In the news

  • Newsletter Edition
The PHG Foundation monthly newsletter features news and views about genetics and genetics research, from a public health perspective. The newsletter is written by staff of the PHG Foundation.

In the news

News story   |   By Dr Philippa Brice   |   Published 30 June 2011

A new initiative to improve global prevention and care for birth defects, Born Healthy, has been launched by the PHG Foundation.

Birth defects (congenital disorders) affect more than eight million babies each year, primarily in low and middle-income countries. As childhood deaths from infectious diseases fall, the burden of birth defects becomes more apparent, causing more than 3 million deaths annually. Children that survive typically face a lifetime of serious disability, associated with increased poverty and often social stigma too. However, up to 70% of birth defects could be either prevented entirely, or recognised and treated promptly to minimise their effects. Relatively simple and affordable interventions such as improved maternal nutrition and vaccination can have a substantial impact.

 

Recognising this, the PHG Foundation has produced a new health needs assessment toolkit to allow health professionals in lower income countries to evaluate birth defects in their own countries or regions, and plan appropriate services to tackle them according to available resources. A three day international expert meeting at the Royal College of Obstetricians and Gynaecologists in London from 27-29 June 2011 brought together experts in birth defects to review trials of the toolkit in South America and make recommendations for further development and distribution.

 

The meeting also saw the launch of Born Healthy, the new global community for all those who want to see governments around the world acting now to tackle birth defects and give their children the healthiest possible start in life. Organisations and individuals can join to show their support and shape the services offered by the community, as well as accessing the toolkit, which will be freely available to all health professionals and planners.


News story   |   By Rebecca Bazeley   |   Published 28 June 2011

Cystic fibrosis (CF) sufferers have been given fresh hope with a new drug that specifically targets the so-called ‘Celtic gene’ mutation (G551D) that is common in Ireland.

 

International trials led by Irish researchers have shown that the drug VX-770 (see previous news) improves lung function and reduces infections in CF patients. It is the first drug to treat the basic defect caused by the CFTR gene mutation (as opposed to the symptoms), by opening the defective ion channel in lung cells, allowing proper lung clearance of bacteria.

 

Stuart Elborn from Queen's University, Belfast commented: "The development of this drug is significant because it is the first to show that treating the underlying cause of Cystic Fibrosis may have profound effects on the disease, even among people who have been living with it for decades". It is hoped the new drug will be licensed for use in patients by 2012.

Comment: Ireland has the highest proportion of people with cystic fibrosis in the world; 1 in 19 people are carriers for the disease, compared with one in 25 for the UK. The Celtic mutation causes only some cases of CF (which can arise from more than a thousand different mutations in the CFTR gene), but researchers claim the drug could help all those with mutations that prevent function of the CFTR ion channel. Other drugs are in development that are intended to target other types of mutation such as the most common Delta F508, which blocks transport of the CFTR ion channel to the correct position on cell membranes. 


News story   |   By Rebecca Bazeley   |   Published 27 June 2011

High-throughput gene-targeting is being used to speed up completion of a knock-out mouse library that is set to be a major biological resource.

 

Researchers at the Wellcome Trust Sanger Institute are pioneering the work that uses a high-throughput gene-targeting pipeline allowing them to precisely engineer hundreds of genes every month. The Sanger team, in collaboration with colleagues in Germany and the United States, has so far inactivated more than 9,000 genes in mouse embryonic stem cells. It is on track to knock out 7,500 more in the next few years.

 

Each bespoke knockout in the Sanger group's library contains an added 'conditional allele'. This allows scientists to disrupt gene function in a living mouse at any body site and at any point in the animal's development by the addition of enzymes that recognize the inserted allele. By this means, the loss of the gene does not affect the mouse until the point of disruption.

 

Work on the library of cell lines by the International Knockout Mouse Consortium, began in 2006. To date, nearly 17,000 different genes have been knocked out, leaving only around 3,000 more to go.

"This resource will be of enormous benefit, not just to the mouse genetic community but to every scientist, every company looking at mammalian physiology, and of course everyone who wants to design better drugs and better health care" said Steve Brown, director of the Mammalian Genetics Unit at MRC Harwell, UK, adding: "It is one of the most significant biological resources in the past century of science, and I don't think I'm overstating the case here”. 


