The association between tobacco smoking and coronary heart disease

Transcription

1 International Journal of Epidemiology, 2015, doi: /ije/dyv124 Advance Access Publication Date: 13 July 2015 Reprints and Reflections Reprints and Reflections The association between tobacco smoking and coronary heart disease Reuel A Stallones, M.D. I. Introduction Nearly everything that can be said about smoking and heart disease has been. The literature is now so large and so confusing that there is little hope of ever compressing it into a coherent and consistent summary statement. There is support somewhere for almost every shading of opinion, from the view that smoking is directly, causally related to the disease to the idea that there may be no real association between the two. Weighing the evidence presented does not offer a ready solution to the dilemma, for the weight of evidence may shift very rapidly with changing tides of popularity for one view or another. Careful evaluation of the available data is obviously desirable, but all studies have defects and the relative merits of one over another is subjectively assessed and the assessment is subject to imponderable biases of the evaluation. In a general way, a number of criteria for the evaluation of the causal significance of an association can be stated. 1. The strength of the association. There can be little doubt that the importance of an association increases as its strength increases. Exceptions can be noted without detracting from the general applicability of this rule. 2. The specificity of the association. This rule cannot be applied blindly, either, but together with the first rule determine the precision with which one component of an associated pair can be used to predict the occurrence An unpublished memorandum to the US Surgeon General s Advisory Committee on Smoking and Health, June 28 and July 19, This memorandum has been published from an internal document which was never edited for publication. The Editors have corrected what appeared to be errors to the best of their ability. A copy of the original report is available on the International Journal of Epidemiology website courtesy of the University of Minnesota Archives, University of Minnesota Twin Cities. of the other. This is most important in judging the causal significance of the relation between them. In this connection, prediction of an unlikely event is of greater significance than prediction of a common occurrence. 3. The consistency of the association. This concept is related to the prior ones, but includes the notion that different studies, using different methods, done in different populations should yield similar conclusions. 4. The precedence of the causal component of the association. Within the limitations of methods of measurement the component of the association which is presumed to be causal must precede the other. 5. The coherence of association. Along with all the other requirements, an association of a factor with a disease process should be coherent with the known facts of the biology of that disease. This may be impaired by insufficient or incorrect concepts of pathogenesis but eventually all the information must fit into an ordered structure. The application of these rules may be modified by knowledge of the precision with which the variables may be measured and by whether a factor is considered to be necessary or contributory and sufficient or insufficient. All of these considerations must be involved in the judgement of the importance of smoking as a causative factor in the etiology of coronary heart disease. II. The Nature of the Association A. Indirect Measures of the Association Observations of different aspects of the co-variation of smoking and CHD are commonplace and, while they testify to the presence of an association between the two, are often couched in such broad generalities that they do not generate much confidence in their reliability. These 735

2 736 International Journal of Epidemiology, 2015, Vol. 44, No. 3 observations have been summarised in Smoking and Health 1 and by Bronte-Stewart. 2 Briefly, they are these. 1. During the last half-century both cigarette smoking and CHD have been increasing in a generally similar fashion, at least in Great Britain and in the United States. 2. Males smoke more than females and have the higher rates of CHD. The increasing trend of cigarette smoking began first in males. 3. When the CHD mortality rates were lower than they are at present, there was a definite gradient by social class in Great Britain, with the higher rates associated with higher social status. This may have been related to social class variation in cigarette smoking. 4. There is a fair positive correlation between CHD death rates and cigarette consumption for different countries (see Figure 2 in ref 2). 2 All of these arguments are tenuous and to them must be added the suggestion that some s in CHD between different population groups (such as the between urban and rural residents) are not in accord with the smoking differentials. These problems of inconsistency of correlation of this kind are not unique to the problem of smoking and CHD. Given the difficulties of measuring these variables precisely, one may conclude that a real association might be present in just such a vague and inconclusive manner. B. Direct Measures of the Association The requirement for a direct measure of the association is that both variables, smoking and coronary heart disease, be determined in the same population. 