EPIDEMIOLOGY AND THE ART OF THE SOLUBLE

897

Epidemiology EPIDEMIOLOGY AND THE ART OF THE SOLUBLE* M. G. MARMOT

Department of Community Medicine, University College London; and Middlesex Hospital Medical School, 66-72 Gower Street, London WC1E 6EA

COMMUNITY medicine is concerned with the health of The practice of community medicine includes other disciplineseconomics, planning and evaluation, and management-but epidemiology provides the scientific foundations for decisions about public health. Is it reasonable to suggest that epidemiology provides scientific evidence? Epidemiology certainly provides fertile ground for controversy, like any branch of science that deals with important public issues. The committee on medical aspects of food policy (COMA) recommended a reduction in dietary intake of satured fat to prevent coronary heart disease (CHD), but commented that the evidence "falls short of proof , .2 One of the signatories to the COMA report, apparently having second or third thoughts, considered that the evidence "falls far short of proof’3-an implication that we can measure distance from an absolute called proof. This lust for absolute "proof represents a view of science that is mistaken, dangerously so, since it interferes with two types of endeavour: translating scientific evidence into public health policy and pursuing research into the social causation of ill-health. "Good scientists study the most important problems they think they can solve," Sir Peter Medawar wrote.4 "No scientist is admired for failing in the attempt to solve problems that are beyond his competence. The most he can hope for is the kindly contempt earned by the utopian politician. If politics is the art of the possible, research is surely the art of the soluble. Both are immensely practical-minded affairs ..."4

communities, and epidemiology is its basic science.’

SCIENCE AND POLICY

The scientific problem of the prevention of CHD is sufficiently soluble to allow the formulation of policy. First, the reasons for the controversy over diet and CHD. In simplified form, the protagonists of the saturated fat/ CHD theory argue that: (a) within a population, plasma cholesterol level is strongly associated with CHD occurrence; (b) human experiments show that changes in the amount and type of dietary fat are correlated with changes in plasma cholesterol level; (c) international comparisons between populations show a correlation between dietary consumption of saturated fat and both plasma cholesterol and CHD mortality; and (d) this is supported by experimental evidence in animals. Antagonists to this view: (a) doubt the validity of international correlations; (b) point to the lack of correlation, within a population, between both dietary fat and plasma cholesterol and dietary fat and clinical CHD (correlations have, in fact, recently been found); and (c) take the disappointing results of mass intervention trials as evidence that changes in diet and other risk factors are ineffective. There is also a pragmatic or tactical objection. It is argued *Based

on an

25, 1985

inaugural lecture given

at

University College London on Nov

Fig 1-5-year age-adjusted CHD death rates/1000 for

325 384 white

aged 35-57 screened for the MRFIT programme, by smoking habit, diastolic blood-pressure, and serum cholesterol level (in mg/dl). males

although blood pressure, plasma cholesterol, and smoking are good predictors of CHD (fig 1), the misclassification rate is too high to make intervention feasible. Many of those in the high-risk group will undergo changes needlessly as they would not have suffered from the disease in the first place. In addition, some people fear that a

that

reduction

in

saturated

fat

intake

or

an

increase

in

harm.

polyunsaturates might actually The defenders of the theory counter by pointing out that: (a) the most expensive of the intervention trials, the American MRFIT (Multiple Risk Factor Intervention Trial), was not negative but inconclusive because (i) there was only a 2% net difference in plasma cholesterol between intervention and control groups, (ii) the disease rate in the volunteers in the trial was too low to detect a significant difference, and (iii) there was a possibility that the benefit of diet change and stopping smoking was countered by a toxic effect of drugs in a sub-group of those treated for hypertension; (b) Peto’s pooled analysis of 19 controlled trials of cholesterol lowering showed that a 10% reduction in plasma cholesterol corresponds to a 20% reduction in CHD incidence; and (c) the determinants of cause

individual risks of disease may be different from the determinants of population risks. Rose has elaborated on this last point by showing that the difference in plasma cholesterol distribution between CHD cases and non-cases within a high-risk population, such as that of the USA, is less than the difference between a high-risk and a low-risk population. Furthermore, data from the Whitehall study showed that although smoking is strongly related to CHD, the major cause of death in non-smokers in Britain is also CHD (table).6 The concept of population risk provides the rationale for a population strategy of prevention. If the aim is to shift the risk curve of the whole population to the left, the precision of our classification of which individuals will and which will not get CHD is less relevant. And so the controversy goes on. There is not certain proof of the theory. But if we are interested in the causes of disease in

898 AGE-ADJUSTED PROPORTIONS OF DEATHS DUE TO SELECTED CAUSES AMONG SMOKERS AND NON-SMOKERS: WHITEHALL CIVIL SERVANTS AGED

40-64

antagonists changed their scientific positions as a result of the trial. Similar unresponsiveness greeted publication of the Lipid Research Centres cholestyramine trial and the WHO European trial.

