News

24 December 2009We would like to extend our warm wishes for the holiday season to all of our readers.

We are taking a short break, and will resume with news and updates to the website early in the new year.

21 December 2009In the US, regulators have approved thirteen new lines of human embryonic stem (HES) cells for use by federally-funded researchers, with many more new lines expected to be approved soon if they are found to meet ethical requirements (see BBC news). The current NIH Guidelines for Human Stem Cell Research were established this year after President Barack Obama moved to ease previously strict regulation put in place by the previous administration (see previous news). The National Institutes of Health (NIH) may establish a central repositary for the storage and distribution of approved HES cell lines in the face of demand for new lines.

Work using stem cells derived from alternative sources also continues, and US researchers recently announced promising results - researchers rarely announce results that are not in some way promising - from trials to treat damaged corneas in mice using human umbilical cord stem cells (see BBC news). It is hoped that regenerative medicine using stem cells could eventually help address a serious shortage of organs (including corneas) available for transplantation.

In Italy, scientists have lost a legal appeal against proposals from the health ministry for stem-cell biology funding that specifically exclude HES cells, despite the fact that the use of HES cells is not prohibited (see Nature news). However, the stem cell research community in India will welcome news that construction of a major new Institute for Stem Cell Biology and Regenerative Medicine (inStem) in Bangalore has begun (see Science news) following government approval in July (see Indian Express news).

17 December 2009The ‘Manchester Manifesto’ is a new document from a group convened to consider the current system of ownership and management of science and innovation. Produced by a group led by John Sulston of the Institute for Science, Ethics and Innovation at the University of Manchester and Joseph Stiglitz of the Brooks World Poverty Institute, the brief document identifies the key goal of science as being to ‘serve the public good by generating knowledge to meet human needs and purposes’. Of note, thirty of the fifty signatories are from the University of Manchester.

Unsurprisingly, given their predominantly academic backgrounds, the group concludes that pure (basic) scientific research is ‘clearly in the public interest, since curiosity expands knowledge’ but also note that technical innovation provides additional economic benefits to society. The group asserts that current models of management and commercialisation of science and technology – including the system of patenting scientific inventions, and of intellectual property and licensing relating to patents – restrict public access to the benefits of research. The manifesto states that restrictions imposed by current systems are ‘contrary to the needs of scientific inquiry and are inimical to openness and transparency’, adding that effects are most severe on public, not-for-profit, small and developing country enterprises.

It calls for urgent consideration of alternative new models – claiming that modification of the current intellectual property system would have only limited impact – and states that regulation of frameworks for innovation should seek to promote and balance factors including public benefit, trust between stakeholders, and addressing local and global welfare and resource inequities.

Comment: This brief new document, besides being a clear plea for continued investment in basic research (possibly in reaction to new UK emphasis on translational research and the adoption and diffuusion of new technologies and products) raises some interesting issues with respect to the inequities related to scientific commercialisation.

Some of the principles and concerns are very valid. For example, there is ongoing opposition to patenting of human gene sequences and criticism of their negative impact of patient access to affordable genetic tests; in a current US lawsuit the Association for Molecular Pathology is contesting the legality of existing patents for the BRCA1 and BRCA2 genes held by Myriad Genetics and the University of Utah Research Foundation as contrary to prohibitions on patenting ‘products of nature’ [Lenzer J (2009) BMJ 339, doi: 10.1136/bmj.b4899]

The stated aim of the manifesto to ‘build a better future for humanity’ is likewise a compelling one. Certainly, the PHG Foundation believes that health is an essential prerequisite for human development and is concerned with making the health benefits of science available to vulnerable populations based on need (see About us).

However, the manifesto wholly fails to recognise the critical role of the commercial sector in funding and conducting applied research, and the necessity of some form of system to protect intellectual property in order to retain sufficient economic imperatives for companies to continue their heavy investment in research and innovation. Critical responses to the document, such as the assertion that it is ‘ill-informed and misleading’ are therefore unsurprising.

15 December 2009 Synthetic biology refers to the artificial construction of novel biological systems or organisms; building on genetic engineering techniques, some researchers are using synthetic genomics to create new organisms (see previous news story). Societal and regulatory issues in this field have been discussed and a report commissioned by the BBSRC’s Bioscience for Society Panel highlighted some key issues including uncontrolled release, bioterrorism, patenting and the creation of monopolies, trade and global justice and creating artificial life (see previous news).

