Haplotype-relative-risk ($\widehat{\mathrm{OR}}=\frac{wz}{xy}$)

The haplotype-relative-risk design compares transmitted alleles to the corresponding untransmitted parental copies, used as internal controls for an affected offspring. If allele-1/allele-2 transmitted counts are $w,x$ and untransmitted counts are $y,z$, the allele-1 odds ratio estimate is $wz/(xy)$. An unmatched Pearson chi-squared test of independence treats this as a two-by-two table. The transmission disequilibrium test instead keeps parent-specific pairing and uses only discordant transmissions. The sampling assumptions of the unmatched calculation and any missing-parent reconstruction must be justified separately.