Biomedical subjects

Audrey Sabbagh

Publications and source records attributed to Audrey Sabbagh.

6 recordsLinked to original sources

PubMed2006

Data-mining methods as useful tools for predicting individual drug response: application to CYP2D6 data.

OBJECTIVES: Selecting a maximally informative subset of polymorphisms to predict a clinical outcome, such as drug response, requires appropriate search methods due to the increased dimensionality associated with looking at multiple genotypes. In this study, we investigated the ability of several pattern recognition methods to identify the most informative markers in the CYP2D6 gene for the prediction of CYP2D6 metabolizer status. METHODS: Four data-mining tools were explored: decision trees, random forests, artificial neural networks, and the multifactor dimensionality reduction (MDR) method. Marker selection was performed separately in eight population samples of different ethnic origin to evaluate to what extent the most informative markers differ across ethnic groups. RESULTS: Our results show that the number of polymorphisms required to predict CYP2D6 metabolic phenotype with a high accuracy can be dramatically reduced owing to the strong haplotype block structure observed at CYP2D6. MDR and neural networks provided nearly identical results and performed the best. CONCLUSION: Data-mining methods, such as MDR and neural networks, appear as promising tools to improve the efficiency of genotyping tests in pharmacogenetics with the ultimate goal of pre-screening patients for individual therapy selection with minimum genotyping effort.

Cytochrome P-450 CYP2D6↗

PubMed2006

SNP selection at the NAT2 locus for an accurate prediction of the acetylation phenotype.

PURPOSE: Genetic polymorphisms in the N-acetyltransferase 2 gene determine the individual acetylator status, which influences both the toxicity and efficacy profile of acetylated drugs. Determination of an individual's acetylation phenotype prior to initiation of therapy, through DNA-based tests, should permit to improve therapy response and reduce adverse events. However, due to extensive linkage disequilibrium between markers within NAT2, the genotyping of closely spaced markers yields highly redundant data: testing them all is expensive and often unnecessary. The objective of this study is to establish the optimal strategy to define, in the genetic context of a given ethnic group, the most informative set of single-nucleotide polymorphisms that best enables accurate prediction of acetylation phenotype. METHODS: Three classification methods have been investigated (classification trees, artificial neural networks and multifactor dimensionality reduction method) in order to find the optimal set of single-nucleotide polymorphisms enabling the most efficient classification of individuals in rapid and slow acetylators. RESULTS: Our results show that, in almost all population samples, only one or two single-nucleotide polymorphisms would be enough to obtain a good predictive capacity with no or only a modest reduction in power relative to direct assays of all common markers. In contrast, in Black African populations, where lower levels of linkage disequilibrium are observed at NAT2, a larger number of single-nucleotide polymorphisms are required to predict acetylation phenotype. CONCLUSION: The results of this study will be helpful for the design of time- and cost-effective pharmacogenetic tests (adapted to specific populations) that could be used as routine tools in clinical practice.

Acetylation↗

PubMed2005

Inferring haplotypes at the NAT2 locus: the computational approach.

BACKGROUND: Numerous studies have attempted to relate genetic polymorphisms within the N-acetyltransferase 2 gene (NAT2) to interindividual differences in response to drugs or in disease susceptibility. However, genotyping of individuals single-nucleotide polymorphisms (SNPs) alone may not always provide enough information to reach these goals. It is important to link SNPs in terms of haplotypes which carry more information about the genotype-phenotype relationship. Special analytical techniques have been designed to unequivocally determine the allocation of mutations to either DNA strand. However, molecular haplotyping methods are labour-intensive and expensive and do not appear to be good candidates for routine clinical applications. A cheap and relatively straightforward alternative is the use of computational algorithms. The objective of this study was to assess the performance of the computational approach in NAT2 haplotype reconstruction from phase-unknown genotype data, for population samples of various ethnic origin. RESULTS: We empirically evaluated the effectiveness of four haplotyping algorithms in predicting haplotype phases at NAT2, by comparing the results with those directly obtained through molecular haplotyping. All computational methods provided remarkably accurate and reliable estimates for NAT2 haplotype frequencies and individual haplotype phases. The Bayesian algorithm implemented in the PHASE program performed the best. CONCLUSION: This investigation provides a solid basis for the confident and rational use of computational methods which appear to be a good alternative to infer haplotype phases in the particular case of the NAT2 gene, where there is near complete linkage disequilibrium between polymorphic markers.

