Pharmacogenetics and Precision Medicine
Wearable devices for non-invasive, ambulatory seizure monitoring and prediction - also offered as MBiomedSc
Supervisors: Prof. Patrick Kwan, Prof. Terence O’Brien
Projects site: Department of Medicine (RMH), University of Melbourne
Contact: Professor Patrick Kwan, E: patrick.kwan@unimelb.edu.au
Project description: The development of reliable, accurate, non-invasive methodologies for continuous, long-term seizure monitoring is a critical part of the precision medicine approach in epilepsy management. While the gold standard for diagnosing and detecting seizures remains inpatient simultaneous EEG and video recording, it is costly and impractical for extended use outside the hospital setting. Conventional outpatient seizure monitoring relies on self-completing seizure diary which is inexpensive but highly inaccurate. There is a need for novel technologies that combine low cost, non-invasiveness with reliability for extended seizure monitoring. This project aims to develop an integrated wearable sensor system for the clinical management of seizures in patients with epilepsy. The device will be tested in patients admitted for video-EEG monitoring at the Royal Melbourne Hospital.
Stroke and epilepsy a bi-directional relatinship? - also offered as MBiomedSc
Supervisors: Prof. Patrick Kwan, Prof. Bernard Yan
Projects site: Melbourne Brain Centre, The Royal Melbourne Hospital
Contact: Prof. Patrick Kwan, E: patrick.kwan@unimelb.edu.au; A/Prof. Bernard Yan, E: Bernard.Yan@mh.org.au
Project description: Stroke is one of the leading causes of acquired epilepsy in industrialised countries. Seizures are a major complication in stroke survivors and are associated with increased mortality and poorer functional recovery. Patients with post-stroke seizures have increased risk of in-hospital complications, leading to prolonged hospitalisation. Conversely, patients with epilepsy also have an increased risk of de novo stroke, the reasons for which are unclear. Utilising our access to local and international databases, this project aims to identify the biomarkers, including clinical, genomic, and radiological factors predictive of post-stroke epilepsy and post-epilepsy stroke. The findings will shed new lights in understanding the patho-mechanisms of these disorders. The project will be based on the expanding RMH stroke database with several thousands of patients recruited, as well as the epilepsy database of new onset patients.
Clinical utility of clinical whole exome sequencing for epilepsy - also offered as MBiomedSc
Supervisor: Prof. Patrick Kwan
Projects site: Department of Medicine (RMH), University of Melbourne
Contact: Professor Patrick Kwan, E: patrick.kwan@unimelb.edu.au
Project description: Genetic variants have been found to cause epilepsy as well as affect how people respond to treatment. Whole exome sequencing is a new method of genetic testing that has the advantage of being able to screen all the genes in a person. Currently it is mainly being used for research purposes. The purpose of this prospective study is to find out whether whole exome sequencing offers value for money when used in the clinical setting to help diagnose people with epilepsy.
Development of a low cost, point-of-care diagnostic test to prevent abacavir hypersensitivity
Supervisors: Prof Patrick Kwan, Prof Stan Skafidas
Project sites: Department of Medicine (Royal Melbourne Hospital), Centre for Neural Engineering
Contact: Professor Patrick Kwan, E: patrick.kwan@unimelb.edu.au
Project description: Abacavir is a nucleoside analog reverse transcriptase inhibitor (NRTI) used to treat HIV and AIDS. 5-8% people develop hypersensitivity to abacavir. It has been found that abacavir hypersensitivity is strongly associated with HLA-B*57:01, and pre-therapy HLA testing is recommended by regulatory agencies and all major treatment guidelines. However, conventional testing is laboratory based with long turnaround time and is not accessible or affordable for people living in developing countries where many people with HIV live.
A monoclonal antibody that recognises HLA-B*57:01 has been developed. This project aims to use this antibody to develop a simple, rapid, low cost HLA-B*57:01 test kit.
Express ambulatory point-of-care molecular diagnosis - also offered as MBiomedSc
Supervisors: Professor Patrick Kwan, Dr Marian Todaro
Project Site: Department of Medicine (RMH), Melbourne Brain Centre (Parkville), Centre for Neural Engineering
Contact: Patrick Kwan, Department of Medicine (RMH) E: patrick.kwan@unimelb.edu.au;
Project Description: This is an inter-disciplinary, technology driven program with multiple projects that aim to develop point-of-care molecular diagnostics for a range of important diseases, including epilepsy, HIV infection, coeliac disease, and malaria. Conventional laboratory tests have been indispensable for disease diagnosis. However, their high costs and need for skilled personnel to operate complicated equipment have limited their abilities to cope with escalating demand from the growing population, and the need for application in resource poor and remote areas. Therefore, development of portable, on-site, point-of-care (POC) testing devices has become increasingly important in medical research. POC testing performed at the time of consultation will allow the results to be used for making immediate, informed clinical decisions on patient care. In short, it will transform medical practice.