Report of a story in the news   |   By Dr Philippa Brice   |   Published 18 June 2011

UK researchers have created the first samples of induced pluripotent stem (iPS) cells from a Parkinson’s disease patient, as part of a project to create a bank of nerve cells

Skin cells from patients will be used to create a ‘brain bank’ of specialised brain cells for medical research, allowing study of the progressive deterioration of the diseased nerve cells and testing of potential treatments (see previous news). 

Our view:

Project leader Dr Richard Wade Martins of Oxford University said: "The brain is an inaccessible organ and you can't get bits of people's brain to study very easily. But what we have here is a disease in a dish". 

Keywords : parkinsonsStem Cells

Report of a story in the news   |   By Dr Philippa Brice   |   Published 21 June 2011

Scientists have announced details of a new international project to sequence the genomes of 5,000 insects and arthropods of medical and agricultural importance over the next five years. 

The i5K initiative will mine the genome data to better understand insect biology, and seek new ways of intervening to prevent the transmission of human diseases, or to protect important crops or livestock. Founders are calling on researchers to sign up to report work already underway in this area, to propose important genomes that should be sequenced, and to forge new collaborations. 

Our view:

Many infectious diseases of major public health importance have a lifecycle that involves insect or arthropod vectors. Identifying key genes within such vectors could provide vital clues towards strategies to block transmission of disease agents. Ensuring that food sources are protected could also have a significant impact on health. 


News story   |   By Dr Philippa Brice   |   Published 20 June 2011

March of Dimes, the US based organisation that works to improve the health of babies and combat birth defects, has called for corn masa flour to be fortified with folic acid.

 

Folic acid fortification is one public health strategy to ensure that pregnant women receive sufficient folic acid, and essential vitamin, to prevent neural tube defects (NTDs) such as spina bifida in their unborn children. The practice is already used in the US for selected cereal products such as wheat flour, and there has been a significant drop in the incidence of NTDs since it was introduced in 1998.

Now, the March of Dimes is keen to reduce the rate further, particularly among Mexican Americans, who commonly use corn masa flour for staple foods such as tortillas and tamales. Medical director Alan Fleischman said: “Despite the fact that fortification has given thousands of babies a healthy start in life, it is imperative we address this serious health problem in the Hispanic community”. However, FDA approval will be required for such a measure. 



News story   |   By Dr Anna Pokorska-Bocci   |   Published 14 June 2011

BGI-Shenzhen and the University Medical Centre, Hamburg have released a preliminary genome sequence of the deadly E.coli strain linked to the recent outbreak in Germany.

 

The bacterial genome was sequenced using the latest ion semiconductor sequencing technology, and sequences from related E.coli strains were used as references. Though incomplete, the data has been made available to the scientific community because of its public health importance.

 

The results show that the outbreak strain genome is a mosaic (mix) of genes from a number of known strains, with the serotype 0104. A strain of this serotype was previously involved in an outbreak in US, but the two strains are not genetically identical. Eight antibiotic-resistance genes have been identified in the new strain, but as yet no virulence genes that could explain the unusually severe effects of infection have been revealed so far.

 

Comment: The rapid availability of genetic data on the deadly E.coli strain is an excellent example of direct application of new sequencing technologies to human health. The speedy release and dissemination of the sequencing data, helped by social media such as Twitter, has allowed scientists around the globe to compare genome sequences from different bacterial strains and isolates.

Keywords : DNA Technologies

Report of a story in the news   |   By Dr Philippa Brice   |   Published 13 June 2011

A new resource of epigenetic maps is in development for use by researchers. 

The Reference Epigenome Mapping Consortium, part of the Roadmap Epigenomics Program funded by the US NIH, are creating a ‘community resource’ of genome-wide epigenetic maps from different human cell types.  More than a hundred samples from adult and fetal cells, including stem cells, are being mapped for core epigenetic features including histone modifications, DNA methylation and chromatin accessibility, along with gene expression data connected with these features. 

