£100M for whole patient genomes – revolutionising genetic diagnostics or squandering NHS cash?

On 10th December 2012, UK Prime Minister David Cameron launched a Report on the Strategy for UK Life Sciences One Year On by announcing that the Government has earmarked £100 million to “sequence 100,000 whole genomes of NHS patients at diagnostic quality over the next three to five years”. This ambitious initiative – which will focus initially on cancer, rare diseases and infectious diseases – aims to train a new generation of genetic scientists, stimulate the UK life sciences industry and “revolutionise” patient care.

There is no doubt that this investment offers a major opportunity for the UK to firmly establish itself as a world-leader in medical genomics. However, deciding how best to use the £100M to maximise patient benefit will be a challenge. There are numerous implementation issues, outlined in the PHG Foundation’s response to the announcement. Not least of these is the urgent need for informatics provision to facilitate storage, processing, annotation, interpretation and secure access to both genomic and phenotypic data. This will involve determining appropriate ethical and operational standards across a broad range of questions.

But there is one particularly crucial question that needs to be answered early on: what is the most appropriate assay to use for clinical implementation? All the literature released by the Government, and quoted extensively by the press, states quite categorically that the money will be used for “sequencing whole genomes”. Surely this can’t really be true? (I certainly hope it’s just coincidence that if you multiply a £1000 genome by 100,000 patients you reach the magic figure of £100 million…) If it is the case, there are several major problems.

It would be a mistake to implement whole genome sequencing in the NHS now.

Firstly, although the Government’s Report asserts that “we will soon be able to sequence a human genome for less than £1000”, we can’t actually do this at the moment. In fact, according to data from the US National Human Genome Research Institute, a genome cost $7,666 (around £5k) about a year ago. Even if this were to become possible in the next year or so, the £1000 price-tag  for sequencing excludes the substantial costs of labour, informatics and training. At this early stage in planning,  it is still unclear how the money will be divvied up, but I think we could safely assume that given these additional and essential costs, perhaps only half the money might be available for generating the sequence itself. Which will not stretch anywhere near 100,000 whole patient genomes.

Secondly, the interpretation of whole genome sequence data is still in its infancy. While we are starting to get to grips with interpreting the pathogenicity of variants in known genes, variants in the other 98% of the genome remain essentially a mystery. This problem is confounded by the reduced analytical accuracy of current next generation sequencing machines for whole genomes versus targeted multigene or exome sequencing, as the depth of coverage may be substantially lower in coding regions. There is a currently a significant trade-off between the extent of coverage (i.e. whole versus partial genomes) and the depth of coverage (i.e. guaranteed accuracy of particular targeted regions). So opting for genomes instead of gene-targeted approaches may actually reduce the diagnostic yield! This is major problem for rare disease sequencing, as the ability to accurately call novel variants in key pathogenic genes may be sacrificed, thus preventing a diagnosis. It is even more of a problem for cancer genome sequencing due to sample heterogeneity; if just a few percent of tumour cells have the critical mutation, high read depths are essential for cancer diagnosis, prognosis and stratifying treatments. Although low average read depths have been successfully applied in population datasets such as the 1000 Genomes Project, a read depth of at least 30x is needed at every possibly causal site (not as an average across the genome) for diagnostic purposes, and even greater for low prevalence somatic mutations.

Finally, we also need to ask: what is the most appropriate test to use in each population? For diagnosing rare diseases, a parent-offspring trio model using exome sequencing is now well established in the literature. This approach allows many thousands of variants to be filtered down to a handful of possible candidates that can then be evaluated, which typically results in a high diagnostic yield. Currently, a whole parent-offspring trio could have their exomes sequenced for less than the cost of a single whole genome. In cancer, the few hundred genes known to be associated with cancer development, progression and treatment response could be targeted and sequenced for the cost of a single gene test, offering a high diagnostic yield across all cancers. High quality data could be obtained using formalin-fixed paraffin-embedded tumour samples which are already collected in hospitals around the country. Moreover, unlike whole genome sequencing, there would be no need to sequence the individual’s germline genome for comparison as population variation data could be used as a normal control dataset, effectively halving the cost of the test. And for infectious diseases (about which I know very little, so won’t say very much), the only sensible approach at this stage would be microbial sequencing not human genome sequencing.

So why the obsession with whole patient genomes? The genome has become a cultural and political icon, a proxy for the incredible achievements of modern science and a beacon of hope for the future of medicine. And it will undoubtedly become an important tool in years to come. But at this point in time, the difficulties involved in clinical interpretation mean that whole genome sequencing simply does not offer either sufficient value for money or clinical utility for mainstream use.

Whole genomes are currently expensive, inaccurate and hard to interpret. More research is needed before they could be implemented in mainstream medicine and many countries are already engaged in major genomic research endeavours. However,the UK National Health Service almost uniquely has the potential to directly translate this technology and embed genomics into clinical practice – an opportunity which could be wasted if the difficulties with interpreting whole genome data decimate the diagnostic rate. The alternative approaches enabled by next generation sequencing – namely multigene targeted sequencing – would increase not only the number of patients who could be sequenced but also the proportion who receive a diagnosis from this initiative.

NHS money should be spent on intelligent genomic strategies that offer the most benefit to the most patients.

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5 Responses to “£100M for whole patient genomes – revolutionising genetic diagnostics or squandering NHS cash?”

  • Vincent Plagnol

    Thank you for the post Caroline, that is very informative.

    This being said I am quite a bit more positive about this announcement than you are. I do not know exactly what the NHS invests per patient to diagnose a rare genetic disorder, but I think this is quite high currently. If this initiative can start shifting this business to more modern sequencing technologies this would be a valuable outcome.

