World Hepatitis Day: Prospects for the Future – Guest blog by Paul Klenerman and colleagues

“World Hepatitis Day…does not usually make the headlines in the same way that World AIDS day does, but viral hepatitis affects about half a billion people globally (perhaps 1 in 12 of the global population) and so the relative publicity associated with World Hepatitis Day does not accurately reflect the importance of hepatitis as a public-health problem.”

In this World Hepatitis Day blog ahead of the formal publication of their Perspective article in PLoS Medicine, Paul Klenerman, Vicki Fleming and Ellie Barnes of the University of Oxford describe research by Christian Drosten and colleagues about a new low-cost diagnostic test for Hepatitis C for use in developing countries. The research was recently published in PLoS Medicine.

The Perspective article by Paul Klenerman and colleagues will be formally published in PLoS Medicine on 16th June 2009.

What Are the Prospects for Controlling Hepatitis C?

Paul Klenerman*, Vicki Fleming, Ellie Barnes

May 19 this year marked World Hepatitis Day [1].This event does not usually make the headlines in the same way that World AIDS Day does, but viral hepatitis affects about half a billion people globally (perhaps one in 12 of the global population), and so the relative publicity associated with World Hepatitis Day does not accurately reflect the importance of hepatitis as a public health problem.

The two major hepatitis viruses—hepatitis C virus (HCV) and hepatitis B virus (HBV)—share a number of features. Both viruses are readily spread through the transfer of infected blood or blood products. Both cause persistent infections and share an insidious progression after decades of asymptomatic carriage that creates a huge burden of end-stage liver disease and liver cancer. Thus, both viruses are major public health problems across the globe. However, there are substantial differences between these infections in terms of the risk groups affected, the geographical distribution of the viruses, and the tools at our disposal to deal with them.

Prospects for Controlling HBV and HCV

For HBV we have a well-established vaccine and an emerging panel of well-tolerated oral agents for the treatment of chronic infection. Although there is still a massive burden of complex and severe infection to tackle, the pathway towards effective combination therapy has already been trodden in HIV, and careful clinical trials in this area for HBV should bring some clarity. Delivery of such drug combinations in resource-poor settings where the prevalence of carriage is high will create its own significant challenges.

For HCV we have no current vaccine, and current therapies are toxic, complex, and expensive, as well as only partially effective. Treatment is further complicated by HIV coinfection, which is increasingly encountered in some risk groups [2]. So why is the prevention and treatment of HCV infections apparently so far behind that of HBV infections? One reason is that HCV was only identified in 1989, and only successfully cultured in 2005 [3,4]. However, the major biological hurdle to controlling HCV is the hTuge diversity of the virus, both within patients and among populations [5].

HCV is an RNA-based virus with a variable genome and the capacity to evolve over time to evade drug and immunologic pressure. HCV has coevolved with human populations for centuries, if not millennia [6], and has diversified widely over this period (Figure 1). By comparison, the phylogenetic tree of HIV is much more compact because this virus has had less than a century in which to diversify in humans.

The net result of this diversification is the existence of seven major genotypes of HCV (the last added very recently) that share less than 80% sequence homology with one another, and more than 50 HCV subtypes [7]. Although these genotypes may have arisen over long periods as endemic strains in geographically distinct regions (e.g., genotype 6 in southeast Asia [8]), most have now spread globally. Genotype 1 is particularly common in western Europe and the United States, although genotype 3 is also now very common in the United Kingdom as a result of its spread through intravenous drug–using populations and through immigration from the Indian subcontinent.

Multiple genotypes occur in many other viruses, including HBV, but their importance in HCV is particularly high because both the duration and success rate of current treatments for HCV infection (pegylated interferon-alpha and ribavirin) are highly genotype dependent. Thus, genotypes 2 and 3 are typically associated with much greater response rates than genotypes 1 and 4 (70%–80% long-term clearance versus 40%–50%) and require shorter treatment periods (six months versus one year) [9]. The biological basis for these differences is unclear—the genomes of these genotypes are so diverse that such differences could result from multiple complex changes. Even within a single genotype (e.g., genotype 1), the fundamental mechanisms behind relative resistance to treatment of different HCV subtypes are not fully defined, although an interferon-sensitivity determining region has been described [10].

The Role of Nucleic Acid Tests for HCV

Given these important clinical and virologic differences between HCV genotypes, robust and sensitive nucleic acid tests for HCV have a major role to play in virus detection and in guiding treatment and thus are at the core of current clinical practice in developed countries. However, these tests are relatively complex molecular tests and are therefore not universally available. Additionally, they may not be equally sensitive at detection of all genotypes. In a recent article in PLoS Medicine, however, Christian Drosten and colleagues described a new approach to nucleic acid testing in HCV [11].

The authors generated a test based on a highly conserved region in the 3? end of the virus (most current tests are based on the 5? end) and validated their assay to show that it was sensitive in detection of a wide range of genotypes from geographically diverse populations. They also attempted to reduce the overall cost of their approach and have thus provided a novel system that uses an open (i.e., nonproprietary) protocol that might be particularly appropriate for resource-poor settings. This new assay is potentially an important step forward for laboratories in such regions and, if rolled out effectively, could provide novel information relevant to the prevalence, clinical impact, and treatment response of HCV genotypes that are currently poorly studied—most clinical analyses, and vaccine and treatment trials have focused on genotype 1.

