Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data
| العنوان: | Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data |
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| المؤلفون: | Kelly M. Bakulski, Michael S. Kobor, Janine F. Felix, John K. Wiencke, Brock C. Christensen, Lucas A. Salas, Robert Lyle, Devin C. Koestler, Kristina Gervin, Liesbeth Duijts, Henriëtte A. Moll, Karl T. Kelsey, Menno C. van Zelm, Meaghan J Jones |
| المساهمون: | University of Manitoba, Pediatrics, Epidemiology, Erasmus MC other |
| المصدر: | Clinical Epigenetics Clinical epigenetics, vol 11, iss 1 Clinical Epigenetics, 11(1):125. BioMed Central Ltd. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cell type heterogeneity, Computer science, Clinical Sciences, Gestational Age, Deconvolution, Computational biology, Reference dataset, Epigenesis, Genetic, Paediatrics and Reproductive Medicine, Databases, Umbilical cord blood, 03 medical and health sciences, 0302 clinical medicine, Genetic, Pregnancy, Databases, Genetic, Genetics, Humans, Leverage (statistics), Gene Regulatory Networks, Molecular Biology, Genetics (clinical), Selection (genetic algorithm), 030304 developmental biology, 0303 health sciences, pickCompProbes, Cell type composition, Human Genome, Confounding, Methodology, Computational Biology, dNaM, Filter (signal processing), DNA Methylation, Fetal Blood, DNAm, 030104 developmental biology, minfi, IDOL, 030220 oncology & carcinogenesis, DNA methylation, Female, Selection method, Algorithms, Epigenesis, Developmental Biology |
| الوصف: | BackgroundUmbilical cord blood (UCB) is commonly used in epigenome-wide association studies of prenatal exposures. Accounting for cell type composition is critical in such studies as it reduces confounding due to the cell specificity of DNA methylation (DNAm). In the absence of cell sorting information, statistical methods can be applied to deconvolve heterogeneous cell mixtures. Among these methods, reference-based approaches leverage age appropriate cell-specific DNA-methylation profiles to estimate cellular composition. In UCB, four reference datasets comprising DNAm signatures profiled in purified cell populations have been published using the Illumina 450K and 850K EPIC arrays. These datasets are biologically and technically different, and currently there is no consensus on how to best apply them. Here, we systematically evaluate and compare these datasets and provide recommendations for reference-based UCB deconvolution.ResultsWe first evaluated the four reference datasets to ascertain both the purity of the samples and the potential cell cross-contamination. We filtered samples and combined datasets to obtain a joint UCB reference. We selected deconvolution libraries using two different approaches: automatic selection using the top differentially methylated probes from the functionpickCompProbesin minfi and a standardized library selected using the IDOL (Identifying Optimal Libraries) iterative algorithm. We compared the performance of each reference separately and in combination, using the two approaches for reference library selection, and validated the results in an independent cohort (Generation R Study, n=191) with matched FACS measured cell counts. Strict filtering and combination of the references significantly improved the accuracy and efficiency of cell type estimates. Ultimately, the IDOL library outperformed the library from the automatic selection method implemented inpickCompProbes.ConclusionThese results have important implications for epigenetic studies in UCB as implementing this method will optimally reduce confounding due to cellular heterogeneity. This work provides guidelines for future reference-based UCB deconvolution and establishes a framework for combining reference datasets in other tissues. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1868-7083 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7a76bd27ecf794d73d604aea6600161fTest http://hdl.handle.net/10852/69848Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7a76bd27ecf794d73d604aea6600161f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18687083 |
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