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Considering these figures, we can postulate that in our cohort the effect of the family history criterion might be somewhat underestimated.
In our research cohort, the percentage of BRCA1/2 mutation carriers under patients who fulfilled the family history criterion and/or the bilateral/multiple breast cancer criterion was 13.7% (Supplementary Table 3A).
Instead, the hierarchy is intended as an organizational tool allowing clear identification of DUs based on four key generalizable concepts: reproductive isolation (criterion 1), phylogeographic history (criterion 2), local adaptation (criterion 3) and significant biogeographic separation (criterion 4).
A sensitivity analysis was performed by making the family history criterion less specific: all breast cancer cases with at least one family member with breast cancer at the time of diagnosis were taken into account instead of only cases with more than two relatives with breast and/or other cancer (at least one must have had breast cancer).
In the sensitivity analyses in which the family history criterion was made less stringent, that is, all women with at least one relative with breast cancer were considered to fulfill the criterion, overall the results did not change and confirmed the original results, although the effects found were less pronounced (Supplementary Tables 3B and 4).
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This becomes evident in comparing the predictive performance of our models in the invaded range computed with a random selection of variables and a model derived from natural history criteria (Figure 5A, B).
The AUC value of our model for invasive records derived from natural history criteria was higher than all AUC values obtained from random variable selection confirming a better prediction ability (AUC ranges seven random variables: native: 0.987 0.994, invasive: 0.587 0.847, AUC ranges five random variables: native: 0.977 0.994, invasive: 0.569 0.855; AUC data set 'natural history' = 0.861).
This latitudinal decrease in predictive performance was confirmed when testing the models using only invasive records between 26° N and S as test points (N = 62; Figure 6D, E; AUC range seven random variables: 0.356 0.708; AUC range five random variables: 0.279 0.749), whereas our model derived from natural history criteria performed well here (Figure 6C, AUC = 0.795).
Møller et al (2007) reported that family history criteria detect <50% of the BRCA mutation carriers.
These findings indicate that the high-risk clinical history criteria were effective in identifying patients with higher mutation probabilities.
30 This very small subpopulation can be identified from the very large general population on the basis of family history criteria and genetic testing.
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