OPINION AND PREJUDICE

populations, then we must study disease where it occurs-in populations-so precluding experimental proof. One way out of the difficulty would be to apply the set of criteria, attributed to Bradford Hill, used to assess the causal nature of an association: strength, doseresponse, consistency, independence, coherence, biological plausibility, and prediction. The American Society of Clinical Nutrition convened a committee to review the scientific evidence underpinning a number of dietary recommendations. The committee made public its deliberations.’ Every member was asked to rate each association between diet and disease according to criteria akin to Bradford Hill’s and the scores were collated (fig 2). Although each member was reviewing the same evidence and using the same criteria to judge it, there was marked

disagreement. We are all supposed to be Popperians these days. Science proceeds not by deriving general laws from observations and not by proving hypotheses, but by flights of the imagination (conjectures) followed by rigorous attempts at falsification (refutations).8 A hypothesis is never shown to be true, rather it withstands the attempts to falsify it. But Popper’s notion of crucial experiments leading to rejection of hypotheses does not happily suit cardiovascular epidemiology. MRFIT was a vast enterprise involving scores of medical scientists in the USA pooling their collective resources to investigate, and for all, whether intervention worked-a crucial experiment. But I suspect that few of the protagonists/ once

Fig 2-Voting by committee on associations between diet and disease. * = median score; length of box = 25th to 75th centile; x = median distance from the median; o=outlying votes. Associations between: 1. Dietary cholesterol and arteriosclerotic disease. 2. Saturated and unsaturated dietary fat and arteriosclerotic disease. 3. Joint effect of 1 and 2.

When facts collide with theories, scientists are far more likely to discard or explain away the facts than the theory. An intervention trial on middle-aged men carried out for 5-7 years cannot reverse a lifetime of unhealthy eating. If facts are inconvenient, scientists may even prefer to change them rather than reject the original theory. At a meeting of the American Heart Association council on epidemiology in 1975, data were presented showing that the mean plasma cholesterol levels of the US population had risen between the early ’60s and the early ’70s although the rate of CHD mortality was falling. When these data were published by the National Center for Health Statistics, three years later, however, they showed that mean cholesterol levels had fallen over the period. The National Center informed me that, due to changes in laboratory methods, the later figures had been revised downwards by 7%. The facts did not fit the theory, so

questioned and ultimately changed-legitimate practice. When I first contemplated this adherence to opinion rather

they

were

scientific

than fact,9 I considered it an indictment of our science. But the situation is more complex. Independent evidence now shows that US cholesterol levels have indeed declined. In retrospect, the scientists who changed the facts were probably correct to do so. The facts made so little sense that an error must have been made. But it is a worrying thought that if the facts had fit the theory, it might have been left to the opposition to question their validity. I asked one of the principal protagonists of the diet/CHD theory, in 1977, what evidence would lead him to refute it. He replied he could think of none. Popper might describe such a belief as religious and not scientific. But Lakatos" considered that scientists have a central core belief (such as the diet/CHD theory) that they do not give up, on which their research programme rests. They gather information to test offshoots of the central core. My discussant of 1977 advanced several explanations for the conflicting findings. Many have subsequently been supported by new evidence, that is, withstood falsification. My colleague’s commitment to a theory gave him the motivation to defend it. Such creative prejudice should be distinguished from the stubborn post-hocism that clings to a theory in the face of mounting evidence to the contrary. In Lakatos’ terms, creative prejudice corresponds to a progressive research programme, as opposed to a degenerating one. This account may be useful to judge research programmes in retrospect. But which is the more progressive research programme today: the harmful effects of sucrose on chronic disease or the beneficial effects of dietary fibre? And how do we decide? Other influences also come into play. In general, the same people who question the validity of international statistics also wonder whether polyunsaturates are harmful and question the power of risk factors to predict. There is no logical connection between these three objections, which derive, I believe, as much from ideological or political belief as from scientific judgment. Discussion of the scientific evidence soon turns into political discussions: to the right of the political spectrum are those whose scientific doubts

