It is important that healthcare provided in crisis settings is based on the best available research evidence. We reviewed guidelines for child and perinatal health care in crisis situations to determine whether they were based on research evidence, whether Cochrane systematic reviews were available in the clinical areas addressed by these guidelines and whether summaries of these reviews were provided in Evidence Aid.Broad internet searches were undertaken to identify relevant guidelines. Guidelines were appraised using AGREE and the clinical areas that were relevant to perinatal or child health were extracted. We searched The Cochrane Database of Systematic Reviews to identify potentially relevant reviews. For each review we determined how many trials were included, and how many were conducted in resource-limited settings.Six guidelines met selection criteria. None of the included guidelines were clearly based on research evidence. 198 Cochrane reviews were potentially relevant to the guidelines. These reviews predominantly addressed nutrient supplementation, breastfeeding, malaria, maternal hypertension, premature labour and prevention of HIV transmission. Most reviews included studies from developing settings. However for large portions of the guidelines, particularly health services delivery, there were no relevant reviews. Only 18 (9.1%) reviews have summaries in Evidence Aid.We did not identify any evidence-based guidelines for perinatal and child health care in disaster settings. We found many Cochrane reviews that could contribute to the evidence-base supporting future guidelines. However there are important issues to be addressed in terms of the relevance of the available reviews and increasing the number of reviews addressing health care delivery. Populations in crisis settings such as those resulting from natural disasters like earthquake, famine and flood, as well as man-made disasters like civil war, are at substantial risk of trauma and illness. The risks of disease and death are particularly increased for infants, children and women giving birth. Health care providers in disaster settings work with limited infrastructure, equipment, supplies and training. Given the constrained resources with which they work, health care providers in these settings cannot afford to waste time or money on ineffective or harmful treatments.Organisations working in disaster settings are developing an awareness of the need for their practice to be based on evidence of effectiveness. Clinical practice guidelines (CPGs) and other research-based tools are increasingly being used to support effective decision-making, and many humanitarian aid organisations have developed their own guidelines or adapted World Health Organization (WHO) guidelines. However, it has been suggested that there is a lack of evidence-based guidelines for child and perinatal health care in crisis situations , and WHOhttp://www.evidenceaid.org. Evidence Aid brings together information from Cochrane reviews on the effects of health care interventions relevant to the aftermath of a natural disaster or other large scale health care emergency. It aims to provide quick access to reliable information about which interventions work, which don't work, and which might be harmful.The Cochrane Collaboration supports development and dissemination of high quality, systematic reviews of health research. After the devastating tsunami affecting the Pacific Rim in December 2004, The Cochrane Collaboration aimed to contribute to the relief effort by highlighting evidence relevant to people making decisions about health care in crisis situations through a website called Evidence Aid In late 2007 The Cochrane Collaboration funded an evaluation of the effectiveness of Evidence Aid, which included an exploration of the ways in which Evidence Aid could contribute to meeting the health information needs of humanitarian organisations. In parallel with the evaluation of Evidence Aid, we reviewed existing guidelines for child and perinatal health care in crisis situations to determine what areas of clinical practice were addressed by these guidelines, and whether summaries of Cochrane systematic reviews relevant to these clinical areas were provided in Evidence Aid.In this study we had several aims;• to identify existing guidelines for perinatal and child health in crisis settings and examine whether these guidelines were explicitly based on research evidence,• to determine whether relevant Cochrane systematic reviews were available in the clinical areas addressed by these guidelines and to ascertain whether summaries of these reviews were provided in Evidence Aid.We undertook a broad search to identify existing guidelines for child and perinatal health care in crisis situations. We searched guideline websites, websites of humanitarian organisations and aid networks, and the internet using Google, with search terms including (emergency OR disaster OR crisis) AND .Guideline websites included:http://www.guidelines.gov• US National Guidelines Clearinghouse http://www.g-i-n.net,• Guidelines International Network http://www.sign.ac.uk• The Scottish Intercollegiate Guidelines Network http://www.nice.org.uk,• The National Institute for Health and Clinical Excellence, http://www.nzgg.org.nz• The New Zealand Guidelines Group http://www.nhmrc.gov.au• The National Health and Medical Research Council Humanitarian organisations and aid networks websites included:http://www.who.int• The World Health Organization http://ochaonline.un.org/• United Nations Office for the Coordination of Humanitarian Affairs http://www.icrc.org,• The International Committee of the Red Cross http://www.msf.org,• Medecins Sans Frontieres http://www.care.org• CARE http://www.sphereproject.org• SPHERE http://www.reliefweb.int.