Whitehead, John, 1950-, Kelly, P. J. (Patrick J.), Zhou, Yinghui, Stallard, Nigel, Thygesen, Helene and Bowman, Clive. (2009) Action following the discovery of a global association between the whole genome and adverse event risk in a clinical drug-development programme. Pharmaceutical Statistics, Vol.8 (No.4). pp. 287-300. ISSN 1539-1604

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Abstract

Observation of adverse drug reactions during drug development can cause closure of the whole programme. However, if association between the genotype and the risk of an adverse event is discovered, then it might suffice to exclude patients of certain genotypes from future recruitment. Various sequential and non-sequential procedures are available to identify an association between the whole genome, or at least a portion of it, and the incidence of adverse events. In this paper we start with a suspected association between the genotype and the risk of an adverse event and suppose that the genetic subgroups with elevated risk can be identified. Our focus is determination of whether the patients identified as being at risk should be excluded from further studies of the drug. We propose using a utility function to determine the appropriate action, taking into account the relative costs of suffering an adverse reaction and of failing to alleviate the patient's disease. Two illustrative examples are presented, one comparing patients who suffer from an adverse event with contemporary patients who do not, and the other making use of a reference control group. We also illustrate two classification methods, LASSO and CART, for identifying patients at risk, but we stress that any appropriate classification method could be used in conjunction with the proposed utility function. Our emphasis is on determining the action to take rather than on providing definitive evidence of an association.

Item Type:	Journal Article
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Pharmacogenetics -- Research, Drugs -- Testing -- Safety measures, Decision making -- Moral and ethical aspects, Utility theory
Journal or Publication Title:	Pharmaceutical Statistics
Publisher:	John Wiley & Sons Ltd.
ISSN:	1539-1604
Date:	October 2009
Volume:	Vol.8
Number:	No.4
Page Range:	pp. 287-300
Identification Number:	10.1002/pst.357
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
References:	1 Dudbridge F, Koeleman BPC. Rank truncated product of p-values, with application to genomewide association scans. Genetic Epidemiology 2003; 25: 360-366. Links 2 Wille A, Hoh J, Ott J. Sum statistics for the joint detection of multiple disease loci in case-control association studies with SNP markers. Genetic Epidemiology 2003; 25: 350-359. Links 3 Xiong M, Zhao J, Boerwinkle E. Generalized T2 test for genome association studies. American Journal of Human Genetics 2002; 70: 1257-1268. Links 4 Zaykin DV, Zhivotovsky LA, Westfall PH, Weir BS. Truncated product method for combining p-values. Genetic Epidemiology 2002; 22: 170-185. Links 5 Kelly P, Stallard N, Zhou Y, Whitehead J, Bowman C. Sequential genomewide association studies for monitoring adverse events in clinical evaluation of new drugs. Statistics in Medicine 2006; 25: 3081-3092. Links 6 Roses AD. Pharmacogenetics and drug development: the path to safer and more effective drugs. Nature Reviews Genetics 2004; 5: 643-655. Links 7 Roses AD. Genome-wide screening for drug discovery and companion diagnostics. Expert Opinion in Drug Discovery 2007; 2: 489-501. Links 8 Breslow NE, Day NE. The analysis of case-control studies. Statistical methods in cancer research, Vol. 1. International Agency for Research on Cancer: Lyon, France, 1980. 9 Fielding AH. Cluster and classification techniques for the biosciences. Cambridge University Press: Cambridge, 2007. 10 Tibshirani R. Regression shrinkage and selection via the Lasso. Journal of Royal Statistical Society Series B 1996; 58: 267-288. Links 11 Efron B, Hastie T, Johnstone I, Tibshirani R. Least angle regression. Annals of Statistics 2004; 32: 407-451. Links 12 Park MY, Hastie T. L1-regularisation path algorithm for generalized linear models. Journal of the Royal Statistical Society, Series B 2007; 69: 659-677. Links 13 Genkin A, Lewis DD, Madigan D. Large-scale Bayesian logistic regression for text categorization. Technometrics 2007; 49: 291-304. Links 14 Yuan M, Lin Y. Model selection and estimation in regression with grouped variables. Journal of Royal Statistical Society, Series B 2006; 68: 49-67. Links 15 Goeman J. The penalized package. Available at: http://cran.r-project.org/doc/packages/penalized.pdf, 2007. 16 R Development core team. The R manuals. Available at: http://cran.r-project.org/manuals.html, 2008. 17 Breiman L, Friedman JH, Olshen RA, Stone CJ. Classification and regression trees. Wadsworth: Belmont, CA, 1984. 18 Ripley BD. Pattern recognition and neural networks. Cambridge University Press: Cambridge, 1996. 19 Ripley B. Tree: classification and regression trees. Available at: http://cran.r-project.org/doc/packages/tree.pdf. 2007. 20 Troyanskaya O, Cantor M, Sherlock G, Brown P, Hastie T, Tibshirani R, Botsterin D, Altman R. Missing value estimation methods for DNA microarrays. Bioinformatics 2001; 17: 520-525. Links 21 Graven P, Wahba G. Smoothing noisy data with spline functions. Numerische Mathematik 1979; 31: 377-403. Links 22 Hastie T, Tibshirani RFriedman J. The elements of statistical learning. Springer: Berlin, 2001. 23 Izmirlian G. Application of the random forest classification algorithm to a SELDI-TOF proteomics study in the setting of a cancer prevention trial. Annals of the New York Academy of Sciences 2004; 154-174. Links 24 Díaz-Uriarte R, Alvarez de Andrés S. Gene selection and classification of microarray data using random forest. BMC Bioinformatics 2006; 7: 3. Links 25 Lindley DV. Making decisions. Wiley: London, 1971.
URI:	http://wrap.warwick.ac.uk/id/eprint/2487

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