Accounting for unobserved covariates with varying degrees of estimability in high-dimensional biological data

DOI10.1093/BIOMET/ASZ037zbMATH Open1435.62396arXiv1801.00865OpenAlexW2973427420WikidataQ91386939 ScholiaQ91386939MaRDI QIDQ5212908FDOQ5212908

Authors: Chris McKennan, Dan L. Nicolae 

Publication date: 30 January 2020

Published in: Biometrika (Search for Journal in Brave)

Abstract: An important phenomenon in high dimensional biological data is the presence of unobserved covariates that can have a significant impact on the measured response. When these factors are also correlated with the covariate(s) of interest (i.e. disease status), ignoring them can lead to increased type I error and spurious false discovery rate estimates. We show that depending on the strength of this correlation and the informativeness of the observed data for the latent factors, previously proposed estimators for the effect of the covariate of interest that attempt to account for unobserved covariates are asymptotically biased, which corroborates previous practitioners' observations that these estimators tend to produce inflated test statistics. We then provide an estimator that corrects the bias and prove it has the same asymptotic distribution as the ordinary least squares estimator when every covariate is observed. Lastly, we use previously published DNA methylation data to show our method can more accurately estimate the direct effect of asthma on methylation than previously published methods, which underestimate the correlation between asthma and latent cell type heterogeneity. Our re-analysis shows that the majority of the variability in methylation due to asthma in those data is actually mediated through cell composition.

Full work available at URL: https://arxiv.org/abs/1801.00865

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zbMATH Keywords

unwanted variationconfoundingunobserved covariatesbatch effectcell-type heterogeneityhigh-dimensional factor analysis

Mathematics Subject Classification ID

Factor analysis and principal components; correspondence analysis (62H25) Applications of statistics to biology and medical sciences; meta analysis (62P10) Statistical aspects of big data and data science (62R07) Protein sequences, DNA sequences (92D20)

Cited In (6)

• Adaptive estimation in multivariate response regression with hidden variables
• Exploring causal mechanisms and quantifying direct and indirect effects using a joint modeling approach for recurrent and terminal events
• Inference in High-Dimensional Multivariate Response Regression with Hidden Variables
• Unifying and generalizing methods for removing unwanted variation based on negative controls
• Estimating and Accounting for Unobserved Covariates in High-Dimensional Correlated Data
• Estimation and inference in metabolomics with nonrandom missing data and latent factors

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