7463

Saturday IO September I966

INCIDENCE AND PREDICTION OF

ISCHÆMIC HEART-DISEASEIN LONDON BUSMEN

J. N. MORRISD.Sc. Lond., F.R.C.P., D.P.H.

DIRECTOR

AUBREY KAGAN*M.B. Lond., M.R.C.P., D.P.H.

MEMBER

D. C. PATTISONM.B. Birm., D.Obst., D.P.H.

MEMBER

M. J. GARDNERB.Sc. Durh., Dip. Math. Stat.

MEMBER

MEDICAL RESEARCH COUNCIL’S SOCIAL MEDICINE RESEARCH UNIT,THE LONDON HOSPITAL, LONDON E.1

P. A. B. RAFFLEM.D. Lond., D.P.H., D.I.H.

DEPUTY CHIEF MEDICAL OFFICER,LONDON TRANSPORT BOARD, LONDON S.W.1

BETWEEN 1956 and 1960 A. K. examined a sample of687 drivers and male conductors working on LondonTransport’s central buses. The examination includedmany factors known, or suspected, to be related to

ilie incidence of ischxmic heart-disease, and about 5years later D. C. P. re-examined the men. 93% havenow been seen (or have died) and useful medical infor-mation is available on most of the remainder. Duringthis follow-up we found that ischaemic heart-disease haddeveloped in 47 of the men. We describe here theincidence of the disease in terms of the observationsmade at the initial examination and attempt to see howindividuals at high and low risk might be predicted.

Methods

We examined the men in first-aid, or similar rooms, ingarages when they came off duty and under conditions as

uniform as possible. The examination included a familial,personal, and clinical history, blood-pressure readings,urinalysis, standard 12-lead electrocardiography at rest,measurements of physique and skin-fold thickness, and

blood-lipid estimations. The 7% of the men who have notbeen directly accounted for were not atypical for any of thevariables investigated. All examination findings are confidentialbetween the unit, the men, and, as required, their generalpractitioners; by agreement of all parties no information on anyindividual has been disclosed to the London Transport Board.Crireria of Ischcemic Heart-diseaseWe have classified the disease into four clinical categories

and give the number of cases which developed during follow-up.I (" sudden death from ischaemic heart-disease).-Death

within 24 hours of the first clinical attack. There were 7 casesduring the 5 years; in 6 the diagnosis was confirmed at necropsy.

II (myocardial infarction not " suddenly " fatal).-27 othermen had suffered a typical first infarction as judged by standardclinical and electrocardiographic criteria; 3 of them diedwithin a few days. In 25 cases diagnosis was confirmed by aconsultant in the National Health Service.

III (angina).-Questioning elucidated that 7 men not

.ncluded in category II had developed angina of effort duringthe 5 years.IV (Q’QS changes).-6 of the men developed these major

abnormalities on the electrocardiogram (corresponding to the* Present address: World Health Organisation, Geneva, Switzerland.

Minnesota code 11-2’ Blackburn et al. [1960]); they had noother evidence of ischaemic heart-disease. Changes were

agreed by three observers.At the initial examination, 20 men were found to have

ischxmic heart-disease of categories II/IV; they have not beenconsidered further in this incidence study. We are dealingtherefore with a sample of 667 busmen-who when firstexamined had no evidence of infarction or angina nor apathological Q wave-47 of whom developed ischaemic heart-disease during 5 years of observation .

Results

INCIDENCE OF ISCHNMIC HEART-DISEASE

Age6 of the 128 men who were in their forties when first

examined newly developed the disease (an incidence-rate

TABLE I-INCIDENCE OF ISCHIEMIC HEART-DISEASE IN SAMPLE OF

LONDON BUSMEN DURING 5 YEARS, BY AGE AT INITIAL EXAMINATION

Figures in parentheses are incidence-rates calculated from very smallnumbers of cases.

All men were born in the British Isles. ‘

‘

during the period of observation of 4-7 per 100 men); andso on for other ages (table I). The average period ofobservation was just over 5 years and most men were seenat 4-6 years. Thus table I also gives the incidence-rates per100 man-years of observation. These rates are just undera fifth of the former rates and since this was true through-out the analysis they will not be quoted further. (In thetables, we give incidence-rates per 100 men during theperiod of observation described as " 5 years ", though itaveraged just over 5 years.)

TABLE 11-INCIDENCE OF ISCH1E.1GIIC HEART-DISEASE IN CONDUCTORS

AND DRIVERS DURING 5 YEARS, BY AGE AT INITIAL EXAMINATION

* When standardised on the age-structure of the conductors this was 8-6 per100 men in 5 years. -

Allowing for consistency by age, p<0’05, for occupational difference.The rates per 100 man-years of observation were 0-9 in the conductors and

1-7 in the drivers, the drivers’ rate again being standardised for age.

