CORRESPONDENCE * All letters must be typed with double spacing and signed bt all authors. * No letter should be more than 400 words. * For letters on scientific subjects we normally reserve our correspondence columns for those relating to issues discussed recently (within six weeks) in the BMJ. * We do not routinely acknowledge letters. Please send a stamped addressed envelope ifyou would like an acknowledgment. * Because we receive many more letters than we can publish we may shorten those we do print, particularly when we receive several on the same subject.
Variations in reported serum alkaline phosphatase activities SIR, -Serum alkaline phosphatase activity is often used as a screening test for vitamin D deficiency in children. Unfortunately, different laboratories use different methods for the assay, which leads to a good deal of confusion. For example, a child was referred by his general practitioner to my outpatient clinic recently because of an increased alkaline phosphatase activity. The assay had been done in another hospital, which gives results twice those in this hospital, and our result was well within the normal range. I checked the five Birmingham hospitals which have paediatric units and found that one still reports in King-Armstrong units and four in international units per litre; of these four, three report figures twice those of the fourth. If this is representative of the situation in Britain it is surely not acceptable. Isn't it time the clinical chemists got their act together? D P ADDY
Department of Paediatnrcs, Dudley Road Hospital, Birmingham B 18 7QH
Aspirin use and chronic diseases SIR,-I am surprised that the BMJ published the article on aspirin use and chronic diseases by Dr Annlia Paganini-Hill and colleagues. ' Before explaining this statement, I must declare an interest in aspirin. As president of the European Aspirin Foundation (a body established by a number of aspirin and aspirin product manufacturers) I need to evaluate all new evidence on aspirin so as to be able to advise members of its importance. The authors seem to make the fundamental error of assuming that once an association has been established it is proof that one occurrence was the cause of the other. Bradford Hill established the substantial list of criteria that must be satisfactorily met before such a conclusion is drawn.2 The paper makes no attempt to meet these criteria, nor do the authors discuss why they think it unnecessary. That the error is fundamental is easily shown by selecting a perfect association that is entirely without causal significance. No doubt a study among couples where snoring of one was a problem to the other would show that it was always the one who went to sleep first who was the snorer. It would be ludicrous to conclude that going to sleep quickly was a cause of snoring. A second, equally naive mistake may mean that the associations found have mistakenly been thought to be significant when they could well have
116
been due to chance alone. At the p=005 level the statistics are merely saying that such an event would, on average, occur entirely by chance once in twenty studies. From the paper it is itnpossible to know how many associations were looked for, as it is clear that there were many others that have not been reported-for instance, looking for associations with other cancers. The paper found seven associations at the 0-05 level, which would be the expected chance finding in 140 attempts to find associations. So whether any of them, and if so which, were real and which were the chance findings cannot be known from the data published. There seems to be an element of bias in that the one association that was favourable to aspirin (preventing peptic ulcers in women) is explained away in the discussion, but no attempt has been made to see if alternative explanations exist for any of the unfavourable associations. For instance, though angina sufferers were excluded, we must presume that at the selection stage any who were having atypical and as yet undiagnosed pain of ischaemic origin would be included and thus would have increased the incidence of cardiovascular disease in the groups taking aspirin. After all, it would not be unreasonable to expect that people with pain would be more likely to take analgesics. Collins and Turner showed that in Australia frequent users of analgesics were more likely than the rest to be smokers.' Smoking is a known cause of both cancer and cardiovascular disease, yet the smoking habits of the groups are not mentioned. The subjects were asked about all self administered analgesics, but nothing is included about how combination products were treated and there are no results for these and other analgesicssurely important omissions. I believe that this quality of work would not be accepted as establishing any positive virtue for a pharmaceutical; why then should it be accepted as establishing that a drug is dangerous? For my own part, I cannot accept that on its own it established anything about aspirin, or that it refutes any of the very substantial data that have led to the generally accepted view that aspirin is neither carcinogenic nor teratogenic in therapeutic doses. The quality of the positive data showing that aspirin is effective in preventing some vascular accidents is so strong that this questionable set of results ought not to have any effect on our overall assessment of its usefulness. G R FRYERS
Oxted RH8 9HS 1 Paganini-Hill A, Chao A, Ross RK, Henderson BE. Aspirin use and chronic diseases: a cohort studv of the elderly. Br Mledj 1989;299: 1247-50. 2 Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295-300. 3 Collins E, Turner G. Maternal effects of regular salicslatc ingestion in pregnancv. Lancet 1975;ii:335-8.
