Newborn genome program
Doctors and anyone who has had a baby in the UK will be familiar with the newborn blood test, which checks newborns for nine rare conditions that benefit from early treatment. In mid-2023, the NHS and Genomic England hope to take this to the next level, carrying out a pilot study on WGS of newborns to extend testing to many other rare diseases. If the pilot is successful, WGS for newborns will be implemented into NHS routine care.6
The aim of the study is very focused: the NHS will only analyze genome sequences for conditions that emerge in childhood and for which clinical interventions exist, rather than returning every possible piece of information, says Simon Wilde, director of engagement at Genomics England . Guidelines such as these are the result of a careful public engagement program carried out in light of Genomic England’s experience with the 100,000 Genomes project. Audience acceptance is key to the program’s success, says Wilde.
The team is also consulting with rare disease experts to ensure all reportable conditions have treatment pathways and care packages available. “It’s about making sure you have everything in place before you start.”
The results of the first public dialogue exercise showed that the public is supportive of the technology, provided certain conditions and guarantees are met. These include data privacy and informed consent. “That’s what we were able to carry forward and at least start thinking: What would a genomic sequencing program look like in children?” says Wilde.
The team is also investigating factors such as the best time during pregnancy to approach women with information about the program.7 “We need to make sure that the offering we make is acceptable, understandable, and works for parents,” says Attach.
The project will start in the summer of 2023 and aims to sequence up to 100,000 newborn genomes in the first instance, with the option to go further if necessary.8
Genomics England recently launched a research programme, in partnership with the NHS, called Cancer 2.0. “This isn’t clinical yet, but it has clinical intent,” says Moss. Cancer 2.0 has two main goals: to explore new DNA sequencing technologies and merge imaging data with genomic data, to develop new knowledge about cancer, and to improve diagnosis and treatment.
New sequencing technologies focus on nanopore sequencing, which can read long sections of DNA and thus detect changes involving large portions of the genome that are difficult to detect with current ‘short read’ technologies. This is important because “structural variations seem increasingly directly drugable,” says Moss. He can simultaneously detect DNA methylation patterns that are critical to understanding epigenetic contributions to cancer.
The imaging arm of the Cancer 2.0 project involves integrating radiology and digital pathology images with genome data from 15,000 cancer patients in the 100,000 Genomes Project. In collaboration with Leeds Teaching Hospitals NHS Trust and the National Pathology Imaging Co-operative, the project will create an extensive dataset of over 250,000 digital pathology images, together with detailed diagnostic information from pathology reports.9
Combining the tumor’s molecular features with spatial imaging should provide much more specificity about a patient’s response to treatment, Moss says. “The treatment response to drugs doesn’t always depend simply on the molecular biology of the tumor, but also on the microenvironment of the tumor,” she explains. Applying machine learning to data should also provide deeper insights into the disease and cancer treatments.10 Eventually, it may be possible to use these algorithms to diagnose cancers in the clinic.
How well a drug works, the risk of negative side effects, and what the optimal dose is can vary greatly between patients. Much of this variability is influenced by genetics, and researchers have identified variants that influence patient response to more than 40 drugs. Testing for these variants, known as pharmacogenomics, is still limited within the NHS. But initiatives are underway to broaden the range of tests available and even to take a proactive approach of testing patients before they need treatment and recording the results for future reference, say Munir Pirmohamed, clinical pharmacologist, and David Weatherall , chair of medicine at the University of Liverpool.
A small number of genetic tests for adverse drug reactions are already available on the NHS, including the HLAB57 test for hypersensitivity to the anti-HIV drug abacavir and dihydropyrimidine dehydrogenase (DPD) deficiency to prevent severe toxicity from a class of anticancer drugs known as fluoropyrimidines.11 This identifies patients who should receive lower doses of the drugs to minimize adverse side effects.
But there is a clear need to expand these tests to cover more drugs.12 In addition, a growing number of drug makers are requiring genetic testing of their drugs to guide dosing. Some of these tests are not available on the NHS and must be carried out privately. “It’s important to think about how we can make sure we make it available because people will develop adverse effects that we could have prevented,” says Pirmohamed. Being able to better predict the effectiveness of medications will help doctors avoid trial and error in treating some conditions such as depression and select the best medications faster. “Even if it increases the predictability a bit, then we could reduce some suffering for our patients,” says Pirmohamed.
Pirmohamed’s work shows how dramatic this reduction can be. In 2004, her team demonstrated that genetic testing for abacavir hypersensitivity was cost-effective.13 By 2006, all NHS HIV clinics were using the test, and rates of hypersensitivity dropped from 5%-7% to less than 1%.
Instead of single-gene testing, Pirmohamed and his colleagues are advocating for panel tests, in which patients are typed for a set of variants and these are stored in the patient’s electronic health record. “You already have the data available rather than having to redo it,” she says. Her team is working with Our Future Health, an upcoming research program that aims to recruit five million UK residents. Pirmohamed’s team designed the gene chip that will be used to type participants for pharmacogenomic variants.14 Ethical discussions are still ongoing, but it is possible that the data will be returned to individual participants.
Another project Pirmohamed is contributing to, UP-Gx,15 recently led the Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions,16 study which recruited 6900 people from across Europe, including patients from the Royal Liverpool University Hospital. The study preemptively tested participants with a panel of 40 markers in 13 genes associated with drug responses. Physicians used this information when prescribing drugs for patients in the test group (those in the control group received standard care) with the goal of reducing adverse drug reactions. The study data is now under review in a medical journal.
The field is not without its hurdles: Like many other genomics projects, pharmacogenomics suffers from a lack of ethnic diversity in its subjects of study. For example, the NHS currently tests for four variants in the DPD gene, but these variants all come from populations of European ancestry, says Pirmohamed. There is no testing for rare variants of DPD in patients with African ancestry, meaning they could be misclassified as wild-type. Pirmohamed is currently working on a project in the UK and internationally to identify more of these variants across a range of ethnicities. She also has an ongoing project to develop genetic tests for warfarin dosage in sub-Saharan African populations.
Eventually, a patient’s entire genome sequence could be recorded and then queried for pharmacogenomic data, Pirmohamed says. But patients need to be involved in the design of these services. “They have to understand what the advantages are, but also the limitations,” says Pirmohamed. Providing pharmacogenomics also means creating clinical decision support systems so that primary and secondary care physicians don’t have to spend a lot of time trying to decipher genetic test results, she adds. Another issue is the application of pharmacogenomics to people taking multiple drugs, a particular problem in elderly patients.
Pirmohamed sees pharmacogenomics as an evolution, rather than a revolution, in clinical practice. “The way I see it, the predictivity we have right now is pretty low,” says Pirmohamed. “If we can get the predictivity up for certain drugs to over 50%, over 60%, then we’re doing a much better job than we’re doing right now.”
Data security and privacy are sensitive areas when it comes to gaining and maintaining public trust in technologies such as genomic medicine.
Finding, obtaining and maintaining consent are key, says Wilde. Ongoing public engagement and the development of best practices for data management is ‘a key part of what we do’, she says, and has been since the 100,000 Genomes project began. “It’s something we take very seriously. It’s something we know is a current issue and will continue to be.
Genomics England works on a model where it obtains consent before data is stored and ensures that people understand what it might be used for, how anonymous it might be and what safeguards are in place. “What we would like to do is try to talk about what the potential risks and benefits might be, but ultimately make sure that people have a choice whether to participate in the first place,” says Wilde. “But if they ever have second thoughts or, for whatever reason, they no longer want to take it, that there are mechanisms in place to have their data removed and destroyed.”