Variance Components Genetic Association Test for Zero-inflated Count Outcomes

TL;DR

This paper introduces a new variance components score test for detecting genetic associations with zero-inflated count outcomes, common in biomedical studies, demonstrating improved power over existing methods especially with correlated markers.

Contribution

The paper presents a novel statistical test tailored for zero-inflated count data, extending SNP-set testing frameworks like SKAT to handle mixture distributions with structural zeros.

Findings

The method shows superior power compared to existing tests.

Application to Alzheimer's data reveals significant associations with APOE.

The test effectively detects associations with both zero-inflation and count parameters.

Abstract

Commonly in biomedical research, studies collect data in which an outcome measure contains informative excess zeros; for example when observing the burden of neuritic plaques in brain pathology studies, those who show none contribute to our understanding of neurodegenerative disease. The outcome may be characterized by a mixture distribution with one component being the `structural zero' and the other component being a Poisson distribution. We propose a novel variance components score test of genetic association between a set of genetic markers and a zero-inflated count outcome from a mixture distribution. This test shares advantageous properties with SNP-set tests which have been previously devised for standard continuous or binary outcomes, such as the Sequence Kernel Association Test (SKAT). In particular, our method has superior statistical power compared to competing methods, especially when there is correlation within the group of markers, and when the SNPs are associated with both the mixing proportion and the rate of the Poisson distribution. We apply the method to Alzheimer's data from the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP), where as proof of principle we find highly significant associations with the APOE gene, in both the `structural zero' and `count' parameters, when applied to a zero-inflated neuritic plaques count outcome.