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28 September 2007The Nuffield Council on Bioethics last week released its most recent Report entitled The forensic use of bioinformation: ethical issues. Following its public consultation on the subject last year (see previous news), the Council deals with the central questions of police powers in Britain to obtain biological evidence, to retain it, and to search databases (primarily the UK National DNA Database) for various purposes. The Report is confined to the discrete issues of fingerprinting and DNA in the context of criminal justice as a means of addressing current controversies about the proper balance between police powers and individual rights to liberty, autonomy and privacy.
The Council concludes that while the need to fight crime justifies the use of biological evidence, effective governance and regulation are essential. Importantly, it asserts that ‘the establishment of a population-wide forensic DNA database cannot be justified at the current time’, on the basis that the costs, both economic and in terms of intrusion to privacy, outweigh the potential benefits. It finds, however, that the authority to take and retain fingerprints and biological samples without consent is warranted where individuals are arrested on suspicion of involvement of serious violent or sexual offences. Where the alleged offences are minor, or individuals are not ultimately charged or convicted, the Council cautions against taking and storing of DNA without consent. Further, it recommends that samples of DNA provided in such circumstances be removable from the national database upon request, and that DNA from children should not be retained without good reason.
As with any genetic information, it is noted that the full extent and implications of the information provided by DNA samples are not well understood by all audiences. The Report recommends that legal professionals and juries should receive more guidance to assist their understanding of the meaning of DNA evidence, and that the police should not routinely seek ‘ethnic inferences’ from DNA analysis.
Finally, the Council makes a strong recommendation in favour of the institution of a statutory basis for the regulation of forensic databases and retained biological samples. The regulatory framework should, it suggests, delegate specific powers for the oversight of research and requests for access to an appropriate independent body or official.
28 September 2007The UK’s Human Genetics Commission, which advises the Government on scientific advances in genetics, and in particular on their ethical, legal and social implications, has published its response to the Discrimination Law Review’s consultation on proposals for a Single Equality Bill for Great Britain (see previous news article). In its response the HGC calls for comprehensive legal protection against ‘discrimination on any genetic grounds’ – a recommendation that goes far beyond the question asked in the consultation document, which refers only to the “discrimination on the grounds of genetic predisposition to disease”.
The HGC rejects the Discrimination Law Review’s suggestion that there is little evidence of a current problem, presenting an Appendix listing anecdotal reports of alleged ‘genetic discrimination’ in the UK and elsewhere. The examples presented cover a broad range of situations including prejudice against people with diagnosed genetic conditions, inappropriate applications of DNA tests, unjustified use of family history information, and social stigmatisation of families affected by highly penetrant genetic disease. The HGC notes that clinicians report that people are reluctant to take DNA tests that may be important for their health, because of fears that test results may be used to their disadvantage by third parties such as employers or insurance companies. Genetics researchers also encounter the twin difficulties of extremely burdensome regulation to protect research participants’ privacy and autonomy, while at the same time being unable to foresee all possible future uses of DNA sequence data or to guarantee its complete security; the suggestion is that legislation to outlaw genetic discrimination would remove both of these problems. The HGC believes that “opportunities for genetic discrimination will increase” as knowledge and technology advance, justifying pre-emptive legislation.
Any legislation outlawing ‘genetic discrimination’ or ‘discrimination on any genetic grounds’ would have to define the term ‘genetic’. Unfortunately, the HGC’s response is completely silent on this key question. Its discussion covers far more than just DNA-based information, ranging through family history (which integrates both genetic and shared environmental effects), highly penetrant diseases that are predominantly diagnosed by phenotypic features, and weakly penetrant DNA polymorphisms that interact with environmental factors to affect susceptibility to common disease. The only logical conclusion from the HGC’s suggestions is that the proposed legislation should apply to any human trait with a genetic component – in other words to all human characteristics and all ways of measuring or detecting them. It is difficult to see how such a law could be drafted or could operate. Rather than calling for legislation, a more effective approach would be to lobby for resources for the thorough evaluation and appropriate use of all biomedical tests (DNA-based or otherwise), and to champion a more rational and modern understanding of genetics. These arguments are developed more fully in the PHG Foundation’s response to the Discrimination Law Review’s consultation.
