Helen Tremlett
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2019)
Few population-based, methodologically rigorous studies have evaluated the association between mental health and health behaviours in MS. The goal of this dissertation is to contribute to the broader understanding of these relationships and their potential impact on MS. This dissertation was based on two main cohorts: 1) a multi-site clinic-based longitudinal cohort from across Canada; 2) a population-based health administrative and clinical cohort in British Columbia. A large (n=949) sample of MS patients were recruited from four Canadian MS clinics. Participants completed a series of questionnaires at three visits over two years. The prevalence of psychiatric comorbidities (depression [35%] and anxiety [54%]), and adverse health behaviours (smoking [24%] and non-adherence to disease-modifying therapies (DMTs) [22%]) was high. Alcohol dependence was associated with increased odds of anxiety (Odds Ratio (OR):1.84;95% confidence interval (CI):1.32–2.58) and depression (OR:1.53;95%CI:1.05–2.23), as was smoking (anxiety OR:1.29;95% CI:1.02–1.63; depression OR:1.37;95%CI:1.04–1.78). Non-adherence (
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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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Multiple sclerosis (MS) is a putative autoimmune disease of the central nervoussystem, affecting many adults of childbearing age. Although extensive research hasexamined the association between MS and traditional perinatal outcomes (i.e. cesareansection, birth weight and preterm birth), other important outcomes are understudied,partly due to existing methodological challenges. Using comprehensive populationbaseddatabases including the British Columbia (BC) MS Database, BC PerinatalDatabase Registry, Vital Statistics Birth Registry, Population Data BC Consolidation Fileand Census GeoData, this dissertation investigated the association between MS (andrelated clinical factors) with: labour induction and augmentation; obstetrical epidural andspinal anesthesia; length of birth hospitalization in mothers and their newborns; as wellas birth outcomes in fathers with MS. Overall, individuals with MS were not at increasedrisk for the investigated outcomes compared to the general population with theexception that multiparous women with MS had higher rates of epidural anesthesiacompared to multiparous women in the general population. Within MS women, thosewith longer disease duration had less epidural anesthesia and those with greaterdisability had more labor induction. Men with greater MS disability tended to fatheroffspring with lower mean birth weight, but their newborns were still within the normalrange for the general population.Individuals with MS who wish to have children must also decide betweeninitiating disease-modifying drug (DMD) early to minimize relapses (i.e. MS attacks) ordelaying/stopping therapy prior to conception to avoid potential fetal harm from in uteroDMD exposure. This dissertation explored perinatal outcomes in women and men with iiiMS exposed to DMDs and includes a systematic review of DMD exposure on perinatal outcomes. Data from BC suggest that DMD exposure in men and women with MS does not increase the risk of unfavorable perinatal outcomes. However, best evidence from the systematic review indicates that interferon-beta exposure in women with MS is associated with preterm birth, lower mean birth weight and shorter mean birth length in newborns; nonetheless, growth parameters of exposed newborns remained within normal values for the general population and preterm births tended to be close to term.
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News Releases
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Common treatment for multiple sclerosis may prolong life (18 Mar 2019)
Publications
- Adherence to disease-modifying therapies for multiple sclerosis and subsequent hospitalizations. (2017)
Pharmacoepidemiology and drug safety, - Age Related Multiple Sclerosis Severity Score: Disability ranked by age. (2017)
Multiple sclerosis (Houndmills, Basingstoke, England), - An 'epidemic' of multiple sclerosis and falling infection rates? Reflecting on comparisons made and the rising MS incidence in Bach's NEJM 2002 Figure. (2017)
European journal of neurology, - Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case-control study protocol for dimethyl fumarate-induced lymphopenia. (2017)
BMJ open, - Author response: Evaluating the safety of β-interferons in MS: A series of nested case-control studies. (2017)
Neurology, - Bayesian analysis of pair-matched case-control studies subject to outcome misclassification. (2017)
