The significance of not finding a gene

As more investigators conduct extensive whole-genome linkage scans for comp lex traits, interest is growing in meta-analysis as a way of integrating th e weak or conflicting evidence from multiple studies. However, there is a b ias in the most commonly used meta-analysis linkage technique (i.e., Fisher 's [1925] method of combining of P values) when it is applied to many nonpa rametric (i.e., model free) linkage results. The bias arises in those metho ds (e.g., variance components, affected sib pair, extremely discordant sib pairs, etc.) that truncate all "negative evidence against linkage" into the single value of LOD = 0. If incorrectly handled, this bias can artificiall y inflate or deflate the combined meta-analysis linkage results for any giv en locus. This is an especially troublesome problem in the context of a gen ome scan, since LOD = 0 is expected to occur over half the unlinked genome. The bias can be overcome (nearly) completely by simply interpreting LOD = 0 as a P value of 1/2In(2) approximate to .72 in Fisher's formula.