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1.  Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A Systematic Review of Guidelines for In Vivo Animal Experiments 
PLoS Medicine  2013;10(7):e1001489.
Background
The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address.
Methods and Findings
We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria—most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.
Conclusions
By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The development process for new drugs is lengthy and complex. It begins in the laboratory, where scientists investigate the causes of diseases and identify potential new treatments. Next, promising interventions undergo preclinical research in cells and in animals (in vivo animal experiments) to test whether the intervention has the expected effect and to support the generalization (extension) of this treatment–effect relationship to patients. Drugs that pass these tests then enter clinical trials, where their safety and efficacy is tested in selected groups of patients under strictly controlled conditions. Finally, the government bodies responsible for drug approval review the results of the clinical trials, and successful drugs receive a marketing license, usually a decade or more after the initial laboratory work. Notably, only 11% of agents that enter clinical testing (investigational drugs) are ultimately licensed.
Why Was This Study Done?
The frequent failure of investigational drugs during clinical translation is potentially harmful to trial participants. Moreover, the costs of these failures are passed onto healthcare systems in the form of higher drug prices. It would be good, therefore, to reduce the attrition rate of investigational drugs. One possible explanation for the dismal success rate of clinical translation is that preclinical research, the key resource for justifying clinical development, is flawed. To address this possibility, several groups of preclinical researchers have issued guidelines intended to improve the design and execution of in vivo animal studies. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the authors identify the experimental practices that are commonly recommended in these guidelines and organize these recommendations according to the type of threat to validity (internal, construct, or external) that they address. Internal threats to validity are factors that confound reliable inferences about treatment–effect relationships in preclinical research. For example, experimenter expectation may bias outcome assessment. Construct threats to validity arise when researchers mischaracterize the relationship between an experimental system and the clinical disease it is intended to represent. For example, researchers may use an animal model for a complex multifaceted clinical disease that only includes one characteristic of the disease. External threats to validity are unseen factors that frustrate the transfer of treatment–effect relationships from animal models to patients.
What Did the Researchers Do and Find?
The researchers identified 26 preclinical guidelines that met their predefined eligibility criteria. Twelve guidelines addressed preclinical research for neurological and cerebrovascular drug development; other disorders covered by guidelines included cardiac and circulatory disorders, sepsis, pain, and arthritis. Together, the guidelines offered 55 different recommendations for the design and execution of preclinical in vivo animal studies. Nineteen recommendations addressed threats to internal validity. The most commonly included recommendations of this type called for the use of power calculations to ensure that sample sizes are large enough to yield statistically meaningful results, random allocation of animals to treatment groups, and “blinding” of researchers who assess outcomes to treatment allocation. Among the 25 recommendations that addressed threats to construct validity, the most commonly included recommendations called for characterization of the properties of the animal model before experimentation and matching of the animal model to the human manifestation of the disease. Finally, six recommendations addressed threats to external validity. The most commonly included of these recommendations suggested that preclinical research should be replicated in different models of the same disease and in different species, and should also be replicated independently.
What Do These Findings Mean?
This systematic review identifies a range of investigational recommendations that preclinical researchers believe address threats to the validity of preclinical efficacy studies. Many of these recommendations are not widely implemented in preclinical research at present. Whether the failure to implement them explains the frequent discordance between the results on drug safety and efficacy obtained in preclinical research and in clinical trials is currently unclear. These findings provide a starting point, however, for the improvement of existing preclinical research guidelines for specific diseases, and for the development of similar guidelines for other diseases. They also provide an evidence-based platform for the analysis of preclinical evidence and for the study and evaluation of preclinical research practice. These findings should, therefore, be considered by investigators, institutional review bodies, journals, and funding agents when designing, evaluating, and sponsoring translational research.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001489.
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health professionals; its Patient Network provides a step-by-step description of the drug development process that includes information on preclinical research
The UK Medicines and Healthcare Products Regulatory Agency (MHRA) provides information about all aspects of the scientific evaluation and approval of new medicines in the UK; its My Medicine: From Laboratory to Pharmacy Shelf web pages describe the drug development process from scientific discovery, through preclinical and clinical research, to licensing and ongoing monitoring
The STREAM website provides ongoing information about policy, ethics, and practices used in clinical translation of new drugs
The CAMARADES collaboration offers a “supporting framework for groups involved in the systematic review of animal studies” in stroke and other neurological diseases
doi:10.1371/journal.pmed.1001489
PMCID: PMC3720257  PMID: 23935460
2.  Relationship between Funding Source and Conclusion among Nutrition-Related Scientific Articles 
PLoS Medicine  2007;4(1):e5.
Background
Industrial support of biomedical research may bias scientific conclusions, as demonstrated by recent analyses of pharmaceutical studies. However, this issue has not been systematically examined in the area of nutrition research. The purpose of this study is to characterize financial sponsorship of scientific articles addressing the health effects of three commonly consumed beverages, and to determine how sponsorship affects published conclusions.
Methods and Findings
Medline searches of worldwide literature were used to identify three article types (interventional studies, observational studies, and scientific reviews) about soft drinks, juice, and milk published between 1 January, 1999 and 31 December, 2003. Financial sponsorship and article conclusions were classified by independent groups of coinvestigators. The relationship between sponsorship and conclusions was explored by exact tests and regression analyses, controlling for covariates. 206 articles were included in the study, of which 111 declared financial sponsorship. Of these, 22% had all industry funding, 47% had no industry funding, and 32% had mixed funding. Funding source was significantly related to conclusions when considering all article types (p = 0.037). For interventional studies, the proportion with unfavorable conclusions was 0% for all industry funding versus 37% for no industry funding (p = 0.009). The odds ratio of a favorable versus unfavorable conclusion was 7.61 (95% confidence interval 1.27 to 45.73), comparing articles with all industry funding to no industry funding.
Conclusions
Industry funding of nutrition-related scientific articles may bias conclusions in favor of sponsors' products, with potentially significant implications for public health.
In 111 scientific articles on nonalcoholic beverages, articles with all industry funding were more than 7 times more likely to have favorable conclusions compared with articles with no industry funding.
Editors' Summary
Background.
Much of the money available for doing medical research comes from companies, as opposed to government agencies or charities. There is some evidence that when a research study is sponsored by an organization that has a financial interest in the outcome, the study is more likely to produce results that favor the funder (this is called “sponsorship bias”). This phenomenon is worrying, because if our knowledge about effectiveness and safety of medicines is based on biased findings, patients could suffer. However, it is not clear whether sponsorship bias extends beyond research into drugs, but also affects other types of research that is in the public interest. For example, research into the health benefits, or otherwise, of different types of food and drink may affect government guidelines, regulations, and the behavior patterns of members of the public. Were sponsorship bias also to exist in this area of research, the health of the wider public could be affected.
Why Was This Study Done?
There is not a great deal of evidence about whether sponsorship bias affects nutritional research (scientific studies that look at the relationship between food and/or drink, and health or disease states). Therefore, the group of researchers here set out to collect information from published nutritional research papers, to see if the type of sponsorship for the research studies was in any way linked with whether the main conclusions were favorable or unfavorable to the sponsor.
What Did the Researchers Do and Find?
The research study reported here used the scientific literature as a source of data. The researchers chose to examine one particular area of nutrition (nonalcoholic drinks including soft drinks, juices, and milk), so that their investigation would not be affected too much by variability between the different types of nutritional research. Using literature searches, the researchers identified all original research and scientific review articles published between January 1999 and December 2003 that examined soft drinks, juices, and milk; described research carried out in humans; and at the same time drew conclusions relevant to health or disease. Then, information from each published article was categorized: the conclusions were coded as either favorable, unfavorable, or neutral in relation to the health effects of the products being studied, and the article's funding was coded as either all industry (ie, food/drinks companies), no industry, or mixed. 206 published articles were analyzed and only 54% declared funding. The researchers found that, overall, there was a strong association between the type of funding available for these articles and the conclusions that were drawn. Articles sponsored exclusively by food/drinks companies were four to eight times more likely to have conclusions favorable to the financial interests of the sponsoring company than articles which were not sponsored by food or drinks companies.
What Do These Findings Mean?
These findings suggest that a high potential for bias exists in research into the health benefits or harms of nonalcoholic drinks. It is not clear from this research study why or how this bias comes about, but there are many different mechanisms that might cause it. The researchers suggest that certain initiatives might help to reduce bias, for example, increasing independent funding of nutrition research.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040005.
Conflict of Interest definition from Wikipedia (Wikipedia is an internet encyclopedia that anyone can edit)
The International Committee of Medical Journal Editors provides standard guidelines for practices at medical journals, including a section on sponsorship, authorship, and accountability
The Committee on Publication Ethics is a forum for journal editors to discuss issues related to the integrity of the scientific record, and it provides guidelines for editors and case studies for reference
The Good Publication Practice guidelines outline standards for responsible publication of research sponsored by pharmaceutical companies
doi:10.1371/journal.pmed.0040005
PMCID: PMC1764435  PMID: 17214504
3.  BioPP: a tool for web-publication of biological networks 
BMC Bioinformatics  2007;8:168.
Background
Cellular processes depend on the function of intracellular molecular networks. The curation of the literature relevant to specific biological pathways is important for many theoretical and experimental research teams and communities. No current tool supports web publication or hosting of user-developed large scale annotated pathway diagrams. Sharing via web publication is needed to allow real-time access to the current literature pathway knowledgebase, both privately within a research team or publicly among the outside research community. Web publication also facilitates team and/or community input into the curation process while allowing centralized control of the curation and validation process. We have developed new tool to address these needs. Biological Pathway Publisher (BioPP) is a software suite for converting CellDesigner Systems Biology Markup Language (CD-SBML) formatted pathways into a web viewable format. The BioPP suite is available for private use and for depositing knowledgebases into a newly created public repository.
Results
BioPP suite is a web-based application that allows pathway knowledgebases stored in CD-SBML to be web published with an easily navigated user interface. The BioPP suite consists of four interrelated elements: a pathway publisher, an upload web-interface, a pathway repository for user-deposited knowledgebases and a pathway navigator. Users have the option to convert their CD-SBML files to HTML for restricted use or to allow their knowledgebase to be web-accessible to the scientific community. All entities in all knowledgebases in the repository are linked to public database entries as well as to a newly created public wiki which provides a discussion forum.
Conclusion
BioPP tools and the public repository facilitate sharing of pathway knowledgebases and interactive curation for research teams and scientific communities. BioPP suite is accessible at
doi:10.1186/1471-2105-8-168
PMCID: PMC1885811  PMID: 17519033
4.  “A Good Personal Scientific Relationship”: Philip Morris Scientists and the Chulabhorn Research Institute, Bangkok 
PLoS Medicine  2008;5(12):e238.
Background
This paper examines the efforts of consultants affiliated with Philip Morris (PM), the world's leading transnational tobacco corporation, to influence scientific research and training in Thailand via the Chulabhorn Research Institute (CRI). A leading Southeast Asian institute for environmental health science, the CRI is headed by Professor Dr. Her Royal Highness Princess Chulabhorn, the daughter of the King of Thailand, and it has assumed international significance via its designation as a World Health Organization (WHO) Collaborating Centre in December 2005.
Methods and Findings
This paper analyses previously confidential tobacco industry documents that were made publicly available following litigation in the United States. PM documents reveal that ostensibly independent overseas scientists, now identified as industry consultants, were able to gain access to the Thai scientific community. Most significantly, PM scientist Roger Walk has established close connections with the CRI. Documents indicate that Walk was able to use such links to influence the study and teaching of environmental toxicology in the institute and to develop relations with key officials and local scientists so as to advance the interests of PM within Thailand and across Asia. While sensitivities surrounding royal patronage of the CRI make public criticism extremely difficult, indications of ongoing involvement by tobacco industry consultants suggest the need for detailed scrutiny of such relationships.
