Internationa! Journal of Epidemiology© International Epidemiological Association 1985

Vol. 14, No. 1Printed in Great Britain

Sick Individuals and Sick PopulationsGEOFFREY ROSE

Rose G (Department of Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E7HT, UK). Sick individuals and sick populations. International Journal of Epidemiology 1985, 14: 32-38.Aetiology confronts two distinct issues: the determinants of individual cases, and the determinants of incidence rate. Ifexposure to a necessary agent is homogeneous within a population, then case/control and cohort methods will fail todetect it: they will only identify markers of susceptibility. The corresponding strategies in control are the 'high-risk'approach, which seeks to protect susceptible individuals, and the population approach, which seeks to control thecauses of incidence. The two approaches are not usually in competition, but the prior concern should always be todiscover and control the causes of incidence.

THE DETERMINANTS OF INDIVIDUAL CASESIn teaching epidemiology to medical students, I haveoften encouraged them to consider a question which Ifirst heard enunciated by Roy Acheson: 'Why did thispatient get this disease at this time?'. It is an excellentstarting-point, because students and doctors feel anatural concern for the problems of the individual.Indeed, the central ethos of medicine is seen as anacceptance of responsibility for sick individuals.

It is an integral part of good doctoring to ask notonly, 'What is the diagnosis, and what is thetreatment?' but also, 'Why did this happen, and couldit have been prevented?'. Such thinking shapes theapproach to nearly all clinical and laboratory researchinto the causes and mechanisms of illness. Hyper-tension research, for example, is almost wholly pre-occupied with the characteristics which distinguishindividuals at the hypertensive and normotensive endsof the blood pressure distribution. Research intodiabetes looks for genetic, nutritional and metabolicreasons to explain why some people get diabetes andothers do not. The constant aim in such work is toanswer Acheson's question, 'Why did this patient getthis disease at this time?'.

The same concern has continued to shape thethinking of all of us who came to epidemiology from abackground in clinical practice. The whole basis of thecase-control method is to discover how sick and healthyindividuals differ. Equally the basis of many cohortstudies is the search for 'risk factors', which identify

Department of Epidemiology, London School of Hygiene and TropicalMedicine, Keppel Street, London WC1E 7HT, UK.Based on a lecture to the Xth Scientific Meeting of the InternationalEpidemiological Association, 27 August 1984, Vancouver.

certain individuals as being more susceptible to disease;and from this we proceed to test whether these riskfactors are also causes, capable of explaining why someindividuals get sick while others remain healthy, andapplicable as a guide to prevention.

To confine attention in this way to within-populationcomparisons has caused much confusion (particularlyin the clinical world) in the definition of normality.Laboratory 'ranges of normal' are based on what iscommon within the local population. Individuals with'normal blood pressure' are those who do not stand outfrom their local contemporaries; and so on. What iscommon is all right, we presume.

Applied to aetiology, the individual-centredapproach leads to the use of relative risk as the basicrepresentation of aetiological force: that is, 'the risk inexposed individuals relative to risk in non-exposed'individuals'. Indeed, the concept of relative risk hasalmost excluded any other approach to quantifyingcausal importance. It may generally be the best measureof aetiological force, but it is no measure at all ofaetiological outome or of public health importance.

Unfortunately this approach to the search for causes,and the measuring of their potency, has to assume aheterogeneity of exposure within the study population.If everyone smoked 20 cigarettes a day, then clinical,case-control and cohort studies alike would lead us toconclude that lung cancer was a genetic disease; and inone sense that would be true, since if everyone isexposed to the necessary agent, then the distribution ofcases is wholly determined by individual susceptibility.

Within Scotland and other mountainous parts ofBritain (Figure 1, left section)1 there is no discerniblerelation between local cardiovascular death rates andthe softness of the public water supply. The reason isapparent if one extends the enquiry to the whole of the

32

SICK INDIVIDUALS AND SICK POPULATIONS 33

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FIGURE 1 Relation between water quality and cardiovascular mortality in towns of the UK.'

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UK. In Scotland, everyone's water is soft; and thepossibly adverse effect becomes recognizable onlywhen study is extended to other regions which have amuch wider range of exposure (r= -0.67). Even moreclearly, a case-control study of this question withinScotland would have been futile. Everyone is exposed,and other factors operate to determine the varying risk.