Statistics in medicine, - Comorbidity increases the risk of relapse in multiple sclerosis: A prospective study. (2017)
Neurology, - Concussion may not cause multiple sclerosis. (2017)
Annals of neurology, - Determinants of neurological disease: Synthesis of systematic reviews. (2017)
Neurotoxicology, - Determinants of non-adherence to disease-modifying therapies in multiple sclerosis: A cross-Canada prospective study. (2017)
Multiple sclerosis (Houndmills, Basingstoke, England), - Disability progression in aggressive multiple sclerosis. (2017)
Multiple sclerosis (Houndmills, Basingstoke, England), - Disease-Modifying Therapies and Adherence in Multiple Sclerosis: Comparing Patient Self-Report with Pharmacy Records. (2017)
Neuroepidemiology, - Effect of adherence to the first-generation injectable immunomodulatory drugs on disability accumulation in multiple sclerosis: a longitudinal cohort study. (2017)
BMJ open, - Environmental modifiable risk factors for multiple sclerosis: Report from the 2016 ECTRIMS focused workshop. (2017)
Multiple sclerosis (Houndmills, Basingstoke, England), - Evaluating the safety of β-interferons in MS: A series of nested case-control studies. (2017)
Neurology, - Factors associated with onset, relapses or progression in multiple sclerosis: A systematic review. (2017)
Neurotoxicology, - From bugs to brains: The microbiome in neurological health. (2017)
Multiple sclerosis and related disorders, - Genetic variation associated with the occurrence and progression of neurological disorders. (2017)
Neurotoxicology, - Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. (2017)
The Lancet. Neurology, - Increased incidence and prevalence of psoriasis in multiple sclerosis. (2017)
Multiple sclerosis and related disorders, - Infection-related health care utilization among people with and without multiple sclerosis. (2017)
Multiple sclerosis (Houndmills, Basingstoke, England), - Primary and secondary progressive MS have a similar age at onset of progression - NO. (2017)
Multiple sclerosis (Houndmills, Basingstoke, England), - The gut microbiome in human neurological disease: A review. (2017)
Annals of neurology, - The Gut Microbiota and Pediatric Multiple Sclerosis: Recent Findings. (2017)
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, - The multiple sclerosis microbiome? (2017)
Annals of translational medicine, - A population-based study comparing multiple sclerosis clinic users and non-users in British Columbia, Canada. (2016)
European journal of neurology, - Adherence and persistence to drug therapies for multiple sclerosis: A population-based study. (2016)
Multiple sclerosis and related disorders, - Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: A prospective multisite study. (2016)
Multiple sclerosis (Houndmills, Basingstoke, England), - Association between the use of selective serotonin reuptake inhibitors and multiple sclerosis disability progression. (2016)
Pharmacoepidemiology and drug safety, - Associations between the gut microbiota and host immune markers in pediatric multiple sclerosis and controls. (2016)
BMC neurology, - Children of chronically ill parents: Relationship between parental multiple sclerosis and childhood developmental health. (2016)
Multiple sclerosis (Houndmills, Basingstoke, England), - Chronic lung disease and multiple sclerosis: Incidence, prevalence, and temporal trends. (2016)
Multiple sclerosis and related disorders, - Comparison of statistical approaches dealing with time-dependent confounding in drug effectiveness studies. (2016)
Statistical methods in medical research, - Comparison of Statistical Approaches for Dealing With Immortal Time Bias in Drug Effectiveness Studies. (2016)
American journal of epidemiology, - Differing trends in the incidence of vascular comorbidity in MS and the general population. (2016)
Neurology. Clinical practice, - Examining the effects of comorbidities on disease-modifying therapy use in multiple sclerosis. (2016)
Neurology, - Fatigue and Comorbidities in Multiple Sclerosis. (2016)
International journal of MS care, - Five-minute Apgar score as a marker for developmental vulnerability at 5 years of age. (2016)
Archives of disease in childhood. Fetal and neonatal edition, - Gut microbiota composition and relapse risk in pediatric MS: A pilot study. (2016)
Journal of the neurological sciences, - Gut microbiota in early pediatric multiple sclerosis: a case-control study. (2016)
European journal of neurology, - Health-related quality of life in multiple sclerosis: Direct and indirect effects of comorbidity. (2016)
Neurology, - Incidence of Mood or Anxiety Disorders in Children of Parents with Multiple Sclerosis. (2016)