Our view:

Epigenetic maps already completed of human embryonic stem (HES) cells and induced pluripotent stem (iPS) cells have reportedly shown significant differences, with potential implications for the development of stem cell therapeutics - although other work reported earlier this year that epigenetic and transcriptional profiles had revealed high levels of equivalence between HES and iPS cells (see previous news). 

Keywords : EpigeneticsStem Cells

News story   |   By Dr Philippa Brice   |   Published 8 June 2011

The World Health Organization (WHO) has launched a new project to identify the leading priorities for genomics to address important public health issues in developing countries.

 

These top ten ‘Grand Challenges’ will be the foremost policy and research priorities for ensuring that genomics is harnessed effectively for maximum public health benefit in developing countries. Suggestions are to be identified via consultation with ‘leading international scientific and public health experts’ and the shortlist assessed by a Scientific Board according to criteria relating to likely feasibility and impact for each proposal.

 

The final top ten will be presented to WHO Member States in 2012 to guide countries' research and public health strategies on genomics to improve public health’.

 

Comment: It is a common misconception that genomics has nothing to offer low and middle-income countries with much more limited health resources. In fact, genomics can sometimes offer new and more cost-effective solutions to major health problems, whether via ‘leapfrog’ technologies, or new ways of using existing genomics knowledge in a different environment.

As a leading world centre for public health genomics, the PHG Foundation is delighted to form part of the Scientific Board for this WHO initiative, and looks forward with great interest to moving towards realising genuine genomics-driven solutions to developing world health problems. 


News story   |   By Dr Philippa Brice   |   Published 6 June 2011

A survey of European clinical geneticists has revealed opposition to direct-to-consumer (DTC) genetic testing.

 

Of the 131 respondents to the University of Leuven study, 90% reportedly felt that predictive DTC genetic testing should require direct medical supervision (ie. not really be DTC). Smaller majorities also favoured outright prohibition of DTC prenatal gender testing (69%), DTC genome scans (63%) and preconception disease carrier testing (53%).

 

One key concern is that patients do not understand test results and require subsequent expert explanation; 43% of respondents had discussed the results of DTC tests with consumers who subsequently sought their advice. The other worry relating to predictive testing is that the tests are not clinically useful, and may over-estimate risk.

 

This is supported by the findings of a second study led by Professor Cecile Janssens’ research group in Leiden, the Netherlands, which compared risk predictions for eight common diseases from DTC genetic test providers deCODEme and 23andMe, based on simulated data. The researchers found that reported designations of ‘increased risk’ for people with certain genetic variants were based on relatively slight increases above the general population risk.

 

The researchers feel that the DTC tests give a distorted impression of risk based wholly on genetics. Professor Janssens noted that other environmental risk factors such as diet, exercise and smoking typically have a much greater impact on the risk of complex diseases than genetic factors, saying: "We are all aware of the ethical problems surrounding DTC genetic testing, but this study also confirms that their predictions are inaccurate".

 

Comment: Many of these concerns are about communication - how accurately providers explain risk, how well consumers understand it, and what the clinical implications of DTC genetic test results are, if any. There is certainly a need for improvement in this area, and possibly to reduce the direct impact of commercial testing on health service geneticists - but a ban or tighter regulation of such tests is probably not the right way to achieve this.

 

Is it reasonable to ban consumers from accessing services that they may not be able to obtain via health services, such as preconception screening? As previously commented, what about individual autonomy and choice? Also, it should be noted that whilst clinical geneticists have an expert understanding of these issues, they are also inevitably commenting with a degree of bias.


Report of a story in the news   |   By Dr Philippa Brice   |   Published 3 June 2011

An early-stage clinical trial of gene therapy for Parkinson’s disease (PD) has reported promising results at the American Society of Gene and Cell Therapy (ASGCT) conference. 

Oxford BioMedica’s ProSavin, which is injected directly to the brain, delivers genes that direct production of the neurotransmitter dopamine; PD is caused by the progressive loss of dopamine-producing cells in the brain, resulting in impaired control of movements. The therapeutic produced an average reduction of 43% in symptoms of shaking and stiffness for the nine patients in the trial, with no serious side-effects reported. 