The International Association of Synthetic Biology (IASB), a consortium of leading companies in this field and was formed in order to work with governments and other stakeholders to develop best practices ensuring that this field develops in a safe and responsible way. As part of this remit, they have released a code of conduct for gene synthesis (see press release). The Code gives a comprehensive set of Best Practices for DNA sequence screening, customer screening and ethical, safe and secure conduct in gene synthesis. These have been modelled after biosecurity procedures currently implemented by gene synthesis companies and were developed further following a workshop involving key stakeholders. The Code is aimed at companies as well as academic and public institutions that practice gene synthesis. More specifically it has been “expressly designed to guide companies and other entities engaged in the synthesis of double stranded DNA of minimum 200 base pairs in length and multi-gene constructs.” Along with outlining general considerations, the best practices cover, risk assessment, record keeping, cooperation with authorities, sequence screening, response to identified threats and customer screening.

The IASB is planning to reach out to others in the industry to sign up to this standard and are hoping to develop a certificate which characterizes institutions that are committed to this code of conduct. The formation of a technical expert group on biosecurity and a database on virulence factors, which would contain data on sequence level virulence factors and pathogenicity has also been discussed by the IASB. This would allow exchange of data on screening decisions, thereby facilitating the sequence screening procedure of the Code. 

15 December 2009 When the House of Lords published their Report on Genomic Medicine in July 2009, they argued that the pace of change requires a new strategic phase for genomics in health services. By contrast, the Government response published on December 14th largely rehearses past achievements and attempts to make current processes fit future needs without acknowledging the scale and complexity of what will be required.

The Government response explicitly rejects the publication of a new Government White paper on genomic medicine, which formed one of the central recommendations of the House of Lords Genomic Medicine Report. Whilst there is a commitment to establish a cross-departmental Human Genomics Strategy Group (HGSG) which will have responsibility for developing a vision for genomics in the NHS, including limited workforce and bioinformatics planning, in the main the response from Government seems disappointingly lacking in substance.

The Government, for example, does not recognise that current structures and mechanisms to commission and provide genetic testing for single gene disorders are inadequate. Even our present knowledge and capabilities in single gene disorders are not reflected in equitable practice across the UK and there is no doubt that this gap will widen significantly in the next few years. The expectation that commissioning in genomics within mainstream medicine will somehow be improved through World Class Commissioning without setting out in any way how this will be driven, is complacent.

As a further example, as knowledge of genomics and complex disorders gains pace, the response on bioinformatics shows that the Government does not appear to understand the need to start putting infrastructure in place now if the NHS is going to respond adequately to the genomic revolution even though the actual benefits may be some time coming. The Government agreed to 'carefully consider' recommendations about a new Bioinformatics Institute but again does not seem to have recognised the urgency of the need nor the magnitude of the task if we are to develop the necessary capacity and capability to support the integration of genomics information into practice.

It is not our intention at present to provide a detailed commentary on the Government response. Both the original Report and the Government response require and deserve more detailed thought. To that end the PHG Foundation is undertaking a series of consultations with key stakeholders in conjunction with Cambridge University Centre for Science and Policy - a process that will result in a detailed response to the House of Lords Report in late Spring 2010.

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11 December 2009The UK National Health Service (NHS) has launched a consultation on a proposed pilot scheme to speed up access to new therapeutics for patients with rare diseases. Normally, novel treatments must be thoroughly evaluated and approved according to strict criteria by the National Institute for Health and Clinical Excellence (NICE), the body that produces guidance on treatments and interventions for the NHS. In some cases – and particularly in the case of rare diseases that individually affect only relatively small numbers of people – it may not be possible to generate adequate data for the rigorous demonstration of cost-effectiveness required by NICE (and hence for NHS funding of the treatment) – for example, because the smaller numbers of patients make demonstration of efficacy slow even where novel therapeutics may actually offer significant benefit in terms of patient outcomes.

Many genetic diseases fall into the category of rare diseases, although in fact collectively their public health impact (and the burden they place upon health services) is significant, so that moves towards a ‘one size does not fit all’ system that can respond more flexibly to different requirements to assess needs and costs for less common conditions are highly desirable.

