Past exam of the mathematics course of the University of Cambridge 2005 iii Paper 45 1 i Solution Created 2026-10-03 Updated 2026-10-14
Parametric linkage analysis specifies a disease-transmission model: the mode of inheritance, disease-allele frequency and penetrance of each genotype. Combining these with Mendelian segregation and the recombination fraction gives a pedigree likelihood. One can estimate the recombination fraction or compare a linked model, , with the unlinked model, , using a likelihood-ratio test or LOD score. Incomplete penetrance and unobserved genotypes are accommodated by summing over the possible underlying inheritance states.
Nonparametric linkage analysis instead tests whether relatives with the same disease phenotype share marker alleles identical by descent more often than expected from their pedigree. For example, affected-sib-pair analysis compares sharing among affected full siblings with its Mendelian null distribution. It avoids specifying a complete disease-penetrance model and disease-allele frequency. “Model-free” still assumes an inheritance model for the marker, correct family relationships and a justified treatment of genetic-study ascertainment; it does not mean assumption-free.
Past exam of the mathematics course of the University of Cambridge 2005 iii Paper 45 1 vi Solution 2026-10-14
Put and . The usual recombination fraction range gives , and the preceding likelihood function becomesTo see its relation to nonparametric linkage analysis, use Bayes' theorem and the constant disease probability to obtain the affected-pair marker-sharing probabilitiesTheir multinomial likelihood has exactly the same -dependent kernel, since its extra factor is constant. Set and . Then , and is the total number of shared ancestral copies. At fixed , the Fisher-Neyman factorization theorem makes a sufficient statistic. The observed mean shared proportion is , and the binomial likelihood kernel givesThe unlinked null is , whereas linkage corresponds to , or expected shared proportion . If , the constrained likelihood is maximized at the unlinked null. For , its log likelihood ratio iswhose derivative in is . Hence it orders samples exactly by excess IBD sharing. Under this fully penetrant recessive model, parametric linkage testing and a one-sided test of the overall IBD-sharing proportion use the same information. This is allele-sharing sufficiency for recessive linkage, not a general equivalence for all disease models. Use limiting values for terms such as , and assume for the estimators.