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Seven Countries Study: Addendum By Henry Blackburn, MD Stadium Gate 27
The research of Keys and collaborators had grown rapidly during World War II. The small faculty of the laboratory traded the teaching of physiology to physical education students for the space of the visiting coaches' locker rooms underneath the bleachers of the stadium. There, researches on the biology of human starvation, which became classics, were carried out. Over the years, the underground facility expanded steadily, eventually occupying the entire south wing of the stadium. Those who trained and visited there still look back with great nostalgia on the scientific activity and collegiality in that unique setting. The work on human biology, and on the population phenomena causing mass diseases, was satisfying for all participants, a different satisfaction perhaps from those of other subterranean researches (eg. Enrico Fermi's atomic facility located under the University of Chicago stadium!) Gate 27 housed the coordinating staff of the Seven Countries Study and the principal offices of Ancel Keys, Henry Taylor and me. It also housed the Seven Countries chemistry and nutrition laboratories; the data-editing, analysis and statistical center; and was the site of ongoing researches and training of Seven Countries collaborators from around the world. These activities are described in greater detail in another volume, The Seven Countries Study: A Scientific Adventure in Cardiovascular Disease Epidemiology. In 1967, Alessandro Menotti took over in large part the Seven Countries coordination responsibilities, following his training at the London School of Hygiene and at the University of Minnesota. Since his 1993 retirement, the coordination is shared between the University of Minnesota and the National Institute of Public Health in The Netherlands. Menotti remains a part-time professor at Minnesota. At the outset of the Seven Countries Study, a firm collaboration in methods development grew between us and Geoffrey Rose at the London School of Hygiene and Tropical Medicine. We wrote together a manual embracing all cardiovascular disease survey methods under the aegis of the World Health Organization. The Third Edition of that manual, Cardiovascular Survey Methods, is in preparation under the chairmanship of Russell Luepker, now head of the Division of Epidemiology at the School of Public Health in Minnesota. Here I recount the development of the Minnesota Code which was a part of our central preparations for the Seven Countries Study. In the 1950s, when most systematic population studies of heart disease began, it became important to have standard and quantitative means to compare disease rates. Diagnoses indicated on death certificates, or made by physicians with different training, might easily result in spurious differences. Even independent diagnoses by specially trained physicians were highly variable. The need for comparability in clinical assessment led us to consider the electrocardiogram as an objective measure for assessing heart disease. This is because electrocardiograms can indicate heart disease manifestations of greatest interest, that is, death and scars of heart muscle (infarction), increased muscle mass (hypertrophy), and disturbances of rhythm or conduction. The electrocardiogram seemed particularly promising because it was an objective graphic record, amenable to standard procedures of collection, measurement, and classification. It also seemed ideal because it was so acceptable, painless, simple, and inexpensive.
Our first approach was to compile all existing electrocardiographic criteria and attempt to sort them into quantitative classes. Where this was not possible, "reasonable" criteria were devised and empirically tested for sensitivity and specificity in well-defined populations containing different proportions of normal subjects versus patients with specific abnormalities. All these criteria were assembled, unambiguously described, rank-ordered by magnitude and amplitude according to a clinical impression of their importance, and assigned code numbers. The resulting classes were quantitative, mutually exclusive, and generally relevant to disease states. They were objectively described as Q-QS waves, or negative T-waves, etc. rather than given clinically diagnostic labels. Finally, records from many different living populations were classified and evaluated for "reasonableness" of the population distributions obtained. Test-retest reliability improved among the physicians closely involved in development of the code - Pentti Rautaharju, Sven Punsar, Gunnar Blomqvist, and me. Early on, between 1958 and 1959, we sent to other investigators in population studies an early version of the criteria and code. Someone, possibly Frederick Epstein at the University of Michigan or Geoffrey Rose or Ian Higgins in London, termed it the "Minnesota Code." They began to use the criteria and provide suggestions for minor revisions, and were generally enthusiastic about an increasing ability to classify prevalence and incidence data quantitatively. About this time, we also shared records to assess variation among our coding. Despite the use of unambiguous and quantitative criteria, and our awareness of standard procedure, the coding variation was surprisingly large. The extent of observer variability should have been anticipated. Clear definitions and objective criteria do not guarantee, in themselves, similar application by different observers. Consequently, we gave more attention to the conditions of electrocardiographic recording and to measurement, coding procedures, and rules. Measuring devices were developed, particularly for assessing Q-wave duration, to improve borderline classifications. Rules were devised to account for pattern variation between beats. The system was generally shored up by quality control procedures and standardization, a system of duplicate, independent readings with adjudication of differences. The "final" Minnesota Code and procedure was published in Circulation, in 1960. By the early 1960s, the burden of coding still lay mainly on me and a few visiting physicians in the Laboratory of Physiological Hygiene. Meanwhile, the volume of electrocardiograms increased from many population studies. Our high level of interest during the developmental phases of the coding system was replaced by boredom with what was becoming a tedious chore. At about the same time, independently, Rose in London and I in Minnesota hit upon an idea - to make coding by technicians practical. My resolution of the issue grew out of a special experience with electrocardiographic coding recounted here: In the summer of 1962, I was solicited by the National Health Examination Survey of the National Center for Health Statistics to classify electrocardiograms on 6,000 individuals, a true sample of the entire U.S. population. I agreed to do it as a summertime occupation. It offered the princely reward of twenty-five cents a record, and seemed a worthwhile undertaking - until I received the actual shipment of electrocardiograms. They came as unmounted strips stowed in tiny cardboard cubicles as