The new ‘Innovation Pass’ scheme, announced earlier this year by the UK Government as part of the new Office for Life Sciences (OLS) Blueprint (see Central Office of Information news) will allow selected new therapeutics to be made available via the NHS from 2010/2011 for three years. It is hoped that this will simultaneously allow patient access and generate data that could support subsequent full NICE appraisal, with priority to be given to areas of the greatest patient need. 

The Department of Health is now running a consultation for stakeholders to comment on the plans. The consultation notes that the Innovation Pass, currently intended to focus on treatments, could also be extended to include medical technologies and diagnostics, and specifically queries whether this is advisable. This might, for example, include new genetic tests.

The consultation closes on 8th February 2010.

8 December 2009The cancer biobanking organisation onCore UK was established with a stated mission to inform, coordinate and develop cancer biobanking to enable research towards the discovery and development of new interventions against cancer. This involved two key roles: promotion of cancer biobanking, and serving as an active national cancer biobank resource.

Following a decision made earlier this year, onCore UK will no longer undertake the latter role. In a public statement explaining the decision, onCore UK says that ‘a standardised national approach has been difficult to achieve’ for biosample collection and that ‘the needs for biobanking can be effectively fulfilled by local biobank activity’. Instead, the organisation will focus solely on the promotion of cancer biobanking in the research and health service communities, subject to Charity Commission approval since onCore is a charitable body.

OnCore is funded by the Department of Health (England), the Medical Research Council and Cancer Research UK. It is not clear to what extent this strategic decision to cease biobanking may have been influenced by a harsher economic climate; the statement that biobanking needs can be effectively met by local biobanks seems somewhat at odds with the founding principles, which set out to provide high-quality cancer tissue samples to support large-scale research studies on the basis that individual biobanks and collections did not allow this. 

Now, onCore must dispose of the tissue samples currently held in the biobank facility and is seeking to distribute them to ensure that they can benefit medical research. It is advertising the availability of a collection of 300,000 human tissue samples from various parts of the body and including all major diseases, as well as healthy tissue samples, collected over much of the twentieth century up to 1978. Applications are invited from bona fide researchers for ethically approved research purposes (see website for details). Fees will be charged ‘to allow onCore UK to recover some of the costs of storing the collection’.

3 December 2009The Icelandic company deCODE filed for bankruptcy last week, causing concern over the future of the samples and data it holds. The deCODE database is a highly valued resource amongst researchers, since it is unique in the extent of its coverage of a highly genetically homogenous population; the resource is thought to include the anonymised DNA samples and linked medical records of around 140,000 of Iceland’s total population of 320,000.

deCODE reportedly plans to sell most of its assets to the US venture capitalists Saga Investments; however, the CEO of deCODE Kari Stefansson has repeatedly pointed out that the data and samples in the database will not be included in the sale. Dr Sefansson has responded to the most prominent articles covering the bankruptcy online, such as those carried by The Times and Nature, using their comment facility directly. In each instance his response emphasizes that:

The database resource is actually controlled and managed by a subsidiary of deCODE - Islensk Erfdagreining (IE) – which is also responsible for carrying out consumer testing under the deCODEme service.

IE will likely be sold as a going concern, which should have no effect on the way that it operates.

IE does not own the samples or data that it possesses; the database operates on the basis that these are owned by the individuals who donated them, and so in Dr Stefansson’s words they “cannot be put in a box and taken somewhere else”.

However, as the bioethics website Genomics Law Report points out in its analysis of the case, whoever the new management of the database is, they will presumably aim to do all they can to maximise profits from the resource, and “within the range of allowable uses... deCODE’s new owner may choose to change or even expand its use of that information”. The precise range of what those uses are could well end up being decided in court.

It is worth asking the question though, even if the worse case scenario were to occur (presumably that access to the database and samples be handed over to others), how much would it actually matter? There appears to be a deep instinctive worry over unknown parties having access to one’s genetic information, but what would, or could, a third party actually do with this information that could cause harm to those who donated it? The information in the deCODE database is anonymised and is in the form of SNP data only, which has no real diagnostic or privacy implications at all. Those who donated samples to deCODE (albeit on a default opt-in basis) did so in the understanding that the company would run studies on the pooled data to identify therapeutic targets and develop drugs and diagnostic products for profit, which they have been unable to do. The important thing for science is that the database remain available for research; the ongoing question for those involved in deCODE and similar enterprises is whether it will be ever be possible to make a profit from commercial DNA databases.

