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      Reliability of a novel approach for reference-based cell type estimation in human placental DNA methylation studies

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          Abstract

          The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we examine the performance of a newly available reference-based cell type estimation approach and compare it to an often-used reference-free cell type estimation approach, namely RefFreeEWAS, in placental genome-wide DNAm samples taken at birth and from chorionic villus biopsies early in pregnancy using three independent studies comprising over 1000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s00018-021-04091-3.

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          The sva package for removing batch effects and other unwanted variation in high-throughput experiments.

          Heterogeneity and latent variables are now widely recognized as major sources of bias and variability in high-throughput experiments. The most well-known source of latent variation in genomic experiments are batch effects-when samples are processed on different days, in different groups or by different people. However, there are also a large number of other variables that may have a major impact on high-throughput measurements. Here we describe the sva package for identifying, estimating and removing unwanted sources of variation in high-throughput experiments. The sva package supports surrogate variable estimation with the sva function, direct adjustment for known batch effects with the ComBat function and adjustment for batch and latent variables in prediction problems with the fsva function.
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            Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays.

            The recently released Infinium HumanMethylation450 array (the '450k' array) provides a high-throughput assay to quantify DNA methylation (DNAm) at ∼450 000 loci across a range of genomic features. Although less comprehensive than high-throughput sequencing-based techniques, this product is more cost-effective and promises to be the most widely used DNAm high-throughput measurement technology over the next several years. Here we describe a suite of computational tools that incorporate state-of-the-art statistical techniques for the analysis of DNAm data. The software is structured to easily adapt to future versions of the technology. We include methods for preprocessing, quality assessment and detection of differentially methylated regions from the kilobase to the megabase scale. We show how our software provides a powerful and flexible development platform for future methods. We also illustrate how our methods empower the technology to make discoveries previously thought to be possible only with sequencing-based methods. http://bioconductor.org/packages/release/bioc/html/minfi.html. khansen@jhsph.edu; rafa@jimmy.harvard.edu Supplementary data are available at Bioinformatics online.
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              Single-cell reconstruction of the early maternal–fetal interface in humans

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                Author and article information

                Contributors
                thorsten.braun@charite.de
                katri.raikkonen@helsinki.fi
                darina@psych.mpg.de
                Journal
                Cell Mol Life Sci
                Cell Mol Life Sci
                Cellular and Molecular Life Sciences
                Springer International Publishing (Cham )
                1420-682X
                1420-9071
                3 February 2022
                3 February 2022
                2022
                : 79
                : 2
                : 115
                Affiliations
                [1 ]GRID grid.419548.5, ISNI 0000 0000 9497 5095, Department of Translational Psychiatry, , Max Planck Institute of Psychiatry, ; Munich, Germany
                [2 ]GRID grid.4372.2, ISNI 0000 0001 2105 1091, International Max Planck Research School for Translational Psychiatry, ; Munich, Germany
                [3 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of Psychology and Logopedics, Faculty of Medicine, , University of Helsinki, ; Helsinki, Finland
                [4 ]GRID grid.14758.3f, ISNI 0000 0001 1013 0499, Finnish Institute for Health and Welfare, ; Helsinki, Finland
                [5 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Cardiovascular Science, Queen’s Medical Research Institute, , University of Edinburgh, ; Edinburgh, UK
                [6 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Institute for Molecular Medicine Finland, , HiLIFE, University of Helsinki, Human Genetics, ; Helsinki, Finland
                [7 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Medical and Clinical Genetics, , University of Helsinki and Helsinki University Hospital, ; Helsinki, Finland
                [8 ]GRID grid.412330.7, ISNI 0000 0004 0628 2985, Department of Obstetrics and Gynecology, Faculty of Medicine and Health Technology, Center for Child, Adolescent and Maternal Health, , Tampere University Hospital and University of Tampere, ; Tampere, Finland
                [9 ]GRID grid.15485.3d, ISNI 0000 0000 9950 5666, Children’s Hospital, , Helsinki University Hospital and University of Helsinki, ; Helsinki, Finland
                [10 ]GRID grid.416135.4, ISNI 0000 0004 0649 0805, Department of Child and Adolescent Psychiatry, , Erasmus MC, Sophia Children’s Hospital, ; Rotterdam, The Netherlands
                [11 ]GRID grid.15485.3d, ISNI 0000 0000 9950 5666, Department of Obstetrics and Gynecology, , Helsinki University Central Hospital, ; Helsinki, Finland
                [12 ]GRID grid.413727.4, ISNI 0000 0004 0422 4626, Hyvinkää Hospital, , Helsinki and Uusimaa Hospital District, ; Hyvinkää, Finland
                [13 ]GRID grid.7468.d, ISNI 0000 0001 2248 7639, Department of Experimental Obstetrics, , Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), ; Berlin, Germany
                [14 ]GRID grid.7468.d, ISNI 0000 0001 2248 7639, Department of Obstetrics, , Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), ; Berlin, Germany
                [15 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of General Practice, , University of Helsinki, ; Helsinki, Finland
                [16 ]GRID grid.428673.c, ISNI 0000 0004 0409 6302, Folkhälsan Research Center, ; Helsinki, Finland
                [17 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Department of Obstetrics and Gynaecology and Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, Singapore
                [18 ]GRID grid.185448.4, ISNI 0000 0004 0637 0221, Singapore Institute for Clinical Sciences, , Agency for Science, Technology and Research (A*STAR), ; Singapore, Singapore
                [19 ]GRID grid.412326.0, ISNI 0000 0004 4685 4917, Faculty of Medicine, PEDEGO Research Unit, MRC Oulu, , Oulu University Hospital and University of Oulu, ; Oulu, Finland
                [20 ]GRID grid.5947.f, ISNI 0000 0001 1516 2393, Department of Clinical and Molecular Medicine, , Norwegian University of Science and Technology, ; Trondheim, Norway
                [21 ]GRID grid.7468.d, ISNI 0000 0001 2248 7639, Institute of Medical Psychology, , Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), ; Berlin, Germany
                [22 ]GRID grid.266093.8, ISNI 0000 0001 0668 7243, Department of Pediatrics, Development, Health, and Disease Research Program, , University of California, ; Irvine, CA USA
                [23 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Department of Psychiatry and Behavioral Sciences, , Emory University School of Medicine, ; Atlanta, GA USA
                Author information
                http://orcid.org/0000-0002-1050-0098
                Article
                4091
                10.1007/s00018-021-04091-3
                8813756
                35113241
                61d1345f-b593-4a00-a93e-9caf53c6e2f0
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 August 2021
                : 24 November 2021
                : 13 December 2021
                Funding
                Funded by: Academy of Finland
                Award ID: 1284859
                Award ID: 12848591
                Award ID: 312670
                Award ID: 1324596
                Award ID: 311617
                Award ID: 269925
                Award ID: 1312670
                Award ID: 128789
                Award ID: 1287891
                Award Recipient :
                Funded by: Max Planck Institute of Psychiatry (2)
                Categories
                Original Article
                Custom metadata
                © Springer Nature Switzerland AG 2022

                Molecular biology
                cell type estimation,dna methylation,human placenta,chorionic villi,reference-based deconvolution,reference-free deconvolution

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