Question regarding TDT/DFAM with mother-child duo data (include_duos hardcoded to 0)

[Yujin Kim]

Dear Christopher,

I am currently am preparing to run a Transmission Disequilibrium Test (TDT).

My dataset has a specific structure: it consists entirely of mother-child duos (father information is completely missing). 

While trying to understand how PLINK handles missing parents during these tests, I reviewed the PLINK 1.9 source code (specifically family.c). I noticed that the get_trios_and_families function accepts an include_duos parameter. However, when this function is called within the tdt(), dfam(), and qfam() functions, the parameter is hardcoded to 0 (e.g., retval = get_trios_and_families(..., 0, multigen);). As a result, my duo families are entirely skipped during the analysis.

I have two questions regarding this:

1. Could you kindly explain the statistical or algorithmic reasoning behind forcing the exclusion of duos in these family-based association tests? I suspect it might be related to the difficulty of properly testing the null hypothesis of a 50:50 transmission rate without both parents, but I would greatly appreciate your expert insight.

2. Given my data structure, is writing a custom script (e.g., in R or Python) to manually count the transmitted/untransmitted alleles from heterozygous mothers and performing a binomial test the only statistically sound workaround? Or is there a specific method or flag in PLINK 1.9 (or PLINK 2.0) that I might have missed that can handle this duo-only scenario?

Thank you very much for your time and for maintaining such an invaluable tool.

Sincerely,

Yujin

[Chris Chang]

This is outside PLINK's scope.  The TDT is based on variants where both parental genotypes are known, and at least one is heterozygous.  For duos, one parental genotype is unknown, so the TDT can't be used.

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