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M H Dizier

Publications and source records attributed to M H Dizier.

At least 19 recordsLinked to original sources
PubMed2003

Testing linkage and gene x environment interaction: comparison of different affected sib-pair methods.

The aim of this study was to compare, under different models of gene-environment (G x E) interaction, the power to detect linkage and G x E interaction of different tests using affected sib-pairs. Methods considered were: 1) the maximum likelihood lod-score (MLS), based on the distribution of parental alleles identical by descent (IBD) in affected sibs; 2) the sum of the MLS (sMLS) calculated in affected sib-pairs with 2, 1, or 0 sibs exposed; 3) the predivided sample test (PST), which compares the IBD distribution between affected sib-pairs with 2, 1, or 0 sibs exposed; 4) the triangle test statistic (TTS), which uses the IBD distribution among discordant affected sib-pairs (one exposed, one unexposed); and 5) the mean interaction test (MIT), based on the regression of the proportion of alleles shared IBD among affected sib-pairs on the exposure among sib-pairs. The MLS, sMLS, and MIT allow detection of linkage. However, the sMLS and MIT account for a possible G x E interaction without testing it. In contrast, the PST and the TTS allow detection of both linkage and G x E interaction. Results showed that when exposure cancels the effect of the gene, or changes the direction of this effect (i.e., the protective allele becomes the risk allele), the PST, sMLS, and MIT may provide, under some models, greater power to detect linkage than the MLS. Under models where exposure changes the direction of the effect of the gene, the TTS test may also be more powerful than the other tests accounting for G x E interaction. Under the other models, the MLS remains the most powerful test to detect linkage. However, only the PST and TTS allow the detection of G x E interaction.

Environment↗
PubMed2002

[Construction and validation of a respiratory epidemiological questionnaire].

This paper illustrates the principles of construction and validation of an epidemiological questionnaire by using various aspects of the questionnaire prepared for the Epidemiological Study of the Genetic and Environmental Factors in Asthma, Bronchial Hyper-responsiveness and Atopy (EGEA). Standardised international questionnaires (for adults and children) were adapted and augmented for the requirements of the study. New areas in relation to international epidemiological studies are described (detailed descriptions of asthma and allergic rhinitis, trigger factors exposure tovarious environmental factors and family history). Various aspects of validation are discussed: the acceptibility by the study of missing data in the description of asthmatic symptoms, the construct validity for a score for allergic rhinitis, the reliability of a new self-administered questionnaire for perceived hyper responsiveness to various stimuli and the validity of reported family history using information obtained from family members. Some of these elements could be used in the context of other clinical and epidemiological studies. The complete questionnaire, together with the source of the questions, instructions for interviewers and the method of coding are presented in an appendix available on the internet (http://www.splf.org/bbo/revues-articles/RMR/depotElectronique/2001-110_Kauffmann/Kauffmann2002.htm) which supplements the printed paper.

Asthma↗
PubMed2001

Triangle test statistic in discordant sib pairs: test of genetic heterogeneity of asthma and atopy in CSGA families.

The purpose of our study was to detect genetic heterogeneity (i.e., different genotype relative risks of genetic factor) between atopic and non-atopic asthma and between atopy associated or independent of asthma. Genetic heterogeneity was tested in the Caucasian Collaborative Study on the Genetics of Asthma families using the TTS (triangle test statistic) and the predivided sample test. The TTS was proposed to detect both linkage and intra-sib-pair genetic heterogeneity; such heterogeneity may exist if the sibs differ for a factor on which the penetrances of the putative linked gene depend. The TTS has been applied to asthmatic pairs discordant for atopy and atopic sib pairs discordant for asthma. To confirm genetic heterogeneity detected by the TTS, the predivided sample test was also applied among concordant and discordant sib pairs. The analyses detected a genetic factor on chromosome 8p that could be involved in atopy with different genotype relative risks according to whether asthma is present. This would suggest a pleiotropic effect of this genetic factor in asthma and atopy. Two other regions located on chromosomes 8q and 20p were detected for genetic heterogeneity with asthma and atopy, respectively, but the factor of heterogeneity could be independent from the presence of atopy or asthma, respectively. It could be a characteristic of the disease such as the severity or the presence of an environmental factor.

Adult↗
PubMed2001

Homogeneity of asthma genome scan results.

Three different samples of families with asthmatic patients, the German data set and the CSGA data set subdivided into Caucasian and African American groups, were analyzed using the maximum lod score statistic. Although different scores were obtained in each sample, the Wald's likelihood homogeneity test did not reveal any significant genetic heterogeneity. This may be due to the very large variance of the model-free linkage statistics.