899 appear to be conflated with concern about civil liberty and to the far left are those who feel that disease frequency will not change until capitalism is smashed. I suspect (a) a correlation between political belief and willingness to recommend dietary changes for the population, and (b) that readiness to recommend change affects individual views of the scientific evidence rather than the reverse. Scientists who are reluctant to recommend population changes find the evidence less convincing than those who are ready for action. It is appropriate to consider the uses to which data will be put; research does not proceed in an ideological vacuum. My plea is for an attempt to distinguish ideological prejudice from scientific prejudice. We should separate our judgment of the scientific merits of the argument from our discussion of future policy. Removing political prejudice from the discussion, however, still leaves the question of deciding whether the evidence supporting a theory justifies recommendations. The argument that we should wait for certainty is an argument for never taking action-we shall never be certain. Let us remember Medawar’s art of the soluble, and apply the art of judgment. What is the likely balance of benefit and risk between advocating no dietary change and the COMA recommendations to reduce dietary fat from 40% to 3507o energy? Most informed commentators would agree that the balance of likely benefit favours a reduction in fat intake. And I would agree. We have a responsibility to pass on to the public our best judgments regarding living healthily. It is necessary to make these judgments while research on the subject still continues. SCIENCE AND EPIDEMIOLOGICAL RESEARCH

We are pursuing the reasons for ethnic differences I 1,12 and social class differences in disease. As long as we concentrate on diet and smoking, we are on relatively safe ground. As soon as we begin to consider psycho-social factors, particularly stress, we are told that stress cannot be defined or measured and therefore cannot be studied. In effect, if it cannot be studied it does not exist and therefore is not on the agenda for discussion on prevention of disease. Unless we include psycho-social factors in scientific discourse, we rule out as irrelevant the possible effects on health of the whole area of relationships between people and between people and society. Community medicine must grapple with social and ethnic differences in disease, the effects of unemployment and of stress at work and at home. But there are a number of methodological issues.

(i) Interaction of Social and Biological Why do the Japanese have the lowest rate of CHD of any industrialised country? Their diet is low in saturated fat and it has been suggested that Japanese society has low levels of stress because of its cohesive social structure and high degree of social support. We studied Japanese immigrants and observed a gradient in CHD occurrence that increased from Japan to Hawaii to California. There was undoubtedly a change in dietary fat but, from studies of the Californian Japanese, we had evidence that the degree of westernisation (and presumed loss of social support) was related to CHD independent of other risk factors. 13 In the Whitehall study, the problem was more complicated. Administrators in the civil service have one-third the CHD mortality of the lowest grades (messengers, &c) over 10 years. Smoking and physical inactivity were more common in men of the lower grades. To discover if psycho-social factors had

independent effect, we controlled for these and other risk factors, and discovered that, although they were strongly related to CHD, conventional risk factors accounted for only an

40% of the difference. 14 We had also to take into account biological factors acting now and earlier in life. There was a variation in height by grade of employment. 21’ 1% of the administrators were 6 feet or more in height compared to 8 -7% of the lowest grades. Short height was related to CHD mortality, independent of current grade. Height reflects social/nutritional background in infancy (as well as genetic factors) and is related to social mobility-upwardly mobile men were taller than those staying closer to their class of

origin.

(ii) Proximity and Specificity Social factors act further back in the causal chain than, say, smoking and their relationship to disease may therefore be less constant, depending on the constancy of the relationship between social class and intermediaries such as smoking. 15s Social factors may also have quite general effects. In the Whitehall study, we observed that grade of employment was related equally to rates of cardiovascular disease, noncardiovascular disease, and a range of specific causes. This finding potentially leads to two types of research. One explains the relationship between grade of employment and rates of chronic bronchitis, lung cancer, CHD, renal disease, and so on by the clustering of specific causes such as air pollution, smoking, diet, infections, and so on. The other argues that such general effects have a general cause: people in a lower social position are less resistant to a variety of specific "toxic" agents and this lower resistance may be due to a lower degree of social support.