Epidemiology is often defined in terms of study ofthe determinants of the distribution of the disease; butwe should not forget that the more widespread is aparticular cause, the less it explains the distribution ofcases. The hardest cause to identify is the one that isuniversally present, for then it has no influence on thedistribution of disease.

THE DETERMINANTS OF POPULATIONINCIDENCE RATEI find it increasingly helpful to distinguish two kinds ofaetiological question. The first seeks the causes ofcases, and the second seeks the causes of incidence.'Why do some individuals have hypertension?' is aquite different question from 'Why do some popula-tions have much hypertension, whilst in others it israre?'. The questions require different kinds of study,and they have different answers.

Figure 2 shows the systolic blood pressure distribu-tions of middle-aged men in two populations—Kenyannomads2 and London civil servants.3 The familiarquestion, 'Why do some individuals have higher blood

X30° Kenyan nomads

London civil servants

60 80 100 120 110SYSTOLIC B.P.(mn.Hg)

FIGURE 2 Distributions of systolic blood pressure in middle-aged men in two populations.^

180 200

34 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

pressure than others?' could be equally well asked ineither of these settings, since in each the individualblood pressures vary (proportionately) to about thesame extent; and the answers might well be much thesame in each instance (that is, mainly genetic variation,with a lesser component from environmental andbehavioural differences). We might achieve a completeunderstanding of why individuals vary, and yet quitemiss the most important public health question,namely, 'Why is hypertension absent in the Kenyansand common in London?'. The answer to that questionhas to do with the determinants of the populationmean; for what distinguishes the two groups isnothing to do with the characteristics of individuals, itis rather a shift of the whole distribution—a massinfluence acting on the population as a whole. To findthe determinants of prevalence and incidence rates, weneed to study characteristics of populations, notcharacteristics of individuals.

A more extreme example is provided by the popula-tion distributions of serum cholesterol levels4 in EastFinland, where coronary heart disease is very common,and Japan, where the incidence rate is low: the twodistributions barely overlap. Each country has menwith relative hypercholesterolaemia (although theirdefinitions of the range of 'normal' would no doubtdisagree), and one could research into the genetic andother causes of these unusual individuals; but if wewant to discover why Finland has such a high incidenceof coronary heart disease we need to look for thosecharacteristics of the national diet which have soelevated the whole cholesterol distribution. Withinpopulations it has proved almost impossible todemonstrate any relation between an individual's dietand his serum cholesterol level; and the same applies tothe relation of individual diet to blood pressure and tooverweight. But at the level of populations it is adifferent story: it has proved easy to show strongassociations between population mean values forsaturated fat intake versus serum cholesterol level andcoronary heart disease incidence, sodium intake versusblood pressure, or energy intake versus overweight.The determinants of incidence are not necessarily thesame as the causes of cases.

HOW DO THE CAUSES OF CASES RELATE TOTHE CAUSES OF INCIDENCE?This is largely a matter of whether exposure variessimilarly within a population and between populations(or over a period of time within the same population).Softness of water supply may be a determinant ofcardiovascular mortality, but it is unlikely to beidentifiable as a risk factor for individuals, because

exposure tends to be locally uniform. Dietary fat is, Ibelieve, the main determinant of a population'sincidence rate for coronary heart disease; but it quitefails to identify high-risk individuals.

In the case of cigarettes and lung cancer it sohappened that the study populations contained aboutequal numbers of smokers and non-smokers, and insuch a situation case/control and cohort studies wereable to identify what was also the main determinant ofpopulation differences and time trends.

There is a broad tendency for genetic factors todominate individual susceptibility, but to explainrather little of population differences in incidence.Genetic heterogeneity, it seems, is mostly much greaterwithin than between populations. This is the contrarysituation to that seen for environmental factors. Thusmigrants, whatever the colour of their skin, tend toacquire the disease rates of their country of adoption.