2 December 2009The independent UK government advisory body the Human Genetics Commission (HGC) has released a new report on the controversial National DNA database. Nothing to hide, nothing to fear? calls for the police DNA database, the largest of its kind in the world, to be established in law through new primary legislation that explicitly defines the permitted and prohibited uses of the DNA records. The report also calls for much clearer regulation of the database, including an independent oversight body, strengthening of the National DNA Database Ethics Group, and an independent appeals procedure for people who are not charged with or convicted of any crime to have their DNA removed.

It is proposed that a Royal Commission is also set up ‘to give focus to, and to learn from, the public debate, and to ensure that its outcomes will be taken forward and reflected in future legislation’. Recent public consultation revealed widespread concerns about the National DNA database (see previous news), and the new report itself discusses anecdotal evidence that the police are encouraged to detain members of the public for the primary purpose of taking DNA samples for the database. There are additional concerns relating to unfair discrimination in this respect, with a disproportionate number of young black men having their DNA profiles recorded (see Times article). Interestingly, the report specifically recommends that the police themselves should be required to submit their own DNA samples to the database as a condition of employment.

Other recommendations include collaborative work with European centres to standardise markers (to facilitate cross-border crime investigation) and research to determine the true ‘forensic utility’ of the database – that is, just how effective it actually is in combating crime. HGC Chair Professor Jonathan Montgomery said: "…there has been a steady 'function creep', allowing more and more people’s DNA to be kept, but it is not clear that this is matched by an improvement in securing convictions.  There needs to be a regular review of the positive value we get from the database" (see press release). Another concern voiced in the report is the issue of ‘function creep’ – making gradual new uses of the database without sufficient debate, with the contentious example of behavioural genetics cited – and ‘function leap’, the application of the database for completely new purposes such as biometric identity cards or linkage to electronic health records.

Comment: The HGC report is in some respects ill-timed, coming so soon after a recent Government climb-down from plans to allow continued retention of DNA samples from unconvicted people (see previous news). However, there is still an urgent need to address the current problems with the database and the HGC proposals are sensible, offering clarity for the police whilst addressing public worries about civil liberty, discrimination and wider concerns about how the use of genomic information might expand in the future.

22 December 2009The most common known enzyme defect in humans is glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder. G6PD plays an essential role in protecting cells from oxidative damage, this is particularly important for red blood cells which are at substantial risk due to their role as oxygen carriers. Mutation in this enzyme can lead to anaemia, which is usually as a result of exposure to infections, certain foods or medication. In newborns, symptoms may include neonatal jaundice, caused as a result of the breakdown of red blood cells. G6PD deficiency is particularly prevalent in parts of Africa, the Middle East, and South Asia, which are also regions of the world where malaria is endemic and consanguinity is high. Although it has been suggested that G6PD mutations offer protection against malaria, much like mutations that cause sickle cell disease, a clear link had not been made between these mutations and infection with malaria parasites.

In an article published in Science, Louicharoen et al. investigated if one particular variant of the G6PD gene known as Mahidol, had an effect on survival following infection with two different species of the malaria parasite - plasmodium vivax and plasmodium falciparum [Louicharoen et al. (2009) Science 326:1546-1549]. Through genotyping the region encompassing the G6PD gene of individuals from a particular ethnic group in Thailand – the Karen, the researchers were able to identify alleles that had recently undergone positive selection. The Mahidol allele was shown to have undergone recent strong positive selection in this population, suggesting that possession of this allele was advantageous. They then went on to investigate how possession of this variant influences parasite numbers, by following clinical episodes of malaria in individuals whose G6PD-Mahidol genotype was known. The density and species of parasite they were infected with was monitored over a seven year period. Although possession of the Mahidol variant had no effect on the number of clinical cases of malaria caused by either parasite, it did have an effect on parasite density. The mean P.vivax density was reduced by 30% in females who were heterozygous for the variant and 61% in those who were homozygous in comparison to females who did not posses this particular variant. In males who can only possess one copy of this mutation as it lies on the X-chromosome, parasite density was reduced by 40%. Possession of this genotype did not influence the density of P.falciparum.

The mechanism by which this protection is conferred is not known. The authors postulate that it may be due to the increased sensitivity of P.vivax to oxidative stress. As G6PD deficiency leads to increased oxidative stress in red blood cells, this may in turn have a negative influence on the parasite. As such, individuals who possess this mutation have some protection against malaria.

