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Front Genet. 2014 Jul 1;5:188. doi: 10.3389/fgene.2014.00188. eCollection 2014.

An alternative hypothesis testing strategy for secondary phenotype data in case-control genetic association studies.

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Department of Biostatistics, University of Colorado Aurora, CO, USA.
Department of Epidemiology, University of Colorado Aurora, CO, USA.
Department of Biostatistics, Harvard School of Public Health Boston, MA, USA ; Channing Laboratory, Harvard Medical School Boston, MA, USA ; Institute for Genomic Mathematics, University of Bonn Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE) Bonn, Germany.


Motivated by the challenges associated with accounting for the ascertainment when analyzing secondary phenotypes that are correlated with case-control status, Lin and Zeng have proposed a method that properly reflects the case-control sampling (Lin and Zeng, 2009). The Lin and Zeng method has the advantage of accurately estimating effect sizes for secondary phenotypes that are normally distributed or dichotomous. This method can be computationally intensive in practice under the null hypothesis when the likelihood surface that needs to be maximized can be relatively flat. We propose an extension of the Lin and Zeng method for hypothesis testing that uses proportional odds logistic regression to circumvent these computational issues. Through simulation studies, we compare the power and type-1 error rate of our method to standard approaches and Lin and Zeng's approach.


ascertainment; case-control study; genetic association; proportional odds logistic regression; secondary phenotype

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