key: cord-1035518-kpckcyp6 authors: Morabia, Alfredo title: Pandemics and methodological developments in epidemiology history date: 2020-06-12 journal: J Clin Epidemiol DOI: 10.1016/j.jclinepi.2020.06.008 sha: 79e1a145c79197330a203ceb54fc54167864339c doc_id: 1035518 cord_uid: kpckcyp6 • Catastrophic pandemics since the 17(th) century appear to have spurred innovative methods, concepts, and institutions in epidemiology; • The plague, cholera, tuberculosis, influenza, and HIV/AIDS left a longstanding imprints on epidemiologic methods and concepts; • Pandemics may generate an urgent need for methods that overcome the inadequacy of older methods; • Covid-19 specific contribution could be a greater understanding of population thinking beyond academic and professional circles. comparable, and can therefore be a source of scientific knowledge. The properties of events in populations could not even have been suspected before the 17 th century because there were no data to observe them. A comparative health science had remained elusive because the lifecourse of individuals, the only observation available to physicians, is unpredictable and incomparable. Thus, the surveillance system built up to restrain the disruptive consequences of the plague, the catastrophic pandemic of the time, appears to have provided the foundation to the most decisive methodological advance in the history of social and human sciences: the discovery of population thinking Cholera Before the 19 th century, cholera had been endemic in certain parts of Asia but remained localized until faster means of transportation and routes made it feasible for sick travelers to survive the trip from, say Bombay, India, to Marseille, France, or from Rotterdam, Netherlands, to New York or Cartagena, Colombia. Since then cholera spread in waves or pandemics. The second pandemic (1826-1837) reached Europe, North Africa and North America. The third (1841-59) also reached Central and South America. These pandemics were scary. During the 1831-32 pandemic, the case fatality ratio in Vienna, Austria, was 49.02% of 4,360 cases. (6) In an official report about the 1832 cholera pandemic in Paris and its surroundings, 48.6% of 4,907 medically-certified cholera deaths of all ages occurred in the first 24 hours. (6)((7), p.70) It was speculated that the stench emanating from rotten material caused cholera if inhaled by susceptible persons. Susceptibility was an individual trait and there was no way of proving it existed. However, John Snow believed there was some kind of still unobserved living thing that could multiply in the water supply and that caused the cholera syndrome when ingested from water or food or from sleeping in infected linen. He conducted a well-known survey -different from his investigation of the outbreak related to the water pump in Broad Street -that allowed him to compare Londoners residing in the same parishes, equally exposed to stench and air pollution, but drinking water of different degrees of cleanliness. Leaden pipe belonging to private companies conveyed water from sections of the Thames, one contaminated and one not, to tanks and then from these tanks to pumps situated in the individual houses.((8), p. 16, 46-47) Thus, the pandemics of cholera, the greatest pandemic of the 19 th century, stimulated the first use at a population scale of a comparative study design to explore a causal association. Group comparison has become the other defining trait of epidemiology besides population thinking. Tuberculosis has affected human populations probably since the Neolithic, as the bacillus is thought to have adapted to human from domesticated cattle in dwellings shared promiscuously by humans and animals. (9) In 1900 many in public health believed that susceptibility to tuberculosis was hereditary. Persons with tuberculosis in 1900 affluent Western societies did not die consumed by their disease anymore as had been the case until the first half of the 19 th century. They could have offspring. Eugenicists feared that, at some point, every human being would become susceptible to tuberculosis, leading to the extinction of the human species. The perception of tuberculosis then was analogous to a pandemic. Of all diseases, it had become the main killer. However, no methods existed to study whether persons with tuberculosis had a survival advantage: the latency between infection and diagnosis was long and the cross-sectional surveys that had been used in the 19 th century, by John Snow for example, were biased because they comprised only selected survivors. Precisely for this reason, the German physician, Wilhelm Weinberg, invented a new design, referred to today as a cohort study, never used as neatly and at this scale before. Using population registries of Stuttgart, in Germany, he followed 20,000 children from birth to age 20, comparing those from families in which a parent had died from tuberculosis with children from families in which the parent had not died from tuberculosis.(10) Children from tuberculous parents lived shorter lives. Tuberculosis conferred no selection advantage and did not threaten the human species with extinction. Weinberg's report is equivalent to a textbook of epidemiology, which described in detail the new design and analytic methods of his study. His review of hundreds of thousands of records, individual follow up of dozens of children, and complex computations without calculator, was a huge endeavor unlikely to have been deemed worthwhile if it weren't for the hope of an enormously important outcome. Comparative cohort studies will turn out to be a key determinant for the achievements of the subsequent chronic disease epidemiologic research. Until 1918 public health was overseen by health officers and civil servants. In April 1918, The HIV pandemic unsettled epidemiology at first because epidemiologists had become used in the 20 th century to studying chronic diseases and were taken by surprise by this resurgence of infectious scourges. Since World War II, the epidemiologic corpus of study designs had been substantially refined but the tools