1. The Strength of the Association It should be noted here that the relative frequency of smoking in persons with and without CHD is not the same as the relative frequency of CHD in persons who smoke and those who do not. Fortunately, few of the former kind of estimates are to be found and they need not be given special consideration. One, the report by Buechley et al., 3 based on interviews in the California Health Survey, showed that persons reporting CHD smoked an average of 16 cigarettes per day, while a group of matched comparison subjects smoked an average of 10 cigarettes per day. This kind of result would be expected, given an association between smoking and CHD, but does not provide an appropriate measure of the strength of the association; that is, the magnitude of the excess risk of smokers over nonsmokers. An estimate of the excess risk flows quite naturally from the several prospective studies of mortality and morbidity which have been reported. The simplest and most direct measure of the strength of the association between smoking and CHD is some expression of the ratio of the rates for smokers to the rates for non-smokers. A similar expression, used by some authors, is the ratio of observed to expected cases, when the number of expected cases has been computed by applying the rates for non-smokers to the population of smokers. When this is done, using age-, sex-, or other characteristic-specific rates, the resulting statistic, usually based on 100, has been termed a standardized morbidity or mortality ratio. Tables 1, 2, and 3 present the findings of a number of studies from which the strength of the association can be judged. Although the Framingham data are not in complete accord, partly because of a considerable variation in the different estimates emanating from that study, there is fairly good evidence to support the following statements: a. Cigarette smokers have about twice as much coronary heart disease as non-smokers, whether measured by deaths, prevalence, or the incidence of new events. b. The excess risk of smokers over non-smokers increases with increasing amount of smoking. This finding is more tenuous than the first one, and cannot be asserted firmly in view of the variable results from different studies. c. The excess risk of smokers over non-smokers tends to decrease with age, so that over 60 years of age there is probably no between the two groups. This conclusion is not supported by all studies, but is a bit more firmly established than No. 2. d. The excess risk of smokers over non-smokers is confirmed largely (perhaps entirely) to myocardial infarction. Data bearing on this point are available in only a few studies and the studies are inconsistent. 2. The Specificity of the Association The specificity of the association must also be considered. Berkson has pointed out very trenchantly the lack of specificity, that in the studies by Doll and Hill, Hammond and Horn, and Dorn, smoking was found to be associated with an increased risk of dying from a variety of diseases. The mortality ratios are summarised in Table 4. From this material, the following alternative conclusions may be drawn: a. The specificity of the excess risk for all causes where the excess is significant is demonstrated by the failure to find an excess risk for all of the causes. b. Since an excess risk is demonstrated for a variety of conditions, the excess risk for no single condition can be considered specific.

3 International Journal of Epidemiology, 2015, Vol. 44, No Table 1. Ratios of mortality rates due to coronary heart disease of male smokers to non-smokers, by age and amount smoked; selected studies Age group Hammond and Horn Cigarettes smoked per day Total (Age adj.) Doll and Hill Total (Age adj.) Mills Buechley, Drake, Breslow * Framingham Study Dorn Total (Age adj.) * Persons smoking 1 pack/day or more were compared with those smoking less than 1 pack/day (including non-smokers) Table 2. Ratios of prevalence of coronary heart disease of male smokers to nonsmokers, by age and amount smoked; selected studies Age group Cigarettes smoked per day Spain and Nathan Under 51* 1.8 Total Edwards, McKeown, Whitfield Over * Persons smoking 40 cigarettes/day or more were compared with those smoking less than 40 cigarettes/day (including non-smokers). c. The specificity of the excess risk may be evaluated in terms of relative magnitude for the different causes. The selection among these alternatives is, in my opinion, a Hobson s choice. 3. The Consistency of the Association In all the material presented thus far, the consistency of findings in different studies has been remarkable. There is almost complete unanimity that there is an association between smoking and CHD, and disagreement between studies is largely in terms of specifics. This situation would obtain if: a. There is a real association between smoking and CHD. b. These studies all incorporated some unknown source of bias which created a spurious association. c. Prevailing doctrine was established early with subsequent suppression (voluntary, we trust) of contrary findings. Since in epidemiologic circles there are more iconoclasts than icons, the third explanation seems to me

