Making Genomics Part of the Clinical Routine

For 10 weeks after her birth, Mackenzie Casella was the picture of happy and healthy baby girl.

Nine weeks later, however, she started crying at the end of every feeding, prompting her mom, Rachel, to take Mackenzie to a lactation specialist1. While the consultant found nothing wrong with the feeding per se, she noticed that Mackenzie seemed a little floppy.

The Casellas received the devastating news not long after: Mackenzie had spinal muscular atrophy, a genetic, progressive and ultimately fatal condition that destroys motor neurons in the spine, leading to muscle wasting. In October 2017, Mackenzie passed away at 7 months and 11 days old.

Neither of Mackenzie’s parents had any history of SMA and they had taken all the standard prenatal tests, but it never occurred to them that they could both be carriers of a rare genetic mutation—nor were they offered a genetic screen that could have helped them avoid the ordeal entirely.

Less than year later, as part of a larger genomics research initiative, the Australian government earmarked around AUD$20 million to assess the feasibility of offering genomic carrier screening to couples across the country. This study is called Mackenzie’s Mission2, and has recently completed reproductive carrier screening of over 9000 couples from around Australia., using genomic testing and screening of over 1200 genes for disorders that cause severe disability or early mortality.

Making the Case for Clinical Genomics

Mackenzie’s Mission was the first research program funded through the Australian Government’s $AUD500M investment in genomic research (the Genomics Health Futures Mission). This investment followed on from the establishment of a nationwide approach to integrate cutting-edge genomic research into clinical practice, and the formation of a network of professionals called Australian Genomics.

Australian Genomics was founded in 2016, just as genomic sequencing was fast becoming a diagnostic norm in many countries. It has since grown to include more than 450 investigators, 100 organisational partners and 32 clinical recruitment sites around Australia. Over the years, Australian Genomics has established flagship pilot programmes and national clinical and research networks in different rare diseases and cancers, enrolling over 5,000 study participants in total to demonstrate the clinical utility and cost effectiveness of genomic testing. The group has also launched several projects to build a solid infrastructural foundation for the mainstreaming of genomic testing – including genomic data management, ethics and health economics.

“The goal was, first of all, to build national networks of expertise involving every state and territory, so that our implementation strategy wasn’t fragmented,” said Professor Kathryn North, who leads Australian Genomics, adding that they also sought to “grow a genomics-literate workforce.”

Crucial to the early and continued success of Australian Genomics was understanding how to present a strong health economics case for their projects to drum up support from both policymakers and colleagues.

Beginning in 2014, for example, even before Australian Genomics was born, Australian researchers commenced a study in 100 kids who were presumed to have rare and genetic disorders. The standard of care at the time, which included imaging and blood tests, led to a diagnosis in about one in ten patients at a cost of around AUD$26,000 per diagnosis. When the team incorporated genomic sequencing, their diagnostic rate jumped to around 55 percent, while cost dropped to AU$6,0003.

These striking findings, along with many other similar initiatives, formed part of a proposal that in May 2020, pushed the government to cover the genomic sequencing costs for kids presenting with a condition that was likely genetic in nature.

For North, this was a clear demonstration of how to make advanced genomic technologies more accessible to patients—and of the potential to do the same for other diseases. “We do that by demonstrating that it’s clinically useful,” she said, “but also by demonstrating how cost-effective it is.”

A Philosophy of Integration

“The goal of Australian Genomics is to demonstrate the clinical effectiveness and the cost-effectiveness of genomics,” North added, “and to also work out the practical strategies of how we can integrate it into our health system.”

Indeed, integration across many levels is a core philosophy of Australian Genomics. To ensure the healthy uptake of genomic technologies in hospitals, North says that clinicians themselves are asked to participate in research teams. The group also collaborates with different specialists to guarantee that they are applying genomic sequencing in the most appropriate way possible.

The point of convergence for all of these medical professionals—from primary physicians to cardiologists and nephrologists to clinical geneticists, and even research scientists—is patient care. Demonstrating that genome sequencing leads to concrete, measurable improvements in patient management can turn clinicians themselves into advocates of its integration into medical practice.

Australian Genomics is also integrating internationally, working with the Global Alliance for Genomics and Health, as well as many of its member organizations, to advance precision medicine worldwide.

On this point, North said that Singapore’s own precision medicine programme is doing a wonderful job. “I’m very impressed by how there’s been an international landscape analysis,” she pointed out, adding that such careful and thorough planning allows the national initiative to be the best it can be by learning from different efforts around the world and adopting international best practice.

Beyond its global character, Singapore’s precision medicine efforts are also highlighting the country’s unique strengths and  rich ethnic diversity. Keeping this in mind helps the initiative not just produce high-quality genetic data, but also drive tangible value that the everyday Singaporean can appreciate and benefit from.

“I think you’ve embarked on a great initiative that’s going to be world-leading, and that should be a source of national pride,” said North.

References:

1. Saunders, A. (2020, May 30). This Baby Will Save Lives. PRIMER. Retrieved September 8, 2022, from https://primer.com.au/mackenzie-casella-sma/

2. Mackenzie’s Mission. About Mackenzie’s Mission (2019). https://www.mackenziesmission.org.au/what-is-mackenzies-mission/

3. Stark Z, Schofield D, Alam K et al: Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet Med 2017.