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The genetics of acute lung injury: looking back and pointing the way forward

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Critical Care

BioMed Central

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      Abstract

      Individual genetic factors have long been suspected of playing a major role in susceptibility to acute lung injury and acute respiratory distress syndrome. Flores and colleagues evaluate the quality of published studies testing the relationships between variation in candidate genes and susceptibility to lung injury syndromes or worsened outcome in patients with these conditions. Their results demonstrate that while important advances have been made in this area, attention should be paid to improving the methodology of future studies in order to minimize the chances of publishing false-positive results.

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      Most cited references 10

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      Replication validity of genetic association studies.

      The rapid growth of human genetics creates countless opportunities for studies of disease association. Given the number of potentially identifiable genetic markers and the multitude of clinical outcomes to which these may be linked, the testing and validation of statistical hypotheses in genetic epidemiology is a task of unprecedented scale. Meta-analysis provides a quantitative approach for combining the results of various studies on the same topic, and for estimating and explaining their diversity. Here, we have evaluated by meta-analysis 370 studies addressing 36 genetic associations for various outcomes of disease. We show that significant between-study heterogeneity (diversity) is frequent, and that the results of the first study correlate only modestly with subsequent research on the same association. The first study often suggests a stronger genetic effect than is found by subsequent studies. Both bias and genuine population diversity might explain why early association studies tend to overestimate the disease protection or predisposition conferred by a genetic polymorphism. We conclude that a systematic meta-analytic approach may assist in estimating population-wide effects of genetic risk factors in human disease.
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        Replicating genotype-phenotype associations.

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          A comprehensive review of genetic association studies.

          Most common diseases are complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. It has been proposed that common genetic variants, including single nucleotide polymorphisms (SNPs), influence susceptibility to common disease. This proposal has begun to be tested in numerous studies of association between genetic variation at these common DNA polymorphisms and variation in disease susceptibility. We have performed an extensive review of such association studies. We find that over 600 positive associations between common gene variants and disease have been reported; these associations, if correct, would have tremendous importance for the prevention, prediction, and treatment of most common diseases. However, most reported associations are not robust: of the 166 putative associations which have been studied three or more times, only 6 have been consistently replicated. Interestingly, of the remaining 160 associations, well over half were observed again one or more times. We discuss the possible reasons for this irreproducibility and suggest guidelines for performing and interpreting genetic association studies. In particular, we emphasize the need for caution in drawing conclusions from a single report of an association between a genetic variant and disease susceptibility.
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            Author and article information

            Affiliations
            [1]Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Bulfinch 148, 55 Fruit Street, Boston, MA 02114, USA
            Contributors
            Journal
            Crit Care
            Critical Care
            BioMed Central
            1364-8535
            1466-609X
            2009
            12 January 2009
            : 13
            : 1
            : 108
            2688096
            cc7132
            19183434
            10.1186/cc7132
            Copyright © 2009 BioMed Central Ltd
            Categories
            Commentary

            Emergency medicine & Trauma

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