AMERICAN
Journal of Epidemiology VOL. 102
DECEMBER, 1975
NO. 6
Reviews and Commentary INTERNATIONAL STUDIES IN EPIDEMIOLOGY D. D. REID1
The use of comparisons in disease experience in different countries as an approach to problems in etiology has a long and respectable history. In Sir George Baker's classic study of Devonshire colic in the 18th century (1), for example, the crucial observations that pin-pointed the nature of the pathogen came from within and between country comparisons. In England itself, the colic was not seen in the counties of Worcester, Gloucester and Hereford where cider was as popular as in Devon. But Baker remembered the clinically identical condition seen in France where litharge had been added to sour wine and produced the classical signs of lead poisoning. The use in Devon of lead vessels in making and storing cider had obviously achieved the same results. The recognition of lead as the source of colic common to two countries thus completely dismissed Huxham's theory that the origin of the disease in Devon lay in the nature of the apples used there to make cider. Argument from comparison rather than by -analogy is the commoner approach in international epidemiology and the studies in the 19th century by Sir Percival Pott and others (2) on the etiology of scrotal cancer in chimney sweeps were early exam-
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Formerly AMERICAN JOURNAL OF HYGIENE © 1975 by The Johns Hopkins University School of Hygiene and Public Health
pies of this principle. Contrasts were made between the relatively high rates of death from the disease in England and the low rates in France, Germany and Belgium. This disparity might be attributed to differences between the hard or stone coal used in England and the brown coal used on the Continent. The more likely, if less palatable conclusion, was that the standards of protective clothing and personal hygiene of the English chimney sweeps left much to be desired when set against those of their contemporaries in other countries. VITAL STATISTICS AS A STARTING POINT
Mortality statistics in general and international statistics in particular are a much criticized source of information on disease experience; and they are often too readily dismissed as "not worth the paper they are written on." But their indications are sometimes ignored to the peril of the public health. The rising tide of mortality from lung cancer in several western countries between the two World Wars was dismissed by some as an artifact of better diagnosis of primary tumors of bronchus and improvement in the recognition and reporting of the disease (3). Many thousands died from this cause in England and Wales long before case control and prospec1 Department of Medical Statistics and Epidemiol- tive studies confirmed what might have ogy, London School of Hygiene and Tropical Medicine, Keppel Street (Gower Street) London WC1E been inferred from a simple inspection of the close association between the death 7HT, England. 469
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Norwegians had the lowest rate for each of those three causes of death. Some preliminary inquiries (10) suggested that there were international differences in conventions of diagnostic nomenclature which might explain, for example, the reported British excess of "chronic bronchitis." One approach (11) to this problem is the presentation of a series of "standard cases" as defined by clinical histories and post-mortem findings to representative groups of certifying physicians in each country. By such means, divergence between national habits can be detected, as in an American preference for more specific terms such as "bronchiectasis" or a tendency for them to cite coronary heart disease as the underlying cause of death in complex conditions where there are both cardiovascular and respiratory components of the terminal illness. On the other hand, it was shown that, within broad categories the three national groups of physicians were reasonably consistent in their allocation of cases to underlying cause. This finding implied that the reported differences in mortality by broad cause grouping could not be dismissed as artifactual and that further investigation was justified. T H E INTERPRETATION OF INTERNATIONAL PATTERNS IN MORTALITY
The principles of analysis in studies of international patterns of mortality are simply extensions of traditional methods to this particular field. A consistent upward trend in the death rate from cirrhosis of the liver in several western countries in the post war period left little doubt that this was a real phenomenon which was likely to be the result of increasing supplies of alcoholic beverages (12). But a disparity in experience can be even more informative as in the divergent trends of increase in mortality from this cause in the United States and the much lower rates in the United Kingdom where excise duties were relatively heavier and the hours of drinking more closely regulated. Not only did this
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rates from lung cancer in various advanced countries and the level of cigarette consumption there (4). Similarly, probably because of their relatively small scale and the rather special populations covered, early American prospective inquiries in Framingham (5) and Albany (6) gave no clear indication of the relevance of cigarette smoking to the risk of death from coronary heart disease. Yet such an association, now confirmed by the accumulation of large-scale evidence (7), was obvious in the correlation of arteriosclerotic heart disease mortality and national levels of cigarette consumption (8). It is easy, by the exercise of hindsight, to cite missed clues hidden in the tangled thicket of international mortality. The problem is to distinguish such clues from statistical artifacts of one kind or another. Gross differences in death rates may be obvious but the crucial question is whether they are true expressions of differing disease experience in the countries concerned and, if they are, what is their explanation? At the simplest level, death rates as reported to the World Health Organization may be much affected by national habits and conventions in the handling of death certificates. One study (9) has shown that, given the same set of death certificates, the vital statistical offices of several countries will code and classify them into the major categories of the International List with reasonable consistency. More important, however, are international differences in conventions of diagnostic labeling of the more specific clinical condition by physicians in different countries. There are, for example, major differences in the reported death rates for men aged 45-64 from various forms of chest and heart disease between the United States, the United Kingdom and Norway—countries with similar levels of sophistication in clinical practice. The Americans had the highest mortality from coronary heart disease, the British the highest rate for both malignant and nonmalignant diseases of the lung while the
INTERNATIONAL STUDIES IN EPIDEMIOLOGY
