Despite these seemingly positive findings, some studies have found associations in the opposite direction to that predicted, i.e., the risk allele for ADHD seems to confer a protective effect on the endophenotype.55–57 These conflicting results and failures to replicate (see Kebir et al.60 for a comprehensive review and meta-analysis) have led to “a failure to establish a consistent pattern of findings on the modes of action of known risk genes [in] the current literature.”43 This situation strongly emphasizes the need to consider and refine the methodologic approach to selecting endophenotypes for molecular genetic research. Although means comparison analyses can be easily employed by nonstatisticians and have certain intuitive appeal, they are subject to several limitations: neither the familial variance underlying the measurement nor the covariance with ADHD can be parsed into separable genetic and environmental components;61 the amount of familial sharing is not explicitly quantified; and it is difficult to compare between measurements. SEM of twin data addresses all three of these problems. To the authors’ knowledge, only one study has directly compared the results of SEM and means comparison
