Statistical approaches for the detection of heterozygotes for biotinidase deficiency

We applied and evaluated 3 statistical approaches for the detection of heterozygotes for biotinidase deficiency in a randomly selected population of French adults. The first method, which used a cutoff value to dichotomize the population, lacked sensitivity. The second approach calculated the probability of heterozygosity for a given enzyme activity through the application of Bayes theorem to the normal density functions of the enzyme distributions of the obligate heterozygote and the test populations. A priori values of the means and standard deviations (SDs) of the genotypic distributions were used. This method was sufficiently sensitive for both population screening and genetic counseling, but requires prior knowledge of the frequency of the deficient gene (q). The third approach was similar to the second, however, maximum likelihood estimates of the means and SDs of the genotypic distributions were calculated and used to determine the probability of heterozygosity for a given enzyme activity. This method was as sensitive as the second method and is appropriate for screening populations for which there is little prior information about the gene frequency and the genotypic distributions. This method can also be used to estimate the gene frequency of the disorder within a given ethnic or racial population. Using this method, we estimated the frequency of heterozygotes (2pq) in the French population to be 0.012, which was similar to that estimated from the results of neonatal screening for biotinidase deficiency. These methods can be used to detect heterozygotes and to estimate the gene frequency of other inherited enzyme deficiencies.