cancer and stroke are both unusually common as causes of death in Japan the high salt diet in that country may be an important cause of both (15). Inevitably, correlation studies in international mortality are at best a useful source of informed speculation. Although suggestive associations between disease and some factor may be uncovered, their interpretation may be obscured by covert relationships with some other factors that have not been measured but which may be the underlying cause of the disease in question. There is much collateral evidence about the role of diet in coronary heart disease and the pattern of international mortality is certainly consistent with a proposition of cause and effect. Unfortunately, we are dealing with a stage army where the same country may appear in many guises. Countries with high fat diets also tend to be technically advanced communities with high levels of cigarette consumption and low levels of arduous physical exertion at work—both factors relevant to the onset or severity of coronary heart disease. Conversely, developing countries have a different experience of infectious disease. Viewed in proportional terms, coronary heart disease in them is liable to appear infrequent in hospital where acute infections are much more numerous—quite apart from the possible effect of chronic infection itself in lowering the risk of arteriosclerosis. Another confounding factor may be race; and where there is a manifest genetic basis as in G6PD deficiency in Jews (16), international comparisons which may point to some environmental cause may be misinterpreted. A more general problem, however, is the risk of inferring from a correlation in national groups between mortality from coronary heart disease and colon cancer that they have some causal factor such as a high fat diet in common. In the particular context of international studies, this pitfall has been exposed by further investigation, either by case control (17) or prospective inquiries (18). They
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international contrast strengthen the evidence on causation but it also pointed the way to effective public health action. Again, simple division by age and sex can be useful. In Europe, the pattern of respiratory mortality differs in different ways at different ages (13). In infancy and childhood, the agrarian countries of Eastern Europe like Romania and Bulgaria have the highest death rate from pneumonia and bronchitis presumably as a reflection of poorer living standards there. In adult life, however, the highest death rates are found in the more heavily industrialized countries of the West where exposure to dust and fumes may be important causes, but the marked male preponderance in countries where cigarette consumption is high strongly suggests that this habit may explain much more of the international variation in mortality from chronic respiratory disease. At a more sophisticated level, it is sensible to inspect the relationship between national levels of mortality from a specific cause with corresponding levels of consumption of some article of diet or fuel. Such exploratory correlations can be a search for further evidence of an association that may mean causation to follow up an impression gained perhaps from clinical experience. But it can equally well be a systematic dredging operation where there are no obvious prima facie links between one of a range of possible causes of death from a specific disease. One example of this approach is the demonstration of a significant correlation between high fat diet and mortality from cancer of the colon (14). Another notes the association between the death rates from different diseases in different countries with the implied inference that, when two diseases both appear to be frequent in some countries and infrequent in others, they are likely to have some cause in common. The smoking-related diseases such as lung cancer and coronary heart disease are typical of such a situation. Less obvious, but perhaps more intriguing, is the suggestion that since gastric
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showed that, within individuals, a high blood cholesterol which might be the result of a high fat diet was not related to the risk of developing cancer of the colon. Consistency of diagnostic standards is clearly of crucial importance in international comparisons of mortality particularly when specific diseases are of prime interest; and much effort has gone into field surveys using standard diagnostic tests and criteria to validate the contrasts seen in national mortality statistics. Their aim is to supplement the quantity of death certification data by the quality of clinical assessment of population samples. Inevitably, their value is restricted to those conditions that are common enough to make it feasible, by surveys on a modest scale, to detect any major disparity in frequency between different countries. The wide variation in death rates in middle-aged men in coronary heart disease or chronic obstructive lung disease, for example, has led to development in the adoption of defined criteria for their diagnosis and the standardization of clinical methods of assessment. This development has been vital in permitting sound comparisons between the frequency of disease in different countries. But it also ensures precise communication about these conditions between clinicians working in different countries with different concepts and conventions in the diagnosis and classification of the various forms of cardio-respiratory disease. This development includes codes for the classification of electrocardiographic findings and questionnaires designed to elicit in a uniform manner the particular items of clinical history, e.g., of chronic phlegm production, that indicate specific disease. Such items can then be grouped into constellations of signs or symptoms to define cardiovascular or respiratory syndromes of successive degrees of severity. This is not to say that definition in itself will ensure comparability but it is an essential first step. Many
Ideally, field surveys designed to validate the indications of disparity in disease frequency indicated by mortality statistics should be carried out on truly representative samples of the national populations concerned; and, within the usual limitations of selective non-response, this has been done using self-administered questionnaires distributed by post. In other circumstances, the choice of populations for detailed clinical survey has been dictated by the need to minimize travel and maximize the contrasts involved. In the Seven Country study of coronary heart disease, for example, the populations surveyed include the population of Greek villages and a group of railroad employees in Minnesota (20). This may entail some problems in interpretation of results, for such groups may not be typical of their country's population as a whole. Moreover, the physical activity or domestic or social environment and habits may reflect their occupation rather than the general national experience. The latter problem, but not the first, may be resolved by comparing the physical status of groups of men living
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INTERNATIONAL FIELD SURVEYS
practical problems remain as in the question of translation of questions and the often subtle differences in the meaning of everyday phrases in different languages. There may be in certain national cultures, social conventions which inhibit the admission of pain or other disagreeable symptoms especially to an interviewer of the opposite sex. Much can be done to minimize such disturbing influences by the use of the more anonymous approach of a self-administered questionnaire and training and testing field observers on standard records, e.g., of interviews or electrocardiographic tracings. The principles and practice are set out in a World Health Organization monograph (19) on epidemiologic methods in cardiovascular disease but they have also been fruitfully applied in the international studies of psychiatric disorders such as schizophrenia in very different cultural conditions.
