A statistical test for detecting and characterizing departures from additivity in drug/chemical combinations

In this paper, we propose a test of additivity in a combination of drugs/chemicals based on the interaction index. The test is developed for data resulting from an experiment involving single-agent exposure groups and s combination groups of interest. The testing procedure begins with an overall size a test of additivity with s degrees of freedom. When this test is rejected, single degree-of-freedom tests combined with post hoc corrections for multiple testing are developed to determine which dose combinations are associated with departure from additivity. The method is illustrated using data associated with a patent application for a two-drug combination.

[1]  A. Agresti.  An introduction to categorical data analysis , 1997 .

[2]  M. Berenbaum.  The expected effect of a combination of agents: the general solution. , 1985, Journal of theoretical biology.

[3]  P. McCullagh,et al.  Generalized Linear Models , 1972, Predictive Analytics.

[4]  A Cowan,et al.  Statistical analysis of drug-drug and site-site interactions with isobolograms. , 1989, Life sciences.

[5]  P. Holland,et al.  Discrete Multivariate Analysis. , 1976 .

[6]  XXI.—An Experimental Research on the Antagonism between the Actions of Physostigma and Atropia , 1871 .

[7]  M. Berenbaum,et al.  A method for testing for synergy with any number of agents. , 1978, The Journal of infectious diseases.

[8]  Y. Hochberg.  A sharper Bonferroni procedure for multiple tests of significance , 1988 .

[9]  S G Machado,et al.  A direct, general approach based on isobolograms for assessing the joint action of drugs in pre-clinical experiments. , 1994, Statistics in medicine.

[10]  C. Kelly,et al.  Monotone smoothing with application to dose-response curves and the assessment of synergism. , 1990, Biometrics.

[11]  S. Loewe.  The problem of synergism and antagonism of combined drugs. , 1953, Arzneimittel-Forschung.

[12]  A. Agresti,et al.  Categorical Data Analysis , 1991, International Encyclopedia of Statistical Science.

[13]  B. Cabana,et al.  A study of the interaction of the hypnotic effects and of the toxic effects of chloral hydrate and ethanol. , 1970, The Journal of pharmacology and experimental therapeutics.

[14]  M. Prichard,et al.  A three-dimensional model to analyze drug-drug interactions. , 1990, Antiviral research.

[15]  R. D'Agostino,et al.  A Suggestion for Using Powerful and Informative Tests of Normality , 1990 .

[16]  M C Berenbaum,et al.  Criteria for analyzing interactions between biologically active agents. , 1981, Advances in cancer research.

[17]  Chris Gennings,et al.  A Statistical Approach to the Construction and Analysis of Isobolograms , 1988 .

[18]  S. Holm.  A Simple Sequentially Rejective Multiple Test Procedure , 1979 .

[19]  Chris Gennings,et al.  Utilizing Concentration-Response Data from Individual Components to Detect Statistically Significant Departures from Additivity in Chemical Mixtures , 1995 .

[20]  Berenbaum Mc.  What is synergy? , 1989, Pharmacological reviews.