554

TABLE ill-INCIDENCE OF ISCHUEMIC HEART-DISEASE IN CONDUCTORS AND DRIVERS DURING 5 YEARS, BY AGE AND CASUAL SYSTOLIC-

z

BLOOD-PRESSURE LEVEL AT INITIAL EXAMINATION

The quartile points (mm. Hg) for each column were, from high to low: (1) 153, 137, 125; (2) 161, 143, 131; (3) 165, 153, 143; (4) 153,135,125; (5) 171153, 137; and (6) 175, 159, 145.

* 1 case was aged 39, a driver, systolic B.P. 128 mm. Hg. t The casual pressure of 3 men was not recorded.

OccupationTable 11 gives incidence-rates of ischaemic heart-disease

for conductors and drivers separately. As expected(Morris et al. 1953, Morris 1964), the conductors ofthese double-decker buses have a lower incidence. This,again as expected, is particularly evident in early middleage but the number of men under 50 is very small.At the time of their initial examination most of the

men had been in the same job for over 20 years; only 4of the 47 men who developed ischaemic heart-disease hadbeen driving or conducting for less than 10 years, a fractiontypical of the whole sample.On average, drivers earned only a few shillings per

week more than conductors and standards of living arethus about the same.

Blood-pressureThe incidence is strongly associated with the casual

systolic blood-pressure (s.B.P.). This was taken very soonafter the man entered the examination room and while hewas sitting. We used the same standard manual mercurysphygmomanometer (cuff 14 cm.) throughout and readthe levels to the nearest even number.We divided the drivers into four groups, by using the

quartile points of the distribution of casual systolic B.P.for each 10-year age-group to produce as nearly equal"

quarters " as possible. Thus (table ill) the drivers inthe top quarters had levels over 153 mm. Hg at ages40-49; over 171 at 50-59; and over 175 at 60-69; thesedrivers may be considered to have " high " blood-pressure. We divided the conductors in the same way.Next, we identified the new cases of ischaemic heart-disease within the quarters; the results are shown in

table in. There are 23 in the high quarters (lastcolumn of the table) and 6 in the low quarters. Theincidence among the hypertensive men (those in the" high " quarters), is several times that in the low"

quarters. Grouping the men into quarters is a useful, ifarbitrary, way of handling the data, but the number ofnew cases did not permit a finer breakdown.

Fig. la gives the incidence in terms of casual systolicB.P. for all the men, regardless of age or occupation.

Again there were 23 in the " high " quarter and 6 iathe " low "; the net result of the distribution of new casesis the same as in table ill. This is so, with only minordifferences, throughout the analysis and further resultsare simplified as in fig. la.

Systolic and diastolic B.P. in middle age are highlycorrelated, but the casual diastolic reading by itself isnot quite so effective a predictor, the number of newcases from high to low quarters being: 19, 16, 5, and 7.B.P. was also taken at rest and after mild exercise; simplecombinations of these various pressures, for example byadding the three systolic or diastolic readings together,have not been more powerful in identifying futureischaemic heart-disease than the casual systolic (ordiastolic) reading alone.Very few of the men in the high quarters of S.B.P,

distributions initially had any symptoms referable (evenwith hindsight) to the cardiovascular system and, of

course, none showed evidence of ischaemic heart-disease,No systematic search was made for " secondary"hypertension other than analysis for proteinuria.

Blood-pressure and OccupationThere are two connections between S.B.P., occupation,

. = New case oF ischaemic heart-disease, a complete row is ten cases

Fig. 1-Incidence of ischaemic heart-disease in sample of London busmen during 5 years by findings at initial examination

555

i ABLE IV-INCIDENCE OF ISCHPEMIC HEART-DISEASE IN CONDUCTORS

AXD DRIVERS DURING 5 YEARS, BY CASUAL SYSTOLIC BLOOD-PRESSURELEVEL AT INITIAL EXAMINATION

664 men.I Standardisation by indirect method.’ Niorbidity ratios " are 190 &plusmn;40 and 69 &plusmn; 14.There was 1 case among the 7 conductors whose systolic B.P. was 200 mm. Hg

and over, and 2 among the 16 such drivers.

and ischxmic heart-disease. Drivers aged over 50 havehigher S.B.P. than conductors-higher average pressuresand more men with " high " pressures (table ill). Thisis a factor, therefore, in the higher incidence of thedisease among drivers. Secondly, there is an indicationthat at the same level of S.B.P. drivers have a higherincidence than conductors (table iv).Incidence in Relation to Initial Blood-lipid LevelsWe took a sample of blood from each man and the

Courtauld Institute made various estimations for us.