INTERNATIONAL STUDIES IN EPIDEMIOLOGY
INTERNATIONAL
DIFFERENCES HISTORY
IN
NATURAL
Prevalence surveys of this kind have the added advantage that, if the individual concerned can be followed up for five or 10 years they allow a further comparison of the natural history of the specific disease in different national environments. This approach has already been adopted using cancer registration to identify cases and then record their subsequent survival times. By this means, it was shown that cancer of the cervix led to death much more rapidly in patients in selected hospitals in England than in comparable patients in the United States (23). Prevalence surveys of slowly progressive chronic disease in different countries may also indicate international differences in their natural history. Compared with results in Britain, a survey in a small New Hampshire town showed a similar prevalence of mild bronchitis but a much lower level of more serious disease with evidence of ventilatory obstruction (24). In recent years, there has been an increasing emphasis on the divergent clinical forms seen in different countries. In countries with high death rates from cancer of the colon, for example, the sigmoid-cecum ratio is higher than in low risk countries. Moreover, high death rates are associated with a high prevalence of
adenomatous polyps (25). In future, then, the distribution of both possible precursor lesions and the differing manifestations of the malignant lesion itself will be used to fill in the epidemiologic picture. MIGRANT STUDIES
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in different countries but pursuing the same occupation and thus uniform in their job demands and social status in the community. At the same time, recording their habits such as smoking allows some correction to be made in the final comparison for this important factor. By such an approach, the high death rate from chronic bronchitis and emphysema in the United Kingdom compared with the United States and Norway has been shown as reflected in a high prevalence of chronic lung disease in men working as drivers of service vehicles in urban areas of England and lower rates in similar areas in both the United States (21) and Norway (22).
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A special form of international study deals with the disease experience of those who have changed the living environment of one country for another. It is "an experiment on the grandest scale" in as much as people of the same racial stock move often to very different conditions or stocks from varying origins may live together in the same environment. The spread of the British to the far corners of the earth is an example of the first while the aggregation of people of very different origins in the United States illustrates the second. These massive movements of populations thus afford an opportunity of answering questions on the impact on health that such changes might bring or the residual and lasting effects of a childhood spent in one environment even after change to a new one. The study of migrant populations has been particularly productive in the field of cancer research. A study in 1929 pointed to differences in the rates of death from cancer of various sites among immigrants from different origins living in Boston (26). This has been followed up by nationwide analyses of mortality among the foreignborn in the United States which confirm and amplify the earlier work (27). In general, death rates, as from cancer of the bowel, among migrants to the United States lie between those of their native country and those of their country of adoption. The inference is that environmental factors including diet, which change on migration, are important in the causation of the disease. Again, individuals of the same British stock migrating from the United Kingdom where mortality from lung cancer is high to countries as far apart as South Africa (28) and Canada (29),
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may also be collected. Much can then be done by adjusting for differences between migrant and population groups in circumstances or habits, such as smoking, relevant to either chest or heart disease. In comparing siblings on either side of the Atlantic, the fact that the chance of having a sibling in the home country depends on family size which in turn may be related to the risk of respiratory disease. In such a situation, statistical adjustment is essential. Interaction, in the sense that the influence of one etiologic factor may be enhanced in the presence of high levels of another, may be of special importance in international studies. In the BritishNorwegian migrant investigation, for example, the relationship of smoking to frequency of chronic phlegm production in population samples is evident in both Norway (31) and Great Britain (32). In the British sample, however, the prevalence rates were particularly high among cigarette smokers living in the most heavily polluted areas of the country. This comparison also illustrates one of the analytical advantages of international studies in allowing the separation of an urban from a pollution effect for although there was a small rural-urban gradient in prevalence in Some of these problems can be mini- Norway, this gradient was much more mized if not entirely overcome. In the marked in Britain where the effects of British-Norwegian study, for example, the smoke pollution are added to the respiraresults of morbidity survey and long-term tory hazards of urban life. Such a separafollow up in British migrants to the United tion is more difficult in within-country States are being compared in turn with studies where urbanization and pollution those in the Norwegians—another migrant may be highly correlated. group from Europe of similar racial stock—and in representative samples of A CURRENT EXAMPLE OF A MIGRANT STUDY the contemporary population of both the International studies thus have their United Kingdom and Norway (30). To scientific limitations as well as logistic and account for the possibility that migrants practical problems inherent in their concome from particular social or family duct. Nevertheless, they do offer some groups, the results for migrants in the prospect of answering questions on the United States are also being compared effect of environments on health in a with those for their siblings who have unique and often satisfying manner. The remained in either the United Kingdom or articles on the Japanese-American series of Norway. Ancillary information on migra- migrant studies published in this issue tion history, smoking and other factors (33-37) illustrate their potential and the
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retain, to some degree, a higher death rate from the disease than their native-born contemporaries. The conditions of early life in the United Kingdom or the continuation of habits acquired before leaving it thus seem to affect the risk of death from malignant disease of the lung. These inferences from the experience of migrants are, however, subject to some limitations. Migrants are inevitably a selected group. Those who choose to leave their mother country are likely to be the fitter and more enterprising members of a family. On the other hand, they may include many for whom migration is a manifestation of temperamental instability. Since economic pressures often precipitate migration, those moving are likely to come from the deprived part of the community and the poorer regions of the country. Immigration laws enforcing clinical examination can exclude those with the most serious physical and mental disabilities. It is thus difficult to be sure about the net result in terms of health of these various elements of selection. Further, when an individual changes from one culture to another, and perhaps very different one, he is subject to the physical and mental problems of adaptation to his new milieu.