26 September 2007BBC News Online has reported the launch of a gene expression test that could improve the accuracy of the diagnosis of prostate cancer. Currently, a blood test is available that detects raised levels of a protein called prostate serum antigen (PSA); men with a high PSA score may be offered a prostate biopsy to determine whether cancerous cells are present in the prostate. The problem is that the PSA test has relatively poor specificity and positive predictive value, limiting its clinical value. For every 100 men with elevated blood levels of PSA, only about 30 subsequently have a positive biopsy. Management of these patients is then difficult, as they may have to undergo repeated painful and distressing biopsies despite never developing the disease.
A company called Gen-Probe has developed a more accurate, non-invasive test based on measuring expression levels of a gene called PCA3 in a urine sample. The PCA3 gene is over-expressed in about 95% of prostate cancers. The Progensa PCA3 test reportedly has substantially better specificity and positive predictive values than the PSA test but, at £200 per test compared with £10 for the PSA test, is unlikely to be adopted for routine use in the NHS. A Horizon Scanning Technology Briefing Paper produced by the National Horizon Scanning Centre at the University of Birmingham in December 2006 summarises the characteristics of the PCA3 test and suggests that it may prove useful in men who have raised PSA levels but a negative prostate biopsy (thus potentially sparing them repeated biopsies) or in men with slightly raised PSA levels or other clinical symptoms that suggest the possibility of prostate cancer.
26 September 2007In the last few months, multiple genome-wide association (GWA) studies have been published showing the basis of genetic susceptibility to numerous rare chronic diseases, including multiple sclerosis [International Multiple Sclerosis Consortium (2007), NEJM 357(9);851-862], sporadic amyotrophic lateral sclerosis [Dunckley T et al. (2007) NEJM 357(8): 775-788], Crohn’s disease [Raelson JV et al. PNAS (2007) 104(37): 14747-14752], rheumatoid arthritis [Plenge RM et al. NEJM (2007) 357(12):1199-1209] and restless legs syndrome [Winkelmann J et al. (2007) Nat Genet 39(8): 1000-1006].
Over the same time period, GWA studies were also published on more common diseases including cardiovascular disease, several cancers and both type 1 and 2 diabetes. Indeed, an entire supplementary issue of the open access journal BMC Medical Genetics was dedicated to genome-wide scans in the Framingham heart study. With advances in sequencing technologies and the increasing availability of fast and accurate sequencing machines, we can expect to see a rising number GWA studies uncovering ever more subtle genetic effects. As the sheer volume of data from GWA studies increases, databases are being set up to provide a public repository for all types of data describing the interaction between genotype and phenotype. Already in existence is the Genotype and Phenotype (dbGaP) database run by the National Centre for Biotechnology Information (NCBI) in the United States, inside which data from a number of reports including the Framingham heart study is already housed. A new initiative to create a European Genotype Archive (EGA) is also currently underway at the European Bioinformatics Institute (EBI) in the UK.
Amongst studies of diverse populations and seemingly unconnected diseases, some common themes are starting to emerge. For example, the association between autoimmune diseases and the major histocompatibility complex (the human leukocyte antigen system), which plays an integral role in the immune system, is now well established for multiple disorders. An increasing number of autoimmune diseases are also associated with variants in one or more of the interleukin receptors, which are activated by cytokines released by white blood cells as a means of communication. The identification of genetic similarities that underpin susceptibility to different but related disorders underlines the power of genome-wide association studies to identify low penetrance, causal variants of complex disease.
However, such associations can be difficult to demonstrate due to the low penetrance and often low prevalence of most causal genetic variants associated with complex diseases. The effect of any given allele is generally very small and can only be verified through huge datasets, independent studies and robust meta-analyses. For example, a small but significant association between the interleukin-7 receptor and multiple sclerosis has been confirmed through the combined data from three independent studies involving over 17,000 subjects. [The International Multiple Sclerosis Consortium (2007), NEJM 357(9);851-862; Gregory SG et al (2007), Nature Genetics 39(9): 1083-1091; Lundmark F et al (2007) Nature Genetics 39(9): 1108-1113].
