Informative-Transmission Disequilibrium Test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspring
Version of Record online: 22 NOV 2006
© 2006 Wiley-Liss, Inc.
Volume 31, Issue 2, pages 115–133, February 2007
How to Cite
Guo, C.-Y., Lunetta, K. L., DeStefano, A. L., Ordovas, J. M. and Adrienne Cupples, L. (2007), Informative-Transmission Disequilibrium Test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspring. Genet. Epidemiol., 31: 115–133. doi: 10.1002/gepi.20195
- Issue online: 10 JAN 2007
- Version of Record online: 22 NOV 2006
- Manuscript Accepted: 4 OCT 2006
- Manuscript Revised: 30 AUG 2006
- Manuscript Received: 24 FEB 2006
- National Heart, Lung and Blood Institute's Framingham Heart Study. Grant Number: N01-HC-25195
- multiple affecteds;
- unaffected siblings;
- nuclear families;
To date, there is no test valid for the composite null hypothesis of no linkage or no association that utilizes transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. Since the unaffected siblings also provide information about linkage and association, we introduce a new strategy called the informative-transmission disequilibrium test (i-TDT), which uses transmission information from heterozygous parents to all of the affected and unaffected offspring in ascertained nuclear families and provides a valid chi-square test for both linkage and association. The i-TDT can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. We show that the transmission/disequilibrium test (TDT) (Spielman et al.  Am. J. Hum. Genet. 52:506–516) is a special case of the i-TDT, if the study sample contains only case-parent trios. If the sample contains only affected and unaffected offspring without parental genotypes, the i-TDT is equivalent to the sibship disequilibrium test (SDT) (Horvath and Laird  Am. J. Hum. Genet. 63:1886–1897. In addition, the test statistic of i-TDT is simple, explicit and can be implemented easily without intensive computing. Through computer simulations, we demonstrate that power of the i-TDT can be higher in many circumstances compared to a method that uses affected offspring only. Applying the i-TDT to the Framingham Heart Study data, we found that the apolipoprotein E (APOE) gene is significantly linked and associated with cross-sectional measures and longitudinal changes in total cholesterol. Genet. Epidemiol. © 2006 Wiley-Liss, Inc.