International Centre for Health and Society, Department of Epidemiology and Public Health, University College London, 119 Torrington Place, London WC1E 6BT, UK. E-mail: m.marmot{at}ucl.ac.uk
Real authors, as opposed to those of us who write scientific prose, are mixed on the question of re-reading. Some claim not to be able to bear reading their previous writing. Others depend on it. One author finds re-reading what she has just written an essential part of the creative process. Robert Browning when asked to re-read and then interpret one of his poems replied something like: when I wrote that only God and Robert Browning knew what it meant; now only God knows.
I find it odd to re-read, odder still to write a commentary on a paper that I had written more than 16 years ago.1 The infelicities of style set my teeth on edge. The difficulty I had of knowing the difference between a drink and a unit and of calculating precisely how many grams of alcohol are in a bottle of wine are just plain embarrassing. (While re-reading, I went back to other things I had written on alcohol and found another arithmetical error that was worsereference withheld.) Wordsworth wrote of his youth I cannot paint what then I was.2(p. 105) Regrettably, I can.
Of perhaps more interest than a mixture of personal hubris and self-indulgencethey are closely connectedis what has and has not changed on the question of alcohol and the heart. I want to use this to reflect on several issues, some of which were touched on in that 1984 review and some not. (In writing this I do not have the benefit of knowing what other commentators have to say on that article.)
Criticism and the growth of knowledge
This was the title of an important collection of writings on the philosophy of science edited by Imre Lakatos and which could be seen as Thomas Kuhn's summary of his reactions to Karl Popper and Kuhn's critics reactions to him.3 The different philosophers of science differ on their views on how science does or should proceed. Criticism emerges as a strong part of it. I wrote that 1984 review in response to criticism.
I had published a report from the Whitehall study in 1981 (with Martin Shipley who is my close colleague after more than 20 years of publishing together, and Geoffrey Rose) entitled Alcohol and mortality: a U-shaped curve.4 The stimulus for this was twofold. Klatsky, at Kaiser Permanente in California had published papers showing that moderate alcohol was protective against coronary heart disease (CHD).5 Nancy Day and Robin Room, who were at Berkeley when I was there in the early 1970s, had published analyses showing that non-drinkers had higher mortality than drinkers. They raised the question of separating the drink from the drinker.6 Pearl, as far as I was aware, was the first to draw attention to the U shape of the relation of alcohol consumption to mortality. The copy of his 1926 book in the library of the London School of Hygiene is inscribed To Major Greenwood, a noble drinking pal.7 Re-reading Pearl before I wrote this, I now cannot find a reference to the U-shaped curve and wonder where I did find the term if not from him. He studied a sample of working men, resident in Baltimore Maryland, and showed that moderate drinking of alcoholic beverages did not shorten life. On the contrary moderate steady drinkers exhibited somewhat lower rates of mortality and greater expectation of life than did abstainers. His study confirmed that heavy drinkers exhibited considerably increased rates of mortality, as compared with abstainers or moderate drinkers.
Among the responses to my 1981 article were three types of criticism: alcohol consumption was determined with imprecision; non-drinkers included people who had given up drinking because they were ill or who had not taken up drinking for the same reason; non-drinkers differed from drinkers in other ways that put the non-drinkers at risk of CHD. These were later summarized by Shaper.812 The 1984 review was a response to those criticisms. The criticisms were all credible and a priori were possible reasons why the apparent protective effect of alcohol on CHD might not be causal. I set out in that 1984 paper why I judged the criticisms, although important, to be misplaced. Misplaced in the sense that they did not, in my view, provide the reasons why moderate drinkers had lower CHD rates than non-drinkers. I returned to the issue in 1991,13 199514 and 1998.15 My view of the causal nature of the association was strengthened by findings subsequent to 1984. Differences between non-drinkers and drinkers, other than alcohol, do not appear to account for the lower CHD rate in moderate drinkers. A recent systematic review of 42 studies confirmed the protective effect of regular moderate alcohol consumption on CHD.16 A recent Study from Scotland, not in that systematic review, found no robust relation between consumption of alcohol and mortality from coronary heart disease.17 They did find that men who consumed 814 units a week had a relative CHD mortality rate of 0.79 (0.61 to 1.01) compared to non-drinkers after adjustment for own and father's social class, other socioeconomic characteristics and markers of baseline illness.
