- Email: [email protected]
Risk-factor epidemiology
associations, and the
benefit will ultimately and most importantly accrue. In support of this submission I cite the US physician Charles H Mayol who in 1927 stated "The safest thing for a patient is to be in the hands of a man engaged in teaching medicine. In order to be a teacher of medicine the doctor must always be a student". For the future I would submit that we are all or at least should all be continuing medical (education) students.
such
one between smoking and lung would be treated as being just as unreliable as that between smoking and cervical cancer. We suggest that this blanket approach is unscientific and that the improved design and analysis of observational studies will allow us to improve our specification of what we know-and what we do not know-about how diseases develop.
Fergus Gleeson
Andrew N Phillips,
Royal College of Surgeons in Ireland, Teaching Centre, James Connolly Memorial Hospital, Blanchardstown, Dublin 15, Ireland
University Department of Public Health, Royal Free Hospital School of Medicine, London NW3 2PF, UK; and Department of Public Health, University of Glasgow
1 Daintith J, Isaacs A, eds. Medical quotes. Oxford: Facts on File, 1989:
1
cancer
199.
George Davey Smith
Koot M, Keet
IPM, Vos AHV, et al. Prognostic value of human immunodeficiency virus type 1 biological phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med 1993; 118: 681-88.
Risk-factor epidemiology
2
SiR-How can pathogenic mechanisms in disease be studied? Controlled experiments in animals suffer from uncertainty over extrapolation to man and clinical experiments are rarely ethical or practical in this context. This essentially leaves observational studies, usually involving comparison of disease rates between individuals with different levels of factors suspected of a causal role. Given the lack of real control-in that one cannot dictate that the differences in levels of the suspected causal factor are the only differences between individuals-such studies will always be susceptible to confounding. Studies of this design are not, as Skrabanek suggests in his commentary (Dec 18/25, p 1502), confined to risk-factor epidemiology, nor are the statistical methods for dealing with confounding. An example is the suggestion that certain strains of HIV are associated with faster progression to AIDS because they deplete CD4 lymphocyte counts more rapidly. An alternative explanation is that such strains merely reflect a weakened immune system and have no direct causal role. Multivariate Cox proportional hazards models have been used to try to disentangle such confounding.1 It is becoming clear, however, that multiple regression models cannot control confounding properly if the factors under investigation are not measured precisely, and this accounts in part for some of the curious results that risk-factor epidemiology produces.2 In the paper that prompted Skrabanek’s article we suggested that measurement precision should be given a higher priority relative to sample size.3 This should help to reduce bias in evaluation of potentially causal factors, even though smaller sample sizes would lead to wider confidence intervals around estimates of association with disease. This is precisely the opposite of Skrabanek’s interpretation of our work as "narrow[ing] confidence intervals of spurious associations", and his critics in your issue of Feb 12 (p 420) do not make this point. Besides the improvements in design that we suggest,3 sensitivity should be studied thoroughly at the stage of data analysis. Investigators should estimate the degrees of bias that could be introduced into their study and build that into their statistical analysis. Associations that do not survive such sensitivity analysis should be treated with a high degree of scepticism. This is essentially what Cornfield and colleagues did in 1959, during the great debate about smoking and lung cancer. They showed that that association was robust to reasonable assumptions about the confounding influences of atmospheric pollution, urban living, and occupation.4 By contrast, the association between smoking and cervical cancer is not robust and the possibility that it is entirely explained by certain papillomaviruses cannot yet be excluded.5 Skrabanek seems to think that since it is impossible to guarantee the veracity of observed associations we should stop looking. This is equivalent to preferring blindness to the risk of being deceived by an optical illusion. By denying the possibility of improving observational studies he would have us ignore all
3
4
5
Davey Smith G, Phillips AN. Declaring independence: why we should be cautious. J Epidemiol Commun Health 1990; 44: 257-58. Phillips AN, Davey Smith G. The design of prospective epidemiological studies: more subjects or better measurements? J Clin Epidemiol 1993; 46: 1203-11. Cornfield J, Haenszel W, Hammond EC, Lilienfeld AM, Shimkin MB, Wynder EL. Smoking and lung cancer: recent evidence and a discussion of some questions. J Natl Cancer Inst 1959; 22: 173-203. Phillips AN, Davey Smith G. Cigarette smoking as a potential cause of cervical cancer: has confounding been controlled? Int J Epidemiol (in press).
