Tobacco Documents Online

ideology or ce of modest d retain this ttainablc by ~t.so unfair", of scientific the prospect trophic and :trospect, as warrant the .L CIGARETTES, CANCER, AND STATISTICS* SEVEN OR EIOHT years ago, those of us interested in such things in England heard of a rather remarkable piece of research carried out by Dr. Bradford Hill and his colleagues of the London School of IIygiene. We heard, indeed, that it was thought that hc had made a remarkable discovery to the effect that smoking was an important cause of lung cancer. Dr. Bradford tIill was a well-known Fellow of the Royal Statistical Society, a member of Council, and a past pre.sident--a man of great modesty and transparent honesty. Most of us thought at that time, on heari,~g the nature of the evidence, which I hope to make clear a little later, that~'a good /~rima fade case had been made for further investigation. But time has passed, and although further investigation, in a sense, has taken place, it has consisted very largely of the repetition of observations of the same kind as t.hosc which Hill and his colleagues called attention to several years ago. I read a recent article to the effect that nineteen different investigations in different parts of the world had all concurred in confirming Dr. Hill's findings. I think they l~ad concurred, but I think they were mere repetitions of evidence of the same kind, and it is necessary to try to examine whether that kind is sufficient for any scientific conclusion. The need for such scrutiny was brought home to me very forcibly about a year ago in an annotation published by the British Medical Association's .Journal, leading up to the almost shrill conclusion that it was necessary that every device of modern publicity should be employed to bring home to the world at large this terrible danger. When I read that, I wasn't sure that I liked "all the devices of modern publicity", and it seemed to me that a moral distinction ought to be • Lecture delivered at Michigan State Univer~|ty. I!

drawn at this point. Thcrc is thc attitudc of a man (may I say, I think it is an entirely rational attitude and one within his own competcnce to judge) who says, "There sccms to be some dangcr--I can't assess whether it is infinltcsimal or serious. This habit of mine of smoking isn't vcry important to me. I will givc up smoking as a kind of insurance against a danger which I am quite unable to assess." That seems to me a perfectly rational attitude. What is not quite so much the work of a good citizcn is. to plant fear in the minds of perhaps a hundred million smokers throughout the worldq to plant it with the aid of all the means of modern publicity backed by. public money, without knowing for certain that they have anything to be afraid of in the particular habit. against which the propaganda is to be directed. After all, a large number of the smokcrs of the world are not very clever, perhaps not very strong-minded. The habit is an insidious one, difficult to break, and consequently in many, many cases there would be implanted what a psychologist might recognize as a grave conflict. If there is cause for fear, let there be warning. But there is no reason for this in the first rational response that I described --that does not require scientific proof that there is reason to fear. There is only the possibility that there is reason. Before one interferes with the peacc of mind and habits of others, it seems to me that the scientific evidence~the exact weight of the evidence frcc from emotion~should be rather carefully examined. I may say, I am not alone in this. I have bccn interested to note that leading statisticians in this country also-and I contact a good many statisticians both in my own country and here~are exceedingly sceptical of the claim that decisive evidence has been obtained. In the popular press, the matter seems to be argued, as always, a little off the simplest lines. For example, I find people saying, "These statisticians think this "~" These statisticians think that", or representing that this kind of evidence which ha~ been pro- duced has been attacked as being merely statistical. How I ahould be the last pe~on to. attack evidence for being merely statistical, because concerned with th~ bc carried out, the data suppllcd give really conclusi Progress has bcc: A large part of th~ field, has become cautions, entirely u in the expcrimenta agrlculturc, where attention of leading which emcrgcd in randomization, ant! We under'stand t| it is necessary in diminishing the er essential in a more of the estimation Although replica[ .cient without theI is, the assignment / manurial treatment or diffcrc~t metho~ purpose, in such the experiment, an which it is subjec brought home to that human judgn that if one tries to numbers very far f card of an ordina~ it's not so well kn~ cards are thought numbers are thou and that the Quee~ .clivi.ty of the hun

