Maternal age and risk of type 1 diabetes in children

BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7300.1489/a (Published 16 June 2001) Cite this as: BMJ 2001;322:1489

Flawed analysis invalidates conclusions

  1. Graham Byrnes, biostatistician (Graham.Byrnes@mh.org.au)
  1. Clinical Epidemiology and Health Service Evaluation Unit, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
  2. Department of Epidemiology and Public Health, Queen's University Belfast, Belfast BT12 6BJ
  3. Department of Clinical Science, Umeå University, S-90185 Umeå, Sweden
  4. Department of Paediatrics, Pécs University, H-7623 Pécs, József A. u. 7, Hungary On behalf of the EURODIAB Substudy 2 Study Group.
  5. Department of Paediatrics, University of Auckland, Auckland, New Zealand
  6. Section of Epidemiology, National Institute of Public Health, N-0403 Oslo, Norway
  7. Aker Diabetes Research Centre, Aker University Hospital, Oslo, Norway
  8. Diabetes and Metabolism, Division of Medicine, University of Bristol, Southmead Hospital, Bristol BS10 5NB

    EDITOR—The conclusion drawn by Bingley et al, of dependence on both birth order and maternal age, is a tempting explanation of previous ambiguous results.1 I believe, however, that their study is seriously flawed in the analysis of data, to an extent that the results are completely meaningless.

    There are three apparent problems.

    Firstly, the cohort studied consists of children with a sibling diagnosed with type 1 diabetes. Hence every only child in the study must be a case. Roughly half of the 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. 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, compared with only 495 of 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. The results Bingley et al obtain are therefore consistent with the null hypothesis of no association between maternal age or birth order with type 1 diabetes.

    Secondly, Cox regression is essentially a form of nested case-control study and 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 …

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