A Linear Mixed Model Spline Framework for Analysing Time Course 'Omics' Data

PLoS One. 2015 Aug 27;10(8):e0134540. doi: 10.1371/journal.pone.0134540. eCollection 2015.

Abstract

Time course 'omics' experiments are becoming increasingly important to study system-wide dynamic regulation. Despite their high information content, analysis remains challenging. 'Omics' technologies capture quantitative measurements on tens of thousands of molecules. Therefore, in a time course 'omics' experiment molecules are measured for multiple subjects over multiple time points. This results in a large, high-dimensional dataset, which requires computationally efficient approaches for statistical analysis. Moreover, methods need to be able to handle missing values and various levels of noise. We present a novel, robust and powerful framework to analyze time course 'omics' data that consists of three stages: quality assessment and filtering, profile modelling, and analysis. The first step consists of removing molecules for which expression or abundance is highly variable over time. The second step models each molecular expression profile in a linear mixed model framework which takes into account subject-specific variability. The best model is selected through a serial model selection approach and results in dimension reduction of the time course data. The final step includes two types of analysis of the modelled trajectories, namely, clustering analysis to identify groups of correlated profiles over time, and differential expression analysis to identify profiles which differ over time and/or between treatment groups. Through simulation studies we demonstrate the high sensitivity and specificity of our approach for differential expression analysis. We then illustrate how our framework can bring novel insights on two time course 'omics' studies in breast cancer and kidney rejection. The methods are publicly available, implemented in the R CRAN package lmms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts / immunology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Biomarkers / blood
  • Bone Marrow / drug effects
  • Breast Neoplasms / genetics
  • Cluster Analysis
  • Computer Simulation
  • Data Interpretation, Statistical
  • Female
  • Gene Expression Regulation, Fungal
  • Gene Expression Regulation, Neoplastic
  • Genomics / methods*
  • Graft Rejection / blood
  • Humans
  • Kidney Transplantation
  • Linear Models
  • MCF-7 Cells
  • Mice
  • Proteins / metabolism
  • Proteomics / methods*
  • Saccharomyces / genetics

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Proteins

Associated data

  • GEO/GSE27440
  • GEO/GSE36253

Grants and funding

This work was supported by the Wound Management Innovation established and supported under the Australian Government’s Cooperative Research Centres Program to JS; the Australian Cancer Research Foundation for the Diamantina Individualised Oncology Care Centre at The University of Queensland Diamantina Institute to KALC; and the Australian Research Council Discovery Early Career Researcher Award (project number DE120101127) to EH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.