Conclusions
The establishment of close links with the CRI advances industry strategies to influence scientific research and debate around tobacco and health, particularly regarding secondhand smoke, to link with academic institutions, and to build relationships with national elites. Such strategies assume particular significance in the national and regional contexts presented here amid the globalisation of the tobacco pandemic. From an international perspective, particular concern is raised by the CRI's recently awarded status as a WHO Collaborating Centre. Since the network of WHO Collaborating Centres rests on the principle of “using national institutions for international purposes,” the documents presented below suggest that more rigorous safeguards are required to ensure that such use advances public health goals rather than the objectives of transnational corporations.
Jeff Collin and Ross MacKenzie analyze tobacco industry documents and find that Philip Morris consultants were able to gain access to a Thai research institute that is a WHO Collaborating Centre.
Editors' Summary
Background.
Tobacco use kills 5.4 million people a year (one person every six seconds) and accounts for one in ten adult deaths worldwide. Globally, the use of tobacco is on the rise, especially in developing countries, which have become a major target for tobacco industry marketing. The tobacco industry has worked hard to try and influence public perceptions about the risks of smoking and the risk of inhaling secondhand smoke (passive smoking). The industry has used a variety of tactics to downplay the health hazards of smoking or inhaling secondhand smoke—two examples are publishing articles casting doubts about the health hazards of tobacco and funding research that is biased toward giving pro-industry results. Another tactic is for tobacco industry consultants to try and gain entry to universities and other academic centers to see if they can influence research and teaching activities.
Why Was This Study Done?
The researchers were concerned that consultants from the tobacco company Philip Morris had gained access to an academic research center in Thailand called the Chulabhorn Research Institute (CRI). The CRI is an internationally renowned teaching institution for a variety of scientific disciplines, including environmental toxicology (the study of how chemicals in the environment, such as tobacco smoke, can affect human health), biomedicine, and biotechnology. The institute has secured funding from the Thai government, the Association of Southeast Nations and the United Nations Development Programme. In 2005 the institute's environmental toxicology unit was designated a World Health Organization (WHO) Collaborating Centre. WHO Collaborating Centres are “institutions such as research institutes, parts of universities or academies, that are designated by the Director-General of the WHO to carry out activities in support of the WHO's programs” (http://www.who.int/collaboratingcentres/en/). The researchers were concerned that Philip Morris consultants had been able to develop relationships with the CRI to help advance the company's interests.
What Did the Researchers Do and Find?
The researchers analyzed previously confidential tobacco industry documents that were made publicly available online following litigation in the United States. They searched two online collections of industry documents—the Legacy Tobacco Documents Library and Tobacco Documents Online—as well as the online collections operated by US-based tobacco companies. They found that consultants to Philip Morris were able to gain access to the scientific community in Thailand. A Philip Morris scientist named Roger Walk was able to establish close connections to the CRI, and he used these connections to influence research and teaching activities at the CRI on environmental toxicology. Walk was also able to build relationships with government officials and scientists in Thailand to help advance the interests of Philip Morris in the country and across Asia.
What Do these Findings Mean?
This study provides evidence that the tobacco industry has established close links with a research institute in Thailand that collaborates with the WHO, and has been able to influence the institute's teaching curriculum and research. Such links are of great concern to the public health community, which is working hard to reduce deaths and disease due to tobacco. These links raise the possibility that the tobacco industry is managing to influence medical research and teaching at academic institutions. The WHO has stated that a firewall is in place between itself and the tobacco industry—but the study authors argue, based on their findings, that “this firewall is not impenetrable.” The study findings, they conclude, highlight a challenge posed to international tobacco control efforts, especially with respect to Article 5.3 of an international treaty called the WHO Framework Convention on Tobacco Control; Article 5.3 addresses the need to protect public health policies from the vested interests of the tobacco industry. The authors say that better safeguards must be put in place to prevent tobacco companies from thwarting public health goals.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050238.
The Legacy Tobacco Documents Library contains over 9.7 million documents created by tobacco companies
Tobacco Documents Online contains over 4 million tobacco industry documents
Over 900 WHO Collaborating Centres are at work in 99 Member States on many health disciplines
The WHO held an inquiry in 2000 into possible tobacco industry influence over the organization (and over other UN agencies), and has published its recommendations in response to this inquiry
The WHO Framework Convention on Tobacco Control is an international treaty on controlling tobacco
doi:10.1371/journal.pmed.0050238
PMCID: PMC2605886  PMID: 19108600
5.  The Impact of eHealth on the Quality and Safety of Health Care: A Systematic Overview 
PLoS Medicine  2011;8(1):e1000387.
Aziz Sheikh and colleagues report the findings of their systematic overview that assessed the impact of eHealth solutions on the quality and safety of health care.
Background
There is considerable international interest in exploiting the potential of digital solutions to enhance the quality and safety of health care. Implementations of transformative eHealth technologies are underway globally, often at very considerable cost. In order to assess the impact of eHealth solutions on the quality and safety of health care, and to inform policy decisions on eHealth deployments, we undertook a systematic review of systematic reviews assessing the effectiveness and consequences of various eHealth technologies on the quality and safety of care.
Methods and Findings
We developed novel search strategies, conceptual maps of health care quality, safety, and eHealth interventions, and then systematically identified, scrutinised, and synthesised the systematic review literature. Major biomedical databases were searched to identify systematic reviews published between 1997 and 2010. Related theoretical, methodological, and technical material was also reviewed. We identified 53 systematic reviews that focused on assessing the impact of eHealth interventions on the quality and/or safety of health care and 55 supplementary systematic reviews providing relevant supportive information. This systematic review literature was found to be generally of substandard quality with regards to methodology, reporting, and utility. We thematically categorised eHealth technologies into three main areas: (1) storing, managing, and transmission of data; (2) clinical decision support; and (3) facilitating care from a distance. We found that despite support from policymakers, there was relatively little empirical evidence to substantiate many of the claims made in relation to these technologies. Whether the success of those relatively few solutions identified to improve quality and safety would continue if these were deployed beyond the contexts in which they were originally developed, has yet to be established. Importantly, best practice guidelines in effective development and deployment strategies are lacking.
Conclusions
There is a large gap between the postulated and empirically demonstrated benefits of eHealth technologies. In addition, there is a lack of robust research on the risks of implementing these technologies and their cost-effectiveness has yet to be demonstrated, despite being frequently promoted by policymakers and “techno-enthusiasts” as if this was a given. In the light of the paucity of evidence in relation to improvements in patient outcomes, as well as the lack of evidence on their cost-effectiveness, it is vital that future eHealth technologies are evaluated against a comprehensive set of measures, ideally throughout all stages of the technology's life cycle. Such evaluation should be characterised by careful attention to socio-technical factors to maximise the likelihood of successful implementation and adoption.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
There is considerable international interest in exploiting the potential of digital health care solutions, often referred to as eHealth—the use of information and communication technologies—to enhance the quality and safety of health care. Often accompanied by large costs, any large-scale expenditure on eHealth—such as electronic health records, picture archiving and communication systems, ePrescribing, associated computerized provider order entry systems, and computerized decision support systems—has tended to be justified on the grounds that these are efficient and cost-effective means for improving health care. In 2005, the World Health Assembly passed an eHealth resolution (WHA 58.28) that acknowledged, “eHealth is the cost-effective and secure use of information and communications technologies in support of health and health-related fields, including health-care services, health surveillance, health literature, and health education, knowledge and research,” and urged member states to develop and implement eHealth technologies. Since then, implementing eHealth technologies has become a main priority for many countries. For example, England has invested at least £12.8 billion in a National Programme for Information Technology for the National Health Service, and the Obama administration in the United States has committed to a US$38 billion eHealth investment in health care.
Why Was This Study Done?
Despite the wide endorsement of and support for eHealth, the scientific basis of its benefits—which are repeatedly made and often uncritically accepted—remains to be firmly established. A robust evidence-based perspective on the advantages on eHealth could help to suggest priority areas that have the greatest potential for benefit to patients and also to inform international eHealth deliberations on costs. Therefore, in order to better inform the international community, the authors systematically reviewed the published systematic review literature on eHealth technologies and evaluated the impact of these technologies on the quality and safety of health care delivery.
What Did the Researchers Do and Find?
The researchers divided eHealth technologies into three main categories: (1) storing, managing, and transmission of data; (2) clinical decision support; and (3) facilitating care from a distance. Then, implementing methods based on those developed by the Cochrane Collaboration and the NHS Service Delivery and Organisation Programme, the researchers used detailed search strategies and maps of health care quality, safety, and eHealth interventions to identify relevant systematic reviews (and related theoretical, methodological, and technical material) published between 1997 and 2010. Using these techniques, the researchers retrieved a total of 46,349 references from which they identified 108 reviews. The 53 reviews that the researchers finally selected (and critically reviewed) provided the main evidence base for assessing the impact of eHealth technologies in the three categories selected.
In their systematic review of systematic reviews, the researchers included electronic health records and picture archiving communications systems in their evaluation of category 1, computerized provider (or physician) order entry and e-prescribing in category 2, and all clinical information systems that, when used in the context of eHealth technologies, integrate clinical and demographic patient information to support clinician decision making in category 3.
The researchers found that many of the clinical claims made about the most commonly used eHealth technologies were not substantiated by empirical evidence. The evidence base in support of eHealth technologies was weak and inconsistent and importantly, there was insubstantial evidence to support the cost-effectiveness of these technologies. For example, the researchers only found limited evidence that some of the many presumed benefits could be realized; importantly, they also found some evidence that introducing these new technologies may on occasions also generate new risks such as prescribers becoming over-reliant on clinical decision support for e-prescribing, or overestimate its functionality, resulting in decreased practitioner performance.
What Do These Findings Mean?
The researchers found that despite the wide support for eHealth technologies and the frequently made claims by policy makers when constructing business cases to raise funds for large-scale eHealth projects, there is as yet relatively little empirical evidence to substantiate many of the claims made about eHealth technologies. In addition, even for the eHealth technology tools that have proven to be successful, there is little evidence to show that such tools would continue to be successful beyond the contexts in which they were originally developed. Therefore, in light of the lack of evidence in relation to improvements in patient outcomes, as well as the lack of evidence on their cost-effectiveness, the authors say that future eHealth technologies should be evaluated against a comprehensive set of measures, ideally throughout all stages of the technology's life cycle, and include socio-technical factors to maximize the likelihood of successful implementation and adoption in a given context. Furthermore, it is equally important that eHealth projects that have already been commissioned are subject to rigorous, multidisciplinary, and independent evaluation.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000387.
The authors' broader study is: Car J, Black A, Anandan C, Cresswell K, Pagliari C, McKinstry B, et al. (2008) The Impact of eHealth on the Quality and Safety of Healthcare. Available at: http://www.haps.bham.ac.uk/publichealth/cfhep/001.shtml
More information is available on the World Health Assembly eHealth resolution
The World Health Organization provides information at the Global Observatory on eHealth, as well as a global insight into eHealth developments
The European Commission provides Information on eHealth in Europe and some examples of good eHealth practice
More information is provided on NHS Connecting for Health
doi:10.1371/journal.pmed.1000387
PMCID: PMC3022523  PMID: 21267058
6.  Financial Conflicts of Interest and Reporting Bias Regarding the Association between Sugar-Sweetened Beverages and Weight Gain: A Systematic Review of Systematic Reviews 
PLoS Medicine  2013;10(12):e1001578.
Maira Bes-Rastrollo and colleagues examine whether financial conflicts of interest are likely to bias conclusions from systematic reviews that investigate the relationship between sugar-sweetened beverages and weight gain or obesity.
Please see later in the article for the Editors' Summary
Background
Industry sponsors' financial interests might bias the conclusions of scientific research. We examined whether financial industry funding or the disclosure of potential conflicts of interest influenced the results of published systematic reviews (SRs) conducted in the field of sugar-sweetened beverages (SSBs) and weight gain or obesity.
Methods and Findings
We conducted a search of the PubMed, Cochrane Library, and Scopus databases to identify published SRs from the inception of the databases to August 31, 2013, on the association between SSB consumption and weight gain or obesity. SR conclusions were independently classified by two researchers into two groups: those that found a positive association and those that did not. These two reviewers were blinded with respect to the stated source of funding and the disclosure of conflicts of interest.