The plasma was analysed by the micromethod 10 ofCohn et al. (1950) into fractions containing the oc and &bgr;hpoproteins. Cholesterol in these fractions and in the

o6onal plasma was determined by the Liebermann-Burchard reaction as described by Dodds and Mills

’1959). Total plasma-cholesterol in 607 men-measuredregardless of season of year, time of day, or time of lastmeal-is a good predictor (fig. lb), with 19 new casesin the high quarter and 5 in the low. P-lipoproteincholesterol seems to be the effective fraction-19, 11, 6,and 3 new cases occurring in the quarters from high tolow-but the number of estimations was less again (544men). With oc-lipoprotein cholesterol the figures are 6cases in the high quarter, then 10, 14, and 9 in the otherquarters. The very-low-density lipoproteins, Sf20-400,that carry much of the plasma-triglyceride (Gofman et al.1966) were also estimated. They showed an iriconsistenttrend with incidence of ischsemic heart-disease; we willreport when more cases have accumulated.Drivers have substantially higher blood-lipid levels

than do conductors of the same age, and this is anotherfactor in the higher incidence of ischasmic heart-diseasein the drivers.These connections between age, occupation, S.B.P., and

blood-lipid levels and the subsequent incidence ofischsmic heart-disease are the main findings; we reportbriefly on five others, none of them statistically significant.Parental MortalityThe circumstances of the examination were not suitable for

taking a detailed family history of health but we did try to getinformation on age of parents at death (Morrison and Morris1960). The 5 years’ incidence of ischasmic heart-disease is 9-1per 100 among busmen one or both of whose parents died at40-64 (they are later described as " positive " in this respect),and 59 per 100 in men whose parents lived to age 65.

Stature

The incidence of ischasmic heart-disease is greatest amongthe shortest men (fig. lc), and the same is true measuring‘=

sittmg-height ". Gertler and White (1954) have noted this2ociation. There is no excess of high S.B.P. among the 160snortest men, but the 40 hypertensive (as defined) in this groupna.e a particularly high incidence-with 10 new cases, com-

pared to 7 in the other 120 men of similar height. The shorthypertensive men who developed the disease were not particu-larly obese, nor did they have especially high blood-cholesterollevels.

ObesityWe measured skin-fold thickness at three sites (the triceps,

subscapular, and suprailiac) on the right side of the body, usinga Harpenden calliper (Edwards et al. 1955). There is a trend forincreasing incidence of ischasmic heart-disease with increasingfatness; this is most striking for the skin-fold thickness at thesuprailiac crest (fig. ld).Cigarette Smoking

Unfortunately, the number of men who had never smokedcigarettes was small (45 of the 667 in the sample). But cigarettesmokers at the time of the initial examination do show a

greater incidence of ischaemic heart-disease than all currentnon-smokers-7-9 and 4-7 per 100 men, respectively.Electrocardiographic Abnormalities at Initial Examination

.

The electrocardiogram was taken at rest using a portabledirect writer (Phillips). We consider three types of change tobe important while not acceptable as isch2emic heart-disease.Abnormalities (Minnesota code) were noted in 68 cases as

follows: 59 cases with ST depression and/or T-wave flatteningor inversion (iVi-g, Vj-g); 6 cases with left ventricular pre-ponderance with ST/T wave changes as above (IIIl); and 3cases with left bundle-branch block (vili). Three observers

agreed on these findings.When first seen, then, 68 of the men presented such

abnormality without evidence of ischasmic heart-disease.8 of them (12%) subsequently developed the disease comparedwith 6-5% of the 599 men who did not show such changes.

In the 599 men, we include 37 with miscellaneous electro-

cardiographic changes of left ventricular hypertrophy, rightbundle-branch block, sinus arrhythmia, &c. As a group thesemen show about the same incidence of ischxmic heart-disease

during the 5 years as the rest of the 599 men; numbers aretoo small for calculations to be done for individualabnormalities.

Other Factors

Many other factors were examined and found to haveno or negligible relationship, taken singly or in variouscombinations, to the development of ischaemic heart-disease. These include body-weight, relative weight,ponderal index, arm circumference, waist, biacromialdiameter, chest expansion, haemoglobin level, civil state,number of siblings and children, social class of father, andalcohol consumption. We will not mention these further.

MULTIPLE FACTORS AND INDIVIDUAL RISK

Levels of S.B.P. and plasma-cholesterol thus standout as predictors of the incidence of ischaemic heart-disease.. The correlation between S.B.P. and plasma-cholesterol is low (r = -i-0-28 for 604 men) and manymen with " high " levels of one have " low " levels of theother. Together (fig. 2) "high" levels of S.B.P. or

cholesterol contain about three-quarters of the new casesof ischaemic heart-disease. For this population, therefore,we may postulate that the 40% of the men with eitherlevel " high " (or both) contain the epidemic disease.These 34 new cases occurred among 240 men; their indivi-dual risk of having ischaemic heart-disease within the 5years is thus 1 in 7 (and almost exactly the same on life-table calculation for the varying periods of follow-up). Weattempted next to improve prediction of individual riskby considering actual values of s.B.P. and cholesterol andnot merely the quarter of the distribution in which theyoccurred; and by including at the same time the otherseven factors reported. Several investigations have shownthese to be relevant; in the present study they behave as

556

Fig. 2-Incidence of ischsemie heart-disease in London busmenduring 5 years by casual systolic B.P. and plasma-cholesterol atinitial examination.