Our view:

Gene therapies no longer excite media interest in the way they once did; there was perhaps a general disappointment that effective delivery and sustained expression of therapeutic genes proved to be a lot more difficult than originally envisaged. However, applications for a range of relatively common conditions such as PD and forms of cancer, as well as rare genetic disorders, are steadily progressing towards clinical application. It isn’t a quick fix, but for serious conditions gene therapy may offer real hope. 

Keywords : parkinsonsGene Therapy

Research articles

Analysis of a study published in a science journal   |   By Dr Sowmiya Moorthie   |   Published 23 June 2011
Study: Effectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis
By: et al. (4 authors total)
In: The Lancet Infectious Diseases
Link: http://dx.doi.org/doi:10.1016/S1473-3099(11)70104-9
What this study set out to do:

Systematically review the literature to identify what components of an antenatal syphilis screening programme work effectively.

How they went about it:

Electronic databases were searched to identify studies between 1974 and 2009 that reported on effectiveness of syphilis screening and on the effectiveness of antenatal interventions in relation to three outcomes: increased uptake of syphilis screening, increased treatment rates and reduction in adverse pregnancy. Data on study design and population, components of the intervention and control groups, outcomes and the risk of bias were extracted from included studies.

Outcome:

In all, ten articles (out of 787) were included in the final. Taken together these studies looked at 41,049 women and the outcomes of interventions such as introducing point of care testing and same day treatments. Although the effects of such interventions varied between the studies, the trend was towards an increased uptake of screening and decrease in adverse outcomes such as perinatal deaths, stillbirth and congenital syphilis.

Conclusion:

Adverse effects of maternal syphilis such as perinatal deaths and stillbirths can be reduced by 50% through interventions to improve the coverage and effectiveness of antenatal screening programmes. Investing in such screening programmes would have beneficial effects for maternal and neonatal health.

Our view:

Syphilis is the cause of many stillbirths, newborn deaths and birth defects in low and middle-income countries; this systematic review demonstrates how simple and effective interventions can lead to significant improvements in maternal and child health. As mentioned in the accompanying commentary, although proven cost-effective measures for prevention are available, the lack of recognition of the problem is a major barrier to solving this issue.  This is the case for many birth defects; the PHG Foundation will next week launch a new tool to help these countries develop simple, cost-effective health services (see Born Healthy).


Analysis of a study published in a science journal   |   By Dr Sowmiya Moorthie   |   Published 21 June 2011
Study: Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumours
By: et al. (15 authors total)
In: Nature Medicine
Link: http://dx.doi.org/doi:10.1038/nm.2390
What this study set out to do:

See if genetically engineered viral vectors containing normal human cDNA can be used to express a broad range of antigens and elicit an immune response against tumour cells. 

How they went about it:

A viral vector containing cDNA from normal human prostate tissue was engineered so that it expressed altered self antigens. This viral vector was then injected into the blood or prostate tissue of mice to investigate the immune response. It was also injected into mice with established prostate tumours to see if the immune response would affect the tumours.

Outcome:

Injection of the viral vector into mice resulted in the expression of tissue specific (prostate) antigens and an immune response against them. Intravenous injection was preferable as injection to the prostate caused swelling. Injection into mice with established tumours led to initial tumour regression (shrinking) with subsequent aggressive recurrence. However, sequential vaccination with vectors expressing different sets of cDNA prevented tumour recurrence.

Conclusion:

This approach presents a novel paradigm for cancer therapy by demonstrating a method of presenting a diverse array of undefined tumour antigens to the immune system that reduces the emergence of treatment resistant tumours. The additional advantage of this technique is that the vectors do not have to be delivered in a tumour targeted fashion and can be produced easily for clinical use.

Our view:

Development of vaccines against cancer is hampered by the ability of tumour cells to mutate and evade the body’s immune system. The approach described here allows a more complete picture of the tumour to be presented to the immune system and overcomes the problems of having to isolate and identify tumour specific antigens.  The fact that this approach can lead to tumour regression without the need for additional therapy is very promising and has implications for the treatment of a wide range of cancers. However, the availability of a vaccine is still some years away due to the need for further research to ensure its effectiveness and safety for use in humans. 


