1. Genotype Assignment Options

The jPAP system presently allows for seven Genotype Assignment (GA) options, enumerated in the sub-sections below. The actual list available at any given time on the Genotype Assignment Node in ModEd depends on the structure of the model as defined on the nodes above it.

The available options do not depend on the number of loci or number or alleles per locus, but they do take into account the inheritance modes set on the loci and the presence of a Category Status Node assignment. As one can see dynamically in the parameter table pane, when the GA option changes, the available parameters in the parameter table may change depending on their types. Those parameters indexed by genotype will reflect the current GA, and some parameter types may appear or disappear as the GA change cascades down to restrict the available PAM selections, some of which support only particular GA options.

1. Autosomal inheritance

This is the standard model for autosomal inheritance.

2. X-linked inheritance

This is the standard model for X-linked inheritance.

3.Parent-specific autosomal

This extension of autosomal inheritance distinguishes between heterozygotes according to the parental origin of each allele. This distinction allows the penetrance or transmission probabilities to differ between the two types of heterozygotes. For example, parent-specific autosomal genotype assignments allow you to independently estimate parameters describing age of onset in maternally- and paternally-transmitted disease.

4. Parent-specific X-linked

This extension of X-linked inheritance distinguishes between heterozygotes according to the parental origin of each allele. This distinction allows the penetrance or transmission probabilities to differ between the two types of heterozygotes.

5. Category-specific autosomal

This extension of autosomal inheritance allows you to classify individuals in two categories and independently specify the penetrance or transmission probabilities for all genotypes. Possible dichotomies for separate parameter specification include males and females, nonsmokers and smokers, unmedicated individuals and individuals taking medication. Corresponding to the assignments of genotypes for females (category 2) before males (category 1), category 2 always precedes category 1 in the genotype order.

The genotype order for category-specific autosomal inheritance equals the order for the autosomal/X-linked mixed GA.

6. Autosomal/X-linked mixed

The autosomal/X-linked mixed model [Hasstedt & Skolnick 1984] encompasses both autosomal and X-linked inheritance. Therefore, successively comparing the likelihoods of the autosomal and X-linked models to the likelihood of the general model tests the two modes of inheritance. Rejection of both modes of inheritance suggests an intermediate form of transmission that is not interpretable as genetic. Alternatively, the general form of the autosomal/X-linked admixture option (described in the next subsection) more realistically assumes that alleles with each mode of inheritance occur in the sample. However, the admixture model requires more parameters than the mixed model and may not be not realistic for a single pedigree.

The autosomal/X-linked mixed model includes three genotypes for males. When the parameters correspond to X-linkage, the frequency of the third genotype equals 0. You must define the alleles to specify phenotypic equivalence between the second and third genotypes; a dominant model has the normal allele first; a recessive model has the disease allele first; a codominant model is nonsensical.

Transmission probabilities from a father with genotype 2 distinguish between autosomal and X-linked inheritance. If both the son and daughter allele transmission probabilities equal ½, you obtain autosomal inheritance. If the son allele transmission probability equals 1 and the daughter allele transmission probability equals 0, you obtain X-linked inheritance. All the other transmission probabilities assume their Mendelian values.

Frequency module papfqax assumes Hardy-Weinberg equilibrium for females and generational equilibrium for males. The frequencies in males of the three genotypes equal:

p²τ/[q + (p - q)τ]
pq/[q + (p - q)τ]
q²(1-τ)/[q + (p - q)τ]

where τ represents the son's allele transmission probability. If τ = ½, you obtain autosomal frequencies; if τ = 1, you obtain X-linked frequencies. Module papfqax restricts the model to 1 locus with 2 alleles.

7. Autosomal/X-linked admixture

The autosomal/X-linked admixture model encompasses both autosomal and X-linked inheritance. Therefore, successively comparing the likelihoods of the autosomal and X-linked models to the likelihood of the general model tests the two modes of inheritance. Rejection of both submodels supports heterogeneity in the mode of inheritance. Alternatively, the autosomal/X-linked mixed option (described in the previous subsection) requires fewer parameters for testing the alternative modes of inheritance, but has an unrealistic general model.

An autosomal/X-linked admixture model requires a minimum of two loci, one autosomal and one X-linked. The submodels, autosomal or X-linked inheritance, restrict locus 1 or 2, respectively, to 1 allele. Additional loci may represent markers linked to the autosomal or X-linked form.