to study causes of disease were restricted to fixed exposures and outcomes well defined in time (e.g., to tobacco and lung cancer). (17) The epidemiologic usage of the causal concepts of confounding, interaction and mediation was still in their infancy. (18) When the first cases of Kaposi's sarcoma were reported in 1981, epidemiologists focused on non-infectious exposures such as recreational drugs, which fitted the tobacco-lung cancer model. (19, 20) The viral nature of the disease was established by virologists in laboratories. (21) A major question from then on was the assessment of the efficacy of HIV/AIDS time-varying treatments. Contemporaneously, a fresh approach to causality, now known as the potential outcome framework and the corresponding causal models, was occurring, inspired by work in the analysis of randomized controlled trials. (22) (23) (24) The first application of these developments in epidemiology was unrelated to the HIV/AIDS epidemic.(25) They looked appropriate to handle the "healthy worker effect," an up-to-then intractable methodological issue in occupational epidemiology: when studying the effect of an occupational exposure on a disabling illness, sick workers, who terminate employment early, are at increased risk of death even though no further exposed, resulting in a biased assessment of the association among the healthier workers remaining in the study. These causal models The cases of the plague, cholera, tuberculosis, influenza and HIV/AIDS seem to indicate that these pandemics have spurred major methodological developments in epidemiology. However, one may argue that pandemics and development of methods are in reality two separate, independent narratives that, by chance, appear to be chronologically associated. For example, the recollection of specific methodological developments may, in retrospect, make us associate them with specific pandemics that occurred at about the same time. However, this type of reverse causality would not be true for the 1918 influenza pandemic. The Great Influenza long appeared ,as Major Greenwood put it, "epidemiology's crux" because of the lack of major work or influential epidemiologic work that emerged from In favor of the causal link is the difficulty of finding counterexamples of minor epidemics which led to methodological breakthroughs of the same magnitude as those described above for pandemics. In the 18 th century the Royal Society innovated in designing a comparative study of the mortality associated with natural smallpox infection and that provoked by variolation.(31) It involved a subtle analysis of the bills of mortality and an intercontinental physician survey. Natural smallpox was ten times more lethal than variolation, a finding leading to a wave of smallpox inoculation, at least in the UK. In his 1747 non-randomized trial on board a naval warship James Lind allegedly compared 6 treatments, a single one of which (citrus fruits) was effective in curing scurvy.(32) But these 18 th century methodological breakthroughs were minor compared to the discovery of population thinking which gave birth to all population-based sciences we know today, such as demography, statistics, sociology, evolutionary genetics, and so on. In the 19 th century the researches of PCA Louis (33) and Ignaz Semmelweis (34) were innovative in their own ways, but their long-term methodological legacy is not comparable to that of Snow. In the 20 th century the refinement of the case-control study design was induced by etiologic research on cancer (35) and cardiovascular diseases,(36) which were on the rise and progressively replacing acute infectious diseases and tuberculosis as public health priorities. The epidemic of pellagra also led to methodologically innovative work by Joseph Goldberger. (37) But none of this work rivals the contribution of Wilhem Weinberg (38) which opened the way to the study of chronic disorders, including the elucidation of the health effects of smoking,(39) by rigorously establishing the methodological basis of cohort studies and survival analysis. Finally, no disease or epidemic has shaken the conceptual foundations of causal inference in epidemiology as much as the HIV/AIDS epidemic. It may be that the critical conditions of a pandemic stimulate an urgent fresh look at older methods which failed to prevent the disasters. Above all, the common trait of pandemics is the unusual, immediate, surrounding, unavoidable presence of death, in neighbors, relatives and friends. Similar situations did not occur in other epidemics, such as smallpox in the 18 th century, any of the acute infectious diseases such as diphtheria, measles, and so on in the 19 th century, (40) or the cancer and cardiovascular epidemics of the 20 th century. These were all real epidemics, with their toll of deaths and suffering, but they did not halt movement in society and make people urgently reflect on the limits and the dead ends of the available methods. However, my argument would be weakened if one could argue that the link with pandemics is not specific and that innovative methods and concepts in epidemiology have followed other types of happenings. My thesis could also be disproved by Covid-19, if the pandemic does not shatter an important dimension of epidemiologic methods. I would speculate that its consequences will be comparable to those of 1918 Influenza. We have now schools of public health all over the world and academic epidemiology is thriving. Still, population thinking remains esoteric outside of academia and public health. This may be changing. Never in the past have we collectively considered what an epidemic curve is, what herd immunity is, and how we can act together to affect the progression of the epidemic. Population thinking may become mainstream and, if it does, this will have huge consequences on the society we will build when the ordeal is over. Enigmas of Health and Disease: How Epidemiology Helps Unravel Scientific Mysteries Epidemiology's 350th Anniversary History of Epidemiological Methods and Concepts. 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