The LOD score is useful as a threshold for detection, as observed in the concordance of predicted sensitivity and measured sensitivity from the virtual tumor approach (Fig. 2a, solid grey vs. dashed line; Fig. 2b, solid lines vs. circles). Nonetheless, the LOD score cannot be immediately translated into the probability that a variant is due to true mutation rather than to sequencing error because the LOD score is calculated under an assumption of independent sequencing errors and accurate read placement. As we discuss below, these assumptions are incorrect and as a result, although direct application of the LOD score accurately estimates the sensitivity to detect a mutation, it substantially underestimates the false positive rate.
