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Table of Contents
Vol. 63, No. 3-4, 2007
Issue release date: March 2007
Section title: Original Paper
Hum Hered 2007;63:175–186
(DOI:10.1159/000099830)

Adaptive Two-Stage Analysis of Genetic Association in Case-Control Designs

Zheng G.a · Song K.b · Elston R.C.c
aOffice of Biostatistics Research, National Heart, Lung and Blood Institute, Bethesda, Md., bGlaxoSmithKline, King of Prussia, Pa., and cDepartment of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA
email Corresponding Author

Abstract

We study a two-stage analysis of genetic association for case-control studies. In the first stage, we compare Hardy-Weinberg disequilibrium coefficients between cases and controls and, in the second stage, we apply the Cochran- Armitage trend test. The two analyses are statistically independent when Hardy-Weinberg equilibrium holds in the population, so all the samples are used in both stages. The significance level in the first stage is adaptively determined based on its conditional power. Given the level in the first stage, the level for the second stage analysis is determined with the overall Type I error being asymptotically controlled. For finite sample sizes, a parametric bootstrap method is used to control the overall Type I error rate. This two-stage analysis is often more powerful than the Cochran-Armitage trend test alone for a large association study. The new approach is applied to SNPs from a real study.

© 2007 S. Karger AG, Basel


  

Key Words

  • Conditional power
  • Genomewide association
  • Hardy-Weinberg disequilibrium
  • Self-replication
  • Trend test

References

  1. Risch NJ, Merikangas K: The future of genetic studies of complex human diseases. Science 1996;273:1516–1517.
  2. Risch NJ: Searching for genetic determinants in the new millennium. Nature 2000;405:847–856.
  3. Klein RJ, Zeiss C, Chew EY, Tsai J-Y, Sackler RS, Haynes C, Henning AK, San-Giovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in aged-related macular degeneration. Science 2005;308:385–389.
  4. Schaid DJ, McDonnell SK, Hebbring SJ, Cunningham JM, Thibodeau SN: Nonparametric tests of association of multiple genes with human diseases. Am J Hum Genet 2005;76:780–793.
  5. Wang K, Sheffield VC: A constrained-likelihood approach to marker-trait association studies. Am J Hum Genet 2005;77:768–780.
  6. Benjamini Y, Hochberg Y: Controlling the false discovery rate – a practical and power approach to multiple testing. J R Stat Soc Ser B 1995;57:289–300.
  7. Thomas DC, Haile RW, Duggan D: Recent developments in genomewide association scans: A workshop summary and review. Am J Hum Genet 2005;77:337–345.
  8. Hao K, Niu T, Xu X, Fang Z, Xu X: Single-nucleotide polymorphisms of the KCNS3 gene are significantly associated with airway hyperresponsiveness. Hum Genet 2005;116:378–383.
  9. Van Steen K, McQueen MB, Herbert A, Raby B, Lyon H, DeMeo DL, Murphy A, Su J, Datta S, Rosenow C, Christman M, Silverman EK, Laird NM, Weiss ST, Lange C: Genomic screening and replication using the same data set in family-based association testing. Nat Genet 2005;37:683–691.
  10. Zheng G, Song K, Elston RC: Combining trend tests for genome-wide association studies: A double trend test. Applied Stat 2006:submitted.
  11. Song K, Elston RC: A powerful method of combining measures of association and Hardy-Weinberg disequilibrium for fine-mapping in case-control studies. Stat Med 2006;25:105–126.
  12. Sasieni PD: From genotypes to genes: Doubling the sample size. Biometrics 1997;53:1253–1261.
  13. Freidlin B, Zheng G, Li Z, Gastwirth JL: Trend tests for case-control studies of genetic markers: Power, sample size and robustness. Hum Hered 2002;53:146–152.
  14. Zheng G, Freidlin B, Li Z, Gastwirth JL: Choice of scores in trend tests for case-control studies of candidate-gene associations. Biometrical J 2003;45:335–348.

