This study has limitations. First, as in any meta-analysis, sample heterogeneity could not be completely avoided. Studies had diverse ascertainment schemes, with some designed to recruit dependent cases for one particular substance. Some studies recruited from the general population while others recruited potentially more extreme cases from treatment centers. Hence, over- and under-representation of phenotypes were present in contributing datasets, and the severity of dependence, degree of co-morbid dependence, and prevalence of substance exposure varied. Reduced proportions of exposed controls would reduce effective sample size and power for a study. But overall, uniform phenotype definitions were an important design feature to ameliorate effects of heterogeneity. Although some bias may have occurred, it seems unlikely to have been systematic in either direction. Similarly, it seems unlikely that systematic bias would have occurred due to differences between studies that contributed to this meta-analysis and those that declined to participate.
