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MLML2R: an R package for maximum likelihood estimation of DNA methylation and hydroxymethylation proportions

Samara F. Kiihlhttp://orcid.org/https://orcid.org/0000-0002-8484-8556 1 , Maria Jose Martinez-Garrido 2 , Arce Domingo-Relloso 2 , Jose Bermudez 2 ,  and Maria Tellez-Plaza 3
  • 1 Department of Statistics, State University of Campinas, Campinas, Sao Paulo 13083-859, Brazil
  • 2 University of Valencia, Department of Statistics and Operations Research, Valencia 46100, Spain
  • 3 Institute for Biomedical Research Hospital Clinic of Valencia, Valencia 46010, Spain
Samara F. KiihlORCID iD: https://orcid.org/0000-0002-8484-8556, Maria Jose Martinez-Garrido
  • University of Valencia, Department of Statistics and Operations Research, Valencia 46100, Spain
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, Arce Domingo-Relloso
  • University of Valencia, Department of Statistics and Operations Research, Valencia 46100, Spain
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, Jose Bermudez
  • University of Valencia, Department of Statistics and Operations Research, Valencia 46100, Spain
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and Maria Tellez-Plaza
  • Institute for Biomedical Research Hospital Clinic of Valencia, Valencia 46010, Spain
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Abstract

Accurately measuring epigenetic marks such as 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) at the single-nucleotide level, requires combining data from DNA processing methods including traditional (BS), oxidative (oxBS) or Tet-Assisted (TAB) bisulfite conversion. We introduce the R package MLML2R, which provides maximum likelihood estimates (MLE) of 5-mC and 5-hmC proportions. While all other available R packages provide 5-mC and 5-hmC MLEs only for the oxBS+BS combination, MLML2R also provides MLE for TAB combinations. For combinations of any two of the methods, we derived the pool-adjacent-violators algorithm (PAVA) exact constrained MLE in analytical form. For the three methods combination, we implemented both the iterative method by Qu et al. [Qu, J., M. Zhou, Q. Song, E. E. Hong and A. D. Smith (2013): “Mlml: consistent simultaneous estimates of dna methylation and hydroxymethylation,” Bioinformatics, 29, 2645–2646.], and also a novel non iterative approximation using Lagrange multipliers. The newly proposed non iterative solutions greatly decrease computational time, common bottlenecks when processing high-throughput data. The MLML2R package is flexible as it takes as input both, preprocessed intensities from Infinium Methylation arrays and counts from Next Generation Sequencing technologies. The MLML2R package is freely available at https://CRAN.R-project.org/package=MLML2R.

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SAGMB publishes significant research on the application of statistical ideas to problems arising from computational biology. The range of topics includes linkage mapping, association studies, gene finding and sequence alignment, protein structure prediction, design and analysis of microarrary data, molecular evolution and phylogenetic trees, DNA topology, and data base search strategies.

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