In this age of systematic reviews and meta-analyses, the methods used in my 1984 paper look a little quaint. I would argue that such quaint methods have advantages. Two characteristics of the studies made them unlikely candidates for meta-analyses, heterogeneity of methods and heterogeneity of populations studied. It was precisely this heterogeneity that weighed in favour of causation. If a range of different methods led to the same conclusion, it made artefact a less likely reason for the association. This is close to Bradford Hill's consistency. I argued that if non-drinkers have higher CHD rates in populations as diverse as Yugoslavs, Puerto Ricans, white male residents of Framingham, women in a retirement community in Los Angeles, white male civil servants in London, Japanese physicians, Japanese Americans in Hawaii then confounding was less plausible. Because statistical control for measured confounders had not explained away the association, the confounding argument had to revolve around logic rather than statistical analyses of confounders that had not been measured.
Those of us engaged in this debate in the 1980s and 1990s, behaved with the passion of those who have had new insight into a problem. It is salutary to re-read Pearl. Compare his description of confounding with that in a modern epidemiological paper. It has been suggested by many persons, at different times, that the similarity in the mortality rates of abstainers and moderate drinkers, or the possible slight superiority of the moderates as compared with the abstainers, is mainly due to factors not connected directly with alcohol at all. This argument, in one form, runs as follows: The abstainer is really a poor risk, and knows it, or believes that he knows it. He therefore abstains from alcohol, thinking that it will do harm to his already poor health. On the contrary the moderate drinker is an average, healthy sort of person who is in fact a good insurance risk. It is then concluded that if the persons in the moderate group had been abstainers instead of moderate drinkers, they would have shown a greatly superior duration of life, on the average, to the real abstainers. The reason they have in fact only about the same, or a little higher expectation of life, is because their real vital superiority to the abstainer group has been curtailed by the harmful biological effects of their moderate drinking.7(p. 170)
Pearl asks himself what he would do to control confounding if he were conducting an animal experiment on alcohol. His answer is to compare sibs in a litter randomly assigned to drinking and non-drinking. His best approximation is to find, in his sample, 94 male abstainers who had 113 moderate drinking brothers. He shows that the abstainers have higher mortality than the moderate drinkers.
Pearl also quotes Stevenson's discussion of differences in temperament between the typical teetotaller, and drinker. Stevenson's summary is that on the one hand, then, we have the combination of drink and the devil, and on the other hand of teetotalism and the crank.7(p. 171) While not subscribing to the terminology, we did examine an aspect of this question in the Whitehall II study. We showed that the lower plasma fibrinogen level in drinkers compared to abstainers could not be explained by a number of different psychosocial factors.18
Beverage type
There was a great deal of interest then, as now, in whether wine may be more protective than other beverages. All round the world small groups of healthy readers religiously consume their red wine because of its presumed antioxidant properties. I concluded in 1984 that the findings do not at the moment, implicate one type of drink over another (this was one of the sentences where I do not now disagree with the thought so much as the way it was expressed). There are at least three reasons why wine could appear to be more protective: it may contain substances other than alcohol, biophenols for example; wine drinkers may be different from other beverage consumers e.g. higher socioeconomic position;13 the pattern of drinking wine may differ from the pattern of drinking other beverages.
The lack of consideration of patterns of drinking was a major omission from the literature and my 1984 review. Two recent pieces of evidence, one from Keil and one from my own group, confirm my view that it is the alcohol in wine that is protective rather than other substances, although pattern of drinking may be important. In Bavaria and the Czech Republic the predominantly beer-drinking population drink beer somewhat like people in Mediterranean countries drink wine: with meals as a daily occurrence. In both these populations non-drinkers have higher CHD rates than regular beer drinkers.19,20
This demonstration that beer may be as protective as wine if drunk in the same way, is an interesting example of how epidemiological studies can throw light on the mechanism question. It is not the case that epidemiology is limited to demonstrating associations but can say little on why they come about. The presumed extra protection afforded by wine led to a search for the protective properties of wine other than alcohol. If it is true that beer drunk in the same way as wine has the same protective effect it should divert attention towards alcohol and the patterns of consumption.
