National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children

The purpose of the study is (1) to identify and collect samples from children and adults who take drugs and have adverse drug reactions AND children and adults who take drugs and do not experience any adverse drug effects; (2) to determine if genetic differences between the two groups contribute to causing the adverse drug reactions; and (3) to develop patient specific drug dosing guidelines to prevent future adverse drug reactions. We also wish to compare the use of prescription drugs, medical and hospital services and vital statistics between BC participants who experience adverse drug reactions and those who do not. Study hypothesis: Genetic differences may contribute to patients' response to drugs and may be responsible for adverse drug reactions.

CPNDS will identify ADR predictive markers by comparing DNA and plasma samples from patients that suffer ADRs with samples from control populations that are stratified by medication type and age. The GATC will obtain its clinical material for ADR patients mainly, from hospital-based active surveillance network across Canada's major hospitals. 1\. CPNDS will examine known SNPs in candidate genes related to the ADR (i.e. drug metabolism genes, drug transporter genes, drug target genes, and other disease-specific genes or genes related to the physiological pathway of the ADR.) 2. CPNDS will discover novel ADR predictive SNPs and mutations by sequencing DNA samples from our patient cohorts. CPNDS will also genotype and sequence DNA samples from populations of controls that received the same drugs, but did not suffer ADRs; and a second population of control patients who represent a random sample of the population of known ethnic backgrounds. Novel ADR predictive SNPs and mutations will be functionally validated by pharmacokinetic approaches applied to time course analysis of drug concentrations for each specific genotype. Pharmacokinetic studies will also be used to determine the drug concentration in patients to characterize possible mechanisms of the ADR, translating into rational approaches to the choice of candidate genes to be examined in the genomic analyses. The cost-effectiveness of an ADR screening program for the prevention of ADRs in children and adults will be calculated in detailed health-economic studies.