• ReliefWeb To be included guidelines had to be explicitly developed to provide guidance on health care interventions for child and perinatal conditions in crisis situations. Guidelines which provided policy, training or other guidance, but did not provide recommendations to guide decisions on provision of particular health care interventions were excluded as were guidelines that were not specifically developed to be implemented in crisis or emergency settings. We only included guidelines published in English. Selection criteria were applied independently by four reviewers, and disagreements resolved through discussion.As recommended by the AGREE Collaboration, included guidelines were appraised by four reviewers using the AGREE criteria, which are the standard for appraising the quality of evidence-based guidelines . GuideliTwo reviewers created a list of the clinical areas  addressed by each included guideline that were relevant to perinatal or child health.http://www.thecochranelibrary.com Issue 2, 2008; using simple text word and MeSH searches of the title, abstract and keywords, to identify potentially relevant reviews. We searched only for Cochrane systematic reviews as this was part of a project exploring how Evidence Aid, which was developed by the Cochrane Collaboration and provides summaries of Cochrane systematic reviews, could contribute to meeting the health information needs of humanitarian organisations.For each clinical area extracted from the guidelines, we searched The Cochrane Database of Systematic Reviews For each potentially relevant review, one reviewer read the 'Description of Studies' section, 'Characteristics of Included Studies' table and 'References' section to determine how many trials were included in the review, and how many of these trials were conducted in a developing setting.Fourteen potentially relevant guidelines were identified and six guidelines met selection criteria -9 Table and 2. OHowever, none of the included guidelines were explicitly based on systematic searches of research literature, or had recommendations that were clearly linked to research evidence (AGREE criteria 8 & 12). As a result none of the guidelines were assessed using the full AGREE instrument. One guideline did not include any references, one included references in a "Further reading" section and three included references, but these were not directly linked to the recommendations of the guideline. None of the guidelines included any Cochrane or other systematic reviews as references. None of the included guidelines described the methods by which they were developed.Table The "Infant and Young Child Feeding in Emergencies" guideline  producedFor the Valid International Guideline "Community-based Therapeutic Care (CTC) A Field Manual" , which fThere were 34 Cochrane reviews and 10 protocols potentially relevant to the World Health Organization's "Guiding principles for feeding infants and young children during emergencies"  guidelinFor the guideline addressing antenatal care "Antenatal Guidelines For Primary Health Care In Crisis Conditions"  producedThe "Emergency Field Handbook: A Guide For UNICEF Staff"  producedThe WHO "Manual for the health care of children in humanitarian emergencies" aims to Of the total of 198 Cochrane systematic reviews that were identified as being potentially relevant to the content of the included guidelines, 18 (9.1%) have summaries in Evidence Aid. Links to the full text of the reviews are provided for a further twelve (6.1%).Echoing what has been found previously , we wereIt is possible to imagine a world where guidelines in all areas of clinical practice would provide recommendations based on systematic reviews of the best available evidence, integrated with clinical expertise and patient preferences. Cochrane reviews would be available to answer every clinical question, and after searching the Cochrane Database of Systematic Reviews, guidelines would be written, and we could be confident that the recommended care was based on a solid foundation of research evidence. However this ideal is unlikely to ever be achieved. Existing evidence-based guideline development methods are time-consuming and resource-intensive and often produce guidelines which are only applicable in a narrow range of contexts. Guideline developers do not always search for the best available research evidence, or do not document the methods used so that the evidence base on which the guidelines are developed cannot be established. Cochrane systematic reviews are not available to cover every possible clinical question, and many do not address issues of applicability and generalisability. In many areas primary research is not available, or is not directly relevant to the guideline being developed. These problems are exacerbated by the fact that it is very difficult to carry out primary research in crisis settings, and that most health research is carried out in well resourced settings, to address the health concerns of well resourced populations. As a result there is less primary research available relevant to crisis settings and potentially fewer relevant systematic reviews.In spite of the barriers to the production of systematic reviews relevant to crisis settings, our results demonstrate that there are Cochrane reviews available which have the potential to support health care decision-making in perinatal and child health in crisis settings. A large number of potentially relevant reviews were identified. The great majority of the identified reviews include some studies that were undertaken in resource-poor settings, however very few, if any, were conducted in crisis settings. The contribution Cochrane reviews can make in the crisis setting is further limited in a number of important ways.The Cochrane Database of Systematic Reviews includes few reviews on health system issues, focusing more on reviews of clinical interventions. While we only included guidelines that addressed