Overview: The Seven Countries Study in Brief
By Henry Blackburn, MD
Ancel Keys at Minnesota, and his colleagues in seven countries, posed the hypothesis that differences among populations in the frequency of heart attacks and stroke would occur in some orderly relation to physical characteristics and lifestyle, particularly composition of the diet, and especially fats in the diet.
To test this idea we carried out surveys from 1958 to 1970 in populations of men aged 40-59, in eighteen areas of seven countries, with follow-up for deaths in the cohorts up to the present day. The formal surveys were undertaken after successful pilot experiences in Finland, Italy, and Greece in 1956 and 1957. Most of the areas were stable and rural and had wide contrasts in habitual diet. In those days, we did not consider involving women because of the great rarity of cardiac events among them, and the invasiveness of our field examinations.
The Seven Countries Study is the prototypical comparison study of populations, made across a wide range of diet, risk, and disease experience. It was the first to explore associations among diet, risk, and disease in contrasting populations (ecologic correlations). Central chemical analysis of foods consumed among randomly selected families in each area, plus diet-recall measures in all the men, allowed an effective test of the dietary hypothesis. The study was unique for its time, in standardization of measurements of diet, risk factors, and disease; training its survey teams; and central, blindfold coding and analysis of data.
There were, of course, limitations: the relatively small number of units for ecological correlations; the selection of the samples in the different geographic areas in part for reasons of convenience; and the technical challenges of conducting surveys across cultures by national teams, often working under difficult field conditions.
The core of investigators was recruited by Ancel Keys and the study coordinated from the Laboratory of Physiological Hygiene, located in offices under Memorial Stadium, Gate 27, at the University of Minnesota. I served as Project Officer in the early years, while Henry Taylor directed the Railroad Study, the U.S. component of the Seven Countries Study. A few years into the study, central coordination of data was shifted to Alessandro Menotti at the University of Rome. All field studies were carried out under the aegis of a National Heart Institute grant. Local support was always substantial, however, in that the central grant only averaged about $25,000 a year per collaborating center. Both public and private sources, as well as the World Health Organization, provided direct and logistic support.
The study has been criticized for the method in which populations were selected for the study, and the way that the population (ecologic) correlations, with limited numbers of units, were carried out. These days, the configuration of populations for such internal and international comparisons is strengthened by the random selection of greater numbers of units. But the Seven Countries Study was state-of-the-art for its time, and the concept ahead of its time. Ecologic correlations are relatively weak in arriving at causal inference about disease. However, they are crucial indicators of population causes of disease, and of public health preventive strategies, where the epidemiologic evidence is congruent with that from the laboratory and the clinic.
The Seven Countries Study, more than any other cardiovascular disease study, has directed attention to the causes of population rates of disease, while confirming the importance of an individual’s risk within populations. It documented major differences in the mass phenomena related to differences in disease rates, and it demonstrated the degree to which composition of the diet — particularly levels of saturated fatty acids and mean serum cholesterol levels — predict present and future population rates of coronary heart disease.
The predictive equations derived from the population correlations provide the general rule, while departure from prediction points up important exceptions, such as the excess of coronary heart disease in East Finland and its rarity in Crete. These exceptions, in turn, have provided impetus to further research into causal factors other than dietary saturated fatty acids and cholesterol.
Ancel Keys, Principal Investigator
The concept of the Seven Countries Study arose independently in the minds of innovative physicians and investigators, who were interested in heart diseases beyond the clinic, and at the same time, were capable of synthesizing evidence from clinic, laboratory, and the population. Keys gave the concept its bold design, and provided the critical vision and leadership to bring about the study.
The background of the study lies in Keys’s application of physiological principles and knowledge to health, in a quantitative human biology that he called physiological hygiene. The wartime observations and experiments of Keys and colleagues at Minnesota profoundly changed their thinking about the modifiability, by exercise, calorie restriction, and bed rest, of such presumably immutable attributes as body build and type, circulatory responses, and blood pressure and cholesterol levels. Moreover, Keys was facile with computation, including regression equations, which extended the groups’ thinking to correlations among individual levels, and then among population levels, of risk attributes, behavior, and disease rates.
Keys states quite simply that in casting about for major researchable issues in biology and disease at the end of World War II, he was particularly impressed with news reports of the epidemic of heart attacks among executives. He promptly set about to study the characteristics of executives in health with the intent to follow them for the risk of later disease. Inadequate in numbers and ranges of variables, the Minnesota Business and Professional Men’s Study became, nevertheless, the pioneer longitudinal epidemiological study of cardiovascular disease.
But it was Keys’s Sabbatical year at Oxford, and related travels in 1951 1952, that opened his eyes to cultural differences in diet, behavior, and disease risk, and put him in touch with nutritional and clinical scientists beginning to consider such differences. The contrasts they found in risk by social class in Italy, Spain, South Africa, and Japan, set off Keys’ imagination and led to his conceptual formulations of the relation of mass cultural phenomena to the major diseases and their risk. Thus, Keys’ rich preparation and experience led him and his colleagues to a broad view of human biology and health. This was combined with his quick intelligence, clear thinking and writing, and a focused, prodigious energy. All Keys’s background and skills were brought to bear on the Seven Countries Study.
At the same moment in history, opportunities for research grew rapidly with expansion of the review and support role of the National Institutes of Health, and of the new National Heart Institute. At this time, Keys’s match-up with great clinicians completed the picture – such leaders as Paul Dudley White of Boston, Vittorio Puddu of Rome, Noboru Kimura of Japan, John Brock of Capetown, Martti Karvonen of Helsinki, and Christ Aravanis of Athens. All saw beyond the clinic and beyond the individual patient – to the origins of common diseases – in the population and in society.
Keys’ leadership was also crucial to the effective formulation of ideas into grant proposals, and over the years of the study, to synthesis and preparation of the study’s major monographs. All these attributes and practices were in the best ‘Old School’ tradition. Nowadays, academic practice, at least in epidemiology, is perhaps more conducive to true collaboration, with greater sharing of ideas, responsibilities, publications, and credits. But, just as in the families of old, the patriarch of the Seven Countries Study, Ancel Keys, provided priceless experience, superb careers, and a model of excellence for his fortunate colleagues.
Selected References to Seven Countries Study Publications
Keys A, Aravanis C, Blackburn HW, Van Buchem FSP, Buzina R, Djordjevic BS, Dontas AS, Fidanza F, Karvonen MJ, Kimura N, Lekos D, Monti M, Puddu V, Taylor HL. Epidemiologic studies related to coronary heart disease: characteristics of men aged 40-59 in seven countries. Acta Med Scand 1967 (Suppl to vol. 460) 1-392.
Keys A (ed) Coronary heart disease in seven countries. Circulation 1970 (Suppl to vol.41) 1-211.
Keys A, Aravanis C, Blackburn, H, Buzina R, Djordjevic BS, Dontas AS, Fidanza F, Karvonen, MJ, Kimura N, Menotti A, Mohacek I, Nedeljkovic S, Puddu V, Punsar S, Taylor HL, Van Buchem FSP, Seven Countries. A Multivariate Analysis of Death and Coronary Heart Disease.1980. Harvard University Press, Cambridge, MA and London. 1-381.
Kromhout D, Menotti A, and Blackburn H (eds.) The Seven Countries Study: A Scientific Adventure in Cardiovascular Disease Epidemiology. 1994. Brouwer. Utrecht.
Toshima H, Koga Y, and Blackburn H. (eds.) Lessons for Science from the Seven Countries Study. 1995. Springer Verlag, Tokyo