604 men; p< 0-0001.

postulated. All the factors are interrelated, moreover, sothis aspect must also be examined. Many of the inter-relationships-e.g., the strong connection between obesity,blood-lipids and B.P.-are interesting but will not be con-sidered further here. Our concern is with net effects onthe incidence of ischaemic heart-disease.

Discriminant AnalysisWe adopted the method of linear discriminant function

analysis (Fisher 1936, Cornfield 1962). Multivariate

analysis of a large set of data is more practicable now thatthere is direct access to electronic computers and somelibrary programmes are available. In discriminantanalysis, a single " score ", based on the observed valuesof factors, is given to each man. In this instance, thescore is a measure in terms of the factors studied of anindividual’s risk of developing ischaemic heart-disease, andis calculated as a weighted addition of their values. Theweights are determined to produce as small a range ofscores as possible within each of the two groups (with orwithout the disease) and as little overlap as possiblebetween the groups. The efficiency of the discriminantscore for selecting men at greater or lesser risk will beevident to the degree that the new cases have highervalues than the remainder; its efficiency diminishes themore the scores for the two groups overlap. The moreefficient the score in this sense, the better will it be as apredictor of the small group of men (a), who are at aparticularly high risk (b), and among whom the majorityof the future cases in the population will occur (c). At

present in the U.K., about 20% of men, we may estimate,develop clinical ischaemic heart-disease during middle age;in these terms the group is small. (a), (b), and (c) arerelated, each is a function of the other two (the argumentis briefly set out in an appendix to this article).

Theoretical requirements of the mathematical modelunderlying the technique of discriminant analysis are

not strictly met iri the present exercise. Thus, thedistribution of S.B.P. is not normal but skewed;logarithmic transformation while overcoming this makeslittle difference to the power of the discriminant.Moreover, " qualitative " factors, for example whethera man was driver or conductor at the initial examination,had to be included and " quantified ". But we wentahead on the grounds that the first essential of any toolis that it should be useful and, of the multivariate

techniques now available, the discriminant seems thebest for the particular question we are asking.We cannot include all our men in this analysis because

data on some of them are incomplete. The nine factors

already considered are completely specified for 593 men,43 of whom developed ischaemic heart-disease. Thesefactors are:

(X1)Age (in years) at first examination.(X2) History of parental mortality in middle age (negative 0,

positive 1).(Xs) Stature (cm.).(X4) Skinfold thickness at suprailiac crest (mm.).(Xs) Occupation (conductor 0, driver 1).(X6) Current cigarette-smoking (non-smoker 0, smoker 1).(X,) Casual systolic B.P. (mm. Hg).(Xg) Total plasma-cholesterol (mg. per 100 ml.).(Xe) Non-ischaemic electrocardiographic abnormality of the

three types described (absent 0, present 1).It is helpful at this point to think of the natural history

of a chronic disease like ischsemic heart-disease in" stages " (Morris 1964). Thus it is possible to postulate:

(1) the causes in inheritance, experience, and mode of life;(2) the precursor pathology, as causes begin to show effects in

disturbed function and structure, without as yet anyevidence of the disease; then comes the

(3) early incidence as disease, possible reversible, appears;and so on to established and advanced disease, &c.

Several postulated causes of ischaemic heart-disease areincluded in our study, and two evident precursors-high levels of B.P. and plasma-cholesterol-the minorelectrocardiographic abnormalities may be regarded as

Fig. 3-Incidence of ischsemic heart-disease in London busmenduring 5 years by findings at initial examination.

Quarters of men identified by linear discriminant function analysisincluding stated factors (see text).

(a) Causes (X1-XS); r < 0&deg;Ol.(b) Precursors (X&mdash;Xs); p< 0-0001.(c) Causes, precursors, and early disease (X1-X9); r<000001.

593 men.

early disease. So we organised these factors to give somepicture of causes (X1-X6), precursors (X7 and Xs), andearly disease (X9).We consider the causes first. By obtaining a weighted

score (as described) from factors X1-X6, we sought tocombine their individual predictive powers in an effectiveway; at the same time the method indicates the extent towhich the factors are contributing independently-thisis essential in view of known interrelationships, for

example of age, obesity, and occupation. We calculatea score for each of the 593 men, divided them into" quarters " of about 150 and identified the nurnb6of new cases occurring in each. Fig. 3a shows that

these causes by themselves go some way to building a

predictive device : the individual risk of a man with a

high score is several times greater than that of a man

with a low score. Occupation is the most powerful ofthese causes; stature and obesity contribute little to the

prediction in the presence of the other factors.Next we produced a score, using only the measure.

