TY - JOUR

T1 - The significance of not finding a gene

AU - Province, M. A.

N1 - Funding Information:
This work was partially supported by National Institutes of Health grants GM28719 and HL54473.

PY - 2001

Y1 - 2001

N2 - As more investigators conduct extensive whole-genome linkage scans for complex traits, interest is growing in meta-analysis as a way of integrating the weak or conflicting evidence from multiple studies. However, there is a bias 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 nonparametric (i.e., model free) linkage results. The bias arises in those methods (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 artificially inflate or deflate the combined meta-analysis linkage results for any given locus. This is an especially troublesome problem in the context of a genome 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 1/2ln(2) ≅ .72 in Fisher's formula.

AB - As more investigators conduct extensive whole-genome linkage scans for complex traits, interest is growing in meta-analysis as a way of integrating the weak or conflicting evidence from multiple studies. However, there is a bias 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 nonparametric (i.e., model free) linkage results. The bias arises in those methods (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 artificially inflate or deflate the combined meta-analysis linkage results for any given locus. This is an especially troublesome problem in the context of a genome 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 1/2ln(2) ≅ .72 in Fisher's formula.

UR - http://www.scopus.com/inward/record.url?scp=0034887388&partnerID=8YFLogxK

U2 - 10.1086/323316

DO - 10.1086/323316

M3 - Article

C2 - 11481587

AN - SCOPUS:0034887388

VL - 69

SP - 660

EP - 663

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -