Precision medicine for diabetic Individuals: a joint Malaysia-UK Effort (PRIME) project

Malaysia has the highest rate of diabetes in Asia and one of the highest in the world. Adding to this problem is the growing number of obese Malaysian children and adolescents who are now or will be affected by diabetes. The harmful effects of diabetes on the vasculature or blood vessels dominate the complications caused by diabetes. These vascular effects affect the heart (to cause heart attack, stroke and heart failure), feet (leading to amputations), eyes (to cause blindness) and kidneys (to cause kidney failure). This escalating diabetes pandemic with its cardiovascular complications has huge effects both for the affected individual and their society. Despite sugar-lowering diabetic drugs and control of other cardiovascular risk factors, people with diabetes continue to succumb to the cardiovascular-related diseases. While efforts are being made to combat this diabetic epidemic through public health measures, new strategies are clearly needed to address and prevent the cardiovascular complications of diabetes. In the UK, we have pioneered the concept of personalised medicine through the use of genetics to determine who will and will not respond to commonly used drugs in diabetes, as well as for heart protective drugs such as those that lower blood pressure and cholesterol. We have also made substantial inroads in the use of artificial intelligence to analyse digital pictures of patients' retinas to find features that reveal a patient's current disease status and is predictive of future risk of complications such as stroke and heart disease. However, the majority of these studies on how diabetes and the cardiovascular complications arise and how patients respond to medications are from white European ancestry populations despite the fact that diabetes in Europeans is very different to diabetes in Asians. There is therefore an urgent need for detailed research into the specific causes and cardiac consequences of diabetes in Asians including those in Malaysia in order to identify the processes that drive the onset of cardiovascular complications of diabetes that exist in Malaysian ethnicities and use this to understand how best to manage diabetes in Malaysia.

In our proposed PRIME partnership, we propose to build upon the precision medicine expertise in Dundee that includes the on-going £7 million NIHR Global Health Research Unit on Global Diabetes Outcomes Research INdia-Scotland Partnership for Precision medicine in Diabetes - INSPIRED (https://inspired-nihr.com/) project that is exploring specific differences in combinations of genomic, retinal and clinical determinants of complications of diabetes and therapeutic response between Scottish and the South Indian population. The plan is to embed insights from the on-going INSPIRED program into the PRIME project that will add value to each project. Using the available precision medicine expertise in Dundee, we will facilitate knowledge transfer to Malaysia for initial establishment of a similar concept using the Malaysian government initiated The Malaysian Cohort (TMC) study, that is the biggest and most comprehensive population-based cohort study in Malaysia. The overarching objective of the PRIME project is to develop an international collaboration between Dundee and Malaysia that will establish the potential for translation of precision medicine to management of diabetes and its associated cardiovascular complications in Malaysia.

The overarching ambition of the PRIME Partnership programme is to establish inter-disciplinary expertise, build partnerships and a research platform amongst physician scientists, genetic epidemiologists, big data analysts, machine learning scientists and policy makers to cohesively deliver multi-level strategies to augment precision medicine for diabetes in Malaysia. We propose to build upon the precision medicine expertise in Dundee where we have recently established the £7 million NIHR Global Health Research Unit on Global Diabetes Outcomes Research INdia-Scotland Partnership for Precision medicine in Diabetes (INSPIRED) that aims to combine clinical, retinal and molecular information to achieve personalised diabetes treatment in India. The PRIME project we are proposing will leverage the INSPIRED Global Development initiative for the benefit of the Malaysia population. PRIME will involve two large, well phenotyped cohorts individuals with diabetes - the Tayside Bio-resource including GoDARTS (Genetics of Diabetes Audit Research Tayside Scotland) which will have access to 30,000 individuals with genome-wide genotype data with linkage to comprehensive electronic health records and the PRIME cohort within large population based The Malaysian Cohort study that will comprise of 5000 individuals with diabetes in Malaysia. The PRIME project will establish the PRIME cohort that will have their DNA genotyped and their detailed demographic and biophysical data digitised to provide a level of high-quality phenotyping and updated detailed follow-up. The plan is to embed insights from the ongoing INSPIRED programme into the PRIME project to identify at-risk individuals by their phenotypic, genetic and retinal imaging profiles. This will inform tailored population-specific interventions to reduce the impact of diabetes in Malaysia.

The development, training, pilot work in this proposal will directly impact project participants -patients with diabetes, clinicians, researchers and healthcare planners in Malaysia and inform future research activity. This project will inform a pragmatic framework for the development and evaluation of precision medicine that can be rolled out in Malaysia. This project will help position Malaysia as a leader in the field of precision medicine in South East Asia and in the world to improve the health of patients with diabetes.

EXPECTED IMPACTS
1. Development of a high performing and sustainable collaboration between UK and the Malaysian researchers and clinicians
2. Increased capacity building, research infrastructure and knowledge generation in precision medicine in Malaysia
3. Knowledge transfer of project findings to inform precision medicine globally
4. Understanding of the feasibility and practicalities in performing future clinical trials in precision medicine in Malaysia
5. Engagement with the industry though the availability of the resource and expertise within PRIME partnership
6. Establishment of framework for the development and evaluation of precision medicine that can rolled out to South India and other LMICS through the NIHR GCRF funded INSPIRED project in order improve the health of patients with diabetes


DISSEMINATION AND DATA SHARING
We will use a variety of methods to ensure effective and impactful dissemination of the work of the group: an up-to-date project website; presentations at national (Malaysia and UK) and international cardiology and diabetes scientific conferences; peer review publications.
In order to promote the impact of the project findings on policy and practice, we will organise both a face-to-face launch first meeting and an end of project stakeholder event with healthcare policy makers and patient advocacy groups. We will work closely with our Malaysian partners in the format and invitation list for this event. At our first face to face group meeting we will establish a data sharing agreement for the project informed by the procedures of current best practice principles and identify routes for the engagement of stakeholders including local and national healthcare policy makers, patient groups and community representatives.