IDENTIFYING CHROMOSOMAL FRAGILE SITES FROM INDIVIDUALS - A MULTINOMIAL STATISTICAL-MODEL

The inability to identify fragile sites from data for single individua ls remains the major obstacle to determining whether these chromosomal loci are predisposed to cancer-causing and evolutionary rearrangement s. We describe a novel statistical model that is amenable to data from single individuals and that establishes site-specific chromosomal bre akage as nonrandom with respect to the distribution of total breakage. Our method tests incrementally smaller subsets of the data for homoge neity under a multinomial model that assigns equal probabilites to a m aximal set of nonfragile sites and unrestricted probabilities to the r emaining fragile sites with significantly higher numbers of breaks. We show how standardized Pearson's chi-square (Y-2) and likelihood-ratio (G(2)) Statistics can be appropriately used to measure goodness-of-fi t for sparse contingency (individual-based) data in this model. A samp le application of this approach indicates extensive variation in fragi le sites among individuals and marked differences in fragile-site infe rences from pooled as opposed to per-individual data.