Affected-sib-pair analysis

An affected-sib-pair analysis examines marker identity by descent between affected full siblings. Without genetic linkage to the disease locus, the probabilities of sharing zero, one and two copies are $1/4,1/2,1/4$. Excess sharing supplies evidence for linkage under disease models that preferentially transmit a common risk allele to both siblings.

// Target: biology.bigb

For unaffected genetic carriers of a disease with complete penetrance and recessive inheritance, suppose parental marker-disease haplotype phases are equally likely and the marker is fully informative. Write $u=\theta (1-\theta )$ and $v=1/2-u$, where $\theta$ is the recombination fraction. Conditional on sharing a parental marker copy, the probability that both siblings inherit that parent's disease allele is $[(1-\theta {)}^2+{\theta }^2]/2=v$; conditional on inheriting different marker copies it is $\theta (1-\theta )=u$. Independent paternal and maternal transmissions therefore give $L_0=u^2,L_1=uv,L_2=v^2$. Conditional instead on both siblings being affected, the IBD probabilities are $s^2,2s(1-s),(1-s{)}^2$, where $s=2u\in [0,1/2]$.

// Target: biology.bigb

For independent affected sib pairs with IBD counts $n_0,n_1,n_2$, the likelihood function of the recombination fraction is proportional to $s^{2n_0+n_1}(1-s{)}^{2n_2+n_1}$, with $s=2\theta (1-\theta )$. At fixed sample size, the total shared-copy count $2n_2+n_1$ is a sufficient statistic by the Fisher-Neyman factorization theorem. Thus a one-sided likelihood-ratio test has the same ordering as a test for excess mean IBD sharing. This equivalence depends on the stated fully penetrant recessive model and does not extend to arbitrary disease models.

// Target: biology.bigb