GUESS LOD APPROACH - SUFFICIENT CONDITIONS FOR ROBUSTNESS

Analysis of genetic linkage between a disease and a marker locus requi res specifying a genetic model describing both the inheritance pattern and the gene frequencies of the marker and trait loci. Misspecificati on of the genetic model is likely for etiologically complex diseases. In previous work we have shown through analytic studies that misspecif ying the genetic model for disease inheritance does not lead to excess false-positive evidence for genetic linkage provided the genetic mark er alleles of all pedigree members are known, or can be inferred witho ut bias from the data. Here, under various selection or ascertainment schemes we extend these previous results to situations in which the ge netic model for the marker locus may be incorrect, We provide sufficie nt conditions for the asymptotic unbiased estimation of the recombinat ion fraction under the null hypothesis of no linkage, and also conditi ons for the limiting distribution of the likelihood ratio test for no linkage to be chi-squared. Through simulation studies we document some situations under which asymptotic bias can result when the genetic mo del is misspecified. Among those situations under which an excess of f alse-positive evidence for genetic linkage can be generated, the most common is failure to provide accurate estimates of the marker allele f requencies. We show that in most cases false-positive evidence for gen etic linkage is unlikely to result solely from the misspecification of the genetic model for disease or trait inheritance. (C) 1995 Wiley-Li ss, Inc.