But even when statistical significance can be proven from extensive and repeated GWA studies, predicting individual risk from population data is complicated. The complex, non-linear nature of gene-gene and gene-environment interactions, as well as the small contributory effect of each individual allele, means that single gene associations will rarely provide the whole picture. However, although the increased risk associated with each locus may be small, knowledge of multiple risk alleles throughout the genome should ultimately allow the identification of individuals who have a significantly increased risk of certain diseases. It remains to be seen whether population stratification by global genetic risk for specific diseases will eventually allow us to target interventions at those who will benefit the most.
25 September 2007Just a month after the label for the blood-thinning drug warfarin was updated to explain that genetic variation in specific genes influences how patients respond to the drug (see previous news article), the US Food and Drug Agency (FDA) has approved the first genetic test for warfarin sensitivity.
Warfarin is the most widely used anti-coagulant medication in the world, prescribed to over 2 million people a year to prevent blood clots, heart attacks and strokes. Patients can display markedly different responses to the drug, so doses vary enormously between individuals. Achieving the correct dose is critical, as patients who receive too high a dose are at risk of severe bleeding, whilst those who receive too low a dose may remain at risk of life-threatening blood clots.
The Nanosphere Verigene Metabolism Nucleic Acids Test detects particular variations in two genes, CYP2C9 and VKORC1, which are involved in the metabolism and mechanism of action of warfarin respectively. Specific variants of these genes are identified from a patient sample by hybridization to sequence specific probes (oligonucleotides) attached to a microarray. These are subsequently detected using the Verigene System which measures light scattering from gold nanospheres tethered to another complementary oligonucleotide. Depending upon the genotype, patients can then divided into slow, fast or normal warfarin metabolisers and their doses adjusted accordingly.
FDA states that it cleared the test based on a broad range of published literature together with the results of a study, conducted by the manufacturer, on hundreds of DNA samples. ‘In a three site study, the test was accurate in all cases where the test yielded a result, although 8% of the tests could not identify which genetic variants were present.’ Although the Nanosphere test is not intended as a stand-alone tool to determine optimum drug dosage but to be used alongside clinical evaluation and other tools to determine the best treatment for patients, this approval underlines the FDA’s ongoing commitment to personalised medicine.
24 September 2007The BBC has reported that a new type of DNA testing “may help prove if people have had their health damaged by exposure to chemicals” (see BBC news). The technique, known as msds1™, involves exposure of DNA samples from a healthy control to the chemicals in question. A distinctive pattern of gene expression, based on which genes or are up-regulated or down-regulated in response to the chemical of interest, is produced and compared with the gene expression profile of the subject under investigation. Certain ‘molecular signatures’ of exposure to specific chemicals or toxins are used to exclude or prove past exposure to the substance or substances of interest. In some cases proteomic profiling (looking at patterns of protein production, as opposed to gene expression) may also be used. The tests have been developed using multiple control individuals of different gender and ethnicity.
The company that developed the test in association with the University of Illinois, The Cytokine Institute, says that this microarray-based technology can: “determine how human cells and their individual DNA respond when exposed to a chemical and its metabolites. By analyzing gene expression and how 36,000 parameters of an individual’s DNA are affected by specific chemical exposures—such as benzene or asbestos—this technology can determine with 99.9% certainty if a person was injuriously exposed to a particular toxin, thereby offering an impartial methodology for providing scientifically-based evidence” (see press release).
The technology is being marketed for use in employee compensation claims for health problems allegedly caused by chemical exposure in the workplace. It has reportedly been endorsed by the American Bar Association (see Insurance Times article) and admitted as evidence, for both prosecution and defence, in more than twenty legal cases.
Assuming that it is sufficiently rigorous in its ability to discern whether or not cells have been exposed to particular environmental toxins, the test could be a useful evidentiary tool with which to demonstrate chemical exposure and support assertions regarding the potential impact of this exposure on the claimant. As a health and safety measure, it might also be used to monitor chemicals in the workplace in a manner similar to the current monitoring of employees who handle radioactive substances. However, in spite of its potential admissibility for certain purposes, the test does not provide conclusive evidence of the timeframe within which the exposure occurred, or that the molecular change correlated with the exposure was a causative factor in the complainant’s health problem.
