Bruce Carleton: Professor at Department of Pediatrics, UBC Faculty of Medicine

Professor

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Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Teratogenicity and perinatal outcomes associated with epilepsy and the use of antiepileptic drugs (2017)

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.

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The Clinical and Pharmacogenomic Determinants of Interferon Beta Induced Liver Injury in Multiple Sclerosis (2016)

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.

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Asthma drug regimen optimality and health services utilization: a population-based analysis in British Columbia (2013)

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.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

The development, implementation, and evaluation of a DPYD testing program in British Columbia (2023)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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The development of dose-adjusted pharmacogenetic prediction models in pediatric oncology (2022)

Anthracyclines and cisplatin are two widely-used chemotherapeutic agents in the treatment of pediatric cancers. However, their use is limited by severe life-threatening and life-altering adverse drug reactions (ADRs). Anthracyclines cause cardiotoxicity in up to 57% of treated patients, and cisplatin causes permanent hearing loss in 60-70% of patients. Thus, efforts must be made to predict those most susceptible to these ADRs in order to mitigate the risk of toxicity before it occurs. Significant interindividual variability in anthracycline-induced cardiotoxicity and cisplatin-induced ototoxicity has prompted the discovery and replication of several pharmacogenetic variants involved in the development of these ADRs. Clinical practice guidelines have been published outlining the roles of SLC28A3, UGT1A6, and RARG in anthracycline-induced cardiotoxicity, and TPMT in cisplatin-induced ototoxicity. While both anthracycline- and cisplatin-induced toxicities are dose-dependent reactions, no studies have explored the dose-gene relationship in the development of these ADRs. This study seeks to understand how anthracycline/cisplatin dose and pharmacogenetics together contribute to the development of anthracycline- and cisplatin-induced toxicities. In so doing, this work aims to construct dose-adjusted pharmacogenetic prediction models for these ADRs. 595 anthracycline-treated children were stratified into low-dose (≤150mg/m²) and high-dose (>250mg/m²) groups based on cumulative anthracycline dose received, and pharmacogenetic effects in the development of cardiotoxicity were compared. Results revealed that UGT1A6 and RARG risk variants significantly increased cardiotoxicity risk at low-doses (OR 7.18; p=0.0045 and OR 2.76, p=0.057, respectively), while the SLC28A3 protective variant significantly reduced risk at high-doses (OR 0.43, p=0.0093). A separate cohort of 371 cisplatin-treated children were stratified according to cisplatin dose intensity and incidence of ototoxicity was compared. Dose intensity was defined as the amount of cisplatin administered per unit time. Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity (p=9e-07). Further stratification by TPMT-genotype revealed that carriers of ≥1 TPMT variant have increased incidence of ototoxicity compared to their wildtype counterparts, regardless of dose intensity (OR 1.41 per allele, p=0.038). These results may help identify patients able to safely tolerate higher doses of chemotherapy based on their pharmacogenetic profile, as well as those at risk of toxicity even at low exposure-levels.

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The pharmacogenomics of hepatitis C: optimizing effectiveness and safety on treatment (2021)