557

TABLE V-PROFILE OF " LOW " AND " HIGH

"

QUARTERS OF THESAMPLE OF LONDON BUSMEN FOR RISK OF DEVELOPING ISCH&MIC

HEART-DISEASE DURING 5 YEARS

ments of S.B.P. and plasma-cholesterol. The equationshows the weights attaching to the two factors and howthe score is obtained:Score = 0139 x systolic B.P. (mm. Hg) + 0055 x

cholesterol (mg. per 100 ml.) - 34.1.The standard errors of the weights are 0045 for

n.p., and 0025 for plasma-cholesterol; each factoris therefore contributing significantly (p <0-01 andP <0’05, respectively) to the discriminant function. Menwith higher levels of each of these precursors have a

greater risk, men with lower levels a lesser risk of develop-ing ischsemic heart-disease. The quartile points of thedistribution of the combined score are -33, -03, and+31, the lowest score is -139 (a man with systolic B.P.of 100 mm. Hg and plasma-cholesterol of 115 mg. per100 ml.) and the highest + 16-8 (240 mm. Hg, 319 mg.per 100 ml.). The distribution of new cases of ischaemicheart-disease is shown in fig. 3b: over half the cases

occurred in the quarter of men with highest scores.Fig. 3c combines these causes, precursors, and early

disease. Individual prediction is now a little more effectiveagain: 25 new cases were among the men with highscores; about 1 in 6 of them developed ischaemic heart-disease. Dividing the men into five groups (instead offour) for all these factors, yields 21, 10, 6, 6, and 0 newcases in each. If we extend this process to six groups ofabout a hundred men, there are 18 new cases in the groupwith highest scores, then 9, 7, 5, 4, and 0 in the remainder.Early disease (X9) contributes very little.One point is clear: the levels of S.B.P. and plasma-

cholesterol predominate, and adding the other factorsachieves little net improvement in prediction. Comparingfigs. 3b and 3c, it seems that these causes (occupation,obesity, and the rest), operate largely through these pre-cursors. Moreover, comparing figs. 3a and 3b, and in lightof their many known and demonstrated connections, itseems that much of the predictive power of these precursorsis due to these causes.

Finally, for the moment, we contrast in " profile" the+ The effect of the constant (-341) in the equation is that the average score

for all the men is 0. Transforming both factors to the same scale (i.e.,adjusting to the same mean and variance) to compare their independentcontributions, produces weights of 3-36 and 2-37, respectively, bothhaving a standard error of 1-10. These weights are not significantlydiNerent.

sizeable groups of men placed (fig. 3c) in oppositequarters of risk by scores based on all the factors. Interms of these factors, and of the occurrence of new casesof ischaemic heart-disease, the men in the " low " and" high " quarters are very different (table v). In detail,for instance, 37 of the 46 busmen having a casual systolicB.P. reading less than 120 mm. Hg are in the " low "group as are 63 of the 88 men with cholesterol levelsunder 200 mg. per 100 ml. There are many older drivers,smokers, men who are fat and have a bad family historyin the " high " group; and there are many thin conductorswith a good family history and an unblemished electro-cardiograph in the " low " group. Individually, there areinteresting placements of men with high S.B.P. or plasma-cholesterol in the " low " group (none of these men havedeveloped ischaemic heart-disease) through the compen-sating advantages in other factors. In this way we canmove towards a picture of the individual who is susceptibleto ischaemic heart-disease and, equally interesting thoughnot elaborated here, the individual least likely to developthe disease.

Discussion

We comment briefly that these results though limitedin themselves are strongly in line with much Americanwork (Keys et al. 1963, Paul et al. 1963, Chapmanand Massey 1964, Gertler et al. 1964, Doyle 1966,Epstein 1966, Gofman et al. 1966, Kannel et al. 1966,Stamler et al. 1966). Our findings illustrate two advan-tages of prospective studies of incidence. Thus, 10 ofthe 47 new cases were rapidly fatal, and liable to bemissed in a cross-sectional survey at any one time.

Moreover, 6 of the 47 new events had silent Q-waveabnormality only, compared to 9 of the 20 cases foundat the initial examination. The method of sampling(Heady et al. 1961) excluded men absent from workbecause of their first clinical attack of ischaemic heart-disease ; these could have added only another 1-3 cases,probably with acute infarction, to the original 20. Inthis population, therefore, the clinical pictures of incidenceand prevalence are very different. Secondly, the pre-dictive value of any factor, such as B.P., for the develop-ment of ischaemic heart-disease can only be demonstratedprospectively. It is also interesting that hypertension isparticularly related to the incidence of rapidly fatalinfarction. Of 10 men who died within a few days, 8were hypertensive for their age, but there were only7 hypertensive men among the 24 with less severe

infarction. Adequate study of the association of riskfactors with type of disease will need more cases; com-

parison of these findings with the American likewisemust wait.

