCT  from Thailand shows that rotavirus vaccine is effective in reducing the incidence of diarrhoea in children (which we know), and that a neonatal schedule is no less effective and probably more effective than an infant schedule. Giving the vaccine early may reduce the risk of intussusception – apparently a risk with the infant schedule.
— Richard Lilford, CLAHRC WM Director
- Bines JE, At Thobari J, Satria CD, et al. Human Neonatal Rotavirus Vaccine (RV3-BB) to Target Rotavirus from Birth. New Engl J Med. 2018; 378(8): 719-30.
An interesting report in last week’s edition of Nature deals with the topic of serendipity. The report focuses on the work of Ohid Yaqub of the University of Brighton. He classifies serendipity into four different types. In the first type research in one topic area leads to a discovery in another – mustard gas and chemotherapy for example. The second type of serendipity arises when a solution is reached through an unexpected pathway. An example is the development of a lens for people with cataracts based on the discovery that Perspex glass injuries to the eye do not cause an inflammatory reaction. The third mechanism arises when a completely open hunt brings about a discovery, such as with Röntgen’s X-rays. Lastly, some discoveries find a solution to a problem that only arises many years later, such as the use of potassium bromide as a sedative 31 years after it was isolated and used (unsuccessfully) as an iodine substitute.
— Richard Lilford, CLAHRC WM Director
- Nature. The Serendipity Test. Nature. 31 January, 2018
- Yaqub O. Serendipity: Towards a taxonomy and a theory. Res Policy. 2018; 47(1): 169-79.
An important thing to consider when reading research, especially something that shows new and promising results, is to check the conflicts of interests of the authors. For example, we will naturally be more sceptical about a study on breastfeeding if it is authored by researchers with connections to the formula industry, or a study showcasing the effectiveness of a new drug authored by researchers working for the pharmaceutical company. That is not to say that the studies are inherently biased, but that they should be viewed in a different light to studies that do not have such conflicts. As such, it is alarming to read a recent study by Piper, et al. that found that a considerable proportion of the authors of healthcare textbooks had undisclosed conflicts of interest, stemming from patents on medical devices and remuneration from medical product companies. The textbooks chosen were all used in educating and training of physicians, pharmacists and dentists, and as references for treatments, etc. Perhaps textbook publishers need to follow the lead of academic journals and clearly state any conflicts. Until then, make sure to carefully consider what you read in textbooks.
— Peter Chilton, Research Fellow
- Piper BJ, Lambert DA, Keefe RC, Smukler PU, Selemon NA, Duperry ZR. Undisclosed Conflicts of Interests among Biomedical Textbook Authors. AJOB Empir Bioeth. 2018. [ePub].
Recently I found myself holding forth on the above topic in a plenary talk at the International Federation of Fertility Societies combined meeting with the African Fertility Society in Kampala. I made the point that the health economics of infertility raises a number of issues that are not generally considered in the standard canon for health economic assessment of health technology assessments (HTA). Four issues stand out:
- The benefits of infertility treatment are more difficult to capture on a single quality of life (QoL) scale than in the case for standard HTA.
- The standard practice of discounting benefits can be questioned.
- The beneficiaries are more diverse, potentially extending to many family members.
- The issue of whether the lifelong utility of the potential child should be include is controversial.
I shall briefly consider these in turn.
- Benefit – generic quality of life (QoL) scales do not seem up to the job. First, it is very difficult to capture the benefits over a lifetime. The ‘area under the curve’ is the important relevant quantity and this is not well captured in cross-sectional studies. Second, QoL deteriorates when a sub-fertile couple have a baby, as it does for fertile people. I discovered this many years ago in a collaborative study with the Health Economics department at the University of York (unpublished). This finding reinforces the importance of a lifetime perspective. Third, it is doubtful that maximisation of the dimensions captured in a generic QoL scale are the things that people wish to maximise when they decide to have children – there is a deeper purpose in play. So, a utility function based on a direct trade-off would be preferable to a standard generic QoL scale, such as the SF-12 or EQ-5D. This way, the respondent can take a lifetime perspective and factor in all the valued benefits and disbenefits of treatment. Torrance used a standard gamble on a large study of US citizens and measured a disutility of 0.07 (utility 0.93). That is to say, the average respondent would run up to a 7% risk of death to enable them to have a first child. Such a standard gamble method would likely underestimate the utility loss for those who actually experience infertility for reasons David Arnold and I explicated elsewhere. A perhaps better method to capture the benefit over a lifetime would be willingness-to-pay studies and here, in addition to studies at the population level (say using discrete choice methods), studies of revealed preferences are possible. This is because much IVF takes place in an entirely private market. This enables the ‘market clearing’ price for infertility services to be observed (ideally in relation to disposable income). The high proportions of disposable incomes infertile people allocate to infertility treatment, sometimes amounting to catastrophic losses, provides some evidence that Torrance’s study underestimates the trade-offs people will make in order to have children.