INTERNATIONAL STUDIES IN EPIDEMIOLOGY
the upward trend in coronary heart disease in these three Japanese communities. Similarly, the small differences found in average blood pressure are largely attributable to disparity in body weight and are certainly not an obvious explanation for the contrary trend in mortality from stroke. The group emphasizes that these results are based on the results of prevalence surveys. The follow-up on the incidence and mortality from cardiovascular disease should establish whether the conventional risk factors have the same prognostic significance in the three communities as they have elsewhere. Consistency in these relationships will then allow their joint effect in causing the differences in disease experience to be estimated with more confidence. To date, no such explanation is apparent and one may be tempted to speculate on the cultural or other features of American life that prompt the onset of ischemic disease. But before sociologic or cultural explanations are invoked, there is much to be done on a more mundane level. What, for example, is the role as a cause of stroke of the high salt consumption found in this study among the Japanese in Japan? Further, although current smoking habits may be similar, the history of smoking during this century differs greatly between the United States and Japan; and since duration of heavy smoking may be as important as current consumption, does this difference explain any of the past relative immunity to coronary heart disease of the Japanese in Japan? CONCLUSION
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way in which problems may be resolved. The initial stimulus came from the observation that while stroke was a particularly frequent cause of death in Japan and progressively less common among Japanese in Hawaii and California, the opposite was the case for coronary heart disease. A comprehensive and detailed study of death certification practice in these three areas has shown that although differences in procedure exist, as in the American convention of attributing death to coronary heart disease rather than to stroke when both appear in Part I of the death certificate, this divergence in practice could not explain the reported pattern of cardiovascular mortality. The investigating groups have then sought to validate these apparent differences in disease experience by field surveys of representative samples designed to establish the level of coronary heart disease in Japanese living in Japan, Hawaii and California. At the same time, they wished to compare the relation of disease prevalence to known risk factors in these different populations. To this end, they used the now standard methods of clinical appraisal and have exerted such close control over the assessment of biochemical variables that the bias usually involved in international comparisons between the distributions of, for example, cholesterol was precisely ascertained and readily taken into account. The results of these field studies certainly vindicate the indications given by the initial mortality analysis, for the trends in the prevalence of signs and symptoms of coronary heart disease show the predicted increase from low rates in Japan itself to higher rates among the communities who have adopted the American way of life. Risk factors for coronary heart disease, such as cholesterol or triglycerides or postload serum glucose levels, were also consistent in their ranking between the three groups in this study. Nevertheless, neither these factors, nor current smoking habits in Japan, Hawaii or California could explain
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This chronicled experience of one group of investigators in international epidemiology reveals the abiding need in such studies for imagination in conception, perseverance in conduct and, above all, an acceptance of the discipline of standard methods and centralized control over a long period. Migrant studies in particular can be a protracted and frustrating travail but the answers they give, and the fascinating side
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issues they raise, compensate for all the effort that they entail. REFERENCES
Endemial Colic of Devonshire. London, 1767 2. Butlin HT: On cancer of the scrotum in chimneysweeps and others. Br Med J 1:1341-1346; 2:1-6, 66-71, 1892 3. Steiner PE: Incidence of primary carcinoma of the lung with special reference to its increase. Arch Pathol 37:185-195, 1944 4. Dungal N: Lung carcinoma in Iceland. Lancet 2:245-247, 1950 5. Dawber TR, Moore FE, Mann GV: Coronary heart disease in the Framingham Study. Am J Public Health 47:(Part 2) 4-24, 1957 6. Doyle JT, Heslins S, Hilleboe HE: Prospective study of degenerative cardiovascular disease in Albany. Report of three years' experience. I. Ischaemic heart disease. Am J Public Health 47:(Part 2) 25-32, 1957 7. Hammond EC: Smoking in relation to death rates of one million men and women. Natl Cancer Inst Monogr 19:127-204, 1966 8. Reid DD: Cardiorespiratory disease as a field for international research. Am J Public Health 50:53-59, 1960 9. WHO Regional Office For Europe: Studies on the accuracy and comparability of statistics on causes of death. Unpublished WHO Document, Euro215.1/16, 1966 10 Meneely GR: Paul O, Dorn HF, et al: Cardiopulmonary semantics. JAMA 174: 1628-1629, 1960 11 Reid DD, Rose GA: Assessing the comparability of mortality statistics. Br Med J 2:1437-1439, 1964 12 Terris, M: Epidemiology of cirrhosis of the liver: national mortality data. Am J Public Health 57:(Part 2) 2076-2088, 1967 13 WHO Regional Office For Europe. Respiratory disease in Europe: Report on a study. Copenhagen, 1974 14 Wynder EL, Reddy BS: The epidemiology of cancer of the large bowel. Digestive Diseases 19:937-946, 1974 15 Joossens JV: Salt and hypertension, water hardness and cardiovascular death rate. Triangle 12:9-16, 1973 16 Sheba C: Jewish Migration in its historical perspective. Isr J Med Sci 7:1333-1341, 1971 17 Wynder EL, Kajitani T, Ishikawa S, et al: Environmental factors of cancer of the colon and rectum. II. Japanese epidemiological data. Cancer 23:1210-1220, 1969 18 Rose G, Blackburn H, Keys A, et al: Colon cancer and blood cholesterol. Lancet 1:181-183, 1974 19. Rose GA, Blackburn H: Cardiovascular Survey Methods. WHO Monogr Ser No 56, Geneva, 1968 20. Keys A: Coronary heart disease in seven countries. Circulation 41: Suppl 1, 1970
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1. Baker G: An Essay Concerning the Cause of the
