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Revisiting the Wald Test in Small Case-Control Studies With a Skewed Covariate.
American Journal of Epidemiology
|March 31, 2022
Summary
The Hauck-Donner effect (HDE) inflates P values in genetic association studies. A permutation test offers greater power and avoids HDE, making it ideal for small case-control studies.
Area of Science:
- Genetics
- Biostatistics
- Computational Biology
Background:
- The Wald test is standard for case-control association studies.
- The Hauck-Donner effect (HDE) inflates P values when association evidence is strong.
- HDE is a known issue in 2x2 contingency tables.
Purpose of the Study:
- Investigate the Hauck-Donner effect (HDE) in genetic burden analysis.
- Evaluate statistical tests for association in small case-control studies.
- Propose an improved statistical approach for genetic association studies.
Main Methods:
- Analyzed whole-exome sequence data from reference and preterm infant samples.
- Examined burden-based P values in the presence and absence of covariates.
- Compared the performance of Wald, Firth, likelihood ratio, and permutation tests.
Main Results:
- Confirmed the presence of the Hauck-Donner effect (HDE) in genetic burden analysis.
- Identified the HDE's cause as an extension of its effect in contingency tables.
- Demonstrated that the permutation test has higher power than other tested methods and is not affected by HDE.
Conclusions:
- The Hauck-Donner effect (HDE) impacts genetic association studies.
- Permutation testing is a robust and powerful alternative to the Wald test for small sample sizes.
- A permutation-based approach is recommended for analyzing small case-control genetic association studies.
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