The MAX Statistic is Less Powerful for Genome Wide Association Studies Under Most Alternative Hypotheses
DOI:
https://doi.org/10.6000/1929-6029.2017.06.04.2Keywords:
Armitage test, case-control study, efficiency robust statistics, MAX statistic, multiple comparisons, , Type I error.Abstract
Genotypic association studies are prone to inflated type I error rates if multiple hypothesis testing is performed, e.g., sequentially testing for recessive, multiplicative, and dominant risk. Alternatives to multiple hypothesis testing include the model independent genotypic c2 test, the efficiency robust MAX statistic, which corrects for multiple comparisons but with some loss of power, or a single Armitage test for multiplicative trend, which has optimal power when the multiplicative model holds but with some loss of power when dominant or recessive models underlie the genetic association. We used Monte Carlo simulations to describe the relative performance of these three approaches under a range of scenarios. All three approaches maintained their nominal type I error rates. The genotypic c2 and MAX statistics were more powerful when testing a strictly recessive genetic effect or when testing a dominant effect when the allele frequency was high. The Armitage test for multiplicative trend was most powerful for the broad range of scenarios where heterozygote risk is intermediate between recessive and dominant risk. Moreover, all tests had limited power to detect recessive genetic risk unless the sample size was large, and conversely all tests were relatively well powered to detect dominant risk. Taken together, these results suggest the general utility of the multiplicative trend test when the underlying genetic model is unknown.
References
Sasieni PD. From genotypes to genes: doubling the sample size. Biometrics 1997; 53(4): 1253-61. https://doi.org/10.2307/2533494 DOI: https://doi.org/10.2307/2533494
Zheng G, Li Q, Yuan A. Some Statistical Properties of Efficiency Robust Tests with Applications to Genetic Association Studies. Scandinavian Journal of Statistics 2014; 41(3): 762-74. https://doi.org/10.1111/sjos.12060 DOI: https://doi.org/10.1111/sjos.12060
Freidlin B, Zheng G, Li ZH, Gastwirth JL. Trend tests for case-control studies of genetic markers: Power, sample size and robustness. Human Heredity 2002; 53(3): 146-52. https://doi.org/10.1159/000064976 DOI: https://doi.org/10.1159/000064976
Gastwirth JL, Freidlin B. On power and efficiency robust linkage tests for affected sibs. Annals of Human Genetics 2000; 64: 443-53. https://doi.org/10.1046/j.1469-1809.2000.6450443.x DOI: https://doi.org/10.1046/j.1469-1809.2000.6450443.x
Slager SL, Schaid DJ. Case-control studies of genetic markers: Power and sample size approximations for Armitage's test for trend. Human Heredity 2001; 52(3): 149-53. https://doi.org/10.1159/000053370 DOI: https://doi.org/10.1159/000053370
Schaid DJ, Jacobsen SJ. Re: "Biased tests of association: Comparisons of allele frequencies when departing from Hardy-Weinberg proportions" - The authors reply. American Journal of Epidemiology 2001; 154(3): 287-8. https://doi.org/10.1093/aje/154.3.287
Neuhauser M. Exact tests for the analysis of case-control studies of genetic markers. Human Heredity 2002; 54(3): 151-6. https://doi.org/10.1159/000068838 DOI: https://doi.org/10.1159/000068838
Edland SD, Slager S, Farrer M. Genetic association studies in Alzheimer's disease research: challenges and opportunities. Statistics in Medicine 2004; 23(2): 169-78. https://doi.org/10.1002/sim.1706 DOI: https://doi.org/10.1002/sim.1706
Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nature reviews Genetics 2002; 3(5): 391-7. https://doi.org/10.1038/nrg796 DOI: https://doi.org/10.1038/nrg796
Schaid DJ, Jacobsen SJ. Biased tests of association: Comparisons of allele frequencies when departing from Hardy-Weinberg proportions. American Journal of Epidemiology 1999; 149(8): 706-11. https://doi.org/10.1093/oxfordjournals.aje.a009878 DOI: https://doi.org/10.1093/oxfordjournals.aje.a009878
Knapp M. Re: "Biased tests of association: Comparisons of allele frequencies when departing from Hardy-Weinberg proportions". American Journal of Epidemiology 2001; 154(3): 287-8. https://doi.org/10.1093/aje/154.3.287 DOI: https://doi.org/10.1093/aje/154.3.287
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2017 Benjamin Shifflett, Rong Huang, Steven D. Edland
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Policy for Journals/Articles with Open Access
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are permitted and encouraged to post links to their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work
Policy for Journals / Manuscript with Paid Access
Authors who publish with this journal agree to the following terms:
- Publisher retain copyright .
- Authors are permitted and encouraged to post links to their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work .