21. Holland WW, Reid DD, Seltser R, et al: Respiratory disease in England and the United States. Arch Environ Health 10:338-343, 1965 22. Mork T: A comparative study of respiratory disease in England and Wales and Norway. Acta Med Scand 172: Suppl 384, 1962 23. Haenszel W: International collaborative studies of cancer in man: the role of the National Cancer Institute. Natl. Cancer Inst Monogr 40: 75-81, 1974 24. Reid DD, Anderson DO, Ferris BG, et al: An Anglo-American comparison of the prevalence of bronchitis. Br Med J 2:1487-1491, 1964 25. Haenszel W, Correa P: Cancer of the large intestine: epidemiologic findings. Dis Colon Rectum 16:371-377, 1973 26. Lombard HL, Doering CR: Cancer studies in Massachusetts. Cancer mortality in nativity groups. J Prev Med 3:343-361, 1929 27. Haenszel W: Cancer mortality among the foreignborn in the United States. J Natl Cancer Inst 26:37-132, 1961 28. Dean G: Lung cancer in South Africans and British immigrants. Proc R Soc Med 57:984, 1964 29. Coy P, Grzybowski S, Rowe JF: Lung cancer mortality according to birthplace. Can Med Assoc J 99:476-483, 1968 30. Reid DD: Studies of disease among migrants and native populations in Great Britain, Norway and the United States. I. Background and design. Natl Cancer Inst Monogr 19:287-299, 1966 31. Haenszel W, Hougen A: Prevalence of respiratory symptoms in Norway. J Chronic Dis 25:519-544, 1972 32. Lambert PM, Reid DD: Smoking, air pollution and bronchitis in Britain. Lancet 1:853-857, 1970 33. Syme SL, Marmot MG, Kagan A, et al: Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Introduction. Am J Epidemiol 102:477-480, 1975 34. Worth RM, Kato H, Rhoads GG, et al: Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Mortality. Am J Epidemiol 102:481-490, 1975 35. Nichaman MZ, Hamilton HB, Kagan A, et al: Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Distribution of biochemical risk factors. Am J Epidemiol 102:491-501, 1975 36. Winkelstein W Jr, Kagan A, Kato H, et al: Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Blood pressure distributions. Am J Epidemiol 102:502-513, 1975 37. Marmot MG, Syme SL, Kagan A, et al: Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Prevalence of coronary and hypertensive heart disease and associated risk factors. Am J Epidemiol 102:514-525, 1975
Journal of Epidemiology VOL. 102
DECEMBER, 1975
NO. 6
Reviews and Commentary INTERNATIONAL STUDIES IN EPIDEMIOLOGY D. D. REID1
The use of comparisons in disease experience in different countries as an approach to problems in etiology has a long and respectable history. In Sir George Baker's classic study of Devonshire colic in the 18th century (1), for example, the crucial observations that pin-pointed the nature of the pathogen came from within and between country comparisons. In England itself, the colic was not seen in the counties of Worcester, Gloucester and Hereford where cider was as popular as in Devon. But Baker remembered the clinically identical condition seen in France where litharge had been added to sour wine and produced the classical signs of lead poisoning. The use in Devon of lead vessels in making and storing cider had obviously achieved the same results. The recognition of lead as the source of colic common to two countries thus completely dismissed Huxham's theory that the origin of the disease in Devon lay in the nature of the apples used there to make cider. Argument from comparison rather than by -analogy is the commoner approach in international epidemiology and the studies in the 19th century by Sir Percival Pott and others (2) on the etiology of scrotal cancer in chimney sweeps were early exam-
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Formerly AMERICAN JOURNAL OF HYGIENE © 1975 by The Johns Hopkins University School of Hygiene and Public Health
pies of this principle. Contrasts were made between the relatively high rates of death from the disease in England and the low rates in France, Germany and Belgium. This disparity might be attributed to differences between the hard or stone coal used in England and the brown coal used on the Continent. The more likely, if less palatable conclusion, was that the standards of protective clothing and personal hygiene of the English chimney sweeps left much to be desired when set against those of their contemporaries in other countries. VITAL STATISTICS AS A STARTING POINT
Mortality statistics in general and international statistics in particular are a much criticized source of information on disease experience; and they are often too readily dismissed as "not worth the paper they are written on." But their indications are sometimes ignored to the peril of the public health. The rising tide of mortality from lung cancer in several western countries between the two World Wars was dismissed by some as an artifact of better diagnosis of primary tumors of bronchus and improvement in the recognition and reporting of the disease (3). Many thousands died from this cause in England and Wales long before case control and prospec1 Department of Medical Statistics and Epidemiol- tive studies confirmed what might have ogy, London School of Hygiene and Tropical Medicine, Keppel Street (Gower Street) London WC1E been inferred from a simple inspection of the close association between the death 7HT, England. 469
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Norwegians had the lowest rate for each of those three causes of death. Some preliminary inquiries (10) suggested that there were international differences in conventions of diagnostic nomenclature which might explain, for example, the reported British excess of "chronic bronchitis." One approach (11) to this problem is the presentation of a series of "standard cases" as defined by clinical histories and post-mortem findings to representative groups of certifying physicians in each country. By such means, divergence between national habits can be detected, as in an American preference for more specific terms such as "bronchiectasis" or a tendency for them to cite coronary heart disease as the underlying cause of death in complex conditions where there are both cardiovascular and respiratory components of the terminal illness. On the other hand, it was shown that, within broad categories the three national groups of physicians were reasonably consistent in their allocation of cases to underlying cause. This finding implied that the reported differences in mortality by broad cause grouping could not be dismissed as artifactual and that further investigation was justified. T H E INTERPRETATION OF INTERNATIONAL PATTERNS IN MORTALITY