SIR,-Dr Annlia Paganini-Hill and colleagues claim that the daily use of aspirin increased the risk of kidney cancer and ischaemic heart disease. 'This quite unjustified claim has been widely interpreted and publicised by the press as causal,2 and we are already seeing a great number of patients who have stopped taking previously prescribed daily aspirin for the secondary prevention of cardiovascular disease. Although people with a reported history of angina, acute myocardial infarction, and stroke were excluded from the analysis of the incidence of cardiovascular diseases, no mention was made of the reason that 1579 (14%) of the rest of their sample were taking aspirin daily. Clearly, this is important. The results of this study have been interpreted as if people had been randomly allocated to either aspirin or no aspirin. It is clear, however, that those taking aspirin were self selected. At the end of the discussion Dr PaganiniHill and colleagues mention that 30 of 132 people from their sample who were resurveyed in 1988 were taking aspirin to prevent heart disease or stroke or as a blood thinner. Such people may have been at increased risk of ischaemic heart disease by virtue of family history, known hypertension, thrombosis, diabetes, smoking, or drugs at the beginning of the study and may have been taking aspirin for these reasons. It is not clear whether Dr Paganini-Hill and colleagues implied a causal relation between daily aspirin and ischaemic heart disease. Aspirin treatment has been proved to benefit those with a history of cardiovascular disease (secondary prevention),' and it is important that such patients are not dissuaded from taking it. KARIM MEERAN GRAHAM DAVIES Department of Cardiology, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 OHS 1 Paganini-Hill A, Chao A, Ross RK, Henderson BE. Aspirill use and chronic diseases: a cohort study of the elderly. Br Medj7 1989;299:1247-50. (18 November.) 2 Anonymous. Aspirin is bad for the heart. Sun 1989 Nov 17:9. 3 Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. BrMedJ 1988;296:320-31.
SIR,-The paper by Dr Annlia Paganini-Hill and colleagues' shows the pitfalls of drawing conclusions from an observational cohort study, the data for which were gathered solely by three postal questionnaires, each separated by an interval of two years. The subjects represent a highly selected popula-, tion. Those who responded to the questionnaire (61%) are a self selected subset, certainly unrepresentative of the population at large in Europe or the United States. No randomisation or match-
BMJ
VOLUME
300
13 JANUARY 1990
Variations in reported serum alkaline phosphatase activities SIR, -Serum alkaline phosphatase activity is often used as a screening test for vitamin D deficiency in children. Unfortunately, different laboratories use different methods for the assay, which leads to a good deal of confusion. For example, a child was referred by his general practitioner to my outpatient clinic recently because of an increased alkaline phosphatase activity. The assay had been done in another hospital, which gives results twice those in this hospital, and our result was well within the normal range. I checked the five Birmingham hospitals which have paediatric units and found that one still reports in King-Armstrong units and four in international units per litre; of these four, three report figures twice those of the fourth. If this is representative of the situation in Britain it is surely not acceptable. Isn't it time the clinical chemists got their act together? D P ADDY
Department of Paediatnrcs, Dudley Road Hospital, Birmingham B 18 7QH
Aspirin use and chronic diseases SIR,-I am surprised that the BMJ published the article on aspirin use and chronic diseases by Dr Annlia Paganini-Hill and colleagues. ' Before explaining this statement, I must declare an interest in aspirin. As president of the European Aspirin Foundation (a body established by a number of aspirin and aspirin product manufacturers) I need to evaluate all new evidence on aspirin so as to be able to advise members of its importance. The authors seem to make the fundamental error of assuming that once an association has been established it is proof that one occurrence was the cause of the other. Bradford Hill established the substantial list of criteria that must be satisfactorily met before such a conclusion is drawn.2 The paper makes no attempt to meet these criteria, nor do the authors discuss why they think it unnecessary. That the error is fundamental is easily shown by selecting a perfect association that is entirely without causal significance. No doubt a study among couples where snoring of one was a problem to the other would show that it was always the one who went to sleep first who was the snorer. It would be ludicrous to conclude that going to sleep quickly was a cause of snoring. A second, equally naive mistake may mean that the associations found have mistakenly been thought to be significant when they could well have
116
