Robustness of the unified model to shared environmental effects in the analysis of dichotomous traits

Demenais, Florence; Abel, Laurent

doi:10.1002/gepi.1370060140

Cited by 12 publications

(5 citation statements)

References 7 publications

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“…Genetic analysis has its own techniques (i.e., segregation and linkage analysis). One can only establish the existence of a major gene by doing a genetic analysis of several pedigrees or one very large multigenerational pedigree, but care is needed in interpreting results based on one pedigree if variables are skewed in the presence of a sib-sib correlation (Go et al 1978; Eaves 1983; Demenais and Abel 1989). Such studies need to be confirmed by linkage studies.…”

Section: Heterogeneity Within Groupsmentioning

confidence: 99%

Eye Tracking Dysfunction and Schizophrenia: A Critical Perspective

Levy

Holzman

Matthysse

et al. 1993

Schizophrenia Bulletin

276

196

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Eye tracking dysfunction (ETD) has been found in large numbers of schizophrenia patients and their first-degree relatives. Because of the many replications of the central findings, ETD has been proposed as a useful way of expanding the schizophrenia phenotype in genetic studies. We critically review the literature on ETD with respect to issues of measurement and the search for quantitative indices of ETD; syndrome and familial specificity of ETD for schizophrenia; statistical, interpretive, and methodological considerations in the use of mixture analysis; the association of ETD with clinically and psychometrically defined schizotypy; and the questions of trait stability and medication effects.

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Section: Heterogeneity Within Groupsmentioning

confidence: 99%

Eye Tracking Dysfunction and Schizophrenia: A Critical Perspective

Levy

Holzman

Matthysse

et al. 1993

Schizophrenia Bulletin

276

196

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“…To infer segregation of a major gene, the Mendelian transmission of a major effect should fit the data and absence of parent-offspring transmission should be rejected against the general transmission model. It has been shown that tests of these two hypotheses prevent false inference of a major gene [Demenais and Abel, 1989;Demenais et al, 1986;Demenais et al, 1990]. However, false rejection of a major gene effect may occur due to mis-specification of the disease status Parameter value is constrained to equal preceding parameter value and is not estimated in this model.…”

Section: Discussionmentioning

confidence: 97%

Segregation analysis of idiopathic scoliosis: Demonstration of a major gene effect

et al. 1999

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Segregation analysis using a model with age and gender effects was applied to 101 pedigrees ascertained through a proband with idiopathic scoliosis. The transmission probability model was used to detect major gene effect. When we analyzed the pedigrees where affected status was assigned to persons with a Cobb's angle of more than 5 degrees we did not detect a significant major gene effect. However, when the affected status was assigned to persons with pronounced forms of disease only (a curve of at least 11 degrees) a significant contribution of a major causal gene could be established and inheritance could be described according to a dominant major gene diallele model, assuming incomplete sex and age dependent penetrance of genotypes. According to this model, the pronounced forms of idiopathic scoliosis should never occur in the absence of the mutant allele. This indicates that only the carriers of the mutant allele develop pronounced forms of the disease. At the same time, only a fraction of the carriers of the mutant gene should manifest the disease (30% of males and 50% of females).

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“…However, performing the tests of transmission probabilities avoided false inference of a major gene in all replicates. Thus, protection against spurious conclusion of a major gene requires testing both the hypothesis of Mendelian transmission and that of no parent-offspring transmission of the major effect, as shown in previous simulation studies [Demenais and Abel, 1989;Demenais et al, 19921. When the data were generated under a major gene hypothesis with specific mortality due to the disease, the analyses using the UM-mortality class and the RLM led to considerable loss of power for the conclusion of a major gene and serious bias in parameter estimates. These problems were less important using the UM-incidence class.…”

Section: Discussionmentioning

confidence: 99%

Complex segregation analysis of familial diseases with variable age of onset: Comparison of different methods by a simulation study

Abel

Garcia

Demenais

1995

Genetic Epidemiology

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Standard methods of segregation analysis, such as originally developed in the unified model (UM) or the regressive logistic model (RLM) do not account for age of onset, and use instead age at examination. To take into account age of onset, models should be formulated using survival analysis concepts, as it was recently proposed with a model based on a logistic hazard function (LHM). A simulation study was conducted to compare the performances of the three methods (UM, RLM, and LHM) in analyzing generated familial data with variable age of onset. When the data were simulated under a polygenic hypothesis, all analysis models were robust with respect to the false conclusion of a major gene, if the tests of transmission probabilities were performed properly. When the data were generated under a major gene hypothesis, two main results were observed: 1) the use of the LHM markedly increased the power to detect a major gene, in particular when a genotype by age interaction was introduced in the model; and 2) in the situation of disease-specific mortality, the use of either UM (whether specific mortality was accounted for or not) or RLM led to both spurious conclusions and bias in parameter estimates. These latter results obtained with the UM and the RLM can be explained by the violation of one constraint of both models observed in a situation of disease-specific mortality, i.e., given all covariates, the probability of being affected and that of not being affected should sum to 1. The use of methods based on survival analysis concepts is recommended in the study of familial diseases with variable age of onset, especially in the case of a correlation between age of onset and age at examination which is induced by disease-specific mortality.

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Robustness of the unified model to shared environmental effects in the analysis of dichotomous traits

Cited by 12 publications

References 7 publications

Eye Tracking Dysfunction and Schizophrenia: A Critical Perspective

Eye Tracking Dysfunction and Schizophrenia: A Critical Perspective

Segregation analysis of idiopathic scoliosis: Demonstration of a major gene effect

Complex segregation analysis of familial diseases with variable age of onset: Comparison of different methods by a simulation study

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