tightly wrapped cylinders some six to nine feet long. These had to be removed from the case, unrolled, held flat, read, measured, codified, tabulated, rerolled, and reinserted in the packing. The entire process took many times longer than the reading, classification, and tabulation. At the inducement of one penny per record, I was able to enlist the enthusiastic aid of two alert, though very young, non-technical persons who happened to be close at hand that summer. While one, aged six, would extract and unroll the record, the other, aged seven, would hold it down until I coded it and then roll and refile it. Their summer wage was 6,000 cents each, and mine, 6,000 x 23 cents. Their work reduced mine substantially, and nurtured a pleasant relationship among close relatives. After only a few days' experience, from ordinary curiosity, my young assistants could identify P, QRS, and T waves. After a little more time, they were careful to point out to me when a P wave or a T wave was "upside down" or when a Q wave was "big and fat" or an R wave was "too tall," and so on. After a few more days, by which time they spontaneously associated the code numbers I was writing down with tall, flat, inverted, or prolonged waves, it was clear that they could become excellent ECG coders. Having read some thirty-thousand records a year for several years, this experience convinced me it was time to stop. In the fall of 1962, I began recruiting university students and instructing them in the coding procedure. Many hundreds of student coder alumni have, over the decades, helped in this service to national and international population studies, at the same time helping themselves through school. It was not originally my intention to develop a coding system for export, but to develop sound methodological procedures for assigning objective "events" related to cardiac disease for our extensive Minnesota-led surveys. The Minnesota Code became widely used, however, because it met a need in the burgeoning new field of cardiovascular disease epidemiology. It became used internationally when it was included in the World Health Organization monograph series, Cardiovascular Survey Methods, published in 1968. Since then, the code has been expanded and updated to classify endpoints for clinical trials and to better characterize arrhythmias and conduction defects. A manual provides standard procedure for its application. Because the electrocardiogram has a different set of "errors" than clinical assessments, and is independent of them, it complements clinical data from physicians who may inadvertently be biased by knowledge of drugs being administered, etc. A new set of criteria was developed to estimate significant serial change in the electrocardiogram over time. The original 1960 publication in Circulation was recently cited by the Cumulative Index Medicus as one of the more extensively referenced articles in scientific literature. A manual of procedure for training and testing in the Minnesota Code was written by Ron Prineas, Richard Crow, and myself, and was published in 1982. It had long been our intention that electrocardiograms recorded on magnetic tape in field surveys would be read by machine. We have collaborated with numerous computer centers to develop Minnesota Code logic and software programs, most of which have succeeded, more or less. But the differing natures of man and machine also pose a problem. The computer's determination of wave onset and offset, and of baselines, though much more repeatable, is often systematically different from human-visual interpretation. The current strategy of the Minnesota group, with Pentti Rautaharju and the Epicore Electrocardiographic Centers, is to use the computerized Minnesota Code for things the computer does best (i.e., measurement repeatability), and to complement its classification by things that the human does best (i.e., judging baselines and resolving borderline and ambiguous situations, and coding complex arrhythmias). Our groups have demonstrated that combined human-machine adjudication obtains the more reliable and valid electrocardiographic classification. For major new studies, completely automated measurement and classification is now available with NOVACODE, developed by Rautaharju in large part from the extensive experience recorded in the Seven Countries Study. In visual coding of electrocardiograms, there is no absolute "right or wrong" classification. The job is to get as close to the truth, and as repeatably as possible by the means taught in the Minnesota Code manual. After an instruction period, learning occurs best by reading electrocardiograms as rapidly as possible, by making a firm commitment to a code, and then comparing that decision to a standard. As one becomes a more confident and facile coder, the most important thing to remember is to remain scrupulously honest, and to read sets of cardiograms independently of all others' readings. Afterward, it is important to be curious and to compare your independently coded findings with others. Independent coding. This helps one learn causes for coding differences; but in the end, "two heads are better than one." Few student coders at Minnesota go on to medical or health-related careers. However, the coding course allows students to become highly competent in a discipline which to this day remains a "medical mystique." Student coders become experts in detecting, differentiating, and classifying most ECG abnormalities. However, this technical function gives no basis for clinical interpretation of findings, or for the diagnosis of heart disease. Coders should never let themselves be put in a position to misuse their electrocardiographic reading skills outside the research setting. For example, once we had a student who tried to sell her skills as an "electrocardiographic coder" to record rooms in Twin City hospitals. They, of course, had no idea what she was talking about, and called us for fear that she was mentally unbalanced. The Minnesota Code is not standard in hospital practice. Rather, it is a system designed for rigorous population researches and clinical trials. Later, we had another student who read her grandmother's electrocardiogram as it was being made at bedside in the hospital: "Oh, what a nice big 7-1 you have, Grandma. You have a complete left bundle branch block!" It took some hours of medical persuasion, and sedation, to calm the old lady who thought she'd had a heart attack!
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The University of Minnesota Laboratory of Physiological Hygiene, located at Memorial Stadium Gate 27, on the Minneapolis campus, was at the hub of the Seven Countries Study operation from the outset.
Several hurdles quickly emerged, however. Differences among physicians' "impressionistic" reading of electrocardiograms were large. Sizable differences were found even by the same cardiographer at different times. No objective criteria existed for abnormality or for specific cardiac findings, only pattern recognition. Clearly, the challenge of standard criteria and measurement had first to be met before endpoint cardiac "events" and population rates could be reliably assessed and compared.