Features

In brief

Through Singapore’s National Precision Medicine (NPM) programme, multidisciplinary teams are conducting some of Southeast Asia’s most comprehensive population genomics studies, translating big data insights to advanced models of treatment and prevention.

© A*STAR Research

On target for the precision health era

30 Dec 2022

Multidisciplinary efforts across A*STAR are paving the way toward Singapore’s precision medicine vision.

Singapore is one of Asia's most rapidly ageing societies. While longer lifespans are generally considered a positive sign of progress, the quality of those lives also matters. However, health experts predict that a growing proportion of Singapore’s elderly is at risk of chronic lifestyle diseases such as hypertension and diabetes, and will thus put increasing and unsustainable pressure on the healthcare system.

For these concerns about the economics of healthcare, precision medicine could be a promising solution. Where conventional medicine relies on a one-size-fits-all approach—with diagnosis and treatment based on generalised constellations of symptoms and health indicators—precision medicine accounts for the myriad of genetic, environmental and lifestyle differences that exist between individuals. Using this data, early disease detection and intervention will also be possible.

“Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refined diagnoses and tailored treatments, but its most significant impact may be at the population level,” said Patrick Tan, Executive Director of the Genome Institute of Singapore (GIS) at A*STAR, adding that precision medicine could support early interventions to reduce the incidence of late-stage diseases and improve overall population health.

With genetics proposed as the root of up to 30 percent of healthcare outcomes, a key enabler of precision medicine is the availability of individual genomic profiles. However, Asian genomes are underrepresented in genomic research projects and public databases, with most existing discoveries in the field instead based on populations of European ancestry.

Recent efforts by international consortiums such as the Genome Aggregation Database (gnoMAD) and the Trans-Omics for Precision Medicine (TOPMed) programme have attempted to generate more diverse cohorts. Even so, less than 10 percent of individuals within these two databases are of Asian ancestry, Tan explained.

Tan also highlighted a more concerning point, “None of these studies focus on Southeast Asia, a region with a total population of over 670 million people and of considerable genomic and cultural diversity.” He added that the lack of specific data for Southeast Asia presents a significant barrier to the practice of precision medicine in the region.

In response, the Singapore government is taking large steps to address this gap in genomic and precision medicine research, with A*STAR being an agency well-positioned to support these efforts.

Scanning a nation’s genomic landscape

The Singapore government has displayed a commitment to the advancement of precision medicine across the country. As part of its efforts, precision medicine was designated as a priority area of development for Human Health and Potential, one of four domains of strategic importance in the government’s RIE2025 Plan.

A key goal under this domain is the expansion of the country’s National Precision Medicine (NPM) programme, a 10-year roadmap to accelerate biomedical research, improve health outcomes and enhance economic opportunities.

Given Singapore’s genetically diverse population of around 6 million, which includes the three major Asian ethnic groups of Malay, Chinese and Indian, the country’s demographics also make it a natural fit for research aimed at creating similarly diverse genomic datasets for precision medicine.

“The availability of an all-Singaporean database to capture data specific to our multi-ancestral population could help develop more accurate algorithms for prediction and fine-tuned interpretative tools for genetic composition analysis,” said Tan. He also noted that this molecular data could reveal novel disease mechanisms and potential drug targets specific to Asian populations.

However, meeting the NPM’s goals will be no easy feat. In a commentary published in Frontiers in Digital Health in May 2022, a group of Singapore-based experts including A*STAR researchers suggested that the success of the nation’s precision medicine efforts would require “appropriate data collection, data processing and interpretation”, and highlighted the benefits of a multidisciplinary effort to realise the NPM’s visions.

This is where A*STAR’s wide-ranging and multidisciplinary scientific expertise is valuable. For example, GIS’s Precision Medicine and Population Genomics arm—a core focus of the institute since its founding in 2000—is dedicated to supporting precision medicine initiatives in the country. According to Tan, GIS’s strength in genomics and data analytics, as well as knowledge of data infrastructure requirements to host, process and securely store genomic data, positions it as a key contributor to the nation’s precision medicine landscape.

“In addition, other A*STAR research institutes such as the Bioinformatics Institute (BII), the Institute for Infocomm Research (I2R) and the Institute of High Performance Computing (IHPC), with their capabilities in artificial intelligence (AI) and data federation know-how, would also be instrumental in driving data-driven healthcare solutions that harness new insights from Asian genomes to improve patient outcomes,” he shared.

Precision support through partnerships

Just as A*STAR’s academic and research strengths are bringing Singapore’s precision medicine vision to fruition, the agency’s relationships with industry partners are playing a similarly crucial role. A*STAR maintains that strong public-private partnerships are key enablers in the agency’s mission to translate science into real-world impact, a stance particularly evident in how it has supported the NPM’s different phases to date.

