An open problem of some interest in the study of HLA has been the possible existence of transmission distortion in the human HLA complex. In this paper, transmission probabilities are estimated and ...tested using data on HLA A, B and DR loci genotypes of parents and offspring ascertained from the entire population of Finland (Childhood Diabetes in Finland Study) through one or more offspring diagnosed with insulin-dependent diabetes mellitus (IDDM) during the recruitment period from September 1986 to July 1989. First, we show how to get unbiased estimates of transmission probabilities from the family data collected in the disease registry of incident cases. This is accomplished by assuming that transmission of HLA genes to children in the general population is conditionally independent given the parents’genotypes, and the birth dates of all offspring. Based on the sampling (ascertainment) process in the study on Childhood Diabetes in Finland, younger siblings of the index child (the oldest proband) are independent of the ascertainment and therefore give rise to unbiased inference regarding allele transmission. The hypothesis of Mendelian transmission of alleles at each locus was tested using the standard χ² test. Goodness-of-fit of the Mendelian inheritance model to the individual locus data is calculated by maximizing the likelihood function over allele transmission intensities at each locus. The existence of a strong transmission distortion is not supported by this study at the loci considered.
The prevalence of diabetes mellitus and impaired glucose tolerance (IGT) was determined in a random sample of the population aged 45-64 years in three areas of Finland. The two-hour oral glucose ...tolerance test was repeated in subjects whose first test suggested abnormal glucose tolerance. In the final classification, based on the results of the two tests, the age-standardized prevalence of diabetes, according to the WHO criteria was 5.7% (95% confidence interval (CI): 4.3-7.1) in men and 4.6% (95% CI: 3.6-5.0) in women. The prevalence of IGT was 3.1% (95% CI: 2.1-4.1) in men and 5.1% (95% CI: 3.9-6.3) in women. Among those aged 55-64 years the prevalence was 6.9% in men and 7.5% in women. The prevalence of diabetes and IGT were not different between the three areas. The age-specific mean values of fasting and two-hour blood concentrations and the 90th percentiles of the blood glucose distributions were also not different between the areas. The prevalence of IGT and diabetes increased with age more steeply among women than men. The median of fasting blood glucose did not change, but the 90th percentile increased with increasing age. The entire distribution of two-hour blood glucose shifted towards higher values with ageing, but the major increase was seen for the 95th percentile. The majority of the diabetic subjects were aware of their condition. The awareness was better among men than women.
We developed a test statistic based on an approach of Whittemore et al. (1987) to detect space–time clustering for non‐infectious diseases. We extended the spatial test of Whittemore et al. by ...deriving conditional probabilities for Poisson distributed random variables. To combine spatial and time distances we defined a distance matrix D, where dij is the distance between the ith and jth cell in a three‐dimensional space–time grid. Spatial and temporal components are controlled by a weight. By altering the weight, both marginal tests and the intermediate test can be reached. Allowing a continuum from a pure spatial to a pure temporal test, the best result will be gained by trying different weights, because the occurrence of a disease might show some temporal and some spatial tendency to cluster. We examined the behaviour of the test statistic by simulating different distributions for cases and the population. The test was applied to the incidence data of insulin‐dependent diabetes mellitus in Finland. This test could be used in the analysis of data which are localized according to map co‐ordinates, by addresses or postcodes. This information is important when using the Geographical Information System (GIS) technology to compute the pairwise distances needed for the proposed test.
Potts model for haplotype associations Moltchanova, Elena V; Pitkäniemi, Janne; Haapala, Laura
BMC genetics,
12/2005, Letnik:
6 Suppl 1, Številka:
S1
Journal Article
Odprti dostop
Bayesian spatial modeling has become important in disease mapping and has also been suggested as a useful tool in genetic fine mapping. We have implemented the Potts model and applied it to the ...Genetic Analysis Workshop 14 (GAW14) simulated data. Because the "answers" were known we have analyzed latent phenotype P1-related observed phenotypes affection status (genetically determined) and i (random) in the Danacaa population replicate 2. Analysis of the microsatellite/single-nucleotide polymorphism-based haplotypes at chromosomes 1 and 3 failed to identify multiple clusters of haplotype effects. However, the analysis of separately simulated data with postulated differences in the effects of the two clusters has yielded clear estimated division into the two clusters, demonstrating the correctness of the algorithm. Although we could not clearly identify the disease-related and the non-associated groups of haplotypes, results of both GAW14 and our own simulation encourage us to improve the efficiency and sensitivity of the estimation algorithm and to further compare the proposed method with more traditional methods.
Standard regression models for disease incidence data can be used to test for associations between a disease and measured genetic and environmental factors and their interactions. Complications arise ...when the gene is not observed, requiring segregation and linkage analysis approaches, or when the candidate gene(s) are found to be highly polymorphic, as in the HLA region. We propose a Bayesian approach to the latter problem, in which the log relative risks for all alleles at a given locus are taken to be independent and exchangeable, assuming there is no preferential zygotic assortment and negligible recombination. Multi-locus problems can be addressed either by adding exchangeable interaction terms or by adopting a multivariate prior for haplotype effects. Some simulations based on our current work on family studies of IDDM are discussed.
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