We identified 17 SRs (with 18 conclusions). In six of the SRs a financial conflict of interest with some food industry was disclosed. Among those reviews without any reported conflict of interest, 83.3% of the conclusions (10/12) were that SSB consumption could be a potential risk factor for weight gain. In contrast, the same percentage of conclusions, 83.3% (5/6), of those SRs disclosing some financial conflict of interest with the food industry were that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain or obesity. Those reviews with conflicts of interest were five times more likely to present a conclusion of no positive association than those without them (relative risk: 5.0, 95% CI: 1.3–19.3).
An important limitation of this study is the impossibility of ruling out the existence of publication bias among those studies not declaring any conflict of interest. However, the best large randomized trials also support a direct association between SSB consumption and weight gain or obesity.
Conclusions
Financial conflicts of interest may bias conclusions from SRs on SSB consumption and weight gain or obesity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In our daily lives, we frequently rely on the results of scientific research to make decisions about our health. If we are healthy, we may seek out scientific advice about how much exercise to do to reduce our risk of a heart attack, and we may follow dietary advice issued by public health bodies to help us maintain a healthy weight. If we are ill, we expect our treatment to be based on the results of clinical trials and other studies. We assume that the scientific research that underlies our decisions about health-related issues is unbiased and accurate. However, there is increasing evidence that the conclusions of industry-sponsored scientific research are sometimes biased. So, for example, reports of drug trials sponsored by pharmaceutical companies sometimes emphasize the positive results of trials and “hide” unwanted side effects deep within the report or omit them altogether.
Why Was This Study Done?
Although the effects of company sponsors on the conclusions of pharmaceutical research have been extensively examined, little is known about the effects of industry sponsorship on nutrition research, even though large commercial entities are increasingly involved in global food and drink production. It is important to know whether the scientific evidence about nutrition is free of bias because biased information might negatively affect the health of entire populations. Moreover, scientific evidence from nutrition research underlies the formulation of governmental dietary guidelines and food-related public health interventions. In this systematic review, the researchers investigate whether the disclosure of potential financial conflicts of interest (for example, research funding by a beverage company) has influenced the results of systematic reviews undertaken to examine the association between the consumption of highly lucrative sugar-sweetened beverages (SSBs) and weight gain or obesity. Systematic reviews identify all the research on a given topic using predefined criteria. In an ideal world, systematic reviews provide access to all the available evidence on specific exposure–disease associations, but publication bias related to authors' conflicts of interest may affect the reliability of the conclusions of such studies.
What Did the Researchers Do and Find?
The researchers identified 18 conclusions from 17 systematic reviews that had investigated the association between SSB consumption and weight gain or obesity. In six of these reviews, a financial conflict of interest with a food industry was disclosed. Among the reviews that reported having no conflict of interest, 83.3% of the conclusions were that SSB consumption could be a potential risk factor for weight gain. By contrast, the same percentage of reviews in which a potential financial conflict of interest was disclosed concluded that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain, or reported contradictory results and did not state any definitive conclusion about the association between SSB consumption and weight gain. Reviews in which a potential conflict of interest was disclosed were five times more likely to present a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no financial conflict of interest.
What Do These Findings Mean?
These findings indicate that systematic reviews that reported financial conflicts of interest or sponsorship from food or drink companies were more likely to reach a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no conflicts of interest. A major limitation of this study is that it cannot assess which interpretation of the available evidence is truly accurate. For example, the scientists involved in the systematic reviews that reported having no conflict of interest may have had preexisting prejudices that affected their interpretation of their findings. However, the interests of the food industry (increased sales of their products) are very different from those of most researchers (the honest pursuit of knowledge), and recent randomized trials support a positive association between SSB consumption and overweight/obesity. Thus, these findings draw attention to possible inaccuracies in scientific evidence from research funded by the food and drink industry. They do not imply that industry sponsorship of nutrition research should be avoided entirely. Rather, as in other research areas, clear guidelines and principles (for example, sponsors should sign contracts that state that they will not be involved in the interpretation of results) need to be established to avoid dangerous conflicts of interest.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001578.
The Research Ethics Program at the University of California, San Diego provides an overview of conflicts of interest for researchers and details of US regulations and guidelines
The PLOS Medicine series on Big Food examines the activities and influence of the food industry in global health
A PLOS Medicine Research Article by Basu et al. uses mathematical modeling to investigate whether SSB taxation would avert obesity and diabetes in India
A 2012 policy brief from the Yale Rudd Center for Food Policy and Obesity discusses current evidence regarding SSB taxes
The US National Institutes of Health has regulations on financial conflicts of interest for institutions applying to receive funding
Wikipedia has pages on conflict of interest, reporting bias, systematic review, and SSBs (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001578
PMCID: PMC3876974  PMID: 24391479
7.  Tobacco Company Efforts to Influence the Food and Drug Administration-Commissioned Institute of Medicine Report Clearing the Smoke: An Analysis of Documents Released through Litigation 
PLoS Medicine  2013;10(5):e1001450.
Stanton Glantz and colleagues investigate efforts by tobacco companies to influence Clearing the Smoke, a 2001 Institute of Medicine report on harm reduction tobacco products.
Please see later in the article for the Editors' Summary
Background
Spurred by the creation of potential modified risk tobacco products, the US Food and Drug Administration (FDA) commissioned the Institute of Medicine (IOM) to assess the science base for tobacco “harm reduction,” leading to the 2001 IOM report Clearing the Smoke. The objective of this study was to determine how the tobacco industry organized to try to influence the IOM committee that prepared the report.
Methods and Findings
We analyzed previously secret tobacco industry documents in the University of California, San Francisco Legacy Tobacco Documents Library, and IOM public access files. (A limitation of this method includes the fact that the tobacco companies have withheld some possibly relevant documents.) Tobacco companies considered the IOM report to have high-stakes regulatory implications. They developed and implemented strategies with consulting and legal firms to access the IOM proceedings. When the IOM study staff invited the companies to provide information on exposure and disease markers, clinical trial design for safety and efficacy, and implications for initiation and cessation, tobacco company lawyers, consultants, and in-house regulatory staff shaped presentations from company scientists. Although the available evidence does not permit drawing cause-and-effect conclusions, and the IOM may have come to the same conclusions without the influence of the tobacco industry, the companies were pleased with the final report, particularly the recommendations for a tiered claims system (with separate tiers for exposure and risk, which they believed would ease the process of qualifying for a claim) and license to sell products comparable to existing conventional cigarettes (“substantial equivalence”) without prior regulatory approval. Some principles from the IOM report, including elements of the substantial equivalence recommendation, appear in the 2009 Family Smoking Prevention and Tobacco Control Act.
Conclusions
Tobacco companies strategically interacted with the IOM to win several favored scientific and regulatory recommendations.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Up to half of tobacco users will die of cancer, lung disease, heart disease, stroke, or another tobacco-related disease. Cigarettes and other tobacco products cause disease because they expose their users to nicotine and numerous other toxic chemicals. Tobacco companies have been working to develop a “safe” cigarette for more than half a century. Initially, their attention focused on cigarettes that produced lower tar and nicotine yields in machine-smoking tests. These products were perceived as “safer” products by the public and scientists for many years, but it is now known that the use of low-yield cigarettes can actually expose smokers to higher levels of toxins than standard cigarettes. More recently, the tobacco companies have developed other products (for example, products that heat aerosols of nicotine, rather than burning the tobacco) that claim to reduce harm and the risk of tobacco-related disease, but they can only market these modified risk tobacco products in the US after obtaining Food and Drug Administration (FDA) approval. In 1999, the FDA commissioned the US Institute of Medicine (IOM, an influential source of independent expert advice on medical issues) to assess the science base for tobacco “harm reduction.” In 2001, the IOM published its report Clearing the Smoke: Assessing the Science Base for Tobacco Harm and Reduction, which, although controversial, set the tone for the development and regulation of tobacco products in the US, particularly those claiming to be less dangerous, in subsequent years.
Why Was This Study Done?
Tobacco companies have a long history of working to shape scientific discussions and agendas. For example, they have produced research results designed to “create controversy” about the dangers of smoking and secondhand smoke. In this study, the researchers investigate how tobacco companies organized to try to influence the IOM committee that prepared the Clearing the Smoke report on modified risk tobacco products by analyzing tobacco industry and IOM documents.
What Did the Researchers Do and Find?
The researchers searched the Legacy Tobacco Documents Library (a collection of internal tobacco industry documents released as a result of US litigation cases) for documents outlining how tobacco companies tried to influence the IOM Committee to Assess the Science Base for Tobacco Harm Reduction and created a timeline of events from the 1,000 or so documents they retrieved. They confirmed and supplemented this timeline using information in 80 files that detailed written interactions between the tobacco companies and the IOM committee, which they obtained through a public records access request. Analysis of these documents indicates that the tobacco companies considered the IOM report to have important regulatory implications, that they developed and implemented strategies with consulting and legal firms to access the IOM proceedings, and that tobacco company lawyers, consultants, and regulatory staff shaped presentations to the IOM committee by company scientists on various aspects of tobacco harm reduction products. The analysis also shows that tobacco companies were pleased with the final report, particularly its recommendation that tobacco products can be marketed with exposure or risk reduction claims provided the products substantially reduce exposure and provided the behavioral and health consequences of these products are determined in post-marketing surveillance and epidemiological studies (“tiered testing”) and its recommendation that, provided no claim of reduced exposure or risk is made, new products comparable to existing conventional cigarettes (“substantial equivalence”) can be marketed without prior regulatory approval.
What Do These Findings Mean?
These findings suggest that tobacco companies used their legal and regulatory staff to access the IOM committee that advised the FDA on modified risk tobacco products and that they used this access to deliver specific, carefully formulated messages designed to serve their business interests. Although these findings provide no evidence that the efforts of tobacco companies influenced the IOM committee in any way, they show that the companies were satisfied with the final IOM report and its recommendations, some of which have policy implications that continue to reverberate today. The researchers therefore call for the FDA and other regulatory bodies to remember that they are dealing with companies with a long history of intentionally misleading the public when assessing the information presented by tobacco companies as part of the regulatory process and to actively protect their public-health policies from the commercial interests of the tobacco industry.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001450.
This study is further discussed in a PLOS Medicine Perspective by Thomas Novotny
The World Health Organization provides information about the dangers of tobacco (in several languages); for information about the tobacco industry's influence on policy, see the 2009 World Health Organization report Tobacco interference with tobacco control
A PLOS Medicine Research Article by Heide Weishaar and colleagues describes tobacco company efforts to undermine the Framework Convention on Tobacco Control, an international instrument for tobacco control
Wikipedia has a page on tobacco harm reduction (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The IOM report Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction is available to read online
The Legacy Tobacco Documents Library is a public, searchable database of tobacco company internal documents detailing their advertising, manufacturing, marketing, sales, and scientific activities
The University of California, San Francisco Center for Tobacco Control Research and Education is the focal point for University of California, San Francisco (UCSF) scientists in disciplines ranging from the molecular biology of nicotine addiction through political science who combine their efforts to eradicate the use of tobacco and tobacco-induced cancer and other diseases worldwide
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001450
PMCID: PMC3665841  PMID: 23723740
8.  TriMEDB: A database to integrate transcribed markers and facilitate genetic studies of the tribe Triticeae 
BMC Plant Biology  2008;8:72.
Background
The recent rapid accumulation of sequence resources of various crop species ensures an improvement in the genetics approach, including quantitative trait loci (QTL) analysis as well as the holistic population analysis and association mapping of natural variations. Because the tribe Triticeae includes important cereals such as wheat and barley, integration of information on the genetic markers in these crops should effectively accelerate map-based genetic studies on Triticeae species and lead to the discovery of key loci involved in plant productivity, which can contribute to sustainable food production. Therefore, informatics applications and a semantic knowledgebase of genome-wide markers are required for the integration of information on and further development of genetic markers in wheat and barley in order to advance conventional marker-assisted genetic analyses and population genomics of Triticeae species.