Although very simple and cost-effective tests to detect, quantify, or genotype HCV in resource-poor areas could be of great value in future, the overall costs and usefulness of any such test in comparison to other methods and in relation to other public health priorities in such regions will need to be considered carefully. Thus, although conventional PCR methods as used by Drosten and colleagues look promising, non-PCR-based methods such as loop-mediated isothermal amplification (LAMP) also need to be considered, since little specialist equipment is required for LAMP and the sensitivity appears to be high [12]. In the end, however, the definitive test for any new method of HCV analysis will be clinical utility in the field.

The Extreme Viral Diversity of HCV

As we mark World Hepatitis Day, the recent paper by Drosten and colleagues once more draws our attention to one of the key features of HCV: its extreme viral diversity, which brings enormous challenges for the future. The capacity for HCV to evolve creates a complex target for both vaccine and drug development. Nevertheless, recent advances in both these areas provide some cautious hope for the future—at least in the case of genotype 1 infection [13,14]. Key to successful vaccine development will be the generation of effective, sustained, and broad anti-HCV immune responses. However, the immune responses to non–genotype 1 viruses are very poorly described, and recent data suggest that there is relatively little overlap between immune responses to genotypes 1 and 3. Thus, at present it is unclear whether HCV vaccines against specific genotypes will provide any cross-protection against other genotypes [15]. The situation with drugs may be even more complex, with pre-existing diversity even within genotype 1 already providing some level of drug resistance [16].

Future studies of the diverse HCV genotypes that exist globally—hopefully facilitated by the recently published methods—will, therefore, help us understand the overall clinical impact of HCV in affected populations and will determine our potential to intervene. Since HCV emerged from the shadows 20 years ago, it has shown itself to be “smarter than the average virus.” Thus, it may take longer than 20 years for us to put it back into the shadows, and it will probably take all our efforts to do so.

References
1. World Hepatitis Alliance (2009) World Hepatitis Day. Available: http://www.worldhepatitisday.org/. Accessed 11 May 2009.
2. Klenerman P, Kim A (2007) HCV–HIV coinfection: Simple messages from a complex disease. PLoS Med 4: e240. doi:10.1371/journal.pmed.0040240
3. Houghton M (2009) Discovery of the hepatitis C virus. Liver Int 29 (Suppl 1): 82- 88.
4. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, et al. (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.
Nat Med 11: 791-796.
5. Simmonds P (2004) Genetic diversity and evolution of hepatitis C virus—15 years on. J Gen Virol 85: 3173-3188.
6. Pybus OG, Charleston MA, Gupta S, Rambaut A, Holmes EC, et al. (2001) The epidemic behavior of the hepatitis C virus. Science 292: 2323-2325.
7. Kuiken C, Simmonds P (2009) Nomenclature and numbering of the hepatitis C virus. Methods Mol Biol 510: 33-53.
8. Pybus OG, Barnes E, Taggart R, Lemey P, Markov PV, et al. (2009) Genetic history of hepatitis C virus in East Asia. J Virol 83: 1071-1082.
9. Zeuzem S, Berg T, Moeller B, Hinrichsen H, Mauss S, et al. (2009) Expert opinion on the treatment of patients with chronic hepatitis C. J Viral Hepat 16: 75-90.
10. Torres-Puente M, Cuevas JM, Jimenez-Hernandez N, Bracho MA, Garcia-Robles I, et al. (2008) Genetic variability in hepatitis C virus and its role in antiviral
treatment response. J Viral Hepat 15: 188-199.
11. Drexler JF, Kupfer B, Petersen N, Grotto RMT, Rodrigues SMC, et al. (2009) A novel diagnostic target in the hepatitis C virus genome. PLoS Med 6: e1000031. doi:10.1371/journal.pmed.1000031
12. Nagamine K, Hase T, Notomi T (2002) Accelerated reaction by loop-mediated isothermal amplification using loop primers. Mol Cell Probes 16: 223-229.
13. Thompson AJ, McHutchison JG (2009) Review article: Investigational agents for chronic hepatitis C. Aliment Pharmacol Ther 29: 689-705.
14. Thimme R, Neumann-Haefelin C, Boettler T, Blum HE (2008) Adaptive immune responses to hepatitis C virus: From viral immunobiology to a vaccine. Biol Chem 389: 457-467.
15. Schulze Zur Wiesch J, Lauer GM, Timm J, Kuntzen T, Neukamm M, et al. (2007) Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non-genotype 1 infection. Blood 110: 1559-1569.
16. Gaudieri S, Rauch A, Pfafferott K, Barnes E, Cheng W, et al. (2009) Hepatitis C virus drug resistance and immune-driven adaptations: Relevance to new antiviral therapy. Hepatology 49: 1069-1082.
17. Bao Y, Bolotov P, Dernovoy D, Kiryutin B, Zaslavsky L, et al. (2008) The influenza virus resource at the National Center for Biotechnology Information. J Virol 82: 596-601.
18. Combet C, Penin F, Geourjon C, Deleage G (2004) HCVDB: Hepatitis C virus sequences database. Appl Bioinformatics 3: 237-240.
19. Division of AIDS, National Institute of Allergy and Infectious Diseases (2009) HIV databases. Available: http://www.hiv.lanl.gov/. Accessed 11 May 2009.

