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Introduction to Transmission Disequilibrium Test

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Am J Hum Genet. 52(3):506-16. ... Eur J Hum Genet 9:301 306. Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM. ... Genet Epidemiol 26:61 69. 17 ... – PowerPoint PPT presentation

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Title: Introduction to Transmission Disequilibrium Test


1
Introduction to Transmission Disequilibrium Test
  • Yixuan Chen
  • 4/25/08

2
Outlines
  • Transmission Disequilibrium Test
  • Fundamentals
  • Description of the test
  • Pros and Cons
  • Haplotype-based TDT

3
Transmission Disequilibrium Test (TDT)
  • Spielman RS, McGinnis RE, Ewens WJ. (1993)
  • Transmission test for linkage disequilibrium the
    insulin gene region and insulin-dependent
    diabetes mellitus (IDDM). Am J Hum Genet.
    52(3)506-16.
  • A family-based association test to test for the
    presence of genetic linkage between a genetic
    marker and a trait.

4
Background
  • An association between disease and marker may be
    due to disequilibrium between linked loci.
  • Association can occur in the absence of linkage
  • For example, as a result of population
    stratification
  • Thus it is not valid to use the presence of
    association as a test for linkage if population
    stratification is a possibility.

5
TDT Overview
  • The TDT considers parents who are heterozygous
    for an allele associated with disease and
    evaluates the frequency with which that allele or
    its alternate is transmitted to affected
    offspring.
  • The advantage
  • It does not require data either on multiple
    affected family members or on unaffected sibs.
  • The disadvantage
  • It can detect linkage between the marker and the
    disease locus only if association (due to linkage
    disequilibrium) is present.

6
One Affected Child per Family
  • Assume that
  • a disease locus D, with disease allele D1, and a
    normal allele D2
  • a marker locus with codominant alleles M1 and M2.
  • Suppose that
  • a sample of n such single-child families
  • at the marker M, a total of 4n parental alleles
  • 2n are transmitted and the other 2n are not
    transmitted

7
One Affected Child per Family (c1)
8
Chi-square Test
  • Chi-square Test
  • Oi an observed frequency
  • Ei an expected (theoretical) frequency,
    asserted by the null hypothesis
  • n the number of possible outcomes of each
    event.
  • 4n(w-y)2/(wy)(4n-w-y)

9
Validation of Statistic
  • Ott J (1989) Statistical properties of the
    haplotype relative risk. Genet Epidemiol 6127-130

10
Validation of Statistic (c1)
Only the data from heterozygous M1M2 parents
should be used in the test
11
Valid Test Statistic
12
Two Affected Children per Family
13
More than Two Affected Children in a Family
14
TDT Advantages
  • The TDT may be much more sensitive than haplotype
    sharing tests, with the same data.
  • The TDT uses simpler family data.
  • The TDT is not affected by population
    stratification.

15
TDT Disadvantages
  • The TDT will not detect linkage between disease
    and marker unless there is also population
    association (linkage disequilibrium).
  • The TDT does not make use of all family
    information, especially of founders.

16
Extension to Haplotypes
  • The simplest way is to treat haplotypes as
    multi-allelic markers.

17
FBAT
  • FBAT implements a broad class of Family Based
    Association Tests, adjusted for population
    admixture.
  • Horvath S, Xu X, Laird NM. 2001. The family based
    association test method strategies for studying
    general genotype-phenotype associations. Eur J
    Hum Genet 9301306.
  • Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST,
    Laird NM. 2004. Family-based tests for
    associating haplotypes with general phenotype
    data application to asthma genetics. Genet
    Epidemiol 266169.

18
Haplotype-based FBAT
  • Find the compatible haplotype configurations
    (mating types) for the families
  • Compute the conditional probabilities of the
    families
  • The statistic

19
Haplotype-based FBAT (c1)
  • It is natural to estimate the weights wGjk by the
    conditional probability of observing Gjk given
    that it is compatible with gj.
  • FBAT uses an expectation-maximization (EM)
    algorithm to estimate haplotype frequencies from
    which the weights are calculated.

20
THANK YOU
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