Headlining the NPM’s first phase was the Singaporean 10,000 Genomes (SG10K) project, which saw the collection of whole-genome sequences from 10,000 consenting and healthy Singaporean volunteers from Malay, Chinese and Indian ethnic backgrounds. By the end of this first phase in 2021, these genomes were used to establish the Singapore Reference Genome, the largest Asian database of whole genomes to date.

A*STAR’s joint lab partnership with genomic company NovogeneAIT Genomics proved an invaluable asset in this endeavour. “The partnership provided access to the latest Illumina HiSeq X-based whole genome sequencing (WGS) and bioinformatics analysis. Their centre devoted a significant portion of its sequencing capability to support the programme, and its proximity to GIS also sped up logistics arrangements for samples and data transfer, enabling the timely completion of the 10,000 genomes,” said Tan.

Through a new multiyear partnership with Illumina, NovogeneAIT Genomics will also carry out genome sequencing for the NPM’s ongoing second phase, which expands Phase I’s scope more than tenfold. Phase II aims to provide whole-genome sequences for 100,000 healthy Singaporeans and an additional 50,000 people with specific diseases, to create Southeast Asia’s most comprehensive consented population genomics study, SG100K. Through new insights into the Asian genome and data-driven healthcare solutions, NPM Phase II intends to transform healthcare in Singapore and improve patient outcomes.

Tan, who also heads Precision Health Research, Singapore (PRECISE)—the government’s central coordinating entity for Phase II’s implementation—believes that the partnership with NovogeneAIT Genomics will allow local sequencing companies to benefit from training and certification in the use of Illumina’s proprietary platforms, allowing those companies to access new regional and international markets.

Alongside these partnerships, A*STAR’s GIS and BII will continue to support SG100K with their genomics and bioinformatic capabilities. GIS, for instance, has set up a high-throughput automated DNA extraction lab to ensure high-quality DNA is extracted from SG100K samples.

Refining data into targeted insights

With an increasingly large pool of genomic data to sift through, researchers are turning to the computational powers of bioinformatics to make the data useful. Sebastian Maurer-Stroh, Executive Director of BII, explained that bioinformatics can process, visualise and interpret data systematically and on a large scale, revealing patterns usually indecipherable by traditional analytical tools.

“The methods we have developed and continue to improve on at BII are well suited to interpret changes in genomic information collected through the NPM programme,” said Maurer-Stroh.

As with all precision medicine endeavours, data processing is equally as important as its collection: specifically, the processing of vast datasets produced by projects such as SG10K and SG100K, encompassing the integrated genomic and phenotypic data of tens of thousands of individuals.

In this area, a crucial A*STAR contribution to the NPM programme’s first phase was the establishment of national Genomic Web Services. These are accessible through the SG10K_Health web portal and allow users to query the SG10K dataset for information on a range of factors such as protein-drug interactions, polygenic risk scores (PRS) and allele frequencies. To date, the platform offers five services to help researchers distil health insights from SG10K, through invaluable contributions from GIS, BII, I2R and IHPC.

Among the services provided through SG10K_Health is the PRS Web Service, developed by I2R researchers. The team established pipelines for pre-processing and feature engineering to integrate and analyse data from WGS, consumer wearables and questionnaire responses. They then used the data to develop calculation pipelines for PRS—a metric that measures one’s genetic disease risk—of the three major Asian populations within SG10K.

Similarly, IHPC researchers developed SG10K_Health’s Imputation Server, optimising its codes and pipelines to reduce running times for genotype imputation—the process of estimating missing genotypes—for genome-wide association studies (GWAS) based on the same cohort.

A third key service within the portal is one developed by BII together with GIS: SNPdrug3D, which Maurer-Stroh describes as “providing the first complete map of single-nucleotide polymorphism (SNP)-drug 3D interactions both across the human proteome and at a population-wide level”.

SNPs vary widely across individual human genomes; by mapping them to protein structures, SNPdrug3D allows the exploration of how SNP variants affect proteins at sequential and structural levels. These deeper dives, especially into variants involved in protein-drug binding, might in turn shed light on how they impact drug dosing and response in different people.

Using SNPdrug3D and other datasets, researchers at BII have already made some fascinating breakthroughs. “Collectively, we have mapped approximately 5.8 million unique SNP variants from over 80,000 individuals—including around 10,000 from Singapore—to protein structures related to around 6,000 drugs,” shared Maurer-Stroh. From this data, BII researchers have found and experimentally validated previously undefined SNP variants that affect how drugs bind to metabolic enzymes and drug targets.

Creating new insights from the available data will only get faster and more efficient. BII researchers have also since used the data to build a machine learning-based prediction tool that identifies SNP variants that may affect drug metabolism. Insights such as these further pave the way towards Singapore’s precision medicine vision of better and more tailored treatment strategies for patient groups.

