How to use an article about genetic association: B: Are the results of the study valid?
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.
Attia
John
J
Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Hunter MedicalResearch Institute, and Department of GeneralMedicine, John Hunter Hospital, Newcastle, Australia. john.attia@newcastle.edu.au
Ioannidis
John P A
JP
Thakkinstian
Ammarin
A
McEvoy
Mark
M
Scott
Rodney J
RJ
Minelli
Cosetta
C
Thompson
John
J
Infante-Rivard
Claire
C
Guyatt
Gordon
G
D008040:Genetic Linkage; D005819:Genetic Markers; D014644:Genetic Variation; D005826:Genetics, Medical; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns; D010506:Periodicals as Topic; D010641:Phenotype; D015203:Reproducibility of Results; D012196:Review Literature as Topic
D005819:Genetic Markers