Description
The Triticeae mapped expressed sequence tag (EST) database (TriMEDB) provides information, along with various annotations, regarding mapped cDNA markers that are related to barley and their homologues in wheat. The current version of TriMEDB provides map-location data for barley and wheat ESTs that were retrieved from 3 published barley linkage maps (the barley single nucleotide polymorphism database of the Scottish Crop Research Institute, the barley transcript map of Leibniz Institute of Plant Genetics and Crop Plant Research, and HarvEST barley ver. 1.63) and 1 diploid wheat map. These data were imported to CMap to allow the visualization of the map positions of the ESTs and interrelationships of these ESTs with public gene models and representative cDNA sequences. The retrieved cDNA sequences corresponding to each EST marker were assigned to the rice genome to predict an exon-intron structure. Furthermore, to generate a unique set of EST markers in Triticeae plants among the public domain, 3472 markers were assembled to form 2737 unique marker groups as contigs. These contigs were applied for pairwise comparison among linkage maps obtained from different EST map resources.
Conclusion
TriMEDB provides information regarding transcribed genetic markers and functions as a semantic knowledgebase offering an informatics facility for the acceleration of QTL analysis and for population genetics studies of Triticeae.
doi:10.1186/1471-2229-8-72
PMCID: PMC2474609  PMID: 18590523
9.  The Toxic Effects of Cigarette Additives. Philip Morris' Project Mix Reconsidered: An Analysis of Documents Released through Litigation 
PLoS Medicine  2011;8(12):e1001145.
Stanton Glantz and colleagues analyzed previously secret tobacco industry documents and peer-reviewed published results of Philip Morris' Project MIX about research on cigarette additives, and show that this research on the use of cigarette additives cannot be taken at face value.
Background
In 2009, the promulgation of US Food and Drug Administration (FDA) tobacco regulation focused attention on cigarette flavor additives. The tobacco industry had prepared for this eventuality by initiating a research program focusing on additive toxicity. The objective of this study was to analyze Philip Morris' Project MIX as a case study of tobacco industry scientific research being positioned strategically to prevent anticipated tobacco control regulations.
Methods and Findings
We analyzed previously secret tobacco industry documents to identify internal strategies for research on cigarette additives and reanalyzed tobacco industry peer-reviewed published results of this research. We focused on the key group of studies conducted by Phillip Morris in a coordinated effort known as “Project MIX.” Documents showed that Project MIX subsumed the study of various combinations of 333 cigarette additives. In addition to multiple internal reports, this work also led to four peer-reviewed publications (published in 2001). These papers concluded that there was no evidence of substantial toxicity attributable to the cigarette additives studied. Internal documents revealed post hoc changes in analytical protocols after initial statistical findings indicated an additive-associated increase in cigarette toxicity as well as increased total particulate matter (TPM) concentrations in additive-modified cigarette smoke. By expressing the data adjusted by TPM concentration, the published papers obscured this underlying toxicity and particulate increase. The animal toxicology results were based on a small number of rats in each experiment, raising the possibility that the failure to detect statistically significant changes in the end points was due to underpowering the experiments rather than lack of a real effect.
Conclusion
The case study of Project MIX shows tobacco industry scientific research on the use of cigarette additives cannot be taken at face value. The results demonstrate that toxins in cigarette smoke increase substantially when additives are put in cigarettes, including the level of TPM. In particular, regulatory authorities, including the FDA and similar agencies elsewhere, could use the Project MIX data to eliminate the use of these 333 additives (including menthol) from cigarettes.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The tobacco industry in the United States has recognized that regulation of its products was inevitable as early as 1963 and devoted increasing attention to the likelihood of regulation by the US Food and Drug Administration in the mid-1990s, which finally became law in 2009. In addition, the World Health Organization (WHO) Framework Convention on Tobacco Control (WHO FCTC), which came into force in June 2003, includes provisions addressing the regulation of the contents of tobacco products and the regulation of tobacco product disclosures. Although these steps represent progress in tobacco control, the events of the past few decades show the determination of the tobacco industry to avoid regulation, including the regulation of additives. In the United States, executives of the tobacco company Philip Morris (PM) recognized the inevitability of regulation and responded by initiating efforts to shape legislation and regulation by reorganizing its internal scientific activities and conducting scientific research that could be used to shape any proposed regulations. For example, the company conducted “Project MIX,” a study of chemical constituents in and toxicity of smoke produced by burning cigarettes containing three different combinations of 333 cigarette additives that “were constructed to resemble typical commercial blended cigarettes.” The resulting four papers published in Food and Chemical Toxicology in January 2002 concluded that there was no evidence of substantial toxicity attributable to the cigarette additives studied.
Why Was This Study Done?
The use of cigarette additives is an important concern of the WHO, FDA, and similar national regulatory bodies around the world. Philip Morris has used the published Project MIX papers to assert the safety of individual additives and other cigarette companies have done similar studies that reached similar conclusions. In this study, the researchers used documents made public as a result of litigation against the tobacco industry to investigate the origins and design of Project MIX and to conduct their own analyses of the results to assess the reliability of the conclusions in the papers published in Food and Chemical Toxicology.
What Did the Researchers Do and Find?
The researchers systematically examined tobacco industry documents in the University of California San Francisco Legacy Tobacco Documents Library (then about 60 million pages made publicly available as a result of litigation) and used an iterative process of searching, analyzing, and refining to identify and review in detail 500 relevant documents.
The researchers found that in the original Project MIX analysis, the published papers obscured findings of toxicity by adjusting the data by total particulate matter (TPM) concentration. When the researchers conducted their own analysis by studying additives per cigarette (as was specified in the original Project MIX protocol), they found that 15 carcinogenic chemicals increased by 20%. The researchers also reported that, for unexplained reasons, Philip Morris deemphasized 19 of the 51 chemicals tested in the presentation of results, including nine that were substantially increased in smoke on a per cigarette basis of additive-added cigarettes, compared to smoke of control cigarettes.
The researchers explored the possibility that the failure of Project MIX to detect statistically significant changes in the toxicity of the smoke from cigarettes containing the additives was due to underpowered experiments rather than lack of a real effect by conducting their own statistical analysis. This analysis suggests that a better powered study would have detected a much broader range of biological effects associated with the additives than was identified in Philip Morris' published paper, suggesting that it substantially underestimated the toxic potential of cigarette smoke and additives.
The researchers also found that Food and Chemical Toxicology, the journal in which the four Project MIX papers were published, had an editor and 11 of its International Editorial Board with documented links to the tobacco industry. The scientist and leader of Project MIX Edward Carmines described the process of publication as “an inside job.”
What Do These Findings Mean?
These findings show that the tobacco industry scientific research on the use of cigarette additives cannot be taken at face value: the results demonstrate that toxins in cigarette smoke increase substantially when additives are put in cigarettes. In addition, better powered studies would probably have detected a much broader range of adverse biological effects associated with the additives than identified to those identified in PM's published papers suggesting that the published papers substantially underestimate the toxic potential combination of cigarette smoke and additives.
Regulatory authorities, including the FDA and similar agencies elsewhere who are implementing WHO FCTC, should conduct their own independent analysis of Project MIX data, which, analyzed correctly, could provide a strong evidence base for the elimination of the use of the studied additives (including menthol) in cigarettes on public health grounds.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001145.
For PLoS Medicine's own policy on publishing papers sponsored by the tobacco industry see http://www.plosmedicine.org/static/policies.action#funders
The World Health Organization (WHO) provides information on the Framework Convention on Tobacco Control (FCTC)
The documents that the researchers reviewed in this paper can be found at the Legacy Tobacco Documents Library
doi:10.1371/journal.pmed.1001145
PMCID: PMC3243707  PMID: 22205885
10.  Signaling network of dendritic cells in response to pathogens: a community-input supported knowledgebase 
BMC Systems Biology  2010;4:137.
Background
Dendritic cells are antigen-presenting cells that play an essential role in linking the innate and adaptive immune systems. Much research has focused on the signaling pathways triggered upon infection of dendritic cells by various pathogens. The high level of activity in the field makes it desirable to have a pathway-based resource to access the information in the literature. Current pathway diagrams lack either comprehensiveness, or an open-access editorial interface. Hence, there is a need for a dependable, expertly curated knowledgebase that integrates this information into a map of signaling networks.
Description
We have built a detailed diagram of the dendritic cell signaling network, with the goal of providing researchers with a valuable resource and a facile method for community input. Network construction has relied on comprehensive review of the literature and regular updates. The diagram includes detailed depictions of pathways activated downstream of different pathogen recognition receptors such as Toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors and nucleotide-binding oligomerization domain-like receptors. Initially assembled using CellDesigner software, it provides an annotated graphical representation of interactions stored in Systems Biology Mark-up Language. The network, which comprises 249 nodes and 213 edges, has been web-published through the Biological Pathway Publisher software suite. Nodes are annotated with PubMed references and gene-related information, and linked to a public wiki, providing a discussion forum for updates and corrections. To gain more insight into regulatory patterns of dendritic cell signaling, we analyzed the network using graph-theory methods: bifan, feedforward and multi-input convergence motifs were enriched. This emphasis on activating control mechanisms is consonant with a network that subserves persistent and coordinated responses to pathogen detection.
Conclusions
This map represents a navigable aid for presenting a consensus view of the current knowledge on dendritic cell signaling that can be continuously improved through contributions of research community experts. Because the map is available in a machine readable format, it can be edited and may assist researchers in data analysis. Furthermore, the availability of a comprehensive knowledgebase might help further research in this area such as vaccine development. The dendritic cell signaling knowledgebase is accessible at http://tsb.mssm.edu/pathwayPublisher/DC_pathway/DC_pathway_index.html.
doi:10.1186/1752-0509-4-137
PMCID: PMC2958907  PMID: 20929569
11.  CMKb: a web-based prototype for integrating Australian Aboriginal customary medicinal plant knowledge 
BMC Bioinformatics  2008;9(Suppl 12):S25.
Background
The customary medicinal plant knowledge possessed by the Australian Aboriginal people is a significant resource. Published information on it is scattered throughout the literature, in heterogeneous data formats, and is scattered among various Aboriginal communities across Australia, due to a multiplicity of languages. This ancient knowledge is at risk due to loss of biodiversity, cultural impact and the demise of many of its custodians. We have developed the Customary Medicinal Knowledgebase (CMKb), an integrated multidisciplinary resource, to document, conserve and disseminate this knowledge.
Description
CMKb is an online relational database for collating, disseminating, visualising and analysing initially public domain data on customary medicinal plants. The database stores information related to taxonomy, phytochemistry, biogeography, biological activities of customary medicinal plant species as well as images of individual species. The database can be accessed at . Known bioactive molecules are characterized within the chemoinformatics module of CMKb, with functions available for molecular editing and visualization.
Conclusion
CMKb has been developed as a prototype data resource for documenting, integrating, disseminating, analysing multidisciplinary customary medicinal plant data from Australia and to facilitate user-defined complex querying. Each species in CMKb is linked to online resources such as the Integrated Taxonomic Information System (ITIS), NCBI Taxonomy, Australia's SpeciesLinks-Integrated Botanical Information System (IBIS) and Google images. The bioactive compounds are linked to the PubChem database. Overall, CMKb serves as a single knowledgebase for holistic plant-derived therapeutics and can be used as an information resource for biodiversity conservation, to lead discovery and conservation of customary medicinal knowledge.
doi:10.1186/1471-2105-9-S12-S25
PMCID: PMC2638165  PMID: 19091025
12.  Automatic Figure Ranking and User Interfacing for Intelligent Figure Search 
PLoS ONE  2010;5(10):e12983.