 

18 December 2009 Earlier this year, researchers from the Genome Centre at Washington University were the first to sequence the genome from a cancer cell (see previous news). They used high-throughput parallel sequencing to identify single nucleotide variants (SNVs – including SNPs and indels) in tumour cells from a patient with acute myeloid leukaemia [Ley TJ  et al. Nature (2008) 456: 66-71]. Two further articles published this week in the journal Nature, describe the employment of a similar technique in order to catalogue all mutations in the genome of two cancers (see press release). Both studies used next generation sequencing technologies to compare DNA from cancer cells with that from healthy tissue in order to identify all variants unique to these particular cancer cells. In addition, they were also able to catalogue these variants as either driver mutations or passenger mutations. Driver mutations are those that are causally implicated in development of the cancer and are typically found in cancer genes. Passenger mutations are caused by a mutagenic environment (e.g. cigarette smoke), but do not influence the development of cancer. However, as they are passed on to daughter cancer cells, studying these mutations can give insights into the development and pathogenesis of the cancer.

Pleasance et al. compared the genome of a small-cell lung cancer cell line with that of a normal lymphoblastoid cell line, both of which had been derived from a 55 year old male with small-cell lung carcinoma (SCLC) [Pleasance et al. (2009) Nature doi10.1038/nature08629]. They identified 22, 910 substitutions, 65 indels, 334 copy number variations and 58 structural variants. Tobacco a major risk factor for lung cancer contains many chemical that act as carcinogens by binding to DNA and chemically modifying it in a characteristic fashion, thereby leaving particular mutation signatures. Mutations caused by carcinogens in tobacco can be identified by looking for these signatures; in this study the majority of the observed mutations had a profile that would be expected if tobacco was the carcinogen. The sequencing of the genome from a cell line derived from a 43 year old male with melanoma also yielded similar findings [Pleasance et al. (2009) Nature doi10.1038/nature08658]. 33, 345 somatic base substitutions, 66 indels and 37 rearrangements were identified. They dominant mutational signature reflected damage caused by ultraviolet light exposure. The researchers were also able to identify areas where DNA repair processes had been attempted.

Comment: Human cancer cells typically exhibit numerous genetic aberrations, ranging from point mutations through to complete chromosome duplications. The systematic identification of these mutations can give insights into the mutational processes that lead to cancer. This endeavour has been helped by developments in sequencing technologies. Although work still needs to be done to identify the causative mutations from all those identified, cataloguing cancer genomes in such a way may ultimately lead to better prevention and treatment.

11 December 2009It has been widely suggested that findings from genome-wide association studies could be combined with population data in order to produce estimates of absolute risk for numerous common complex diseases (see previous news). This information could either be used to stratify populations into risk categories in order to better target preventative interventions such as screening (see previous news), or to estimate an individual’s risk of particular diseases, as is currently offered by numerous direct-to-consumer (DTC) genomics companies (see previous news).

 

Whilst it is generally acknowledged that these risk estimates have a large uncertainty associated with them, the size of that uncertainty is rarely well communicated. This problem has recently been addressed in two different ways. The first offers a quantitative approach to the problem, by attempting to quantify the size of the uncertainty associated with risk prediction using breast cancer as an example [Yang Q. et al. Am J Hum Genet (2009) 85:786-800]. Researchers found more than a 3-fold difference in the risk estimates using just a single SNP (in the FGFR2 gene), and a range of 6-21% for the absolute lifetime risk of breast cancer in women carrying five high-risk SNPs. The major contributor to this uncertainty was differences in the underlying population incidence rates of the disease; smaller contributions are also made by varying genotype frequencies, different estimates of individual effect sizes and alternative assumptions about interaction between genes.

 

A rather different approach to this problem has been taken by one of the latest entrants to the DTC market, Pathway Genomics. Instead of providing customers with figures for their absolute or relative risks, the company communicates risk by using a series of colours depending on the potential significance of the result; for example, green denotes below average risk, beige indicates average risk, and yellow through red signify various levels of above average risk (see review at Bio-IT World). Whilst this may be somewhat disappointing to some consumers, who are now accustomed to receiving quantitative relative and absolute risk estimates from many of the other providers, it has the advantage of explicitly acknowledging the inherent uncertainty of genomic risk estimates, and may also go some way to addressing the problem of frequently changing risk profiles as more associations are found (see previous news).

