Fast and robust adjustment of cell mixtures in epigenome-wide association studies with SmartSVA

Jun Chen, Ehsan Behnam, Jinyan Huang, Miriam F. Moffatt, Daniel J. Schaid, Liming Liang, Xihong Lin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Background: One problem that plagues epigenome-wide association studies is the potential confounding due to cell mixtures when purified target cells are not available. Reference-free adjustment of cell mixtures has become increasingly popular due to its flexibility and simplicity. However, existing methods are still not optimal: increased false positive rates and reduced statistical power have been observed in many scenarios. Methods: We develop SmartSVA, an optimized surrogate variable analysis (SVA) method, for fast and robust reference-free adjustment of cell mixtures. SmartSVA corrects the limitation of traditional SVA under highly confounded scenarios by imposing an explicit convergence criterion and improves the computational efficiency for large datasets. Results: Compared to traditional SVA, SmartSVA achieves an order-of-magnitude speedup and better false positive control. It protects the signals when capturing the cell mixtures, resulting in significant power increase while controlling for false positives. Through extensive simulations and real data applications, we demonstrate a better performance of SmartSVA than the existing methods. Conclusions: SmartSVA is a fast and robust method for reference-free adjustment of cell mixtures for epigenome-wide association studies. As a general method, SmartSVA can be applied to other genomic studies to capture unknown sources of variability.

Original languageEnglish (US)
Article number413
JournalBMC genomics
Issue number1
StatePublished - May 26 2017


  • Cell mixture
  • DNA methylation
  • Epigenome-wide association
  • Surrogate variable analysis

ASJC Scopus subject areas

  • Biotechnology
  • Genetics


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