Becoming parents after 100? SIR-A few months ago, when a 63-year-old celebrity was interviewed about his baby, people hardly batted an eye. But a 62-year-old woman expecting a child through egg donation sparked international concern,l,2 reflecting an entrenched bias that women above a certain age should not become pregnant.3 The unease probably stems from the former evolutionary absolute that menopausal women could not conceive4while men can father children into old age. In addition, before 1940 or so, the life expectancy of women was 20 years less than it is today so that women in their 60s were nearing the end of their lives. The man and the woman referred to have something else very important in common-namely, a younger spouse. With myopic focus on the age of the individual, too little attention has been paid to the couple who will become the child’s family. Men are becoming much more involved in child rearing and in some families the father is the primary care-giver. Single parent adoption by both men and women is commonplace, as is artificial insemination of single women. Should a mother die early in her child’s life, her younger husband can provide good and sustained parental care.5 We propose that instead of focusing on the upper age limit for a woman to become a parent5 the debate should be redirected at the combined ages of the couple, with case-bycase consideration of the health and vigour of the older partner. If one parent is old, the other should be young. If both are old, limits should be set. We suggest that gamete donation be considered in the context of the family unit it will establish. An appropriate guideline could be that couples refrain from initiating parenthood when their combined ages exceed 100. Machelle M
Seibel, Moshe Zilberstein, Sharon Seibel
Faulkner Centre for
1 2 3 4
5
Reproductive Medicine, Boston, MA 02130, USA
Dean M. New controversies over assisted conception. Lancet 1994; 343: 165. Anon. Too old at 59? Nature 1994; 367: 2. Benagiano G. Pregnancy after the menopause: a challenge to nature? Hum Reprod 1993; 8: 1344-45. Sauer MV, Paulson RJ, Lobo RA. Pregnancy after age 50: application of oocyte donation to women after the natural menopause. Lancet 1993; 341: 321-23. Flamigni C. Egg donation to women over 40 years of age. Hum Reprod 1993; 8: 1343-44.
603
benefit will ultimately and most importantly accrue. In support of this submission I cite the US physician Charles H Mayol who in 1927 stated "The safest thing for a patient is to be in the hands of a man engaged in teaching medicine. In order to be a teacher of medicine the doctor must always be a student". For the future I would submit that we are all or at least should all be continuing medical (education) students.
such
one between smoking and lung would be treated as being just as unreliable as that between smoking and cervical cancer. We suggest that this blanket approach is unscientific and that the improved design and analysis of observational studies will allow us to improve our specification of what we know-and what we do not know-about how diseases develop.
Fergus Gleeson
Andrew N Phillips,
Royal College of Surgeons in Ireland, Teaching Centre, James Connolly Memorial Hospital, Blanchardstown, Dublin 15, Ireland
University Department of Public Health, Royal Free Hospital School of Medicine, London NW3 2PF, UK; and Department of Public Health, University of Glasgow
1 Daintith J, Isaacs A, eds. Medical quotes. Oxford: Facts on File, 1989:
1
cancer
199.
George Davey Smith
Koot M, Keet
IPM, Vos AHV, et al. Prognostic value of human immunodeficiency virus type 1 biological phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med 1993; 118: 681-88.