1 or :lant ainst ~ tO ~uch is of ld-- iicity that labit. dl, a cver, ]ious ;nize there ribed )n to iu of exact ather is. I t this ,th in ,f the pular ffthe Fhese ~'~ or pro- ~ow I Icrcly statistical, because for a great part of my work I have.been concerned with the problem of how experimentation should be carried out, how reasonin~ processes should be applied to the data supplied by experimentation or by survey so as to give really conclusive answers. Progress has been made during the last twenty-five years. A large part of the educated world, at least in the statistical field, has become aware that, by taking certain specific pre- cautions, entirely unchallengabl~ conclusions can be obtained in the experimental field. The work was done primarily in agriculture, where problems of experimentation attracted the attention of leading agronomists at an early time. The keywords which emerged in the course of these inquiricsoreplication, randomization, and control--are now widely understood. We understand that replication is required for two purposes: it is necessary in order to add precision to our results by diminishing the error to which they are subject, and it is essential in a more important way, as supplying the only means of the estimation of such error. Although replication is essential in this way, it is not suffi- cient without the added precaution of randomization, that is, the assignment of the different treatmcntsowhich may be manurial treatments, or different varieties of agricultural crops, or different methods of tillage~to the plots set aside for the purpose, in such way at random as to guarantee the validity of the experiment, and in particular of the estimate of error to which it is subject. This necessity for randomization was brought home to agriculturists largely because it was found that human judgment was very liable to err in this matter, that if one tries to think of numbers at random, one thinks of numbers very far from at random. If one tries to think of a card of an ordinary playing deck, it's well known (perhaps it's not so well known--it is known to me, at least) that red cards are thought of more readily than black cards, that odd numbers are thought of more readily than even-numbers, and that the Queen of Diamonds is a hot favourite. This pro- clivi.ty of the human, mind affects any consciously guided

choice o1" assignment of material. Agriculturists, at least, do not trust themselves to choose plots and say that they have been chosen at random. They use decks of cards or, more expeditiously, in recent years, some of these large collections of random sampling numbers which some of you may have teen at the ends of books of tables and perhaps wondered what on earth they can be for. They are in constant use in the design of experiments. There is a logical aspect, toorofrandomization which needs emphasls in this connection. Supposing we have an association --an observable and verifiable association--between two things. I remember Professor Udny Yule in England pointing to one wh;ch illustrates my purpose sufficiently well. He said that in the years in which a large number of apples were imported into Great Britain, there were also a large number of divorces. The correlation was large, statistically significant at a high level of significance, unmistakable. But no one, fortunately, drew the conclusion that the apples caused the divorces or that the divorces caused the apples to be imported. The early logicians would say that post hoe is not the same as propler hoc, or in other words~as it would be put in the early years of our century, when statisticians had had perhaps ten years' experience of the correlation coefficient as a means of research--that correlation is not causation. The fact is that if two factors, A and B, are associated~clearly, positively, with statistical significance, as I say--it may be that A is an important cause of B, it may be that B is an important cause of A, it may be that something else, let us say X, is an im- portant cause of both. If, now, ,4, the supposed cause, has been randomized--has been randomly assigned to the material from which the reaction is seen~then one may exclude at a blow the possibility that B causes A, or that X causes A. We know pcffcct!y well w!mt causes A~the fall of the dice or the chances of the random sampling numbers, and nothing else. But in the case where randomization has not been possible, these other possibilities lie wide open and thould be excluded, or at least every effort should be made to exclude them, before w¢ can assert that I ~pokc to Bradford was entirely unwilli proved. Hc said he was certainly u,~will made vociferously dr reporting to the Me~ to the Amcrican C totally impossible, so kind. It is not the fa the fault of Hill or 1 duce evidence in whi been laid under a t. thousand more chos, have been under con aday. If that type. be no difficult),. The principles of~ were developed ir~ t' them was greater or rapidly and ~ealthil And I suppose durin books have been wri pally to make clear x~ applications in chcmi But the most dif. principles has alway because you can do ~ good for it, feeling t do so. But no onef~ not fccl~that it is ri. probably will do hi~ mentatlou has not b, There is a movcmc~: trials, let us say, of~ way that an imparti the old may be obt~