Figure 1 Legend

Complete genome trees of the hepatitis C virus, HIV-1 (M-group), and the hemagglutinin region of influenza A. Nucleotide sequences were randomly selected from their respective databases representing each of the major subtypes from each virus [17–19]. Only non-recombinant genomes were included. Maximum likelihood trees were built using GARLI (Genetic Algorithm for Rapid Likelihood Inference, available at http://www.nescent.org/). Trees have been drawn to the same scale.

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Should Patients be Told of Better Care Elsewhere?

This was a question posed by Denise Grady in an article in the New York Times earlier this month. Her piece outlined the arguments in a PLoS Medicine debate on the ethical responsibilities of doctors towards their patients that was published back in October.

The debate examined the question of whether a surgeon treating patients with cancer whose treatment results are not as good as those at another hospital, has an ethical obligation to tell to his or her patients about the better results at hospitals elsewhere. And although the debate did not attract a lot of attention in the wider media when it was published, it has recently fuelled considerable and thoughtful comment on the New York Times site and on blogs.

Recounting the experience of a relative who had rectal cancer and who chose to travel to receive better treatment despite trusting her local hospital, Denise Grady moves on to discuss each point of view in the debate.

Leonidas Koniaris and Nadine Housri – at the University of Miami – argue that physicians do have a responsibility to inform patients of these disparities in treatment results. In major cancer surgery in particular, they say, the experience of the medical team is especially important and can lead to very different outcomes. Koniaris – a specialist in cancers of the gastrointestinal tract and sarcomas – stated that he has informed his patients about other doctors who have better results than him at treating pancreatic cancer and liver tumors.

The New York Times article also summarizes the argument taken by David Shalowitz in the debate. Shalowitz, a bioethicist, says that this obligation to disclose information about other medical centers would lead to untenable conflicts of interest. And further complications to the apparently simple question are drawn out by Robert Weil, a neurosurgeon, who discusses the logistical hurdles when it comes to comparing hospitals.

Does the burden of disclosing data fall on the hospital or on the doctor? How can a local community hospital be compared with a big teaching hospital and is it fair to compare across states, populations or even nations, Weil asks. (Seizing this last point, a physician writing in response to the New York Times article felt obliged to tell American readers that they could “receive better care in Canada, Norway, Great Britain, France and most other industrialized countries… [that] do not allow health insurance executives to make your health care decisions for you in order to increase their profits.”)

Many of the 111 comments in response to the New York Times article were vehemently of the view that doctors have a responsibility to inform patients of better care elsewhere. But other interesting discussion points were raised, including whether, in the age of the internet, patients have a duty to better inform themselves about their their own health problems and who is best to serve them.

Sharing the new interest in the debate – which, according to Google Analytics, was downloaded twice as many times in the week following the New York Times article than it had been for the preceding three months put together – were the blogs Pure Pedantry and Target Health.

Pure Pedantry, a blog by a PhD/MD student at the Mount Sinai School of Medicine, suggested that multiple sclerosis may be another example aside from cancer where the experience of a team treating the disease was crucial and therefore the right to inform patients of the success of other hospitals is particularly important.

“This sort of informed consent does not need to be adversarial; it is just admitting your strengths and weaknesses”, the blog argues.

This echoes the outlook of Marcel Horowitz, a physician who submitted a reader response to the PLoS Medicine debate. He suggests that the “personal maturity and personal ethics” that come with the ability to inform patients about your limitations as a physician should form part of medical training.

What do you think? Contribute your thoughts on the debate.

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Blogging on bias

Publication bias became a big blogging topic last week as a PLoS Medicine paper was picked up by several influential sites. Lisa Bero and colleagues found that a quarter of trials submitted to the Food and Drug Administration between 2001 and 2002 in support of new drugs applications remain unpublished a year after the fact. The study also found that among the published results, unexplained discrepancies between the FDA submission and the published studies tended to lead to more favourable presentations of the drugs.

For the past two weeks it has been the most viewed paper on the PLoS Medicine website and discussion of the paper has passed from blog to blog, including:

- Wired (“Drug Companies Cook Books, Misleading Doctors”).

The Wired science blog, which has resulted in fifteen comments so far, highlights the discrepancy found in the study between results submitted to the FDA and those published in medical journals, and the key pieces of trial data that vanished in the published results. “The main thing that jumped out at me was the addition and deletion of primary outcomes. Those are the most important outcomes of a trial. To find that one disappeared from a paper, or just appeared in a paper, is pretty amazing to me,” Lisa Bero is quoted in the piece.

- Economist (“Absence of Evidence”).

There are twelve comments in response to the Economist’s question: “Do drug firms suppress unfavourable information about new products?” The print and online versions of the Economist also make reference to the perspective by An-Wen Chan that we published alongside the study, which argues that all key trials documents should be made public. “It has taken decades for trial registration and results disclosure to be implemented; hopefully, for the sake of patients, public access to full protocols and regulatory agency submissions will come much sooner”, says Chan in the perspective.