Risk-factor epidemiology
2
SiR-How can pathogenic mechanisms in disease be studied? Controlled experiments in animals suffer from uncertainty over extrapolation to man and clinical experiments are rarely ethical or practical in this context. This essentially leaves observational studies, usually involving comparison of disease rates between individuals with different levels of factors suspected of a causal role. Given the lack of real control-in that one cannot dictate that the differences in levels of the suspected causal factor are the only differences between individuals-such studies will always be susceptible to confounding. Studies of this design are not, as Skrabanek suggests in his commentary (Dec 18/25, p 1502), confined to risk-factor epidemiology, nor are the statistical methods for dealing with confounding. An example is the suggestion that certain strains of HIV are associated with faster progression to AIDS because they deplete CD4 lymphocyte counts more rapidly. An alternative explanation is that such strains merely reflect a weakened immune system and have no direct causal role. Multivariate Cox proportional hazards models have been used to try to disentangle such confounding.1 It is becoming clear, however, that multiple regression models cannot control confounding properly if the factors under investigation are not measured precisely, and this accounts in part for some of the curious results that risk-factor epidemiology produces.2 In the paper that prompted Skrabanek’s article we suggested that measurement precision should be given a higher priority relative to sample size.3 This should help to reduce bias in evaluation of potentially causal factors, even though smaller sample sizes would lead to wider confidence intervals around estimates of association with disease. This is precisely the opposite of Skrabanek’s interpretation of our work as "narrow[ing] confidence intervals of spurious associations", and his critics in your issue of Feb 12 (p 420) do not make this point. Besides the improvements in design that we suggest,3 sensitivity should be studied thoroughly at the stage of data analysis. Investigators should estimate the degrees of bias that could be introduced into their study and build that into their statistical analysis. Associations that do not survive such sensitivity analysis should be treated with a high degree of scepticism. This is essentially what Cornfield and colleagues did in 1959, during the great debate about smoking and lung cancer. They showed that that association was robust to reasonable assumptions about the confounding influences of atmospheric pollution, urban living, and occupation.4 By contrast, the association between smoking and cervical cancer is not robust and the possibility that it is entirely explained by certain papillomaviruses cannot yet be excluded.5 Skrabanek seems to think that since it is impossible to guarantee the veracity of observed associations we should stop looking. This is equivalent to preferring blindness to the risk of being deceived by an optical illusion. By denying the possibility of improving observational studies he would have us ignore all
3
4
5
Davey Smith G, Phillips AN. Declaring independence: why we should be cautious. J Epidemiol Commun Health 1990; 44: 257-58. Phillips AN, Davey Smith G. The design of prospective epidemiological studies: more subjects or better measurements? J Clin Epidemiol 1993; 46: 1203-11. Cornfield J, Haenszel W, Hammond EC, Lilienfeld AM, Shimkin MB, Wynder EL. Smoking and lung cancer: recent evidence and a discussion of some questions. J Natl Cancer Inst 1959; 22: 173-203. Phillips AN, Davey Smith G. Cigarette smoking as a potential cause of cervical cancer: has confounding been controlled? Int J Epidemiol (in press).
Becoming parents after 100? SIR-A few months ago, when a 63-year-old celebrity was interviewed about his baby, people hardly batted an eye. But a 62-year-old woman expecting a child through egg donation sparked international concern,l,2 reflecting an entrenched bias that women above a certain age should not become pregnant.3 The unease probably stems from the former evolutionary absolute that menopausal women could not conceive4while men can father children into old age. In addition, before 1940 or so, the life expectancy of women was 20 years less than it is today so that women in their 60s were nearing the end of their lives. The man and the woman referred to have something else very important in common-namely, a younger spouse. With myopic focus on the age of the individual, too little attention has been paid to the couple who will become the child’s family. Men are becoming much more involved in child rearing and in some families the father is the primary care-giver. Single parent adoption by both men and women is commonplace, as is artificial insemination of single women. Should a mother die early in her child’s life, her younger husband can provide good and sustained parental care.5 We propose that instead of focusing on the upper age limit for a woman to become a parent5 the debate should be redirected at the combined ages of the couple, with case-bycase consideration of the health and vigour of the older partner. If one parent is old, the other should be young. If both are old, limits should be set. We suggest that gamete donation be considered in the context of the family unit it will establish. An appropriate guideline could be that couples refrain from initiating parenthood when their combined ages exceed 100. Machelle M
Seibel, Moshe Zilberstein, Sharon Seibel
Faulkner Centre for
1 2 3 4
5
Reproductive Medicine, Boston, MA 02130, USA
Dean M. New controversies over assisted conception. Lancet 1994; 343: 165. Anon. Too old at 59? Nature 1994; 367: 2. Benagiano G. Pregnancy after the menopause: a challenge to nature? Hum Reprod 1993; 8: 1344-45. Sauer MV, Paulson RJ, Lobo RA. Pregnancy after age 50: application of oocyte donation to women after the natural menopause. Lancet 1993; 341: 321-23. Flamigni C. Egg donation to women over 40 years of age. Hum Reprod 1993; 8: 1343-44.
603