Estimating the efficacy and efficiency of cascade genetic screening

Screening for genetic variants that predispose individuals or their offspri ng to disease may be performed at the general population level or may inste ad be targeted at the relatives of previously identified carriers. The latt er strategy has come to be known as "cascade genetic screening." Since the carrier risk of close relatives of known carriers is generally higher than the population risk, cascade screening is more efficient than population sc reening, in the sense that fewer individuals have to be genotyped per detec ted carrier. The efficacy of cascade screening, as measured by the overall proportion of carriers detected in a given population, is, however, lower t han that of population-wide screening, and the respective inclusion rates v ary according to the population frequency and mode of inheritance of the pr edisposing variants. For dominant mutations, we have developed equations th at allow the inclusion rates of cascade screening to be calculated in an it erative fashion, depending upon screening depth and penetrance. For recessi ve mutations, we derived only equations for the screening of siblings and t he children of patients. Owing to their mathematical complexity, it was nec essary to study more extended screening strategies by simulation. Cascade s creening turned out to result in low inclusion rates (<1%) when aimed at th e identification of heterozygous carriers of rare recessive variants. Consi derably higher rates are achievable, however, when screening is performed t o detect covert homozygotes for frequent recessive mutations with reduced p enetrance. This situation is exemplified by hereditary hemochromatosis, for which up to 40% of at-risk individuals may be identifiable through screeni ng of first-to third-degree relatives of overt carriers (i.e., patients); t he efficiency of this screening strategy was found to be <similar to>50 tim es higher than that of population-wide screening. For dominant mutations, i nclusion rates of cascade screening were estimated to be higher than for re cessive variants. Thus, some 80% of all carriers of the factor V Leiden mut ation would be detected if screening were to be targeted specifically at fi rst-to third-degree relatives of patients with venous thrombosis. The relat ive cost efficiency of cascade as compared with population-wide screening ( i.e., the overall savings in the extra managerial cost of the condition) is also likely to be higher for dominant than for recessive mutations. This n otwithstanding, once screening has become cost-effective at the population level, it can be expected that cascade screening would only transiently rep resent an economically viable option.