title: Analysis of Case-Parent Trios Using a Loglinear Model with Adjustment for Transmission Ratio Distortion.
abstract: Transmission of the two parental alleles to offspring deviating from the Mendelian ratio is termed Transmission Ratio Distortion (TRD), occurs throughout gametic and embryonic development. TRD has been well-studied in animals, but remains largely unknown in humans. The Transmission Disequilibrium Test (TDT) was first proposed to test for association and linkage in case-trios (affected offspring and parents); adjusting for TRD using control-trios was recommended. However, the TDT does not provide risk parameter estimates for different genetic models. A loglinear model was later proposed to provide child and maternal relative risk (RR) estimates of disease, assuming Mendelian transmission. Results from our simulation study showed that case-trios RR estimates using this model are biased in the presence of TRD; power and Type 1 error are compromised. We propose an extended loglinear model adjusting for TRD. Under this extended model, RR estimates, power and Type 1 error are correctly restored. We applied this model to an intrauterine growth restriction dataset, and showed consistent results with a previous approach that adjusted for TRD using control-trios. Our findings suggested the need to adjust for TRD in avoiding spurious results. Documenting TRD in the population is therefore essential for the correct interpretation of genetic association studies.
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University Montréal, QC, Canada.
authors.forename: Lam O
authors.initials: LO
authors.lastname: Huang
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University Montréal, QC, Canada.
authors.forename: Claire
authors.initials: C
authors.lastname: Infante-Rivard
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill UniversityMontréal, QC, Canada; Department of Psychiatry, McGill UniversityMontréal, QC, Canada; Douglas Mental Health University InstituteMontréal, QC, Canada.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Labbe
keywords: Transmission Ratio Distortion; case-parent triad; case-parent trios; family-based association analysis; intrauterine growth restriction; intrauterine growth retardation; log-linear model; meiotic drive