Nuclear families with one affected child are sampled using the parental haplotypes not transmitted as a control.
While similar to the genotype relative risk (RR), the HRR provides a solution to the problem of population stratification by only sampling within family trios.
The original method proposed by Falk and Rubinstien fell under scrutiny in 1989, when Ott showed the equivalence of HRR to the classical RR method[2] demonstrating that the HRR holds only when there is zero chance of recombination between a disease locus and its markers.
Some research uses both HRR and TDT for their ability to complement each other since one result may give no association while the other will.
A positive association result from both TDT and HRR means there is strong evidence that a link exists and vice versa.
For example, both HRR and TDT methods were used in a study looking for polymorphism in D2 and D3 dopamine receptor in association with schizophrenia and neither found any evidence for linkage,[6] making an actual role of those genes in the etiology of the mental disorder all the more unlikely.
This model represents a case which there is a single locus where all genotypes may lead to expression of the allele in its most simplified definition.