This test provides an example of one of the wider potential applications of emerging genomic technologies, although it appears to have been developed using cells taken from healthy controls that were subsequently exposed to particular chemicals; the gene expression profiles were then compared with those from test subjects. It is questionable whether experimental exposure of isolated cells is truly comparable with past exposure of cells in the context of a human body, in terms of the resulting gene expression profiles. Ultimately, though, with greater understanding of the highly elaborate interactions in the human body in health and disease, at systemic, cellular and molecular levels, such tests could be used for a range of purposes, including monitoring disease processes and therapeutic effects.
21 September 2007In a rapid response to the previously reported publication by Wald et al proposing population screening of children for FH, familial hypercholesterolaemia (see previous news), Humphries and Hadfield, whilst agreeing that it is desirable to “find more patients with this life- threatening but treatable disorder”, have affirmed some of the potential problems of such an approach, including cost-efficacy and consent [Humphries SE, Hadfield G (2007) BMJ September 14]. They report the results of their recent pilot of cascade testing, funded by the Department of Health, which found that cascade testing was feasible, desirable, cost-effective and acceptable to patients and clinicians. Recommendations based on this pilot are said to be that implementation would require:
Humphries and Hadfield also point out that the National Institute for Health and Clinical Excellence (NICE) are in the process of developing clinical guidelines for the identification and management of patients with FH, due for publication in August 2008.
While they do not dismiss the idea of screening babies, they propose rather that cascade testing from the estimated 15,000 FH patients already attending lipid clinics should be the starting point for increased detection of cases. They also caution that they found the overlap in cholesterol levels between individuals with and without FH to be much greater than that used in the model of Wald et al., which could mean a high rate of false-negative or false-positive results, depending on the cut-off values selected.
21 September 2007The call by UK Health Secretary Alan Johnson for a review of the consent procedures required for organ donation (see BBC news, 20th September) is intriguing as the Human Tissue Authority (HTA), the organisation responsible for regulating organ donation, rejected any review of the law in this area at their public meeting on 6 September 2007 on the basis that consent for organ donation had been thoroughly debated by Parliament when the Human Tissue Bill was scrutinised by Parliament in 2004. Indeed the HTA press release commenting on similar proposals made by the Chief Medical Officer in July pointed to a possible detrimental effect on other areas regulated by the Act stating that ‘the HTA believes that a system of presumed consent for organ transplantation might undermine current provisions in the HT Act for fully informed consent for other purposes, such as body donation for medical science or removal of tissue at autopsies’.
The availability of organs for transplantation is contingent both upon the timing of the removal of organs as well as the consent processes which support donation, and it is part of the statutory remit of the HTA to issue codes of practice relating to various regulatory functions, including a code on the definition of death. The sensitivity of this task is perhaps reflected by the fact that despite assistance from the Academy of Medical Royal Colleges, a final form of the code remains to be published. Recent reports from California of criminal proceedings brought against a transplantation surgeon on the basis of hastening death to procure organs for transplantation, highlights the difficulties of formulating policy in this area.
All this suggests that the procurement of organs for transplantation should not be viewed in isolation. Public trust in the medical profession was severely shaken by the succession of scandals which prompted the implementation of the Human Tissue Act. Indeed the integrated approach to consent which was established by the Act, was commended as a means of rebuilding public trust and as proof of a transition from outdated paternalistic models of medical care. For this reason, any prospective review of the consent model to be used in transplantation should consider not only the advantages and disadvantages of whether everyone in England should be put on the organ donor register unless they opt out, but also the effect such legislation would have on other areas regulated by the Act. The use of human material for research is crucial in developing better health care and effective treatments. If the Government finds a utilitarian approach persuasive in the context of saving the lives of those dying from organ failure, perhaps they should also consider revisiting other areas of the Human Tissue Act where using tissue to save lives is also in the public interest.
