title: Blood-based profiles of DNA methylation predict the underlying distribution of cell types: a validation analysis.
abstract: The potential influence of underlying differences in relative leukocyte distributions in studies involving blood-based profiling of DNA methylation is well recognized and has prompted development of a set of statistical methods for inferring changes in the distribution of white blood cells using DNA methylation signatures. However, the extent to which this methodology can accurately predict cell-type proportions based on blood-derived DNA methylation data in a large-scale epigenome-wide association study (EWAS) has yet to be examined. We used publicly available data deposited in the Gene Expression Omnibus (GEO) database (accession number GSE37008), which consisted of both blood-derived epigenome-wide DNA methylation data assayed using the Illumina Infinium HumanMethylation27 BeadArray and complete blood cell (CBC) counts among a community cohort of 94 non-diseased individuals. Constrained projection (CP) was used to obtain predictions of the proportions of lymphocytes, monocytes and granulocytes for each of the study samples based on their DNA methylation signatures. Our findings demonstrated high consistency between the average CBC-derived and predicted percentage of monocytes and lymphocytes (17.9% and 17.6% for monocytes and 82.1% and 81.4% for lymphocytes), with root mean squared error (rMSE) of 5% and 6%, for monocytes and lymphocytes, respectively. Similarly, there was moderate-high correlation between the CP-predicted and CBC-derived percentages of monocytes and lymphocytes (0.60 and 0.61, respectively), and these results were robust to the number of leukocyte differentially methylated regions (L-DMRs) used for CP prediction. These results serve as further validation of the CP approach and highlight the promise of this technique for EWAS where DNA methylation is profiled using whole-blood genomic DNA.
authors.affiliation: Department of Community and Family Medicine; Geisel School of Medicine at Dartmouth College; Lebanon, NH USA.
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.forename: Brock
authors.initials: B
authors.lastname: Christensen
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Scott M
authors.initials: SM
authors.lastname: Langevin
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
mesh_terms: D001772:Blood Cell Count; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism
keywords: DNA methylation; cell mixture analysis; leukocytes; mixture deconvolution; whole-blood
references.citation: J Clin Oncol. 2011 Mar 20;29(9):1133-9
references.pmid: 21343564
references.citation: Adv Exp Med Biol. 2013;754:233-52
references.pmid: 22956505
references.citation: PLoS One. 2012;7(7):e41361
references.pmid: 22848472
references.citation: PLoS One. 2012;7(10):e46705
references.pmid: 23071618
references.citation: PLoS One. 2009 Dec 18;4(12):e8274
references.pmid: 20019873
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14716-21
references.pmid: 19617551
references.citation: Nature. 2010 Sep 16;467(7313):338-42
references.pmid: 20720541
references.citation: Environ Health Perspect. 2013 Aug;121(8):971-7
references.pmid: 23757598
references.citation: Thorax. 2009 May;64(5):374-80
references.pmid: 19131450
references.citation: J Thorac Oncol. 2010 Jun;5(6):778-85
references.pmid: 20421821
references.citation: Int J Dermatol. 2011 Jun;50(6):697-704
references.pmid: 21595664
references.citation: BMC Bioinformatics. 2012 May 08;13:86
references.pmid: 22568884
references.citation: Epidemiology. 2010 Nov;21(6):819-28
references.pmid: 20805753
references.citation: Am J Hum Genet. 2008 Mar;82(3):696-711
references.pmid: 18319075
references.citation: Biostatistics. 2007 Jan;8(1):118-27
references.pmid: 16632515
references.citation: Nat Rev Genet. 2010 Mar;11(3):191-203
references.pmid: 20125086
references.citation: Environ Health Perspect. 2012 Oct;120(10):1425-31
references.pmid: 22851337
references.citation: PLoS Genet. 2009 Aug;5(8):e1000602
references.pmid: 19680444
references.citation: Cancer Res. 2009 Jan 15;69(2):599-608
references.pmid: 19147574
references.citation: World J Gastrointest Oncol. 2012 Jun 15;4(6):138-44
references.pmid: 22737275
references.citation: Chemosphere. 2013 Apr;91(4):475-80
references.pmid: 23305747
references.citation: Diabetes Care. 2005 Jul;28(7):1710-7
references.pmid: 15983324
references.citation: Epigenetics. 2011 Feb;6(2):236-46
references.pmid: 20962591
references.citation: Blood. 2011 May 12;117(19):e182-9
references.pmid: 21427290
references.citation: J Trauma. 2010 Apr;68(4):843-52
references.pmid: 19996805
references.citation: BMC Med Genomics. 2011 Dec 16;4:84
references.pmid: 22171553
references.citation: Bioinformatics. 2011 Jun 1;27(11):1496-505
references.pmid: 21471010
references.citation: PLoS One. 2011 Mar 24;6(3):e18223
references.pmid: 21455317
references.citation: Chest. 2001 Jan;119(1):105-14
references.pmid: 11157591
references.citation: Genome Res. 2008 Sep;18(9):1518-29
references.pmid: 18577705
references.citation: PLoS One. 2012;7(6):e39220
references.pmid: 22745719
references.citation: PLoS Genet. 2007 Sep;3(9):1724-35
references.pmid: 17907809
references.citation: Epigenetics. 2012 Mar;7(3):291-9
references.pmid: 22430805
references.citation: Nat Biotechnol. 2013 Feb;31(2):142-7
references.pmid: 23334450
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 16;109 Suppl 2:17253-60
references.pmid: 23045638
references.citation: Cancer Epidemiol Biomarkers Prev. 2012 Aug;21(8):1293-302
references.pmid: 22714737
references.citation: PLoS One. 2010 Mar 15;5(3):e9692
references.pmid: 20300621
references.citation: Epigenetics. 2006 Jan-Mar;1(1):55-60
references.pmid: 17998806
references.citation: Environ Health. 2010 Aug 09;9:48
references.pmid: 20696069