Paediatric and perinatal epidemiology, - Modelling disease progression in relapsing-remitting onset multiple sclerosis using multilevel models applied to longitudinal data from two natural history cohorts and one treated cohort. (2016)
Health technology assessment (Winchester, England), - Multiple sclerosis in men: management considerations. (2016)
Journal of neurology, - Peripartum depression in parents with multiple sclerosis and psychiatric disorders in children. (2016)
Multiple sclerosis (Houndmills, Basingstoke, England), - Physical comorbidities increase the risk of psychiatric comorbidity in multiple sclerosis. (2016)
Brain and behavior, - Sex differences in comorbidity at diagnosis of multiple sclerosis: A population-based study. (2016)
Neurology, - THE AUTHORS REPLY. (2016)
American journal of epidemiology, - A longitudinal model for disease progression was developed and applied to multiple sclerosis. (2015)
Journal of clinical epidemiology, - Beta-interferon exposure and onset of secondary progressive multiple sclerosis. (2015)
European journal of neurology, - Comorbidity is associated with pain-related activity limitations in multiple sclerosis. (2015)
Multiple sclerosis and related disorders, - Differences in the burden of psychiatric comorbidity in MS vs the general population. (2015)
Neurology, - Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator. (2015)
The Lancet. Neurology, - Health-related quality of life in patients with longstanding 'benign multiple sclerosis'. (2015)
Multiple sclerosis and related disorders, - High incidence and increasing prevalence of multiple sclerosis in British Columbia, Canada: findings from over two decades (1991-2010). (2015)
Journal of neurology, - Impact of parental multiple sclerosis on early childhood development: A retrospective cohort study. (2015)
Multiple sclerosis (Houndmills, Basingstoke, England), - Multiple sclerosis in older adults: the clinical profile and impact of interferon Beta treatment. (2015)
BioMed research international, - Risk factors associated with the onset of relapsing-remitting and primary progressive multiple sclerosis: a systematic review. (2015)
BioMed research international, - Serum proteomics in multiple sclerosis disease progression. (2015)
Journal of proteomics, - The systematic search for risk factors in multiple sclerosis. (2015)
The Lancet. Neurology, - A review of safety-related pregnancy data surrounding the oral disease-modifying drugs for multiple sclerosis. (2014)
CNS drugs, - Assessment of cancer risk with β-interferon treatment for multiple sclerosis. (2014)
Journal of neurology, neurosurgery, and psychiatry, - Association between beta-interferon exposure and hospital events in multiple sclerosis. (2014)
Pharmacoepidemiology and drug safety, - Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. (2014)
Neurology, - Birth outcomes in newborns fathered by men with multiple sclerosis exposed to disease-modifying drugs. (2014)
CNS drugs, - Birth outcomes of pregnancies fathered by men with multiple sclerosis. (2014)
Multiple sclerosis (Houndmills, Basingstoke, England), - Characteristics associated with drug-induced liver injury from interferon beta in multiple sclerosis patients. (2014)
Expert opinion on drug safety, - Children and adolescents adjustment to parental multiple sclerosis: a systematic review. (2014)
BMC neurology, - Children of chronically ill parents: the silence of research. (2014)
Child: care, health and development, - Investigation of heterogeneity in the association between interferon beta and disability progression in multiple sclerosis: an observational study. (2014)
European journal of neurology, - Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review. (2014)
Obstetrics and gynecology, - Marginal structural Cox models for estimating the association between β-interferon exposure and disease progression in a multiple sclerosis cohort. (2014)
American journal of epidemiology, - Performance of administrative case definitions for comorbidity in multiple sclerosis in Manitoba and Nova Scotia. (2014)
Chronic diseases and injuries in Canada, - UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model. (2014)
BMJ open, - A proposed methodology to estimate the cumulative life-time UVB exposure using geographic information systems: An application to multiple sclerosis. (2013)
Multiple sclerosis and related disorders, - Birth hospitalization in mothers with multiple sclerosis and their newborns. (2013)
Neurology, - Characterising aggressive multiple sclerosis. (2013)
Journal of Neurology, Neurosurgery, and Psychiatry, - Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. (2013)
Neurology, - Interferon beta and long-term disability in multiple sclerosis. (2013)
JAMA neurology, - Labor induction and augmentation in women with multiple sclerosis. (2013)
