Correlation-Adjusted Simultaneous Testing for Ultra High-dimensional Grouped Data

TL;DR

This paper introduces a novel correlation-adjusted testing procedure for high-dimensional grouped data, improving false discovery control and power in identifying differentially methylated probes in epigenetics research.

Contribution

The paper develops the CAST method that accounts for dependence among probes, providing more accurate FDR control and increased power over existing methods.

Findings

CAST outperforms benchmark methods in simulations.

CAST maintains FDR control across various group sizes.

Applied to bladder cancer data, CAST identifies both known and novel DMPs.

Abstract

Epigenetics plays a crucial role in understanding the underlying molecular processes of several types of cancer as well as the determination of innovative therapeutic tools. To investigate the complex interplay between genetics and environment, we develop a novel procedure to identify differentially methylated probes (DMPs) among cases and controls. Statistically, this translates to an ultra high-dimensional testing problem with sparse signals and an inherent grouping structure. When the total number of variables being tested is massive and typically exhibits some degree of dependence, existing group-wise multiple comparisons adjustment methods lead to inflated false discoveries. We propose a class of Correlation-Adjusted Simultaneous Testing (CAST) procedures incorporating the general dependence among probes within and between genes to control the false discovery rate (FDR). Simulations demonstrate that CASTs have superior empirical power while maintaining the FDR compared to the benchmark group-wise. Moreover, while the benchmark fails to control FDR for small-sized grouped correlated data, CAST exhibits robustness in controlling FDR across varying group sizes. In bladder cancer data, the proposed CAST method confirms some existing differentially methylated probes implicated with the disease (Langevin, et. al., 2014). However, CAST was able to detect novel DMPs that the previous study (Langevin, et. al., 2014) failed to identify. The CAST method can accurately identify significant potential biomarkers and facilitates informed decision-making aligned with precision medicine in the context of complex data analysis.