Fig. 3 demonstrates some of the possibilities of" explaining " the occurrence of epidemic ischaemic heart-disease in middle-aged men: but greater explanation canbe expected all along the front. Thus, fig. 3a surely under-states the position on causes. The number of men is small,especially those aged under 50, but apart from this, thedata do little justice to the cigarette smoking (Doyle et al.1964) or the genetic (Epstein 1964) contributions to thextiology; and the

" personality " factor is virtually ignored(if the findings of Rosenman et al. [1966] are confirmed,this last may prove to be a major gap). The observationstake a step further the hypothesis that physical activityof occupation is a protection against ischaemic heart-disease. The levels of S.B.P. and blood-lipids seem to beimportantly involved: middle-aged conductors have lowerlevels of both. But, even in this instance, it may be

558

questioned whether this is the best test of the hypothesis,whether bus conductors are typical of " active " workers-they seem to have almost as high an incidence of ischsemicheart-disease as physicians (Morris 1963). Such studiesneed to be repeated on general population samples,including physically active occupations without the

particular nervous strains of bus-conducting. We

ignored nutrition, but in the present study it seems to playno part in determining casual blood-lipid levels (Morriset al. 1963), nor is there much evidence for its effect onB.P. The diet of drivers and conductors is very similar,although conductors eat more calories per lb. body-weight(Marr 1966).At the stage of measurement of precursors, also, better

methods can be expected. &bgr;-lipoprotein cholesterol mayyet prove a more powerful predictor than total cholesterol.Casual S.B.P., which is proving so predictive, is at presentmeasured crudely; perhaps this can be remedied (Holland1963), though it could be that its usefulness lies in theway it is measured at present. Adjusting B.P. for arm-circumference and body-weight (Lancet 1966) makes

very little difference to our findings. Factors not includedmay also be useful predictors-e.g., blood-sugar (Epstein1966). Of 15 busmen with glycosuria at the initial

examination, 1 has developed ischxmic heart-disease, butno loading tests were done. Similarly, the attempt todetect early disease should include a challenge (Rumballand Acheson 1963, Bruce and Yarnall 1966).More powerful prediction thus will probably come, as

also may easier methods (although the tests used at presentcould readily be done in a few minutes by any doctor, orhis auxiliary, with the backing of a modern laboratory).At the most elementary stage of all-the diagnosis ofthe disease-there is much scope for improvement. Weused a clinical rather than epidemiological approach(Reid et al. 1966). And at the other end, better mathe-matical models will surely come; the linear discriminantfunction (designed for addition of normally distributedvariables exerting direct effects) by no means simulateswhat is already known of the natural history of ischsemicheart-disease. The results of the present exercise are

interesting enough, but the inadequacy of the model isevident in the very modest improvement of predictionachieved by fig. 3 over the simple sums in fig. 2.

In conclusion we raise some larger issues. There is anew optimism that the modern epidemic of ischaemicheart-disease of middle age can be controlled. In the first

place, investigators are adjusting themselves to the idea of" multiple causes "-their existence, identity, how theyconnect, and that conceivably there is no essential causeexcept perhaps for some threshold of nutrition which mustbe reached. Public-health campaigns relating to thesecauses-e.g., education on the dangers of cigarette smok-ing or on the need for sedentary workers to take regularexercise-could be effective. But the dominant hopetoday is that action at the stage of precursor pathology(hypertension and hypercholesterolaemia in particular:may still achieve true primary prevention. Individual:shown to be susceptible will be identified and prophylacticmeasures directed at them. Prevention will be translatecinto the clinical field.

In these terms, three-quarters of the total incidence(fig. 2) is already a worthwhile prediction: this is thmain community problem. Reduction of disease in thi

high-risk group to that of the remainder would reducthe overall incidence among the busmen by about half

And an individual riskover 5 years of 1 in 7

(about five times that ofthe remainder) is alreadyserious enough to warrantattempts at individual pre-vention. Moreover, the

prediction is for the next5 years only. Trends ofvascular disease with agesuggest that the incidencein a further 5-year periodwill be the same at least:the high individual risk

may eventually become 1in 3, or even more, for thewhole span of middle age.In the long run, thenumber of " false-posi-tives " treated on such a

simple method of identi-fying susceptibles mightnot be unreasonably large.Cerebrovascular disease

Fig. 4-Incidence of cardiovas-cular disease in London bus.men during 5 years by casualsystolic B.P. level at initialexamination.

664 men; P < 0-00001.

Age-standardised incidence-rates per 100 men in 5 years in thefour quarters are 22-3, 76, 92,and 5-2 from " high " to " low ".2 men developed two conditions,but are counted only once.

has also to be considered. Even in middle age numbersare appreciable, and its incidence is strongly connectedwith levels of S.B.P. if not of blood-lipids. Fig. 4 showsthe 5-year incidence of recognised new major vasculardisease in these busmen relative to initial systolic B,P.