at least one area of clinical practice, several of the included guidelines had substantial sections addressing establishing, prioritising or evaluating healthcare programs, and there is a clear need for evidence to support decision-making in these areas. The Cochrane Collaboration's contribution to synthesising research about health care delivery systems is currently limited, though may increase through the work of the Effective Practice and Organisation of Care group within the Collaboration. The critical need for this kind of evidence was also identified in our interviews with potential users of Evidence Aid as part of the broader Evidence Aid evaluation.The large number of protocols for systematic reviews that are potentially relevant to the included guidelines suggests that the Cochrane Collaboration's contribution to the evidence-base of guidelines for perinatal and child health in crisis settings is likely to grow into the future. However the majority of these protocols address areas similar to those addressed in existing reviews, and the reviews arising from these protocols will not address the gap in evidence relating to health care delivery systems. This gap might be addressed by establishing processes to prioritise reviews in these areas of identified need and substantial morbidity and mortality.Also, while The Cochrane Collaboration is developing methods for reviews of diagnostic studies, the Cochrane Database of Systematic Reviews does not currently include reviews of diagnosis, but only therapy. As a result, Cochrane reviews cannot inform decisions about diagnostic approaches, limiting their potential contribution to clinical practice guidelines.Several issues impact on the potential relevance of the Cochrane reviews identified. One is the context in which most of the primary studies included in systematic reviews are conducted. The majority of these primary studies are undertaken in stable, developed countries, rather than unstable, resource-poor settings, where large scale emergencies are most common, and have the largest impact on increasing morbidity and mortality. This was particularly clear in the Cochrane reviews evaluating the impact of various forms of dietary supplementation. In many of these reviews the primary studies were not carried out in populations, like those seen in crisis situations, where dietary deficiencies are common. The effects of the supplements evaluated are likely to be very different in these settings, compared to those in which the studies were largely carried out. This highlights the importance of documenting the context of primary research studies included in systematic reviews.When evidence-based guidelines make recommendations for practice, they often use evidence which was generated in contexts that are different from the one in which the guideline will be applied. In some situations evidence is available that was generated in a very similar context. However where this type of immediately relevant evidence is not available, guideline developers rely on other evidence, and draw conclusions about whether and/or how it is likely to apply in their context. The degree to which the context impacts on the applicability of the research varies with the nature of the clinical practice.It is difficult to tightly define terms like 'crisis', 'disaster' and 'emergency'. We chose a very broad definition "crisis settings such as those resulting from natural disasters like earthquake, famine and flood, as well as man-made disasters like civil war", designed to be inclusive, but to differentiate from what might be considered 'stable' situations in resource-poor settings. However the threshold between crisis and non-crisis is essentially arbitrary and there will always be grey areas. There are many examples where 'normal' conditions in resource-poor settings have deteriorated so that they could reasonably be described as crisis situations and also where crisis situations have become so chronic and entrenched that they are essentially 'stable'.In developing guidelines for crisis situations, there will be times when it is appropriate to base recommendations on evidence established in stable situations and other times when the evidence must be generated in crisis settings to be relevant to the practice in question. Similarly some guidelines developed for use in stable situations may be relevant and appropriate for use in crisis situations. The nature of crisis situations varies widely. Crises arise from many different causes, and take place in contexts with widely varying health infrastructure, staff availability, geography and underlying health problems, etc. All of these factors will affect the relevance of research and guidelines generated in other settings.A second factor impacting on the potential relevance is the availability of the interventions evaluated in the Cochrane reviews. While we attempted to include only those reviews addressing interventions which were potentially feasible in crisis settings (guided by the interventions recommended by the guidelines themselves); in the aftermath of emergencies, clinicians are often working with a very limited toolkit of equipment and drugs, and these may vary from one situation to another. As a result, some of the reviews which we believe might be potentially relevant may recommend interventions which are not affordable or practical in some crisis settings. However, the large number of potentially relevant Cochrane reviews identified suggests that, even taking these factors into account, Cochrane reviews can still make a substantial contribution to supporting health care decision-making in these contexts.A relatively small percentage of the Cochrane reviews identified as being potentially relevant to informing guidelines for perinatal and child health in crisis settings currently have summaries in Evidence Aid. So the results