High Penetrance (β1 = 2)                         β2 = 0.7                       β2 = 1.6 Model Bias% SE RMSE Bias% SE RMSE Independent -33.80 0.080 0.348 -54.75 0.082 0.553 Frailty -4.99 0.097 0.136 -23.41 0.100 0.259 2-gene model -7.90 0.115 0.170 -14.22 0.110 0.198                                                        Low Penetrance (β1 = 1)                         β2 = 0.7                       β2 = 1.6 Model Bias% SE RMSE Bias% SE RMSE Independent -12.82 0.076 0.156 -24.36 0.070 0.254 Frailty -2.36 0.085 0.116 -13.48 0.078 0.163 2-gene model 0.44 0.099 0.133 -2.11 0.092 0.126 Bias% = Bias×100

Table 3: (Second gene variation) Estimating the log hazards ratio of major gene effect in the presence of a second gene: Bias, robust standard error (SE) and root mean square error (RMSE) in comparison of the three models.