Statistical approaches for the detection of heterozygotes for biotinidase deficiency
ABSTRACT 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.
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ABSTRACT: We screened 163,000 newborn filter-paper blood samples for serum biotinidase deficiency (McKusick 25326) and found 15 probands: three had complete deficiency (incidence 18.4 cases per million live births, 95% confidence interval 4-54 cases per million); the others had partial deficiency. The positive predictive value of the test for either form of biotinidase deficiency was 9.86%. We found seasonal variation in biotinidase activity in filter-paper blood samples. The cost per test was Can.$0.27 (1987 dollar value) and per case of complete deficiency ascertained, $15,500. Family studies indicated that complete serum biotinidase deficiency is a homozygous phenotype and partial deficiency is the heterozygous form. Homozygous cases were treated with biotin and have shown no clinical manifestations (55 patient-months of observation). None of the heterozygotes (n = 42, age 3 months - 62 years) has clinical manifestations. The number of heterozygotes found by screening was much less than predicted probably because the screening test detects mainly the samples with very low (outlier) biotinidase activity. The variant allele(s) for biotinidase deficiency was more common in French Canadians than in other ethnic groups in Quebec; there was no evidence of regional clustering or founder effect.Journal of Inherited Metabolic Disease 02/1989; 12(2):131-8. DOI:10.1007/BF01800715 · 3.37 Impact Factor
- Journal of Pediatrics 01/1990; 116(1):78-83. DOI:10.1016/S0022-3476(05)81649-X · 3.79 Impact Factor
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ABSTRACT: Biotinidase, the enzyme responsible for recycling the vitamin biotin, is deficient in most individuals with late-onset multiple carboxylase deficiency. Based on clinical criteria, biotinidase deficiency appears to be inherited as an autosomal recessive trait; however, the inheritance of biotinidase serum activity as a quantitative trait has not been studied previously. In this study, both segregation analysis of proband families and the analysis of twin family data were used to determine the relative contributions of a major gene, polygenes and environment to the variation in serum biotinidase activity. Segregation analysis of 24 families of biotinidase-deficient individuals indicated that serum biotinidase activity is determined by the segregation of a single codominant major gene with the variability about the mean of each major genotype attributable to environmental effects. Significant polygenic effects could not be detected by this analysis. Variance component analysis of 128 twin families, which included the twins, their spouses, and their offspring, indicated that 70% of total variance in biotinidase activity is attributable to additive genetic effects, 22% to individual environmental effects, and 8% to shared environmental effects. The model also included an age effect for females. A portion (27%) of the estimated additive variance may be attributed to the segregation of the major gene. This study emphasizes the usefulness of studying multiple data sets representing different types of family relationships.American Journal of Medical Genetics 08/1993; 47(2):231-40. DOI:10.1002/ajmg.1320470218 · 3.23 Impact Factor