Method Designed to Respect Molecular Heterogeneity Can Profoundly Correct Present Data Interpretations for Genome-Wide Expression Analysis

Chih-Hao Chen, Chueh-Lin Hsu, Shih-Hao Huang, Shih-Yuan Chen, Yi-Lin Hung, Hsiao-Rong Chen, Yu-Chung Wu, Li-Jen Su and Lee Hc

PLOS ONE, 2015, vol. 10, issue 3, 1-16

Abstract: Although genome-wide expression analysis has become a routine tool for gaining insight into molecular mechanisms, extraction of information remains a major challenge. It has been unclear why standard statistical methods, such as the t-test and ANOVA, often lead to low levels of reproducibility, how likely applying fold-change cutoffs to enhance reproducibility is to miss key signals, and how adversely using such methods has affected data interpretations. We broadly examined expression data to investigate the reproducibility problem and discovered that molecular heterogeneity, a biological property of genetically different samples, has been improperly handled by the statistical methods. Here we give a mathematical description of the discovery and report the development of a statistical method, named HTA, for better handling molecular heterogeneity. We broadly demonstrate the improved sensitivity and specificity of HTA over the conventional methods and show that using fold-change cutoffs has lost much information. We illustrate the especial usefulness of HTA for heterogeneous diseases, by applying it to existing data sets of schizophrenia, bipolar disorder and Parkinson’s disease, and show it can abundantly and reproducibly uncover disease signatures not previously detectable. Based on 156 biological data sets, we estimate that the methodological issue has affected over 96% of expression studies and that HTA can profoundly correct 86% of the affected data interpretations. The methodological advancement can better facilitate systems understandings of biological processes, render biological inferences that are more reliable than they have hitherto been and engender translational medical applications, such as identifying diagnostic biomarkers and drug prediction, which are more robust.

Date: 2015
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121154 (text/html)
https://journals.plos.org/plosone/article/file?id= ... 21154&type=printable (application/pdf)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0121154

DOI: 10.1371/journal.pone.0121154

Access Statistics for this article

More articles in PLOS ONE from Public Library of Science
Bibliographic data for series maintained by plosone ().