Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Searching for the link between parental age and Type 1 diabetes
- Helen Pattison (11 August 2000)
-
Flawed analysis invalidates conclusions
- Graham Byrnes (12 August 2000)
-
Maternal age and risk of type 1 diabetes in children
- Lars C Stene, Geir Joner (14 August 2000)
-
Other secular trends may explain the associations with diabetes risk
- Alistair J Gunn, Wayne S Cutfield, Paul L Hofman, Craig Jeferries (4 September 2000)
-
The Influence of Paternal Age
- L B Raschka (2 October 2000)
-
Relative risks by maternal age are biased
- Chris Patterson (20 November 2000)
|
|
|||
|
Helen Pattison, Senior Lecturer The Medical School, Birmingham University
Send response to journal:
|
Given access to such a potentially rich data source, Bingley et al do not seem to have recorded data which could illuminate the link between parental age and Type 1 diabetes in childhood. Those women (and men) who delay childbearing can be distinguished from those who have children in their teens and twenties on several social, occupational and behavioural variables. These will lead to differences in exposure to possible environmental factors. The long term use of oral contraceptives may also be confounded with maternal age at birth of first child. Are these data available for further exploration of the links the authors have established? |
|||
|
|
|||
|
Graham Byrnes, Biostatistician Royal Melbourne Hospital
Send response to journal:
|
The conclusion drawn by Bingley et. al., of dependence on both birth order and maternal age, is a tempting explanation of previous ambiguous results. However I believe the present study is seriously flawed in the analysis of data, to an extent that the results are completely meaningless. There are three apparent problems: 1. The cohort studied is comprised of children with a sibling diagnosed with Type 1 diabetes. Hence every only-child in the study must be a case. Roughly half of children from two child families will be cases and so on. This immediately produces an (inverse) association between the number of siblings and the diagnosis of type 1 diabetes. To see this clearly, suppose that cases occur purely at random. To make the numbers easy, suppose the incidence is 1%. Now select 1000 only child cases and 1000 cases with a single sibling. We now see that almost half of the 2010 expected cases will be only children, but none of the non -cases! Moreover, birth-order relates to family size: an only child cannot be a second-born. So of our hypothetical 3000 children with 2010 cases, 1505 cases will be expected to be first-born, as compared with only 495 off 990 non-cases: a risk-ratio of 1.5. The dependence on maternal age then follows immediately if we allow that women who have their first child later tend to have fewer children. Hence the results the authors obtain are entirely consistent with the null hypothesis of no association between maternal age or birth-order with type 1 diabetes. 2. Cox regression is essentially a form of nested case-control study. As such it relies on the assumption that the events are independent. This does not seem a reasonable assumption when the study contains many sets of siblings, so the confidence intervals calculated are probably too small. 3. It is not clear how the result would generalise to a population of women who have not had a diabetic child. The first of the above points is at first sight the most serious, although appropriate re-analysis could over-come it: only-children should be excluded and a single control selected from each family to eliminate the family-size effect. However it is hard to see how one would ever circumvent point 3. Sincerely, Graham Byrnes, BSc PhD |
|||
|
|
|||
|
Lars C Stene, Research fellow; Paediatrician National Institute of Public Health, Oslo; Aker Diabetes Research Centre, Oslo, Geir Joner
Send response to journal:
|
Bingley et al. (1) reported an association between increased age of the mother at delivery and increased risk of type 1 diabetes in children. It is possible that the simultaneous increase in diabetes and maternal age in the population during the period of recruiting families have lead to a spurious association confounded by unknown factors that have caused the rise in incidence of diabetes and are simply correlated with increased maternal age in the population over time. Since siblings are usually born within a few years time span, birth year has been controlled to some extent, but not completely. Adjusting the analyses for year of birth should control such potential confounding. Since Bingley et al. did not state that adjustment for birth year have been done, we are left with the question whether the observed association is at least partly due to such confounding. Furthermore, it is possible that genetic susceptibility as indicated by having a sibling with type 1 diabetes increases the relative risk conferred by a high maternal age. If so, the data presented by Bingley et al. would not be generalisable to the general population (2). The claim that ‘matching for genetic susceptibility’ is an advantage compared to studies using population controls (1) only applies if genetic susceptibility is a confounder and not an effect modifier. Genetic