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January 14, 2009

How to Use an Article About Genetic Association: B: Are the Results of the Study Valid?

Author Affiliations

Author Affiliations: Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Hunter Medical Research Institute, and Department of General Medicine, John Hunter Hospital, Newcastle, Australia (Dr Attia); Department of Hygiene and Epidemiology, University of Ioannina, School of Medicine, Ioannina, Greece, and Center for Genetic Epidemiology and Modeling, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts (Dr Ioannidis); Clinical Epidemiology Unit, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (Dr Thakkinstian); Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Newcastle, Australia (Mr McEvoy); Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, New Lambton, Australia, and Centre for Information Based Medicine, Faculty of Health, University of Newcastle, Hunter Medical Research Institute, Newcastle, Australia (Dr Scott); Respiratory Epidemiology and Public Health, National Heart and Lung Institute, Imperial College, London, England (Dr Minelli); Department of Health Sciences, University of Leicester, Leicester, England (Dr Thompson); Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, Montreal, Canada (Dr Infante-Rivard); and the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada (Dr Guyatt).

JAMA. 2009;301(2):191-197. doi:10.1001/jama.2008.946

In the first article of this series, we reviewed the basic genetics concepts necessary to understand genetic association studies. In this second article, we enumerate the major issues in judging the validity of these studies, framed as critical appraisal questions. Was the disease phenotype properly defined and accurately recorded by someone blind to the genetic information? Have any potential differences between disease and nondisease groups, particularly ethnicity, been properly addressed? In genetic studies, one potential cause of spurious associations is differences between cases and controls in ethnicity, a situation termed population stratification. Was measurement of the genetic variants unbiased and accurate? Methods for determining DNA sequence variation are not perfect and may have some measurement error. Do the genotype proportions observe Hardy-Weinberg equilibrium? This simple mathematic rule about the distribution of genetic groups may be one way to check for errors in reading DNA information. Have the investigators adjusted their inferences for multiple comparisons? Given the thousands of genetic markers tested in genome-wide association studies, the potential for false-positive and false-negative results is much higher than in traditional medical studies, and it is particularly important to look for replication of results.

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