Multiple sclerosis (Houndmills, Basingstoke, England), - Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance. (2013)
BMC neurology, - Obstetrical epidural and spinal anesthesia in multiple sclerosis. (2013)
Journal of neurology, - Oligoclonal bands and cerebrospinal fluid markers in multiple sclerosis: associations with disease course and progression. (2013)
Multiple sclerosis (Houndmills, Basingstoke, England), - Prevalence and incidence of ischemic heart disease in multiple sclerosis: A population-based validation study. (2013)
Multiple sclerosis and related disorders, - Retinal nerve fiber layer thickness in benign multiple sclerosis. (2013)
Multiple sclerosis (Houndmills, Basingstoke, England), - Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance. (2013)
Expert review of neurotherapeutics, - Suspected autoimmune hepatitis and primary biliary cirrhosis unmasked by interferon-beta in a multiple sclerosis patient. (2013)
Multiple sclerosis and related disorders, - The incidence and prevalence of multiple sclerosis in Nova Scotia, Canada. (2013)
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, - The potential role of pharmacogenomics in the prevention of serious adverse drug reactions in multiple sclerosis. (2013)
Multiple sclerosis and related disorders, - The utility of administrative data for surveillance of comorbidity in multiple sclerosis: a validation study. (2013)
Neuroepidemiology, - Treatment optimization in MS: Canadian MS Working Group updated recommendations. (2013)
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, - Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. (2012)
JAMA, - Cancer risk in multiple sclerosis: findings from British Columbia, Canada. (2012)
Brain : a journal of neurology, - Characteristics of multiple sclerosis in aboriginals living in British Columbia, Canada. (2012)
Multiple sclerosis (Houndmills, Basingstoke, England), - Epidemiology in multiple sclerosis has had its day: there are no more unanswered questions--no. (2012)
Multiple sclerosis (Houndmills, Basingstoke, England), - Hospital admissions and MS: temporal trends and patient characteristics. (2012)
The American journal of managed care, - Long-term persistence with the immunomodulatory drugs for multiple sclerosis: a retrospective database study. (2012)
Clinical therapeutics, - Natural, innate improvements in multiple sclerosis disability. (2012)
Multiple sclerosis (Houndmills, Basingstoke, England), - Perinatal outcomes in women with multiple sclerosis exposed to disease-modifying drugs. (2012)
Multiple sclerosis (Houndmills, Basingstoke, England), - Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada. (2012)
Journal of neurology, neurosurgery, and psychiatry, - Rising prevalence of vascular comorbidities in multiple sclerosis: validation of administrative definitions for diabetes, hypertension, and hyperlipidemia. (2012)
Multiple sclerosis (Houndmills, Basingstoke, England), - Temporal trends of disability progression in multiple sclerosis: findings from British Columbia, Canada (1975-2009). (2012)
Multiple sclerosis (Houndmills, Basingstoke, England), - The incidence and prevalence of fibromyalgia are higher in multiple sclerosis than the general population: A population-based study. (2012)
Multiple sclerosis and related disorders, - The incidence and prevalence of thyroid disease do not differ in the multiple sclerosis and general populations: a validation study using administrative data. (2012)
Neuroepidemiology, - The risks for falls and fractures in multiple sclerosis. (2012)
Neurology, - High-dose frequency beta-interferons increase the risk of liver test abnormalities in multiple sclerosis: a longitudinal study. (2011)
Multiple sclerosis (Houndmills, Basingstoke, England), - Neonatal and delivery outcomes in women with multiple sclerosis. (2011)
Annals of neurology, - Symptomatic liver injury (hepatotoxicity) associated with administration of complementary and alternative products (Ayurveda-AP-Mag Capsules(®)) in a beta-interferon-treated multiple sclerosis patient. (2011)
European journal of neurology, - The psychosocial and cognitive impact of longstanding 'benign' multiple sclerosis. (2011)
Multiple sclerosis (Houndmills, Basingstoke, England), - Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS. (2010)
Neurology, - Disease onset in familial and sporadic primary progressive multiple sclerosis. (2010)
Multiple sclerosis (Houndmills, Basingstoke, England), - Factors associated with delay to medical recognition in two Canadian multiple sclerosis cohorts. (2010)
Journal of the neurological sciences, - Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. (2010)
Annals of neurology, - New perspectives in the natural history of multiple sclerosis. (2010)
