Alcohol, Harry Keen, retirement and Cuban epidemiology

I did my first liver biopsy on a man who had had a ‘well man’ check-up at a private hospital. He had liver function tests just outside the normal range and had been referred for a diagnosis. The likelihood of harm from my inexperience in conducting a liver biopsy far outweighed any potential diagnostic gain as it seemed to me unlikely that he had any serious pathology—but refusal was not an option. In this issue, Kunutsor and colleagues report findings from a systematic review of observational studies examining the association between liver function tests and all-cause mortality, which showed increased relative risks of 1.60 and 1.38 comparing the bottom with the top third of the gamma-glutamyl transferase and alkaline phosphatase distributions, respectively.1 So perhaps I was being too hasty in my assumption that raised liver function tests in apparently healthy people are of little consequence. A more detailed reading of this review showed that, surprisingly, unpublished data from a single study (which scored lower than other studies on quality and did not adjust for alcohol consumption) provided 90% of the evidence summarized. The inclusion of this study—but not others that have published relevant data on cause-specific mortality and could therefore provide all-cause mortality data2–4—raises questions about the robustness of the search strategy and the inclusion criteria used. Fraser, commenting on this article, notes that the mechanisms by which raised liver enzymes cause disease are not tractable by an analysis of all-cause mortality.5 More detailed cause-specific studies are needed, preferably set in the context of a prospective studies collaboration using individual participant data with adjustment for the obvious confounding factors, particularly alcohol. Alcohol accounts for a large proportion of the global burden of disease6 and also for entertaining times at international meetings. Two of our diversions in this issue concern alcohol. The first was written by a statistician, Martin Gardner, and was designed by first-year medical students.7 Gardner was renowned for his ability to make statistics accessible and helped many epidemiologists, clinicians and students design much better studies. He is famous for his work on the link between radiation and childhood leukaemia, postulating that paternal exposure to radiation before conception played a causal role in leukaemia in offspring—the Gardner hypothesis. Unfortunately he died in 1993 before this debate was fully explored. The second diversion was written by a senior statistician and a senior epidemiologist and used a novel ‘evolving’ design influenced by alcohol and two of the authors—the roles of the other authors is unclear but may have involved actually buying the beer, going to the bar to get it, or driving the first and senior authors home.8 In their favour, both studies had a hypothesis, the first that medical students could not tell the difference between light and bitter beers and the second, that all lagers taste the same. Both studies came to rather similar conclusions with evidence supporting these null hypotheses, highlighting design features that could have biased the findings and suggesting refinements for future research. Having participated myself in ‘me-too’ beer trials in India, where Kingfisher has crushed the alternatives and is now the only Indian beer readily available, and in Malawi where the local beer—Kuche Kuche—was not even passably drinkable, I am pleased to discover that a new beer—Chill—has recently been launched there. The Ikale Collaboration is open for new members. Harry Keen, who died in April 2013, was a notable clinician scientist who was equally conversant with epidemiological methods and basic science. In this issue we reprint one of his papers, originally published in the now defunct Guy’s Hospital Reports journal, describing the associations between urinary albumin excretion and blood glucose levels following a glucose tolerance test conducted in an epidemiological study in Bedford, UK.9 His aims were to determine whether urinary albumin was already present at the time of diagnosis of diabetes and whether the degree of urinary albumin could help in interpretation of ‘borderline’ abnormal glucose tolerance tests. The study demonstrated that urinary albumin excretion (now termed microalbuminuria) was greater in people with diabetes and those with borderline abnormal glucose tolerance than in those with normal tests. Moreover, an association between systolic blood pressure and urinary albumin excretion in diabetic participants was found, suggesting that treatment of hypertension in diabetics might reduce the likelihood of developing renal impairment. Keen, writing to Per-Henrik Groop in February 2013, described his discovery of how to measure microalbuminuria: ‘I sat and listened to a couple of young chaps called Randle and Hales describe this natty two antibody method of measuring insulin in plasma and thinking Eureka—that’s how we can measure low concentrations of albumin in the newly found diabetics of Bedford, went back to Guy’s, immunised a bunch of guinea pigs with human albumin and—as they say—the rest is history’. Professor emeritus Harry Keen, 1925–2013. ‘Clinical scientists are rarely awarded the Nobel Prize for Medicine’ state Viberti and Karalliedde,10 implying that Keen’s major contributions to diabetes were of this order of importance. Peter Higgs, the physicist who identified the particle now named the Higgs boson, commented on receiving his Nobel Prize for Physics this year: ‘Today I would not get an academic job. I don’t think I would be regarded as productive enough’.11 Higgs’ key paper was published in Physical Review Letters in 1964. He only authored 10 further papers before retiring. Trends in assessing ‘quality’ in higher education and in health care result in the current generation of clinical scientists finding themselves on a merry-go-round of audits, evaluations, reaccreditations, 360-degree appraisals, grant-getting and publishing everything regardless of its importance—leaving insufficient time for thinking—a rather useful activity for scientists. Our commentators illustrate how Keen’s findings have led to advances in treatment and understanding of the pathophysiology of diabetes.10,12 As Jarrett describes, Professor John Butterfield (subsequently Baron Butterfield) was instrumental in devizing the Bedford study, persuading the local medical officer to switch his proposed screening study on glaucoma to diabetes.13 Butterfield also had the good sense to delegate establishing the study to Keen and Roy Acherson, leaving himself free to embark on a career in higher education and politics. Butterfield was