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American Journal of Human Genetics Sep 1998Maximum-likelihood analysis (via LOD score) provides the most powerful method for finding linkage when the mode of inheritance (MOI) is known. However, because one must...
Maximum-likelihood analysis (via LOD score) provides the most powerful method for finding linkage when the mode of inheritance (MOI) is known. However, because one must assume an MOI, the application of LOD-score analysis to complex disease has been questioned. Although it is known that one can legitimately maximize the maximum LOD score with respect to genetic parameters, this approach raises three concerns: (1) multiple testing, (2) effect on power to detect linkage, and (3) adequacy of the approximate MOI for the true MOI. We evaluated the power of LOD scores to detect linkage when the true MOI was complex but a LOD score analysis assumed simple models. We simulated data from 14 different genetic models, including dominant and recessive at high (80%) and low (20%) penetrances, intermediate models, and several additive two-locus models. We calculated LOD scores by assuming two simple models, dominant and recessive, each with 50% penetrance, then took the higher of the two LOD scores as the raw test statistic and corrected for multiple tests. We call this test statistic "MMLS-C." We found that the ELODs for MMLS-C are >=80% of the ELOD under the true model when the ELOD for the true model is >=3. Similarly, the power to reach a given LOD score was usually >=80% that of the true model, when the power under the true model was >=60%. These results underscore that a critical factor in LOD-score analysis is the MOI at the linked locus, not that of the disease or trait per se. Thus, a limited set of simple genetic models in LOD-score analysis can work well in testing for linkage.
Topics: Chromosome Mapping; Genes, Dominant; Genes, Recessive; Heterozygote; Homozygote; Humans; Likelihood Functions; Lod Score; Models, Genetic; Models, Statistical
PubMed: 9718328
DOI: 10.1086/301997 -
Nature Genetics Dec 1995
Topics: Algorithms; Humans; Lod Score; Software
PubMed: 7493007
DOI: 10.1038/ng1295-354 -
Nature Genetics Sep 1993
Topics: Genes; Genetics, Medical; Homosexuality; Humans; Lod Score; Male; Prejudice; Publishing
PubMed: 8220417
DOI: 10.1038/ng0993-1 -
American Journal of Human Genetics Jun 1996The power to detect linkage by the LOD-score method is investigated here for diseases that depend on the effects of two genes. The classical strategy is, first, to...
The power to detect linkage by the LOD-score method is investigated here for diseases that depend on the effects of two genes. The classical strategy is, first, to detect a major-gene (MG) effect by segregation analysis and, second, to seek for linkage with genetic markers by the LOD-score method using the MG parameters. We already showed that segregation analysis can lead to evidence for a MG effect for many two-locus models, with the estimates of the MG parameters being very different from those of the two genes involved in the disease. We show here that use of these MG parameter estimates in the LOD-score analysis may lead to a failure to detect linkage for some two-locus models. For these models, use of the sib-pair method gives a non-negligible increase of power to detect linkage. The linkage-homogeneity test among subsamples differing for the familial disease distribution provides evidence of parameter misspecification, when the MG parameters are used. Moreover, for most of the models, use of the MG parameters in LOD-score analysis leads to a large bias in estimation of the recombination fraction and sometimes also to a rejection of linkage for the true recombination fraction. A final important point is that a strong evidence of an MG effect, obtained by segregation analysis, does not necessarily imply that linkage will be detected for at least one of the two genes, even with the true parameters and with a close informative marker.
Topics: Alleles; Family; Female; Genetic Diseases, Inborn; Genetic Linkage; Genetic Markers; Humans; Lod Score; Male; Models, Genetic; Models, Statistical; Pedigree; Software
PubMed: 8651311
DOI: No ID Found -
American Journal of Human Genetics Oct 1994Determining the mode of inheritance is often difficult under the best of circumstances, but when segregation analysis is used, the problems of ambiguous ascertainment...
Determining the mode of inheritance is often difficult under the best of circumstances, but when segregation analysis is used, the problems of ambiguous ascertainment procedures, reduced penetrance, heterogeneity, and misdiagnosis make mode-of-inheritance determinations even more unreliable. The mode of inheritance can also be determined using a linkage-based method (maximized maximum lod score or mod score) and association-based methods, which can overcome many of these problems. In this work, we determined how much information is necessary to reliably determine the mode of inheritance from linkage data when heterogeneity and reduced penetrance are present in the data set. We generated data sets under both dominant and recessive inheritance with reduced penetrance and with varying fractions of linked and unlinked families. We then analyzed those data sets, assuming reduced penetrance, both dominant and recessive inheritance, and no heterogeneity. We investigated the reliability of two methods for determining the mode of inheritance from the linkage data. The first method examined the difference (delta) between the maximum lod scores calculated under the two mode-of-inheritance assumptions. We found that if delta was > 1.5, then the higher of the two maximum lod scores reflected the correct mode of inheritance with high reliability and that a delta of 2.5 appeared to practically guarantee a correct mode-of-inheritance inference. Furthermore, this reliability appeared to be virtually independent of alpha, the fraction of linked families in the data set, although the reliability decreased slightly as alpha fell below .50.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Female; Genetics, Medical; Humans; Lod Score; Male; Models, Genetic; Models, Statistical; Nuclear Family; Probability
PubMed: 7942860
DOI: No ID Found -
Annals of Human Genetics Jan 1995To detect linkage between a trait and a marker, Morton (1955) proposed to calculate the lod score z(theta 1) at a given value theta 1 of the recombination fraction. If...
