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Hum Hered. 2006;61(2):104-10. Epub 2006 May 24.

Estimating haplotype effects on dichotomous outcome for unphased genotype data using a weighted penalized log-likelihood approach.

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  • 1Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands.



To develop a method to estimate haplotype effects on dichotomous outcomes when phase is unknown, that can also estimate reliable effects of rare haplotypes.


In short, the method uses a logistic regression approach, with weights attached to all possible haplotype combinations of an individual. An EM-algorithm was used: in the E-step the weights are estimated, and the M-step consists of maximizing the joint log-likelihood. When rare haplotypes were present, a penalty function was introduced. We compared four different penalties. To investigate statistical properties of our method, we performed a simulation study for different scenarios. The evaluation criteria are the mean bias of the parameter estimates, the root of the mean squared error, the coverage probability, power, Type I error rate and the false discovery rate.


For the unpenalized approach, mean bias was small, coverage probabilities were approximately 95%, power ranged from 15.2 to 44.7% depending on haplotype frequency, and Type I error rate was around 5%. All penalty functions reduced the standard errors of the rare haplotypes, but introduced bias. This trade-off decreased power.


The unpenalized weighted log-likelihood approach performs well. A penalty function can help to estimate an effect for rare haplotypes.

Copyright 2006 S. Karger AG, Basel.

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