Bias in multipoint linkage analysis arising from map misspecification

Multipoint linkage analysis methods are often used in human genetic studies . Although multipoint methods increase power for a linkage analysis and wil l become essential if use of diallelic markers becomes widespread, the meth ods in use assume an accurate meiotic marker map. Unfortunately, uncertaint ies in estimates of between-marker meiotic distances are large. Also, sex-a veraged maps are generally used, but recombination rates differ in males an d females. Both these types of map misspecification can lead to lod score b ias, but such bias has not previously been systematically quantified. We ex amine multipoint lod score bias arising from these map misspecifications, i n both the presence and absence of actual linkage. We define bias as the ex pected difference between the lod score computed under the misspecified map and that computed under the true map. With actual linkage, any map misspec ification causes negative bias in lod scores, resulting in loss of power to detect linkage. In most cases, bias is modest, only reaching clearly detec table levels when both types of misspecification are substantial. In the ab sence of linkage, map misspecification can cause positive or negative bias: falsely assuming a 1:1 female:male ratio always causes positive bias; usin g too large a distance gives a positive bias; using too small a distance gi ves a negative bias. This bias can inflate the false-positive rate, especia lly when the sample size is modest. We conclude that although current sex-a veraged maps are suitable for a first-pass multipoint screen, the potential for bias from map misspecification should be evaluated in following up res ults from such an analysis. (C) 2000 Wiley-Liss, Inc.