How else to fix the discrepancy between the trials submitted to the FDA and the published results? One of the more cynical comments about the research in response to the Wired blog ( “Hmmmm, big corps, unethical, self serving… TELL ME SOMETHING I DON’T ALREADY KNOW! Better yet, give me some suggestions regarding what I can do about it” ) is answered in Smooth Pebbles, a blog by David Dobbs, a freelance science writer for the New York Times amongst others. He quotes Lisa Bero’s argument that the FDA should be overhauled and run clinical studies itself, as happens with the equivalent agency in Italy:

“The Italian FDA collects money from every drug company that sells drugs in Italy, pools that, and funds drug trials. They fund the sort of head-to-head drug comparisons that companies don’t like to fund. And they have independent people peer-reviewing the trials. It’s a great model,” [Lisa Bero] said.”

A comment in response to Pure Pedantry, a blog by a PhD/MD student at Mount Sinai School of Medicine, also called for new ethical rules for the publication of drug company results.

Some of the other work that Lisa Bero and her colleagues have done to raise awareness about faulty reporting of clinical trials and conflicts of interest can be found in the Loxosceles science blog, which summarizes her talk at the ScienceWriters2008 meeting. This makes reference to a meta-analysis that shows that peer-review is not necessarily a guarantee against bias – a drug company funded study is four times more likely to turn up a result favorable to its own product than is an independent study.

This paper follows research published in PLoS Medicine in September by Ida Sim and colleagues that also investigated the publication status and publication bias of trials submitted to the FDA for a wide variety of approved drugs.

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“There’s no easy way to say this. . .”

A Health in Action paper published in PLoS Medicine recently describes the success of an innovative project called inSPOT – an e-card notification system that enables people who have been diagnosed with a sexually transmitted disease to inform their sexual partners that they may also be at risk.

Whilst news coverage reveled in the dark humour of some of the cards (“Roses are red, violets are blue. I’ve got the clap, and you may have too”, said The Times), it recognized that an easy and anonymous way of informing casual sex partners can help circumvent the stigma and embarrassment attached to sexually transmitted diseases and spread awareness of possible infections.

“We know inSPOT works,” Dr. Jeffrey Klausner, one of the authors of the paper, told the Washington Post. “I see patients, they come in and say they’ve been notified [about having an STD], and their contact is through inSPOT.” And as the Scientific American noted – with one of the e-cards illustrating its report – the e-cards provide specific and up to date disease information: 15.4% of the e-cards were sent for gonorrhea, 14.9% for syphilis, 9.3% for HIV, 11.6% for chlamydia, and 48.8% for other STDs. Given that 19 million new STD cases are diagnosed annually in the United States, this information is desperately needed.

In their evaluation of the project, which was conducted in 20 health jurisdictions in the United States, the authors analyzed rates at which e-card recipients clicked a link embedded in the card that connected to STD information, a map of local testing sites, and links to online resources. Of e-cards sent since December 2005 the “click-through” rates averaged at 26.8%, ranging from 20.4% in Los Angeles to 48.2% in Idaho, resulting in 29,137 people accessing STD testing information as a result of receiving an e-card.

Coverage in CNN and the Daily Telegraph report on the variety of styles that cards can be sent in: from the direct and serious (“Who? What? When? Where? It doesn’t matter. I got an STD; you might have it too”) to those that use puns to catch the attention of the recipient (“I got screwed while screwing, you might have too”). College students across America at Vanderbilt, Northwestern, USC and Yale discussed the merits of the inSPOT website. And in case you were wondering about the site’s susceptibility to pranks, the LA Times health blog quotes the authors as saying “while we prepared for the possibility of misuse…fewer than 10 recipients have reported receiving a card in error.”

The coverage was so extensive one could even speculate that the e-cards were being sent from news organization to news organization. CNN International’s story ranked as the most emailed and fifth most viewed story on October 21st. It quoted the authors to explain that the traditional system of notification through the public health department was struggling:

“Resources of the health department have been decimated. They don’t have the capacity to do that kind of notification anymore. We needed to come up with something to serve the needs, to notify, that would be used and have an impact.”

The authors believe the inSPOT website can have an international impact. It has been translated into Romanian and French, and will soon be available in Spanish as well.

Andrew Hyde, Darcy Gill, Nisha Doshi

Category: In the News, PLoS Medicine | 1 Comment

Guest blog by Richard Smith: More evidence on why we need radical reform of science publishing

PLoS Medicine invited Richard Smith, former editor of the BMJ and
current board member of PLoS, to discuss an essay published this week by Neal Young, John Ioannidis and Omar Al-Ubaydli that argues that the current system of publication in biomedical research provides a distorted view of the reality of scientific data.

More evidence on why we need radical reform of science publishing, Richard Smith

Ask scientists whether they’d prefer an all expenses paid fortnight in the best hotel in San Tropez, a Ferrari, a Cezanne painting, or the publication of one of their original papers in Nature – and most, I’d bet, would go for Nature. Getting published in one of the few elite journals is a very big deal for researchers, but, argues a stimulating paper published in PLoS Medicine, (1) the fact that it is so important is distorting science. And I think that the authors are right.