- Choice of discount rate – The fact that benefits continue to accrue, and may increase, over time, suggests that discounting may not be normative. Given that disbenefits generally precede benefits, it makes little sense to discount from the point of intervention. That said, it is important to factor disbenefits of treatment and downstream costs into the analysis. Disbenefits include the cost and discomfort of treatment and knock-on costs, for example, resulting from an increased risk of prematurity. Conversely, there may be hidden benefits beyond the joys of parenthood – for example, in reduced Intimate Partner Violence.
- Diverse beneficiaries – In ‘normal’ health economics, benefits are hypotheticated on the affected person, even though loved ones also stand to benefit. Loved ones benefit through the improved health of the affected person. Ignoring third party benefits can be condoned on the ‘level playing field’ principle – in a comparison across diseases of middle-age, beneficiaries of various alternative treatments are in a roughly similar position – they have similar numbers of loved ones on average. On this basis, the decision tree can be ‘pruned’. It could be argued that this argument breaks down when comparisons are made across generational lines. In the particular case of infertility, mothers and fathers get direct benefits, as do grandparents and others, not only through the ‘affected’ person, but directly from the child that results from the treatment. For instance, the father is just as much a beneficiary as the mother. Grandparents are not far behind – I can attest to that. On the other hand, factoring these beneficiaries into the equation seems to tilt the playing field too far the other way, i.e. towards infertility services. Factoring the benefits that accrue to all these people would weight services for children in general, and infertility services in particular, very strongly. This is a topic requiring more philosophical analysis and, perhaps, empirical investigation.
- What about the child who would otherwise not have existed – the question of the utility of the hypothetical lives is vexed. Certainty, no-one counts the utility loss from contraception, even when no later ‘replacement child’ is envisaged. On the other hand, the utility of neonatal survival is included in standard economic practice. My preference is not to include this utility, but I am hard-pressed to defend this on a bottom-up, philosophical basis. Richard Hare, the famous Oxford philosopher, did attempt such an analysis and his conclusions support my instinct. Certainly, including the lifetime utility of the child massively improves the cost-benefit ratio of infertility services,[6-8] and if the tax return from the child is included, then a treatment such as IVF becomes a ‘no-brainer’ since it ‘dominates’ – it saves money and yields benefit down to a very low success rate (<6% of so).
What would happen if we:
- Accepted a utility function of 0.9 (close to that of Torrance).
- Ignored other beneficiaries, including the child?
We present such an analysis below. Even under these relatively conservative constraints, IVF is cost-effective in most countries, and could be cost-effective in LMICs if some new idea, such as incubation within the vagina, were used.
Say we gave infertility a disutility of 0.1 over 50 years, undiscounted.
Then, the utility in an infertile couple successfully treated = 5 QALYs undiscounted and 1.1 discounted at 3%.
Let’s say society will pay $100 per QALY.
Then a treatment with a 25% success rate can have a net cost of up to $125 undiscounted, but less than $28 discounted.
— Richard Lilford, CLAHRC WM Director
I thank Sheryl van der Poel for sending some of the references quoted in this article.
- Drummond MF. Methods for the economic evaluation of health care programmes. Oxford: Oxford University Press. 2005.
- Torrance GW. Measurement of Health State Utilities for Economic Appraisal. J Health Econ. 1986; 5: 1-30.
- Arnold D, Girling A, Stevens A, Lilford R. Comparison of direct and indirect methods of estimating health state utilities for resource allocation: review and empirical analysis. BMJ; 2009; 339: b2688.
- Wu AK, Odisho AY, Washington III SL, Katz PP, Smith JF. Out-of-Pocket Fertility Patient Expense: Data from a Multicenter Prospective Infertility Cohort. J Urology. 2014; 191(2): 427-32.
- Stellar C, Garcia-Moreno C, Temmerman M, van der Poel S. A systematic review and narrative report of the relationship between infertility, subfertility, and intimate partner violence. Int J Gynecol Obstet, 2016; 133: 3-8.
- Connolly MP, Pollard MS, Hoorens S, Kaplan BR, Oskowitz SP, Silber SJ. Long-term Economic Benefits Attributed to IVF-conceived Children: A Lifetime Tax Calculation. Am J Manag Care. 2008; 14(9): 598-604.
- Svensson A, Connolly M, Gallo F, Hägglund L. Long-term fiscal implications of subsidizing in-vitro fertilization in Sweden: A lifetime tax perspective. Scand J Pub Health. 2008; 36: 841-9.
- Fragoulakis V & Maniadakis N. Estimating the long-term effects of in vitro fertilization in Greece: an analysis based on a lifetime-investment model. Clinicoecon Outcomes Res. 2013; 5: 247-55.
- Baird DT, Collins J, Egozcue J, et al. Fertility and Ageing. Hum Reprod Update. 2005; 11(3): 261-76.