appointed as Vice Chancellor to Nottingham University in 1970 and was instrumental in developing the clinical Medical School which I attended. Butterfield subsequently advised Margaret Thatcher on NHS reforms and chaired the Health Promotion Trust—a tobacco industry enterprise. What Keen, an ardent supporter of the National Health Service, would have said is unknown but can be glimpsed from an interview he gave for a recent film directed by Ken Loach, The Spirit of 45, which documents the post-World War II determination that a fairer, united society should be created (see http://www.thespiritof45.com/Interviews-Archives/Welfare). The availability of national linked large-scale datasets in Scandinavian countries has transformed their epidemiology. In this issue of IJE, Idring and colleagues explore the question of autism risk among 412 557 Swedish parents and 4746 children with autism.14 Previous studies had treated autism as a single condition and had grouped age categories, whereas in this new study, autism spectrum disorders with and without intellectual disability were the outcomes and continuous parameterization of age was carried out to examine non-linear effects. The study confirmed that the children of older parents have an increased risk of developing autism spectrum disorders but also demonstrated that this risk is higher for autism with intellectual disability. Unlike earlier findings, autism was dependent on co-parental age with increasing maternal age making a greater contribution than paternal age. The non-linear age association found in mothers contrasting with the linear age association in fathers suggest that different mechanisms operate in increasing autism risk—leading hypotheses being increased rates of de novo mutation to explain paternal effects and a more complex multi-factorial aetiology for maternal effects. An early retirement is looking increasingly unlikely for current cohorts of young and middle-aged people as the economic outlook remains uncertain and population ageing and life expectancy continue to rise. Many governments have raised retirement ages in an effort to offset government pension costs—but could this have adverse health consequences? In a prospective study of 617 511 Danish 60-year olds followed for 7 years, Olesen and colleagues15 explored the risk of myocardial infarction among newly retired and retired people compared with active workers, finding that retirement was associated with a small increase in risk of myocardial infarction, supporting earlier findings on cardiovascular disease from a French cohort study.16 Denmark’s national record linkage systems made it possible to determine retirement status and occurrence of myocardial infarction for the individuals making up the cohort—something that the proposed European Union New Regulation on Data Protection seeks to stop—and the International Epidemiology Association is campaigning to overturn.17 This analysis is interesting, but it fails to provide a comprehensive answer to the question of risks of mortality and serious morbidity following retirement. Previous studies indicate that self-reported health improves after retirement but there is still uncertainty about the overall objectively determined health effects of retirement.16,18 I am grateful to George Davey Smith for sending me the following note by William Heberden (1710–1801) on ‘Retirement from Practice’: ‘It was not from a wish to be idle, which no man capable of being usefully employed has a right to be, but because I was willing to give over, before my presence of my thought, judgement and recollection were so impaired, I could not do justice to my patients. It is more desirable for a man to do this a little too soon than a little too late; for the chief danger is on the side of not doing it soon enough’.19 Harry Keen was still conducting a diabetes clinic at the age of 88 and Heberden retired from active practice at 85 years—both well above current retirement ages. Much of the time I wonder what epidemiology is all about these days. In November I was on an assignment to scope a project on Cuban medical education. It was in a meeting with Professor Miguel Márquez, an Ecuadorian long-term resident in Cuba, that I realised how an epidemiological viewpoint was a key to the success of the Cuban health system. Márquez made major contributions to the development of the Cuban health care model after the socialist revolution of 1959. Tackling socio-economic determinants of health with a fundamental redistribution of wealth, provision of education and health care for all were achieved at a time when governments in North America and Europe were either in denial or considering how to avoid dealing with socio-economic inequalities. Importantly, despite the dramatic economic decline in Cuba in 1990 following the collapse of the Soviet Union and strengthening of the United States embargo, education and health policies have been sustained.20 Márquez is now in his 80s and continues to contribute articles and to edit textbooks explaining how the Cuban model operates and should be refined.21,22 In his spare time he now produces revolutionary art in mixed media and is the embodiment of Cuba’s continuing revolution. Professor Miguel Márquez, a leader of the Cuban health revolution. What is remarkable about Cuban medical education is its focus on the importance of health care as an agent of social change and development and the role of the community, both in determining political imperatives and providing the resources for achieving improvements in human development. In Cuban medical education, an epidemiological appraisal of the needs of the population is a fundamental step in setting up a health system. The Cuban success in achieving a large-scale primary health care-orientated workforce and the associated gains in health indicators are well chronicled.23 What is less known is the Cuban commitment to training tens of thousands of doctors and health workers for other countries. Escuela Latinoamérica de Medicina (ELAM) (http://instituciones.sld.cu/elam/) was established in 1998 and has now trained over 20 000 doctors from over 65 different countries. Remarkably, students from the United States have also been accepted for free medical training—and have returned to establish services for poor communities who are unable to access the US system.24 Revitalising medical curricula along Cuban lines, with an epidemiology rooted in solving the problems of local communities, coupled with recruitment of students from disadvantaged backgrounds and teaching the importance of making commitments to local communities by providing health services free at the point of use, seems almost unimaginable. Maybe we should learn from Cuba that revolution is a key ingredient.