Most non-infectious diseases are still of largelyunknown cause. If you take a textbook of medicine andlook at the list of contents you will still find, despite allour aetiological research, that most are still of basicallyunknown aetiology. We know quite a lot about thepersonal characteristics of individuals who aresusceptible to them; but for a remarkably large numberof our major non-infectious diseases we still do notknow the determinants of the incidence rate.

Over a period of time we find that most diseases arein a state of flux. For example, duodenal ulcer inBritain at the turn of the century was an uncommoncondition affecting mainly young women. During thefirst half of the century the incidence rate rose steadilyand it became very common, but now the disease seemsto be disappearing; and yet we have no clues to thedeterminants of these striking changes in incidencerates. One could repeat that story for many conditions.

There is hardly a disease whose incidence rate doesnot vary widely, either over time or between popula-tions at the same time. This means that these causes ofincidence rate, unknown though they are, are notinevitable. It is possible to live without them, and if weknew what they were it might be possible to controlthem. But to identify the causal agent by the traditionalcase-control and cohort methods will be unsuccessful ifthere are not sufficient differences in exposure withinthe study population at the time of the study. In thosecircumstances all that these traditional methods do is tofind markers of individual susceptibility. The cluesmust be sought from differences between populationsor from changes within populations over time.

PREVENTIONThese two approaches to aetiology—the individual and

SICK INDIVIDUALS AND SICK POPULATIONS 35

the population-based—have their counterparts inprevention. In the first, preventive strategy seeks toidentify high-risk susceptible individuals and to offerthem some individual protection. In contrast, the'population strategy' seeks to control the determinantsof incidence in the population as a whole.

The 'High-Risk' StrategyThis is the traditional and natural medical approach toprevention. If a doctor accepts that he is responsible foran individual who is sick today, then it is a short step toaccept responsibility also for the individual who maywell be sick tomorrow. Thus screening is used to detectcertain individuals who hitherto thought they were wellbut who must now understand that they are in effectpatients. This is the process, for example, in thedetection and treatment of symptomless hypertension,the transition from healthy subject to patient beingratified by the giving and receiving of tablets. (Anyonewho takes medicines is by definition a patient.)

What the 'high-risk' strategy seeks to achieve issomething like a truncation of the risk distribution.This general concept applies to all special preventiveaction in high-risk individuals—in at-risk pregnancies,in small babies, or in any other particularly susceptiblegroup. It is a strategy with some clear and importantadvantages (Table 1).

TABLE I Prevention by the 'high-risk strategy': advantages.

1. Intervention appropriate to individual2. Subject motivation3. Physician motivation4. Cost-effective use of resources5. Benefii:risk ratio favourable

Its first advantage is that it leads to interventionwhich is appropriate to the individual. A smoker whohas a cough or who is found to have impairedventilatory function has a special reason for stoppingsmoking. The doctor will see it as making sense toadvise salt restriction in a hypertensive. In suchinstances the intervention makes sense because thatindividual already has a problem which that particularmeasure may possibly ameliorate. If we considerscreening a population to discover those with highserum cholesterol levels and advising them on dietarychange, then that intervention is appropriate to thosepeople in particular: they have a diet-related metabolicproblem.

The 'high-risk' strategy produces interventions thatare appropriate to the particular individuals advised totake them. Consequently it has the advantage ofenhanced subject motivation. In our randomized

controlled trial of smoking cessation in London civilservants we first screened some 20000 men and fromthem selected about 1500 who were smokers with, inaddition, markers of specially high risk for cardio-respiratory disease. They were recalled and a randomhalf received anti-smoking counselling. The results, interms of smoking cessation, were excellent becausethose men knew they had a special reason to stop. Theyhad been picked out from others in their officesbecause, although everyone knows that smoking is abad thing, they had a special reason why it was particu-larly unwise for them.

There is, of course, another and less reputable reasonwhy screening enhances subject motivation, and that isthe mystique of a scientific investigation. A ventilatoryfunction test is a powerful enhancer of motivation tostop smoking: an instrument which the subject does notquite understand, that looks rather impressive, hasproduced evidence that he is a special person with aspecial problem. The electrocardiogram is an evenmore powerful motivator, if you are unscrupulousenough to use it in prevention. A man may feel entirelywell, but if those little squiggles on the paper tell thedoctor that he has got trouble, then he must accept thathe has now become a patient. That is a powerfulpersuader. (I suspect it is also a powerful cause of lyingawake in the night and thinking about it.)

