Several factors limit the interpretation of the study findings. Different diagnostic instruments were used to assess substance dependence (see Table S1 in the online supplement). Although the validity of each of these instruments has been well established, variation between instruments could add noise to the measured behavioral phenotype. This, however, could be an advantage because the extrapolation of significant findings to the general population is also likely to be more robust by virtue of generalizing across different methods of assessment. The absence of nutrition and education information, which are potential confounders, also limits the interpretability of the results. A perennial concern with multisite studies is variation attributable to different scanners and acquisition protocols. This issue was mitigated by using a standard data extraction protocol developed by the ENIGMA project that has been validated in previous multisite reports (20, 28−30) and by the formal consideration of potential site differences in all statistical analyses. As discussed above, the degree of exposure to the various substances was not characterized uniformly across studies, which limits, for instance, the interpretation of the widespread alcohol effects
