Stoppage: An issue for segregation analysis

Abstract

Segregation analysis assumes that the observed family-size distribution (FSD), i.e., distribution of number of offspring among nuclear families, is independent of the segregation ratio p. However, for certain serious diseases with early onset and diagnosis (e.g., autism), parents may change their original desired family size, based on having one or more affected children, thus violating that assumption. Here we investigate "stoppage," the situation in which such parents have fewer children than originally planned. Following Brookfield et al. [J Med Genet 25:181-185, 1988], we define a stoppage probability d that after the birth of an affected child, parents will stop having children and thus not reach their original desired family size. We first derive the full correct likelihood for a simple segregation analysis as a function of p, d, and the ascertainment probability pi. We show that p can be estimated from this likelihood if the FSD is known. Then, we show that under "random" ascertainment, the presence of stoppage does not bias estimates of p. However, for other ascertainment schemes, we show that is not the case. We use a simulation study to assess the magnitude of bias, and we demonstrate that ignoring the effect of stoppage can seriously bias the estimates of p when the FSD is ignored. In conclusion, stoppage, a realistic scenario for some complex diseases, can represent a serious and potentially intractable problem for segregation analysis.

Mutation rates and the evolution of germline structure

“…Where clinical estimates are based on phenotypic recurrence, uncertainty arises in modelling the relationship between genotype and phenotype, the number of loci involved, and controlling for possible environmental factors. Additionally, some phenotypes may be difficult to diagnose consistently, particularly where there is already a diagnosis in siblings, and further potential bias arises from stoppage, whereby parents of an affected child are less likely to have additional children [ 45 , 46 ]. Some of these considerations suggest that clinical estimates might underestimate the true recurrence of de novo germline mutations.…”

Mutation rates and the evolution of germline structure

“…While such a revision may be warranted in places, particularly for recent events within the genus Homo and the speciation of the African great apes, a longer timescale for older events is difficult to reconcile with the primate fossil record. For example, with this rate the 4.7% sequence divergence between apes and old-world monkeys (6) implies a genetic divergence time 47 Myr ago, and hence speciation ~40 Myr ago (assuming a reasonably large ancestral population), whereas the fossil record seems consistent with a divergence no more than [25][26][27][28][29][30] Myr ago (7).…”

“…Where clinical estimates are based on phenotypic recurrence, uncertainty arises in modeling the relationship between genotype and phenotype, the number of loci involved and controlling for possible environmental factors. Additionally, some phenotypes may be difficult to diagnose consistently, particularly where there is already a diagnosis in siblings, and further potential bias arises from stoppage, whereby parents of an affected child are less likely to have additional children (44,45). Some of these considerations suggest that clinical estimates might underestimate the true recurrence of de novo germline mutations.…”

Major contribution of dominant inheritance to autism spectrum disorders (ASDs) in population-based families

“…Without knowledge of the distribution of the number of offspring among families, a correction for stoppage appears to be almost intractable. 22 Therefore, we tested for the existence of stoppage by using the Mann-Whitney U-test, according to a previous study. 23 In brief, if U is the number of times a normal child precedes an affected child in all k sibships, a i is the number of affected children in sibship i, and n i is the number of normal children in sibship i, then,…”