StratoMod: Predicting Sequencing and Variant Calling Errors With Interpretable Machine Learning

Authors

Nathan Dwarshuis
Peter Tonner
Nathan D Olson
Fritz J Sedlazeck
Justin Wagner
Justin M Zook

Publication Date

10-13-2024

Journal

Communications Biology

DOI

10.1038/s42003-024-06981-1

PMID

39397114

PMCID

PMC11471861

PubMedCentral® Posted Date

10-13-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Machine Learning, Humans, Genome, Human, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Software, Genomics, Genetic Variation, Computational models, Genomics

Abstract

Despite the variety in sequencing platforms, mappers, and variant callers, no single pipeline is optimal across the entire human genome. Therefore, developers, clinicians, and researchers need to make tradeoffs when designing pipelines for their application. Currently, assessing such tradeoffs relies on intuition about how a certain pipeline will perform in a given genomic context. We present StratoMod, which addresses this problem using an interpretable machine-learning classifier to predict germline variant calling errors in a data-driven manner. We show StratoMod can precisely predict recall using Hifi or Illumina and leverage StratoMod's interpretability to measure contributions from difficult-to-map and homopolymer regions for each respective outcome. Furthermore, we use Statomod to assess the effect of mismapping on predicted recall using linear vs. graph-based references, and identify the hard-to-map regions where graph-based methods excelled and by how much. For these we utilize our draft benchmark based on the Q100 HG002 assembly, which contains previously-inaccessible difficult regions. Furthermore, StratoMod presents a new method of predicting clinically relevant variants likely to be missed, which is an improvement over current pipelines which only filter variants likely to be false. We anticipate this being useful for performing precise risk-reward analyses when designing variant calling pipelines.

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