of these reviews are only available to those who have access to the full text of The Cochrane Library. As a result The Cochrane Collaboration is missing an opportunity to provide evidence to support humanitarian organisations developing guidelines in these areas. This gap may result from a lack of awareness that the results of these reviews would potentially be valuable in these settings, or, perhaps more likely, from time and resource limitations on the production of the Evidence Aid summaries, a process that requires a substantial investment of time and intellect.This review is limited by our focus on guidelines in the field of perinatal and child health, which may not be representative of the state of guidelines in other areas of emergency health care. However infants, children and pregnant women are particularly at risk in the aftermath of emergencies, and so we feel this focus is reasonable, if largely pragmatic. The review was also limited to those guidelines that were available in English on the internet. High quality evidence-based guidelines relevant to this area may have been developed but not made publicly available. We chose to focus on the health issues surrounding crisis situations, however we acknowledge that these situations also involve environmental, engineering and social problems. Our focus was on health issues as this our area of expertise and this is also the area in which the methods for developing clinical practice guidelines have been established. The study is also limited to assessing the reviews that are available at the current time, which may be different from those available at the time the guidelines were developed, which was not always clear from the guidelines. However the included guidelines were all developed relatively recently, and this study highlights that there is evidence relevant to this area of clinical practice that could be used as the basis of future guideline development.We were unable to identify any explicitly evidence-based guidelines to support decision-making around perinatal and child health care in disaster settings. We found that there are many Cochrane reviews available that have the potential to contribute to the evidence-base supporting guidelines for perinatal and child health in disaster settings in the future, and that most of these reviews include some studies conducted in developing settings. However there are also important issues to be addressed in terms of the relevance of the available reviews and increasing the number of reviews addressing questions of health care delivery.TT undertook a PhD supervised by the Director of the Australasian Cochrane Centre (ACC) which included an evaluation of Evidence Aid, funded through a grant from The Cochrane Collaboration Steering Group Discretionary Fund. HB was previously employed by the ACC. JR and MG both work on projects, unrelated to this project, in which ACC is a collaborator.TT conceived of this project and developed the methodology and data extraction approach, which HB, JR and MG refined. TT and MG undertook the searches. TT, HB, JR and MG applied the AGREE criteria. TT undertook the data extraction with assistance from HB and JR. TT prepared the first draft of this article which HB, JR, MG and TT then revised. TT had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors read and approved the final manuscriptThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/170/prepubTable S1. Details of potentially relevant Cochrane systematic reviews and protocols for each guidelineClick here for file


Clinical practice guidelines are systematically created documents that summarize knowledge and assist in delivering high-quality medicine by identifying evidence that supports best clinical care. They are produced not only by international professional groups but also by local professionals to address locally-relevant clinical practice. We evaluated the methodological rigour and transparency of guideline development in neurology formulated by professionals in a local medical community.We analyzed clinical guidelines in neurology publicly available at the web-site of the Physicians’ Assembly in Croatia in 2012: 6 guidelines developed by Croatian authors and 1 adapted from the European Federation of Neurological Societies. The quality was assessed by 2 independent evaluators using the AGREE II instrument. We also conducted a search of the Cochrane Library to identify potential changes in recommendation from Cochrane systematic reviews included in guideline preparation.The methodological quality of the guidelines greatly varied across different domains. „Scope and Purpose” and „Clarity of Presentation“ domains received high scores  98.5–100] and 97% [77.9–100], respectively), the lowest scores were in “Stakeholder Involvement“ (19% [15.5–34.6]) and “Editorial Independence” (0% [0–19.2]). Conclusions of 3 guidelines based on Cochrane systematic reviews were confirmed in updated versions and one update provided new information on the effectiveness of another antidepressant. Two Cochrane reviews used in guidelines were withdrawn and split into new reviews and their findings are now considered to be out of date.Neurological guidelines used in Croatia differ in structure and their methodological quality. We recommend to national societies and professional groups to develop a more systematic and rigorous approach to the development of the guidelines, timely inclusion of best evidences and an effort to involve target users and patients in the guideline development procedures. Clinical practice guidelines (CPGs) are systematically created documents that summarize the knowledge and assist in delivering high-quality medicine by identifying evidence that supports the best clinical care In order to ensure that guidelines are valid and relevant for practice, it is important that they are prepared in a methodologically