 

Comment: The large uncertainty associated with these risk estimates will come as no surprise to epidemiologists, who are accurately aware of numerous sources of error and bias in all health statistics. Nonetheless, it is likely that many people could be mislead by providing a single numerical risk estimate, with no indication of confidence in that value. It will therefore be interesting to see whether other risk prediction models (including those offered by other DTC genomics companies) will adopt one of these strategies to better communicate the inherent uncertainty in their predictions.

10 December 2009Despite the fact that the modern epidemic of obesity is caused primarily by social and environmental factors – particularly the increasing availability of calorie-rich foods and decreasing levels of physical activity – weight is a highly heritable but genetically heterogeneous trait. According to the World Health Organisation, there were around 1.6 billion adults and 20 million children under the age of five worldwide who were overweight in 2005, and there are expected to be more than 700 million obese adults by 2015. Given the serious health consequences of being overweight, understanding the underlying genetics that predisposes some people to obesity is important not only for developing targeted treatments and preventative strategies, but also for reducing stigmatisation and unfair discrimination.

 

New research has uncovered a rare chromosomal deletion associated with early-onset obesity [Bochukova EG et al. Nature (2009) doi: 10.1038/nature08689]. In order to explore the role of rare copy number variants (CNVs) in obesity, 300 obese Caucasian children (enriched for patients with developmental delay in addition to severe obesity) were compared with over 7,000 population controls using a high resolution DNA microarray. There was a two-fold enrichment of large (>500 kb) rare (<1%) deletions in patients versus controls; in particular, an overlapping deletion in chromosome 16 (at the 16p11.2 locus) was the most common recurrent deletion, occurring in five unrelated patients and a further four cases identified in previous studies (as well as two controls with unknown weight) . These patients were found to have gained weight very rapidly in the first years of life, have elevated plasma insulin levels, and exhibit excessive hunger and high food intake. The deleted region contains numerous genes, including SH2B1, which was already implicated in obesity and encodes a protein involved in energy regulation and glucose metabolism. The authors conclude that “strategies aimed at looking for rare variants near common susceptibility loci may well prove to be fruitful in other common complex diseases”.

 

This discovery has already had a major impact on the lives of the children in this study, several of whom were considered to be at risk of abuse and had attracted the attention of social services because they were so severely obese. Since finding that the children carry this rare 16p11.2 deletion, two cases have already been removed from the protection register and scientists are optimistic about the remaining cases (see The Times).

7 December 2009 In 2006, the Human Genome Epidemiology Network (HuGENet) envisioned the development of ‘field synopses’ whereby succinct summaries of the evidence from genetic epidemiology in a particular field were produced by large consortia and published in peer-reviewed journals [Ioannidis et al. (2006) Nat Genet 38(1):3-5]. A second meeting in 2008 further defined a field synopsis as “a regularly updated snapshot of the current state of knowledge about genetic associations in a particular field of research defined by a disease, phenotype, or family of genes”. Ideally, field synopses [Khoury et al. (2009) Am J Epidemiol 170:269-279]:

1) are freely available to all;

2) incorporate the use of online databases curated by researchers linking genetic variants with the evidence of association;

3) use objective and transparent criteria for grading the credibility of the cumulative evidence;

4) summarise the information from the peer-reviewed literature; and

5) update the information on a regular basis.

The first field synopsis published – and source of the AlzGene Alzheimer’s disease genetic association database – was developed by Bertram et al. and is an excellent example [Bertram et al. (2007) Nat Genet 39(1)17-23].

 
A new field synopsis by Holmes et al. in the Journal PLoS ONE reviews the field of pharmacogenetics to quantify the scope and quality of available evidence to inform future research [Holmes et al. (2009) PLoS ONE 4(12):e7960.doi:10.1371/journal.pone.0007960]. The authors searched the Medline database for pharmacogenetic studies published before 2008, defining them as studies “in which the response (intended outcome/adverse reaction) to drug therapy was examined in relation to genetic variation (germline/somatic) in humans”. Having initially identified over 100,000 articles with their search (the large majority being reviews and commentaries), a total of 1,668 fulfilled all the inclusion criteria. The authors then extracted data from the full text of a randomly selected 10% (161) of these articles, with data being extracted from just the abstracts of the remaining articles.