st, do have more cdom .have ,dered in the needs iation t tWO inting He ; were ~mbcr ificant ~ one, :d the orted. .me aS : early :rhaps means s that tively, :isan cause m im- ~ been J from ~ blow "know hances ~ssible, =luded, before we can agsert that causation has been established. When I spoke to Bradford Hill in the early days of this affair, he was entirely unwilling to claim that causation had been proved. He said he didn't see what else it could be, but he was certainly unwilling to make the claim which is being made vociferously during the l~st year or two by committees • reporting to the Medical Research Gouncil in England, and to the American Gancer Society. Now, randomization is totally impossible, so far as I can judge, in an inquiry of this kind. It is not the fault of the medical investigators. It is not the fault of Hill or Doll or Hammond that they cannot pro- duce evidence in which a thousand children of teen age have been laid under a ban that they shall never smoke, and a thousand more chosen at random from the same age group have been under compulsion to smoke at least thirty cigarettes a day. If that type of experiment could be done, there would be no difficulty. The principles of experimentation~which, as I mentioned, were developed in the agricultural field, where the ne/:d for them was greater or more manifest~have spread, and spread rapidly and healthily, into the other experimental sciences• And I suppose during the last fifteen years a dozen important booLs have been written on the design of experiments, princi- pally to make clear what these principles are in their particular applications in chemistry, physics, biology, or what you maywill. But the most difficult field for the application of thdse principles has always been the medical field. This is partly because you can do things to a r~t or rabbit which may not be good for it, feeling that in a good cause you have a right to do so. But no One feels~and especially a medical man could not feel~that it is right to do things to a human being which probably will do him harm. Gonsequently, deliberate experi- mentation has not been very widely used in the medical field. There is a movement at the present time to organize clinical trials, let us say, of new drugs or of new anfibioticr in such a way that an impartial judgment in comparing the new with the old may be obtained by hospital staffs. And that would

involve applyiag tile new and the old at random to some of the hospital patients. So long as no body of medical opin.ion 'can say with confidence that one is better than the other, or perhaps that in matters usually as complicated as this, for what cases one drug is the better and for what cases the other-- so long as that state of .ignorance remains, it would be perfectly fair, I think, to clear the air by such simple experi- mentation. But manifestly we cannot cxpcrlmcnt with the same freedom that is possible with agricultural animals and laboratory animals in other sciences. For lack of that, medical research has had to rely a good deal on uncontrolled experiments, uncontrolled observations; aud of course from the time of Jenner onwards there were numerous cases where an observant (and also, I may say, an experimental) physician may be able to make out an exceedingly strong case. Jenner's work was not completely passive. And Dr. Suow, who studied and in the end quelled the occurrence of cholera in London, used a very large number of different types of inquiry in order to gain sufficient confirmation of his important conclusion, namel~', that it was faecal contamination in the water supply that was responsible for the cholera, an opinion that is easy to take for granted at the present time, but which in the absence of any knowledge of the organisms concerned--or, indeed, know- ledge that the disease was caused by an organism~was a considerable advance, just as Jenner's was also in the case of smallpox. Consequently, when inconclusive evidence is criti- cised on the ground that it is inconclusive, it is not uncommon for medical men to defend it, perhaps with certain indignation, on the ground that in the past medical science has made notable advances primarily--not solely, never only, but primarily--by the observational method. Now, in the sciences we also have cases in which experimenta- tion is impossible. In astronomy, for example, experimentation, you might say, has only just begun. And in those sciences we must use what I may call sideliglgs. Let me illustrate this possibility with a very few instafices. The ilrst reports of They said that the. in patients was pr~ consumed. That s drawn, and it was or in tile cigar did with lung cancer this was a puzzlin~ three cases. The tobacco p;,sses into indeed, into the lu, is not what one wo and Hill guessed be comparatively c sort should have t dreadful disease. And now I mus~ evldencc it was th~ ning, and in what The first inquir number of diffcrc suffering from mously aided in r lung cancers can are" passed througt reason to think and had not been cancer cases. Arra habits and thcir smokers, pipe sm consumption of to questions. A simi cancer patients questionnaire, and one of them select. as being in hospi~ of the classificatio~