Patterns of drinking
Most of the literature on alcohol and heart disease in 1984, and since, contained little on patterns of drinking. At the time, there was speculation that the high mean alcohol consumption of France, Italy and Spain might, while protecting from CHD, lead to chronic liver disease and certain cancers of the upper aerodigestive tract. By contrast, the lower mean, but more episodic consumption, of Scotland or Finland would convey little protection from heart disease but could lead to cerebrovascular disease, and problems associated with drunkenness.
The findings on beer from Bavaria and the Czech Republic tend to rule out a special role for wine. They do not rule out the possibility that the pattern of drinking may be important. Pharmacologically, binge drinking has to be different from moderate daily drinking. Drinking with meals could change the effect of other dietary nutrients.21
A particular issue has arisen in relation to the mortality crisis in the former Soviet Union. There is speculation that recent rapid trends in mortality are related to binge drinking.22 The two biggest contributors to the East-West gap in mortality in Europe are external causes of death and cardiovascular disease (CVD), mainly CHD. There is little question that binge drinking could increase deaths from accidents and violence. There is, however, a question as to whether the Russian pattern of binge drinking could increase CHD.
I had never described the relation of alcohol to CHD as U shaped. The U applied to total mortality. In my 1984 review, I pointed out that the data on heavy drinking and cardiovascular disease were inconsistent. Some studies of problem drinkers had shown them to be at higher risk of CHD, but studies of alcohol consumption had consistently failed to find an association between heavy drinking and CHD. The apparent discrepancy may be because epidemiological studies are likely to underrepresent people whose drinking has led to severe social problems. This raises the question of whether it is something else about the problem drinkers that puts them at higher risk of CHD.
A recent systematic review16 found 37 prospective studies of alcohol and CVD that met its inclusion criteria. The review confirmed the protective effect of moderate regular alcohol consumption but found only seven studies that examined drinking patterns or heavy drinking. These studies did, in general, find that heavy drinkersbinges, hangovers, intoxication, alcohol treatment, problems with workhad increased risk of cardiac death compared to non-drinkers. It is important scientifically to understand if heavy drinking does have different biological effects from moderate drinking and hence a different relation to cardiac death. Problem drinkers have, in addition, other features that may put them at high risk.
There is also evidence that heavy drinking may increase risk of ischaemic, if not haemorrhagic stroke.14
Interaction or effect modification
In my 1984 review I was so concerned with the question of confounding, that I did not pause to wonder if there might be effect modification. In other words, the evidence suggested that moderate drinkers were at lower risk of CHD because of their drinking, not for some other reason. It did not occur to me to ask, nor did the literature really permit the question, whether the apparent protective effect of alcohol might differ in subgroups of the population. This has still not been the subject of much study. The Nurses Health Study found beneficial effects of alcohol on CHD. These were not seen in the population in the lowest quartile of folate intake.23 Folate is of interest, of course, because increased intake of folic acid is associated with lower levels of plasma homocystine and a presumed consequent reduction in CHD incidence.
These data are therefore consistent with an interaction of alcohol and nutrition. It raises the possibility that in the former Soviet Union, not only may binge drinking be a particular problem but alcohol may not have a protective effect on CHD because of patterns of nutrition that result, among other things, in low folate intake.
The question of interaction is especially relevant when attention broadens beyond CHD to embrace all causes of morbidity and mortality. One obvious factor to be taken into account is age. At younger ages when CHD is uncommon, there will be little protective effect on all-cause mortality. This is clearly seen in a review of three studies of adolescents and five studies of adults with a starting age in their 20s.2426 These studies confirmed the adverse effect on all-cause mortality of heavy drinking and found no consistent protective effect of moderate drinking. They did not report cause of death, but these findings are to be expected if CHD was an infrequent cause of death in these relatively young populations.
