To the Editor: Using meta-analysis, we showed a small but significant association between ADHD and the D4 receptor gene. Dr. Pittelli’s letter about our article highlights common misconceptions about meta-analysis and about psychiatric genetics.
He states that using meta-analysis to reconcile conflicting findings is dubious; that is not true. Meta-analysis provides a statistical framework for determining if a series of studies does or does not support a hypothesis. It provides tests of heterogeneity, which determine if conflicting findings are statistically different, and tests of covariates, which determine if demographic, design, or other factors can account for conflicting findings. Thus, the method of meta-analysis is ideally suited for clarifying apparently inconsistent findings.
Our comments on Dr. Pittelli’s numbered points are as follows:
1. We agree that meta-analysis can be misinterpreted if an original positive finding is included. Dr. Pittelli overlooked our Table 3, which showed that the meta-analysis was significant when this study was excluded.
2. There is no statistical basis for Dr. Pittelli’s assertion that a meta-analysis is biased if it includes a study from the person who performed the meta-analysis. He also overlooked Table 4, which showed that the meta-analysis was significant after omission of our study. Dr. Pittelli claims that research presented at national conferences or solicited from the ADHD Molecular Genetics Network e-mail list is biased; this is incorrect. The main bias of concern to meta-analysis is that negative studies are published, not that conference reports are more positive than published studies. Dr. Pittelli asks why we think it unfortunate that studies of ADHD and the D4 receptor gene have not consistently confirmed their association. It is unfortunate because the use of small study groups to detect small effects obscures findings and inhibits progress.
3. The claim that a meta-analysis of studies of ADHD and the D4 receptor gene must include all other genes tested makes no sense. Studies of different genes test different hypotheses. Mixing apples and oranges does not clarify any statistical analysis.
4. Dr. Pittelli incorrectly claims that whether ADHD genes truly exist remains an unproven assumption. The twin literature about ADHD clearly indicates that ADHD is one of the most heritable of psychiatric disorders
(1). Moreover, the genetics literature is consistent with a multigenic theory of ADHD
(2), despite Dr. Pittelli’s claim that such a theory is circular.
We never claimed that our meta-analysis proved the D4 receptor gene to be a susceptibility gene for ADHD. We concluded that the extant data were strong enough to warrant further studies of the D4 receptor gene and ADHD.
