Problems of reporting genetic associations with complex outcomes

  title={Problems of reporting genetic associations with complex outcomes},
  author={Helen M. Colhoun and Paul M. McKeigue and George Davey Smith},
  journal={The Lancet},
Challenges in reproducibility of genetic association studies: lessons learned from the obesity field
This review addresses classic pitfalls in genetic association studies and provides guidelines for proper discovery and replication Genetic association studies with a specific focus on obesity.
Genetic Association Studies in Ischaemic Stroke
Although hundreds of genetic association studies of ischaemic stroke have been published, the failure to replicate associations has led to scepticism about their findings. Possible explanations for
Obstacles and opportunities in meta-analysis of genetic association studies
In this review, the impacts of Type I error, lack of power, and publication and reporting biases are explored, and the role of multiple testing is discussed.
Overdispersion of allele frequency differences between populations: implications for meta-analyses of genotypic disease associations
A correction of the odds ratio estimate and its confidence interval is shown to be easy to implement using a mixed effects logistic regression and to substantially reduce bias and to give accurate coverage even when there is substantial overdispersion of allele frequency differences between populations.
Meta-analysis of genetic association studies : overview of the methodological issues and proposal of guidelines.
This thesis presents a set of guidelines on how to deal with all methodological issues which require consideration in the meta-analysis of genetic association studies, developed at two levels of sophistication, one relatively simple although methodologically correct, the other more sophisticated but more efficient.
Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases.
Accumulated evidence from searching for candidate gene-disease associations of complex diseases can offer some insights as the field moves toward discovery-oriented approaches with massive genome-wide testing, but estimates are steeply inflated in the presence of modest bias.
Association of genetic loci: Replication or not, that is the question
For the near future, with relatively small sample sizes, association studies can and should be guided by biology.
'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?
Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.


Replication validity of genetic association studies
It is concluded that a systematic meta-analytic approach may assist in estimating population-wide effects of genetic risk factors in human disease.
Association mapping in structured populations.
This article describes a novel, statistically valid, method for case-control association studies in structured populations that uses a set of unlinked genetic markers to infer details of population structure, and to estimate the ancestry of sampled individuals, before using this information to test for associations within subpopulations.
Association study designs for complex diseases
With the discovery of massive numbers of genetic markers and the development of better tools for genotyping, association studies will inevitably proliferate and now is the time to consider critically the design of such studies to avoid the mistakes of the past and to maximize their potential to identify new components of disease.
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results
Specific standards designed to maintain rigor while also promoting communication are proposed for the interpretation of linkage results in genetic studies under way for many complex traits.
Parameters for reliable results in genetic association studies in common disease
Using 2,873 families, a recently published association of the interleukin 12B gene in 422 type I diabetic families was unable to confirm, emphasizing the need for large datasets, small P values and independent replication if results are to be reliable.
Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations.
A checklist for reporting and appraising studies of genotype prevalence and studies of gene-disease associations was developed and focuses on selection of study subjects, analytic validity of genotyping, population stratification, and statistical issues.
Tests and estimates of allelic association in complex inheritance.
  • N. Morton, A. Collins
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1998
Efficiency of the TDT is increased in multiplex families and by inclusion of normal sibs, approaching a case-control design with normal but not hyper normal controls, and efficiency for hypernormal controls is always greater than for random controls.