Analysis of a study published in a science journal   |   By Dr Philippa Brice   |   Published 18 June 2011
Study: Converting nonsense codons into sense codons by targeted pseudouridylation
By:
In: nature
Link: http://dx.doi.org/doi:10.1038/nature10165
What this study set out to do:

To investigate whether pseudouridylation (conversion of uridine into pseudouridine, a chemical isomer with different properties) in mRNA suppresses nonsense codons. Nonsense mutations disrupt gene coding sequences by producing a ‘stop’ or termination signal in the wrong place, resulting in a truncated protein with little or no function. They are associated with a range of serious genetic diseases, including cystic fibrosis, Duchenne muscular dystrophy, beta thalassaemia and haemophilia. 

How they went about it:

The researchers made short artificial RNAs finishing with either a nonsense codon (UAA), a pseudouridylated nonsense codon (YAA) or a cytidine codon (CAA), to see what effect they had in vitro. They then used specific guide RNAs to induce pseudouridylation at a specific point in a reporter gene to look at the effect in vivo

Outcome:

Protein production from RNAs in vitro was essentially absent with the nonsense codon, but restored with the pseudouridylated nonsense codon to almost the same levels as for the normal cytidine codon. The in vivo assays showed low levels of pseudouridylation at the site of interest, and modest levels of suppression of the nonsense codon. The researchers also investigated which amino acids were specified by which pseudouridylated nonsense codons. 

Conclusion:

Artificial guide RNAs can direct the pseudouridylation of mRNA nonsense codons at specific sites leading to nonsense suppression, with potential implications for the treatment of genetic diseases. More broadly, pseudouridylation of mRNA at many more sites (including normal codons) may change their decoding and represent a novel, naturally occurring form of RNA editing, effectively expanding the genetic code. 

Our view:

This paper may herald the opening of another new chapter in the unfolding story of complexity that is the human genome. It was originally thought that deciphering the genetic coding sequences of the genome would reveal the ‘blueprint of life’, but new revelations about the role of different forms of RNA editing and of epigenetic coding have shown the marvellous but often baffling intricacy by which cells can apparently vary their genetic repertoire. This latest discovery is certainly an area for further exploration. 


Analysis of a study published in a science journal   |   By Dr Sowmiya Moorthie   |   Published 16 June 2011
Study: BRAF Mutations in Hairy-Cell Leukemia
By: et al. (36 authors total)
In: New England Journal of Medicine
Link: http://dx.doi.org/10.1056/NEJMoa1014209
What this study set out to do:

To identify somatic mutations within protein coding genes that are present in most people with hairy cell leukemia (HCL) in order to understand the biology of the disease.

How they went about it:

DNA was extracted from normal and tumour cells of a patient with HCL and the exome sequenced using massively parallel sequencing. Comparison with the human genome reference sequence and bioinformatic analysis were used to identify somatic mutations present only in the tumour cells. PCR and Sanger sequencing verified these candidate mutations. Individuals with HCL as well as other blood cancers such as B-cell lymphomas or leukemias were screened for the presence of one particular variant – BRAF V600E. The effect of BRAF inhibitors on downstream cell signalling was also investigated.

Outcome:

Five variants present in the tumour DNA were identified and verified by Sanger sequencing. The BRAF V600E mutation was present in all individuals with HCL but not other blood cancers. A mutation in the BRAF gene results in constitutive activation of downstream signalling proteins MEK and ERK, which was reduced by a specific inhibitor of BRAF.

Conclusion:

The authors conclude that analysis of BRAF mutations maybe used to diagnose HCL by distinguishing it from other blood cancers with the same symptoms, and these mutations could be a target for therapies. This would be especially useful for those individuals who do not respond to current therapies. 

Our view:

The findings reported in this paper have implications for the diagnosis and treatment of HCL as well as providing an insight into the disease. However, the authors need to validate their findings in a larger population. This study also demonstrates how new sequencing technologies can be used in improving our understanding of cancer.