19 September 2007The UK Department of Health has joined with UK Biobank in inviting National Health Service (NHS) patients to join the project. Biobank is currently recruiting people aged 40-69 (see previous news) for an initial health assessment and blood and urine sample donation, after which there will be long-term follow-up of their health outcomes. The project is seeking to recruit half a million people from the UK, and to create a unique data resource for researchers to identify key gene-environment interactions that affect health and disease. Professor Sally Davies, Director General of Research and Development at the Department of Health said: "An important part of the Department of Health's work is to stand behind research aimed at tackling important health problems and improving NHS care. Because of its potential for future generations, the government is glad to join with the Wellcome Trust, the Medical Research Council, and others in supporting UK Biobank” (see GovNet news).
A new (and unrelated) tissue bank has recently been established; OnCore UK is a tissue bank which will store blood and tissue samples donated by NHS cancer patients, for use by suitably approved medical research scientists. Chief executive Brian Clark said: "Many patients want to do something to support research into their disease and to help others in the future…OnCore UK can help people with cancer do this by providing them with an accessible and ethically approved way of donating samples and data” (see BBC news). Donors will have to provide informed consent, and although samples will be linked to personal health data, donor anonymity will be maintained.
14 September 2007Scientific publishers in the US are campaigning against calls for publicly funded research to be made freely available to all. The Association of American Publishers has started a new initiative, The Partnership for Research Integrity in Science and Medicine - the PRISM Coalition – whose stated aim is “to educate policy makers and the American people about the risks posed by government intervention in scholarly publishing”.
PRISM is opposed to the open access policy advocated by the National Institutes of Health (NIH), which requires that NIH-funded research be made available via PubMed Central within 12 months of publication. The House of Representatives has passed this in its new budget, while it is under consideration in the Senate.
PRISM argues that the open access approach is damaging to scientific integrity and in particular to the peer review process, and that it amounts to government censorship of science.
Open access supporters dismiss these claims as ridiculous, pointing out that peer review is based almost completely on the voluntary free labour of the research community, and that neither open access journals nor policies alter the process of publication or peer review.
Early reactions to PRISM have been strong, with several commentators calling for a boycott of the association or for academics to resign from editorial boards of journals published by supporters of PRISM. The Association of Research Libraries has issued a briefing which specifically rebuts the claims made by PRISM.
13 September 2007Women aged 21-35 attending the Newcastle Fertility Centre (NFC) in the north of England are to be offered reduced price in vitro fertilisation (IVF) treatment in exchange for donating some of their oocytes (eggs) for research (see BBC news). Women who agree to donate half of the eggs harvested as part of the IVF process will receive a £1500 reduction in the price of their treatment. Researchers from the North East England Stem Cell Institute will use the donated oocytes to generate human embryonic stem cells, which will then be used for medical research.
The Human Fertilisation and Embryology Authority (HFEA) granted a temporary licence to the North East England Stem Cell Institute last year giving them permission to approach women requesting ‘altruistic egg donation’ (see previous news), and followed this with public consultation leading to a decision earlier this year that women should be allowed to donate their eggs for research if they wanted to (see previous news). This decision required that safeguards to prevent possible coercion of women donors be put in place, and did not permit payment of donors, although expenses of up to £250 were permissible.
NFC Head of Department Professor Alison Murdoch pointed out that egg sharing conferred no additional physical risk to the women and said: “We expect this to open the door to some infertile women who may now find it less difficult to meet the cost of IVF” (see NFC website news). However, others have expressed concern that women donors are being exploited, because women who are unable to access NHS treatment or to afford the full cost of private IVF treatment may be more likely to donate than women who can access NHS treatment, or to pay for IVF.
13 September 2007The US National Institutes of Health (NIH) has announced a new policy for the sharing of data derived from genome-wide association (GWA) studies. Starting in January 2008, all researchers who receive NIH funding to conduct GWAs will have to submit their data to a central database.
These large-scale studies are used to identify associations between particular genetic variations and the presence of a phenotype or disease. NIH considers that sharing the information from many studies in one central repository is likely to increase the potential for developing new approaches to the prevention and treatment of disease, as well as maximising public investment. As stated, ‘the goal of the policy is to advance science for the benefit of the public’.
Plans for the database have been developed taking into account the views of both patients and researchers, who raised issues about whether it might be possible to use the data collected fo