Neurology, - The effect of smoking on the symptoms and progression of multiple sclerosis: a review. (2010)
Journal of inflammation research, - The natural history of secondary progressive multiple sclerosis. (2010)
Journal of neurology, neurosurgery, and psychiatry, - Impact of multiple sclerosis relapses on progression diminishes with time. (2009)
Neurology, - Interferons and multiple sclerosis: is it plausible that beta-IFN treatment could influence the risk of cancer among MS patients? (2009)
Expert review of neurotherapeutics, - Multiple sclerosis and pregnancy: what should we be telling our patients? (2009)
Neurology, - Natural history comparisons of primary and secondary progressive multiple sclerosis reveals differences and similarities. (2009)
Journal of neurology, - Progressive lipoatrophy after cessation of glatiramer acetate injections: a case report. (2009)
Multiple sclerosis (Houndmills, Basingstoke, England), - The natural history of primary progressive multiple sclerosis. (2009)
Neurology, - Adherence to the immunomodulatory drugs for multiple sclerosis: contrasting factors affect stopping drug and missing doses. (2008)
Pharmacoepidemiology and drug safety, - Defining the natural history of MS: the need for complete data and rigorous definitions. (2008)
Multiple sclerosis (Houndmills, Basingstoke, England), - Interferon-beta treatment and the natural history of relapsing-remitting multiple sclerosis. (2008)
Annals of neurology, - Malignant melanoma in a multiple sclerosis patient with persistent neutralizing antibodies to interferon-beta. (2008)
European journal of neurology, - Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. (2008)
Neuroepidemiology, - Natural history of secondary-progressive multiple sclerosis. (2008)
Multiple sclerosis (Houndmills, Basingstoke, England), - Relapses in multiple sclerosis are age- and time-dependent. (2008)
Journal of Neurology, Neurosurgery, and Psychiatry, - Ten years of adverse drug reaction reports for the multiple sclerosis immunomodulatory therapies: a Canadian perspective. (2008)
Multiple sclerosis (Houndmills, Basingstoke, England), - Timing of birth and disease progression in multiple sclerosis. (2008)
Multiple sclerosis (Houndmills, Basingstoke, England), - Longitudinal follow-up of "benign" multiple sclerosis at 20 years. (2007)
Neurology, - Disability progression in multiple sclerosis is slower than previously reported. (2006)
Neurology, - Does the season or month of birth influence disease progression in multiple sclerosis? (2006)
Neuroepidemiology, - Is late-onset multiple sclerosis associated with a worse outcome? (2006)
Neurology, - Liver test abnormalities in multiple sclerosis: findings from placebo-treated patients. (2006)
Neurology, - What went wrong in the natalizumab trials Comment? (2006)
Lancet (London, England), - Coming of age: the use of immunomodulatory therapy in children with multiple sclerosis. (2005)
Neurology, - Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. (2005)
Neurology, - The natural history of primary progressive MS in British Columbia, Canada. (2005)
Neurology, - Elevated aminotransferases during treatment with interferon-beta for multiple sclerosis: actions and outcomes. (2004)
Multiple sclerosis (Houndmills, Basingstoke, England), - Hepatic injury, liver monitoring and the beta-interferons for multiple sclerosis. (2004)
Journal of neurology, - Liver injury associated with the beta-interferons for MS: a comparison between the three products. (2004)
Neurology, - Interrupted therapy: stopping and switching of the beta-interferons prescribed for MS. (2003)
Neurology, - Asthma and multiple sclerosis: an inverse association in a case-control general practice population. (2002)
QJM : monthly journal of the Association of Physicians, - Liver and thyroid function and autoimmunity during interferon-beta 1b treatment for multiple sclerosis. (2002)
Neurology, - Effects of seasons on magnetic resonance imaging-measured disease activity in patients with multiple sclerosis. (2001)
Annals of neurology, - Prescribing for multiple sclerosis patients in general practice: a case-control study. (2001)
Journal of clinical pharmacy and therapeutics, - General practitioners' prescribing data for multiple sclerosis patients indicates a link with asthma. (2000)
The British Journal of General Practice, - Nonprescription medicine use in a multiple sclerosis clinic population. (2000)
British journal of clinical pharmacology, - Use of corticosteroids in multiple sclerosis by consultant neurologists in the United Kingdom. (1998)
Journal of neurology, neurosurgery, and psychiatry, - Oral versus intravenous corticosteroids in acute relapses of multiple sclerosis. (1997)
Lancet (London, England),
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