Genomic studies in AIDS: problems and answers. Development of a statistical model integrating both longitudinal cohort studies and transversal observations of extreme cases
| Autor: | Colette Huber, Jean-François Zagury, Laurent Jacquemin, Houria Hendel, Odile Pons, Philippe Haumont, Sara Tamim |
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| Přispěvatelé: | Kaniewski, Nadine, Epidémiologie et Biostatistique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de biométrie et intelligence artificielle de Jouy (MIA-JOUY), Institut National de la Recherche Agronomique (INRA), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Biométrie, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) |
| Rok vydání: | 2003 |
| Předmět: |
Candidate gene
MESH : Polymorphism Genetic Cross-sectional study HIV Infections MESH : Models Biological MESH: Receptors CCR5 MESH: NAD(P)H Dehydrogenase (Quinone) Cohort Studies MESH : HLA Antigens HLA Antigens Models Receptors NAD(P)H Dehydrogenase (Quinone) MESH : NAD(P)H Dehydrogenase (Quinone) Longitudinal Studies MESH: Longitudinal Studies MESH: Cohort Studies MESH: HLA Antigens MESH : Longitudinal Studies Genetics education.field_of_study MESH : Acquired Immunodeficiency Syndrome MESH : Models Statistical MESH : Receptors CCR5 [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie MESH: HIV Infections General Medicine Statistical No Cohort MESH : Research Support No Cohort study Receptors CCR5 Population MESH : Cohort Studies Human leukocyte antigen Biology Research Support Models Biological Genetic determinism Genetic MESH: Polymorphism Genetic MESH : HIV Infections Humans Polymorphism education Alleles MESH: Acquired Immunodeficiency Syndrome Pharmacology Acquired Immunodeficiency Syndrome Models Statistical Polymorphism Genetic MESH: Humans MESH: Alleles MESH : Humans Haplotype MESH: Models Biological Biological [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie MESH: Research Support No [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie MESH : Alleles CCR5 MESH: Models Statistical Demography |
| Zdroj: | Biomedecine & Pharmacotherapy Biomedecine & Pharmacotherapy, 2003, 57, pp.25-33 |
| ISSN: | 0753-3322 |
| Popis: | Genomic studies developed to understand HIV-1 infection and pathogenesis have often lead to conflicting results. This is linked to various factors, including differences in cohort design and selection, the numbers of patients involved, the influence of population substructure, the ethnic origins of the participants, and phenotypic definition. These difficulties in the interpretation of results are examined through published studies on the role of polymorphisms in HLA and the chemokine receptors genes in AIDS. Our analysis suggests that the use of haplotypes will strengthen the results obtained in a given cohort, and meta-analysis including multiple cohorts to gather large-enough numbers of patients should also allow clarification of the genetic associations observed. A P-value of 0.001 appears to be a good compromise for significance on candidate genes in a genetic study. Due to the generally limited size of available cohorts, results will have to be validated in other cohorts. We developed a model to fit transversal case studies (extreme case-control studies) with longitudinal cohorts (all-stages patients) for observations on two gene polymorphisms of CCR5 and NQO1. Interestingly, we observe a protective effect for the CCR5-D32 mutant allele in 95% of the simulations based on that model when using a population of 600 subjects; however, when using populations of 250 subjects we find a significant protection in only 59% of the simulations. Our model gives thus an explanation for the discrepancies observed in the various genomic studies published in AIDS on CCR5-D32 and other gene polymorphisms: they result from statistical fluctuations due to a lack of power. The sizes of most seroconverter cohorts presently available seem thus insufficient since they include less than a few hundred subjects. This result underlines the power and usefulness of the transversal studies involving extreme patients and their complementarity to longitudinal studies involving seroconverter cohorts. The transposition approach of extreme case-control data into longitudinal analysis should prove useful not only in AIDS but also in other diseases induced by chronic exposure to a foreign agent or with chronic clinical manifestations. © 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved. |
| Databáze: | OpenAIRE |
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