(iii) Measurement In

1979, when discussing his Art of the Soluble, Medawar

"What I meant of course was that the art of research is that of making a problem soluble by finding out ways of getting at it ... very often a solution turns on devising some

wrote:

means

of quantifying phenomena or states..."’6-in a word,

There is no absolute standard of It needs to be precise enough for the purpose at hand. In the Japanese study we had to devise measurements of acculturation predictive of CHD. In our studies of civil servants, we are pursuing the possibility that work stress might be related to increased disease risk. How do we define and measure work stress? Following colleagues in the USA and Sweden,17 we have devised measures that relate to fibrinogen level and so to the likelihood of thrombus measurement. measurement.

formation. 18

(iv) Indirect Approaches The relationship of stress to disease can be studied indirectly. Although psychological stimuli are related to short-term fluctuations in blood pressure, for example, most people remain unconvinced by the evidence, in humans,

linking stress to hypertension. But our randomised controlled trials with Chandra Patel show that relaxation can lead to sustained falls in blood pressure.’9 I started with the problem of translating past research into current policy. I have finished with a number of areas for future research, including the importance of considering psycho-social factors in the causation of disease. Is it too

900

utopian to hope that, in the future, proper methodology will permit vigorous discussion of how to translate research findings into policy ? REFERENCES 1. Smith A. The epidemiological basis of community medicine In: Smith A, ed. Recent advances in Community Medicine 3. Edinburgh: Churchill Livingstone, 1983: 1-10. 2 Diet and cardiovascular disease Committee on Medical Aspects of Food Policy. Report on health and social subjects (28). London: HM Stationery Office, 1984. 3. Oliver MF. Whose responsibility is medical science? Chron Roy Coll Phys Edin 1985; Oct, 245-49. 4. Medawar PB. The art of the soluble. London: Methuen, 1969: 7 5. Rose G. Sick individuals and sick populations. Int J Epidemiol 1985; 14: 32-38. 6. Marmot MG. Changing habits of the community to prevent coronary heart disease. In: Ferguson A, ed. Advanced medicine (20) London: Pitman Publishing, 1984:

139-51 7. Ahrens EH. Introduction. Am J Clin Nutr 1979; 32: 2672-3108 8. Popper K. Conjectures and refutations, the growth of scientific knowledge. New York: Basic Books, 1962. 9. Marmot MG. Facts, opinions and affaires du coeur. Am J Epidemiol 1976, 106: 519-26.

Environmental Health

10. Lakatos I. Falsification and the methodology of scientific research programmes. In: Lakatos I, Musgrave A, eds. Criticism and the growth of knowledge. Cambridge University Press, 1970: 91-96. 11. Marmot MG, Adelstein AM, Bulusu L. Lessons from the study of immigrant mortality Lancet 1984; i: 1455-57 12. McKeigue PM, Marmot MG, Adelstein AM, et al. Diet and risk factors for coronary heart disease in Asians in Northwest London. Lancet 1985; ii: 1086-90. 13. Marmot MG. Acculturation and CHD in Japanese-Americans. Am J Epidemiol 1976; 104: 225-47. 14. Marmot MG. Inequalities in death-specific explanations ofa general pattern. Lancet 1984; i: 1003-06. 15. Marmot MG, Morris JN. The social environment. In Holland WW, Detels R, Knox G, eds. Oxford textbook of public health vol I. Oxford: Oxford University Press, 1984: 97-118. 16 Medawar PB. Advice to a young scientist New York: Harper and Row, 1979 18. 17. Karasek RA, Theorell TGT, Schwartz J, et al. Job, psychological factors and coronary heart disease. Swedish prospective findings and US prevalence findings using a new occupational reference model. In: Denolin H, ed. Psychological problems before and after myocardial infarction. Adv-Cardiol 29. Basel: Karger, 1982. 62-67. 18. Markowe HLJ, Marmot MG, Shipley MJ, et al. Fibrinogen: a possible link between social class and coronary heart disease. Br Med J 1985; 291: 1312-14. 19. Patel C, Marmot MG, Terry DJ, et al. Trial of relaxation in reducing coronary risk. four year follow up. Br MedJ 1985; 290: 1103-06.