Analysis of a study published in a science journal   |   By Dr Philippa Brice   |   Published 15 June 2011
Study: Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders Neuron
By: et al. (17 authors total)
In: Neuron
Link: http://www.ncbi.nlm.nih.gov/pubmed/21658582
What this study set out to do:

Examine the genetic contribution to autistic spectrum disorders (ASDs) by looking at genomic copy-number variants (CNVs) in families. 

How they went about it:

Around 1000 families with a single affected child and at least one unaffected sibling were recruited, and DNA analysed using array-based comparative genomic hybridization (CGH) to search for de novo CNVs , (present in one or more children, but not parents). This genome-wide study was able to detect smaller CNVs than a similar earlier study (see previous news). 

Outcome:

New CNVs were identified in 7.9% of children with ASD, compared with 2% of unaffected siblings. Affected females showed a higher frequency of new mutations (11.7%) than affected males (7.4%), as well as much higher numbers (a median of 15.5 new mutations compared with just 2.0 in males). Most new CNVs were unique, but recurring CNVs were identified at positions on chromosomes 7, 15 and 16. 

Conclusion:

New CNVs contribute to the development of ASDs, but girls are more resistant to disease than boys, possibly because faster early female brain development has a protective effect.  A second paper [Sanders SJ et al. (2011) Neuron 70(5):863-85] uses alternative arrayCGH platforms to analyse a larger group including the same families, with broadly consistent findings. A third paper [Gilman SR et al. (2011) Neuron 70(5):898-907] explores a network of 70 genes thought to be involved in ASD (around 40% perturbed by the mutations observed in this study), and concludes that it is a disease of abnormal synaptic and neuronal connectivity, as previously suggested 

Our view:

This trio of papers provide a fascinating insight into the complex genetics underlying ASDs. Although the genetic theory of the basis of autism presented may not be wholly correct, the potential mechanism for the observed lower frequency of disease in girls is an attractive one. The authors also correctly note that the underlying genetic diversity of ASD may mean that potential treatments could be effective only in very specific sub-groups of patients, and call for exome sequencing of at least 3000 families ‘to identify conclusively the genetic causes of ASDs’. 


Analysis of a study published in a science journal   |   By Dr Sowmiya Moorthie   |   Published 9 June 2011
Study: Parents' Decisions to Screen Newborns for FMR1 Gene Expansions in a Pilot Research Project
By: et al. (8 authors total)
In: Pediatrics
Link: http://dx.doi.org/10.1542/peds.2010-3078
What this study set out to do:

Offer newborn screening for Fragile X Syndrome (FXS) to investigate public willingness to accept screening for conditions that are currently untreatable and would identify newborns as carriers and/or at risk for late-onset conditions. This study provides empirical data on rates of parental consent and their reasons for accepting or declining screening.

How they went about it:

A total of 2137 mothers and their partners were offered screening, including detailed information about the test, follow-up tests and the risks and benefits of screening. A survey form was used to collect basic demographic data and an open-ended question was used to obtain their reasons for accepting or declining screening.

Outcome:

Screening was taken up by 63% of couples, and the decision to accept screening appeared to be influenced by ethnicity and level of education. The primary reason given for accepting was “to know”; other reasons included aiding research and the fact that the testing was non-invasive. A number of reasons were given for declining including not wanting to know and negative feelings about genetic tests, No one reason for declining was predominant.

Conclusion:

Parents made decisions following considerations of many of the risks and benefits of participation. However, analysis of some of the reasons given by parents indicated that the personal, familial and social consequences of Fragile X syndrome may not have been fully understood by all. Further research will examine their reasoning in more detail, as well as assess how parents and children are affected by knowledge obtained from screening. In general there was parental support for newborn screening for FXS as long as informed consent was obtained, but more research is needed on the informed consent process and how best to instigate it.

Our view:

Newborn screening for Fragile X syndrome is a controversial issue (see previous news) and raises several ethical, legal and social issues (see previous news). Both this article and an accompanying commentary highlight the complex and subtle nature of the risks and benefits associated with screening for certain rare genetic conditions in the newborn period, and difficulties in evaluating them using current screening criteria. In addition, ensuring that parents understand and are able to make an informed choice about screening for such conditions also presents difficulties. As technologies that enable expansion of newborn screening panels develop, concomitant development of appropriate methods of evaluating and delivering screening services is becoming increasingly important.


