Other methods have been proposed for the joint analysis of family-based and unrelated samples. Zhu et al. [44] suggest a model that utilizes PCA to estimate the genetic ancestry of sampled individuals. The effect of ancestry is regressed out of both genotypes and phenotypes prior to testing for association. Rather than modeling transmissions, the approach treats families as correlated clusters of observations. This is in contrast to our method, which preserves the family structure inherent in the trio design. Finally, these authors assume that parents and offspring are phenotyped, which is often not the case in practice. Another more general approach is known as ROADTRIPS [45]. This procedure uses a covariance matrix estimated from genome-screen data to correct for unknown population and pedigree structure, as well as accounting for known pedigree information. While this method has the advantage of flexibility, it does not model transmissions within families. Both of these methods work best if the cases and controls are sampled from a common population. When the controls are obtained as a sample of convenience, approaches that regress out the effect of ancestry are not fully robust to confounding [17].
