Transmission disequilibrium test (${\chi }_{\mathrm{TDT}}^2=\frac{(b-c{)}^2}{b+c}$)

For affected offspring and heterozygous parents at a diallelic locus, let $b$ count transmissions of allele 1 with allele 2 untransmitted and $c$ count the reverse. Under the fair-transmission null, conditional on $b+c$, $b$ is binomial with probability $1/2$. The asymptotic statistic is $(b-c{)}^2/(b+c)$, with a one-degree-of-freedom chi-squared null distribution. Homozygous-parent transmissions give no contrast. Conditioning within families protects this test from ordinary population stratification.

If one parent is heterozygous and the other parent's genotype is missing, a homozygous child reveals the observed parent's transmitted allele, whereas a heterozygous child need not. Selecting only revealed transmissions can therefore bias the transmission disequilibrium test. For allele-1 frequency $p$ under random mating and fair transmission, the probabilities of an allele-1 or allele-2 homozygous child from an observed heterozygous parent are $p/2$ and $(1-p)/2$. Among selected homozygous children, the observed allele-1 transmission probability is $p$, not generally $1/2$. A complete-trio analysis avoids this reconstruction rule; methods retaining missing-parent families need an explicit likelihood function or a valid conditional adjustment. Family-based association tests using genotype data with uncertainty discusses this bias.

Combine the untransmitted maternal and paternal alleles into a hypothetical control genotype, paired with the child's transmitted genotype. Even when two heterozygous parents have a heterozygous child and parent-specific phase is ambiguous, the combined untransmitted genotype is unambiguously heterozygous. Such pseudo-controls are matched family controls, not independent random individuals; Hardy-Weinberg principle is therefore not guaranteed merely by this construction.

Under random mating and Hardy-Weinberg equilibrium, label each parental allele by whether it is transmitted. Let $(A,B)$ and $(C,D)$ be the transmitted/untransmitted pairs of two parents. Before ascertainment all four draws are independent with population frequencies $\pi$. If offspring disease weights the transmitted pair by ${\psi }_A{\psi }_C$, thenThe transmitted pair is an affected-case genotype and the untransmitted pair a population family pseudo-control genotype under this homogeneous model. For unordered genotypes, compatible labelled transmissions must be summed. Conditioning on parental genotypes instead removes nuisance population frequencies and gives the usual transmission disequilibrium test.

// Target: statistical-modelling.bigb