Document Type


Publication Date



Background/Aims We propose a modification of the well-known Armitage trend test to address the problems associated with hidden population structure and hidden relatedness in genome-wide case-control association studies.

Methods The new test adopts beneficial traits from three existing testing strategies: the principal components, mixed model, and genomic control while avoiding some of their disadvantageous characteristics, such as the tendency of the principal components method to over-correct in certain situations or the failure of the genomic control approach to reorder the adjusted tests based on their degree of alignment with the underlying hidden structure. The new procedure is based on Gauss-Markov estimators derived from a straightforward linear model with an imposed variance structure proportional to an empirical relatedness matrix. Lastly, conceptual and analytical similarities to and distinctions from other approaches are emphasized throughout.

Results Our simulations show that the power performance of the proposed test is quite promising compared to the considered competing strategies. The power gains are especially large when small differential differences between cases and controls are present; a likely scenario when public controls are used in multiple studies.

Conclusion The proposed modified approach attains high power more consistently than that of the existing commonly implemented tests. Its performance improvement is most apparent when small but detectable systematic differences between cases and controls exist.


This article was originally published in PLOS One, volume 4, issue 6, in 2009. DOI:10.1371/journal.pone.0005825

Peer Reviewed


Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.

Included in

Genomics Commons



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.