Adaptive testing of snp-brain functional connectivity association via a modular network analysis

Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journalConference articlepeer-review

1 Scopus citations

Abstract

Due to its high dimensionality and high noise levels, analysis of a large brain functional network may not be powerful and easy to interpret; instead, decomposition of a large network into smaller subcomponents called modules may be more promising as suggested by some empirical evidence. For example, alteration of brain modularity is observed in patients suffering from various types of brain malfunctions. Although several methods exist for estimating brain functional networks, such as the sample correlation matrix or graphical lasso for a sparse precision matrix, it is still difficult to extract modules from such network estimates. Motivated by these considerations, we adapt a weighted gene co-expression network analysis (WGCNA) framework to resting-state fMRI (rs-fMRI) data to identify modular structures in brain functional networks. Modular structures are identified by using topological overlap matrix (TOM) elements in hierarchical clustering. We propose applying a new adaptive test built on the proportional odds model (POM) that can be applied to a high-dimensional setting, where the number of variables (p) can exceed the sample size (n) in addition to the usual p < n setting. We applied our proposed methods to the ADNI data to test for associations between a genetic variant and either the whole brain functional network or its various subcomponents using various connectivity measures. We uncovered several modules based on the control cohort, and some of them were marginally associated with the APOE4 variant and several other SNPs; however, due to the small sample size of the ADNI data, larger studies are needed.

Original languageEnglish (US)
Pages (from-to)58-69
Number of pages12
JournalPacific Symposium on Biocomputing
Volume0
Issue number212679
DOIs
StatePublished - 2017
Event22nd Pacific Symposium on Biocomputing, PSB 2017 - Kohala Coast, United States
Duration: Jan 4 2017Jan 8 2017

Bibliographical note

Funding Information:
This research was supported by NIH grants R01GM113250, R01HL105397 and R01HL116720, and by the Minnesota Supercomputing Institute.

Funding Information:
Data collection and sharing for this project was funded by the Alzheimer’s Disease Neu-roimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research Development, LLC.; Johnson Johnson Pharmaceutical Research Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Pi-ramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514.

Keywords

  • Brain functional connectivity
  • Functional MRI
  • Proportional odds model
  • Single nucleotide polymorphism
  • WGCNA
  • Weighted gene co-expression network analysis
  • aSPU test

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