Single-marker linkage-disequilibrium (LD) methods cannot fully describe dis
equilibrium in an entire chromosomal region surrounding a disease allele. W
ith the advent of myriad tightly linked microsatellite markers, we have an
opportunity to extend LD analysis from single markers to multiple-marker ha
plotypes. Haplotype analysis has increased statistical power to disclose th
e presence of a disease locus in situations where it correctly reflects the
historical process involved. For maximum efficiency evidence of LD ought t
o come not just from a single haplotype, which may well be rare, but in add
ition from many similar haplotypes that could have descended from the same
ancestral founder but have been trimmed in succeeding generations. We prese
nt such an analysis, called the "trimmed-haplotype method." We focus on chr
omosomal regions that are small enough that disequilibrium in significant p
ortions of them may have been preserved in some pedigrees and yet that cont
ain enough markers to minimize coincidental occurrence of the haplotype in
the absence of a disease allele: perhaps regions 1-2 cM in length. In gener
al, we could have no idea that haplotype an ancestral founder carried gener
ations ago, nor do we usually have a precise chromosomal location for the d
isease-susceptibility locus. Therefore, we must search through all possible
haplotypes surrounding multiple locations. Since such repeated testing obl
iterates the sampling distribution of the test, me employ bootstrap methods
to calculate significance levels. Trimmed-haplotype analysis is performed
on family data in which genotypes have been assembled into haplotypes. It c
an be applied either to conventional parent-affected-offspring triads or to
multiplex pedigrees. We present a method for summarizing the LD evidence,
in any pedigree, that can be employed in trimmed-haplotype analysis as well
as in other methods.