Hepatitis C infection affects an estimated 71 million people globally and is responsible for 399,000 fatalities annually. Research advancing hepatitis C treatment practices are rapidly advancing, with abundant focus given to increasing optimizing efficacy of treatment and safety of the patients taking them. Considered a key drug in treating hepatitis C, sofosbuvir is widely used though expensive. Failed treatments are costly to the healthcare system and expose patients unnecessarily to risks of severe adverse reactions. Treatment failures are presumed to be due to viral or clinical risk factors, while patient-specific genetic factors are largely unexplored. This study recruited 359 real-world patients to assess the influence of genetic variation on the risks sofosbuvir-based treatment failure. The study replicated associations with IFNL4 (rs12979860; OR:2.25, 95%CI:1.15-4.06; P:0.0071), and found variants novel predictors in CES1 (rs115629050 or rs4513095; odds ratio (OR):5.43, 95%CI:1.64-18.01; P:0.0057) which activates sofosbuvir and IL10RB (rs2834167; OR:1.81, 95%CI:1.01-3.24; P:0.047) the receptor for IFNL4. Combining genetic risk factors with treatment regimen choice significantly improved the ability to predict treatment failure (P:0.0080). Once a staple of interferon-based regimens, ribavirin is currently used to increase treatment effectiveness in difficult-to-treat chronic hepatitis C patients. Its usefulness is constrained by the development of ribavirin-induced anemia requiring dosage modification or discontinuation in 30% of treated patients. Genetic variants in ITPA have been identified to predict this adverse effect, however known clinical and genetic factors do not entirely explain the risk. In 188 patients, this study replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04-0.41, P:8.66x10⁻⁵; and rs1544410; OR:1.65, 95%CI:1.01-2.70, P:0.0437). Genome-wide analyses identified a novel association in GYPC (rs6741425; OR:0.12, 95%CI:0.04-0.34, P: 2.94 x10⁻⁶) that protects against ribavirin-induced anemia by increasing erythrocyte structural strength. Addition of GYPC significantly improved the model for predicting ribavirin-induced anemia (P:0.00216) in comparison to ITPA and VDR alone. Overall, patient-specific genetic factors were found to identify patients with double the risk of sofosbuvir treatment failure and five-fold reduced likelihood of serious ribavirin-induced anemia. The implementation of these findings can allow for patients to receive safer, more effective therapy sooner.

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Implementation of pharmacogenetic risk prediction models in pediatric oncology (2019)

Adverse drug reactions (ADRs) are increasingly recognized as important and sometimes irreversible complications of cancer treatment¹,². Anthracyclines and cisplatin, two widely-used chemotherapeutic agents in the treatment of childhood malignancies, have contributed to the increased 5-year survival rates for childhood cancer to over 82% today³. Their use, however, is limited by the occurrence of anthracycline-induced cardiotoxicity in up to 57%⁴ of treated children and cisplatin-induced ototoxicity in 60-70%⁵-⁷ of treated children. Genetic associations for the susceptibility of these two ADRs have been discovered and replicated⁸-¹², and clinical practice guidelines have been published¹³,¹⁴ outlining which associations have sufficient evidence for their use in clinical practice. Based on these clinical practice guidelines, pharmacogenetic risk prediction models that combined several genetic variants into one predicted outcome for anthracycline-induced cardiotoxicity and cisplatin-induced ototoxicity were developed using logistic regression.In this study, pharmacogenetic risk prediction models for two common ADRs were implemented into clinical practice in pediatric oncology at BC Children’s Hospital. Between July 2013 and September 2018, 279 patients were enrolled in the study and have had their pharmacogenetic risk prediction results returned to their treating oncologists. Results have been incorporated into treatment decision-making and have resulted in treatment modifications such as the use of cardioprotective and otoprotective drugs, increased audiological and cardiac monitoring, and the use of results to decide between different treatment protocols. Prospective evaluation of the occurrence of cardiotoxicity and ototoxicity currently demonstrates that pharmacogenetic-tested patients have experienced significantly less cardiotoxicity than previously treated patients that did not receive pharmacogenetic results over the same follow-up period (3.4% versus 11.8%, p=0.0005). Rates of cisplatin-induced ototoxicity in patients that received pharmacogenetic testing were similar to previously-treated patients used to develop the risk prediction model (58.9% versus 66.7%, respectively), and none of the patients that have received treatment modifications as a result of pharmacogenetic testing have developed clinically relevant ototoxicity (≥ grade 2 ototoxicity). Interviews with patients/families (n=11) and oncologists (n=4) demonstrated that patients/families felt more involved in treatment decisions and were reassured by understanding their risk of toxicity. Oncologists indicated that testing helped ensure that treatment and long-term monitoring were appropriate for each patient.

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Pharmacogenomics of warfarin safety and effectiveness in children (2013)

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.

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The pharmacogenomics of vincristine-induced neurotoxicity in paediatric cancer patients with Wilms tumor or rhabdomyosarcoma (2011)

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
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