Author Archive for Caroline Wright

Pertinent and Non-pertinent Genomic Findings

About Guest Co-Author: Dr Ewan Birney is Associate Director of the EMBL European Bioinformatics Institute and a fellow blogger.

The ACMG recommendations on clinical genomic screening released earlier this year generated quite a storm. Criticisms broadly related to:

  • the principle of whether we are ready and able to offer genomic screening to people undergoing exome/genome sequencing (the topic of this post!);
  • to whom the recommendations should apply
  • whether individuals have a right to refuse genomic screening results; and
  • the exact content of the list of genes/variants to be screened.

In the UK, this debate has come into sharp focus following the launch of the NHS 100,000 genome project, where details of data interpretation and data sharing are still rather hazy. The central policy question is clear: in the context of clinical practice, how should we be using genomic data, and with whom, in order to maximise its benefits for patients? (In the context of research, as broad as possible sharing consistent with patient consent is most desirable.) Last month, we published a paper in the BMJ – along with a number of genetic scientists, clinical geneticists and other health specialists – advocating an evidence-based approach that places the emphasis on targeted diagnosis in the short term, and gathering evidence for possible broader uses in future.

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Genomics England and the 100,000 genomes

Genomics-England-logo21The UK’s ambitious plan to sequence 100,000 whole genomes of NHS patients over the next 3-5 years, announced by the UK Prime Minister in December last year, sparked interest and curiosity throughout the UK genetics community. Undeterred by the enormity of the task, a new company, Genomics England Limited (GeL), was set up in June of this year by the Department of Health, tasked with delivering the UK100K genome project. Yesterday, they held what I’m sure will be the first of many ‘Town Hall’ engagement events, to inform and consult clinicians, scientists, patients and the public on their nascent plans.

So what did we learn? First, let’s be clear on the aims. GeL’s remit is to deliver 100,000 whole genome sequences of NHS patients by the end of 2017. No fewer patients, no less sequence. At its peak, GeL will produce 30,000 whole genome sequences per year. There’s no getting away from the fact that this is an extremely ambitious plan! But fortunately, the key people at GeL are under no illusions about the fact that theirs is a near impossible task. Continue reading ‘Genomics England and the 100,000 genomes’

Further reflections on genomic screening

Scales_of_justiceNow the dust has settled, I’ve been reflecting on the controversial recommendation from the American College of Medical Genetics and Genomics (ACMG) that all clinical genomes should be screened for a specific set of conditions. Following the release of the guidelines, the European Society of Human Genetics (ESHG) published its more conservative recommendations, and vigorous debate has continued internationally regarding the wisdom of introducing genomic screening. While I still have some major reservations about the policy (outlined in previous posts), upon reflection there are certainly things some aspects that make a lot of sense…

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ACMG guidelines on IFs – responding to the response…

StethCollage1The ongoing debate about whether, what, when and how to feedback incidental findings (IFs) from whole genome sequencing continues to rage on both sides of the Atlantic following the American College of Medical Genetics and Genomics’ controversial recommendations on reporting IFs released last month. In an unexpected twist, the authors of the guidance have now written “a clarification” in response to the many criticisms that have been raised including here on GenomesUnzipped. The clarification covers five points – autonomy, children, labs, communication and interpretation.

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Why predicting the phenotypic effect of mutations is hard

shutterstock_12830056By now, we’re probably all  familiar with Niels Bohr’s famous quote that “prediction is very difficult, especially about the future”. Although Bohr’s experience was largely in quantum physics, the same problem is true in human genetics. Despite a plethora of genetic variants associated with disease – with frequencies ranging from ultra-rare to commonplace, and effects ranging from protective to catastrophic – variants where we can accurately predict the severity, onset and clinical implications are still few and far between. Phenotypic heterogeneity is the norm even for many rare Mendelian variants, and despite the heritable nature of many common diseases, genomic prediction is rarely good enough to be clinically useful.