Sharing the genomic data

Besides making sense of big data, A*STAR’s safe and efficient data sharing also facilitates collaborations with other A*STAR research institutes. For instance, A*STAR’s Centre for Big Data and Integrative Genomics (c-BIG) is a multi-institutional effort by BII, GIS, IHPC and I2R to address the challenges of big data analytics and integrative genomics for precision medicine in Singapore.

Coordinated by Nicolas Bertin of GIS’s Genome Research Informatics and Data Science Platform, c-BIG combines an extensive genomics data hub with data science and high-performance computing capabilities to develop infrastructure and conduct research projects that support Singapore’s genomics ecosystem. These range from broader genomics reference resources to specific areas such as cancer genomics and toxicity prediction.

Some c-BIG endeavours include CELLHUB, a cellular human body map of one million single-cell transcriptomes, and POLARIS, a development team for clinical-grade genomics software. Notably, c-BIG is also involved in the A*STAR Data Analytics Exchange Platform (A*DAX) for federated data, which facilitates safe data sharing and advanced analytics.

From calculations to clinics

Together with ecosystem partners from industry, academia and other government agencies, A*STAR’s efforts to advance precision medicine have been paying off, with game-changing research findings in recent years.

In one instance, a team of researchers from GIS and A*STAR’s Bioprocessing Technology Institute (BTI) collaborated with the Singapore Eye Research Institute (SERI) to sequence DNA over 20,000 participants across 14 countries—including 1,200 Singaporeans—to uncover a gene that could cause blindness among the elderly. The proverbial needle in a haystack of over 18,000 genes turned out to be CYP39A1.

Meanwhile, working with public hospitals and universities across Singapore, A*STAR researchers from GIS, the Institute of Molecular and Cell Biology (IMCB) and the Institute of Medical Biology (IMB) sequenced the genes of 275 patients and their families recruited from the Singapore Undiagnosed Disease Programme, aiming to speed up diagnoses and improve treatment for those with suspected but unconfirmed genetic disorders.

Within A*STAR, the translation of research into solutions to address national challenges remains a priority. For precision medicine, breakthroughs in A*STAR labs have led to better treatments in the field and more lives saved.

In one example, the A*STAR academics turned ‘accidental entrepreneurs’ behind MiRXES capitalised on research using miRNA as biomarkers for early disease detection. Building on a decade’s worth of research on overlooked genetic material in blood, urine and tears, this spinoff company now makes highly sensitive biopsy test kits that detect gastric cancer early enough to improve patient survival rates and quality of life.

Another A*STAR spinoff, Nuevocor, is similarly built on years of basic research in genetically-linked heart diseases such as dilated cardiomyopathy. Now in its preclinical stage, the biotech company hopes to roll out gene therapies designed to stop heart disease-causing mutations in the LMNA gene and restore cardiac function in at-risk patients.

Nalagenetics is another biotech company with roots in A*STAR, which is focused on personalised disease screening and interventions in Southeast Asia. The company aims to provide accessible end-to-end genetic testing alongside clinical decision support software for physicians and local healthcare systems.

Finally, A*STAR’s Health and Medical Technologies Horizontal Technology Coordinating Office (HMT HTCO) is also developing a ‘diabetes clinic of the future’ in partnership with SingHealth to tackle Asia’s diabetes epidemic. The clinic will use data from the country’s largest diabetes registry, which covers 200,000 patients across a decade of historical data. Given the genetic and cultural differences underlying a predisposition to diabetes, the clinic hopes to thoroughly evaluate and improve the state of diabetes care.

All in all, these examples show how far precision medicine research has come on a national scale, while providing a glimpse of its further potential with the right technology, talent and data. As the NPM programme sets its sights on targeting up to one million Singaporean genome sequences and incorporating more complex social and environmental data, it is certain A*STAR, with its network of research institutes, trained researchers and public and private partnerships, will be a valuable source of support on the road ahead.

In addition to those previously mentioned, the following research and clinical partners are acknowledged for the Precision Medicine work mentioned in the cover feature:

A*STAR’s Singapore Institute for Clinical Sciences (SICS)
KK Women’s and Children’s Hospital (KKH)
Lee Kong Chian School of Medicine, Nanyang Technological University (NTU)
National Healthcare Group (NHG)
National Supercomputing Centre (NSCC) Singapore
National University Health System (NUHS)
National University Hospital (NUH)
National University of Singapore (NUS)
Singapore Eye Research Institute (SERI)
SingHealth Duke-NUS Institute of Precision Medicine (PRISM)
SingHealth Duke-NUS Academic Medical Centre
Tan Tock Seng Hospital (TTSH)

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This article was made for A*STAR Research by Wildtype Media Group