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Open Research Positions
There are numerous opportunities for pursuing doctoral and post-doctoral research using state of the art genotyping and sequencing platforms to identify the genetic determinants of severe adverse drug reactions (ADRs) in paediatric and adult populations. In close collaboration with the CPNDS active surveillance network, genetic association and validation studies are being performed to define ADR causal genes and to develop diagnostic tests to offer personalized therapeutic recommendations for commonly used drugs. Current pharmacogenomics and surveillance focuses are: cisplatin, anthracyclines, vincristine, warfarin, codeine, inhaled corticosteroids, 5-HT3 antagonists (antiemetics), and drugs used in the treatment of Hepatitis C. Other projects include the development of clinical practice guidelines for six drugs, and knowledge translation to implement pharmacogenomic testing in clinical practice.
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2019)
Background and Objectives: Epilepsy complicates 0.3 – 0.7% of all pregnancies in developed countries. There is a lack of consensus on appropriate antiepileptic drug (AED) regimens, folic acid supplementation, delivery management, and breastfeeding guidance. This thesis examines how women with epilepsy in British Columbia (BC) and throughout Canada are being managed to concurrently control seizures, decrease teratogenicity and optimize obstetric and perinatal outcomes.Design and Methods: Using BC linked administrative data, I examined utilization of AEDs, teratogenicity and small for gestational age (SGA) outcomes in infants exposed to newer generation AED monotherapy in utero. Using the Canadian Community Health Survey Cycle 3.1, I compared rates of preconceptual folic acid supplementation and breastfeeding among women with and without epilepsy. Using data from the BC Perinatal Data Registry, I compared rates and indications for induction of labour and cesarean section among women with and without epilepsy.Results: Our study on the BC population demonstrates no risk for both major malformations and SGA outcomes with newer generation AED monotherapy such as gabapentin, topiramate and lamotrigine. While pregabalin was not found to increase the risk for major malformations, it is possible that it does increase the risk for SGA outcomes. Newer generation AEDs were less frequently prescribed during pregnancy than older generation AEDs. Women with epilepsy in Canada were no more likely to supplement with folic acid and were significantly less likely to breastfeed when compared to women without epilepsy. In BC, when compared to women without epilepsy, women with epilepsy were significantly more likely to deliver via cesarean section, induction of labour, assisted vaginal delivery, epidural or general anesthesia. Significant differences observed between women with and without epilepsy in the indications provided for cesarean section included breech, fetal malposition and “Other;” and “Maternal Condition” for those undergoing induction of labour.Conclusion: In women with epilepsy, pregnancy management is best implemented preconceptually. This includes planning for sufficient time to transition to the appropriate AED therapy, and to initiate folic acid supplementation. During preconceptual counselling, women with epilepsy of childbearing age should be apprised of delivery options and encouraged to attempt breastfeeding.
Drug-induced liver injury is a common cause of acute liver failure; it is also the leading reason for a drug’s withdrawal from the market. Interferon-beta (IFN-β) is a commonly used disease-modifying drug for multiple sclerosis (MS) and is generally safe. However, 30-60% of IFN-β exposed patients experience liver aminotransferase elevations, with an unknown proportion experiencing more severe, medically significant elevations. To date, there are no means of predicting who will experience this adverse drug reaction (ADR), although the application of pharmacogenomics could assist with identifying predictive genomic factors. The purpose of this dissertation was to identify predictive factors associated with IFN-β induced liver injury to mitigate toxicity.The research in this dissertation commenced with a review article summarizing the potential application of pharmacogenomics to severe ADRs in MS and a case report of a patient experiencing a hepatic autoimmune-like complication of IFN-β therapy. An original research article followed; utilizing 942 IFN-β exposed MS patients, primarily from Canada. This population-based study examined the rate of liver injury due to IFN-β in MS patients. Approximately 1 in 50 (or 1.9%) IFN-β exposed patients’ experienced liver injury.A pharmacogenomic case-control study followed, involving 182 patients and a genome-wide scan of 785,230 genomic variants, to identify predictors of IFN-β induced liver injury. A genetic variant within synaptotagmin-14 was strongly associated with the ADR (odds ratio 9.83, 95% confidence interval 4.01-24.10, P-value 9.39 x 10-9) and was specific for liver injury from IFN-β and has been previously correlated with hepatic expression of interferon regulatory factor 6. This represents the first genome-wide association study of an ADR from an MS drug and of drug induced liver injury due to a biological therapy.The clinical, demographic and genomic characteristics identified here could modify the risk of experiencing a clinically significant ADR that often results in the cessation of a potentially useful treatment. Predictive characteristics of those at an increased risk will direct preventative strategies, such as enhanced monitoring for early signs of toxicity or alternative treatment regimens. This dissertation contributes towards the personalization of MS therapy and to the broader pharmacogenomic literature on biological therapies.
