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Incorporating Heterogeneity of Maternal Effects for Precisely Detecting Parent-of-Origin Effect

Incorporating Heterogeneity of Maternal Effects for Precisely Detecting Parent-of-Origin Effect. Jingyuan Yang Research Meeting 02/13/2008. PO-LRT Test (Weinberg 1999). Frequencies in Case-Parents Triads. PO-LRT TEST (CONT.). Frequencies in Case-Parents Triads. 211. 121. DD. Dd. Dd.

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Incorporating Heterogeneity of Maternal Effects for Precisely Detecting Parent-of-Origin Effect

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  1. Incorporating Heterogeneity of Maternal Effects for Precisely Detecting Parent-of-Origin Effect Jingyuan Yang Research Meeting 02/13/2008

  2. PO-LRT Test (Weinberg 1999) Frequencies in Case-Parents Triads

  3. PO-LRT TEST (CONT.) Frequencies in Case-Parents Triads 211 121 DD Dd Dd DD Dd dD S2*RM*μ2 =S2*(RP*IM)*μ2 S1*RP*μ2

  4. PO-LRT TEST (CONT.) Frequencies in Case-Parents Triads Odds M>P S2/S1 IMS2/S1 IMS2 IMS1 S1

  5. PO-LRT Test (Cont.) Fit this model by using standard software package, e.g. glm in R Conduct chi-square test on the significance of the coefficient log(IM): H0: log(IM)=0 vs. HA: log(IM)≠0, which is equivalent to H0: IM=1 vs. HA: IM≠1. ↓ No Imprinting ↓ Imprinting

  6. POWER OF PO-LRT TEST Power of detecting Paternal imprinting (more maternal expression) is consistently lower than detecting maternal imprinting ↓ Indicates maternal effect and paternal imprinting (more maternal expression) are confounded |--| |---------------------------------------------------------| ↓ Complete Imprinting ↓ Partial Imprinting

  7. Heterogeneity of Maternal Effects • Assume that maternal affect is proportional to the amount of maternal microchimerism (MMc) • Different levels of MMc could result in heterogeneous maternal effects: Homogeneous Heterogeneous

  8. REFERENCES Quantitative Analysis of the Bidirectional Fetomaternal Transfer of Nucleated Cells and Plasma DNA (2000) Microchimerism: An Investigative Frontier in Autoimmunity and Transplantation (2004) Quantification of maternal microchimerism by HLA-specific real-time polymerase chain reaction: Studies of healthy women and women with scleroderma (2004) Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet β cell microchimerism (2007) ……

  9. PO-GLMM Test Generalized Linear Mixed-Effect Model for Testing Parent-of-Origin Effect Fit this model by using SAS proc GLIMMIX

  10. Compare PO-LRT to PO-GLMM Based on S1=1, S2=3, RP=1, R2=3, 500 simulations, Paternal imprinting

  11. DISCUSSION Gene vs. Marker • Frequencies of disease locus alleles: p and 1-p • Frequencies of marker locus alleles: g and 1-g LD Measure D = ω1 – pg Normalized LD Measure :

  12. DISCUSSION Evaluate performance of PO-LRT and PO-GLMM at markers (instead of disease locus) vs. different normalized LD measures Derive power of score test of log(IM)=0 in terms of p, g and normalized LD measures, I, S1 and S2 , then find out why maternal effect and paternal imprinting (more maternal expression) are confounded Avoid confounding in PO-GLMM

  13. DISCUSSION Distributions of log(S1), log(S2) • Support: • [0, +∞): Detrimental Maternal Effect • (-∞, 0]: Protective Maternal Effect • (-∞, +∞): Mix • Shape: Continuous Discrete Mixture of a point mass and a continuous distribution

  14. Robustness of PO-GLMM GLMM assumes that random effects follow a Normal distribution Assess Robustness of PO-GLMM Discussion

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