Curtis D, Sham PC. Model-free linkage analysis using likelihoods. Am J Hum Genet 1995 57:703-716.

Misspecification of transmission model parameters can produce artefactually negative lod scores at small recombination fractions and in multipoint analysis. To avoid this problem we have tried to devise a test which aims to detect a genetic effect at a particular locus, rather than attempting to estimate the map position of a locus with specified effect. Maximising likelihoods over transmission model parameters as well as linkage parameters can produce seriously biased parameter estimates and so yield tests which lack power for the detection of linkage. However constraining the transmission model parameters to produce the correct population prevalence largely avoids this problem. For computational convenience we recommend that the likelihoods under linkage and non-linkage are independently maximised over a limited set of transmission models, ranging from Mendelian dominant to null effect and from null effect to Mendelian recessive. In order to test for a genetic effect at a given map position, the likelihood under linkage is maximised over admixture, the proportion of families linked. Application to simulated data for a wide range of transmission models in both affected sib pairs and pedigrees demonstrates that the new method is well- behaved under the null hypothesis and provides a powerful test for linkage when it is present. This test requires no specification of transmission model parameters apart from an approximate estimate of the population prevalence. It can be applied equally to sib pairs and pedigrees and since it does not diminish the lod score at test positions very close to a marker it is suitable for application to multipoint data.

Dave Curtis publications