RESUMEN
The gene encoding alpha-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer's disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that alpha-T-catenin is expressed in human brain, and like other alpha-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Abeta deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n > 700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Cromosomas Humanos Par 10/genética , Proteínas del Citoesqueleto/metabolismo , Ligamiento Genético/genética , Proteínas Proto-Oncogénicas/metabolismo , Anciano , Anciano de 80 o más Años , Empalme Alternativo/genética , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/fisiopatología , Química Encefálica/genética , Estudios de Casos y Controles , Línea Celular , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Expresión Génica/genética , Frecuencia de los Genes/genética , Pruebas Genéticas , Genotipo , Humanos , Masculino , Ratones , Polimorfismo Genético/genética , Transducción de Señal/genética , Proteínas Wnt , alfa CateninaRESUMEN
The accuracy of a binary-scale diagnostic test can be represented by sensitivity (Se), specificity (Sp) and positive and negative predictive values (PPV and NPV). Although Se and Sp measure the intrinsic accuracy of a diagnostic test that does not depend on the prevalence rate, they do not provide information on the diagnostic accuracy of a particular patient. To obtain this information we need to use PPV and NPV. Since PPV and NPV are functions of both the accuracy of the test and the prevalence of the disease, constructing their confidence intervals for a particular patient is not straightforward. In this paper, a novel method for the estimation of PPV and NPV, as well as their confidence intervals, is developed. For both predictive values, standard, adjusted and their logit transformed-based confidence intervals are compared using coverage probabilities and interval lengths in a simulation study. These methods are then applied to two case-control studies: a diagnostic test assessing the ability of the e4 allele of the apolipoprotein E gene (ApoE.e4) on distinguishing patients with late-onset Alzheimer's disease (AD) and a prognostic test assessing the predictive ability of a 70-gene signature on breast cancer metastasis.