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Am J Hum Genet. 1998 Mar;62(3):690-7.

Significance levels in complex inheritance.

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  • 1Human Genetics, University of Southampton, Anne Hospital, Southampton, United Kingdom.

Erratum in

  • Am J Hum Genet 1998 Oct;63(4):1252.


A LOD score >=3 is necessary but not sufficient to make a linkage test reliable, and this applies to complex inheritance as well as to major loci. Factors that affect this threshold are considered here. A LOD score as small as 2 is suggestive but is unreliable except as confirmation of either a significant linkage or a strong candidate locus. A threshold as great as 4 is unnecessarily conservative if multipoint tests are used sensibly. Marker density is not a major factor, and biases in the evaluation of LOD scores-especially inadequate allowance for estimation of nuisance parameters in multiple models-are paramount. Allelic association increases resolution for oligogenes within a candidate region and remains the only practical method to locate polygenes. The method sketched here combines multipoint linkage and allelic association to test efficiently for a regional candidate locus.

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