Training a Model for Estimating Leukocyte Composition using Whole-Blood DNA Methylation and Cell Counts as Reference

Abstract

Aim: Whole-blood DNA methylation depends on the underlying leukocyte composition and confounding hereby is a major concern in epigenome-wide association studies. Cell counts are often missing or may not be feasible. Computational approaches estimate leukocyte composition from DNA methylation based on reference datasets of purified leukocytes. We explored the possibility to train such a model on whole-blood DNA methylation and cell counts without the need for purification. Materials & methods: Using whole-blood DNA methylation and corresponding five-part cell counts from 2445 participants from the London Life Sciences Prospective Population Study, a model was trained on a subset of 175 subjects and evaluated on the remaining. Results: Correlations between cell counts and estimated cell proportions were high (neutrophils 0.85, eosinophils 0.88, basophils 0.02, lymphocytes 0.84, monocytes 0.55) and estimated proportions explained more variance in whole-blood DNA methylation levels than counts. Conclusion: Our model provided precise estimates for the common cell types.

Keywords::

• DNA methylation
• estimation of cell proportions
• Infinium 450K
• KAROLA
• leukocyte composition
• LOLIPOP
• white-blood cell distribution

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/full/10.2217/nnm-2016-0091

Acknowledgements

The authors thank the participants and research staff who made the study possible.

Financial & competing interests disclosure

The London Life Sciences Prospective Population study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), the National Institute for Health Research (RP-PG-0407-10371), EU FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The London Life Sciences Prospective Population study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), the National Institute for Health Research (RP-PG-0407-10371), EU FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.