Combining Family and Twin Data in Association Studies to Estimate the Noninherited Maternal Antigens Effect


Correspondence to: Brunilda Balliu, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Post Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail:


It is hypothesized that certain alleles can have a protective effect not only when inherited by the offspring but also as noninherited maternal antigens (NIMA). To estimate the NIMA effect, large samples of families are needed. When large samples are not available, we propose a combined approach to estimate the NIMA effect from ascertained nuclear families and twin pairs. We develop a likelihood-based approach allowing for several ascertainment schemes, to accommodate for the outcome-dependent sampling scheme, and a family-specific random term, to take into account the correlation between family members. We estimate the parameters using maximum likelihood based on the combined joint likelihood (inline image) approach. Simulations show that the inline image is more efficient for estimating the NIMA odds ratios as compared to a families-only approach. To illustrate our approach, we used data from a family and a twin study from the United Kingdom on rheumatoid arthritis, and confirmed the protective NIMA effect, with an odds ratio of 0.477 (95% CI 0.264–0.864).