appropriate process. For this purpose, procedures to assess the methodological quality of CPGs have been developed, most notably the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument Neurology is a rapidly developing field where the new and relevant evidence may have important implications for patients’ health care and outcome prognosis. However, there are only a few guidelines for practice in neurology which been evaluated using a standardized instrument We analyzed 7 neurology guidelines that were available at the web-site of the Croatian Physicians’ Assembly in 2012 We used The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument Two assessors independently performed the rating of guidelines. Each of two evaluators also independently judged the overall quality of the guideline from 1  to 7 . They independently submitted their scores to the third investigator, who then calculated the overall scores The scaled domain score = (Obtained score − Minimum possible score)/(Maximum score − Minimum possible score)×100.where “Obtained score” was the sum of the scores by individual assessors, Maximum score  = 7 (strongly agree)×2×No. items in the domain, and minimum score  = 1 (strongly disagree)×2×No. items in the domain The formula was also used to calculate the overall quality score.We searched the Cochrane Database of Systematic Reviews to identify any potential change of recommendation from the version of the Cochrane systematic reviews included in guideline preparation. The search strategy included the terms from respective guidelines. The date of the Cochrane Library search was 13 May 2012.Out of 7 guidelines, 2 were published within 2 years before the time of analysis, and 4 were published in 2005 or 2006 Table 1.The highest scores for all guidelines were observed in the domains “Scope and purpose” and “Clarity of Presentation”, and there was not much variability in the score among the guidelines Table 2.The domain “Stakeholder Involvement” also received low grades because the views and preferences of the target population  were not often sought. The target users of the guideline were clearly defined only in the Consensus opinion on diagnosing brain death – Guidelines for use of confirmatory tests The scores in the domain “Applicability” were below 50% for all guidelines, because they did not have clear explanation of existing facilitators and barriers that could impact the application of guideline recommendations Table 2.The scores for the domain “Rigour of Development” varied across the guidelines Table 1.The median score for of all guidelines was almost maximal for the “Scope and Purpose” and” Clarity and Presentation” domains and below 32% for other domains except Editorial independence which was 0 Figure 1The inter-rater agreement (weighted kappa) between the two raters ranged from good  to very good  across domains in individual guidelines In 3 out of 7 assessed guidelines, recommendations were partially based on evidence from Cochrane systematic reviews: EFNS guidelines on pharmacological treatment of neuropathic pain Our evaluation of the methodological rigour and transparency of publicly available neurological guidelines used in Croatia demonstrated a general lack of structured procedure for guideline preparation, as well as significant deficiencies in the following domains: “Applicability”, “Editorial Independence” and “Stakeholder Involvement”. A single guideline provided information about the procedure for its updating The limitations of the study include the small number of evaluated guidelines so we did not attempt any statistical conclusion. Our aim was to assess only publicly available guidelines supported by professional groups and societies, as those were considered to be most influential and relevant for the clinical practice in Croatia. Although the AGREE instrument has been tested for validity in different clinical areas and by different professionals The finding of low scores for Croatian guidelines in most of AGREE domains  is similar to the finding for other national guidelines, as recently published for the general population of guidelines and specific otorhinolaryngology guidelines in China Professional societies in neurology and other clinical disciplines, both at national and international levels, should take seriously the finding from our and other studies on the methodological quality of clinical practice guidelines. At a national level, a good approach may be the translation of AGREE instruments and other relevant documentation


The increasing popularity of complementary and alternative medicines in Canada has led to regulatory reforms in Ontario and British Columbia. Yet the evidence for efficacy of these therapies is still a source of debate. Those who are supportive of naturopathic medicine often support the field by claiming that the naturopathic treatments are supported by science and scientific research.To compare provinces that are regulated and unregulated, we examined the websites of 53 naturopathic clinics in Alberta and British Columbia to gain a sense of the degree to which the services advertised by naturopaths are science based.There were very few differences between the provinces in terms of the types of services offered and conditions treated. Many of the most common treatments--such as homeopathy, chelation and colon cleanses--are viewed by the scientific community to be of questionable value and have no scientific evidence of efficacy beyond placebo.A review of the therapies advertised on the websites of clinics offering naturopathic treatments does not support the proposition that naturopathic medicine is a science and evidence-based practice. In recent years, naturopathic medicine has gained popularity as a form of primary care. In fact, a recent Canadian study found that 13% of children with asthma used complementary and alternative