The principles of analysis in studies of international patterns of mortality are simply extensions of traditional methods to this particular field. A consistent upward trend in the death rate from cirrhosis of the liver in several western countries in the post war period left little doubt that this was a real phenomenon which was likely to be the result of increasing supplies of alcoholic beverages (12). But a disparity in experience can be even more informative as in the divergent trends of increase in mortality from this cause in the United States and the much lower rates in the United Kingdom where excise duties were relatively heavier and the hours of drinking more closely regulated. Not only did this
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rates from lung cancer in various advanced countries and the level of cigarette consumption there (4). Similarly, probably because of their relatively small scale and the rather special populations covered, early American prospective inquiries in Framingham (5) and Albany (6) gave no clear indication of the relevance of cigarette smoking to the risk of death from coronary heart disease. Yet such an association, now confirmed by the accumulation of large-scale evidence (7), was obvious in the correlation of arteriosclerotic heart disease mortality and national levels of cigarette consumption (8). It is easy, by the exercise of hindsight, to cite missed clues hidden in the tangled thicket of international mortality. The problem is to distinguish such clues from statistical artifacts of one kind or another. Gross differences in death rates may be obvious but the crucial question is whether they are true expressions of differing disease experience in the countries concerned and, if they are, what is their explanation? At the simplest level, death rates as reported to the World Health Organization may be much affected by national habits and conventions in the handling of death certificates. One study (9) has shown that, given the same set of death certificates, the vital statistical offices of several countries will code and classify them into the major categories of the International List with reasonable consistency. More important, however, are international differences in conventions of diagnostic labeling of the more specific clinical condition by physicians in different countries. There are, for example, major differences in the reported death rates for men aged 45-64 from various forms of chest and heart disease between the United States, the United Kingdom and Norway—countries with similar levels of sophistication in clinical practice. The Americans had the highest mortality from coronary heart disease, the British the highest rate for both malignant and nonmalignant diseases of the lung while the
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cancer and stroke are both unusually common as causes of death in Japan the high salt diet in that country may be an important cause of both (15). Inevitably, correlation studies in international mortality are at best a useful source of informed speculation. Although suggestive associations between disease and some factor may be uncovered, their interpretation may be obscured by covert relationships with some other factors that have not been measured but which may be the underlying cause of the disease in question. There is much collateral evidence about the role of diet in coronary heart disease and the pattern of international mortality is certainly consistent with a proposition of cause and effect. Unfortunately, we are dealing with a stage army where the same country may appear in many guises. Countries with high fat diets also tend to be technically advanced communities with high levels of cigarette consumption and low levels of arduous physical exertion at work—both factors relevant to the onset or severity of coronary heart disease. Conversely, developing countries have a different experience of infectious disease. Viewed in proportional terms, coronary heart disease in them is liable to appear infrequent in hospital where acute infections are much more numerous—quite apart from the possible effect of chronic infection itself in lowering the risk of arteriosclerosis. Another confounding factor may be race; and where there is a manifest genetic basis as in G6PD deficiency in Jews (16), international comparisons which may point to some environmental cause may be misinterpreted. A more general problem, however, is the risk of inferring from a correlation in national groups between mortality from coronary heart disease and colon cancer that they have some causal factor such as a high fat diet in common. In the particular context of international studies, this pitfall has been exposed by further investigation, either by case control (17) or prospective inquiries (18). They
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international contrast strengthen the evidence on causation but it also pointed the way to effective public health action. Again, simple division by age and sex can be useful. In Europe, the pattern of respiratory mortality differs in different ways at different ages (13). In infancy and childhood, the agrarian countries of Eastern Europe like Romania and Bulgaria have the highest death rate from pneumonia and bronchitis presumably as a reflection of poorer living standards there. In adult life, however, the highest death rates are found in the more heavily industrialized countries of the West where exposure to dust and fumes may be important causes, but the marked male preponderance in countries where cigarette consumption is high strongly suggests that this habit may explain much more of the international variation in mortality from chronic respiratory disease. At a more sophisticated level, it is sensible to inspect the relationship between national levels of mortality from a specific cause with corresponding levels of consumption of some article of diet or fuel. Such exploratory correlations can be a search for further evidence of an association that may mean causation to follow up an impression gained perhaps from clinical experience. But it can equally well be a systematic dredging operation where there are no obvious prima facie links between one of a range of possible causes of death from a specific disease. One example of this approach is the demonstration of a significant correlation between high fat diet and mortality from cancer of the colon (14). Another notes the association between the death rates from different diseases in different countries with the implied inference that, when two diseases both appear to be frequent in some countries and infrequent in others, they are likely to have some cause in common. The smoking-related diseases such as lung cancer and coronary heart disease are typical of such a situation. Less obvious, but perhaps more intriguing, is the suggestion that since gastric
