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Sex ratio of the mutation frequencies in haemophilia A: estimation and meta-analysis
Authors:F. R. Rosendaal  A. H. J. T. Bröcker-Vriends  J. C. van Houwelingen  C. Smit  I. Varekamp  H. van Dijck  T. P. B. M. Suurmeijer  J. P. Vandenbroucke  E. Briët
Affiliation:(1) Department of Clinical Epidemiology, University Hospital Leiden, Leiden, The Netherlands;(2) Department of Haematology, University Hospital Leiden, Leiden, The Netherlands;(3) Clinical Genetics Centre Leiden, Leiden, The Netherlands;(4) Department of Medical Statistics, State University Leiden, Leiden, The Netherlands;(5) Dutch Haemophilia Society (NVHP), Amsterdam, The Netherlands;(6) Department of Medical Sociology, State University Groningen, Groningen, The Netherlands;(7) Department of Clinical Epidemiology, University Hospital Leiden, Building 1 CO-P-46, P.O. Box 9600, NL-2300 RC Leiden, The Netherlands
Abstract:Summary A hereditary disease with excess mortality such as haemophilia is maintained in the population by the occurrence of new cases, i.e. mutations. In haemophilia, mutations may arise in female or male ancestors of a lsquonewrsquo patient. The ratio of the mutation frequencies in males over females determines the prior risk of carriership of the mother of an isolated patient. An estimate of this prior risk is required for the application of Bayes' theorem to probability calculations in carriership testing. We have developed a method to estimate the sex ratio of the mutation frequencies; it does not depend on the assumption of genetic equilibrium, nor require an estimate of the reproductive fitness of haemophilia patients and carriers. Information from 462 patients with severe or moderately severe haemophilia A was gathered by postal questionnaires in a survey that included practically all Dutch haemophiliacs. Pedigree analysis was performed for the 189 patients of these 462, who were the first haemophiliacs in their family. By the maximum likelihood method, the ratio of the mutation frequencies in males and females was estimated at 2.1, with a 95% confidence interval of 0.7–6.7. In addition, we performed a meta-analysis of all published studies on the sex ratio of the mutation frequencies. When the results of six studies were pooled, it was estimated that mutations originated 3.1 times as often in males as in females. The 95% confidence interval was 1.9–4.9. This implies that 80% of mothers of an isolated patient are expected to be haemophilia carriers.
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