Tests of trait-haplotype association when linkage phase is ambiguous, appropriate for matched case-control and cohort studies with competing risks.
The impact of competing risks on tests of association between disease and haplotypes has been largely ignored. We consider situations in which linkage phase is ambiguous and show that tests for disease-haplotype association can lead to rejection of the null hypothesis, even when true, with more than the nominal 5 per cent frequency. This problem tends to occur if a haplotype is associated with overall mortality, even if the haplotype is not associated with disease risk. A small simulation study illustrates the magnitude of bias (high type I error rate) in the context of a cohort study in which a modest number of disease cases (about 350) occur over time. The bias remains even if the score test is based on a logistic model that includes age as a covariate. For cohort studies, we propose a new test based on a modification of the proportional hazards model and for case-control studies, a test based on a conditional likelihood that have the correct size under the null even in the presence of competing risks, and that can be used when haplotype is ambiguous.
Flanders
W D
WD
Department of Epidemiology, Rollins School of Public Health, Emory University, 1599 Clifton Road, Atlanta, GA 30322, USA. flanders@sph.emory.edu
Khoury
M J
MJ
Yang
Q H
QH
Austin
H
H
D000368:Aged; D000369:Aged, 80 and over; D025901:Carboxypeptidase B2 / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011655:Pulmonary Embolism / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D020246:Venous Thrombosis / Q000235:genetics
D025901:Carboxypeptidase B2