For rather similar reasons the 'high-risk' approachalso motivates physicians. Doctors, quite rightly, areuncomfortable about intervening in a situation wheretheir help was not asked for. Before imposing advice onsomebody who was getting on all right without them,they like to feel that there is a proper and specialjustification in that particular case.

The 'high-risk' approach offers a more cost-effectiveuse of limited resources. One of the things we havelearned in health education at the individual level is thatonce-only advice is a waste of time. To get results wemay need a considerable investment of counselling timeand follow-up. It is costly in use of time and effort andresources, and therefore it is more effective toconcentrate limited medical services and time where theneed—and therefore also the benefit—is likely to begreatest.

A final advantage of the 'high-risk' approach is thatit offers a more favourable ratio of benefits to risks. Ifintervention must carry some adverse effects or costs,and if the risk and cost are much the same foreverybody, then the ratio of the costs to the benefitswill be more favourable where the benefits are larger.

Unfortunately the 'high-risk' strategy of preventionalso has some serious disadvantages and limitations(Table 2).

36 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

TABLE 2 Prevention by the 'high-risk strategy': disadvantages.

1. Difficulties and costs of screening2. Palliative and temporary—not radical3. Limited potential for (a) individual

(b) population4. Behaviourally inappropriate

The first centres around the difficulties and costs ofscreening. Supposing that we were to embark, as somehad advocated, on a policy of screening for highcholesterol levels and giving dietary advice to thoseindividuals at special risk. The disease process we aretrying to prevent (atherosclerosis and its complications)begins early in life, so we should have to initiatescreening perhaps at the age of ten. However, theabnormality we seek to detect is not a stable lifetimecharacteristic, so we must advocate repeated screeningat suitable intervals.

In all screening one meets problems with uptake, andthe tendency for the response to be greater amongstthose sections of the population who are often least atrisk of the disease. Often there is an even greaterproblem: screening detects certain individuals who willreceive special advice, but at the same time it cannothelp also discovering much larger numbers of 'border-liners', that is, people whose results mark them as atincreased risk but for whom we do not have an appro-priate treatment to reduce their risk.

The second disadvantage of the 'high-risk' strategy isthat it is palliative and temporary, not radical. It doesnot seek to alter the underlying causes of the disease but

to identify individuals who are particularly susceptibleto those causes. Presumably in every generation therewill be such susceptibles; and if prevention and controlefforts were confined to these high-risk individuals,then that approach would need to be sustained yearafter year and generation after generation. It does notdeal with the root of the problem, but seeks to protectthose who are vulnerable to it; and they will always bearound.

The potential for this approach is limited—some-times more than we could have expected—both for theindividual and for the population. There are tworeasons for this. The first is that our power to predictfuture disease is usually very weak. Most individualswith risk factors will remain well, at least for someyears; contrariwise, unexpected illness may happen tosomeone who has just received an 'all clear' reportfrom a screening examination. One of the limitations ofthe relative risk statistic is that it gives no idea of theabsolute level of danger. Thus the Framingham Studyhas impressed us all with its powerful discriminationbetween high and low risk groups, but when we see(Figure 4)5 the degree of overlap in serum cholesterollevel between future cases and those who remainedhealthy, it is not surprising that an individual's future isso often misassessed.

Often the best predictor of future major disease is thepresence of existing minor disease. A low ventilatoryfunction today is the best predictor of its future rate ofdecline. A high blood pressure today is the bestpredictor of its future rate of rise. Early coronary heartdisease is better than all the conventional risk factors as

40 -

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NON-CHD

"140 ISO ISO 220 260 300 340 380 420 460 490 500 +

SERUM CHOLESTEROLFIGURE 3 Percentage distribution of serum cholesterol levels (mg/dl) in men aged 50-62 who did or did not subsequently develop coronaryheart disease (Framingham Study^).

SICK INDIVIDUALS AND SICK POPULATIONS 37

a predictor of future fatal disease. However, even ifscreening includes such tests for early disease, ourexperience in the Heart Disease Prevention Project(Table 3)6 still points to a very weak ability to predictthe future of any particular individual.

