We searched the PubMed database for articles on the methodology of genetic association studies for complex traits or diseases and for linkage disequilibrium mapping. References to population stratification, allelic heterogeneity, allelic spectrum, and sample size were sought. Additionally, we retrieved review papers in key journals by hand-searching our files. For each of the disease-specific examples, tailored searches were done with PubMed. Articles were selected that showed key points or
ReviewProblems of reporting genetic associations with complex outcomes
Section snippets
Is the association study strategy futile?
Can any association study ever be expected to detect genetic determinants of a complex disease? Several researchers have argued that attempts to locate disease genes must account for the complexity of biological and social pathways to disease and the context dependency of the effect of many risk factors.16, 17 In short, the assertion here is that genes do not generally act in a simple additive manner, but through complex networks involving gene-gene and gene-environment interactions, so that
Why are reports of associations between genotype and outcome so frequently inconsistent?
In principle, it is possible to measure associations between genotype and outcome more reliably than in classic epidemiological studies, because biases that are unavoidable in epidemiological studies can be largely eliminated when studying genetic associations. The exposure (genotype) can be measured after disease onset without systematic error. Selection bias in sampling of cases or controls is less serious in genetic association studies than in studies of environmental exposures because it is
Failure to exclude chance as an explanation in some studies, and publication bias
We suggest that failure to exclude chance is the most likely explanation for difficulty in replication of reports of genetic associations with complex diseases. For most diseases of interest, hundreds of known genes are possible candidates, and in most of these genes, dozens of polymorphisms are known or can be easily identified by screening of the gene. Around the world, thousands of such polymorphisms are tested for disease associations every week. Even if none of these genotypes is
Possible approaches to exclusion of results seen by chance
Adoption of more stringent criteria for exclusion of chance as an explanation for noted associations between genotype and outcome will reduce this problem.2, 3 But how stringent should the criteria be?
Reporting subgroup analyses
Even the simplest genetic association study can be analysed in several different ways—for instance, by testing the effects of alleles, genotypes, or haplotypes. Additional analyses by subgroup—eg, age, sex, categories of phenotype—can be undertaken. Subgroup analyses are typically done when no robust main effect is seen, to guarantee publication of some apparently positive finding. Since the number of possible subgroup analyses that can be undertaken is large, significant results obtained in
Replication studies
The recommendation that large case-control banks are needed to test for associations is set against the present reality that most researchers have only small collections available to them. In an attempt to deal with the limitations imposed by these small sample sizes, replication of associations before declaration of evidence as convincing is gaining increasing acceptance.32 However, some clarity about the role of replication studies is needed. These studies do have advantages, in that biases
Keeping publication bias to a minimum
For clinical trials, publication bias is kept to a minimum by prospective registers and systematic reviews.56 For genetic association studies, a different approach is needed, because most negative results will never even reach conference proceedings, protocol papers will not usually have been published to suggest that the study is ongoing, and an effective mechanism for establishment of prospective registers of proposed analyses is not feasible. To propose that journals should publish all
Summary of data in systematic reviews
Even if publication bias can be reduced, and stringent criteria are adopted for declaration of significance, the problem will remain of how to collate this profusion of data to extract useful information. For any given genotype-disease association, considerable effort is needed to assemble all available studies.1 Some databases containing reviews of genetic variants and reported associations with various outcomes already exist: for instance OMIM (Online Mendelian Inheritance in Man)57 and
Search strategy
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