Since clinical isch&aelig;mic heart-disease is so common-

affecting perhaps 20% of middle-aged men-it has to berecognised that individual approaches to its preventionare likely to have only a limited place. The approach to allwho are clearly susceptible would involve more than 20&deg;"of middle-aged men and so, with foreseeable methods ofprevention, would be impracticable. It seems likely thatthe eventual approach will be to combine mass campaignswith personal treatment for special individuals-e,g,.,those who can be identified as early candidates for thedisease, or the most severe disease, for example.

So the grand question is whether reduction of

symptomless hypertension and hypercholesterolxmiafrom early middle age will reduce the subsequentincidence of ischaemic heart-disease. There are signs ofacceptable means of lowering high blood-cholesterol,and a trial is under way to discover whether there is anyadvantage for an otherwise healthy population in doingso. To assess the prophylactic value of long-termlowering of mild and moderate hypertension by large-scale experiment is now an urgent task for preventivemedicine, though it is doubtful if any of the availableagents are suitable. The tantalising situation today inischaemic heart-disease is that the main causes probablyare known, and the main mechanisms also. But how to

prove it, and benefit from the knowledge ? Preventivestudies on an adequate scale if only they can be organise- and they give rise to quite new issues for medicine andthe public-could give the answer. In a situation whereanimal experiment is progressing so slowly, and wheremultiple interrelated factors render human observation sodifficult to interpret, no other method is in sight for

. getting the answer. Such studies in the free-living

. population could have tremendous theoretical importancei in determining whether the evident precursors are in fact. important mechanisms of the disease, in distinguishing. causes from mere association, and in assessing the roles of

559

inheritance, experience, and mode of life in the modemepidemic of ischsemic heart-disease.

SummaryA sample of 667 middle-aged London busmen who

showed no evidence of ischsemic heart-disease whenfirst examined were followed up for 5 years. Duringthis period 47 of them developed the disease-an incidence-rate of 7%. The incidence is higher in later than in earlyniiddle age, in men with a bad family history of parentaldeath, in drivers than conductors, iri cigarette smokers, inthe more obese, and in the shortest men.Levels of casual systolic blood-pressure (S.B.P.) and of

plasma-cholesterol are, however, the predominant pre-dictive factors. Three-quarters of the new cases wereamong the men who were in the top quarter of thedistribution of either S.B.P. or plasma-cholesterol. Therisk, during 5 years, for such an individual of developingthe disease was about 1 in 7-several times the risk forthe remainder.The causes studied strongly affect the levels of S.B.P.

and plasma-cholesterol and seem to be effective mainlythrough the levels of these. Most of the new disease canin fact be explained by these two factors and little

improvement in prediction was obtained by includingthe rest.Since it is clear that men with low B.P. and plasma-

cholesterol are less likely to have ischaemic heart-diseasethan men with high values, the important question todayis whether long-term reduction of hypertension anditypercholesterolsemia will in turn reduce the incidenceof the disease.

Large-scale preventive trials are needed to give theanswer and, generally, new types of population studieswill have to be done to test the reality and relative con-tributions of the multiple causes and mechanisms ofisch&aelig;mic heart-disease which are now postulated.

AppendixHowever a vulnerable or " high risk " group is defined, and

taking:N = number of individuals in the total population (orsample).R = number of individuals in the high-risk group (asdefined).n = number of new cases occurring in the population duringany defined follow-up period.r = number of these new cases in the high-risk group,

then-Incidence of disease during follow-up period in population isn,’N and also:(a) proportion of the population included in the high-risk

group is R/N;(b) incidence of new cases of disease during follow-up period

in high-risk group is r/R; and(c) proportion of the new cases of disease included in high-

risk group is r/n.These ratios are related as shown in the following equation:

Incidence in high-risk group (r/R)=Proportion of all new cases included (r/n)Proportion of population included (R/N)

x Incidence in population (n/N)Also, the individual risk for a man in the high-risk group ofdeveloping the disease is 1 in R/r.At any point of time during the follow-up period the

incidence of new disease in the total population will be known.Thus the incidence (or, derived from it, the individual risk)in a defined high-risk group will be larger when the proportionof new cases of the disease which are included is greater, and

when the high-risk group as a proportion of the total population1S smaller (see equation).

The proportion of new cases of disease included in thehigh-risk group is a measure of the " sensitivity " of themethod by which the vulnerable group is defined-i.e., thesenew cases are true-positives in the sense that the diseasesubsequently develops. The remaining men in the high-riskgroup can be regarded, meanwhile, as " short-term " false-positives, since some of them during further follow-up maydevelop ischaemic heart-disease.We are deeply grateful to the following: the busmen; the London

Transport Board; the officials of the Transport and General WorkersUnion; the chief depot inspectors at the garages; the departmentalstaffs of the operating manager (central buses); the staff administrationofficer and the chief medical officer of the London Transport Board;to Dr. G. L. Mills of the Courtauld Institute of Biochemistry, forthe lipid analyses; to Dr. Marvin Bierenbaum, Dr. Wallace Brigden,Dr. William Evans, and Dr. H. G. Lloyd-Thomas for readingelectrocardiograms; to Mr. W. Abbott and the staff of the LondonHospital Computer Unit; to hospital physicians and pathologists,general practitioners, and Executive Councils in the National HealthService; to the General Register Office and the Ministry of Pensionsand National Insurance; and to our colleagues in the Social MedicineResearch Unit, in particular Miss J. Sullivan, secretary.