The air had been still and the barometric pressure high during each outbreak. Sulphur dioxide and smoke levels had been normal for the city, but in the last outbreak reported nitrogen dioxide levels had been higher than usual,’ which suggested a possible relation between high nitrogen dioxide levels and asthma epidemics. Because there are gaps in the data from emergency rooms and because outbreaks cannot be studied retrospectively, the city’s department of public health organised a multicentre study, by chest services of Barcelona’s main hospitals, of emergency room admissions and air pollution. The study started on Nov 15, 1984. On Nov 26, 1984, there was a significant rise in the number of patients with acute asthma admitted by adult emergency rooms. We describe here this outbreak, which is the first asthma epidemic for which we have data for the entire city. room.

A POINT-SOURCE ASTHMA OUTBREAK

JOSEF M. ANTÓ

JORDI SUNYER Spain

Local Health Institute, Local Council of Barcelona,

ASTHMA COLLABORATIVE GROUP OF BARCELONA*

Epidemiological data for the eighth asthma epidemic in Barcelona were available from the whole city. They reveal a striking space clustering, an hour-time clustering, and simultaneous time and space clustering, which indicate that the outbreak was a pointsource epidemic. Air pollution by smoke and oxides of sulphur and nitrogen was unlikely to have been the cause of the epidemic, as was an unusual level of pollen or fungal spores. The industrial area adjacent to the neighbourhood in which the epidemic occurred was a probable source of the

Summary

cause

of the outbreak INTRODUCTION

ASTHMA

chemical

epidemics have been related to atmospheric ipollution, aeroallergens, and climatic changes.I-6

There have been reports of seven outbreaks of asthma in Barcelona occurring between August 1981, and October, 1983. All these epidemics were detected at the adult emergency room at the Clinic Hospital. More asthma patients than usual were treated during the days of the epidemic at some of the other main hospitals in the city but their records were incomplete. Increases in numbers of asthma admissions were not detected in paediatric emergency rooms.

All outbreaks in Barcelona have shown similar characteristics-a time-cluster of admissions near noon; a large number of patients needing intensive care; and a short interval between the onset of symptoms and arrival at the emergency *Members of group: A. AGUSTÍ-VIDAL, J. M. ANTÓ, X. ARAN, E. AULÍ, J. BONE, J. BOTEY, J. BROQUETAS, A. CADAHIA, M. CLERIES, J. CLOS, R. CORNUDELLA, M. CRUZ, J. CUBELLS, J. CUERVO, J. DE GRACIA, J. ESEVERRI, A. EERRER, F. FIBLA, G. FIGUERAS, A. FUMADO, N. LAMBRUSCHINI, J. LLORENS, G. MASSAGUER, J, MARTÍ, F. MORELL, F. MUÑOZ-LÓPEZ, J. NADAL, T. PIQUÉ, J. ROCA, C. SANJUÁS, J. SÉCULI, J. SERENA, J. SUNYER, E. TAULER, D. TURUGUET, L. VAZQUEZ, I. VIDAL-QUADRAS, P. VILASECA.

SUBJECTS AND METHOpS Since the multicentre study started, the Municipal Institute of Health has received data daily from the emergency rooms of the six participating hospitals-Clinic, Sant Pau, Sant Joan de Deu, Vall d’Hebron, Mar, Esperanca. These hospitals cover 90% of emergency room admissions for the entire city. Patients admitted as emergencies for asthma or chronic bronchitis and living in Barcelona were identified and their age, sex, address, day and hour of arrival, and details of their referral or discharge from the emergency room were recorded. An "emergency room visit for asthma" was defined as a visit during which any diagnosis of asthma was recorded in the emergency room log books. To take account of differences in terminology between hospitals we drew up a list of expressions used that would qualify for inclusion as asthma. Thus we included under the category of asthma the terms asthmatic bronchitis, obstructive bronchitis, spastic bronchitis, bronchial hyperreactivity, asthmatic status, and bronchospasm. Another list was made for chronic bronchitis. We analysed the data for adults and children separately since they are handled in separate emergency

rooms.

During the 10 days following the outbreak we interviewed by telephone 86% of the subjects who qualified for the study. A standardised questionnaire was used to discover how they had felt during the day before the outbreak, when and where their asthma crisis had started, and what they thought was the cause of their attack. Air pollution data were collected by the municipal environment department and by the Barcelona Metropolitan Corporation environment department. Levels of SO2 (acidity method) and smoke (British smoke filter technique) were obtained from sixteen