Transmission Disequilibrium Test
Also known as: TDT, Family-based association test
The Transmission Disequilibrium Test (TDT) is a family-based statistical method for testing genetic association with disease or traits while inherently controlling for population stratification. Developed by Spielman and Ewens in 1993, the TDT examines whether an allele is preferentially transmitted from heterozygous parents to affected children compared to unaffected children. By comparing transmission patterns within families, the TDT avoids the confounding effects of population structure that plague case-control studies, making it particularly valuable in admixed or stratified populations.
Key highlights
- Inherently immune to population stratification and admixture artifacts
- Tests for true genetic association, not association due to ancestry differences
- Relatively simple to perform with basic pedigree data
- Can be combined with case-control data for increased power (via hybrid designs)
- Can be extended to test multiple relatives (FBAT) or quantitative traits
Intuition
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How it works
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When to use it
Use TDT when you have family pedigree data with affected children and can genotype parents. TDT is especially valuable in populations with known or suspected stratification (admixed populations, case-control recruitment from multiple sources). Avoid TDT if parental genotypes are unavailable or when studying diseases with late onset (parents may be unavailable). TDT is less powerful than case-control studies in large homogeneous populations but more robust to stratification.
Strengths & limitations
- Inherently immune to population stratification and admixture artifacts
- Tests for true genetic association, not association due to ancestry differences
- Relatively simple to perform with basic pedigree data
- Can be combined with case-control data for increased power (via hybrid designs)
- Can be extended to test multiple relatives (FBAT) or quantitative traits
- Requires family data and parental genotypes, limiting applicability
- Lower statistical power than large case-control studies
- Cannot use cases without available parents (reduces sample size)
- Assumes Mendelian inheritance; non-Mendelian transmission distortion violates assumptions
- Computationally less efficient than case-control approaches for genome-wide scanning
Common pitfalls
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Applications
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Frequently asked
What is the difference between the TDT and case-control association testing?
Case-control studies compare allele frequencies between affected and unaffected individuals from the population. TDT compares allele transmission patterns within families. TDT is immune to population stratification, while case-control studies are vulnerable unless stratification is controlled statistically.
Why do only heterozygous parents contribute to the TDT?
Homozygous parents transmit only one allele type to offspring, providing no information about relative transmission rates. Only heterozygous parents can transmit either allele, allowing comparison of transmission frequencies between affected and unaffected children.
Can the TDT detect protective alleles?
Yes. A protective allele would show reduced transmission to affected children compared to unaffected children. The TDT statistic captures both risk and protective effects, though the interpretation is opposite (reduced transmission indicates protection).
How many families are needed for adequate TDT power?
Power depends on allele frequency, penetrance, and effect size. For moderate effect sizes, 100–500 informative families (with heterozygous parents and affected offspring) are often needed. Larger sample sizes improve power dramatically. Computer simulation can estimate required sample size for specific scenarios.
Sources
- 1.Spielman, R. S., McGinnis, R. E., & Ewens, W. J. (1993). Transmission test for linkage disequilibrium. American Journal of Human Genetics, 52(3), 506–516.
- 2.Sham, P. C. (1998). Statistics in human genetics. London: Arnold.
- 3.Laird, N. M., & Lange, C. (2006). Family-based designs in the age of large-scale gene-association studies. Nature Reviews Genetics, 7(5), 385–394.
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ScholarGate. (2026, June 3). Transmission Disequilibrium Test. ScholarGate. https://scholargate.app/genetics/transmission-disequilibrium-test