some of opinion ~thcr~ or this, for • other~ ~uld be : experi- freedom boratory research :rimcnts~ time of bservant • be able :ork was I and in ,, mcd a r to gain namely, that was to take )sence of d, know- .--was a e case of : is criti- common ignation, ~ made aly, but :rimenta- entatlon, ences we nstances. The first reports of Hill and Doll made a very simple claim. They said that the additional amount of lung cancer observed in patients was proportional to the amount of tobacco they consumed. That simple conclusion was .quite rapidly with- drawn, and it was admitted that tobacco consumed in the pipe or in tile cigar did not appear to have so close an association with lung cancer as that consumed in the cigarette. And this was a puzzling tiling. After all, tobacco is burned in all three cases. The effluvia, sm,oke, or aerosol from the burning tobacco passes into tile mouth, partly into the throat, partly, indeed, into the lungs, in all three cases. It is not obvious~it is not what one would guess at first sight, it was not what Doll and Hili'guessed at first--that the one sort of smoke should be comparatively or perhaps wholly innocuous and the other sort should have the effect of inducing the beginnings of a dreadful disease. And now I must go back and recall just what the kigd of evidence it was that Hill and Doll laid before us at the begin- ning, and in what ways it has beet) extended by other evidence. The first inquiry was to take about 15oo. patients in a number of different hospitals who had been diagnosed as suffering from lung cancer. Of course the diagnosis is enor- mously aided in recent times by the use of radiology. The lung cancers can be perceived by their shadows when X-rays are' passed through the lungs..Consequently there was good reason to think that these patients~ahhough they were alive and had not been examined post-mortem~really were lung cancer cases. Arrangements were made to record their smoking habits and their smoking history: non-smokers, cigarette smokers, pipe smokers, estimates of the amount .of daily consumption of tobacco in each case, and a number of other questions. A similar number, perhaps a few more, of non- cancer patients from the same hospitals received tile same questionnaire, and the comparison between these two samples, one of them selected as being lung cancer cases and the other as being in hospitals from some other condition, was made of the classification by smoking habit. And it appeared from

that that the cigarette smokers were morc common among the sufferers from lung cancer than they were among other patients, and that within the cigarette smokers, henW clgarcttc smokers were more common among the lung cancer patients than medium or light cigarette smokers. The statement that consumers of tobacco in other forms were associated with lung cancer seems to have largely evapo- rated. I should say a word about it because it represents a common cause of error in statistical investigations, namely, the kind of error which flows from the difficulty of a perfect classification. Everyone can make a rough classification of cigarette smokers or pipe smokers or non-smokers, but there "will be borde.rline cases. There arc people who, though they may prefer a pipe when they have the opportunity, yet may bc constrained by duress, such as in the intervals of a play when there is very little time, to smoke a cigarette. There are also distinguished and expensive restaurants, as well as aircraft, who don't like the customer to pull out a pipe. Consequently there is an overlap in the practices and habits of diffi~rent people; there may not be exactly the same interpretation put on the questionnaire by all the different subjects; and, in fact, a good many pipe smokers may he classified as cigarette smokers, and vice versa. There is bound to be some mixture • or" the classes in any inqniry on a complicated question. "And so the first results did seem to show some effect on pipe smokers and cigar smokers, but it is quite clear that the • amount was much smaller than was at first thought, and certainly no more than might easily arise due to mis- classification. At least it would be very foolish for anyone who Mshed to make a case for saying that cigarette smoking was a cause of lung cancer to bring in the evidence about pipe and cigar smoking. When an unexpected discrepancy occurs, it is a common reaction (I won't say, a failing--it's part really of the scientific discussion which data deserve) to think up some reason for it. This, in effect, may be something like what the logicians would call a "special pleading". That is to say, the making of an assumption, which r. true, but which, if t wise inexplicable. I or, rather, is contai much in pipes. Th~ pipe smokers who But most pipe smC. without paper. An( sumption of paper also, it has been ob tobacco is burned i: in the case of the p is not known to be) condition for prod~ thing quite unexplo tobacco smoke whi. cancer. It is also kn and for cigars is mc is that used in cig source of cigarette prepare the tobacco aware, that the pric in fermentation, weight than is nece: tobacco is rather li~ could claim even--. fermented conditlor cigarettes, that fumes which the bu is full of such things One of the first 1 me on the matter, inhale; pipe smoker or~ an extremely in country, I believe, some don't. When smoking was all rig