4 738 International Journal of Epidemiology, 2015, Vol. 44, No. 3 Table 3. Ratios of incidence rates of coronary heart disease of male smokers to non-smokers, by age and amount smoked; selected studies Age group Cigarettes smoked per day ) * (5.8** Framingham Study * (2.7**) * (1.1**) Total (Age adj.) 2.1*** * $ 1.9* * 2.1* Albany study 31 Total * $ 3.3* 2.8* 4.9* North Dakota Study (-) (1.2 + ) (3.2 + ) (2.1 + ) (2.5 + ) Total (Age adj.) 1.3 (2.2 + ) Paul and Lepper $$ Non-smokers (strictly) excl. of cigars and/or pipes. *M.I. only ** All C.H.D. *** M.I., and sudden death. þ First figure refers to farmers; second to non-farmers; MI and coronary occlusion only. þþ Calculated from table 8 of authors article N.S. rates 3.3/100; S. rates 5.8/100. $ Editorial note: in the original report the reference for this line in Table 3 is the same as for the previous line; both Doyle JT, Dawber TR, Kannel WB, Heslin DS, Kahn HA. Cigarette smoking and coronary heart disease. Combined experience of the Albany and Framingham studies. New Eng J Med. 1962;266: However, only 2 tables in this paper show data for MI and only one of these, Table 2, shows data for men aged In Table 2 the participants are divided into smokers and non-smokers, but not further categorised by smoking status. Our assumption is that these figures were referenced incorrectly in the original. $$ Editorial note: this article is not referenced. It seems likely that it is Paul O, Lepper MH, Phelan WH, Dupertuis GW, Macmillan A, McKean H, Park H. A longitudinal study of coronary heart disease. Circulation. 1963;28: unreasonable. Similarly, I cannot envision a pervasive, maleficent bias of the type called for by the second explanation, so until one is presented, I would discard that theory. Thus I am led to believe that the association is real. 4. The Time Relation of the Associated variables Whether smoking does or does not precede the development of coronary artery disease is mooted. That it precedes the development of clinically manifest coronary artery disease is established by the prospective studies of morbidity in persons free of CHD insofar as can be determined by clinical examination. Thus in assessing causality, this criterion is not of much value. III. Explaining the association To summarize up to this point, the following conclusions seem reasonably well established. 1. Smokers are at greater risk of experiencing myocardial infarction than are non-smokers. 2. The excess risk among the middle aged is approximately two-fold. 3. Generally with increasing age the differential diminishes. In seeking an explanation for the increased risk among smokers, four possibilities may be considered. 1. The association is spurious. 2. Smoking causes myocardial infarction. 3. Smoking is causally related to some, one or many precursors of myocardial infarction. 4. Smoking and myocardial infarction are related through some common factor or factors. For the first premise to hold all the studies presented, conducted at different times, in different populations, using different methods, and by different investigators

5 International Journal of Epidemiology, 2015, Vol. 44, No Table 4. Mortality ratios of current cigarette smokers to nonsmokers by specific cause of death; selected studies 24 (1) Doll, Hill Hammond, Horn 23 Dorn 27 Cancer Lung Prostate Esophagus, buccal 5.06 cavity 2.18 Bladder (GU) Stomach 0.7 (GI) Lymphomas (Hem) Pancreas 1.19 Intestines, rectum Kidney 1.00 Leukemia 0.89 Other 1.30 Respiratory Pneumonia Bronchitis, emphysema Cardiovascular-renal Coronary heart disease 3 Nonrheumatic encarditis 1.55 Hypertension with heart disease General arteriosclerosis 1.46 Hypertension without heart disease 1.41 Cerebral vascular disease Chronic nephritis 1.04 Chronic rheumatic heart disease 0.84 Other Paralysis agitans 0.36 Diabetes 1.18 Ulcer, stomach and duodenum High* High** 2.83 Cirrhosis of the liver Violence Noting *** All causes * Could not be computed, for the rate for nonsmokers was 0. ** Could not be computed for gastric ulcer; 2.16 for duodenal ulcer *** Not stated. Other than not increased. (1) Doll and Hill study includes all smokers. would have to share some undefined, biases leading to a remarkably consistent spurious association. The likelihood of this seems very low. Postulation of a direct causal link between smoking and myocardial infarction suffers from lack of support for any reasonable pathogenetic mechanism. It is conceivable that future research may provide a logical direct link between the two, but for the present, this alternative must be set aside. The third possibility has received considerable attention. Among the factors other than smoking, age, and sex associated with an increased risk of CHD are: 1. High serum lipids 2. Obesity 3. High blood pressure 4. Body habitus 5. Personality type and psychic stress

6 740 International Journal of Epidemiology, 2015, Vol. 44, No. 3 Table 5. Author Study population Serum Cholesterol ( ) Weight Blood Remarks pressure Age group Gofman et al 7 Employed Healthy Men Lipoproteins higher in smokers (Diff. decreased with age) Konttinen 33 Finnish Army -1.5 No No in phospholipids Karvonen 34 E Finland W Finland Helsinki See remarks Smokers lower Skinfolds lower in smokers, Helsinki smokers of Finnish cigarettes had higher chol. than American smokers Thomas 12 Baltimore Medical Students Smokers moderately higher More smokers overweight Kannel 6 Framingham Residents Smokers lighter Blackburn et al 10 Minn. Businessmen 7.7 Smokers lighter Damon 35 Bronte-Stewart 2 No Smokers lower No Students 5.3 No Italian Americans of Watertown, Mass Smokers moderately leaner -18 No -8 No Smokers lower Chol/phospholipids lower in smokers. No in β-chol. Smokers had higher β/α cholesterol