666.25 - Parametric Linkage Analysis Biostatistics 666...

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Parametric Linkage Analysis Biostatistics 666 Lecture 25
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Last Lecture z Elston Stewart Algorithm Can handle large pedigrees Proceeds one nuclear family at a time Limited to small numbers of markers z Calculates conditional probabilities for sections of the pedigree
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Today z Refresher on non-parametric analysis z Parametric linkage analysis Evaluates a specific trait model Disease allele frequencies Probability of disease for each genotype z Successfully mapped >1,000 rare disorders
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Data for a Linkage Study z Pedigree Set of individuals of known relationship z Observed marker genotypes SNPs, VNTRs, microsatellites z Phenotype data for individuals
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Linkage Analysis z Aims to relate sharing of specific chromosomal regions to phenotypic similarity z Parametric methods define explicit relationship between phenotypic and genetic similarity z Non-parametric methods test for increased sharing among affected individuals
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Non-parametric Linkage Analysis z No specific model for disease locus z Evaluates whether segregation at specific locations is "not-random" z Specifically, the objective is to show increased IBD sharing among sets of affected individuals
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Allele Sharing Analysis z Reject random sharing at a particular region z Less powerful than classic methods When disease model is known z More robust than classic methods When disease model is unknown
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Historical References z Penrose (1953) suggested comparing IBD distributions for affected siblings. Possible for highly informative markers (eg. HLA) z Risch (1990) described the MLS method for evaluating the evidence for linkage in affected sibling pair data. z Soon after, large-scale microsatellite genotyping became possible and geneticists attempted to tackle more complex diseases…
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Non-parametric Analysis for Arbitrary Pedigrees z Must rank general IBD configurations which include sets of more than 2 affected individuals Low ranks correspond to no linkage High ranks correspond to linkage z Multiple possible orderings are possible Especially for large pedigrees z Interesting regions are those where IBD configurations with higher rank are more common
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Non-Parametric Linkage Scores z Introduced by Whittemore and Halpern (1994) z
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666.25 - Parametric Linkage Analysis Biostatistics 666...

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