Distribution of Model-based Multipoint Heterogeneity Lod Scores

Department of Clinical Sciences, McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Genetic Epidemiology (Impact Factor: 2.6). 12/2010; 34(8):912-6. DOI: 10.1002/gepi.20535
Source: PubMed


The distribution of two-point heterogeneity lod scores (HLOD) has been intensively investigated because the conventional χ(2) approximation to the likelihood ratio test is not directly applicable. However, there was no study investigating th e distribution of the multipoint HLOD despite its wide application. Here we want to point out that, compared with the two-point HLOD, the multipoint HLOD essentially tests for homogeneity given linkage and follows a relatively simple limiting distribution ½χ²₀+ ½χ²₁, which can be obtained by established statistical theory. We further examine the theoretical result by simulation studies.

Download full-text


Available from: Nathan J Morris, Jan 13, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Linkage analysis was developed to detect excess co-segregation of the putative alleles underlying a phenotype with the alleles at a marker locus in family data. Many different variations of this analysis and corresponding study design have been developed to detect this co-segregation. Linkage studies have been shown to have high power to detect loci that have alleles (or variants) with a large effect size, i.e. alleles that make large contributions to the risk of a disease or to the variation of a quantitative trait. However, alleles with a large effect size tend to be rare in the population. In contrast, association studies are designed to have high power to detect common alleles which tend to have a small effect size for most diseases or traits. Although genome-wide association studies have been successful in detecting many new loci with common alleles of small effect for many complex traits, these common variants often do not explain a large proportion of disease risk or variation of the trait. In the past, linkage studies were successful in detecting regions of the genome that were likely to harbor rare variants with large effect for many simple Mendelian diseases and for many complex traits. However, identifying the actual sequence variant(s) responsible for these linkage signals was challenging because of difficulties in sequencing the large regions implicated by each linkage peak. Current 'next-generation' DNA sequencing techniques have made it economically feasible to sequence all exons or the whole genomes of a reasonably large number of individuals. Studies have shown that rare variants are quite common in the general population, and it is now possible to combine these new DNA sequencing methods with linkage studies to identify rare causal variants with a large effect size. A brief review of linkage methods is presented here with examples of their relevance and usefulness for the interpretation of whole-exome and whole-genome sequence data.
    Full-text · Article · Dec 2011 · Human Heredity
  • [Show abstract] [Hide abstract]
    ABSTRACT: To detect fully penetrant rare recessive variants that could constitute Mendelian subentities of complex diseases, we propose a novel strategy, the HBD-GWAS strategy, which can be applied to genome-wide association study (GWAS) data. This strategy first involves the identification of inbred individuals among cases using the genome-wide SNP data and then focuses on these inbred affected individuals and searches for genomic regions of shared homozygosity by descent that could harbor rare recessive disease-causing variants. In this second step, analogous to homozygosity mapping, a heterogeneity lod-score, HFLOD, is computed to quantify the evidence of linkage provided by the data. In this paper, we evaluate this strategy theoretically under different scenarios and compare its performances with those of linkage analysis using affected sib-pair (ASP) data. If cases affected by these Mendelian subentities are not enriched in the sample of cases, the HBD-GWAS strategy has almost no power to detect them, unless they explain an important part of the disease prevalence. The HBD-GWAS strategy outperforms the ASP linkage strategy only in a very limited number of situations where there exists a strong allelic heterogeneity. When several rare recessive variants within the same gene are involved, the ASP design indeed often fails to detect the gene, whereas, by focusing on inbred individuals using the HBD-GWAS strategy, the gene might be detected provided very large samples of cases are available.
    No preview · Article · Jan 2012 · Human Heredity
  • [Show abstract] [Hide abstract]
    ABSTRACT: This unit describes linkage analysis, an invaluable tool in mapping human disease genes. Linkage analysis is one of several methods used to map genes. Specifically, in linkage analysis, cosegregation of two or more genes (traits) is examined in a family unit to determine if they segregate independently of each other according to Mendel's laws or if they do not segregate independently because of their close physical proximity. The procedures outlined in this unit are not always straightforward, and a number of caveats are presented in the commentary regarding possible complications and confounding factors that may arise. Specific examples are given, but it is not possible to cover all possible scenarios or variables. The intention is to enable the reader to master basic principles used in the linkage approach, and thus be in a position to undertake, with proper consultation, a linkage-analysis study. This unit deals specifically with lod score analysis in Mendelian disorders. Curr. Protoc. Hum. Genet. 83:1.4.1-1.4.31. © 2014 by John Wiley & Sons, Inc.
    No preview · Article · Oct 2014 · Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.]