Transmission disequilibrium test
Encyclopedia
The transmission disequilibrium test (TDT) was proposed by Spielman, McGinnis and Ewens
(1993) as a family-based association test for the presence of genetic linkage
between a genetic marker and a trait. It is an application of McNemar's test
.
A specificity of the TDT is that it will detect genetic linkage
only in the presence of genetic association
.
While genetic association
can be caused by population structure, genetic linkage
will not be affected, which makes the TDT robust to the presence of population structure.
The TDT measures the over-transmission of an allele from heterozygous parents to affected offsprings.
The n affected offsprings have 2n parents. These can be represented by the transmitted and the non-transmitted alleles
and 
at some genetic locus. Summarizing the data in a 2 by 2 table gives:
The derivation of the TDT shows that one should only use the heterozygous parents (total number b+c).
The TDT tests whether the proportions b/(b+c) and c/(b+c) are compatible with probabilities (0.5, 0.5).
This hypothesis can be tested using a binomial (asymptotically chi-square) test with one degree of freedom:
and 
in the table above. In particular, one can show that under nearly all disease models the expected proportion of 
and 
are identical. This result motivates the use of a binomial (asymptotically 
) test to test whether these proportions are equal.
On the other hand, one can also show that under such models the proportions
and 
are not equal to the product of the marginals probabilities 
, 
and 
, 
. A rewording of this statement would be that the type of the transmitted allele is not, in general, independent of the type of the non-transmitted allele. A consequence is that a 
test for homogeneity/independence does not test the appropriate hypothesis, and thus, only heterozygous parents are included.
heterozygous parents. We use the fact that the transmission to different children are independent. The information can be then summarized in three categories:
= number of parents who transmit 
to both children.
= number of parents who transmit 
to one child and 
to another.
= number of parents who transmit 
to both children.
Using the notations of the previous paragraph we have:
leading to the chi-square test statistic:
The Blackwelder and Elston approach uses the total number of haplotypes identical by descent (mean haplotype sharing). This measure ignores the allelic state of a marker and simply compares the number of times a parent transmits the same allele to both affected children with the number of times a different allele is transmitted.
The test statistic is:
Under the null hypothesis
of no linkage the expected proportions of (i, h − i − j, j) are (0.25, 0.5, 0.25). One can derive a simple chi-square statistic with 2 degrees of freedom:
It clearly appears that the total statistic (with two degree of freedom) is the sum of two independent components: one is the traditional linkage measure and the other is the TDT statistic.
The motivating idea for this modification is the fact that, while the transmissions of both allele from parents to a child are independent, the effects of other filial genetic or environmental covariates on penetrance
are the same for both alleles transmitted to the same child. This situation can be important if, for example, the genetic marker is linked to a disease locus with a strong selection against heterozygous individuals. This observation suggests to shift the statistical model from a set of independent transmissions to a set of independent children (see Sasieni (1997) for the corresponding problem in case-control association tests). While this observation does not affect the distribution under the null hypothesis of no linkage, it allows, for some disease models, to design a more powerful test.
In this modified TDT test the children are stratified by parental type and the modified test statistic becomes:
Warren Ewens
Warren Ewens FRS, FAA is an Australian-born professor of biology at the University of Pennsylvania. He concentrates his research on the mathematical, statistical and theoretical aspects of population genetics. Ewens has worked in human population genetics, computational biology, and evolutionary...
(1993) as a family-based association test for the presence of genetic linkage
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
between a genetic marker and a trait. It is an application of McNemar's test
McNemar's test
In statistics, McNemar's test is a non-parametric method used on nominal data. It is applied to 2 × 2 contingency tables with a dichotomous trait, with matched pairs of subjects, to determine whether the row and column marginal frequencies are equal...
.
A specificity of the TDT is that it will detect genetic linkage
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
only in the presence of genetic association
Genetic association
Genetic association is the occurrence, more often than can be readily explained by chance, of two or more traits in a population of individuals, of which at least one trait is known to be genetic....
.
