Overview of the RAE workflow.
Input is a set of patients; tumor DNA, (un) matched non-tumor DNA, and an unrelated reference normal cohort. Tumor and non-tumor samples are quantified, normalized, and subject to quality control. In the assessment phase, individual samples are segmented and a multi-component model is parameterized for each; this produces a detector for single-copy gain, amplification, hemizygous loss, and homozygous deletion. Across all tumors, a unified breakpoint profile (UBP) is derived from the ensemble of segmentation breakpoints, and each region is scored for gain and loss. A background model of random aberrations is constructed with supplemental cleavage and permutation of genomic regions, and p-values are assigned and corrected for multiple hypothesis testing. In the output phase, RAE determines genomic boundaries for regions of interest (ROI), controls for germline and population copy-number variation, and reports statistically significant alterations.