susceptibility to type 1 diabetes in the children must be associated with the mother’s age at delivery in order to be a confounder in studies using population controls, something that is hard to envisage. We have done a cohort analysis of all live-births in Norway between 1984 and 1998 including 1105 children who developed type 1 diabetes, based on linking the Medical Birth Registry of Norway (3) and the National Childhood Diabetes Registry (4). Our study should thus have sufficient power to detect even weak associations. We found no significant association between maternal age and the incidence of type 1 diabetes, neither crude nor after adjustment for birth order and year of birth (Stene & Joner, unpublished observations). In Norway, mean maternal age has increased in recent years, but diabetes incidence has not. However, the criteria for registration of cases dictates that during any period of registration, those who are born later have a younger age at onset. We observed a crude association between maternal age and age at onset among cases similar to that found by Bingley et al., but the association disappeared after adjusting for birth year. We suspect that this would be the case for the data of Bingley et al. too. Lars Chr. Stene
Geir Joner
Reference List 1. Bingley PJ, Douek IF, Rogers CA, Gale EAM. Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study. BMJ 2000; 321:420-424. 2. Andrieu N, Goldstein AM. Use of relatives of cases as controls to identify risk factors when an interaction between environmental and genetic factors exists. Int J Epidemiol 1996; 25:649-657. 3. Irgens LM. The medical birth registry of Norway. Epidemiological research and surveillance thorughout 30 years. Acta Obstet Gynecol Scand 2000; 79:435-439. 4. EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000; 355:873-876. |
|||
|
|
|||
|
Alistair J Gunn, Paediatrician, Paediatrician, Paediatrician, and Clinical Fellow Dept of Paediatrics, University of Auckland, Auckland, New Zealand, Wayne S Cutfield, Paul L Hofman, Craig Jeferries
Send response to journal:
|
The report by Bingley and colleagues of an association between age of the mother and birth order, and risk of type 1 diabetes mellitus in children is of interest but the findings do not seem to be consistent (1). If the age of the mother is associated with a real increase in risk, then it is surprising that subsequent children could possibly have reduced risk given that maternal age must have increased. The hypothesis given to explain the apparent relationship, of more mature immune responses in older women priming the fetal system in some way, is biologically improbable given the functional immaturity of the fetal immune system. Since the cohort spans a significant interval, it is not clear that the authors have adjusted for secular trends that might have been associated with greater risk. The most important of these factors is the trend towards childbirth in older women over the study period. The greatest risk of type 1 diabetes mellitus was reported in the offspring of a very small group of mothers giving birth after 45 years of age (1). There may have been a number of other factors in older woman that could have influenced the reported observation, including assisted reproduction, ethnicity, maternal illness and obesity that were not presented. Other potentially confounding factors not examined include the changing incidences of type 1 diabetes mellitus and the increasing rate of obesity in childhood, which tends to lower the age of onset of children at risk of type one diabetes, because of insulin resistance (2,3). Finally, it appears that type 1 pre-diabetes antibodies were not measured to validate the diagnosis of type 1 diabetes mellitus. Clinical diagnosis based on apparent requirement for insulin therapy or presentation with ketoacidosis is not specific at a time of increasing type 2 diabetes mellitus in children. 1. Bingley PJ, Douek IF, Rogers CA, Gale EA. Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study. BMJ 2000 Aug 12;321(7258):420- 4. 2. Rangasami JJ, Greenwood DC, McSporran B, Smaill PJ, Patterson CC, Waugh NR. Rising incidence of type 1 diabetes mellitus in Scottish children 1984 -93. Arch Dis Child 1997;77:210-13. 3. Kitigawa T, Owada M, Urakami T, Tajima N. Epidemiology of type 1 (insulin dependent) and type 2 (non-insulin-dependent) diabetes mellitus in Japanese children. Diabetes Res Clin Pract 1994;24(suppl):S7-13. |
|||
|
|
|||
|
L B Raschka
Send response to journal:
|
