Background: The goal of linkage analysis is to determine the chromosomal location of the gene(s) for a trait of interest such as a common disease. Three-locus linkage analysis is an important case of multi-locus problems. Solutions can be found analytically for the case of triple backcross mating. However, in the present study of linkage analysis and gene mapping some natural inequality restrictions on parameters have not been considered sufficiently, when the maximum likelihood estimates (MLEs) of the two-locus recombination fractions are calculated.Results: In this paper, we present a study of estimating the two-locus recombination fractions for the phase-unknown triple backcross with two offspring in each family in the framework of some natural and necessary parameter restrictions. A restricted expectation-maximization (EM) algorithm, called REM is developed. We also consider some extensions in which the proposed REM can be taken as a unified method.Conclusion: Our simulation work suggests that the REM performs well in the estimation of recombination fractions and outperforms current method. We apply the proposed method to a published data set of mouse backcross families.

There have been studies on how the asymptotic efficiency of a nonparametric function estimator depends on the handling of the within-cluster correlation when nonparametric regression models are used on longitudinal or cluster data. In particular, methods based on smoothing splines and local polynomial kernels exhibit different behaviour. We show that the generalized estimation equations based on weighted least squares regression splines for the nonparametric function have an interesting property: the asymptotic bias of the estimator does not depend on the working correlation matrix, but the asymptotic variance, and therefore the mean squared error, is minimized when the true correlation structure is specified. This property of the asymptotic bias distinguishes regression splines from smoothing splines.