This innovative project will combine novel biochemical and engineering technologies that will perform molecular diagnosis rapidly using compact ‘smart’ devices at the point of care. The platform technology can be customised for any molecule of interest, including DNA, RNA and protein. There is very strong potential for technological innovation and eventual application and commercialisation of the devices to meet the rapidly expanding need of molecular diagnosis. The global molecular diagnostic market is estimated to be US$21.7 billion in 2014 with projected 5-year compound annual growth rate (CAGR) of 12.5% to reach $45.2 billion in 2020. In this market, POC testing using lab-on-chip systems is the fastest growing segment, valued at >$2 billion in 2014 with CAGR of 16.5% (BCC Research, 2015). This project is open for different students with different skills and background, including:
Molecular biology
Electrical engineering
Electronic engineering
Software engineering
Potential students are strongly encouraged to contact the supervisors to discuss their suitability for the project based on their interests and skills.
Immune self-reactivity triggered by carbamazepine-modified HLA-peptide repertoire - also offered as MBiomedSc
Supervisors: Professor Patrick Kwan, Dr Nicole Mifsud
Project Site: Department of Medicine (RMH), University of Melbourne, Department of Biochemistry & Molecular Biology, Monash University
Contact: Professor Patrick Kwan, Departments of Medicine and Neurology, E: patrick.kwan@unimelb.edu.au
Project description: Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen derived peptide antigens selected by different HLA allotypes. Recently, a growing number of immunologically based drug reactions have been found to be strongly associated with specific HLA alleles. In particular, HLA-B*15:02 and HLA-A*31:01 are associated with severe skin reactions caused by certain antiepileptic drugs, but little is known about the underlying mechanisms of these associations. Recent research has demonstrated that direct binding of the drug to the HLA molecule led to changes in the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides and driving T-cell activation. This project aims to find out whether this mechanism also applies to the case of the interactions between antiepileptic drugs and these HLA alleles.
HLA and its association with skin rashes and drug induced hepatitis: The role of pharmacogenetics to predict anti-epileptic drug side-effect - also offered as MBiomedSc
Supervisors: Dr. Marian Todaro, Dr Slave Petrovski, Prof Terence O’Brien, Prof Patrick Kwan
Project Site: The Comprehensive Epilepsy Program, Department of Neurology, The Royal Melbourne Hospital.
Contact: Dr Marian Todaro T: 9342 7500 E: Marian.Todaro@mh.org.auH; Dr Slave Petrovski E: slavep@unimelb.edu.au; Professor Terence O’Brien T: 8344 5479 E:Hobrientj@unimelb.edu.auH
Project Description: This study aims to investigate the individual responses of patients who developed a rash or drug-induced hepatitis due to an anti-epileptic drug (AED), and link this information to the genetic profile of each patient – in particular that for the human leukocyte antigens (HLA). The results will help to identify genetic markers that could predict when a patient is at risk of having side effects with a particular medication.
Previous experience has shown that individuals vary greatly in their responses to drugs. Although medication is effective and well tolerated in most patients side-effects can necessitate treatment changes. One of the most common, and potential serious, types of side effects to anti-epileptic drugs is hypersensitivity reactions - including generalised skin rashes, Steven Johnson Syndrome (SJS), and drug-induced hepatitis. It has been shown that genetic factors play an important role in determining an individual’s response to medication. Recently, the occurrence of SJS in Asian patients taking carbamazepine has been repeatedly associated with the carriage of a particular HLA antigen, HLA-B*1502. However, this association does not persist in non-Asian populations and HLA associations in other populations, or with other types of AED-induced hypersensitive reactions, have not yet been identified. Understanding why responses vary has the potential to improve the safety and effectiveness of medical treatment for various conditions.
This project will utilize an international unique cohort of more than 400 patients who have been prospectively enrolled and followed following starting treatment with an AED for the first time. The HLA profiles of patients who developed hypersensitivity reactions will be compared with those who took the same drug but did not develop any such reactions. The goal of this research is to eventually allow the choice of medication to be tailored to an individual’s specific genetic profile.
Skills to be learned: Human genomics, immunogenetics, bioinformatics, clinical phenotyping, multivariate statistics.
