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Reply to ‘DNA methylation haplotypes as cancer markers’

Nature Genetics volume 50, pages 1063–1066 (2018)Cite this article

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Diep and Zhang reply: We thank Greally and colleagues1 for pointing out a number of inaccuracies in our publication2 and the issue of potential overfitting, due to incomplete separation of test and training datasets. We have conducted a thorough internal audit and discovered that several components of the analysis indeed mixed training and test datasets and were therefore overfit to the published data. We acknowledge this as a major weakness of our published study. However, we would like to stress that our analysis based on methylation haplotype load and methylation haplotype blocks is reproducible and capable of deconvoluting heterogeneous tissue samples such as plasma DNA. To address the concern of overfitting, we performed an independent analysis of the data while carefully maintaining separation of training and test datasets. The results of this new analysis still support the three major conclusions of the publication2:

  1. 1.

    The haplotype-based metric methylation haplotype load (or MHL) is better able to identify tissue-specific differential methylation than the commonly used average methylation fraction (AMF) metric;

  2. 2.

    The tumor load of a plasma sample can be estimated using cancer tissue methylation markers;

  3. 3.

    The tissue of origin of a cancer plasma sample can be determined using tissue-specific methylation markers.

The haplotype-based metric methylation haplotype load (or MHL) is better able to identify tissue-specific differential methylation than the commonly used average methylation fraction (AMF) metric;

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Fig. 1: Marker discovery and validation workflow.

References

  1. Seoighe, C., Tosh, N. J. & Greally, J. M. Nat. Genet. https://doi.org/10.1038/s41588-018-0185-x (2018).

  2. Guo, S. et al. Nat. Genet. 49, 635–642 (2017).

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  3. Schultz, M. D. et al. Nature 523, 212–216 (2015).

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Author information

Authors and Affiliations

  1. Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA

    Dinh Diep & Kun Zhang

Authors
  1. Dinh Diep
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  2. Kun Zhang
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Contributions

D.D. and K.Z. performed all analyses and wrote the manuscript.

Corresponding author

Correspondence to Kun Zhang.

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Competing interests

D.D. and K.Z. were listed as co-inventors on patent applications related to this study. K.Z. is a co-founder and scientific advisor of Singlera Genomics.

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Diep, D., Zhang, K. Reply to ‘DNA methylation haplotypes as cancer markers’. Nat Genet 50, 1063–1066 (2018). https://doi.org/10.1038/s41588-018-0186-9

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