Statistical considerations for genome-wide scans: Design and application of a novel software package POLYMORPHISM

Objective: Given the cost and complexity of genome-wide scans, optimization of study design is of critical importance. Available algorithms only parti ally satisfy this need. We designed a software package called 'POLYMORPHISM ' to meet these needs. Methods: The program is designed to calculate linkag e parameters for both 'single-point' and 'two-point' settings that are appl icable also to incompletely informative microsatellite markers. In single-p oint analysis, the heterozygosity, polymorphism information content (PIC) a nd linkage information content (LIC) statistics based on marker allele freq uencies are provided. In two-point analysis, joint PIC values for two marke rs, the conditional probability of detecting linkage phase, the frequency o f double heterozygotes and the expected number of informative meioses are c alculated. Results: Results were obtained using S.A.G.E./DESPAIR (Design of Linkage Studies Based on Pairs of Relatives) in addition to applying this program to a Centre d'Etude du Polymorphisme pedigree-derived genotyping da ta set, which estimated critical parameters used in a two-stage genome scan . A single nucleotide polymorphism (SNP)-based one-stage genomic screen str ategy is also considered. Conclusions: LIC values are crucial for getting a ccurate estimates on those parameters that are important for a two-stage ge nome screening study. Optimization of the cost-effectiveness of an SNP-base d genomic screen strategy is possible by modeling a balance between marker information content and marker density. Copyright (C) 2001 S. Karger AG, Ba sel.