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showed that, within individuals, a high blood cholesterol which might be the result of a high fat diet was not related to the risk of developing cancer of the colon. Consistency of diagnostic standards is clearly of crucial importance in international comparisons of mortality particularly when specific diseases are of prime interest; and much effort has gone into field surveys using standard diagnostic tests and criteria to validate the contrasts seen in national mortality statistics. Their aim is to supplement the quantity of death certification data by the quality of clinical assessment of population samples. Inevitably, their value is restricted to those conditions that are common enough to make it feasible, by surveys on a modest scale, to detect any major disparity in frequency between different countries. The wide variation in death rates in middle-aged men in coronary heart disease or chronic obstructive lung disease, for example, has led to development in the adoption of defined criteria for their diagnosis and the standardization of clinical methods of assessment. This development has been vital in permitting sound comparisons between the frequency of disease in different countries. But it also ensures precise communication about these conditions between clinicians working in different countries with different concepts and conventions in the diagnosis and classification of the various forms of cardio-respiratory disease. This development includes codes for the classification of electrocardiographic findings and questionnaires designed to elicit in a uniform manner the particular items of clinical history, e.g., of chronic phlegm production, that indicate specific disease. Such items can then be grouped into constellations of signs or symptoms to define cardiovascular or respiratory syndromes of successive degrees of severity. This is not to say that definition in itself will ensure comparability but it is an essential first step. Many
Ideally, field surveys designed to validate the indications of disparity in disease frequency indicated by mortality statistics should be carried out on truly representative samples of the national populations concerned; and, within the usual limitations of selective non-response, this has been done using self-administered questionnaires distributed by post. In other circumstances, the choice of populations for detailed clinical survey has been dictated by the need to minimize travel and maximize the contrasts involved. In the Seven Country study of coronary heart disease, for example, the populations surveyed include the population of Greek villages and a group of railroad employees in Minnesota (20). This may entail some problems in interpretation of results, for such groups may not be typical of their country's population as a whole. Moreover, the physical activity or domestic or social environment and habits may reflect their occupation rather than the general national experience. The latter problem, but not the first, may be resolved by comparing the physical status of groups of men living
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practical problems remain as in the question of translation of questions and the often subtle differences in the meaning of everyday phrases in different languages. There may be in certain national cultures, social conventions which inhibit the admission of pain or other disagreeable symptoms especially to an interviewer of the opposite sex. Much can be done to minimize such disturbing influences by the use of the more anonymous approach of a self-administered questionnaire and training and testing field observers on standard records, e.g., of interviews or electrocardiographic tracings. The principles and practice are set out in a World Health Organization monograph (19) on epidemiologic methods in cardiovascular disease but they have also been fruitfully applied in the international studies of psychiatric disorders such as schizophrenia in very different cultural conditions.
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Prevalence surveys of this kind have the added advantage that, if the individual concerned can be followed up for five or 10 years they allow a further comparison of the natural history of the specific disease in different national environments. This approach has already been adopted using cancer registration to identify cases and then record their subsequent survival times. By this means, it was shown that cancer of the cervix led to death much more rapidly in patients in selected hospitals in England than in comparable patients in the United States (23). Prevalence surveys of slowly progressive chronic disease in different countries may also indicate international differences in their natural history. Compared with results in Britain, a survey in a small New Hampshire town showed a similar prevalence of mild bronchitis but a much lower level of more serious disease with evidence of ventilatory obstruction (24). In recent years, there has been an increasing emphasis on the divergent clinical forms seen in different countries. In countries with high death rates from cancer of the colon, for example, the sigmoid-cecum ratio is higher than in low risk countries. Moreover, high death rates are associated with a high prevalence of
adenomatous polyps (25). In future, then, the distribution of both possible precursor lesions and the differing manifestations of the malignant lesion itself will be used to fill in the epidemiologic picture. MIGRANT STUDIES
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in different countries but pursuing the same occupation and thus uniform in their job demands and social status in the community. At the same time, recording their habits such as smoking allows some correction to be made in the final comparison for this important factor. By such an approach, the high death rate from chronic bronchitis and emphysema in the United Kingdom compared with the United States and Norway has been shown as reflected in a high prevalence of chronic lung disease in men working as drivers of service vehicles in urban areas of England and lower rates in similar areas in both the United States (21) and Norway (22).
