A Robust Identity-by-Descent Procedure Using Affected Sib Pairs: Multipoint Mapping for Complex DiseasesLiang K.-Y. · Chiu Y.-F. · Beaty T.H.
Departments of aBiostatistics and bEpidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Md., USA
Multipoint linkage analysis is a powerful tool to localize susceptibility genes for complex diseases. However, the conventional lod score method relies critically on the correct specification of mode of inheritance for accurate estimation of gene position. On the other hand, allele-sharing methods, as currently practiced, are designed to test the null hypothesis of no linkage rather than estimate the location of the susceptibility gene(s). In this paper, we propose an identity-by-descent (IBD)-based procedure to estimate the location of an unobserved susceptibility gene within a chromosomal region framed by multiple markers. Here we deal with the practical situation where some of the markers might not be fully informative. Rather the IBD statistic at an arbitrary within the region is imputed using the multipoint marker information. The method is robust in that no assumption about the genetic mechanism is required other than that the region contains no more than one susceptibility gene. In particular, this approach builds upon a simple representation for the expected IBD at any arbitrary locus within the region using data from affected sib pairs. With this representation, one can carry out a parametric inference procedure to locate an unobserved susceptibility gene. In addition, here we derive a sample size formula for the number of affected sib pairs needed to detect linkage with multiple markers. Throughout, the proposed method is illustrated through simulated data. We have implemented this method including exploratory and formal model-fitting procedures to locate susceptibility genes, plus sample size and power calculations in a program, GENEFINDER, which will be made available shortly.
Dr. Kung-Yee Liang
Department of Biostatistics, School of Hygiene and Public Health
Johns Hopkins University
Baltimore, MD 21205 (USA)
Fax +1 410 955 0958
Received: Received: May 21, 1999
Revision received: September 10, 1999
Accepted: October 6, 1999
Number of Print Pages : 15
Number of Figures : 9, Number of Tables : 1, Number of References : 23
Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)
Vol. 51, No. 1-2, Year 2001 (Cover Date: Released October 2000)
Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.ch/journals/hhe