Power for genetic association study of human longevity using the case-control design
Qihua Tan1, Jing Hua Zhao, Dongfeng Zhang
1Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark. qtan@health.sdu.dk
American Journal of Epidemiology
|August 30, 2008
Summary
Investigating genetic associations with longevity requires careful case definition. Using centenarians as cases in gene-longevity studies offers better power than nonagenarians, especially for detecting common variants with large effects.
Area of Science:
- Genetics
- Biostatistics
- Gerontology
Background:
- Gene-longevity association studies often employ case-control designs.
- Longevity is an extreme phenotype of continuous lifespan, lacking a clear definition.
- The validity of case-control studies for longevity requires empirical assessment.
Purpose of the Study:
- To evaluate the efficiency of the case-control design for gene-longevity association studies.
- To assess the impact of defining cases as centenarians versus nonagenarians on statistical power.
- To determine the sample sizes needed to detect genetic effects of varying magnitudes.
Main Methods:
- Simulation of individual lifespans using Danish life tables.
- Assessment of empirical power across different sample sizes and case definitions (centenarians vs. nonagenarians).
- Evaluation of power based on allele frequency, effect size, and mode of inheritance.
Main Results:
- Small centenarian samples detect common alleles with large effects (>20% hazard reduction).
- Large centenarian samples (>1,000) detect minor effect genes (5-10% hazard reduction).
- Power is significantly reduced when using nonagenarians as cases, requiring over 5x larger samples.
Conclusions:
- Centenarian-based case-control studies are feasible for identifying longevity genes.
- The choice of case definition (centenarians) is critical for study power.
- The design is effective for common variants and some rare variants, but less so for rare recessive alleles.
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