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A special form of international study deals with the disease experience of those who have changed the living environment of one country for another. It is "an experiment on the grandest scale" in as much as people of the same racial stock move often to very different conditions or stocks from varying origins may live together in the same environment. The spread of the British to the far corners of the earth is an example of the first while the aggregation of people of very different origins in the United States illustrates the second. These massive movements of populations thus afford an opportunity of answering questions on the impact on health that such changes might bring or the residual and lasting effects of a childhood spent in one environment even after change to a new one. The study of migrant populations has been particularly productive in the field of cancer research. A study in 1929 pointed to differences in the rates of death from cancer of various sites among immigrants from different origins living in Boston (26). This has been followed up by nationwide analyses of mortality among the foreignborn in the United States which confirm and amplify the earlier work (27). In general, death rates, as from cancer of the bowel, among migrants to the United States lie between those of their native country and those of their country of adoption. The inference is that environmental factors including diet, which change on migration, are important in the causation of the disease. Again, individuals of the same British stock migrating from the United Kingdom where mortality from lung cancer is high to countries as far apart as South Africa (28) and Canada (29),
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may also be collected. Much can then be done by adjusting for differences between migrant and population groups in circumstances or habits, such as smoking, relevant to either chest or heart disease. In comparing siblings on either side of the Atlantic, the fact that the chance of having a sibling in the home country depends on family size which in turn may be related to the risk of respiratory disease. In such a situation, statistical adjustment is essential. Interaction, in the sense that the influence of one etiologic factor may be enhanced in the presence of high levels of another, may be of special importance in international studies. In the BritishNorwegian migrant investigation, for example, the relationship of smoking to frequency of chronic phlegm production in population samples is evident in both Norway (31) and Great Britain (32). In the British sample, however, the prevalence rates were particularly high among cigarette smokers living in the most heavily polluted areas of the country. This comparison also illustrates one of the analytical advantages of international studies in allowing the separation of an urban from a pollution effect for although there was a small rural-urban gradient in prevalence in Some of these problems can be mini- Norway, this gradient was much more mized if not entirely overcome. In the marked in Britain where the effects of British-Norwegian study, for example, the smoke pollution are added to the respiraresults of morbidity survey and long-term tory hazards of urban life. Such a separafollow up in British migrants to the United tion is more difficult in within-country States are being compared in turn with studies where urbanization and pollution those in the Norwegians—another migrant may be highly correlated. group from Europe of similar racial stock—and in representative samples of A CURRENT EXAMPLE OF A MIGRANT STUDY the contemporary population of both the International studies thus have their United Kingdom and Norway (30). To scientific limitations as well as logistic and account for the possibility that migrants practical problems inherent in their concome from particular social or family duct. Nevertheless, they do offer some groups, the results for migrants in the prospect of answering questions on the United States are also being compared effect of environments on health in a with those for their siblings who have unique and often satisfying manner. The remained in either the United Kingdom or articles on the Japanese-American series of Norway. Ancillary information on migra- migrant studies published in this issue tion history, smoking and other factors (33-37) illustrate their potential and the
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retain, to some degree, a higher death rate from the disease than their native-born contemporaries. The conditions of early life in the United Kingdom or the continuation of habits acquired before leaving it thus seem to affect the risk of death from malignant disease of the lung. These inferences from the experience of migrants are, however, subject to some limitations. Migrants are inevitably a selected group. Those who choose to leave their mother country are likely to be the fitter and more enterprising members of a family. On the other hand, they may include many for whom migration is a manifestation of temperamental instability. Since economic pressures often precipitate migration, those moving are likely to come from the deprived part of the community and the poorer regions of the country. Immigration laws enforcing clinical examination can exclude those with the most serious physical and mental disabilities. It is thus difficult to be sure about the net result in terms of health of these various elements of selection. Further, when an individual changes from one culture to another, and perhaps very different one, he is subject to the physical and mental problems of adaptation to his new milieu.
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the upward trend in coronary heart disease in these three Japanese communities. Similarly, the small differences found in average blood pressure are largely attributable to disparity in body weight and are certainly not an obvious explanation for the contrary trend in mortality from stroke. The group emphasizes that these results are based on the results of prevalence surveys. The follow-up on the incidence and mortality from cardiovascular disease should establish whether the conventional risk factors have the same prognostic significance in the three communities as they have elsewhere. Consistency in these relationships will then allow their joint effect in causing the differences in disease experience to be estimated with more confidence. To date, no such explanation is apparent and one may be tempted to speculate on the cultural or other features of American life that prompt the onset of ischemic disease. But before sociologic or cultural explanations are invoked, there is much to be done on a more mundane level. What, for example, is the role as a cause of stroke of the high salt consumption found in this study among the Japanese in Japan? Further, although current smoking habits may be similar, the history of smoking during this century differs greatly between the United States and Japan; and since duration of heavy smoking may be as important as current consumption, does this difference explain any of the past relative immunity to coronary heart disease of the Japanese in Japan? CONCLUSION
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way in which problems may be resolved. The initial stimulus came from the observation that while stroke was a particularly frequent cause of death in Japan and progressively less common among Japanese in Hawaii and California, the opposite was the case for coronary heart disease. A comprehensive and detailed study of death certification practice in these three areas has shown that although differences in procedure exist, as in the American convention of attributing death to coronary heart disease rather than to stroke when both appear in Part I of the death certificate, this divergence in practice could not explain the reported pattern of cardiovascular mortality. The investigating groups have then sought to validate these apparent differences in disease experience by field surveys of representative samples designed to establish the level of coronary heart disease in Japanese living in Japan, Hawaii and California. At the same time, they wished to compare the relation of disease prevalence to known risk factors in these different populations. To this end, they used the now standard methods of clinical appraisal and have exerted such close control over the assessment of biochemical variables that the bias usually involved in international comparisons between the distributions of, for example, cholesterol was precisely ascertained and readily taken into account. The results of these field studies certainly vindicate the indications given by the initial mortality analysis, for the trends in the prevalence of signs and symptoms of coronary heart disease show the predicted increase from low rates in Japan itself to higher rates among the communities who have adopted the American way of life. Risk factors for coronary heart disease, such as cholesterol or triglycerides or postload serum glucose levels, were also consistent in their ranking between the three groups in this study. Nevertheless, neither these factors, nor current smoking habits in Japan, Hawaii or California could explain
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This chronicled experience of one group of investigators in international epidemiology reveals the abiding need in such studies for imagination in conception, perseverance in conduct and, above all, an acceptance of the discipline of standard methods and centralized control over a long period. Migrant studies in particular can be a protracted and frustrating travail but the answers they give, and the fascinating side
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issues they raise, compensate for all the effort that they entail. REFERENCES
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