among • other ~,arette aticnts cvapo- ~nts a amcly, perfect ion of : there h they nay be when re also rcraft, uently fferent )n put- ad, in ~arcttc tixture • And n pipe at the :, and , mis- was a )c and mmon .entitle for it. would of an assumption, which might be tt'uc, which might, indccd, not be true, but which, if true, would help to explain what is other- wise inexplicable. For example, the cigarette contains paper, or, rather, is contained by paper• One doesn't smoke paper much in pipes. "l'hcre are, indeed, special papers supplied to pipe smokers who wish to enjoy their tobacco in that way. But most pipe smokers and, I suppose, all cigar smokers, do without paper. And it could be, therefore, that it's the con- sumption of paper that is the really dangerous practice. Then, also, it has been observed that the temperature at which the tobacco is burned is higher in the case of the cigarette titan in the case of the pipe, and, it could be (though it certainly is not known to be) that burning at a higher temperature is a condition for producing something quite unknown, some- thing quite unexplored, something quite hypothetical, in the tobacco smokc which would be capable of producing lung cancer. It is also known that the tobacco used as pipe tobacco and for cigars is more thoroughly fermented before use than is that used in cigarettes, or at least in the predominant source of cigarette tobacco, in Virginia. I think those who prepare the tobacco produced in Virginia are rather acutely aware, that the price per pound is high, there is loss of weight in fermentation, and it is as well not to lose to per cent. more weight than is necessary. And so, on the whole, the Virginia. tobacco is rather lightly fermented. You could imagine.--you could claim even--as a special pleading, that it was the un- fermented condition of the Virginia tobacco, largely used in cigarettes, that was responsible for the supposedly noxious fumes which the burning of such tobacco produces. Discussion is full of such things. One of the first people in the United States that spoke to me.on the matter, a lady, said, "Of course, clgarette smokers inhale; pipe smokers don't." And of course she laid her finger on an extremely important point. Cigarette smokers in this country, I believe, generally inhale. In England, some do and some don't. When I was a little boy, it was thought that smoking was all right and did you no harm, but inhaling w.as ~9

perhaps a perverse practice and might not do you any good. And so, at any rate my generation, and perhaps some decades of younger men, had a certain amount of warning against this particular practice. I imagine it is something llke that that explains the difference in practice between the two countries. Now, Doll and Hill, in their first inquiry~the one that I've gone over approximately--did include in their question- naire, which was put both to the c~neer patients and to the patients from other diseases, the question: "Do you inhale?" And the result came out that there were fewer inhalers among the cancer patients than among the non-cancer patients. That, I think, is an exceedingly important finding. I don't think Hill and Doll thought it an important finding. They said that perhaps the patients didn't understand what inhaling meant! And what makes it far more exasperating, when they put i,uo effect an exceedingly important research, based on the habits of the medical profession, by asking about 6o,ooo doctors in Great Britain to register their smoking habits, and about 40,000 of them did so co-operatively, I am sorry to say that the question about inhaling was not in that questionnaire. I suppose the subject of inhaling had become distasteful to the research workers, and they just wanted to hear as little about inhaling as possible. But it is serious because the docto~ could have known whether they were inhalers or not; they could have known what the word meant; perhaps they would have consulted each other sufficiently to lay down a definition which the rest of us could understand. At any rate, there would have been no alibi if the question had been put to a body of 40,000 physicians. $o, our evidence about inhaling is embarrassing and diffi- cult. There is no doubt that inhaling is more common among heavy cigarette smokers than among light cigarette sn~okers in Great Britain, where inhaling is not nearly a universal practice. There is no doubt that cancer is commoner among the heavy cigarette smokers than among the light cigarette smokers. Oomequently, if inhaling had no effect whatever, • oo you would expect to fi patients than among th be an indirect corrclat with the quantity smo reported everything wa aggregate data, it app fewer inhalers than the: though, if one could who smoke the same nt negative association bct~ me that the world ouglv Before I stop, in fact, is a case for fiathcr rcs areas which would seen would stress the import: • tively easily with ratl~c unmistakably what the is found to be strongly be consonant with the wafted over the surface cancerous and thence a either no association should have to reject causation of cancer. The subject is compl stage that the logical d B causing A, or someth then, that lung cance~ condition which must in those who are goln~t of the causes of smoki be excluded. I don't tla such a cause. But the p~ a certain amount of sli~ of smoking cigarettes m some extent, and I thin irritatlon~a slight dis