Mainstreaming of next-generation sequencing (NGS) technology within the NHS has been a talking point in both the genomics and healthcare sectors for a while now, with major developments like the 100,000 Genomes Project and its follow-up Genomics Medicine Service in the UK, and All of Us in the US, rapidly bringing NGS to the forefront of healthcare and public medical services in those countries. But what is less often discussed is how NGS is being integrated into the clinic at an international scale.

With markedly different healthcare systems and governmental budgets, implementing NGS globally brings with it a large number of challenges and opportunities, not least of which is the current imbalance of data from white European descendants, rather than those of other races or nationalities.

We spoke to Dr. Carlos Prada, Assistant Professor of Clinical Genetics at Cincinnati Children’s Hospital Medical Center within the University of Cincinnati Department of Pediatrics, and Dr. Emma Clement, Consultant in Clinical Genetics at Great Ormond Street Hospital in the UK, to find out more about the challenges of implementing NGS globally, and where that implementation has been successful.

FLG: Several projects and hospitals around the world have now demonstrated that NGS/Whole Genome Sequencing (WGS) can be used in the clinic successfully as a diagnostic tool, particularly in Neonatal Intensive Care Units (NICU) and Paediatric Intensive Care Units (PICU). What lessons have we learnt from these projects that could help improve the use of clinical NGS, and what are we still trying to learn?

CP: NGS/WGS is a good first initial step for diagnostic evaluation, as demonstrated in NICU and the PICU studies. Cost of testing has decreased in a way that is cost-efficient compared to previous first step technologies. The main challenge in both the US and abroad is the lack of inclusion of genetic testing coverage by insurance policies, or the low reimbursement provided by healthcare plans. Collaboration across countries for interpretation of genomic studies has been a very positive and surprising aspect of doing NGS/WGS in the setting of rare diseases. Representation of low-income countries in worldwide genomic databases is low and presents a challenge for the interpretation of findings. 

EC: Our experience during the rapid whole genome sequencing project at Great Ormond Street Hospital has shown that diagnoses can be made quickly in complex disease and in a time frame that is informative for acute patient care. At present this remains within the research realm, is costly and labour-intensive and is not universally available. I think there is important work to be done to try to understand whether this is a beneficial and cost-effective diagnostic strategy for a nationally-funded health service, and if so whether this should be for select patient groups or adopted as a first line diagnostic genomic test for those individuals who are critically unwell.

FLG: How successful have national projects like All of Us in the US and the 100,000 Genomes Project in the UK been at encouraging the integration of NGS into healthcare, particularly with regards to promoting and enabling physician engagement with new technologies?

CP: These two initiatives are needed to facilitate access to genomics and generate public libraries for the interpretation of findings. Integration of healthcare comes as a natural interface for the delivery of results of actionable information that is encountered in these studies. These initiatives also increase awareness and the need for genetics education across all medical specialties. All of Us tries to reach and enrol minorities and under-represented populations, which is very informative when it comes to growing databases. There is a need for initiatives like these ones in developing countries.

EC: The 100,000 Genomes Project has been instrumental in trying to integrate genomic medicine into mainstream patient care within the NHS. The scale of the project and centralised funding has led to engagement and participation from many diverse specialities. The simultaneous national genomic education programmes and local initiatives have been crucial in helping healthcare workers access and understand genomics, and this will continue to be an important focus going forward.

FLG: One of the biggest stumbling blocks for clinical NGS is that this type of testing is very expensive, and it is still uncertain how these tests are going to be paid for, particularly in countries with individual payer systems. How do you think this problem will be overcome in the future?

CP: I think the biggest advantage of NGS is the simplification of workflow in clinical laboratories. This makes it easier for hospitals and healthcare systems to plan the development of such labs, or to partner with experienced programs. Another future advantage of NGS is the constant development of improved software for interpretation and access to public databases. This will facilitate implementation in developing countries. Many countries are moving from karyotyping to NGS/WGS and skipping many previous technologies. This is an exciting time for genetics worldwide. Genomic studies are considered “investigations” by many insurance companies or healthcare systems. Education on how far genomic testing has advanced is important for integration into health care plans and benefits from individual patients and society.

EC: I think my answer to the first question does a lot to answer this, but in addition I’ll say that we are fortunate that the UK government has invested in the 100,000 Genomes Project and the development of a national Genomic Medicine Service. The cost of testing is likely to continue to fall but nevertheless it remains our responsibility as clinicians working within this service to ensure that this resource is used wisely.