    External Resources

  15. Zheng G, Freidlin B, Gastwirth JL: Robust genomic control for association studies. Am J Hum Genet 2006;78:350–356.
  16. Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, Riley J, Purvis I, Xu CF. Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur J Hum Genet 2004;12:395–399.
  17. Salanti G, Amountza G, Ntzani EE, Ioannidis JPA: Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet 2005;13:840–848.
  18. Nielsen DM, Ehm MG,Weir BS: Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998;63:1531–1540.
  19. Wittke-Thompson JK, Pluzhnikov A, Cox NJ: Rational inferences about departure from Hardy-Weinberg equilibrium. Am J Hum Genet 2005;76:967–986.
  20. Weir BS: Genetic Data Analysis II: Methods for Discrete Population Genetic Data. Sunderland, Sinauer, 1996.
  21. 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.
  22. AREDS Research Group: Risk factors associated with age-related macular degeneration: A case-control study in the age-related eye disease study: Age related eye disease study report number 3. Ophthalmology 2000;107:2224–2232.
  23. Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, Branham KEH, Reddick AC, Trager EH, Yoshida S, Bahling J, Filippova E, Elner S, Johnson MW, Vine AK, Sieving PA, Jacobson SG, Richards JE, Swaroop A: Age related macular degeneration: A high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am J Hum Genet 2004;74:482–494.
  24. Friedman DS, OColmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong P, Nemesure B, Mitchell P, Kempen J, Congdon N for The Eye Diseases Prevalence Research Group: Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564–572.
  25. Iyengar SK, Song D, Klein BEK, Klein R, Schick JH, Humphrey J, Millard C, Liptak R, Russo K, Jun G, Lee KE, Fijal B, Elston RC: Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am J Hum Genet 2004;74:20–39.
  26. Tuo J, Bojanowski CM, Chan C-C: Genetic factors of age-related macular degeneration. Prog Retinal Eye Res 2004;23:229–249.
  27. Herbert A, et al: A common genetic variant is associated with adult and childhood obesity. Science 2006;312:279–312.
  28. Prentice, RL, Pettinger, M, Anderson, GL: Statistical issues arising in the Women’s Health Initiative. Biometrics 2005;61:899–941.
  29. Satagopan JM, Venkatraman ES, Begg CB: Two-stage designs for gene-disease association studies with sample size constraints. Biometrics 2004;60:589–597.
  30. Satagopan JM, Verbel DA, Venkatraman ES, Offit KE, Begg CB: Two-stage designs for gene-disease association studies. Biometrics 2002;58:163–170.
  31. Skol AD, Scott LJ, Abecasis GR, Boehnke M: Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 2006;38:209–213.

  

Author Contacts

Dr. Gang Zheng
Office of Biostatistics Research, Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Bethesda, MD 20892 (USA)
Tel. +1 301 435 1287, Fax +1 301 480 1862, E-Mail zhengg@nhlbi.nih.gov

  

Article Information

Received: September 11, 2006
Accepted after revision: November 29, 2006
Published online: February 19, 2007
Number of Print Pages : 12
Number of Figures : 4, Number of Tables : 6, Number of References : 31

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 63, No. 3-4, Year 2007 (Cover Date: March 2007)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

We study a two-stage analysis of genetic association for case-control studies. In the first stage, we compare Hardy-Weinberg disequilibrium coefficients between cases and controls and, in the second stage, we apply the Cochran- Armitage trend test. The two analyses are statistically independent when Hardy-Weinberg equilibrium holds in the population, so all the samples are used in both stages. The significance level in the first stage is adaptively determined based on its conditional power. Given the level in the first stage, the level for the second stage analysis is determined with the overall Type I error being asymptotically controlled. For finite sample sizes, a parametric bootstrap method is used to control the overall Type I error rate. This two-stage analysis is often more powerful than the Cochran-Armitage trend test alone for a large association study. The new approach is applied to SNPs from a real study.

© 2007 S. Karger AG, Basel


  

Author Contacts

Dr. Gang Zheng
Office of Biostatistics Research, Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Bethesda, MD 20892 (USA)
Tel. +1 301 435 1287, Fax +1 301 480 1862, E-Mail zhengg@nhlbi.nih.gov

  

Article Information

Received: September 11, 2006
Accepted after revision: November 29, 2006
Published online: February 19, 2007
Number of Print Pages : 12
Number of Figures : 4, Number of Tables : 6, Number of References : 31

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 63, No. 3-4, Year 2007 (Cover Date: March 2007)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 9/11/2006
Accepted: 11/29/2006
Published online: 2/19/2007
Issue release date: March 2007