The breadth of genomic complexity was really brought home to me a few weeks ago while listening to a range of fascinating talks at the Genomic Disorders 2013 conference. Set against a policy backdrop that includes the recent ACMG guidelines recommending opportunistic screening of 57 genes, and ongoing rumblings in the UK about the 100,000 NHS genomes, the lack of predictability in genomic medicine is rather sobering. For certain genes and diseases, we can or will be able to make accurate and clinically useful predictions; but for many, we can’t and won’t. So what’s the problem? In short, context matters – genomic, environmental and phenotypic. Here are six reasons why genomic prediction is hard, all of which were covered by one or more speakers at Genomic Disorders (I recommend reading to the end – the last one on the list is rather surprising!):

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No choice for you

Guest Co-Author: Dr Anna Middleton is an Ethics Researcher and Registered Genetic Counsellor, based at the Wellcome Trust Sanger Institute, UK.

StethCollage1The American College of Medical Genetics (ACMG) has recently published recommendations for reporting incidental findings (IFs) in clinical exome and genome sequencing. These advocate actively searching for a set of specific IFs unrelated to the condition under study. For example, a two year old child may have her (and her parents’) exome sequenced to explore a diagnosis for intellectual disability and at the same time will be tested for a series of cancer and cardiac genetic variants. The ACMG feel it is unethical not to look for a series of incidental conditions while the genome is being interrogated, conditions that the patient or their family may be able to take steps to prevent. This flies in the face of multiple International guidelines that advise against testing children for adult onset conditions. The ACMG justify this as “a fiduciary duty to prevent harm by warning patients and their families”. They conclude that “this principle supersedes concerns about autonomy”, i.e. the duty of the clinician to perform opportunistic screening outweighs the patients right not to know about other genetic conditions and their right to be able to make autonomous decisions about testing.

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Do we have an obligation to look?

One of the major bioethical debates in clinical genetics and genomics research is the issue of what to do with incidental or secondary findings (IFs) unrelated to the original clinical or research question. Every genome contains thousands of rare variants, including a surprising number of loss of function variants, as well as hundreds of variants associated with common disease and dozens linked with recessive conditions. As whole genome or exome sequencing is used more routinely in non-anonymised cohorts – such as the 100,000 patient genomes to be sequenced by the UK NHS – these variants will be uncovered and linked to an increasing number of individuals. What should we do with them?

Robert Green of Brigham and Women’s Hospital in Boston, who co-chairs the American College of Medical Genetics (ACMG) working group on secondary findings, was quoted in a Nature blog last year saying, “we don’t think it’s going to be a sustainable strategy for the evolving practice of genomic medicine to ignore secondary findings of medical importance”. But just saying it doesn’t make it so. There are still numerous questions that need to be addressed – you can be part of the debate by participating in the Sanger Institute’s Genomethics survey.

Questionnaire web

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£100M for whole patient genomes – an implementation challenge

The recent announcement that the UK Government has earmarked £100 million to “sequence 100,000 whole genomes of NHS patients at diagnostic quality over the next three to five years” raises a number of questions, with which the Department of Health are no doubt grappling as I write. I’ve previously discussed the thorny issue of using targeted versus whole genome sequencing to maximize diagnostic yield and benefit patients. However, one of the great achievements of next generation sequencing technologies is to make the assay – actually sequencing genome (or some portion of it) – one of the easier parts of clinical genomics. Although laboratories will have to be suitably equipped, staffed and flexibly managed to deal with high sample throughput and ever changing scientific specifications, the biggest challenge will be to implement genomic knowledge in the clinic.

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£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.

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Report on clinical genome sequencing

The PHG Foundation, an independent genomics think-tank, has launched a new report on next generation sequencing and its impact on health and health systems. The Report, Next steps in the sequence: the implications of whole genome sequencing for health in the UK can be freely downloaded and aims to provide a comprehensive overview of the many and varied issues relating to clinical genome sequencing.

When planning the work, we were motivated by the astonishingly rapid development of fast, affordable whole genome sequencing (WGS) technologies, which are set to change many aspects of health care. The sheer quantity and complexity of the information generated by genome sequencing, along with ever-changing understanding of the function of genomes in health and disease, presents new challenges for health systems.

The Report reviews the technologies, informatics pipeline and key clinical applications of WGS, and as well as the economic, ethical, legal and social implications and organisational challenges of offering WGS within the UK NHS. The final two policy chapters outline different scenarios for testing, storing and returning results, and contains 10 key recommendations reached with the help of several expert stakeholder workshops.

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