Analysis of a study published in a science journal   |   By Dr Gurdeep Sagoo   |   Published 7 June 2011
Study: Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses.
By:
In: The Journal of the American Medical Association
Link: http://dx.doi.org/10.1001/jama.2011.713
What this study set out to do:

The study authors looked at whether the association effect size of biomarkers (ie. how strongly they are linked to a given disease or physiological state) identified in highly cited studies are accurate or overestimated.

How they went about it:

The researchers searched 24 highly cited biomedical journals for biomarker studies with over 400 citations and a subsequently published meta-analysis on the same association (for the same biomarker and outcome, published in any journal). 

Outcome:

35 highly cited biomarker associations were identified. The majority of these associations were stronger than subsequently published meta-analyses (n = 29, 83%) or single largest studies (n = 30, 86%). Three of the highly cited studies remained the largest study published and two studies actually had smaller effect sizes than the subsequently published largest study. For five associations, the highly cited study estimated the effect size in the opposite direction to that of the largest study. 

Conclusion:

Results in highly cited biomarker studies are often significantly overestimated compared with subsequently reported very large studies and meta-analyses, which are less prone to chance. Some of these biomarkers have no predictive value whereas other may be true but have small or modest effects and limited translation value in clinical use. 

Our view:

Both the authors and an editorial published in JAMA highlight several reasons for these findings, including initial studies being smaller and hence more susceptible to chance, several studies using more extreme cases compared to healthy controls in order to exaggerate findings, and publication bias. Worryingly, the highly cited study typically continues to attract strong citations despite the availability of subsequently published meta-analyses with different and more precise estimates. This review highlights the need for evidence based medicine to apply the best available evidence in clinical decision making.


New reviews and commentaries

Selected new reviews and commentaries, 1 June 2011

Reviews & commentaries : by Dr Philippa Brice

Special BMJ interview with PHG Foundation Chairman Dr Ron Zimmern:

Leapfrogging into the future.

Parry J. BMJ 2011; 342:d2990

 

Getting personal.

Nature. 2011 May 19;473(7347):253-4. 

 

Deploying whole genome sequencing in clinical practice and public health

Berg JS, Khoury MJ, Evans JP. Genet Med. 2011 May 9.

 

Synthetic genomes: The next step for the synthetic genome.

Baker M. Nature. 2011 May 19;473(7347):403, 405-8

 

Genomic Medicine: Genomics and the Eye

Sheffield VC, Stone EM. N Engl J Med. 2011 May 19;364(20):1932-42

 

Down syndrome: Coercion and eugenics.

McCabe LL, McCabe ER. Genet Med. 2011 May 6. 

 

Indigenous genomics.

Hayes V. Science. 2011 May 6;332(6030):639. 

 

Conducting the metabolic syndrome orchestra.

Civelek M, Lusis AJ. Nat Genet. 2011 Jun;43(6):506-8.

 

New modifier loci in cystic fibrosis.

Witt H. Nat Genet. 2011 Jun;43(6):508-9.

 

Stem cells: The growing pains of pluripotency.

Hayden EC. Nature. 2011 May 19;473(7347):272-4.

 

Science as a public enterprise: the case for open data

Boulton G et al. Lancet. 2011 May 14;377(9778):1633-5.

 

Making raw data more widely available.

Vickers AJ. BMJ. 2011 May 4;342:d2323.

 

Clinical research: time for sensible global guidelines.

Lang T, Cheah PY, White NJ. Lancet. 2011 May 7;377(9777):1553-5.

 

Lancet UK Policy Matters: better evidence for better health.

Aldridge RW et al. Lancet. 2011 May 14;377(9778):1631-3. 

 

Value judgements.

Nature. 2011 May 12;473(7346):123-4.

 

WHO needs change.

Bloom BR. Nature. 2011 May 12;473(7346):143-5. 

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