Global Alert and Response (GAR) – Ebola virus disease – World Health Organization (WHO)
Болезнь, вызванная вирусом Эбола (ББВЭ)
Enfermedad por el virus del Ebola
Q&A from Emory Healthcare physicians on Ebola
Two Ebola virus-infected patients discharged from Emory University Hospital – Emory News Center
Ebola Patient Revels in ‘Miraculous Day’ as He and Another Exit Hospital
Both Ebola patients released from Emory hospital
Negative studies
Not finding an association when it was expected is the other side of the coin to finding an association between an exposure and a disease and going through the punctilious process of establishing whether it is causal. Particularly when the expectation was based on repeated results of previous epidemiological studies or on sound results from laboratory studies, a systematic scrutiny is needed of the reasons why no association turned up in a study. Several reasons fall under the heading of `insufficient’: insufficient number of subjects in the study, leading to what is called low `power’ to detect an increase in risk associated with the exposure; insufficient intensity or duration of exposure to induce an observable increase in risk, as may happen with pollutants recently introduced into the environment at low concentrations; insufficient period of observation, as effects like cancer usually appear many years after the onset of the exposure; finally, insufficient variation in exposure between the different groups of people to be compared, making it difficult to detect differences in risk between the groups. In addition, confounders and sources of bias, for example losses of records not occurring at random, can not only create spurious associations but also operate in the opposite direction by masking existing associations. The process of understanding why an expected association did not show up is no less lengthy, laborious, and complex than the process of establishing and judging the nature of an association.
Necessary and sufficient causes
‘The key point is that even if smoking were to be causally related to any disease it is neither a necessary nor a sufficient cause.’ This statement, pronounced in a court by an expert 30 years after the publication of the ‘Smoking and Health’ report that established tobacco smoking as a cause of several diseases, is at the same time correct and misleading. Correct because, for instance, not all lung cancers occur in smokers (although the great majority do), nor do all smokers develop lung cancer. Misleading because it suggests that the only ‘real’ causes of diseases are those that are indispensable to produce all cases, or sufficient to trigger the disease every time they are present, or both. Causes that are necessary and sufficient, or just sufficient, are in fact uncommon in nature, being essentially represented by those inherited genes that constantly produce a genetic disease, such as the bleeding anomaly of haemophilia. Necessary causes are common in the field of infectious diseases, where only the presence of a specific micro-organism defines the disease (e.g. whatever the symptoms, there is no case of tuberculosis without the tuberculosis mycobacterium). Outside these domains, the great majority of causes of disease are, like tobacco smoking, neither necessary nor sufficient, yet they increase, often substantially, the probability (risk) of the disease, and removing or neutralizing them is highly beneficial. As an example, overweight and obesity, discussed before, are causes of diabetes but are neither necessary nor sufficient. In epidemiology, the general term determinant is used as synonymous of cause without prejudicing the detailed nature of the cause, whether necessary, sufficient, and broad, like a type of diet or an occupation, or narrow, like a specific vitamin within the diet or a specific exposure to a chemical pollutant within an occupational setting.
In a nutshell, the basic principle is to distinguish clearly between, no evidence of effect’, that may often occur because no proper study has been done (whatever the reasons), and ‘evidence of no effect’ as emerging from adequate studies. The latter is reassuring while the former is simply uninformative. Thus studies in small communities, as often carried out to assuage legitimate concerns about risks from environmental factors, may be capable of excluding large excess risks but incapable of providing information about possible smaller excesses. A related principle is that the finding of a weak effect, for example a minor increase in asthma risk in people exposed to a chemical, cannot be taken as an indication that the chemical is in itself a weak, hence nearly innocuous, agent because the observable effect depends also on the study characteristics and on the dose of the chemical. Again `evidence of a weak effect’ cannot be taken automatically as `evidence of a weak toxic agent’.
