title: Ages of onset suggestive of genetic anticipation in rheumatoid arthritis multicase sibships can be explained by observational bias.
abstract: OBJECTIVE
  Previous work has suggested that features of genetic anticipation might be present in familial rheumatoid arthritis (RA), but bias is difficult to exclude when looking at disease in two consecutive generations. We used data from the North American Rheumatoid Arthritis Consortium (NARAC) and the Arthritis Research Campaign National repository for RA multicase pedigrees to determine whether differences in age of onset within multicase sibships were supportive of genetic anticipation.
  
  
  METHODS
  RA sibling pairs were identified from both data sets. The period of observation was defined as the time between the first sibling developing RA and the time that the sibship was ascertained for the study. A paired t-test for the difference in ages of RA onset within the pairs was calculated. Ages of conception of the parent were correlated with the age of RA onset.
  
  
  RESULTS
  Information was available for 743 sibships in the NARAC data set and 396 sibships in the Arthritis Research Campaign (ARC) data set. In both data sets, the older siblings had an older age of onset than their younger siblings (39.3 vs 36.9 in the NARAC, and 43.8 vs 40.1 in the ARC data set, both P < 0.001). The two data sets were then stratified into tertiles by a period of observation. In both data sets, there was a progressive decline in the sibling age of onset differences. For the first tertile (shortest observation period), the older sibling had a significantly older age of onset than the younger. This difference decreased in the second tertile, and was not significant in the third tertile (longest observation period). There was no significant correlation between the age of RA onset and the maternal or paternal ages of conception in either data set.
  
  
  CONCLUSIONS
  Features compatible with genetic anticipation in RA multicase sibships are subject to observational bias. This does not support a role for genetic anticipation in familial RA.
authors.affiliation: Department of Rheumatology, Derbyshire Royal Infirmary, Derby, DE1 2QY, UK. deighton@derbyhospitals.nhs.uk
authors.forename: C
authors.initials: C
authors.lastname: Deighton
authors.forename: L A
authors.initials: LA
authors.lastname: Criswell
authors.forename: R F
authors.initials: RF
authors.lastname: Lum
authors.forename: A
authors.initials: A
authors.lastname: Silman
mesh_terms: D000328:Adult; D017668:Age of Onset; D020132:Anticipation, Genetic; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008423:Maternal Age; D008875:Middle Aged; D015588:Observer Variation; D010331:Paternal Age