Neal Young, John Ioannidis, and Omar Al-Ubaydli unusually for a scientific publication use economic concepts to make their case, and by doing so they illustrate the value of crossing disciplinary boundaries. Their argument is built around “the winner’s curse.” Imagine many firms competing for a television franchise. Each will try to work out the value of the franchise, and inevitably there will be a range of bids. If the franchise is simply awarded to the highest bidder then there’s a high chance that that bid is too high, meaning that the winner will lose money — hence “the winner’s curse.” Those who run such bids often recognise the problem of the curse and discount the highest bid or go for a lower bid.

This phenomenon operates in science publishing because the elite journals that accept only a fraction of papers submitted to them go for the “best” and are thus likely to be publishing papers that are suffering from the winner’s curse — for example, in that they give dramatic results that are a considerable distance from the “true” results. They are exciting outliers — and so very attractive to the elite journals. The articles that the high impact journals publish are bound to be atypical and will present a distorted view of science, leading to false conclusions and “misallocation of resources.”

The authors have some empirical evidence to support their argument. A study of the 49 most highly cited papers on medical interventions published in high profile journals between 1990 and 2004 showed that a quarter of the randomised trials and five of six non-randomised studies had been contradicted or found to be exaggerated by 2005. (2) We know too that “positive” drug trials are much more likely to be published than “negative” trials, although we don’t know how much this is the result of conscious manipulation by authors and sponsors and how much the result of “the winner’s curse.” (3-5)

Most scientists read a few high profile journals — and so are fed a systematically distorted view of the evidence. It’s also these journals that are most widely reported in the media and fed to policy makers, so increasing the impact of the distortion.

The hope of many is, of course, that the elite journals are selecting “the best” research — hence providing a way of coping with information overload. But we know from good evidence that peer review is a deeply flawed system and that it’s very hard to know what will be important in the long term. So readers of Nature, Science, and the New England Journal of Medicine are not reading “the best” but the “systematically distorted.”

What might we do about this problem? Young and others suggest a range of options, including preferring publication of negative over positive results — a version of those choosing among bids discounting the highest. It’s hard to see, however, how building such an explicit bias into the system would be helpful. Better might be for editors to pay no attention to whether the results are positive or negative but rather to concentrate simply on the importance of the question being asked and the rigour of the methods. We tried to do this when I was editor of the BMJ, but I’m not sure how successful we were. Inevitably you are excited by an unusual result, and the winner’s curse can surely operate not only in relation to whether the results are positive or negative but also in relation to the “importance” of the question.

For me this paper simply adds to the growing evidence and argument that we need radical reform of how we publish science. I foresee rapid publication of studies that include full datasets and the software used to manipulate them without prepublication peer review onto a large open access database that can be searched and mined. Instead of a few studies receiving disproportionate attention we will depend more on the systematic reviews that will be updated rapidly (and perhaps automatically) as new results appear.

References

1. Young NS, Ioannidis JPA, Al-Ubaydli O (2008) Why Current Publication Practices May Distort Science. PLoS Med 5(10): e201 doi:10.1371/journal.pmed.0050201. Find this paper online.

2. Ioannidis JPA (2005) Contradicted and initially stronger effects in highly cited clinical research. JAMA 2005: 294:218-28. Find this paper online.

3. Lee K, Bacchetti P, Sim I (2008) Publication of Clinical Trials Supporting Successful New Drug Applications: A Literature Analysis PLoS Medicine Vol. 5, No. 9, e191 doi:10.1371/journal.pmed.0050191. Find this paper online.

4. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (2008) Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. NEJM 2008; 358: 252-60. Find this paper online.

5. Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B (2003) Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003;326:1171-1173 (31 May), doi:10.1136/bmj.326.7400.1171 Find this paper online.

Category: PLoS Medicine, Publishing | 3 Comments

Chewing over the Churnalism: PLoS Medicine in NHS Choices

“Few things can make a doctor’s heart sink more in a clinic than a patient brandishing a newspaper clipping”, wrote Ben Goldacre in an article in the BMJ last year. (Especially if that clipping is from the Daily Mail, which has acquired such a reputation for dividing the world up into things that either cause or cure cancer that a blog – the Daily Mail Oncological Ontology Project – is dedicated to keeping a vigilant record).

Journalistic reporting of health studies was evaluated in a recent analysis in PLoS Medicine. Looking at 500 medical news stories that covered treatments, tests, products, and procedures, Gary Schwitzer, Publisher of HealthNewsReview.org, found that most stories failed to adequately address the costs, harms, benefits and the existence of other treatments options. PLoS Medicine‘s related editorial discussed the many reasons why the results of health studies can be sensationalized in the media, one of which is that press releases issued by medical journals are often prone to hype. In her blog Rebecca Walton made reference to the phenomenon of “churnalism” that can rapidly spread a misleading report or hyped release: increasingly online news sites recycle press releases verbatim and as a consequence “a lot of power lies in the hands of the press officer to shape news coverage.”

