Abstract Duplex sequencing enables highly accurate detection of rare somatic mutations, but existing variant callers often rely on protocol-specific heuristics that limit sensitivity, reproducibility, and cross-study comparability. We present DupCaller, a probabilistic variant caller that builds sample-specific error profiles and applies a strand-aware statistical model for mutation detection. Across 50 synthetic datasets, DupCaller identified 1. 25-fold more single-base substitutions (SBSs) and 1. 41-fold more indels than a state-of-the-art method, while exhibiting equal or better precision. In three duplex-sequenced cell lines treated with aristolochic acid, it recovered expected mutational signatures while detecting 3. 5-fold more SBSs and 2. 8-fold more indels. In 93 tissue samples—including neurons, cord blood, sperm, saliva, and blood—DupCaller showed consistent gains, detecting 1. 21- to 2. 7-fold more mutations. Sensitivity scaled with sample duplication rate, yielding approximately 1. 5-fold more mutations under optimal conditions and over 3-fold more in low-duplication samples where other tools falter. These results establish DupCaller as a robust and scalable solution for somatic mutation profiling in duplex sequencing across diverse biological and technical contexts. Citation Format: Yuhe Cheng, Shuvro P. Nandi, Luka Culibrk, Audrey Kristin, Isabella Stuewe, Shams Al-Azzam, Mia Petljak, Ludmil B. Alexandrov. Improved mutation detection in duplex sequencing data with sample-specific error profiles abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB446.
Cheng et al. (Fri,) studied this question.