Individual and population determinants of disease
Recognizing that a factor like tobacco can cause lung cancer hinges on two conditions. First, and rather obviously, on tobacco being actually capable of producing the disease. Second and less obviously, on how much smoking habits vary within the population being studied by the epidemiologist. If everybody smoked exactly 20 cigarettes per day from the ages of 15 to 45, there would be no difference in risk due to tobacco. Tobacco, although the dominant determinant of lung cancer in a population in which everybody smokes, would go completely unrecognized as a cause of the disease. Other factors, such as individual susceptibility, would be the only recognizable determinants by which people in a population with a high and uniform risk due to smoking stand out as being at an even higher risk. The conclusion would be reached that lung cancer is due to individual susceptibility, itself mostly dependent on the genes inherited from the parents: hence lung cancer would come to be regarded as an essentially genetic disease.
This fictional example was proposed in 1985 by Geoffrey Rose in an insightful article (‘Sick individuals and sick populations’) to clarify the distinction between individual and population determinants of disease.
Population determinants, like the uniform smoking habit of the example, are responsible for the overall disease risk in a population, while individual determinants, like the individual susceptibilities, are responsible for the different risks between individuals or groups of individuals within the population. Studies comparing disease risk in groups within a population are suitable to identify the latter, but recognizing determinants that act essentially at the level of the whole population requires analysing and comparing risks between populations of different regions or countries or in the same populations at distinct times. No new principles need to be introduced to these analyses, but they may prove even more complex than those already outlined for studying associations and judging causality within a population.
Because of their general impact, population determinants are of major importance for health. A striking current case that follows the lines of the imaginary tobacco example is overweight and especially its highest degree, obesity. Excess weight basically originates from an imbalance between too many food calories ingested and too little expenditure of those calories through physical activity. Here excessive calorie consumption is the relevant exposure; if everybody or the great majority of the population is exposed nearly uniformly to some (not necessarily large) excess of calories from childhood, as tends to occur today in many high-income countries, the risk of obesity would be similarly high for everybody in the population. However, as in the smoking example, some people will be at an even higher risk than the average due to individual susceptibility, which becomes the main recognizable determinant of obesity. This is what is happening today as `obesity genes’ related to individual susceptibility are discovered, one after the other. They resonate in the media, and even in the scientific press, as the finally (for how long?) found and real causes of obesity. Focusing on genes is scientifically challenging, but it leads us astray if it ignores the main determinant of the overall population risk of obesity, i.e. widespread excessive intake of calories.
Other population determinants have an evident relevance. Polluted waters are a prime scourge in many low-resource countries, causing almost two million deaths worldwide every year. Air pollution affects the health of town dwellers in high- as in middle- and low-income countries. Less evidently, vaccination for a number of diseases such as measles or polio is essentially a population rather than an individual determinant of health and disease.
Vaccination is certainly beneficial to the individual, but for most people the risk of the disease may already be low even without the vaccination.
Vaccination, however, creates a ‘herd immunity’ or group immunity, whereby the chain of transmission of an infectious disease like measles is interrupted, bringing down to almost nil (or nil) the risk for the totality of the population. Other factors, such as being employed or unemployed, low or high level of education, have been known for quite some time to influence directly the health of individuals. More recent studies, however, show that the level of employment or of schooling in a society also acts indirectly as a population determinant of health. Different types of interventions, targeted on single individuals or collectively on the material or social environment, are required to control individual and population determinants of disease.
Tobacco and health
Research on tobacco and health has been a key stimulus for the development of methods of modern epidemiology, including the principles for identifying causes of disease. The survival studies in smokers versus non-smokers fix two moments in the unfolding of epidemiological research, nearly half a century apart.
There is a striking resemblance between the curves, summarizing how long smokers and non-smokers live, but they reflect fundamentally different statuses of knowledge. In 1938, not much was known epidemiologically and the US male curve solicited research to find out why the survival of smokers appeared to be so much poorer. The curves from the cohort of British doctors instead clearly show the result of all the diseases that in the meantime had been shown by epidemiological studies to be consequences of smoking.