Pharmacogenetics: do mutations in CYP 2C19 alter the clinical effectiveness of clopidogrel in patients with cerebrovascular disease? - also offered as MBiomedSc
Supervisors: A/Professor Bernard Yan, A/Professor Peter Mitchell, A/Professor Richard Dowling
Location: Department of Neurology & Department of Radiology, Royal Melbourne Hospital
Contact: A/Professor Bernard Yan, Neurointerventionist, Neurovascular Research Group, Department of Neurology, Royal Melbourne Hospital, T: +61 3 9349 2477 / F: +61 3 9349 4489, Email: bernard.yan@mh.org.au
Project Description: Stroke is the third leading cause of death in Australia. The prevention of recurrent strokes is an important strategy to improve health and reduce medical costs. Globally, anti-platelet agents (aspirin, clopidogrel, prasurgrel etc) are the first-line treatment to prevent further ischaemic events (i.e. strokes). Anti-platelets work by inhibiting platelet aggregation with consequent reduced risk of artery blockages. However, up to 30% of patients are “resistant” to clopidogrel treatment. Of note, activity of clopidogrel is critically dependent on its conversion from the pro-drug to its active form by a member of the P 450 family of enzymes (CYP 2C19). A genetic mutation, e.g. CYP 2C19*2, predicts lower levels of the active form clopidogrel leading to failure of platelet inhibition. We hypothesize that patients with genetic mutations of CYP 2C19 (e.g. CYP2C19*2) will demonstrate clopidogrel failure and increased risk of stroke. The results will have the potential to change clinical practice in the prescription of clopidogrel.
Research Plan: Our project is part of a large pharmacogenenomics project led by Professor Patrick Kwan’s research group. Our research arm focuses on CYP 2C19 genetic mutation and its clinical consequences. Human ethics committee approval has been obtained to test anti-platelet resistance. Inclusions criteria: patients previously exposed to clopidgrel or with plans to start clopidogrel (e.g. aneurysm coiling, pipeline flow diversion device implantation etc). Methods: all patients will be tested for CYP2C19 genetic status by PCR and a novel DNA amplification technique. The patients will be followed clinically and by neuroimaging to identify recurrent cerebral ischaemic events.
A Pharmacogenomics study of the teratogenicity valproate based on the prospective Australian Register for Anti-epileptic Drugs in Pregnancy - also offered as MBiomedSc
Supervisors: Professor Terence O’Brien, Professor Frank Vajda and Dr Slave Petrovski - Epilepsy and Neuropharmacology Group, The Department of Medicine: The Royal Melbourne Hospital.
Project Site: The Department of Medicine (RMH)
Contacts: Terence O’Brien T: 8344 5479 E: obrientj@unimelb.edu.au; Frank Vajda E: vajda@netspace.net.au; Slave Petrovski E: slavep@unimelb.edu.au
Project Description: It is long been recognised that women with epilepsy who become pregnant while taking an anti-epileptic drug (AED) have an increased risk of having a foetus or infant with a birth defect (BD). This is particular high for valproate. Despite the increased risk associated with taking AED in pregnancy, most women with epilepsy who become pregnant, or plan to do so in the near future, cannot simply cease the drugs because of the risk to the health and safety of the mother and child of uncontrolled seizures. The development of methods that would allow the prediction that a specific drug would be associated with a higher risk of a birth defect in a particular woman would be of great potential benefit. There is evidence from family and twin studies that genetic factors may play a role in determining predisposing an individual to having a child with an AED associated birth defect. The Australian Register of Anti-epileptic Drugs in Pregnancy has been established in an attempt to obtain more accurate information about the risks of specific AEDs. This is a prospective, voluntary, telephone interview based study that enrols pregnant women with epilepsy, prior to the outcome of the pregnancy being known, and follows the outcomes of their pregnancies. The study has been running since July 1999, and to date has enrolled more than 1600 pregnant women.
This study will attempt to identify genetic markers that predict the risk of valproate-induced birth defects. Participants will be identified through the Australian Registry of Anti-epileptic drugs in pregnancy. Women with epilepsy who were taking an AED in the first trimester, and their partners, will be offered enrollment. Two types of genetic tests will be performed:
A case-control genetic association studies comparing genetic information from mothers and infants taking a valproate AED during the first trimester with those who were taking the same valproate but did not have a child with a birth defect
A transmission disequilibrium test (TDT), design will be also be employed. This test looks for significant disequilibrium in the transmission of the allele of interest in the patient with a characteristic of interest. It therefore eliminates any potential sources of bias between the affected patients and non-affected controls, which may occur in case-control association studies. Blood for genetic analysis would be taken from the mother, father and child.
Pharmacogenomics in IBD - also offered as MBiomedSc
Supervisors: Professor Finlay Macrae and Prof Les Sheffield
Project Site: Colorectal Medicine and Genetics, The Royal Melbourne Hospital
Contact: Prof Finlay Macrae E: finlay.macrae@mh.org.au
Project description: The Royal Melbourne Hospital, with GenesDX, is pioneering the implementation of a pharmacogenomics clinical support program. In the case of inflammatory bowel disease, this relates to the use of thiopurines. The project will assist in the implementation of the program and its evaluation. It will guage the clinical utility of TPMT genotyping and the clinical decision support tools that will be built into the program, and thiopurine metabolite testing, in the management of inflammatory bowel disease.