What can be done to avoid the cynical dismissal of all attempts by health reporters to explain medical research to public? Ben Goldacre praised the now defunct National Library of Health Hitting the Headlines project to better inform the public and help doctors, who on the basis of the newspaper story may be tempted to just dismiss the research cited by their patients. This has now been been supplanted by the NHS Choices Behind the Headlines service. This site is updated at an impressive rate, analyzing the health stories that break into the national news every day. The site provides a short review of the study that has attracted so much attention, comparing it to the way it is represented by the headlines, before asking what the NHS Knowledge Service can draw from the research.

In the last two weeks two PLoS Medicine papers have featured in NHS Choices Behind the Headlines. One of these was a study by Hans Bisgaard and colleagues which showed an association between mutations in the filaggrin gene (FLG) and ownership of cats with the development of eczema in infancy. The Daily Mail was so concerned about the 8 million cat owners in the United Kingdom that it definitively stated in the headline: “Own a cat and run the risk of eczema.” (This statement rather neatly avoided the fact that if you haven’t got the mutation, having a cat is not going to make you more likely to get eczema). Behind the Headlines listed the strengths and limitations of the study, as the authors do in the discussion section of the freely available article. It pointed out that the FLG mutation has only been estimated to account for about 11% of cases of eczema, so the findings will not apply to the majority of people with eczema. (The study was also covered by the Daily Telegraph, BBC News, New Scientist and Nursing in Practice, all with slightly more moderate headlines).

The second PLoS Medicine study recently reviewed on Behind the Headlines was by Rebecca Slater and colleagues. This research suggested that the currently used pain assessment tools may be underestimating the pain response in infants. The Behind the Headlines review looked at the coverage of the study by the Daily Telegraph and the Daily Mail.

Another attempt to get behind the headlines is the Australia-based Media Doctor. Like HealthNewsReview.org, it uses evaluation criteria to assess the quality of stories in the Australian press. These ten criteria include whether or not the story in question has relied on the press release. A study recently published in PLoS ONE used the ratings provided by the Media Doctor site and concluded that much of the information the public receives about complementary and alternative medicine is inaccurate or incomplete.

In a 2005 PLoS Medicine debate on the roles and responsibilities of the media in disseminating health information, David Henry and Amanda Wilson of the Media Doctor project said that many journalists have indicated to them that “they are prepared to look critically at their own practices.” And although Gary Schwitzer’s analysis of the quality of reporting of health stories in the media finds the majority to be misleading, HealthNewsReview.org does highlight examples of excellent journalism. Hopefully, these various attempts to evaluate the quality of health reporting in the media can provide cause for reflection by all parties involved in the dissemination of news and information — not just journalists, but medical journals, industry, academic institutions and individual clinicians and researchers.

Category: In the News, PLoS Medicine | 2 Comments

County by County Life Expectancy: How Many Americas are There?

Over the past couple of weeks Josh Eveleth and I have answered journalists’ enquiries from many different pockets of the United States about the recently published paper by Majid Ezzati and colleagues. The research, which analyzes mortality data for every county in every US state over four decades, finds a steady increase in mortality inequality across counties between 1983 and 1999.

It provoked an intense debate and discussion nationally, but also at a very local level (the local discussions are particularly interesting for someone whose travels in America have not gone much further than visiting the PLoS San Francisco office and whose experience of Vineland is the Thomas Pynchon novel rather than the New Jersey counties covered by the Vineland Daily Journal).

For example, by making the supporting datasets (and figures and video files) that demonstrate the changes in life expectancy county by county freely available in PLoS Medicine, the Roanoke Times was able to report statistics for Pulaski and Radford counties in Virginia. (An alarming finding from the study – as the New Scientist reported – is that there has been a decline in life expectancy in some of the poorest sections of the population, primarily among women in the Southern States). On a national level, the paper was on the cover of the New York Times Week in Review with former Democratic Vice Presidential Nominee John Edwards commenting that the findings demonstrate how “the wealth and income disparity effectively infiltrates all parts of people’s lives.” Edwards was asked to comment because of his national campaign to end poverty in America by 2036.

Worth listening to are the interviews on NPR’s Science Friday show and the shorter broadcast on Voice of America. As Ezzati makes clear in both of them, on average life expectancy has risen for American men and women since the 1960s, but is from the 1980s that the troubling geographical disparities have worsened and some counties have experienced stagnation and even a decline. This kind of worsening of life expectancy for segments of the population is not something usually associated with developed high-income countries – in the Voice of America interview, Ezzati observes it that this worsening is something that happened after the fall of the Soviet Union when the health and social networks in Eastern Europe collapsed.

In an online interview with the Washington Post Ezzati fields questions and theories about the trends from readers in the West and the East of the country, from San Francisco, California to Eastern Shore, Maryland. He illustrates the point that this worsening of life expectancy is a phenomenon occurring in the United States and not Europe by referring to the Human Mortality Database. This is a project set up by researchers at the University of California, Berkeley and at the Max Planck Institute for Demographic Research in Rostock, Germany, to provide historical mortality data for many countries.

The Economist and the Wall Street Journal (which embedded one of our video files in the blog to complement the story) focused on the impact that diseases linked to smoking or obesity, such as lung cancer and diabetes, have had on life expectancy. ABC News quoted Ezzati to demonstrate that these negative trends have affected women particularly: “one out of five American women have had their health either getting worse or at best not getting better.”

