Applying Emax model and bivariate thin plate splines to assess drug interactions.
We review the semiparametric approach previously proposed by Kong and Lee and extend it to a case in which the dose-effect curves follow the Emax model instead of the median effect equation. When the maximum effects for the investigated drugs are different, we provide a procedure to obtain the additive effect based on the Loewe additivity model. Then, we apply a bivariate thin plate spline approach to estimate the effect beyond additivity along with its 95 per cent point-wise confidence interval as well as its 95 per cent simultaneous confidence interval for any combination dose. Thus, synergy, additivity, and antagonism can be identified. The advantages of the method are that it provides an overall assessment of the combination effect on the entire two-dimensional dose space spanned by the experimental doses, and it enables us to identify complex patterns of drug interaction in combination studies. In addition, this approach is robust to outliers. To illustrate this procedure, we analyzed data from two case studies.
Kong
Maiying
M
Department of Bioinformatics and Biostatistics, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky 40292, USA.
Lee
J Jack
JJ
D000704:Analysis of Variance; D045744:Cell Line, Tumor; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005492:Folic Acid; D005971:Glutamates; D006801:Humans; D008962:Models, Theoretical; D011743:Pyrimidines; D016597:Trimetrexate
D005971:Glutamates; D011743:Pyrimidines; D005492:Folic Acid; C105066:AG 2034; D016597:Trimetrexate