The year 1950 marks a turning point in this research. Three important scientific papers were published in 1950: by Richard Doll and Austin Bradford Hill in the United Kingdom, by Ernest Wynder and Evarts Graham in the United States, and by Morton Levin, Hyman Goldstein, and Paul Gerhardt also in the United States. They are the first rigorous analytical studies of a disease, lung cancer, in relation to tobacco smoking. All three found a much higher frequency of smokers among lung cancer cases than among control subjects.
These findings prompted a rapidly increasing number of epidemiological studies on the relation between smoking and cancers of the lung, other respiratory organs, and other diseases such as chronic bronchitis and myocardial infarction. Soon after their 1950 paper on lung cancer, Doll and Hill, in 1951, enrolled a cohort of some 40,000 British doctors to be followed for several decades recording mortality from different diseases. The choice of doctors had the advantage of involving a population that was rather homogeneous in socio-economic status and not exposed to other airborne toxic agents, unlike workers in many industries. The study stands as a cornerstone in epidemiology and similar follow-up studies on smoking were developed in other populations.
In addition, smoking became a factor to be measured in almost every epidemiological investigation because it could often be a confounder of the effects of other factors. As a result, a mass of information has been accumulating and continues to accumulate to the present day. A 2002 panel of the International Agency for Research on Cancer listed more than 70 main long-term follow-up studies that have investigated smoking-related diseases.
As the survival curve in (a) shows, the point in time at which half (i.e. 50% on the vertical axis) of all subjects alive at the age of 40 are still alive is reached 7.5 years earlier for current smokers than for lifetime non-smokers. In other words, smokers lose on average 7 years of life with respect to never smokers, and those who die between the ages of 35 and 69 lose an average of 22 years. In high-income countries, about one-fifth of all deaths are caused by tobacco smoking, which is responsible worldwide for more than five million deaths every year – more than half of them in middle- and low-income countries. By far the largest proportion of the 1.3 billion smokers in the world today is in these countries, and because the full-blown effects of smoking become manifest after two to three decades of continuing smoking, a huge increase in tobacco-related deaths is to be expected in the future in middle- and low-income countries unless smoking cessation is successfully implemented.
Some projections forecast that in 2020 there will be 9 million deaths due to tobacco, three-quarters of them in middle-and low-income countries. A range of diseases contributes to this toll: cancers of at least 13 organs (including lung, nasal passages, larynx, pharynx, mouth, oesophagus, bladder, and pancreas), cardiovascular diseases, including heart attacks and stroke, and chronic obstructive pulmonary disease (‘chronic bronchitis’). These results are not surprising because tobacco smoke contains almost 5,000 identified chemicals, many of them toxic and more than 50 definitely carcinogenic.
Many of these substances are also found in the second-hand smoke that goes into the environment around smokers to which other people, including non-smokers, are passively exposed. Passive smoking is associated with an increase in risk of several diseases in non-smokers ranging from respiratory ailments in children to myocardial infarction. For lung cancer, more than 50 studies support a causal role of passive smoking involving an increase in risk of about 25%.
Tobacco smoking has emerged as the greatest killer in peacetime. All forms of tobacco use, including pipe smoking, chewing, and sniffing, are noxious even if with less pervasive and strong effects than cigarette smoking.
This gloomy picture is brightened by the fact that preventive efforts, involving a combination of measures, educational campaigns, increasing taxation on tobacco products, and prohibition of smoking in public places, have translated into reduction of tobacco use in several high-income countries. Young people have been less prone to take up smoking habits and appreciable numbers of people have stopped smoking. Duration of exposure to tobacco smoke is crucial for risk, hence the later one starts to smoke (short of not starting at all) and the sooner one manages to stop, the better the health prospect. Stopping at any age is beneficial: in people who started to smoke in early youth, stopping at age 30 reduces the risk of developing lung cancer before age 75 to nearly that of non-smokers, and even stopping at age 50 reduces the risk to one-third with respect to continuing smokers.