While genetic association
Genetic association
Genetic association is the occurrence, more often than can be readily explained by chance, of two or more traits in a population of individuals, of which at least one trait is known to be genetic....
can be caused by population structure, genetic linkage
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
will not be affected, which makes the TDT robust to the presence of population structure.
Description of the test
We first describe the TDT in the case where families consist of trios (two parents and one affected child). Our description follows the notations used in Spielman, McGinnis & Ewens (1993).The TDT measures the over-transmission of an allele from heterozygous parents to affected offsprings.
The n affected offsprings have 2n parents. These can be represented by the transmitted and the non-transmitted alleles
and at some genetic locus. Summarizing the data in a 2 by 2 table gives:  |  | total | |
| Transmitted allele | |||
 | a | b | a + b |
 | c | d | c + d |
| Total | a + c | b + d | 2n |
The derivation of the TDT shows that one should only use the heterozygous parents (total number b+c).
The TDT tests whether the proportions b/(b+c) and c/(b+c) are compatible with probabilities (0.5, 0.5).
This hypothesis can be tested using a binomial (asymptotically chi-square) test with one degree of freedom:
Outline of the test derivation
A derivation of the test consists of using a population genetics model to obtain the expected proportions for the quantities and in the table above. In particular, one can show that under nearly all disease models the expected proportion of and are identical. This result motivates the use of a binomial (asymptotically ) test to test whether these proportions are equal.On the other hand, one can also show that under such models the proportions
and are not equal to the product of the marginals probabilities , and , . A rewording of this statement would be that the type of the transmitted allele is not, in general, independent of the type of the non-transmitted allele. A consequence is that a test for homogeneity/independence does not test the appropriate hypothesis, and thus, only heterozygous parents are included.Extension of the test
The TDT can be readily extended beyond the case of trios. We keep following the notations of Spielman, McGinnis & Ewens (1993). Let us consider a total of heterozygous parents. We use the fact that the transmission to different children are independent. The information can be then summarized in three categories: = number of parents who transmit to both children. = number of parents who transmit to one child and to another. = number of parents who transmit to both children.Using the notations of the previous paragraph we have:
leading to the chi-square test statistic:
Relation with another linkage statistic
The comparison with the more traditional (at least at the time when the TDT was proposed) linkage test proposed by Blackwelder and Elston 1985 is informative.The Blackwelder and Elston approach uses the total number of haplotypes identical by descent (mean haplotype sharing). This measure ignores the allelic state of a marker and simply compares the number of times a parent transmits the same allele to both affected children with the number of times a different allele is transmitted.
The test statistic is:
Under the null hypothesis
Null hypothesis
The practice of science involves formulating and testing hypotheses, assertions that are capable of being proven false using a test of observed data. The null hypothesis typically corresponds to a general or default position...
of no linkage the expected proportions of (i, h − i − j, j) are (0.25, 0.5, 0.25). One can derive a simple chi-square statistic with 2 degrees of freedom:
It clearly appears that the total statistic (with two degree of freedom) is the sum of two independent components: one is the traditional linkage measure and the other is the TDT statistic.
A modified version of the TDT
More recently, Wittkowski KM, Liu X. (2002/2004) proposed a modification to the TDT that can be more powerful under some alternatives, although the asymptotic properties under the null hypothesis are equivalent.The motivating idea for this modification is the fact that, while the transmissions of both allele from parents to a child are independent, the effects of other filial genetic or environmental covariates on penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
are the same for both alleles transmitted to the same child. This situation can be important if, for example, the genetic marker is linked to a disease locus with a strong selection against heterozygous individuals. This observation suggests to shift the statistical model from a set of independent transmissions to a set of independent children (see Sasieni (1997) for the corresponding problem in case-control association tests). While this observation does not affect the distribution under the null hypothesis of no linkage, it allows, for some disease models, to design a more powerful test.
In this modified TDT test the children are stratified by parental type and the modified test statistic becomes:
-
where
is the number of PQ children from parents with the PQ and QQ types.