In parts of the world where ischaemic heart disease (IHD) is relatively uncommon, there will similarly be less protective effect. This is shown by the calculations Murray and Lopez performed for their Global Burden of Disease study. Figure 1 from that study illustrates the effect of alcohol use on deaths caused and averted by alcohol use in men in two regions of the world: established market economies and sub-Saharan Africa. In the latter, at every age, the number of deaths attributed to alcohol use, from injury and alcohol associated diseases, outweighed the protective effects on IHD. In the established market economies, only at age 70 and above do the number of deaths prevented exceed the numbers caused.27 For pre-menopausal women, among whom IHD is uncommon, alcohol has little protective effect.14
Another modifier of the harmful effect of alcohol may be socioeconomic position. Given how consumed I have become with the question of social inequalities in health, I am surprised at how little mention I made of this issue in 1984. By 1991, I had come to speculate on whether the apparent greater protection from wine could arise from the fact that moderate drinkers of wine tend to be of higher social class than moderate drinkers of other beverages.13 In light of the data from the Czech Republic and Bavaria on the protective effect of beer drinking, the question should be whether moderate daily drinkers are of different socioeconomic position compared to non-drinkers. In the first Whitehall study we controlled for employment grade in examining the effect of alcohol on mortality, as did the British Regional Heart Study.8,28
The other intriguing phenomenon to do with social pattern is that, in Britain, neither mean alcohol consumption, nor prevalence of heavy drinking show much of a social gradient. By contrast, as Table 1 shows, there is a social gradient in mortality from many alcohol associated causes.29 This suggests either that the pattern of drinking differs according to social position, or that other factors associated with position in society interact with alcohol to increase the risk of problems associated with drinking. A third possibility is that, although alcohol consumption differs little by social class in social surveys, people with alcohol associated problems are downwardly mobile. If such people are underrepresented in social surveys, this could account for increased mortality at the bottom end of the social distribution despite the lack of a social gradient in alcohol consumption.
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1984 was a happy period of my life in so far as I sat on no committees. The advantage of such a situation is clear. If there be any disadvantage, it may be that there is less possibility for the research to influence policy. At least, that is my current rationalization. I may not have been involved in policy discussions in 1984 but I was concerned in principle. I situated my review of alcohol and the heart within the con-text of the harmful effects of alcohol and I ended without a recommendation.
When subsequently asked to chair a Working Group representing the British Royal Colleges of Physicians, Psychiatrists and General Practitioners, I took this perspective with me.14 We concluded that moderate alcohol consumption was protective from IHD. We were concerned, however, with the other effects of alcohol. Above 21 units a week for men, and 14 for women, the frequency of psychosocial problems increases with amount drunk. Similarly, mortality rates increase with amount drunk. We reviewed 15 studies on alcohol and all-cause mortality in men, and four in women. The largest of the studies, the American Cancer Society Prospective Study of more than a quarter of a million men showed all-cause mortality to increase steadily from one drink a day.30 We concluded therefore that the advice of a sensible limit of 21 units a week for men and 14 for women should stand. Subsequent to our report, a second American Cancer Society Study of relatively affluent, well-educated volunteers showed a similar pattern of alcohol and all-cause mortality: mortality increased from one drink a day, although non-drinkers who smoked were the highest risk group.31
One argument for not recommending an increase in the sensible limit guideline was the risk curve relating individual consumption to morbidity and mortality. The second argument was the population theory of alcohol consumption.32 The argument was that anything that increased the mean consumption of alcohol would be likely to increase the prevalence of heavy drinking. I was somewhat dismayed when a British Government committee ignored our advice and recommended a relaxation of the sensible limit guideline.33 Given the heterogeneity among the 15 studies we reviewed on alcohol and mortality, I was surprised that the Government committee felt able to choose a cutpoint that was slightly different from the one we had endorsed.
The second plank of their argument was that the single population theory might not apply in Britain. Challenged by this, we examined data from the Health Survey for England and showed that across 14 regions there was a clear association between mean consumption and the prevalence of heavy drinking (Figure 2).34
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Afterthoughts
I am still unclear as to whether the benefits of re-reading outweigh the hazards. I am not even sure whether agreeing or disagreeing with what one wrote 16 years ago is the preferable option. If one disagrees, at least one could argue that time and experience have brought a change of view. If one agrees, is it that the younger man got it right, or that there has been little personal intellectual development over the intervening period?
With such uncertainty in mind, I do find myself in broad agreement with what I wrote then. Those scientific views have very much informed my participation in policy discussions. The major scientific areas that need attention relate to patterns of drinking, particularly binge drinking, and interaction with other determinants of morbidity and mortality. If attention is paid to these, we may then be in a better position to gauge the extent to which alcohol consumption may be responsible for trends in morbidity and mortality over time, across social groups and internationally.
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MM is supported by an MRC Research Professorship and by the John D and Catherine T MacArthur Foundation Research Network on Socioeconomic Status and Health.
References
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