Background
Figures are important experimental results that are typically reported in full-text bioscience articles. Bioscience researchers need to access figures to validate research facts and to formulate or to test novel research hypotheses. On the other hand, the sheer volume of bioscience literature has made it difficult to access figures. Therefore, we are developing an intelligent figure search engine (http://figuresearch.askhermes.org). Existing research in figure search treats each figure equally, but we introduce a novel concept of “figure ranking”: figures appearing in a full-text biomedical article can be ranked by their contribution to the knowledge discovery.
Methodology/Findings
We empirically validated the hypothesis of figure ranking with over 100 bioscience researchers, and then developed unsupervised natural language processing (NLP) approaches to automatically rank figures. Evaluating on a collection of 202 full-text articles in which authors have ranked the figures based on importance, our best system achieved a weighted error rate of 0.2, which is significantly better than several other baseline systems we explored. We further explored a user interfacing application in which we built novel user interfaces (UIs) incorporating figure ranking, allowing bioscience researchers to efficiently access important figures. Our evaluation results show that 92% of the bioscience researchers prefer as the top two choices the user interfaces in which the most important figures are enlarged. With our automatic figure ranking NLP system, bioscience researchers preferred the UIs in which the most important figures were predicted by our NLP system than the UIs in which the most important figures were randomly assigned. In addition, our results show that there was no statistical difference in bioscience researchers' preference in the UIs generated by automatic figure ranking and UIs by human ranking annotation.
Conclusion/Significance
The evaluation results conclude that automatic figure ranking and user interfacing as we reported in this study can be fully implemented in online publishing. The novel user interface integrated with the automatic figure ranking system provides a more efficient and robust way to access scientific information in the biomedical domain, which will further enhance our existing figure search engine to better facilitate accessing figures of interest for bioscientists.
doi:10.1371/journal.pone.0012983
PMCID: PMC2951344  PMID: 20949102
13.  Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US 
PLoS Medicine  2006;3(10):e342.
Background
Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case.
Methods and Findings
A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible vCJD contamination in the UK, contributed to a greater sense of urgency and a speedier implementation of regulations in that country. Third, while the results of scientific studies played a prominent role in the construction of regulations in both nations, this role was shaped by existing social and professional networks. In the UK, early focus on a European study implicating B-lymphocytes as the carrier of prion infectivity in blood led to the introduction of a policy that requires universal leukoreduction of blood components. In the US, early focus on an American study highlighting the ability of plasma to serve as a reservoir of prion infectivity led the FDA and its advisory panel to eschew similar measures.
Conclusions
The results of this study yield three important theoretical insights that pertain to the global management of emerging infectious diseases. First, because the perception and management of disease may be shaped by previous experience with disease, especially catastrophic experience, there is always the possibility for over-management of some possible routes of transmission and relative neglect of others. Second, local specificities within a given nation may influence the temporality of decision making, which in turn may influence the choice of disease management policies. Third, a preference for science-based risk management among nations will not necessarily lead to homogeneous policies. This is because the exposure to and interpretation of scientific results depends on the existing social and professional networks within a given nation. Together, these theoretical insights provide a framework for analyzing and anticipating potential conflicts in the international management of emerging infectious diseases. In addition, this study illustrates the utility of qualitative methods in investigating research questions that are difficult to assess through quantitative means.
A qualitative study of US and UK governmental policy statements on the topic of vCJD and blood transfusion transmission identified factors responsible for differences in the policies adopted.
Editors' Summary
Background.
In 1996 in the UK, a new type of human prion disease was seen for the first time. This is now known as variant Creutzfeldt-Jakob disease (vCJD). Prion diseases are rare brain diseases passed from individual to individual (or between animals) by a particular type of wrongly folded protein, and they are fatal. It was suspected that vCJD had passed to humans from cattle, and that the agent causing vCJD was the same as that causing bovine spongiform encephalopathy (or “mad cow disease”). Shortly after vCJD was recognized, authorities in many countries became concerned about the possibility that it could be transmitted from one person to another through contaminated blood supplies used for transfusion in hospitals. Even though there wasn't any evidence of actual transmission of the disease through blood before December 2003, authorities in the UK, US, and elsewhere set up regulations designed to reduce the chance of that happening. At this early stage in the epidemic, there was little in the way of scientific information about the transmission properties of the disease. Both the UK and US, however, sought to make decisions in a scientific manner. They made use of evidence as it was being produced, often before it had been published. Despite this, the UK and US decided on very different changes to their respective regulations on blood donation. Both countries chose to prevent certain people (who they thought would be at greater risk of having vCJD) from donating blood. In the UK, however, the decision was made to remove white blood cells from donated blood to reduce the risk of transmitting vCJD, while the US decided that such a step was not merited by the evidence.
Why Was This Study Done?
This researcher wanted to understand more clearly why the UK and US ended up with different policies: what role was played by science, and what role was played by non-scientific factors? She hoped that insights from this investigation would also be relevant to similar challenges in the future—for example, as many countries try to work out how to control the threat of avian flu.
What Did the Researcher Do and Find?
The researcher searched for all relevant official government documents from the US and UK, as well as scientific papers, published between the time vCJD was first identified (March 1996) and the first instance of vCJD carried through blood (December 2003). She also interviewed people who knew about vCJD management in the US and UK—for example, members of government agencies and the relevant advisory committees. From the documents and interviews, the researcher picked out and grouped shared ideas. Although these documents and interviews suggested that policy making was rooted in scientific evidence, many non-scientific factors were also important. The researcher found substantial uncertainty in the scientific evidence available at the time. The document search and interviews showed that policy makers felt guilty about a previous experience in which people had become infected with HIV/AIDS through contaminated blood and were concerned about repeating this experience. Finally, in the UK, the possibility of blood contamination was seen as a much more urgent problem than in the US, because BSE and vCJD were found there first and there were far more cases. This meant that when the UK made its decision about whether to remove white blood cells from donated blood, there was less scientific evidence available. In fact, the main study that was relied on at the time would later be questioned.
What Do These Findings Mean?
These findings show that for this particular case, science was not the only factor affecting government policies. Historical and social factors such as previous experience, sense of urgency, public pressure, and the relative importance of different scientific networks were also very important. The study predicts that in the future, infectious disease–related policy decisions are unlikely to be the same across different countries because the interpretation of scientific evidence depends, to a large extent, on social factors.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030342.
National Creutzfeldt-Jakob Disease Surveillance Unit, Edinburgh, UK
US Centers for Disease Control and Prevention pages about prion diseases
World Health Organization variant Creutzfeldt-Jakob disease fact sheet
US National Institute of Neurological Disorders and Stroke information about prion diseases
doi:10.1371/journal.pmed.0030342
PMCID: PMC1621089  PMID: 17076547
14.  DAVID Knowledgebase: a gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis 
BMC Bioinformatics  2007;8:426.
Background
Due to the complex and distributed nature of biological research, our current biological knowledge is spread over many redundant annotation databases maintained by many independent groups. Analysts usually need to visit many of these bioinformatics databases in order to integrate comprehensive annotation information for their genes, which becomes one of the bottlenecks, particularly for the analytic task associated with a large gene list. Thus, a highly centralized and ready-to-use gene-annotation knowledgebase is in demand for high throughput gene functional analysis.
Description
The DAVID Knowledgebase is built around the DAVID Gene Concept, a single-linkage method to agglomerate tens of millions of gene/protein identifiers from a variety of public genomic resources into DAVID gene clusters. The grouping of such identifiers improves the cross-reference capability, particularly across NCBI and UniProt systems, enabling more than 40 publicly available functional annotation sources to be comprehensively integrated and centralized by the DAVID gene clusters. The simple, pair-wise, text format files which make up the DAVID Knowledgebase are freely downloadable for various data analysis uses. In addition, a well organized web interface allows users to query different types of heterogeneous annotations in a high-throughput manner.
Conclusion
The DAVID Knowledgebase is designed to facilitate high throughput gene functional analysis. For a given gene list, it not only provides the quick accessibility to a wide range of heterogeneous annotation data in a centralized location, but also enriches the level of biological information for an individual gene. Moreover, the entire DAVID Knowledgebase is freely downloadable or searchable at .
doi:10.1186/1471-2105-8-426
PMCID: PMC2186358  PMID: 17980028
15.  Adherence to HAART: A Systematic Review of Developed and Developing Nation Patient-Reported Barriers and Facilitators 
PLoS Medicine  2006;3(11):e438.
Background
Adherence to highly active antiretroviral therapy (HAART) medication is the greatest patient-enabled predictor of treatment success and mortality for those who have access to drugs. We systematically reviewed the literature to determine patient-reported barriers and facilitators to adhering to antiretroviral therapy.
Methods and Findings
We examined both developed and developing nations. We searched the following databases: AMED (inception to June 2005), Campbell Collaboration (inception to June 2005), CinAhl (inception to June 2005), Cochrane Library (inception to June 2005), Embase (inception to June 2005), ERIC (inception to June 2005), MedLine (inception to June 2005), and NHS EED (inception to June 2005). We retrieved studies conducted in both developed and developing nation settings that examined barriers and facilitators addressing adherence. Both qualitative and quantitative studies were included. We independently, in duplicate, extracted data reported in qualitative studies addressing adherence. We then examined all quantitative studies addressing barriers and facilitators noted from the qualitative studies. In order to place the findings of the qualitative studies in a generalizable context, we meta-analyzed the surveys to determine a best estimate of the overall prevalence of issues. We included 37 qualitative studies and 47 studies using a quantitative methodology (surveys). Seventy-two studies (35 qualitative) were conducted in developed nations, while the remaining 12 (two qualitative) were conducted in developing nations. Important barriers reported in both economic settings included fear of disclosure, concomitant substance abuse, forgetfulness, suspicions of treatment, regimens that are too complicated, number of pills required, decreased quality of life, work and family responsibilities, falling asleep, and access to medication. Important facilitators reported by patients in developed nation settings included having a sense of self-worth, seeing positive effects of antiretrovirals, accepting their seropositivity, understanding the need for strict adherence, making use of reminder tools, and having a simple regimen. Among 37 separate meta-analyses examining the generalizability of these findings, we found large heterogeneity.
Conclusions
We found that important barriers to adherence are consistent across multiple settings and countries. Research is urgently needed to determine patient-important factors for adherence in developing world settings. Clinicians should use this information to engage in open discussion with patients to promote adherence and identify barriers and facilitators within their own populations.
An analysis of qualitative and quantitative studies found consistent barriers to adherence to HIV therapy across multiple settings and countries, ranging from access to medication to problems with complicated regimens.
Editors' Summary
Background.
The World Health Organization has estimated that in 2005, about 38 million people worldwide were living with HIV/AIDS; the mortality caused by HIV/AIDS is very high. Antiretroviral drugs are effective at controlling the disease and extending life span. However, it is important for people to stick to the drug regimens exactly in order to keep levels of HIV low, prevent it from becoming resistant to drugs, and stop the illness from progressing. However, many people find it very difficult to take antiretroviral drugs precisely as they should. There is already some evidence from research studies on the reasons why this is the case. There are two different research approaches taken by these studies: “qualitative” methods, which try to find out about attitudes and behaviors using focus groups, interviews, or other techniques; and “quantitative” methods, which try to find out about peoples' opinions and experience using surveys with set questions for the participants to answer, and then count the different responses.
Why Was This Study Done?
The investigators wanted to put together all of the available evidence from published research studies (called doing a “systematic review”) on which factors affected people's adherence to antiretroviral drugs. They wanted to do a systematic review because it is thought to be a very rigorous way of appraising all the available evidence (although there is considerable debate about the value of using such a method to analyze the results of qualitative research).
What Did the Researchers Do and Find?
The study team searched biomedical literature databases as well as conference abstracts and research registries using a defined set of search queries. They screened all the scientific papers they found; those reporting results of original research into factors affecting antiretroviral adherence were then analyzed in more detail. 84 relevant studies were identified, of which 37 used “qualitative” methods (focus groups, interviews, open-ended questioning) and 47 used “quantitative” methods (surveys). Most of these studies had been carried out in the developed world. Then, the researchers extracted the factors affecting adherence from the original studies, which could be either “positive” factors (helping adherence) or “negative” ones (making adherence more difficult). They classified the factors into four key themes: “patient related” (e.g., seeing positive results, fear of disclosure, being depressed); “beliefs about medication” (e.g., faith in how well the drugs worked, side effects); “daily schedules” (e.g., using reminder tools, disruptions to routine); and “interpersonal relationships” (e.g., trusting relations with health-care provider; social isolation).
