Despite the negative predictions, haplotype-based computational genetic mapping (HBCGM) studies have identified causative genetic factors for many biomedical traits in mice (Table 1). HBCGM results have generated potential new solutions for 21st century public health problems, including treatments for prevention of narcotic drug withdrawal symptoms [4] and for reduction of incisional pain after surgery [5, 6] that are in clinical testing. In an HBCGM experiment, a property of interest is measured in 10 or more inbred mouse strains; genetic factors are then computationally predicted by identifying genomic regions where the pattern of genetic variation (in the form of pre-assembled haplotype blocks) correlates with the distribution of trait values among the inbred strains [7, 8]. The productivity of HBCGM requires explanation, since HBCGM is a type of murine GWAS, which the published simulations and analyses indicate should fail. The reason for the discrepancy between the negative predictions from the modeling studies and the actual HBCGM results is that the modeling studies utilize standard GWAS methodology, but there are very substantial methodological differences between HBCGM and standard methods used in GWAS in
