Longitudinal Risk Assessment of Atorvastatin Calcium Exposure: A Computational Approach to Personalized Medicine in the Context of Genomics and Human Embryonic Stem Cell Biology

In this study, computational mathematical algorithms are used to describe the kinetics of altered gene expression profiles of human disease and embryonic and adult stem cell differentiation in response to subchronic and extrapolated chronic administration of atorvastatin calcium (LipitorRTM). Hi-resolution mRNA microarray data was obtained from a published study at 12 hours, 36 hours, 1 week, and 4 weeks from 11 male subjects with a mean age of 49.0 years +/- 12.5 years post administration of a daily dose of 20 mg atorvastatin calcium. All subjects were previously diagnosed with primary hyperlipidemia and verified to have no history of coronary artery disease. This data was used to generate the primary model for this study. Additional genetic profiles were extrapolated using two mathematical strategies:;First, the Runge Kutta risk assessment method, an explicit iterative method for the approximation of solutions of ordinary differential equations, was used to compute interdependent gene expression vectors as a function of time. Second, Euler's Method was used to generate a prediction for additional gene expression profiles using a correlation function between significant genes in each data set. Extrapolated sets of genes regulated by atorvastatin were generated for 6 months, 1 year, and 5 years and imported into the Ingenuity Pathway Analysis (IPA) software for data and toxicology interpretation. The IPA Global Network is used as the data source for the construction of all biological pathways. Statistically significant biological networks and pathways for toxicity, altered biofunction, and disease were indentified.;RNA microarray data sets of biological states and diseases that maybe contraindicated with atorvastatin calcium administration such as human embryonic development, active of hepatitis C infection, and diabetes mellitus type 2 were also mathematically represented as a function of time. Using a System of Equations approach, we extrapolated new predicted gene expression data for 6 months and 1 year of chronic atorvastatin calcium administration interdependently with microarray signatures of the directed differentiation of H1 human embryonic stem cells (hESCs) to trophectoderm, active hepatitis C infection, and diabetes mellitus type 2 to address possible contraindication events.