Exploring Case-Control Genetic Association Tests Using Phase Diagrams

TL;DR

This paper introduces phase diagrams to compare the power of two genotype-based case-control tests, CAT0.5 and MAX2, using differences in allele frequencies and Hardy-Weinberg disequilibrium to guide test selection.

Contribution

It proposes a novel phase diagram approach for visualizing and selecting between genetic association tests based on disease model parameters.

Findings

Phase boundaries are determined by the angle arctangent of allele frequency and disequilibrium differences.

Using both $ ext{delta}_p$ and $ ext{delta}_\e$ improves test selection accuracy.

Phase diagrams enhance understanding of test power and disease mode inference.

Abstract

Background: By a new concept called "phase diagram", we compare two commonly used genotype-based tests for case-control genetic analysis, one is a Cochran-Armitage trend test (CAT test at $x=0.5$, or CAT0.5) and another (called MAX2) is the maximization of two chi-square test results: one from the two-by-two genotype count table that combines the baseline homozygotes and heterozygotes, and another from the table that combines heterozygotes with risk homozygotes. CAT0.5 is more suitable for multiplicative disease models and MAX2 is better for dominant/recessive models. Methods: We define the CAT0.5-MAX2 phase diagram on the disease model space such that regions where MAX2 is more powerful than CAT0.5 are separated from regions where the CAT0.5 is more powerful, and the task is to choose the appropriate parameterization to make the separation possible. Results: We find that using the difference of allele frequencies ($\delta_p$) and the difference of Hardy-Weinberg disequilibrium coefficients ($\delta_\epsilon$) can separate the two phases well, and the phase boundaries are determined by the angle $tan^{-1}(\delta_p/\delta_\epsilon)$, which is an improvement over the disease model selection using $\delta_\epsilon$ only. Conclusions: We argue that phase diagrams similar to the one for CAT0.5-MAX2 have graphical appeals in understanding power performance of various tests, clarifying simulation schemes, summarizing case-control datasets, and guessing the possible mode of inheritance.