Health Non-smokers Well integrated personality More stable personality Cerebrotonia Psychotype Answers promptly questionnaires Slow Respiratory rate Fewer Sighs and swallows Increased Reflexes Less Alcohol and coffee Smokers Less well integrated personality Less stable personality Viscerotonia Delays answering Rapid More Decreased More 6. Genetic factors 7. Increased blood coagulability 1. Serum lipids and smoking. The data bearing on this point are conflicting (Table 1). The weight of evidence seems to favour the idea that serum cholesterol is higher in smokers than in non-smokers and that the differential decreases with age. Acheson and Jessop, 4 studying men aged 65 to 85 years, found no association between smoking and serum cholesterol or b/a lipoprotein ratio. Nevertheless, Page 5 could demonstrate no acute effect on cholesterol with smoking. From the Framingham data, 6 the higher cholesterol of smokers is not sufficient to account for the higher CHD rates of smokers and this would appear to be true for most of the other groups studied. However, Gofman et al. 7 computed the expected increase in risk of CHD associated with the higher lipoproteins of smokers to be about 1.4. This they compared with Hammond and Horn s observed excess risk of 2. This computation calls

7 International Journal of Epidemiology, 2015, Vol. 44, No for great faith in the predictive value of serum lipoprotein determinations. Krut, Perrin, and Bronte-Stewart studied s in taste perception and food preferences between smokers and non-smokers. 8,9 Smokers tended to prefer salty and spiced foods and ate more fat, especially from meat and eggs. The s were not great but may account, in part, for the observed s in serum lipids. In contrast to this, Blackburn et al. 10 found only a very slight excess of fat intake among smokers. 2. Weight. Table 1 presents the data on weight of smokers and non-smokers. There is no explanation here for the serum lipid findings. Brozek and Keys 11 reported that persons who stopped smoking gained an average of more than eight pounds when measured 1 and 2 years later, and Blackburn, et al. 10, report that this was accompanied by a small rise in cholesterol and a suggestive rise in blood pressure. 3. Blood pressure. Generally smokers do not differ significantly from non-smokers by casual blood pressure measurements (Table 1). Thomas 12 found no s by smoking group in the acute effect of smoking one cigarette. 4. Physique. Thomas 12 classed medical students as nonectomorph, intermediate, and ectomorph according to their ponderal indices. Smokers showed a slight tendency to cluster in the nonectomorph group at the expense of the ectomorph. This was not consistent by degree of smoking and was produced largely by pipe and cigar smokers. Seltzer, 13 studying the association of morphologic measures and smoking in Harvard graduates whose physical measures were taken in 1942, found smokers to be taller, heavier, and generally of larger build than nonsmokers. From largest men to smallest, the groups ordered as follows: cigar smokers, pipe smokers, cigarette smokers, non-smokers. There was no consistent gradation by amount of cigarette smoking. Blackburn et al. 10 presented an anthropometric index, defined as the bicristal plus the biacromial diameters divided by the standing height, for middle aged businessmen. There was no between smokers and non-smokers. 5. Personality Types. Heath 14 presented data on certain psychologic characteristics of the group of Harvard graduates studied by Seltzer. His findings are summarised in Table 2. A comparison of the case records of the five heaviest smokers... with those of five non-smokers chosen at random showed marked contrasts in personalities. The smokers showed great energy, restlessness, seeking for danger, and a kind of independence which keeps them actively engaged in some enterprise which appeals, and they had difficulties with marriage. The non-smokers were steady, dependable, and hard workers, with stable marriages and histories of specialized, noncombat war duties, and they led rather quiet progressive lives. From interviews of a probability sample of residents of Buffalo, New York, Lilienfeld 15 matched non-smokers with smokers for age, sex, race and social status. The questionnaire included 31 items said to discriminate between neurotic and normal persons. Smokers differed from non-smokers to a significant degree on 19 of the 31 items, always on the neurotic side. Smokers were found to marry more often, move more frequently, change jobs more often, (be) hospitalized more often, and participate in more sports than non-smokers. Thomas 12 queried the medical students on habits of nervous tension when faced with stressful situations and although few marked s were found between smokers and non-smokers, the former reported nervous habits more frequently for 17 of 25 questionnaire items, and less frequently on only 2 or 3. There were no marked s between the two groups on a Rossbach test. Friedman and Rosenman 16,17 compared smoking habits of men and women classed by personality type as coronary-prone and not coronary-prone. A higher proportion of the coronary-prone group smoked and their average cigarette consumption was much higher. 6. Twin Studies. There are four reports on twinning and smoking. Fisher 18 presented data on the greater concordance of smoking habits in monozygotic than in dizygotic twins and followed this with a second report 19 which showed the same phenomenon and further showed that among the monozygotic twins there was no between those reared apart and those reared together. Friberg et al. 20 also found greater concordance in smoking habits of monozygotic twin pairs over dizygotic twins. 7. Blood coagulation. Blackburn et al. 21 studied the recalcified plasma stypven clotting time of schizophrenic men and university students in two small series using a cross over experimental design. They found no acute effect associated with smoking. Watts and Bragg 22 observed increased urinary excretion of epinephrine in 11 young adult males during a two hour period following smoking cigarettes. Norepinephrine excretion was decreased but not significantly so. Small groups of smokers and non-smokers were compared for 8