  Many barriers to adherence were common to both developed and developing settings. Some factors were unique to the studies conducted in the developing world, such as financial constraints and problems with traveling to get access to treatment. Fear of disclosure was an important barrier identified in many of the studies.
What Do These Findings Mean?
The researchers combined the results of many different studies and identified factors that help or obstruct adherence to antiretroviral treatment. By identifying influences common to the different settings, greater weight can be placed on the factors that were identified. Only 12 of the studies included in this research were from the developing world, where the majority of HIV/AIDS patients live; hence more work is needed to examine and address the factors influencing antiretroviral adherence in these parts of the world. This study provides researchers and health policy makers with a starting point for changes that might help to ensure greater adherence to antiretroviral treatment.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030438.
Medline Plus information on AIDS medicines (Medline Plus is a service of the US National Library of Medicine and the National Institutes of Health)
Joint United Nations Programme on HIV/AIDS has information about the state of the HIV/AIDS epidemic worldwide
The World Health Organization has an HIV/AIDS program site providing comprehensive information on the HIV/AIDS epidemic worldwide
The World Health Organization pages on antiretroviral therapy
doi:10.1371/journal.pmed.0030438
PMCID: PMC1637123  PMID: 17121449
16.  United States Private-Sector Physicians and Pharmaceutical Contract Research: A Qualitative Study 
PLoS Medicine  2012;9(7):e1001271.
Jill Fisher and Corey Kalbaugh describe their findings from a qualitative research study evaluating the motivations of private-sector physicians conducting contract research for the pharmaceutical industry.
Background
There have been dramatic increases over the past 20 years in the number of nonacademic, private-sector physicians who serve as principal investigators on US clinical trials sponsored by the pharmaceutical industry. However, there has been little research on the implications of these investigators' role in clinical investigation. Our objective was to study private-sector clinics involved in US pharmaceutical clinical trials to understand the contract research arrangements supporting drug development, and specifically how private-sector physicians engaged in contract research describe their professional identities.
Methods and Findings
We conducted a qualitative study in 2003–2004 combining observation at 25 private-sector research organizations in the southwestern United States and 63 semi-structured interviews with physicians, research staff, and research participants at those clinics. We used grounded theory to analyze and interpret our data. The 11 private-sector physicians who participated in our study reported becoming principal investigators on industry clinical trials primarily because contract research provides an additional revenue stream. The physicians reported that they saw themselves as trial practitioners and as businesspeople rather than as scientists or researchers.
Conclusions
Our findings suggest that in addition to having financial motivation to participate in contract research, these US private-sector physicians have a professional identity aligned with an industry-based approach to research ethics. The generalizability of these findings and whether they have changed in the intervening years should be addressed in future studies.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Before a new drug can be used routinely by physicians, it must be investigated in clinical trials—studies that test the drug's safety and effectiveness in people. In the past, clinical trials were usually undertaken in academic medical centers (institutes where physicians provide clinical care, do research, and teach), but increasingly, clinical trials are being conducted in the private sector as part of a growing contract research system. In the US, for example, most clinical trials completed in the 1980s took place in academic medical centers, but nowadays, more than 70% of trials are conducted by nonacademic (community) physicians working under contract to pharmaceutical companies. The number of private-sector nonacademic physicians serving as principal investigators (PIs) for US clinical trials (the PI takes direct responsibility for completion of the trial) increased from 4,000 in 1990 to 20,250 in 2010, and research contracts for clinical trials are now worth more than USṩ11 billion annually.
Why Was This Study Done?
To date, there has been little research on the implications of this change in the conduct of clinical trials. Academic PIs are often involved in both laboratory and clinical research and are therefore likely to identify closely with the science of trials. By contrast, nonacademic PIs may see clinical trials more as a business opportunity—pharmaceutical contract research is profitable to US physicians because they get paid for every step of the trial process. As a result, pharmaceutical companies may now have more control over clinical trial data and more opportunities to suppress negative data through selective publication of study results than previously. In this qualitative study, the researchers explore the outsourcing of clinical trials to private-sector research clinics through observations of, and in-depth interviews with, physicians and other research staff involved in the US clinical trials industry. A qualitative study collects non-quantitative data such as how physicians feel about doing contract research and about their responsibilities to their patients.
What Did the Researchers Do and Find?
Between October 2003 and September 2004, the researchers observed the interactions between PIs, trial coordinators (individuals who undertake many of the trial activities such as blood collection), and trial participants at 25 US research organizations in the southwestern US and interviewed 63 informants (including 12 PIs) about the trials they were involved in and their reasons for becoming involved. The researchers found that private-sector physicians became PIs on industry-sponsored clinical trials primarily because contract research was financially lucrative. The physicians perceived their roles in terms of business rather than science and claimed that they offered something to the pharmaceutical industry that academics do not—the ability to carry out a diverse range of trials quickly and effectively, regardless of their medical specialty. Finally, the physicians saw their primary ethical responsibility as providing accurate data to the companies that hired them and did not explicitly refer to their ethical responsibility to trial participants. One possible reason for this shift in ethical concerns is the belief among private-sector physicians that pharmaceutical companies must be making scientifically and ethically sound decisions when designing trials because of the amount of money they invest in them.
What Do These Findings Mean?
These findings suggest that private-sector physicians participate as PIs in pharmaceutical clinical trials primarily for financial reasons and see themselves as trial practitioners and businesspeople rather than as scientists. The accuracy of these findings is likely to be limited by the small number of PIs interviewed and by the time that has elapsed since the researchers collected their qualitative data. Moreover, these findings may not be generalizable to other regions of the US or to other countries. Nevertheless, they have potentially troubling implications for drug development. By hiring private-sector physicians who see themselves as involved more with the business than the science of contract research, pharmaceutical companies may be able to exert more control over the conduct of clinical trials and the publication of trial results than previously. Compared to the traditional investigatorinitiated system of clinical research, this new system of contract research means that clinical trials now lack the independence that is at the heart of best science practices, a development that casts doubt on the robustness of the knowledge being produced about the safety and effectiveness of new drugs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001271.
The ClinicalTrials.gov website is a searchable register of federally and privately supported clinical trials in the US; it provides information about all aspects of clinical trials
The US National Institutes of Health provides information about clinical trials, including personal stories about clinical trials from patients and researchers
The UK National Health Service Choices website has information for patients about clinical trials and medical research, including personal stories about participating in clinical trials
The UK Medical Research Council Clinical Trials Unit also provides information for patients about clinical trials and links to information on clinical trials provided by other organizations
MedlinePlus has links to further resources on clinical trials (in English and Spanish)
doi:10.1371/journal.pmed.1001271
PMCID: PMC3404112  PMID: 22911055
17.  Promotional Tone in Reviews of Menopausal Hormone Therapy After the Women's Health Initiative: An Analysis of Published Articles 
PLoS Medicine  2011;8(3):e1000425.
Adriane Fugh-Berman and colleagues analyzed a selection of published opinion pieces on hormone therapy and show that there may be a connection between receiving industry funding for speaking, consulting, or research and the tone of such opinion pieces.
Background
Even after the Women's Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women's health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy.
Methods and Findings
We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ = 0.57) and substantial agreement for promotional tone (κ = 0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p = 0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49–4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles.
Conclusion
There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over the past three decades, menopausal hormones have been heavily promoted for preventing disease in women. However, the Women's Health Initiative (WHI) study—which enrolled more than 26,000 women in the US and which was published in 2004—found that estrogen-progestin and estrogen-only formulations (often prescribed to women around the age of menopause) increased the risk of stroke, deep vein thrombosis, dementia, and incontinence. Furthermore, this study found that the estrogen-progestin therapy increased rates of breast cancer. In fact, the estrogen-progestin arm of the WHI study was stopped in 2002 due to harmful findings, and the estrogen-only arm was stopped in 2004, also because of harmful findings. In addition, the study also found that neither therapy reduced cardiovascular risk or markedly benefited health-related quality of life measures.
Despite these results, two years after the results of WHI study were published, a survey of over 700 practicing gynecologists—the specialists who prescribe the majority of menopausal hormone therapies—in the US found that almost half did not find the findings of the WHI study convincing and that 48% disagreed with the decision to stop the trial early. Furthermore, follow-up surveys found similar results.
Why Was This Study Done?
It is unclear why gynecologists and other physicians continue to prescribe menopausal hormone therapies despite the results of the WHI. Some academics argue that published industry-funded reviews and commentaries may be designed to convey specific, but subtle, marketing messages and several academic analyses have used internal industry documents disclosed in litigation cases. So this study was conducted to investigate whether hormone therapy–promoting tone could be identified in narrative review articles and if so, whether these articles were more likely to have been authored by people who had accepted funding from hormone manufacturers.
What Did the Researchers Do and Find?
The researchers conducted a comprehensive literature search that identified 340 relevant articles published between July 2002 and June 2006—the four years following the cessation of the estrogen-progestin arm of the women's health initiative study. Ten authors had published four to six articles, 47 authored two or three articles, and 371 authored one article each. The researchers focused on authors who had published four or more articles in the four-year period under study and, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. After individually analyzing a batch of articles, the readers met to provide their initial assessments, to discuss them, and to reach consensus on tone and scientific accuracy. Then after the papers were evaluated, each author was identified and the researchers searched for authors' potential financial conflicts of interest, defined as publicly disclosed information that the authors had received payment for research, speaking, or consulting on behalf of a manufacturer of menopausal hormone therapy.
Common themes in the 50 articles included arguments that clinical trial results should not guide treatment for individuals and suggestions that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Furthermore, of the ten authors studied, eight were found to have received payment for research, speaking or consulting on behalf of menopause hormone manufacturers, and 30 of 32 articles evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest. Articles promoting the use of menopausal hormone therapy were more than twice as likely to have been written by authors with conflicts of interest as by authors without conflicts of interest. Furthermore, Three authors who were identified as having financial conflicts of interest were authors on articles where sections of their previously published articles were repeated word-for-word without citation.
What Do These Findings Mean?
The findings of this study suggest that there may be a link between receiving industry funding for speaking, consulting, or research and the publication of apparently promotional opinion pieces on menopausal hormone therapy. Furthermore, such publications may encourage physicians to continue prescribing these therapies to women of menopausal age. Therefore, physicians and other health care providers should interpret the content of review articles with caution. In addition, medical journals should follow the International Committee of Medical Journal Editors Uniform Requirements for Manuscripts, which require that all authors submit signed statements of their participation in authorship and full disclosure of any conflicts of interest.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000425.
The US National Heart, Lung, and Blood Institute has more information on the Womens Health Initiative
The US National Institutes of Health provide more information about the effects of menopausal hormone replacement therapy
The Office of Women's Health, U.S. Department of Health and Human Services provides information on menopausal hormone therapy
The International Committee of Medical Journal Editors Uniform Requirements for Manuscripts presents Uniform Requirements for Manuscripts published in biomedical journals
The National Womens Health Network, a consumer advocacy group that takes no industry money, has factsheets and articles about menopausal hormone therapy
PharmedOut, a Georgetown University Medical Center project, has many resources on pharmaceutical marketing practices
doi:10.1371/journal.pmed.1000425
PMCID: PMC3058057  PMID: 21423581
18.  A Multi-Level Model of Information Seeking in the Clinical Domain 
Journal of biomedical informatics  2007;41(2):357-370.
Objective:
Clinicians often have difficulty translating information needs into effective search strategies to find appropriate answers. Information retrieval systems employing an intelligent search agent that generates adaptive search strategies based on human search expertise could be helpful in meeting clinician information needs. A prerequisite for creating such systems is an information seeking model that facilitates the representation of human search expertise. The purpose of developing such a model is to provide guidance to information seeking system development and to shape an empirical research program.
