The invention provides a system and methods for the determination of the pharmacogenomic phenotype of any individual or group of individuals, ideally classified to a discrete, specific and defined pharmacogenomic population(s) using machine learning and population structure. Specifically, the invention provides a system that integrates several subsystems, including (1) a system to classify an individual as to pharmacogenomic cohort status using properties of underlying structural elements of the human population based on differences in the variations of specific genes that encode proteins and enzymes involved in the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics, (2) the use of a pre-trained learning machine for classification of a set of electronic health records (EHRs) as to pharmacogenomic phenotype in lieu of genotype data contained in the set of EHRs, (3) a system for prediction of pharmacological risk within an inpatient setting using the system of the invention, (4) a method of drug discovery and development using pattern-matching of previous drugs based on pharmacogenomic phenotype population clusters, and (5) a method to build an optimal pharmacogenomics knowledge base through derivatives of private databases contained in pharmaceutical companies, biotechnology companies and academic research centers without the risk of exposing raw data contained in such databases. Embodiments include pharmacogenomic decision support for an individual patient in an inpatient setting, and optimization of clinical cohorts based on pharmacogenomic phenotype for clinical trials in drug development.