Genomic studies in XXXX : problems and answers. Development of a statistical model integrating both longitudinal cohort studies and transversal observations of extreme cases.

@entity1 @entity2858 @entity5075 @entity5878 @entity281 @entity791 @entity24669
Genomic studies developed to understand @entity2858 @entity281 and pathogenesis have often lead to conflicting results. This is linked to various factors, including differences in cohort design and selection, the numbers of @entity1 involved, the influence of population substructure, the ethnic origins of the @entity1 , 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 @entity791 . 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 @entity1 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 @entity1 ) for observations on two gene polymorphisms of @entity5075 and @entity5878 . Interestingly, we observe a protective effect for the @entity5075 - @entity24669 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 @entity791 on @entity5075 - @entity24669 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 @entity1 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 @entity791 but also in other diseases induced by chronic exposure to a foreign agent or with chronic clinical manifestations.