Design:
The information seeking process was modeled as a complex problem-solving activity. After considering how similarly complex activities had been modeled in other domains, we determined that modeling context-initiated information seeking across multiple problem spaces allows the abstraction of search knowledge into functionally consistent layers. The knowledge layers were identified in the information science literature and validated through our observations of searches performed by health science librarians.
Results:
A hierarchical multi-level model of context-initiated information seeking is proposed. Each level represents (1) a problem space that is traversed during the online search process, and (2) a distinct layer of knowledge that is required to execute a successful search. Grand strategy determines what information resources will be searched, for what purpose, and in what order. The strategy level represents an overall approach for searching a single resource. Tactics are individual moves made to further a strategy. Operations are mappings of abstract intentions to information resource-specific concrete input. Assessment is the basis of interaction within the strategic hierarchy, influencing the direction of the search.
Conclusion:
The described multi-level model provides a framework for future research and the foundation for development of an automated information retrieval system that uses an intelligent search agent to bridge clinician information needs and human search expertise.
doi:10.1016/j.jbi.2007.09.005
PMCID: PMC2384229  PMID: 18006383
information retrieval; information seeking; online searching; search strategies; problem solving; user expertise; cognitive model; clinician information needs; intelligent agent
19.  Experiences with Policing among People Who Inject Drugs in Bangkok, Thailand: A Qualitative Study 
PLoS Medicine  2013;10(12):e1001570.
Using thematic analysis, Kerr and colleagues document the experiences of policing among people who inject drugs in Bangkok and examine how interactions with police can affect drug-using behaviors and health care access.
Please see later in the article for the Editors' Summary
Background
Despite Thailand's commitment to treating people who use drugs as “patients” not “criminals,” Thai authorities continue to emphasize criminal law enforcement for drug control. In 2003, Thailand's drug war received international criticism due to extensive human rights violations. However, few studies have since investigated the impact of policing on drug-using populations. Therefore, we sought to examine experiences with policing among people who inject drugs (PWID) in Bangkok, Thailand, between 2008 and 2012.
Methods and Findings
Between July 2011 and June 2012, semi-structured, in-depth interviews were conducted with 42 community-recruited PWID participating in the Mitsampan Community Research Project in Bangkok. Interviews explored PWID's encounters with police during the past three years. Audio-recorded interviews were transcribed verbatim, and a thematic analysis was conducted to document the character of PWID's experiences with police. Respondents indicated that policing activities had noticeably intensified since rapid urine toxicology screening became available to police. Respondents reported various forms of police misconduct, including false accusations, coercion of confessions, excessive use of force, and extortion of money. However, respondents were reluctant to report misconduct to the authorities in the face of social and structural barriers to seeking justice. Respondents' strategies to avoid police impeded access to health care and facilitated transitions towards the misuse of prescribed pharmaceuticals. The study's limitations relate to the transferability of the findings, including the potential biases associated with the small convenience sample.
Conclusions
This study suggests that policing in Bangkok has involved injustices, human rights abuses, and corruption, and policing practices in this setting appeared to have increased PWID's vulnerability to poor health through various pathways. Novel to this study are findings pertaining to the use of urine drug testing by police, which highlight the potential for widespread abuse of this emerging technology. These findings raise concern about ongoing policing practices in this setting.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In many countries, the dominant strategy used to control illegal drugs such as heroin and methamphetamine is criminal law enforcement, a strategy that sometimes results in human rights abuses such as ill-treatment by police, extrajudicial killings, and arbitrary detention. Moreover, growing evidence suggests that aggressive policing of illicit drug use can have adverse public-health consequences. For example, the fear engendered by intensive policing may cause people who inject drugs (PWID) to avoid services such as needle exchanges, thereby contributing to the HIV/AIDS epidemic. One country with major epidemics of illicit drug use and of HIV/AIDS among PWID is Thailand. Although Thailand reclassified drug users as “patients” instead of “criminals” in 2002, possession and consumption of illicit drugs remain criminal offenses. The 2002 legislation also created a system of compulsory drug detention centers, most of which lack evidence-based addiction treatment services. In 2003, the Thai government launched a campaign to suppress drug trafficking and to enrol 300,000 people who use drugs into treatment. This campaign received international criticism because it involved extensive human rights violations, including more than 2,800 extrajudicial killings of suspected drug users and dealers.
Why Was This Study Done?
Drug-related arrests and compulsory detention of drug users are increasing in Thailand but what is the impact of current policing practices on drug users and on public health? In this qualitative study (a study that aims for an in-depth understanding of human behavior), the researchers use thematic analysis informed by the Rhodes' Risk Environment Framework to document the social and structural factors that led to encounters with the police among PWID in Bangkok between 2008 and 2012, the policing tactics employed during these encounters, and the associated health consequences of these encounters. The Risk Environment Framework posits that a range of social, political, economic, and physical environmental factors interact with each other and shape the production of drug-related harm.
What Did the Researchers Do and Find?
Between July 2011 and June 2012, the researchers conducted in-depth interviews with a convenience sample (a non-random sample from a nearby population) of 42 participants in the Mitsampan Community Research Project, an investigation of drug-using behavior, health care access, and drug-related harms among PWID in Bangkok. Respondents reported that policing activities had intensified since rapid urine toxicology screening became widely available and since the initiation of a crackdown on drug users in 2011. They described various forms of violence and misconduct that they had experienced during confrontations with police, including false accusations, degrading stop and search procedures, and excessive use of force. Urine drug testing was identified as a key tool used by the police, with some respondents describing how police caused unnecessary humiliation by requesting urine samples in public places. It was also reported that the police used positive test results as a means of extortion. Finally, some respondents reported feeling powerless in relation to the police and cited fear of retaliation as an important barrier to obtaining redress for police corruption. Others reported that they had adopted strategies to avoid the police such as staying indoors, a strategy likely to impede access to health care, or changing their drug-using behavior by, for example, injecting midazolam rather than methamphetamine, a practice associated with an increased risk of injection-related complications.
What Do These Findings Mean?
These findings suggest that the policing of PWID in Bangkok between 2008 and 2012 involved injustices, human rights abuses, and corruption and highlight the potential for widespread misuse of urine drug testing. Moreover, they suggest that policing practices in this setting may have increased the vulnerability of PWID to poor health by impeding their access to health care and by increasing the occurrence of risky drug-using behaviors. Because this study involved a small convenience sample of PWID, these findings may not be generalizable to other areas of Bangkok or Thailand and do not indicate whether police misconduct and corruption is highly prevalent across the all police departments in Bangkok. Nevertheless, these findings suggest that multilevel structural changes and interventions are needed to mitigate the harm associated with policing of illicit drug use in Bangkok. These changes will need to ensure full accountability for police misconduct and access to legal services for victims of this misconduct. They will also need to include ethical guidelines for urine drug testing and the reform of policies that promote repressive policing and compulsory detention.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001570.
This study is further discussed in a PLOS Medicine Perspective by Burris and Koester
Human Rights Watch, a global organization dedicated to defending and protecting human rights, has information about drug policy and human rights, which includes information on Thailand
The Global Commission on Drug Policy published a report in June 2012 entitled “The War on Drugs and HIV/AIDS: How the Criminalization of Drug Use Fuels the Global Pandemic” (available in several languages)
The Global Commission on HIV and the Law published a report in July 2012 entitled “HIV and the Law: Risk, Rights and Health” (available in several languages), the Open Society Foundations have prepared a briefing on this report
More information about the Mitsampan Community Research Project is available
doi:10.1371/journal.pmed.1001570
PMCID: PMC3858231  PMID: 24339753
20.  Big Data Analytics in Immunology: A Knowledge-Based Approach 
BioMed Research International  2014;2014:437987.
With the vast amount of immunological data available, immunology research is entering the big data era. These data vary in granularity, quality, and complexity and are stored in various formats, including publications, technical reports, and databases. The challenge is to make the transition from data to actionable knowledge and wisdom and bridge the knowledge gap and application gap. We report a knowledge-based approach based on a framework called KB-builder that facilitates data mining by enabling fast development and deployment of web-accessible immunological data knowledge warehouses. Immunological knowledge discovery relies heavily on both the availability of accurate, up-to-date, and well-organized data and the proper analytics tools. We propose the use of knowledge-based approaches by developing knowledgebases combining well-annotated data with specialized analytical tools and integrating them into analytical workflow. A set of well-defined workflow types with rich summarization and visualization capacity facilitates the transformation from data to critical information and knowledge. By using KB-builder, we enabled streamlining of normally time-consuming processes of database development. The knowledgebases built using KB-builder will speed up rational vaccine design by providing accurate and well-annotated data coupled with tailored computational analysis tools and workflow.
doi:10.1155/2014/437987
PMCID: PMC4090507  PMID: 25045677
21.  On the Growth of Scientific Knowledge: Yeast Biology as a Case Study 
PLoS Computational Biology  2009;5(3):e1000320.
The tempo and mode of human knowledge expansion is an enduring yet poorly understood topic. Through a temporal network analysis of three decades of discoveries of protein interactions and genetic interactions in baker's yeast, we show that the growth of scientific knowledge is exponential over time and that important subjects tend to be studied earlier. However, expansions of different domains of knowledge are highly heterogeneous and episodic such that the temporal turnover of knowledge hubs is much greater than expected by chance. Familiar subjects are preferentially studied over new subjects, leading to a reduced pace of innovation. While research is increasingly done in teams, the number of discoveries per researcher is greater in smaller teams. These findings reveal collective human behaviors in scientific research and help design better strategies in future knowledge exploration.
Author Summary
It is of great interest to understand the patterns and mechanisms of scientific knowledge growth, but such studies have been hampered by the lack of ideal cases in which the structure of the knowledge is known, the knowledge is quantifiable, and the process of knowledge discovery is well understood and documented. The biological knowledge about a species is in part described by its protein interaction network and genetic interaction network. Here, we conduct a temporal meta-analysis of three decades of discoveries of protein interactions and genetic interactions in baker's yeast to reveal the tempo and mode of the growth of yeast biology. We show that the growth is exponential over time and that important subjects tend to be studied earlier. However, expansions of different domains of knowledge are highly heterogeneous and episodic such that the temporal turnover of knowledge hubs is much greater than that expected by chance. Familiar subjects are preferentially studied over new subjects, leading to a reduced pace of innovation. While research is increasingly done in teams, the number of discoveries per researcher is greater in smaller teams. These findings reveal collective human behaviors in scientific research and help design better strategies in future knowledge exploration.
doi:10.1371/journal.pcbi.1000320
PMCID: PMC2649443  PMID: 19300476
22.  The Structural Biology Knowledgebase: a portal to protein structures, sequences, functions, and methods 
The Protein Structure Initiative’s Structural Biology Knowledgebase (SBKB, URL: http://sbkb.org) is an open web resource designed to turn the products of the structural genomics and structural biology efforts into knowledge that can be used by the biological community to understand living systems and disease. Here we will present examples on how to use the SBKB to enable biological research. For example, a protein sequence or Protein Data Bank (PDB) structure ID search will provide a list of related protein structures in the PDB, associated biological descriptions (annotations), homology models, structural genomics protein target status, experimental protocols, and the ability to order available DNA clones from the PSI:Biology-Materials Repository. A text search will find publication and technology reports resulting from the PSI’s high-throughput research efforts. Web tools that aid in research, including a system that accepts protein structure requests from the community, will also be described. Created in collaboration with the Nature Publishing Group, the Structural Biology Knowledgebase monthly update also provides a research library, editorials about new research advances, news, and an events calendar to present a broader view of structural genomics and structural biology.
doi:10.1007/s10969-011-9106-2
PMCID: PMC3123456  PMID: 21472436
Protein; Protein production; Structural biology; Structural databases; Structural genomics; Theoretical models
23.  KA-SB: from data integration to large scale reasoning 
BMC Bioinformatics  2009;10(Suppl 10):S5.