To detect linkage between a trait and a marker, Morton (1955) proposed to calculate the lod score z(theta 1) at a given value theta 1 of the recombination fraction. If z(theta 1) reaches +3 then linkage is concluded. However, in practice, lod scores are calculated for different values of the recombination fraction between 0 and 0.5 and the test is based on the maximum value of the lod score Zmax. The impact of this deviation of the test on the probability that in fact linkage does not exist, when linkage was concluded, is documented here. This posterior probability of no linkage can be derived by using Bayes' theorem. It is less than 5% when the lod score at a predetermined theta 1 is used for the test. But, for a Zmax of +3, we showed that it can reach 16.4%. Thus, considering a composite alternative hypothesis instead of a single one decreases the reliability of the test. The reliability decreases rapidly when Zmax is less than +3. Given a Zmax of +2.5, there is a 33% chance that linkage does not exist. Moreover, the posterior probability depends not only on the value of Zmax but also jointly on the family structures and on the genetic model. For a given Zmax, the chance that linkage exists may then vary.
Topics: Genetic Markers; Humans; Lod Score; Probability
PubMed: 7762980
DOI: 10.1111/j.1469-1809.1995.tb01610.x -
Clinical Genetics Aug 1987From a large Danish material of random families we selected families with dyslexia as reported by the families themselves and as recorded by a dyslexia institute. Among...
From a large Danish material of random families we selected families with dyslexia as reported by the families themselves and as recorded by a dyslexia institute. Among five "backcross families" studied for chromosome 15 polymorphisms we found only negative lod scores, and at theta = 0.10 a negative score of -3.42; i.e., in our material we did not find any confirmation of the indication of linkage between dyslexia and a chromosome 15 polymorphism found in part of their material by Smith et al. (1983, 1986).
Topics: Chromosomes, Human, Pair 15; Denmark; Dyslexia; Female; Genetic Linkage; Humans; Lod Score; Male; Polymorphism, Genetic
PubMed: 3652490
DOI: 10.1111/j.1399-0004.1987.tb03337.x -
Genetic Epidemiology 1990A computer-simulation method is presented for determining and correcting for the effect of maximizing the lod score over disease definitions, penetrance values, and...
A computer-simulation method is presented for determining and correcting for the effect of maximizing the lod score over disease definitions, penetrance values, and perhaps other model parameters. The method consists of simulating the complete analysis using marker genotypes randomly generated under the assumption of free recombination. It is applicable as a "post-treatment" to linkage analyses of any trait with an uncertain mode of inheritance and/or disease definition. When the method is applied to a linkage analysis of schizophrenia versus chromosome 5 markers, we find that, in this specific case, the P-value associated with a maximum lod score of 3 is equal to 0.0003. We also find that a lod score of 3.0 should be "deflated" by approximately 0.3 to 1 units, and, by tentative extrapolation, the observed lod score of 6.5 should be "deflated" by 0.7 to 1.5 units.
Topics: Chromosomes, Human, Pair 5; Computer Simulation; Genetic Linkage; Genetic Techniques; Humans; Lod Score; Models, Genetic; Schizophrenia
PubMed: 2227370
DOI: 10.1002/gepi.1370070402 -
A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers.BMC Genetics Dec 2005Complex diseases are often reported along with disease-related traits (DRT). Sometimes investigators consider both disease and DRT phenotypes separately and sometimes...
Complex diseases are often reported along with disease-related traits (DRT). Sometimes investigators consider both disease and DRT phenotypes separately and sometimes they consider individuals as affected if they have either the disease or the DRT, or both. We propose instead to consider the joint distribution of the disease and the DRT and do a linkage analysis assuming a pleiotropic model. We evaluated our results through analysis of the simulated datasets provided by Genetic Analysis Workshop 14. We first conducted univariate linkage analysis of the simulated disease, Kofendrerd Personality Disorder and one of its simulated associated traits, phenotype b (fear/discomfort with strangers). Subsequently, we considered the bivariate phenotype, which combined the information on Kofendrerd Personality Disorder and fear/discomfort with strangers. We developed a program to perform bivariate linkage analysis using an extension to the Elston-Stewart peeling method of likelihood calculation. Using this program we considered the microsatellites within 30 cM of the gene pleiotropic for this simulated disease and DRT. Based on 100 simulations of 300 families we observed excellent power to detect linkage within 10 cM of the disease locus using the DRT and the bivariate trait.
Topics: Databases, Genetic; Fear; Genetics, Population; Humans; Lod Score; Penetrance; Personality Disorders; Quantitative Trait, Heritable
PubMed: 16451570
DOI: 10.1186/1471-2156-6-S1-S113 -
Human Heredity 2004We here consider the null distribution of the maximum lod score (LOD-M) obtained upon maximizing over transmission model parameters (penetrance values, dominance, and...
We here consider the null distribution of the maximum lod score (LOD-M) obtained upon maximizing over transmission model parameters (penetrance values, dominance, and allele frequency) as well as the recombination fraction. Also considered is the lod score maximized over a fixed choice of genetic model parameters and recombination-fraction values set prior to the analysis (MMLS) as proposed by Hodge et al. The objective is to fit parametric distributions to MMLS and LOD-M. Our results are based on 3,600 simulations of samples of n = 100 nuclear families ascertained for having one affected member and at least one other sibling available for linkage analysis. Each null distribution is approximately a mixture p(2)(0) + (1 - p)(2)(v). The values of MMLS appear to fit the mixture 0.20(2)(0) + 0.80chi(2)(1.6). The mixture distribution 0.13(2)(0) + 0.87chi(2)(2.8). appears to describe the null distribution of LOD-M. From these results we derive a simple method for obtaining critical values of LOD-M and MMLS.
Topics: Alleles; Genetic Linkage; Genotype; Humans; Likelihood Functions; Linkage Disequilibrium; Lod Score; Models, Genetic; Models, Statistical; Recombination, Genetic; Statistics, Nonparametric; Time Factors
PubMed: 15133311
DOI: 10.1159/000077388