 
Most articles reported results from prospective studies based in Europe or North America and largely focused on common diseases such as cancer and cardiovascular disease, as well as neurological and psychiatric disorders. Over 500 genes were investigated with 10 of these genes included in studies with over 10,000 participants. Thirty-one meta-analyses of 29 genes were identified, and a further 107 genes were identified as being the subject of at least four studies but lacking a meta-analysis. Despite some well conducted, high-quality research, small sample size was generally a problem showing little evidence of increase over time. Other problems with the literature included the use of surrogate (as opposed to more clinically relevant) outcomes, subgroup analyses with multiple hypothesis testing (possibly leading to lack of reporting for those hypotheses not reaching statistical significance), and highlighted a lack of research in other areas and populations. In almost 75% of cases, the reviewed studies provide nominally significant results (suggesting not all findings are real), although the authors do not focus on any actual meta-analysis results.

 
Comment: This field synopsis highlights a problem of large numbers of opinion-based articles such as reviews and commentaries over actual primary research studies. This has possibly contributed to the high expectation for the delivery of personalised medicine with little actual ‘delivery’ so far. The authors highlight current parallels with the problems faced by the field of common disease genetics a decade ago. At that time, large efforts were made to collate the evidence in a systematic and comprehensive manner, undertake large collaborative projects of primary research as well as conducting large meta-analyses, encourage greater transparency in reporting including publishing null findings, and place a greater importance on independent replication. Recent improvements in technology have also undoubtedly advanced research with genome-wide association studies producing more robust data. In addition to implementing these improvements in future pharmacogenetic study design, online databases like AlzGene provide continuously updated evidence snapshots to be available allowing researchers to focus on the knowledge gaps that emerge. By utilising all these advances and improvements in the gene-disease association field, researchers can develop the field of pharmacogenetics and help it to realise the goal of personalised medicine, although if ten years behind common complex disease genetics, there is still some way to go.

1 December 2009A practical guide to interpretation and clinical application of personal genomic screening.
Edelman E, Eng C. BMJ. 2009 Oct 29;339:b4253. doi: 10.1136/bmj.b4253.

Genome-wide association studies and human disease: from trickle to flood.
Visscher PM, Montgomery GW. JAMA. 2009 Nov 11;302(18):2028-9.

Human genetics illuminates the paths to metabolic disease.
O'Rahilly S. Nature. 2009 Nov 19;462(7271):307-314.

Next generation disparities in human genomics: concerns and remedies.
Need AC, Goldstein DB. Trends Genet. 2009 Nov;25(11):489-94.

Genetic discrimination: problem or paradox?
http://www.genomicslawreport.com/index.php/2009/11/09/genetic-discrimination-problem-or-paradox/

DNA sequencing. No genome left behind.
Pennisi E. Science. 2009 Nov 6;326(5954):794-5. 

Common disorders are quantitative traits.
Plomin R, Haworth CM, Davis OS. Nat Rev Genet. 2009 Dec;10(12):872-8

Epigenomics: Methylation matters.
Schübeler D. Nature. 2009 Nov 19;462(7271):296-297.

Evidence for a common pathway linking neurodegenerative diseases.
Shulman JM, De Jager PL. Nat Genet. 2009 Dec;41(12):1261-2.

Induced pluripotent stem cells and reprogramming: seeing the science through the hype.
Belmonte JC, Ellis J, Hochedlinger K, Yamanaka S. Nat Rev Genet. 2009 Dec;10(12):878-83. 

Synthetic biology: understanding biological design from synthetic circuits.
Mukherji S, van Oudenaarden A. Nat Rev Genet. 2009 Dec;10(12):859-71. Epub 2009 Nov 10.

The applications of pharmacogenetics to prescribing: what is currently practicable?
Pirmohamed M. Clin Med. 2009 Oct;9(5):493-5.

MicroRNAs and cancer epigenetics: a macrorevolution.
Davalos V, Esteller M. Curr Opin Oncol. 2009 Nov 10.

Putting leprosy on the map.
Maiden MC. Nat Genet. 2009 Dec;41(12):1264-6.

Sceptical optimism: a new take on global health data.
Birnbaum J et al. Lancet. 2009 Nov 21;374(9703):1730-1.

Access denied?
Nature. 2009 Nov 19;462(7271):252.

Bioengineered human skin from embryonic stem cells.
Schlüter H, Kaur P. Lancet. 2009 Nov 21;374(9703):1725-6.

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