The study is a troubling but fascinating reminder of how huge the United States is and how wide the disparities within it are. Whilst John Edwards spoke of “two Americas” in the 2004 Presidential election campaign, a 2005 PLoS Medicine paper by Majid Ezzati and colleagues established “eight Americas” in terms of mortality disparities across race and counties. In the Voice of America interview, Ezzati says he hopes the new study raises awareness about health care in America and prompts monitoring of those being left behind in order to understand what kind of policies and interventions can reverse the decline in life expectancy.

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Prozac and Placebos: Review of a Media Maelstrom

Last week we had the interesting experience of watching how a PLoS Medicine meta-analysis of anti-depressant drug trials generated a furore in the media. It featured on the front page of four UK national newspapers (the Guardian, the Telegraph, the Independent and the Times), was the leading item on the BBC News and prompted stories in Time, the Wall Street Journal and the Economist.

The paper not only posed questions about the benefits of antidepressants, it revealed how many clinical trial results do not see the light of day. But whilst the issues relating to it continue to be debated – a discussion leads the Guardian Science Weekly Podcast this week– some of the headlines in the media maelstrom misrepresented the study.

Irving Kirsch and colleagues used Freedom of Information legislation in the United States (see the methods section) to get access to both published and unpublished clinical trials of several SSRI/SNRI antidepressants, including fluoxetine (Prozac), that had been submitted to the Food and Drug Administration for approval. Analyzing the full dataset, which included studies of varying duration and quality, the researchers found no clinically significant difference between a patient’s response to the placebo and these antidepressants for most depressed people. Their analysis did find clinically relevant effects for a subset of the most severely depressed patients.

The headlines started appearing at 1am GMT on Tuesday 26th, as soon as the embargo ended. The front page of the Independent (“Antidepressant drugs don’t work – official study”), the Guardian (“Prozac, used by 40 million people, does not work”) and the Times (“Depression drugs don’t work, finds data review”) all opted for an outright statement that antidepressants don’t work. But the study does not show that antidepressants do not work. Rather, the evidence reviewed in this analysis did not show these antidepressants to produce enough of a beneficial effect over the placebo to be termed clinically significant. Language Log, a linguistics blog, gives an account of how some journalists got tangled up in their own sentences when trying to describe the results. (Thanks to Rebecca Walton for pointing this one out).

Time Magazine opted for a slightly different presentation (“Antidepressants Hardly Help”), pointing out that there is a difference between “statistical significance” and “clinical significance.” The article quotes the authors directly to say that only those “at the upper end of the very severely depressed category” get a clinically significant benefit. It also makes reference to the Hamilton Depression Rating Scale: the tool used by UK authorities to determine clinical significance.

The interview on the BBC Radio 4 Today programme touched upon the crucial issues in the space of five minutes. It features a debate between Irving Kirsch and Richard Tiner of the Association of British Pharmaceutical Industry. Irving Kirsch summarizes the results of the study, before they dispute whether or not NICE (National Institute for Health and Clinical Excellence), the body guiding clinicians in the UK, could get access to all of the information that they needed. This item makes the point – missing from some of the other coverage – that people taking antidepressants should not change their behavior on the basis of this report or the headlines. If worried, they should consult their doctor.

So some of the headlines were off the mark, but one good thing that can come out of the coverage is a re-ignition of the debate in the media about the importance of having access to all clinical trials data – not just the positive results pushed for publication by pharmaceutical companies.

In Bad Science, Ben Goldacre also sees the real importance of the study lies in the “fascinating story of buried data.” Noting that the authors had to use the Freedom of Information Act to get all the data from the FDA, he says the fact that “medical academics should need to use that kind of legislation to obtain information about trials on pills which are prescribed to millions of people is absurd.” The Independent ran an article to explain publication bias to a wider audience. In her Comment is Free piece, Sarah Boseley asks whether we can trust that the licensing authorities have all the data they need to approve drugs.

In comparison with the wall to wall headlines the study got in the UK, there was less coverage in the United States. Although the study was covered in North America (Fox News linked to the paper and CTV covered it in Canada, amongst others), of the major American papers we only found that the Wall Street Journal has original coverage. As Washington Monthly remarked (with bloggers theorizing), this is interesting considering that the study uses clinical trials data from the Food and Drug Administration, the licensing authority in the United States.

Pulse reports that NICE are to consider unpublished data on antidepressants before their guidance on depression is published later this year, so the ramifications of the study are set to continue. In the light of the PLoS Medicine study the Guardian returned to the earlier story that the UK government plans to train additional therapists to combat the difficulties that patients have in accessing non-pharmaceutical forms of therapy for depression.

Hopefully some informed debate about drugs and depression in general can come out of all of this coverage. Read some of the reader responses that we’ve received – in particular the compelling response by Jeanne Lenzer and Shanon Brownlee, which does a good job of suming up the most important implications of the study. They write:

“The take home message of Kirsch’s analysis is that it is difficult if not impossible to come to conclusions about the relative merits and risk of medications when only parts (usually positive parts) of the data are available. The problem of publication bias is so powerful that it has certainly distorted interventions besides antidepressants – a problem we discuss in our commentary in this week’s BMJ“.

