Haplotype-based score test for linkage in nuclear families

We estimated haplotype frequencies using the parental and affected offspring's genotypes and then constructed a transmission/non-transmission table for the parental haplotypes transmitted to the offspring. We then proposed a test for checking the marginal homogeneity in the table. Because the cells in the table were dependent due to the uncertainty of the parental haplotypes, we adopted a randomization procedure to estimate the significance of the observed test statistic. Simulations show that our test performs well on a nominal level and has a monotone power, which increases as the relative risk increases. With our test, there was no evidence of genetic linkage between the ACE gene and hypertension in the Korean adolescent cohort.We developed a score test for linkage and used simulations to demonstrate that our test performs well at a nominal level. Under some situations where the diversity of haplotypes is low, the proposed test gained a little power over the method based on only variances between marginal differences in a transmission/non-transmission table.For linkage and/or association studies based on haplotypes, molecular haplotyping can be done for each individual, but at a high cost. Instead, statistical methods such as Clark's algorithm [1], the EM algorithm [2], or Gibb's sampler method [3], are commonly used to reconstruct haplotypes. The likelihood ratio test, which is based on the difference between the sum of the log-likelihoods of the case and control groups and the log-likelihood of the combined data, is usually used for case-control association studies [4], while the TDT is used for linkage and/or association studies in nuclear families. The latter compares the frequency of transmitted parental haplotypes with that of non-transmitted parental haplotypes to an affected offspring. One of the difficulties with the TDT is that there is uncertainty in estimating haplotype frequencies from parental genotypes. Wilson [5] and Clayton and Jones [6] proposed