Bias in using family history as a risk factor in case-control studies of disease

In many case-control studies of common diseases, investigators use family history information to assess familial aggregation of the disease and the influence of genetic factors. Positive family history among first-degree relatives is often used as a risk factor, and its odds ratio is calculated. Although the limitations of this approach have been discussed, it is not clear how much impact such limitations could have on measuring familial aggregation. To assess this impact, we compare odds ratios derived from using a positive family history in case-control studies with measures of relative risk derived from comparing lifetime risks of disease among first-degree relatives of case subjects with those among first-degree relatives of control subjects. Positive family history is a function of the number of relatives, the background risk of disease, the age distribution of relatives, and the correlation in risk among relatives. It can be shown that even without case-control differences in the number or ages of relatives, positive family history tends to overestimate relative risk measures applied to individual relatives. This overestimation is accentuated with increasing frequency of the disease, with increasing number of relatives, and for diseases with earlier age at onset. It is further affected by even small case-control differences in family size and age distribution of relatives. As such, positive family history is not a stable indicator of familial aggregation across different case-control studies of the same disease.