Number of Print Pages: 12
Number of Figures: 4
Number of Tables: 6

ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Risch NJ, Merikangas K: The future of genetic studies of complex human diseases. Science 1996;273:1516–1517.
  2. Risch NJ: Searching for genetic determinants in the new millennium. Nature 2000;405:847–856.
  3. Klein RJ, Zeiss C, Chew EY, Tsai J-Y, Sackler RS, Haynes C, Henning AK, San-Giovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in aged-related macular degeneration. Science 2005;308:385–389.
  4. Schaid DJ, McDonnell SK, Hebbring SJ, Cunningham JM, Thibodeau SN: Nonparametric tests of association of multiple genes with human diseases. Am J Hum Genet 2005;76:780–793.
  5. Wang K, Sheffield VC: A constrained-likelihood approach to marker-trait association studies. Am J Hum Genet 2005;77:768–780.
  6. Benjamini Y, Hochberg Y: Controlling the false discovery rate – a practical and power approach to multiple testing. J R Stat Soc Ser B 1995;57:289–300.
  7. Thomas DC, Haile RW, Duggan D: Recent developments in genomewide association scans: A workshop summary and review. Am J Hum Genet 2005;77:337–345.
  8. Hao K, Niu T, Xu X, Fang Z, Xu X: Single-nucleotide polymorphisms of the KCNS3 gene are significantly associated with airway hyperresponsiveness. Hum Genet 2005;116:378–383.
  9. Van Steen K, McQueen MB, Herbert A, Raby B, Lyon H, DeMeo DL, Murphy A, Su J, Datta S, Rosenow C, Christman M, Silverman EK, Laird NM, Weiss ST, Lange C: Genomic screening and replication using the same data set in family-based association testing. Nat Genet 2005;37:683–691.
  10. Zheng G, Song K, Elston RC: Combining trend tests for genome-wide association studies: A double trend test. Applied Stat 2006:submitted.
  11. Song K, Elston RC: A powerful method of combining measures of association and Hardy-Weinberg disequilibrium for fine-mapping in case-control studies. Stat Med 2006;25:105–126.
  12. Sasieni PD: From genotypes to genes: Doubling the sample size. Biometrics 1997;53:1253–1261.
  13. Freidlin B, Zheng G, Li Z, Gastwirth JL: Trend tests for case-control studies of genetic markers: Power, sample size and robustness. Hum Hered 2002;53:146–152.
  14. Zheng G, Freidlin B, Li Z, Gastwirth JL: Choice of scores in trend tests for case-control studies of candidate-gene associations. Biometrical J 2003;45:335–348.

    External Resources

  15. Zheng G, Freidlin B, Gastwirth JL: Robust genomic control for association studies. Am J Hum Genet 2006;78:350–356.
  16. Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, Riley J, Purvis I, Xu CF. Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur J Hum Genet 2004;12:395–399.
  17. Salanti G, Amountza G, Ntzani EE, Ioannidis JPA: Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet 2005;13:840–848.
  18. Nielsen DM, Ehm MG,Weir BS: Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998;63:1531–1540.
  19. Wittke-Thompson JK, Pluzhnikov A, Cox NJ: Rational inferences about departure from Hardy-Weinberg equilibrium. Am J Hum Genet 2005;76:967–986.
  20. Weir BS: Genetic Data Analysis II: Methods for Discrete Population Genetic Data. Sunderland, Sinauer, 1996.
  21. 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.
  22. AREDS Research Group: Risk factors associated with age-related macular degeneration: A case-control study in the age-related eye disease study: Age related eye disease study report number 3. Ophthalmology 2000;107:2224–2232.
  23. Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, Branham KEH, Reddick AC, Trager EH, Yoshida S, Bahling J, Filippova E, Elner S, Johnson MW, Vine AK, Sieving PA, Jacobson SG, Richards JE, Swaroop A: Age related macular degeneration: A high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am J Hum Genet 2004;74:482–494.
  24. Friedman DS, OColmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong P, Nemesure B, Mitchell P, Kempen J, Congdon N for The Eye Diseases Prevalence Research Group: Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564–572.
  25. Iyengar SK, Song D, Klein BEK, Klein R, Schick JH, Humphrey J, Millard C, Liptak R, Russo K, Jun G, Lee KE, Fijal B, Elston RC: Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am J Hum Genet 2004;74:20–39.
  26. Tuo J, Bojanowski CM, Chan C-C: Genetic factors of age-related macular degeneration. Prog Retinal Eye Res 2004;23:229–249.
  27. Herbert A, et al: A common genetic variant is associated with adult and childhood obesity. Science 2006;312:279–312.
  28. Prentice, RL, Pettinger, M, Anderson, GL: Statistical issues arising in the Women’s Health Initiative. Biometrics 2005;61:899–941.
  29. Satagopan JM, Venkatraman ES, Begg CB: Two-stage designs for gene-disease association studies with sample size constraints. Biometrics 2004;60:589–597.
  30. Satagopan JM, Verbel DA, Venkatraman ES, Offit KE, Begg CB: Two-stage designs for gene-disease association studies. Biometrics 2002;58:163–170.
  31. Skol AD, Scott LJ, Abecasis GR, Boehnke M: Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 2006;38:209–213.