TABLE 3 Five-year incidence of myocardial infarction in the UKHeart Disease Prevention Project.

Enlry characteristic

Risk factors alone'Ischaemia''Ischaemia' + risk factorsAll men

% o fmen

15162

100

% of Mlcases

324112

100

MI incidencerate %

711224

This point came home to me only recently. I havelong congratulated myself on my low levels of coronaryrisk factors, and I joked to my friends that if I were todie suddenly, I should be very surprised. 1 even'speculated on what other disease—perhaps coloncancer—would be the commonest cause of death for aman in the lowest group of cardiovascular risk. Thepainful truth is that for such an individual in a Westernpopulation the commonest cause of death—by far—iscoronary heart disease! Everyone, in fact, is a high-riskindividual for this uniquely mass disease.

There is another, related reason why the predictivebasis of the 'high-risk' strategy of prevention is weak. Itis well illustrated by some data from Alberman7 whichrelate the occurrence of Down's syndrome births tomaternal age (Table 4). Mothers under 30 years areindividually at minimal risk; but because they are sonumerous, they generate half the cases. High-riskindividuals aged 40 and above generate only 13% of thecases.

The lesson from this example is that a large numberof people at a small risk may give rise to more cases ofdisease than the small number who are at a high risk.

TABLE 4 Incidence of Down's syndrome according to maternal age.1

Maternalage (years)

< 3 030-3435-3940-44> 4 5

All ages

Risk ofDown's syndrome

per 1000births

0.71.33.7

13.134.6

1.5

Total birthsin age group

(as % ofall ages)

781650.950.05

100

% of totalDown's syndrome

occurring inage group

512016112

100

This situation seems to be common, and it limits theutility of the 'high-risk' approach to prevention.

A further disadvantage of the 'high-risk' strategy isthat it is behaviourally inappropriate. Eating, smoking,exercise and all our other life-style characteristics areconstrained by social norms. If we try to eat differentlyfrom our friends it will not only be inconvenient, butwe risk being regarded as cranks or hypochondriacs. Ifa man's work environment encourages heavy drinking,then advice that he is damaging his liver is unlikely tohave any effect. No-one who has attempted any sort ofhealth education effort in individuals needs to be toldthat it is difficult for such people to step out of line withtheir peers. This is what the 'high-risk' preventivestrategy requires them to do.

The Population StrategyThis is the attempt to control the determinants ofincidence, to lower the mean level of risk factors, toshift the whole distribution of exposure in a favourabledirection. In its traditional 'public health' form it hasinvolved mass environmental control methods; in itsmodern form it is attempting (less successfully) to altersome of society's norms of behaviour.

The advantages are powerful (Table 5). The first is

TABLE 5 Prevention by the 'population strategy': advantages.

1. Radical2. Large potential for population3. Behaviourally appropriate

that it is radical. It attempts to remove the underlyingcauses that make the disease common. It has a largepotential—often larger than one would have expected—for the population as a whole. From Framinghamdata one can compute that a 10 mm Hg lowering of theblood pressure distribution as a whole wouldcorrespond to about a 30% reduction in the totalattributable mortality.

The approach is behaviourally appropriate. If non-smoking eventually becomes 'normal', then it will bemuch less necessary to keep on persuading individuals.Once a social norm of behaviour has become acceptedand (as in the case of diet) once the supply industrieshave adapted themselves to the new pattern, then themaintenance of that situation no longer requires effortfrom individuals. The health education phase aimed atchanging individuals is, we hope, a temporarynecessity, pending changes in the norms of what issocially acceptable.

Unfortunately the population strategy of preventionhas also some weighty drawbacks (Table 6). It offers

38 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

TABLE 6 Prevention by the 'population strategy': disadvantages.

