One limitation is that, as we stated in The Extended Fixed Attribute Dynamics Method section and expressed mathematically in Formulas A4 and A5 in the Appendix 1, both the FAD method employed in this article to produce the estimates of Tables 1-3 and the conventional case-control statistical genetic approach assume that (a) the initial distributions of the genetic variant and (b) their association with longevity do not differ substantially between cohorts of long-lived individuals and younger controls. However, although restricting our analysis to a single ethnic group (Han Chinese) residing in Southern China and classifying the samples by gender as well may reduce and hopefully minimize the bias, we are aware that there may still be bias because of potential violation of the assumptions (a) and (b); and we do not know to what degree these assumptions may be violated in the real world. This implies that the results of the OR of survival probability from middle age to age 100+ measuring the general, independent, and joint effects of the FOXO genotypes based on data from the cases (centenarians) and controls (middle-age group), presented in Tables 1-3, may be subject to a bias of unknown magnitude because of confounding with birth cohorts of centenarians and middle-age individuals. Similar cautions were also raised in previous studies following the case-control approach (26), and the potential bias needs to be evaluated in the future when more sophisticated cohort follow-up data sources become available. Although Li and colleagues (6) have done the replication analyses on the general effects of FOXO1A on longevity using female samples from Southern and Northern China, we are not able to perform the replication for the independent, joint, and GG interaction effects.