Background
The analysis of information in the biological domain is usually focused on the analysis of data from single on-line data sources. Unfortunately, studying a biological process requires having access to disperse, heterogeneous, autonomous data sources. In this context, an analysis of the information is not possible without the integration of such data.
Methods
KA-SB is a querying and analysis system for final users based on combining a data integration solution with a reasoner. Thus, the tool has been created with a process divided into two steps: 1) KOMF, the Khaos Ontology-based Mediator Framework, is used to retrieve information from heterogeneous and distributed databases; 2) the integrated information is crystallized in a (persistent and high performance) reasoner (DBOWL). This information could be further analyzed later (by means of querying and reasoning).
Results
In this paper we present a novel system that combines the use of a mediation system with the reasoning capabilities of a large scale reasoner to provide a way of finding new knowledge and of analyzing the integrated information from different databases, which is retrieved as a set of ontology instances. This tool uses a graphical query interface to build user queries easily, which shows a graphical representation of the ontology and allows users o build queries by clicking on the ontology concepts.
Conclusion
These kinds of systems (based on KOMF) will provide users with very large amounts of information (interpreted as ontology instances once retrieved), which cannot be managed using traditional main memory-based reasoners. We propose a process for creating persistent and scalable knowledgebases from sets of OWL instances obtained by integrating heterogeneous data sources with KOMF. This process has been applied to develop a demo tool , which uses the BioPax Level 3 ontology as the integration schema, and integrates UNIPROT, KEGG, CHEBI, BRENDA and SABIORK databases.
doi:10.1186/1471-2105-10-S10-S5
PMCID: PMC2755826  PMID: 19796402
24.  Statins in the Treatment of Chronic Heart Failure: A Systematic Review 
PLoS Medicine  2006;3(8):e333.
Background
The efficacy of statin therapy in patients with established chronic heart failure (CHF) is a subject of much debate.
Methods and Findings
We conducted three systematic literature searches to assess the evidence supporting the prescription of statins in CHF. First, we investigated the participation of CHF patients in randomized placebo-controlled clinical trials designed to evaluate the efficacy of statins in reducing major cardiovascular events and mortality. Second, we assessed the association between serum cholesterol and outcome in CHF. Finally, we evaluated the ability of statin treatment to modify surrogate endpoint parameters in CHF.
Using validated search strategies, we systematically searched PubMed for our three queries. In addition, we searched the reference lists from eligible studies, used the “see related articles” feature for key publications in PubMed, consulted the Cochrane Library, and searched the ISI Web of Knowledge for papers citing key publications.
Search 1 resulted in the retrieval of 47 placebo-controlled clinical statin trials involving more than 100,000 patients. CHF patients had, however, been systematically excluded from these trials. Search 2 resulted in the retrieval of eight studies assessing the relationship between cholesterol levels and outcome in CHF patients. Lower serum cholesterol was consistently associated with increased mortality. Search 3 resulted in the retrieval of 18 studies on the efficacy of statin treatment in CHF. On the whole, these studies reported favorable outcomes for almost all surrogate endpoints.
Conclusions
Since CHF patients have been systematically excluded from randomized, controlled clinical cholesterol-lowering trials, the effect of statin therapy in these patients remains to be established. Currently, two large, randomized, placebo-controlled statin trials are under way to evaluate the efficacy of statin treatment in terms of reducing clinical endpoints in CHF patients in particular.
A systematic review found that patients with heart failure have been excluded from randomised controlled trials on the use of statins. Evidence from other studies on the effectiveness of statins for patients with heart failure is weak and conflicting.
Editors' Summary
Background.
When medical researchers test a drug—or some other treatment—for a particular medical condition, they often decide not to include in their study anyone who has, in addition to the disease they are interested in, certain other health problems. This is because including patients with two or more conditions can complicate the analysis of the results and make it hard to reach firm conclusions. However, excluding patients in this way can result in uncertainty as to whether treatments are effective for anyone who suffers from the disease in question, or just for people like those who took part in the research.
A great deal of research has been conducted with drugs known as statins, which lower cholesterol levels in the blood. (A raised level of cholesterol is known to be a major risk factor for cardiovascular disease, which causes heart attacks and strokes.) As a result of this research, statins have been accepted as effective and safe. They are now, in consequence, among the most commonly prescribed medicines. Heart failure, however, is not the same thing as a heart attack. It is the name given to the condition where the muscles of the heart have become weakened, most often as a result of aging, and the heart becomes gradually less efficient at pumping blood around the body. (Some people with heart failure live for many years, but 70% of those with the condition die within ten years.) It is common for people with cardiovascular disease also to have heart failure. Nevertheless, some researchers who have studied the effects of statins have made the decision not to include in their studies any patients with cardiovascular disease who, in addition, have heart failure.
Why Was This Study Done?
The researchers in this study were aware that patients with heart failure have often been excluded from statin trials. They felt it was important to assess the available evidence supporting the prescription of statins for such patients. Specifically, they wanted to find out the following: how often have patients with heart failure been included in statin trials, what evidence is available as to whether it is beneficial for patients with heart failure to have low cholesterol, and what evidence is there that prescribing statins helps these patients?
What Did the Researchers Do and Find?
They did not do any new work involving patients. Instead, they did a very thorough search for all relevant studies of good quality that had already been published and they reviewed the results. “Randomized clinical trials” (RCTs) are the most reliable type of medical research. The researchers found there had been 47 such trials (involving over 100,000 patients) on the use of statins for treating cardiovascular disease, but all these trials had excluded heart failure patients. They found eight studies (which were not RCTs) looking at cholesterol levels and heart failure. These studies found, perhaps surprisingly, that death rates were higher in those patients with heart failure who had low cholesterol. However, they also found 18 studies (again not RCTs) on the use of statins in patients with heart failure. These 18 studies seemed to suggest that statins were of benefit to the patients who received them.
What Do These Findings Mean?
The evidence for or against prescribing statins for people with heart failure is limited, conflicting, and unclear. Further research involving RTCs is necessary. (Two such trials are known to be in progress.)
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030333.
General information about statins is available from the Web site of Patient UK
The American Heart Association Web site is a good source of information about all types of heart disease, including heart attacks and heart failure
For a definition of randomized controlled trials see Wikipedia, a free online encyclopedia that anyone can edit
More detailed information about the quality of evidence from medical research may be found in the James Lind Library
doi:10.1371/journal.pmed.0030333
PMCID: PMC1551909  PMID: 16933967
25.  Selection in Reported Epidemiological Risks: An Empirical Assessment 
PLoS Medicine  2007;4(3):e79.
Background
Epidemiological studies may be subject to selective reporting, but empirical evidence thereof is limited. We empirically evaluated the extent of selection of significant results and large effect sizes in a large sample of recent articles.
Methods and Findings
We evaluated 389 articles of epidemiological studies that reported, in their respective abstracts, at least one relative risk for a continuous risk factor in contrasts based on median, tertile, quartile, or quintile categorizations. We examined the proportion and correlates of reporting statistically significant and nonsignificant results in the abstract and whether the magnitude of the relative risks presented (coined to be consistently ≥1.00) differs depending on the type of contrast used for the risk factor. In 342 articles (87.9%), ≥1 statistically significant relative risk was reported in the abstract, while only 169 articles (43.4%) reported ≥1 statistically nonsignificant relative risk in the abstract. Reporting of statistically significant results was more common with structured abstracts, and was less common in US-based studies and in cancer outcomes. Among 50 randomly selected articles in which the full text was examined, a median of nine (interquartile range 5–16) statistically significant and six (interquartile range 3–16) statistically nonsignificant relative risks were presented (p = 0.25). Paradoxically, the smallest presented relative risks were based on the contrasts of extreme quintiles; on average, the relative risk magnitude was 1.41-, 1.42-, and 1.36-fold larger in contrasts of extreme quartiles, extreme tertiles, and above-versus-below median values, respectively (p < 0.001).
Conclusions
Published epidemiological investigations almost universally highlight significant associations between risk factors and outcomes. For continuous risk factors, investigators selectively present contrasts between more extreme groups, when relative risks are inherently lower.
An evaluation of published articles reporting epidemiological studies found that they almost universally highlight significant associations between risk factors and outcomes.
Editors' Summary
Background.
Medical and scientific researchers use statistical tests to try to work out whether their observations—for example, seeing a difference in some characteristic between two groups of people—might have occurred as a result of chance alone. Statistical tests cannot determine this for sure, rather they can only give a probability that the observations would have arisen by chance. When researchers have many different hypotheses, and carry out many statistical tests on the same set of data, they run the risk of concluding that there are real differences where in fact there are none. At the same time, it has long been known that scientific and medical researchers tend to pick out the findings on which to report in their papers. Findings that are more interesting, impressive, or statistically significant are more likely to be published. This is termed “publication bias” or “selective reporting bias.” Therefore, some people are concerned that the published scientific literature might contain many false-positive findings, i.e., findings that are not true but are simply the result of chance variation in the data. This would have a serious impact on the accuracy of the published scientific literature and would tend to overestimate the strength and direction of relationships being studied.
Why Was This Study Done?
Selective reporting bias has already been studied in detail in the area of randomized trials (studies where participants are randomly allocated to receive an intervention, e.g., a new drug, versus an alternative intervention or “comparator,” in order to understand the benefits or safety of the new intervention). These studies have shown that very many of the findings of trials are never published, and that statistically significant findings are more likely to be included in published papers than nonsignificant findings. However, much medical research is carried out that does not use randomized trial methods, either because that method is not useful to answer the question at hand or is unethical. Epidemiological research is often concerned with looking at links between risk factors and the development of disease, and this type of research would generally use observation rather than experiment to uncover connections. The researchers here were concerned that selective reporting bias might be just as much of a problem in epidemiological research as in randomized trials research, and wanted to study this specifically.
What Did the Researchers Do and Find?
In this investigation, searches were carried out of PubMed, a database of biomedical research studies, to extract epidemiological studies that were published between January 2004 and October 2005. The researchers wanted to specifically look at studies reporting the effect of continuous risk factors and their effect on health or disease outcomes (a continuous risk factor is something like age or glucose concentration in the blood, is a number, and can have any value on a sliding scale). Three hundred and eighty-nine original research studies were found, and the researchers pulled out from the abstracts and full text of these papers the relative risks that were reported along with the results of statistical tests for them. (Relative risk is the chance of getting an outcome, say disease, in one group as compared to another group.) The researchers found that nearly 90% of these studies had one or more statistically significant risks reported in the abstract, but only 43% reported one or more risks that were not statistically significant. When looking at all of the findings reported anywhere in the full text for 50 of these studies, the researchers saw that papers overall reported more statistically significant risks than nonsignificant risks. Finally, it seemed that in the set of papers studied here, the way in which statistical analyses were done produced a bias towards more extreme findings: for datasets showing small relative risks, papers were more likely to report a comparison between extreme subsets of the data so as to report larger relative risks.
What Do These Findings Mean?
These findings suggest that there is a tendency among epidemiology researchers to highlight statistically significant findings and to avoid highlighting nonsignificant findings in their research papers. This behavior may be a problem, because many of these significant findings could in future turn out to be “false positives.” At present, registers exist for researchers to describe ongoing clinical trials, and to set out the outcomes that they plan to analyze for those trials. These registers will go some way towards addressing some of the problems described here, but only for clinical trials research. Registers do not yet exist for epidemiological studies, and therefore it is important that researchers and readers are aware of and cautious about the problem of selective reporting in epidemiological research.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040079.
Wikipedia entry on publication bias (note: Wikipedia is an internet encyclopedia that anyone can edit)
The International Committee of Medical Journal Editors gives guidelines for submitting manuscripts to its member journals, and includes comments about registration of ongoing studies and the obligation to publish negative studies
ClinicalTrials.gov and the ISRCTN register are two registries of ongoing clinical trials
doi:10.1371/journal.pmed.0040079
PMCID: PMC1808481  PMID: 17341129

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