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Journal of Statistical Theory and Practice

, Volume 7, Issue 1, pp 95–106 | Cite as

Individualized Dosing for Multiple Ordered Groups of Patients

  • I. Das
  • S. Mukhopadhyay
  • H. Xu
Article

Abstract

In this article, the problem of dose finding in Phase I clinical trials for a heterogeneous patient population is considered. A new interval-based nonparametric design is proposed that stratifies the patients into multiple groups of varying sizes according to their susceptibility to toxicity and finds the maximum tolerable dose (MTD) in each group. The proposed design allows for sharing of patient information between groups, thus increasing the efficiency in identifying the group MTDs correctly, especially in patient groups with low prevalence. The convergence results for the proposed algorithm are presented. Various simulation studies are performed to illustrate the new methodology.

Keywords

Interval-based design nonparametric Phase I polymorphism warfarin 

AMS Subject Classification

62P10 

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References

  1. Babb, J. S., and A. Rogatko. 2001. Patient specific dosing in a cancer phase I clinical trial. Stat Med., 20, 2079–2090.CrossRefGoogle Scholar
  2. Bekele, B. N., L. Yisheng, and J. Yuan. 2009. Risk-group-specific dose finding based on an average toxicity score. Biometrics, 66, 541–548.MathSciNetCrossRefGoogle Scholar
  3. Daly, A. K. 2009. Pharmacogenomics of anticoagulants: Steps toward personal dosage. Genome Med., 1, 1–10.CrossRefGoogle Scholar
  4. Durham, S. D., N. Flournoy, and W. F. Rosenberger. 1997. A random walk rule for phase I clinical trials. Biometrics, 53, 745–760.CrossRefGoogle Scholar
  5. Elias, D. J., and E. J. Topol. 2008. A big step forward for individualized medicine: Enlightened dosing of warfarin. Eur. J. Hum. Genet., 16, 532–534.CrossRefGoogle Scholar
  6. Ivanova, A., N. Flournoy, and Y. Chunga. 2007. Cumulative cohort design for dose-finding. J. Stat. Plan. Inf., 137, 2316–2327.MathSciNetCrossRefGoogle Scholar
  7. Ivanova, A., A. M. Haghighi, S. G. Mohanty, and S. D. Durham. 2003. Improved up-and-down designs for phase I trials. Stat. Med., 22, 69–82.CrossRefGoogle Scholar
  8. Ivanova, A., and K. Wang. 2006. Bivariate isotonic design for dose-finding with ordered groups. Stat. Med., 25, 2018–2026.MathSciNetCrossRefGoogle Scholar
  9. Lee, C. R. 2004. CYP2C9 genotype as a predictor of drug disposition in humans. Methods Find. Exp. Clin. Pharmacol., 26, 379–355.MathSciNetCrossRefGoogle Scholar
  10. Millican, E. A., P. A. Lenzini, P. E. Milligan, L. Grosso, C. Eby, E. Deych, G. Grice, J. C. Clohisy, R. L. Barrack, R. Stephen, J. Burnett, D. Voora, S. Gatchel, A. Tiemeier, and B. F. Gage. 2007. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Am. Soc. Hematol., 110, 1511–1515.Google Scholar
  11. O’Quigley, J., and X. Paoletti. 2003. Continuous reassesment method for ordered groups. Biometrics, 59, 430–440.MathSciNetCrossRefGoogle Scholar
  12. O’Quigley, J., L. Z. Shen, and A. Gamst. 1999. Two-sample continual reassessment method. J. Biopharm. Stat., 9, 17–44.CrossRefGoogle Scholar
  13. Schwarz, U. I. 2003. Clinical relevance of genetic polymorphisms in the human CYP2C9 gene. Eur. J. Clin. Invest., 33, 23–30.CrossRefGoogle Scholar
  14. Sconce, E. A., T. I. Khan, H. A. Wynne, P. Avery, L. Monkhouse, B. P. King, P. Wood, P. Kesteven, A. K. Daly, and F. Kamali. 2005. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: Proposal for a new dosing regimen. Blood, 106, 2329–2333.CrossRefGoogle Scholar
  15. Stroke Prevention in Atrial Fibrillation Investigators. 1996. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke prevention in atrial fibrillation III randomised clinical trial. Lancet, 348, 633–638.CrossRefGoogle Scholar
  16. Stylianou, M., and N. Flournoy. 2002. Dose finding using the biased coin up-and-down design and isotonic regression. Biometrics, 58, 171–177.MathSciNetCrossRefGoogle Scholar
  17. Thall, P. F., H. Q. Nguyen, and E. H. Estey. 2008. Patient-specific dose finding based on bivariate outcomes and covariates. Biometrics, 64, 1126–1136.MathSciNetCrossRefGoogle Scholar
  18. Yuan, Z., and R. Chappell. 2004. Isotonic designs for phase I cancer clinical trials with multiple risk groups. Clini. Trials, 1, 499–508.CrossRefGoogle Scholar

Copyright information

© Grace Scientific Publishing 2013

Authors and Affiliations

  1. 1.Department of MathematicsIndian Institute of Technology BombayMumbaiIndia
  2. 2.Department of BiostatisticsMedical College of GeorgiaAugustaUSA

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