FLG: The majority of available genomic and healthcare data is skewed towards populations of European descent, which impacts its utility when working with patient populations of different ethnic backgrounds. What work is currently being done to address this issue, and what more could we be doing?

CP: This is an area of high need. Programs like All of Us and the 100,000 Genomes Project are missing in South America and other regions. There are many private or government programs but there is no integration or public databases in most developed countries. Precision medicine and genomics are growing and many applications in medicine and lifestyle will facilitate ongoing integration into our lives. Education and partnership between institutions with expertise in genomics and developing countries are a major step to close the gap. There are clear benefits of collaboration on both sides and this helps to develop the infrastructure and knowledge for the integration of genomics.

EC: I think that acknowledging this is an issue is an important first step, so we can understand the limitation of current data sets when interpreting genomic data from ethnic minorities. The data set produced from the 100,000 Genomes Project will include many individuals from ethnic minorities. As a general principal we need to try and engage individuals from diverse ethnic backgrounds and as a global community share the data sets that we do have.

FLG: The delocalisation of clinical data is necessary to ensure that physicians using NGS testing have the greatest chance of identifying disease-linked variants, but there can be significant legal challenges when sharing medical data internationally. What systems are currently in place to support data delocalisation, and how could we better enable these types of international collaborations?

CP: This is a big challenge and every country has different regulations and limitations. Developing academic, government, and industry collaborations are key in moving this forward and facilitating the advancement of healthcare. Telemedicine is a good example of how we can deliver care across borders as applications continue to grow. Data delocalisation is important and is the basis for global collaborations.

EC: This is an ongoing challenge. Within the research sector this is often less of an issue if consent allows sharing of data. Within the diagnostic setting I think there needs to be a fundamental change in approach to consent and ownership of data to allow open collaboration in the field of rare disease. Such discussions should ideally be part of a fully-informed consent conversation at the time of genomic testing. Some progress has been made: for example, 13 European countries have signed a declaration for delivering cross-border access to their genomic information. Any data sharing however needs to be mindful of data security and needs to take care that individuals cannot be identified by their genomic data.

FLG: How is NGS testing being introduced into routine healthcare in your country or, if it isn’t yet, what are the major challenges preventing it?

CP: I have experience outside the US in two Caribbean countries: Colombia and the Dominican Republic. NGS is being used more often in both countries at tertiary care institutions, with some success. Early identification of rare disorders and management interventions are achievable goals. There is a big learning curve but there is local talent and opportunities to help with NGS integration outside the US. Unstable governments and healthcare policies are a major challenge for access to healthcare and quality.

EC: NGS testing is already available diagnostically in the UK in various forms. Panel testing and exome sequencing have been available through the NHS for some time. Many clinicians have also had access to WGS over the last few years through the 100,000 Genomes Project within the research setting. With the introduction of the NHS Genomic Medicine Service over the next few months, NGS will be increasingly accessible to clinical geneticists and also mainstream colleagues. Whole genome sequencing is also likely to be available for use diagnostically in certain situations. It is hoped that genomic medicine will soon be embedded in patient care in the NHS.

FLG: How do you foresee genomic medicine changing over the next five years, and over the next twenty years? What advances would you like to see?

CP: In the next five years NGS/WGS will be our established first diagnostic step for unrecognised disorders at evaluation or disorders with polygenic etiologies. Most specialties in medicine will need to increase genomics knowledge as we discover the basis for diseases, and treatments are developed based on genomic alterations (as with many of the cancer therapeutics). In the next 20 years, precision medicine based in genomics with individualised care will be key for prevention and life style modifications. Novel technologies like gene therapy and gene editing will be an option for the management and prevention of many diseases.

EC: I think that the availability of genomic testing is likely to increase, and the cost and time taken to reach diagnoses will fall. As we curate large data sets we would anticipate that interpretation of genomic data will continue to improve and that we make progress in solving the cases that have to date remained elusive. I think that it is likely that genomic testing will routinely be considered earlier (perhaps at the beginning?) in a diagnostic pathway. Ultimately we must be hopeful that improved knowledge of the working of the genome leads to prevention of disease and more therapeutic options for those patients affected by genetic conditions.