Editor. The Bart's - Oxford Study Group reported on the influence of maternal age at delivery and the risk of type 1 diabetes in the child. 1 Paternal age was also found to be increased. Whereas there is a correlation between maternal age and paternal age, I propose that paternal age itself can be an independent determinant of genetic abnormalities. The aging process was reported to be associated with increased mutation rate in the male gametogenesis. 2 Illnesses reported to show increased incidence with increased paternal age include achondroplasis, acrocephalosyndactily, myositis ossificans progressiva, Marfan syndrome, Apert syndrome, basal cell naevus syndrome, Waardenburg syndrome, Crouzon syndrome, oculo-dental-digital syndrome, Treacher-Collins syndrome, schizophrenia, 3 and Alzheimer's Disease. 4 The illness related to advanced paternal age could be transmitted to future generations. Increased maternal grandpaternal age was reported in relation to classical hemophilia and Lesch-Nyhan disease. 5 It is proposed that further study of the influence of paternal age upon the health of the offspring could yield valuable information. L.B. Raschka M.D., 1. Bingley P J, Douek I F, Rogers C A, Gale E A M. Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: Prospective population based family study., BMJ 2000; 321: 420 -424 (12 August) 2. Vogel F, Mutation in Man. In Emery A E H, Rimoin D L, eds. Principles and practice of medical genetics. Churchill Livingstone, Edinburough, London, Melbourne and New York 1983: 26-48 3. Raschka L B. Paternal age and schizophrenia. Magyar Andrologia 1998/ 2; 111: 47-50 4. Bertram L, Busch R, Spiegl M, Lautenschlager M T, Muller U, Kurz A. Paternal age is a risk factor for Alzheimer disease in the absence of a major gene. Neurogenetics 1998; 1: 277-280 5. World Health Organization. Prevention of avoidable mutational disease: Memorandum from a WHO Meeting. World Health Organization Meeting. Bull. of World Health Organization. 1986 |
|||
|
|
|||
|
Chris Patterson, Senior Lecturer in Medical Statistics Queen's University Belfast
Send response to journal:
|
Graham Byrnes (BMJ rapid responses) has drawn attention to problems with the statistical analysis in the paper by Bingley and colleagues(1) and makes some pertinent points. Although statisticians familiar with survival analysis techniques may have spotted methodological problems in this paper, the less statistical reader might have been suspicious about the very high risks of diabetes among the offspring of families in the study depicted in Figure 1, especially in the oldest maternal age groups where fewer than 40% of offspring would be predicted to be free of diabetes by 20 years of age. Bingley and colleagues have ascertained families through affected children (probands) and have then applied survival analysis techniques to all the offspring in these families, including probands, with age at diagnosis of affected children as the end-point and follow-up in unaffected children censored at their age on the date of last contact. This strategy will result in ascertainment bias which will lead to overestimation of the risk of diabetes in these families. We can be certain that the mothers in this study will grow older and some will have more children the majority of whom will not develop diabetes. These children, together with ageing existing younger children in the family, will contribute to improving the rates of diabetes free survival in the analysis depicted in Figure 1, particularly in the oldest maternal age categories. By ignoring these children Bingley and colleagues introduce biases into the relative risks for maternal age categories displayed in their table. Their plot of estimated risks in Figure 3 obtained by extrapolating these relative risks to birth cohorts in England and Wales is also flawed. We have conducted a large case-control study involving over 1,000 cases of childhood type 1 diabetes and over 2,000 controls drawn from eight European centers(2) in which we collected data on the family history of type 1 diabetes in the siblings of both cases and controls. To explore the possible extent of these biases, we have re-analysed the data from the cases and their siblings using the same strategy as was employed by Bingley and her colleagues with follow-up ending at the time of our contact with the families. The results we obtained are shown in the left side of the Table below and are similar to the results in Bingley’s paper. However, when we analysed our own data using appropriate statistical methodology by comparing the distribution of maternal age in cases with the corresponding distribution in controls using the Mantel Haenszel odds ratio pooled over our eight centres we found a much weaker relationship with maternal age (right side of table) more in keeping with the results in the published literature. These findings were little altered by adjustment for potential confounding variables. Table Comparison of the association between maternal age and type 1 childhood diabetes obtained using two analyses. Inappropriate analysis Appropriate analysis Maternal Age Relative hazard (95% CI) Odds ratio (95% CI) <20 1.00 1.00 20-24 1.45 (1.07, 1.96) 1.03 (0.75, 1.42) 25-29 1.89 (1.40, 2.54) 1.30 (0.94, 1.79) 30-34 2.32 (1.70, 3.16) 1.39 (0.99, 1.96) 35+ 2.88 (2.05, 4.05) 1.42 (0.95, 2.14) We conclude that the inappropriate statistical analysis employed by Bingley and colleagues gives rise to bias which considerably exaggerates the association between type 1 diabetes and maternal age. C.C. Patterson
G. Dahlquist
G Soltész
on behalf of the EURODIAB Substudy 2 Study Group References (1) Bingley PJ, Douek IF, Rogers CA, Gale EAM on behalf of the BOX (Bart’s-Oxford) Study Group. Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study. BMJ 2000; 321: 420-4 (12 Aug). (2) Dahlquist GG, Patterson C, Soltész G for the EURODIAB Substudy 2 Study Group. Perinatal risk factors for childhood Type 1 diabetes in Europe. Diabetes Care 1999: 22: 1698-1702 |
|||