### 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