8 742 International Journal of Epidemiology, 2015, Vol. 44, No. 3 hour excretion of catechol amines and no was found. Although not all of the studies are in accord on all points, the following conclusions seem justified: a. Smokers generally have higher serum cholesterol levels than non-smokers. 1. This is not sufficient to account for the differential in CHD rates between smokers and non-smokers. 2. The mechanism to explain this association is not clear, and the association may arise through the common association of cholesterol and smoking with CHD. b. Data are insufficient properly to evaluate the association of other serum lipids with smoking. c. Neither overweight nor hypertension are consistently associated with smoking. d. There is an appreciable genetic factor involved in the determination of smoking habits. e. Smokers are more active, more nervous, more restless, less contemplative and less well adjusted than nonsmokers. Thus smokers have been found to differ from nonsmokers according to a variety of parameters, some of which may be related to the development of CHD. So far the only way in which smoking may be directly linked in a causal way to CHD is through the effect of smoking on blood coagulability, either by a direct effect of smoking on platelets or by way of increased epinephrine (and perhaps norepinephrine) excretion. This is highly speculative but is an attractive lead for further investigation. IV. Conclusions Now let s see if all of this activity has taken us any place. We are still confronted by a choice between two hypotheses: 1. Smoking is in some way involved in the causation of CHD, or 2. Smoking is associated with CHD in some incidental way, not as a causative factor. Faced with these alternatives, our response may vary with the sphere of activity involved. 1. The scientific response is obvious. Since the data are inadequate to resolve the question, we must seek more data. These hypotheses suggest many lines of inquiry and whichever may be shown to be correct, the search for an answer must add greatly to our knowledge of CHD. 2. The personal response is the choice of each individual. This will be determined by personal prejudice, personality and emotion as well as intellectual assessment of the evidence. For various reasons, I believe the second hypothesis is correct, but I have no notion of the extent to which this belief is influenced by factors other than scientific ones. Therefore, I can apply this belief only to my own actions. 3. The social response is the troublesome one, because this must determine official attitudes and actions. I believe the social response must be to accept the first alternative as a working hypothesis and act accordingly. That this is not scientifically justifiable must be granted, nor should official action impair the right of each individual to determine his own fate. However, the social response that is called for is a massive endeavour to discourage smoking using fully the not inconsiderable resources of the Federal and State Governments. This is a gamble, which if correctly taken balances enormous social gain as against an appreciable economic loss, if the actions are successful. References 1. Smoking and Health. [This reference is incomplete in the original report. The Editors suspect it could be an early draft of Smoking and health: report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, DC: Public Health Service, (DHEW publication no. (PHS) ] 2. Bronte-Stewart B. Cigarette smoking and ischemic heart disease. Brit. Med. J. 1961;1: Buechley RW, Drake RM, Breslow L. Relationship of amount of cigarette smoking to coronary heart disease mortality rates in men. Circulation 1958;18: Acheson RM, Jessop WJ. Tobacco smoking and serum lipids in old men. Brit Med J 1961;2: Page IH, Lewis LA, Moinuddin M. Effect of cigarette smoking on serum cholesterol and lipoprotein concentrations. J Amer Med Assn 1959;171: Kannel WB. Informed summary report to the committee. Smoking and CHD in the Framingham study. [This reference is incomplete in the original report, the Editors have tried to locate it to no avail.] 7. Gofman JW, Lindgren FT, Strisower B, delalla O, Glasier F, Tamplin A. Cigarette smoking, serum lipoproteins, and coronary heart disease. Geriatrics 1955;10: Krut LH, Perrin MJ, Bronte-Stewart B. Taste perception in smokers and non-smokers. Brit Med J 1961;1: Perrin MJ, Krut LH, Bronte-Stewart B. Smoking and Food Preferences. Brit Med J 1961; 1(5223): Blackburn H, Brozek J, Taylor HL, Keys A. Comparison of cardiovascular and related characteristics in habitual smokers and non-smokers. Ann N. Y. Acad. Sci 1960;90: Brozek J, Keys A. Changes of body weight in normal men who stop smoking cigarettes. Science 1957;125:1203.