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No Such Thing as a Free Lunch (or Gift or Sample)

Are the staggering amounts spent by drug companies on marketing justified by their innovation in drug development? Not according to a Policy Forum in PLoS Medicine which has stimulated a great deal of debate across blogs and news sites over the past couple of weeks.

The analysis by Marc-Andre Gagnon and Joel Lexchin dispels the image promoted by the pharmaceutical industry that it is “research-driven, innovative, and life-saving.” The data they obtained from IMS (a market research company that surveys pharmaceutical companies for information on drug promotion) and CAM (who survey doctors instead of firms) demonstrates the extent to which the industry is actually driven by marketing. They find that for 2004 nearly twice as much was spent on promotional activities than on research and development.

That’s US $61,000 spent on promotion per physician in the United States, as Howard Brody of the University of Texas Medical Branch exclaimed in his blog before reflecting upon the lack of transparency in the industry. As ABC Television News reported, Gagnon and Lexchin suggest that there are other promotional revenues that won’t have been captured by the market research data. (These include the ghostwriting of articles in medical journals by drug company employees, the subject of a PLoS Medicine essay last September).

Concern about direct to consumer advertising of drugs was prominent in the Consumerist – an influential consumer affairs blog – which clocked up over 50 comments in response to the paper. In Canada, CBC News made reference to the practice known as detailing (drug reps visiting doctors to persuade them to promote specific drugs, as described in a previous PLoS Medicine Policy Forum). However, Gagnon and Lexchin go on to say that the extent of detailing could be underestimated by the IMS data which obtains its figures direct from the industry. Readers of the Sci Guy blog of the Houston Chronicle expressed concern about how physicians can be compromised by gifts and drug samples, prompting a post from No Free Lunch, an organization dedicated to convincing physicians that such gifts represent a conflict of interest.

A statement from PhRMA (Pharmaceutical Research and Manufacturers of America (PhRMA) – quoting its own figures to counter the analysis – was in the Peterborough Examiner. (For those of you in the UK, that’s Peterborough, Ontario not Peterborough, Cambridgeshire).

Fittingly, for authors who took the opportunity of publishing a French translation of the abstract with their the study, media coverage also came in Le Figaro. For those of you adept in other languages, you can read the coverage in Italy (La Repubblica), Argentina (Clarin) and Germany (Der Spiegel).

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Fearsome foursome factors of longevity

Following the recent blog that related a PLoS paper to end of year excess, this week a PLoS Medicine study evaluating the combined impact of four healthy forms of behaviour was devoured by journalists keen to remind us to stick to New Year resolutions. This was certainly the approach of the New Scientist who let their readers know that no matter how “fat or unhealthy you already are” the conclusions of the study by Kay-Tee Khaw and colleagues are important. Conducted amongst 20,000 participants in the UK, the study found that those who are non-smokers, take exercise, have a moderate alcohol intake and eat five servings of fruit and vegetables a day live on average an additional fourteen years of life compared with people who adopt none of these behaviours.

The BBC were also quick to report on the paper – even reproducing one of the figures – and by midday on Tuesday it had jumped to the most viewed article and the one that was emailed most to friends. Interviewed on the BBC Television News Nick Wareham, one of the authors of the paper, stressed that even small changes in behaviour can have a significant impact on the health of populations. Elsewhere in the UK, the paper was picked up by the Guardian and the Telegraph.

“Isn’t it all quite obvious?” asked a comment responding to the Daily Mail article about the research. Whilst there is overwhelming evidence that individual aspects of lifestyle – such as smoking and diet – affect health and longevity, the study Kay-Tee Khaw and colleagues quantified the combined impact of four, an approach that is not usually taken. The research forms part of the European Prospective Investigation into Cancer and Nutrition (EPIC): conducted across ten European countries, it is the largest investigation into diet and health ever undertaken. Certainly scepticism amongst the general public is one of the many factors that makes the translation of research into public health policy complex – the subject of our editorial – and this was also evident on the other side of the Atlantic in response to coverage by the Washington Post and Chicago Tribune amongst others. “With all these good habits, there’s still a chance you’ll be killed while out on a hiking trail” was one of the cheerful comments replying to the San Francisco Chronicle’s article. Those hoping for an immediate extension to their lifespan were disappointed by Dr. Kim Mulvihill, a columnist for CBS, who helpfully pointed out that people who adopt these four behaviours do not “automatically gain 14 years.” “The 14 years is an average across the population of what’s theoretically possible” realized Tim Armstrong for CBC in Canada. Down Under, the paper was covered in the Sydney Morning Herald and the Australian.

One of the key things about the paper as made evident in the methods section – in contrast to the usual confusing barrage of information from medical journals, government reports and the popular media – was the use of simple health indicators to score participants in the questionnaire for the study. The authors state that an analysis of how the combined health behaviours affect quality of life is also needed (although the four factors are not thought to rule out watching the cricket and drinking a beer, which will leave one public health expert interviewed for the Age in Melbourne relieved). Nevertheless, the results of the study do suggest that these four achievable lifestyle changes could have a marked improvement on the health of middle-aged and older people, which is particularly important given the ageing population in the UK and other European countries.

You can respond to the freely available article through our reader response system.

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