Is There Anticipation in the Age of Onset of Familial Lymphoid Cancers?

Dongmeng Liu1, Samantha Jones2,3, Ruth Thomas2, Graham W Slack4, Joseph M Connors4, Angela Brooks-Wilson2,5, and Jinko Graham1

1. Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada; 2. Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada; 3. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; 4. Centre for Lymphoid Cancers, British Columbia Cancer Agency, Vancouver, BC, Canada; 5. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada

Anticipation is a phenomenon in which the age of onset of a disease decreases as it is passed on to the next generation in a family. Anticipation has been observed in familial lymphoid cancers. However, in some studies, the observation may be an artifact of ascertainment of families with multiple affected relatives. A shorter duration of follow-up in a younger generation may lead to oversampling of younger affected children. Parent generations with late onset may be oversampled because cases with an earlier age of onset may have limited reproductive capability. One possible solution to the potential oversampling of younger affected children and older affected parents is to restrict analysis to “comparable parent-child pairs”, where only the affected parents and affected children are taken into consideration and the onset age must be lower than the interview age for each person. The advantage of using “comparable pairs” is that the ages of onset are no longer viewed as truncated by age at interview, so that truncation bias is averted. Standard statistical methods such as the t-test and random effects model may then be applied to test for the presence of anticipation. We apply these methods to the comparable parent-child pairs in lymphoid cancer affected families. Comparable parent-child pairs were extracted from 265 lymphoid-cancer affected families obtained from a study of families enriched for lymphoid cancers including non-Hodgkin and Hodgkin lymphoma, chronic lymphocytic leukemia and myeloma. We fit random effects models to the differences in age of onset between affected parent and child pairs and use the bootstrap to evaluate the statistical significance of anticipation. For families with more than one comparable parent-child relationship, we also analyze the data by taking the average of parents’ and children’s ages of onset, respectively, and applying the paired t-test and permutation t-test. We find no evidence of anticipation in either analysis.