title: A systematic evaluation of high-dimensional, ensemble-based regression for exploring large model spaces in microbiome analyses.
abstract: BACKGROUND
  Microbiome studies incorporate next-generation sequencing to obtain profiles of microbial communities. Data generated from these experiments are high-dimensional with a rich correlation structure but modest sample sizes. A statistical model that utilizes these microbiome profiles to explain a clinical or biological endpoint needs to tackle high-dimensionality resulting from the very large space of variable configurations. Ensemble models are a class of approaches that can address high-dimensionality by aggregating information across large model spaces. Although such models are popular in fields as diverse as economics and genetics, their performance on microbiome data has been largely unexplored.
  
  
  RESULTS
  We developed a simulation framework that accurately captures the constraints of experimental microbiome data. Using this setup, we systematically evaluated a selection of both frequentist and Bayesian regression modeling ensembles. These are represented by variants of stability selection in conjunction with elastic net and spike-and-slab Bayesian model averaging (BMA), respectively. BMA ensembles that explore a larger space of models relative to stability selection variants performed better and had lower variability across simulations. However, stability selection ensembles were able to match the performance of BMA in scenarios of low sparsity where several variables had large regression coefficients.
  
  
  CONCLUSIONS
  Given a microbiome dataset of interest, we present a methodology to generate simulated data that closely mimics its characteristics in a manner that enables meaningful evaluation of analytical strategies. Our evaluation demonstrates that the largest ensembles yield the strongest performance on microbiome data with modest sample sizes and high-dimensional measurements. We also demonstrate the ability of these ensembles to identify microbiome signatures that are associated with opportunistic Candida albicans colonization during antibiotic exposure. As the focus of microbiome research evolves from pilot to translational studies, we anticipate that our strategy will aid investigators in making evaluation-based decisions for selecting appropriate analytical methods.
authors: J. Craig Venter Institute, 9704, Medical Center Drive, Rockville, Maryland, 20850, US. jyoti.shankar@gmail.com.
authors: Jyoti
authors: J
authors: Shankar
authors: J. Craig Venter Institute, 9704, Medical Center Drive, Rockville, Maryland, 20850, US. shpakoo@gmail.com.
authors: Sebastian
authors: S
authors: Szpakowski
authors: Los Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, 1124 West Carson Street, Torrance, California, 90509, US. nsolis@labiomed.org.
authors: Norma V
authors: NV
authors: Solis
authors: J. Craig Venter Institute, 9704, Medical Center Drive, Rockville, Maryland, 20850, US. smounaud@jcvi.org.
authors: Stephanie
authors: S
authors: Mounaud
authors: Los Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, 1124 West Carson Street, Torrance, California, 90509, US. hliu@labiomed.org.
authors: Hong
authors: H
authors: Liu
authors: J. Craig Venter Institute, 9704, Medical Center Drive, Rockville, Maryland, 20850, US. llosada@jcvi.org.
authors: Liliana
authors: L
authors: Losada
authors: J. Craig Venter Institute, 9704, Medical Center Drive, Rockville, Maryland, 20850, US. wnierman@jcvi.org.
authors: William C
authors: WC
authors: Nierman
authors: Los Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, 1124 West Carson Street, Torrance, California, 90509, US. sfiller@ucla.edu.|David Geffen School of Medicine, University of California at Los Angeles, California, 90095, US. sfiller@ucla.edu.
authors: Scott G
authors: SG
authors: Filler
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001499:Bayes Theorem; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology*; D003198:Computer Simulation; D064307:Microbiota; D015233:Models, Statistical; D012107:Research Design
chemical_list: D000900:Anti-Bacterial Agents
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