    Whole genome may still be a waste today but whole exome is probably not. And there may not be any substantial difference in price between sequencing an exome or a targeted approach for a few 100s of genes. Lastly, data analysis can, should and will be largely automated, especially if one discards most of the data and only considers a subset of reliable genes that are generally free of false positive (because the sequence is unique and clean enough).I think this analytical cost will soon become relatively small.

    So in my opinion, especially if this money is spent on people who would already receive some sort of genetic testing, the cost may be much lower than expected, and eventually generate savings. We’ll have to sort the analytical and data storage issues at some point anyway, and now is as good a time as any. So we might as well get started. Plenty of initiatives like this one will start all over the US I suspect, so the timing is probably right.

  • Hi Caroline
    thank you for an excellent analysis of many of the key practical questions raised by the government’s plan. I expressed some concerns about this initiative when it was announced (see
    A grand bargain?). Your point about the alternative testing options for tumour profiling are particularly pertinent, given that the Technology Strategy Board have alread invested a considerable amount on a tumour profiling project focused on clinical implementation (see TSB announcement).
    Your argument that this initiative arises in part because of the iconic status of the genome is telling, but I would suggest that underpinning this initiative is an unhealthy obsession with the technological cutting-edge and mistaken assumptions about the benefits of first-mover advantage. I have yet to hear a convincing argument about how UK PLC can ensure that we capture the value of our £100M investment (particularly given the likelihood of Oxford Gene Technology being acquired by Illumina, as the Cambridge-based Solexa was previously).
    When the Roche Amplichip came onto the US market in 2004 it was the first FDA-approved pharmacogenetic microarray. It was a cutting-edge technology which promised to deliver a new era of personalised medicine. It has been a commercial failure which has enjoyed only very limited clinical uptake. Its weakness was not the platform technology, but the lack of robust evidence to support clinical implementation of CYP450 testing.
    It is no coincidence that the last major government announcement on the future of genomics (the 2003 Genetics White Paper) singled out pharmacogenetics as the low-hanging fruit of the genomic revolution and promised a major investment in the area (the UK warfarin pharmacogenetics trial). The failure(thus far) of warfarin pharmacogenetics (a project heavily promoted as a poster child for personalised medicine, not least by senior FDA officials in the USA) illustrates the difficulties in picking winners in biotechnology.
    Your post illustrates that there are multiple competing visions of how genomics will enter the practice of medicine – given the failure of previous visions, we need a broad and open debate about our genomic future(s). The government’s December announcement was made without broad stakeholder engagement, it is only to be hoped that public discussion now can provide a useful and constructive corrective.

  • Interesting points. I agree with you that whole genome sequencing will not deliver much at present, exome sequencing has a higher probability of delivering clinically valuable information. Yet we must also consider that the mining of the non coding genome will be advanced by the sequencing of many genomes with complete annotation. I welcome 100M£ but I also expect these money to go into genomes as well as into tools and research. I think the most important issue now is the matching between mutations and drugs, at least in oncology where we expect major effects on therapy.

  • We need £1B not £100M, if the UK is gong to lead the world rather than say “me too”.

    A great post on a subject that has huge potential to impact UK genomic-medicine positively. I’d agree with Vincent’s sentiments about positivity though. It is too easy to point to the potential problems and lack of details with the current plan, although those very clearly need pointing out. Stuart makes the very valid point that the announcement seemed to come out of nowhere with little substance.

    I’d say we may need 50x coverage for somatic analysis which is the norm in ICGC.

    Genomes will always be more expensive than exomes, and exome will be more expensive than targeted sequencing. Without limitless sequencing capacity turnaround time always has to be considered and this is one of three major issues I see for the NHS (clinical benefit, cost, turnaround). Personally I favour targeted approaches as I believe they are more digestible by users (from my research-sequencing experience).
    TSB have pushed into targeted sequencing as Stuart points out and that project should be reviewed as part of the evidence for investment at the level the government has suggested. There is already a large effort within the NHS to sequence many 1000′s of exomes so the clinicians are well aware of the paradigm that is rapidly becoming established in the USA.

    But I do think the government is right to focus the discussion on genomes, it makes good headlines and is easier to explain to the public as almost everyone has heard of the Human Genome Project. As long as the details of the project are focussed on getting the most benefit for patients and the NHS then the announcement can surely be welcomed.
    The biggest problem I see is that this is not new money. £100M is a reasonably large investment but not as big as it could have been and it comes from somewhere else in the NHS. Why not pump £1B into genomic-medicine, this would be small beer compared to the Bank bailout, would stimulate highly-skilled job creation and drive genomic medicine into almost every area we need it in.

    Currently there is no facility in the UK that could process 100,000 Human genomes at £1000 each, using today’s HiSeq 2000 at 4 lanes per genome; for 30-50x coverage you would need to run one instrument every day until the year 2700! Assuming the UK will complete this in 10 years we’d need around 70 HiSeq 2000s, which co-incidentally is not far off current UK capacity. However buying that many new instruments would gobble up almost half the budget. It turns out we need £500 genomes instead!

    I don’t see Oxford Nanopore Technologies brining out a viable product that this project can start using for at least another two years, probably longer.

    Lastly, there is a real risk that under EU tendering laws this project could be run outside the UK or potentially in China. That would see almost all the jobs move out of the UK and would be a bad news story. Far better to build new infrastructure here in the UK and not ins the South-East where staff and space are expensive.

    PS: Will I see you on the steering committee meeting next month?

  • How will exome sequencing help us flag non-coding mutations, indels, CNVs, etc. that result in phenotypic changes? Part of the reason for the poor success of GWAS is that the causative factors often lie outside of exons and genes. SNPs in upstream promoters, transcription factor binding sites, enhancers, etc.

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