Adult↗
PubMed2001

Indication of linkage and genetic heterogeneity of asthma according to age at onset on chromosome 7q in 107 French EGEA families.

It is generally believed that an early age at the onset of disease is associated with a stronger genetic component. Our aim here was to investigate both linkage and genetic heterogeneity of asthma, the latter corresponding to different genotype relative risks of a putative linked gene according to age at onset of asthma. This analysis was conducted in 107 French EGEA families with at least two asthmatic siblings, considering 157 markers that were part of our previous genome screen, using the TTS (the Triangle Test Statistic) which has been developed to detect both linkage and intra-sibpair genetic heterogeneity. This test has been applied to 38 asthmatic sib-pairs discordant for age at the onset of asthma. To confirm the existence of genetic heterogeneity, we also used the predivided sample test (PST) which compares the IBD (identity by descent) distribution of marker alleles between asthmatic sib-pairs concordant (67) and discordant (38) for the age at onset. The cutoff point used for the age at onset was 4 years, the median age at onset in our sample of asthmatic sibs. Linkage and genetic heterogeneity for a region located on chromosome 7q (at 109 cM from pter) were indicated by both tests, TTS (P=0.005, P>0.5 after correction for multiple testing) and PST (P=0.0001, 0.015 after correction). These results suggest a genetic factor on 7q involved in asthma with genotype relative risks differing according to age at onset of disease.

Age of Onset↗
PubMed2001

[Epidemiological study of genetic and environmental factors in asthma, bronchial hyperresponsiveness and atopy. Protocol and potential selection bias].

BACKGROUND: The EGEA study combines a case-control study and a family study to assess genetic and environmental risk factors and their interactions for asthma, bronchial hyperresponsiveness and atopy. Information is scanty regarding potential selection biases, in particular regarding familial ressemblance in epidemiological surveys of this kind. METHODS: Asthmatic probands (adult and paediatric) were recruited in chest clinics of six clinical centres. Controls were mostly population-based (electoral rolls) for adults and recruited in surgery departments for children. RESULTS: The population examined includes 348 nuclear families ascertained by one asthmatic and 416 controls, totalling 1847 subjects (EGEA I) and an additional sample of 40 families ascertained by two asthmatic siblings (EGEA II). Potential biases for the various types of analyses have been studied. Quantification of the consequences of the greater participation of probands with a parental history of asthma shows it does not introduce a major bias in the estimates of familial resemblance. Cases and controls showed a good comparability regarding sex, age, area of residence and familial geographical origin, allowing proper associations studies for environmental and candidate genetic factors. CONCLUSIONS: The case-control component of the study will allow to perform studies on environmental factors and association studies for various genetic polymorphisms. Using the family base collected, segregation and genetic linkage/association analyses with DNA markers may be performed.

Adult↗
PubMed2000

Segregation analysis of IgE levels in 335 French families (EGEA) using different strategies to correct for the ascertainment through a correlated trait (asthma).

The main objective of this study was to search for a major gene controlling total serum immunoglobulin E (IgE) levels, an intermediate phenotype for asthma and allergy. We studied 335 French nuclear families of the EGEA study (Epidemiological study of the Genetics and Environment of Asthma), ascertained through asthmatic probands (123 are parents in the family, 212 children). Segregation analyses were performed by regressive models, which can take into account a major gene effect, various sources of familial covariation (genetic and/or environmental) as well as measured risk factors (i.e. , age, sex, smoking habits). Different strategies were considered to account for the mode of ascertainment of the families through a correlated trait (asthma): the ascertainment mode was either ignored (strategy A) or taken into account by adjusting IgE levels for the position in the family, i.e., probands, blood relatives, spouses (strategy B) or excluding the asthmatic children-probands and computing the likelihood of each family conditionally on parents' IgE levels (strategy C). Whereas a major gene effect could not be detected with strategy A, strategies B and C showed evidence for the transmission of a dominant major gene for high IgE levels, which was more significant with strategy B. This gene does not interact with any of the covariates and is responsible for approximately 15% of IgE variation (the allele frequency is 0.65).

Adolescent↗
PubMed2000

The triangle test statistic (TTS): a test of genetic homogeneity using departure from the triangle constraints in IBD distribution among affected sib-pairs.

