 Haplotype-relative-risk (HRR) is a family based method for determining gene allele association to a disease  . Nuclear families with one affected child are sampled using the parental haplotypes not transmitted as a control. While similar to  genotype relative risk (RR),  HRR provides a solution to the problem of population stratification by only sampling within family trios.  HRR method was first proposed by Rubinstein in 1981 then detailed in 1987 by Rubinstein and FalkFalk CT, Rubinstein P (1987) "Haplotype relative risks: and easy reliable way to construct a proper control sample for risk calculations". Ann Hum Genet 51:227-233 and is an important tool in genetic association studies. The original method proposed by Falk and Rubinstien fell under scrutiny in 1989, when Ott showed the equivalence of HRR to the classical RR methodWoolf B (1955) "On estimating the relation between blood group and disease". Ann Human Genet 19:251-253 demonstrating  the HRR holds only when there is zero chance of recombination between  disease locus and its markers.Ott J (1989) statistical properties of the haplotype relative risk. Genetic Epidemiol 6:127-130 This led to the adoption of the transmission disequilibrium test as the more commonly used method for association linkage; Yet, when the recombination factor for a gene marker and its locus are >0 there is no tendency for false positives seen .Knapp,Seuchter,Baur (1987) "The haplotype-relative-risk" (HRR) method for analysis of association in nuclear families. Am J Hum Genet 52:1085-10093,1993 While  HRR method has been shown as an effective means of avoiding population stratification another family based associations test known as the transmission disequilibrium testa b c Spielman RS, McGinnis RE, Ewens WJ (Mar 1993). "Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM)". Am J Hum Genet. 52 (3): 506–16. . or, TDT is more commonly used because of its more simplified algorithms . Some research uses both HRR and TDT for their ability to complement each other since one result my 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 found no linkagein both tests; Ambròsio, Kennedy, Macciardi, macoedo, Valente, Dourado, oliveria, Carlos, Pato (2004)"Family association study between DRD2 and DRD3 gene polymorphisms and schizophrenia in a portuguese population". Psychiatry Research 125:185-191 showing absolutely no possible association .
The Haplotype-relative-risk (HRR) method is a family-based method for determining gene allele association to a disease in the presence of actual genetic linkage . 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 HRR method was first proposed by Rubinstein in 1981 then detailed in 1987 by Rubinstein and FalkFalk CT, Rubinstein P (1987) "Haplotype relative risks: and easy reliable way to construct a proper control sample for risk calculations". Ann Hum Genet 51:227-233 and is an important tool in genetic association studies. The original method proposed by Falk and Rubinstien fell under scrutiny in 1989, when Ott showed the equivalence of HRR to the classical RR methodWoolf B (1955) "On estimating the relation between blood group and disease". Ann Human Genet 19:251-253 demonstrating that the HRR holds only when there is zero chance of recombination between a disease locus and its markers.Ott J (1989) statistical properties of the haplotype relative risk. Genetic Epidemiol 6:127-130 Yet, even when the recombination factor for a locus and its genetic markers is >0 HRR estimates are still more conservative than RR estimates .Knapp,Seuchter,Baur (1987) "The haplotype-relative-risk" (HRR) method for analysis of association in nuclear families. Am J Hum Genet 52:1085-10093,1993 While the HRR method has proven an effective means of avoiding population stratification biases, another family-based association test known as the transmission disequilibrium testa b c Spielman RS, McGinnis RE, Ewens WJ (Mar 1993). "Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM)". Am J Hum Genet. 52 (3): 506–16. . , or TDT, is more commonly used . 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, Ambròsio, Kennedy, Macciardi, macoedo, Valente, Dourado, oliveria, Carlos, Pato (2004)"Family association study between DRD2 and DRD3 gene polymorphisms and schizophrenia in a portuguese population". Psychiatry Research 125:185-191 making an actual role of those genes in the etiology of the mental disorder all the more unlikely .
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