Modeling of Correlated Errors Across Reads

Foreign read detection (FRD) detects mismapped reads. FRD modifies the probability calculation to account for the possibility that a subset of the reads were mismapped. Instead of assuming that mapping errors occur independently per read, FRD estimates the probability that a burst of reads is mismapped, by incorporating such evidence as MAPQ and skewed AF.

Mapping errors typically occur in bursts, but treating mapping errors as independent error events per read can result in high confidence scores in spite of low MAPQ and/or skewed AF. One possible strategy to mitigate overestimation of confidence scores is to include a threshold on the minimum MAPQ used in the calculation. However, this strategy can discard evidence and result in false positives.

FRD extends the legacy genotyping algorithm by incorporating an additional hypothesis that reads in the pileup might be foreign reads (ie, their true location is elsewhere in the reference genome). The algorithm exploits multiple properties (skewed allele frequency and low MAPQ) and incorporates this evidence into the probability calculation.

Sensitivity is improved by rescuing FN, correcting genotypes, and enabling lowering of the MAPQ threshold for incoming reads into the variant caller. Specificity is improved by removing FP and correcting genotypes.

The base quality drop off (BQD) algorithm detects systematic and correlated base call errors caused by the sequencing system. BQD exploits certain properties of those errors (strand bias, position of the error in the read, base quality) to estimate the probability that the alleles are the result of a systematic error event rather than a true variant.

Bursts of errors that occur at a specific locus have distinct characteristics differentiating them from true variants. The base quality drop off (BQD) algorithm is a detection mechanism that exploits certain properties of those errors (strand bias, position of the error in the read, low mean base quality over said subset of reads at the locus of interest) and incorporates them into the probability calculation.