been due to chance alone. At the p=005 level the statistics are merely saying that such an event would, on average, occur entirely by chance once in twenty studies. From the paper it is itnpossible to know how many associations were looked for, as it is clear that there were many others that have not been reported-for instance, looking for associations with other cancers. The paper found seven associations at the 0-05 level, which would be the expected chance finding in 140 attempts to find associations. So whether any of them, and if so which, were real and which were the chance findings cannot be known from the data published. There seems to be an element of bias in that the one association that was favourable to aspirin (preventing peptic ulcers in women) is explained away in the discussion, but no attempt has been made to see if alternative explanations exist for any of the unfavourable associations. For instance, though angina sufferers were excluded, we must presume that at the selection stage any who were having atypical and as yet undiagnosed pain of ischaemic origin would be included and thus would have increased the incidence of cardiovascular disease in the groups taking aspirin. After all, it would not be unreasonable to expect that people with pain would be more likely to take analgesics. Collins and Turner showed that in Australia frequent users of analgesics were more likely than the rest to be smokers.' Smoking is a known cause of both cancer and cardiovascular disease, yet the smoking habits of the groups are not mentioned. The subjects were asked about all self administered analgesics, but nothing is included about how combination products were treated and there are no results for these and other analgesicssurely important omissions. I believe that this quality of work would not be accepted as establishing any positive virtue for a pharmaceutical; why then should it be accepted as establishing that a drug is dangerous? For my own part, I cannot accept that on its own it established anything about aspirin, or that it refutes any of the very substantial data that have led to the generally accepted view that aspirin is neither carcinogenic nor teratogenic in therapeutic doses. The quality of the positive data showing that aspirin is effective in preventing some vascular accidents is so strong that this questionable set of results ought not to have any effect on our overall assessment of its usefulness. G R FRYERS
Oxted RH8 9HS 1 Paganini-Hill A, Chao A, Ross RK, Henderson BE. Aspirin use and chronic diseases: a cohort studv of the elderly. Br Mledj 1989;299: 1247-50. 2 Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295-300. 3 Collins E, Turner G. Maternal effects of regular salicslatc ingestion in pregnancv. Lancet 1975;ii:335-8.
SIR,-Dr Annlia Paganini-Hill and colleagues claim that the daily use of aspirin increased the risk of kidney cancer and ischaemic heart disease. 'This quite unjustified claim has been widely interpreted and publicised by the press as causal,2 and we are already seeing a great number of patients who have stopped taking previously prescribed daily aspirin for the secondary prevention of cardiovascular disease. Although people with a reported history of angina, acute myocardial infarction, and stroke were excluded from the analysis of the incidence of cardiovascular diseases, no mention was made of the reason that 1579 (14%) of the rest of their sample were taking aspirin daily. Clearly, this is important. The results of this study have been interpreted as if people had been randomly allocated to either aspirin or no aspirin. It is clear, however, that those taking aspirin were self selected. At the end of the discussion Dr PaganiniHill and colleagues mention that 30 of 132 people from their sample who were resurveyed in 1988 were taking aspirin to prevent heart disease or stroke or as a blood thinner. Such people may have been at increased risk of ischaemic heart disease by virtue of family history, known hypertension, thrombosis, diabetes, smoking, or drugs at the beginning of the study and may have been taking aspirin for these reasons. It is not clear whether Dr Paganini-Hill and colleagues implied a causal relation between daily aspirin and ischaemic heart disease. Aspirin treatment has been proved to benefit those with a history of cardiovascular disease (secondary prevention),' and it is important that such patients are not dissuaded from taking it. KARIM MEERAN GRAHAM DAVIES Department of Cardiology, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 OHS 1 Paganini-Hill A, Chao A, Ross RK, Henderson BE. Aspirill use and chronic diseases: a cohort study of the elderly. Br Medj7 1989;299:1247-50. (18 November.) 2 Anonymous. Aspirin is bad for the heart. Sun 1989 Nov 17:9. 3 Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. BrMedJ 1988;296:320-31.
SIR,-The paper by Dr Annlia Paganini-Hill and colleagues' shows the pitfalls of drawing conclusions from an observational cohort study, the data for which were gathered solely by three postal questionnaires, each separated by an interval of two years. The subjects represent a highly selected popula-, tion. Those who responded to the questionnaire (61%) are a self selected subset, certainly unrepresentative of the population at large in Europe or the United States. No randomisation or match-
BMJ
VOLUME
300
13 JANUARY 1990
