Performance comparison of deletion detection in high and low coverage Illumina sequencing data from NA12878. We analyzed an approximately 50X coverage dataset of the NA12878 genome from the Illumina Platinum Genomes dataset. We tested LUMPY’s performance under four different variant calling scenarios. First, ‘LUMPY (pe + sr)’ considered both paired-end (pe) and split-read (sr) alignments (using YAHA) from NA12878. Second, ‘LUMPY with prior’ considered pe and sr alignments as well as 1000 Genomes variants as prior evidence. Third, ‘LUMPY trio’ considered pe and sr alignments for NA12878 as well as alignments from her parents (NA12891 and NA12892). Lastly, ‘LUMPY with CNVnator’ integrated pe and sr alignments with copy number loss predictions made by CNVnator (read depth (rd)). DELLY considered pe and sr alignments, GASVPro considered pe alignments and rd, and Pindel considered sr alignments. Sensitivity and FDR were estimated using two truth sets: 3,376 non-overlapping validated deletions from Mills et al. , and 4,095 deletions that were predicted by at least one tool and validated by PacBio or Moleculo alignments. (A) SV detection sensitivity and FDR on a 5X coverage subsample of the original data. LUMPY pe + sr was more sensitive than both GASVPro and Pindel and had either an equivalent or better FDR. DELLY was more sensitive than LUMPY pe + sr, but also had a higher FDR. Prior evidence or parental genomes improved LUMPY sensitivity. Given the low coverage, the read-depth signal was weak and only a small number of CNVs clustered with paired-end or split-read calls. (B) SV detection sensitivity and FDR on the original 50X coverage data. LUMPY pe + sr, DELLY, and Pindel had similar sensitivity in the Mills et al. truth set, and in the PacBio/Moleculo truth set DELLY had the highest sensitivity and FDR. LUMPY pe + sr had the next best sensitivity and the lowest FDR.