The proportions of affected sibs sharing 2, 1 or 0 identical by descent parental marker alleles have been shown to conform to the 'triangle constraints' (Suarez, 1978; Holmans, 1993). It has also been shown (Dudoit & Speed, 1999) that the constraints are verified provided certain assumptions hold. In this study we explore a realistic situation in which the constraints fail due to the presence of a factor in which the sibs differ, a factor on which penetrance depends. This factor may be a characteristic of the trait (severe vs. mild form), or the presence/absence of an associated trait or an environmental factor. We show that under such situations, using the triangle constraints may lead to important loss of power to detect linkage by the MLS test. We propose here an alternative approach in order to detect both linkage and heterogeneity.

Alleles↗
PubMed2000

Genome screen for asthma and related phenotypes in the French EGEA study.

A genome-wide search was conducted in 107 nuclear families with at least two siblings with asthma, as part of the French EGEA study. A two-stage analysis strategy was applied to the 107 families divided into two independent subsets of 46 and 61 families, where all regions detected in the first set of families were tested for replication in the second set. In addition, all regions reported by published genome scans in different populations were examined in the total sample. A total of 254 markers were typed in the first set of families and 70% of them in the second set. Linkage was investigated by model-free methods for asthma and four asthma-related phenotypes: bronchial responsiveness (BR), skin test response, total immunoglobulin E (IgE) levels, and eosinophil count. The two-stage analysis led to the detection of three regions: 11p13 for IgE, 12q24 for eosinophils, and 17q12-21 for asthma and skin tests. Among the regions reported by published genome screens, seven were found in the 107 French EGEA families: three being already detected by the two-stage analysis, 11p13 (p = 0.005), 12q24 (p = 0.0008), and 17q12-21 (p = 0.001), and four additional ones, 1p31 (p = 0.005) for asthma, 11q13 (p = 0.006) for IgE, 13q31 (p = 0.001) for eosinophils, and 19q13 (p = 0.02) for BR.

Adolescent↗
PubMed1999

Indication of linkage of serum IgE levels to the interleukin-4 gene and exclusion of the contribution of the (-590 C to T) interleukin-4 promoter polymorphism to IgE variation.

Previous segregation analysis of a sample of 234 randomly selected Australian families showed evidence for a recessive major gene controlling serum immunoglobulin E (IgE) levels independently of the specific response to allergens (SRA). Since linkage has been recently reported between serum IgE levels and the 5q candidate region spanning the interleukin-4 (IL-4) gene, we investigated whether the recessive major gene detected by segregation analysis was linked to the IL-4 region and whether polymorphisms within the IL-4 gene were associated with IgE levels. Both sib-pair method and combined segregation and linkage analysis using the regressive models were applied to our data. Whereas there was no evidence of linkage of total IgE levels to the IL-4 region, an indication of linkage (P values ranging between 0.01 and 0.03) was found between IgE levels adjusted for SRA and two IL-4 polymorphisms: one dinucleotide repeat in intron 2 of the IL-4 gene and a single nucleotide (-590 C to T) polymorphism in the IL-4 promoter. However, the putative IL-4 linked gene did not appear to be in linkage disequilibrium with either of these two polymorphisms. A contribution of the IL-4 promoter polymorphism, presumed to be a potential functional variant influencing IgE variation, was also excluded.

Adolescent↗
PubMed1999

Segregation analysis of the specific response to allergens: a recessive major gene controls the specific IgE response to Timothy grass pollen.

Segregation analysis of the specific response to allergens (SRA) was performed in a sample of 234 randomly selected Australian families using the regressive models. Various SRA phenotypes were considered using broad and narrow definitions of these phenotypes, according to the type of test used, skin test or RAST test, and the specificity of the response to allergen. Strong evidence for familial dependencies among blood relatives was shown for most SRA phenotypes, especially when using a broad definition. There was no evidence for a Mendelian factor accounting for the familial transmission of these broadest phenotypes, which may involve multiple factors preventing the clear detection of a major effect with Mendelian transmission. However, segregation of a Mendelian recessive major gene was detected for one SRA sub-phenotype, the IgE response to a single allergen, Timothy grass pollen, measured by the RAST test. Identification of a specific SRA phenotype controlled by a major gene may have important implications for further linkage studies.

Adolescent↗
PubMed1999

Departure from the triangle constraints in discordant sib pairs: a test for genetic heterogeneity.

