The transmission disequilibrium test (TDT) is a simple means to detect
association which should only be positive if the marker allele is lin
ked to the disease locus, but it cannot be used if parents of affected
subjects are unavailable, as can occur when the disease has a late ag
e of onset. Although one can sometimes deduce parental genotypes using
the siblings of affected cases, reliance on this procedure can introd
uce bias and may also result in discarding many families which could p
rovide useful information. Instead, it is shown that the use of unaffe
cted siblings as controls is, like the TDT, robust against bias due to
population stratification and other sources, and is expected only to
produce positive results when a marker is both associated and linked w
ith the disease locus. The method can have much less power than a case
-control study using unrelated controls, but this can be guarded again
st by seeking unaffected siblings which are genotypically distinct fro
m cases and by focusing only on alleles which are different within pai
rs of cases and controls. This yields a pair-wise test for association
which can be used for multiallelic markers in a manner exactly analog
ous to the extended TDT (ETDT). The use of siblings as controls is sim
ple, robust, practical and worthy of further consideration.