9 International Journal of Epidemiology, 2015, Vol. 44, No Thomas CB. Characteristics of smokers compared with nonsmokers in a population of healthy young adults, including observations on family history, blood pressure, heart rate, body weight, cholesterol and certain psychological traits. Ann Intern Med 1960;53: Seltzer CG. Morphologic constitution and smoking. J Amer. Med. Assn. 1963;183: Heath CW. Differences between smokers and non-smokers. A.M.A. Arch. Int. Med 1958;101: Lilienfeld AM. Emotional and other selected characteristics of cigarette smokers and non-smokers as related to epidemiological studies of lung cancer and other disease. J Natl. Cancer Inst. 1959;22: Friedman M, Rosenman RH. Association of specific overt behaviour pattern with blood and cardiovascular findings. Blood cholesterol, blood blotting time, incidence of arcus senilis, and clinical coronary artery disease. J. Amer. Med. Assn. 1959;169: [This reference is blank in the original report, the Editors suspect it could be: Friedman M, Roseman RH. Overt behavior pattern in coronary disease. Detection of overt behaviour pattern A in patients with coronary disease by a new psychophysiological procedure. JAMA 1960; 173: ] 18. Fisher RA. Lung cancer and cigarettes? Nature 1958;182: Fisher RA. Cancer and smoking (Letter to the Editor). Nature 1958;182: Friberg L, Kaij L, Dencker SJ, Jonsson E. Smoking habits of monozygotic and dizygotic twins. Brit Med J 1959;1: Blackburn H, Orma E, Härtel G, Punsar S. Tobacco smoking and blood coagulation: acute effect on plasma stypven time. Amer. J. Med. Sci. 1959;238: Watts DT, Bragg AD. Effect of smoking on the urinary output of epinephrine and norepinephrine in man. J. Appl. Physiol. 1956;9: Hammond EC, Horn D. Smoking and death rates report on forty-four months of follow-up of 187,783 men. II. Death rates by cause. JAMA 1958;166: Doll R, Hill AB. Lung cancer and other causes of death in relation to smoking. A second report on the mortality of British doctors. Brit Med J. 1956;2: Mills CA, Porter MM. Tobacco smoking and automobiledriving stress in relation to deaths from cardiac and vascular disease. Am J Med Sci 1957;234: Special tabulations of the Framingham Study data prepared for the Surgeon General s Advisory Committee on Smoking and Health. 27. Dorn HF. Tobacco consumption and mortality from cancer and other diseases. Pub. Health. Rep. 1959;74: Spain DM, Nathan DJ. Smoking habits and coronary atherosclerotic heart disease. JAMA 1961;177: Edwards F, McKeown T, Whitfield AGW. Association between smoking and disease in men over sixty. Lancet 1959;1: Doyle JT, Dawber TR, Kannel WB, Heslin DS, Kahn HA. Cigarette smoking and coronary heart disease. Combined experience of the Albany and Framingham studies. New Eng J Med. 1962;266: Doyle JT, Heslin AS, Hilleboe HE, Formel PF. Early diagnosis of ischemic heart disease. New Eng J Med 1959;261: Zukel WJ, Lewis RH, Enterline PE, Painter RC, Ralston LS, Fawcett RM, Meredith AP, Peterson B. A sort-term community study of the epidemiology of coronary heart disease. Am J Pub Health 1959;49: Konttinen A. Cigarette smoking and serum lipids in young men. Brit Med J 1962;1: Karvonen M, Orma E, Keys A, Fidanza F, Brozek J. Cigarette smoking, serum cholesterol, blood pressure, and body fatness. Observations in Finland. Lancet 1959; 1: Damon A. Constitution and smoking in Italian-American factory workers. Proc Amer. Ass. Phys. Anthrop. 1962;20:67 8.