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Journal of Statistical Physics

, Volume 172, Issue 1, pp 143–155 | Cite as

On Statistical Modeling of Sequencing Noise in High Depth Data to Assess Tumor Evolution

  • Raul Rabadan
  • Gyan Bhanot
  • Sonia Marsilio
  • Nicholas Chiorazzi
  • Laura Pasqualucci
  • Hossein Khiabanian
Article

Abstract

One cause of cancer mortality is tumor evolution to therapy-resistant disease. First line therapy often targets the dominant clone, and drug resistance can emerge from preexisting clones that gain fitness through therapy-induced natural selection. Such mutations may be identified using targeted sequencing assays by analysis of noise in high-depth data. Here, we develop a comprehensive, unbiased model for sequencing error background. We find that noise in sufficiently deep DNA sequencing data can be approximated by aggregating negative binomial distributions. Mutations with frequencies above noise may have prognostic value. We evaluate our model with simulated exponentially expanded populations as well as data from cell line and patient sample dilution experiments, demonstrating its utility in prognosticating tumor progression. Our results may have the potential to identify significant mutations that can cause recurrence. These results are relevant in the pretreatment clinical setting to determine appropriate therapy and prepare for potential recurrence pretreatment.

Keywords

87.23.Kg 87.18.Tt 87.18.Wd 87.18.Vf 02.50.-r 

Notes

Acknowledgements

The authors gratefully acknowledge the constructive feedback of Mohammad Hadigol and Alexandra Jacunski. R.R. acknowledges funding from the NIH (U54CA193313, R01CA185486, and R01CA179044). H.K. acknowledges support from the ACS (IRG-15-168-01), Rutgers Cancer Institute (P30CA072720), and Rutgers Office of Advanced Research Computing (NIH 1S10OD012346-01A1).

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Authors and Affiliations

  1. 1.Department of Systems BiologyColumbia UniversityNew YorkUSA
  2. 2.Department of Physics and AstronomyRutgers UniversityPiscatawayUSA
  3. 3.The Feinstein Institute for Medical Research, Northwell HealthManhassetUSA
  4. 4.Institute for Cancer GeneticsColumbia UniversityNew YorkUSA
  5. 5.Rutgers Cancer Institute of New JerseyRutgers UniversityNew BrunswickUSA

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