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A comparison of popular TDT‐generalizations for family‐based association analysis
Author(s) -
Hecker Julian,
Laird Nan,
Lange Christoph
Publication year - 2019
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.22181
Subject(s) - pedigree chart , linkage disequilibrium , disequilibrium , transmission disequilibrium test , population stratification , genetic association , type i and type ii errors , association test , genetics , robustness (evolution) , association (psychology) , linkage (software) , statistics , biology , mathematics , genotype , psychology , medicine , haplotype , gene , ophthalmology , single nucleotide polymorphism , psychotherapist
Abstract The transmission disequilibrium test (TDT) is the gold standard for testing the association between a genetic variant and disease in samples consisting of affected individuals and their parents. In practice, more complex pedigree structures, that is siblings with no parents, or three‐generational pedigrees with possibly missing genotypes, are common. There are several generalizations of the TDT that are suitable for use with arbitrary pedigree structures. We consider three such frequently used generalizations, family‐based association test, pedigree disequilibrium test, and generalized disequilibrium test, that have accompanying software and compare them regarding validity and power in the single variant setting. We use simulations to study the effects of population admixture, populations whose genotypes are not in Hardy–Weinberg equilibrium (HWE), different pedigree structures, and the presence of linkage. Whereas our results show that some TDT generalizations can have a substantially increased Type 1 error, these tests are often used in substantive research without caveats about the validity of their Type 1 error. For the association analysis of rare variants in sequencing studies, region‐based extensions of the TDT generalizations, that rely on the postulated robustness of the single variant tests, have been proposed. We discuss the implications of our results for these region‐based extensions.