For any genetic model, Holmans showed that the proportions of affected sibs sharing 2, 1, or 0 identical-by-descent parental marker alleles are constrained to belong to a specific triangle. The triangle constraints do not hold when the sib phenotypes are determined by different models. We test the rejection of triangle constraints on affected sib pairs discordant for severity, to determine whether different models control the severe and mild forms of the disease in the simulated data. With this method we show that a locus on chromosome 5 plays a different role in the two forms of the disease.

Genetic Linkage↗
PubMed1999

EGEA (Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy)-- descriptive characteristics.

The Epidemiological study on the Genetics and Environment of Asthma (EGEA) was planned to assess genetic, environmental risk factors and their interactions for asthma and for the two related traits of bronchial hyperresponsiveness and atopy. The population examined includes 348 nuclear families ascertained by one asthmatic (213 adult and 135 paediatric probands) and 416 controls, totalling 1,847 subjects (EGEA I). Prevalences of asthma, skin prick test response, high IgE and bronchial hyperresponsiveness were for parents, siblings, and offspring of cases intermediate between cases and spouses or controls, both in adults and children, confirming the familial resemblance for asthma and related traits. With an additional sample of 40 families ascertained by two asthmatic siblings (EGEA II), a total of 119 families with two asthmatic siblings has been ascertained for a genome screening.

Adolescent↗
PubMed1997

Epidemiological study of the genetics and environment of asthma, bronchial hyperresponsiveness, and atopy: phenotype issues.

The Epidemiological Study of the Genetics and Environment of Asthma (EGEA) combined a case-control study and a family study. The total sample of 1,854 consisted of 348 patients with asthma selected through chest clinics and 416 control subjects and nuclear families ascertained through the cases. The protocol included standardized questionnaires, bronchial responsiveness, allergen skin-prick tests according to international protocols, total serum immunoglobulin E (IgE) level measurements, and blood eosinophilia. Criteria used to select subjects with asthma and determine asthma status of relatives for affected sibling pair linkage analysis are described. Based on figures from the 348 asthma cases of the EGEA study, issues relative to the definition of severe asthma and intermediate phenotypes such as bronchial responsiveness and allergic markers are discussed. Given the phenotypic heterogeneity involved, relevant phenotypes that may lead to the detection of genetic factors will depend on the hypothesis tested. Standardization of primary data and subphenotypes is a prerequisite for pooling data, which will be needed in the future to better understand the genetics and environmental factors of asthma.

Adolescent↗
PubMed1996

Conclusion of LOD-score analysis for family data generated under two-locus models.

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.

Alleles↗
PubMed1995

Detection of a recessive major gene for high IgE levels acting independently of specific response to allergens.

The genetic control of the total IgE, the immunoglobulins E involved in allergy, remains still unclear. Although high IgE levels were found to be determined by a recessive major gene in several studies, other modes of inheritance were also reported. Moreover, at least two different genetic mechanisms controlling the IgE regulation have been suggested: one involved in the specific IgE response and the other one in the nonspecific response. To better understand the genetic mechanisms controlling IgE variation, we performed segregation analysis of IgE levels by ignoring or taking into account the specific response to allergens (SRA). Analyses were conducted using the class D regressive model, in a sample of 234 Australian nuclear families randomly selected during the winter months, when IgE levels are the lowest (basal). SRA, when included as a covariate in the model, was defined by one of the three following criteria: (1) raised specific IgE level for one or more allergens, (2) positive skin test for one or more allergens, and (3) at least one of the (1) or (2) criteria. When the presence of SRA is ignored, the familial transmission of total IgE level is compatible with the segregation of a recessive major gene and residual familial correlations. When the presence of SRA is accounted for in the analysis, whether defined by criteria (1), (2), or (3), there is still evidence for a recessive major gene controlling IgE levels but residual familial correlations are no longer significant. In addition, no interaction between this major gene and SRA is shown here. Our results suggest that this gene, which accounts for 28% of the variation of the trait, may be involved in the control of basal IgE production, independently of specific response to allergens.

Adolescent↗
PubMed1995

Modeling the role of two susceptibility loci by the MASC method.

Two susceptibility genes, in linkage disequilibrium with alleles of the markers D1G31 and D5G23, have been identified for the disease in the simulated data set of Problem 1. Here we apply the MASC (marker association segregation chi-square) method to model the joint effect of these two genes, by testing two-locus models. The model we obtain, that is the most parsimonious and that best fits the data, corresponds to a direct involvement of the alleles D1G31-8 and D5G23-7, with a nonmultiplicative effect of the two alleles. This was indeed assumed in the true model used for simulating the data.

Alleles↗