1. Small benefit lo individual ('Prevention Paradox')2. Poor motivation of subject3. Poor motivation of physician4. Benefit:risk ratio worrisome

only a small benefit to each individual, since most ofthem were going to be all right anyway, at least formany years. This leads to the Prevention Paradox:* 'Apreventive measure which brings much benefit to thepopulation offers little to each participating indi-vidual'. This has been the history of public health—ofimmunization, the wearing of seat belts and now theattempt to change various life-style characteristics. Ofenormous potential importance to the population as awhole, these measures offer very little—particularly inthe short term—to each individual; and thus there ispoor motivation of the subject. We should not besurprised that health education tends to be relativelyineffective for individuals and in the short term. Mostlypeople act for substantial and immediate rewards, andthe medical motivation for health education isinherently weak. Their health next year is not likely tobe much better if they accept our advice or if they rejectit. Much more powerful as motivators for healtheducation are the social rewards of enhanced self-esteem and social approval.

There is also in the population approach only poormotivation of physicians. Many medical practitionerswho embarked with enthusiasm on anti-smokingeducation have become disheartened because theirsuccess rate was no more than 5 or 10%: in clinicalpractice one's expectation of results is higher. Gratefulpatients are few in preventive medicine, where successis marked by a non-event. The skills of behaviouraladvice are different and unfamiliar, and professionalesteem is lowered by a lack of skill. Harder to overcomethan any of these, however, is the enormous difficultyfor medical personnel to see health as a populationissue and not merely as a problem for individuals.

In mass prevention each individual has usually only asmall expectation of benefit, and this small benefit caneasily be outweighed by a small risk.8 This happened inthe World Health Organization clofibrate trial,9 wherea cholesterol-lowering drug seems to have killed morethan it saved, even though the fatal complication ratewas only about 1/1000/year. Such low-order risks,which can be vitally important to the balance sheet ofmass preventive plans, may be hard or impossible todetect. This makes it important to distinguish two

approaches. The first is the restoration of biologicalnormality by the removal of an abnormal exposure (eg,stopping smoking, controlling air pollution, moderat-ing some of our recently-acquired dietary deviations);here there can be some presumption of safety. This isnot true for the other kind of preventive approach,which leaves intact the underlying causes of incidenceand seeks instead to interpose some new, supposedlyprotective intervention (eg, immunization, drugs,jogging). Here the onus is on the activists to produceadequate evidence of safety.

CONCLUSIONSCase-centred epidemiology identifies individualsusceptibility, but it may fail to identify the underlyingcauses of incidence. The 'high-risk' strategy ofprevention is an interim expedient, needed in order toprotect susceptible individuals, but only for so long asthe underlying causes of incidence remain unknown oruncontrollable; if causes can be removed, susceptibilityceases to matter.

Realistically, many diseases will long continue to callfor both approaches, and fortunately competitionbetween them is usually unecessary. Nevertheless, thepriority of concern should always be the discovery andcontrol of the causes of incidence.

REFERENCES1 Pocock S J, Shaper A G, Cook D G « al. British Regional Heart

Study: geographic variations in cardiovascular mortality andthe role of water quality. Brit Med J 1980; 283: 1243-9.

2 Shaper A G. Blood pressure studies in East Africa. In: The Epi-demiology of Hypertension. J Stamler, R Stamler, T NPullman (eds). New York, Grune and Stratten, 1967.pp 139-45.

3 Reid D D, Brett G Z, Hamilton P J S et al. Cardiorespiratorydisease and diabetes among middle-aged male civil servants.Lancet 1974; 1:469-73.

4 Keys A. Coronary heart disease in seven countries. American HeartAssociation Monograph Number 29. American Heart Associa-tion, New York, 1970.

5 Kannel W B, Garcia M J, McNamara P M el al. Serum lipid pre-cursors of coronary heart disease. Human Palhol 1971; 2:129-51.

6 Heller R F, Chinn S, Tunstall Pedoe H D et al. How well can wepredict coronary heart disease? Findings in the UnitedKingdom Heart Disease Prevention Project. Brit Med J 1984;288: 1409-11.

7 Alberman E, Berry C. Prenatal diagnosis and the specialist incommunity medicine. Community Med 1979; 1: 89-96.

8 Rose G. Strategy of prevention: lessons from cardiovascular disease.Brit MedJ 1981; 282: 1847-51.

' Committee of Principal Investigators. A co-operative trial in theprimary prevention of ischaemic heart disease. Br Heart J1978; 40: 1069-118.