Algorithms↗

PubMed2005

New method for surname studies of ancient patrilineal population structures, and possible application to improvement of Y-chromosome sampling.

Several studies showed that surnames are good markers to infer patrilineal genetic structures of populations, both on regional and microregional scales. As a case study, the spatial patterns of the 9,929 most common surnames of the Netherlands were analyzed by a clustering method called self-organizing maps (SOMs). The resulting clusters grouped surnames with a similar geographic distribution and origin. The analysis was shown to be in agreement with already known features of Dutch surnames, such as 1) the geographic distribution of some well-known locative suffixes, 2) historical census data, 3) the distribution of foreign surnames, and 4) polyphyletic surnames. Thus, these results validate the SOM clustering of surnames, and allow for the generalization of the technique. This method can be applied as a new strategy for a better Y-chromosome sampling design in retrospective population genetics studies, since the idenfication of surnames with a defined geographic origin enables the selection of the living descendants of those families settled, centuries ago, in a given area. In other words, it becomes possible to virtually sample the population as it was when surnames started to be in use. We show that, in a given location, the descendants of those individuals who inhabited the area at the time of origin of surnames can be as low as approximately 20%. This finding suggests 1) the major role played by recent migrations that are likely to have distorted or even defaced ancient genetic patterns, and 2) that standard-designed samplings can hardly portray a reliable picture of the ancient Y-chromosome variability of European populations.

Chromosomes, Human, Y↗

PubMed2004

Decreasing the effects of horizontal gene transfer on bacterial phylogeny: the Escherichia coli case study.

Phylogenetic reconstructions of bacterial species from DNA sequences are hampered by the existence of horizontal gene transfer. One possible way to overcome the confounding influence of such movement of genes is to identify and remove sequences which are responsible for significant character incongruence when compared to a reference dataset free of horizontal transfer (e.g., multilocus enzyme electrophoresis, restriction fragment length polymorphism, or random amplified polymorphic DNA) using the incongruence length difference (ILD) test of Farris et al. [Cladistics 10 (1995) 315]. As obtaining this "whole genome dataset" prior to the reconstruction of a phylogeny is clearly troublesome, we have tested alternative approaches allowing the release from such reference dataset, designed for a species with modest level of horizontal gene transfer, i.e., Escherichia coli. Eleven different genes available or sequenced in this work were studied in a set of 30 E. coli reference (ECOR) strains. Either using ILD to test incongruence between each gene against the all remaining (in this case 10) genes in order to remove sequences responsible for significant incongruence, or using just a simultaneous analysis without removals, gave robust phylogenies with slight topological differences. The use of the ILD test remains a suitable method for estimating the level of horizontal gene transfer in bacterial species. Supertrees also had suitable properties to extract the phylogeny of strains, because the way they summarize taxonomic congruence clearly limits the impact of individual gene transfers on the global topology. Furthermore, this work allowed a significant improvement of the accuracy of the phylogeny within E. coli.

DNA, Bacterial↗

PubMed2002

Parental genotypes in the risk of a complex disease.

Our understanding of the genetic etiology of complex disorders is still elusive. According to the common-variant/common-disease hypothesis, frequent functional polymorphisms are the best candidates for disease-susceptibility alleles. Implicitly, we also assume that disease-susceptibility alleles are preferentially transmitted from parents to the affected offspring and that this effect can be captured by the transmission/disequilibrium test (TDT). However, our study of genetic predisposition to childhood acute lymphoblastic leukemia suggests that a focus on the patient's genotype might, in certain instances, be misleading. Our results indicate that, at least at some loci, parental genetics might be of primary importance in predicting the risk of cancer in this pediatric model of a complex disease. Consequently, in addition to TDT, other complementary strategies will need to be simultaneously applied to dissect genetic predisposition to complex disorders.

Case-Control Studies↗