Requests for reprints should be addressed to J. N. M., M.R.C.Social Medicine Research Unit, the London Hospital, London E.I.

REFERENCES

Armitage, P. (1955) Biometrics, 11, 375.Blackburn, H., Keys, A., Simonson, E., Rautaharju, P., Punsar, S. (1960)

Circulation, 21, 1160.Bruce, R. A., Yarnall, S. R. (1966) J. chron. Dis. 19, 473.Chapman, J. M., Massey, F. J. (1964) ibid. 17, 933.Cohn, E. J., Gurd, F. R. N., Surgenor, D. M., Barnes, B. A., Brown, R. K.,

Derouaux, G., Gillespie, J. M., Kahnt, F. W., Lever, W. E., Lin, C. H.,Mittleman, D., Mouton, R. F., Schmid, K., Uroma, E. (1950) J. Am.chem. Soc. 72, 465.

Cornfield, J. (1962) Fedn Proc. Fedn Am. Socs exp. Biol. 21, 58.Dodds, C., Mills, G. L. (1959) Lancet, i, 1160.Doyle, J. T. (1966) Mod. Concepts cardiovasc. Dis. 35, 81.

&mdash; Dawber, T. R., Kannel, W. B., Kinch, S. H., Kahn, H. A. (1964)J. Am. med. Ass. 190, 886.

Edwards, D. A. W., Hammond, W. H., Healy, M. J. R., Tanner, J. M.,Whitehouse, R. H. (1955) Br. J. Nutr. 9, 133.

Epstein, F. H. (1964) Am. Heart J. 67, 445.&mdash; (1966) Proc. R. Soc. Med. (in the press).

Fisher, R. A. (1936) Ann. Eugen. 7, 179.Gertler, M. M., White, P. D. (1954) Coronary Heart Disease in Young

Adults. Cambridge, Massachusetts.&mdash; &mdash; Cady, L. D., Whiter, H. H. (1964) Am. J. med. Sci. 248, 377.

Gofman, J. W., Young, W., Tandy, R. (1966) Isch&aelig;mic Heart Disease,Atherosclerosis, and Longevity. Livermore, California.

Heady, J. A., Morris, J. N., Kagan, A., Raffle, P. A. B. (1961) Br. J. prev.soc. Med. 15, 143.

Holland, W. W. (1963) in Epidemiology: Reports on Research and Teaching1962 (edited by J. Pemberton); p. 271. Oxford.

Kannel, W. B., Dawber, T. R., McNamara, P. M. (1966) J. Iowa med. Soc.56, 26.

Keys, A., Taylor, H. L., Blackburn, H., Brozek, J., Anderson, J. T.,Simonson, E. (1963) Circulation, 28, 381.

Lancet (1966) i, 414.Marr, J. W. (1966) Unpublished.Morris, J. N. (1963) Proc. R. Soc. B. 159, 65.

&mdash; (1964) Uses of Epidemiology. Edinburgh.&mdash; Heady, J. A., Raffle, P. A. B., Roberts, C. G., Parks, J. W. (1953)

Lancet, ii, 1053, 1111.&mdash; Marr, J. W., Heady, J. A., Mills, G. L., Pilkington, T. R. E. (1963)

Br. med. J. i, 571.Morrison, S. L., Morris, J. N. (1960) Lancet, ii, 829.Paul, O., Lepper, M. H., Phelan, W. H., Dupertuis, G. W., MacMillan, A.,

McKean, H., Park, H. (1963) Circulation, 28, 20.Reid, D. D., Holland, W. W., Humerfelt, S., Rose, G. (1966) Lancet, i,

614.Rosenman, R. H., Friedman, M., Straus, R., Wurm, M., Jenkins, D.,

Messinger, H. B., Kositcheck, R., Hahn, W., Werthessen, N. T. (1966)J. Am. med. Ass. 195, 86.

Rumball, A., Acheson, E. D. (1963) Br. med. J. i, 423.Stamler, J., Berkson, D. M., Lindberg, H. A., Hall, Y., Miller, W.,

Mojonnier, L., Levinson, M., Cohen, D. B., Young, Q. D. (1966)Med. Clins N. Am. 50, 229.

" Sociology annexes a bit from history, a bit from economics,and a bit from psychology.... To those of us who look in fromthe outside, it appears that neither history nor economics norpsychology is an exact science, and a mixture of the three-inthe hands of enthusiasts who are not trained historians oreconomists or psychologists-is even less likely to be so."-MERVYN JONES, New Statesman, Sept. 2, 1966, p. 313.