Background: Drug therapy is the mainstay medical treatment for asthma patients. Many asthma patients (up to 70%) receive suboptimal drug therapy. Inadequate use of inhaled corticosteroids (ICS) has been associated with increased emergency department (ED) visits and hospital admissions for asthma. To understand patients’ asthma drug use in British Columbia (B.C.) and improve health outcomes, this study describes the burden of asthma, identifies patients who received suboptimal asthma drug regimens according to asthma clinical practice guidelines, and examines the link between regimen optimality and health services utilization for asthma in an entire population with treated asthma in BC from 1996 to 2009.Methods: A cohort of 336,901 asthma patients between 5–55 years of age was identified using provincial health services utilization data from 1996 to 2009. Annual patient medication dispensings of short-acting bronchodilators (SABA) with or without ICS were categorized into optimal or suboptimal regimens based on the asthma clinical practice guidelines. The association between regimen optimality and health services utilization was examined in one-year, as well as during a 14-year study period, using logistic regression models and Cox Proportional regression models, respectively.Results: The prevalence (~2%) and incidence (0.7%) of asthma was stable in patients 5-55 years of age in B.C. from 1996 to 2009. Asthma-related specialist visits, ED visits and hospital admissions declined by over 50% during the study period. In 2009, patients with suboptimal regimens had significantly greater risk of using health services than patients with optimal regimens of SABA and/or ICS. Over time, switching from a suboptimal to an optimal drug regimen was associated with a 30% reduction in the use of hospital services for asthmaiii(hazard ratio (HR) 0.71; 95% CI 0.54 – 0.93), and a 50% reduction in the use of ED services for asthma (HR 0.49; 95% CI 0.33 – 0.73).Conclusions: Much of the healthcare burden associated with asthma is preventable by optimizing drug therapy, in particular, with improved ICS adherence. Identifying patients with suboptimal asthma management practices is a critical step in reducing the burden of asthma on the healthcare system and ultimately improving the quality of life of asthma patients.
Master's Student Supervision (2010 - 2018)
Use of the anticoagulant warfarin for thromboembolic disease prophylaxis is limited by alarge inter-patient dose variability and high risk of adverse drug reactions (ADRs).Polymorphisms in twogenes,CYP2C9andVKORC1, have consistently been shown to beassociated with warfarin dose requirements in adults. However, evidence ontheimportanceof genetics in warfarin therapyin childrenis limited.Further paediatricstudies are requiredto understand the predictive factors contributing to dose variation and to help preventwarfarin-induced ADRsin children.In this study we aimed to assess the contribution of genotypes andclinical factors to warfarindose and related outcomes in children.Clinical and geneticdata was collected from 93patientsless than 19years of agewho received warfarin therapy. DNA was genotyped for93single nucleotide polymorphismsusing a custom assay.Associations betweenCYP2C9/VKORC1/CYP4F2genotypes andtherapeutic dose, time to therapeutic INR/time toover-anticoagulation, and incidence of adverse drugreactionswere analyzed.Additionalvariants in genes involved invitamin Kand coagulation pathways were tested for anassociationwith warfarin dose.76.3% of dose variability was explained by weight, indication,VKORC1!1639G/A andCYP2C9*2/*3,with genotypes accounting for 21.1% of variability.There was a strongcorrelation (R²=0.68;p4 (p=0.024)during theinitiation of therapy.Anadditional variant inCYP2C9(rs7089580) was significantly associated with warfarin dose ina multivariate model.This study confirms the importance ofVKORC1/CYP2C9genotypesfor warfarindose andclinical outcomesin children and validates a pediatric-specific genotype-based dosingalgorithm.Furthermore, we identified an additional variant inCYP2C9of potentialrelevance for warfarin dosing in children.
Vincristine is one of the most effective and widely utilized antineoplastic agents.However, the clinical utility of this drug is limited by severely debilitating vincristineinducedneurotoxicities (VIN). Previous studies have associated VIN with geneticpolymorphisms in genes involved in the metabolism and transportation of vincristine,including CYP3A4, CYP3A5, and ABCB1. However, the findings of such studies have notbeen consistently reproduced. This study hypothesizes that there are specific variants ingenes involved in general drug absorption, metabolism, distribution, excretion, and toxicity(ADME-Tox) that affect the individual susceptibility to VIN in patients with Wilms tumorand rhabdomyosarcoma.Detailed clinical data was collected from 140 patients with Wilms tumor andrhabdomyosarcoma by retrospective chart review. VIN cases were characterized by type ofneurotoxicity, and severity was evaluated using a validated clinical grading system foradverse events (NCI-CTCAE v4.03). A customized Illumina GoldenGate Panel was used togenotype 4,536 single nucleotide polymorphisms (SNPs) in candidate genes involved in themetabolism and transportation pathway of vincristine, as well as in genes broadly involved inADME-Tox.None of the SNPs that were previously reported to be associated with VIN werefound to be significantly associated (p-value