Hum Hered 2002;53:146–152

Trend Tests for Case-Control Studies of Genetic Markers: Power, Sample Size and Robustness

Freidlin B.a · Zheng G.c · Li Z.b,d,e · Gastwirth J.L.b,e
aBiometric Research Branch and bBiostatistics Branch, National Cancer Institute, Rockville, Md., cOffice of Biostatistics Research, National Heart, Lung and Blood Institute, Bethesda, Md., dBiostatistics Center, George Washington University, Rockville, Md., and eDepartment of Statistics, George Washington University, Washington, D.C., USA
email Corresponding Author

 goto top of outline Key Words

  • Candidate gene associations
  • Cochran-Armitage trend test
  • MAX test
  • Maximin efficiency robust test
  • Power approximation
  • Sample size

 goto top of outline Abstract

The Cochran-Armitage trend test is commonly used as a genotype-based test for candidate gene association. Corresponding to each underlying genetic model there is a particular set of scores assigned to the genotypes that maximizes its power. When the variance of the test statistic is known, the formulas for approximate power and associated sample size are readily obtained. In practice, however, the variance of the test statistic needs to be estimated. We present formulas for the required sample size to achieve a prespecified power that account for the need to estimate the variance of the test statistic. When the underlying genetic model is unknown one can incur a substantial loss of power when a test suitable for one mode of inheritance is used where another mode is the true one. Thus, tests having good power properties relative to the optimal tests for each model are useful. These tests are called efficiency robust and we study two of them: the maximin efficiency robust test is a linear combination of the standardized optimal tests that has high efficiency and the MAX test, the maximum of the standardized optimal tests. Simulation results of the robustness of these two tests indicate that the more computationally involved MAX test is preferable.

Copyright © 2002 S. Karger AG, Basel

 goto top of outline References
  1. Sasieni PD: From genotypes to genes: Doubling the sample size. Biometrics 1997;53:1253–1261.
  2. Cohcran WG: Some methods for strengthening the common chi-squared tests. Biometrics 1954;10:417–451.
  3. Armitage P: Tests for linear trends in proportions and frequencies. Biometrics 1955;11:375–386.
  4. Tarone RE, Gart JJ: On the robustness of combined tests for trends in proportions. J Am Stat Assoc 1980;75:110–116.
  5. Slager SL, Schaid DJ: Case-control studies of genetic markers: Power and sample size approximations for Armitage’s test for trend. Hum Hered 2001;52:149–153.
  6. Gastwirth JL: The use of maximin efficiency robust tests in combining contingency tables and survival analysis. J Am Stat Assoc 1985;80:380–384.
  7. Podgor MJ, Gastwirth JL, Mehta CR: Efficiency robust tests of independence in contingency tables with ordered classifications. Stat Med 1996;15:2095–2105.
  8. Whittemore AS, Tu I-P: Simple, robust linkage tests for affected sibs. Am J Hum Genet 1998;62:1228–1242.
  9. Freidlin B, Podgor MJ, Gastwirth JL: Efficiency robust tests for survival or ordered categorical data. Biometrics 1999;55:883–886.
  10. Shih M, Whittemore AS: Allele-sharing among affected relatives: Non-parametric methods for identifying genes. Stat Methods Med Res 2001;10:27–55.

    External Resources

  11. Shahbazi M, Pravica P, Nasreen N, Fakhoury H, Fryer AA, Strange RC, Hutchinson PE, Osborne JE, Lear JT, Smith AG, Hutchinson IV: Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 2002;359:397–401.
  12. Vogel F, Motulsky AG: Human Genetics: Problems and Approaches, ed 3. New York, Springer, 1997.
  13. Ott J: Analysis of Human Genetic Linkage, ed 3. Baltimore, JHU Press, 1999.

 goto top of outline Author Contacts

Boris Freidlin
Biometric Research Branch
National Cancer Institute
MSC 7434, Bethesda, MD 20892 (USA)

 goto top of outline Article Information

Received: January 31, 2002
Accepted: March 28, 2002
Revision received: March 22, 2002
Published online: June 11, 2009
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 8, Number of References : 13

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)

Vol. 53, No. 3, Year 2002 (Cover Date: Released July 2002)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (Print), eISSN: 1423–0062 (Online)

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