medicine (CAM) to treat their asthma , includiHowever, the growth in naturopathic medicine has not been welcomed by all. Many critics contend that naturopathy treatments are not supported by scientific evidence . Others http://www.bcna.ca/files_3/naturophatic.php. The website for the Association of Accredited Naturopathic Medical Colleges similarly states that, "diagnoses and therapeutics are science based and increasingly evidence based" http://www.aanmc.org/careers/todays-naturopathic-doctors.php.In response, a variety of commentators, including many involved in the profession, have stated that the remedies provided by naturopathic practitioners are supported by solid research. Indeed, claims of scientific rigor have emerged as central to the push for expanded scopes of practice and mainstream acceptance. For example, the British Columbia Naturopathic Association (BCNA) claims that, "[t]here is a wealth of research, both controlled and double-blind clinical studies, showing the scientific basis and validity of naturopathic protocols" But is this true? Are the treatments that are offered by naturopaths science based? In order to explore this question, we examined the websites for naturopathic clinics in Alberta, where naturopaths are not regulated, and British Columbia, where they are. The sample, which was obtained using the Alberta Association of Naturopathic Practitioner's registration list and the BC Naturopathic Association ND list, totaled 53 websites for each province. The goal of this survey was to gain a sense of the degree to which the services advertised by naturopaths are, in a broad sense, science based.What did we find? A list of largely scientifically unsupportable treatments and services aturopathic medicine is patient treatment in the best possible way; personal, individual, caring as well as evidence based and scientific." http://www.abbottnaturopathic.com/While naturopaths are undoubtedly providing other services that have a stronger evidence base , this review of what they advertise as their core services paints a picture of a profession that has embraced practices that are remarkably unscientific. Despite this reality, many of the clinic websites also claim that their services are "evidence" and/or "science" based. One website declares that their therapies are "derived largely from scientific research conducted by the same universities, laboratories and medical schools that do the research on drugs and surgery" To be fair, some may argue that the evidence surrounding practices like homeopathy, hair analysis, colon cleansing and chelation is not as settled as we claim. It is true that both a lack of funding for CAM research  and methodological challenges  means thThere is no doubt that other healthcare professionals, including physicians, provide therapies that are not supported by solid empirical evidence. And a wide range of social forces, including a pervasive industry bias, often distorts the evidence that is used . These aIf the naturopathic medicine were truly "science based", as so often claimed by the advocates of the field, would they still be providing homeopathy as one of their core treatments? Would chelation and colon cleanses be marketed on so many of the clinics' websites?Patients should have the option to access a wide range of healthcare practitioners. But this choice should be as informed as possible. As should the policy debates associated with the regulation of naturopaths' scope of practice. This is particularly so given the types of conditions they seek to address. While one could argue that homeopathic treatment for the common cold is harmless, treatment for conditions such as allergies, cardiovascular problems, fertility issues and cancer raises serious ethical and legal questions. It is misleading to imply that the core services provided by naturopaths - as disclosed on clinic websites - are based on sound scientific evidence or, at least, that there is a scientific consensus about their efficacy. According to clinic websites, allergy testing and treatment are among the most common services provided in both BC and Alberta , yet there is no scientific consensus for the efficacy of naturopathic methods for testing or treatment ,6. It caAs noted in a recent speech by the President of the American Association of Naturopathic Physicians, "if our profession is to be taken seriously by the larger world of medicine, we must speak in a language that everyone can understand and appreciate. That language is the language of science." . We coulThe authors declare that they have no competing interests.TC designed the study, CR collected the data, both authors contributed to drafts of the manuscript and approved the final manuscript.


The development of evidence-based clinical practice guidelines has gained wide acceptance in high-income countries and reputable international organizations. Whereas this approach may be a desirable standard, challenges remain in low-income settings with limited capacity and resources for evidence synthesis and guideline development. We present our experience using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for the recent revision of the Kenyan pediatric clinical guidelines focusing on antibiotic treatment of pneumonia.A team of health professionals, many with minimal prior experience conducting systematic reviews, carried out evidence synthesis for structured clinical questions. Summaries were compiled and distributed to a panel of clinicians, academicians and policy-makers to generate recommendations based on best available research evidence and locally-relevant contextual factors.We reviewed six eligible articles on non-severe and 13 on severe/very severe pneumonia. Moderate quality evidence suggesting similar clinical outcomes comparing amoxicillin and cotrimoxazole for non-severe pneumonia received a strong recommendation against adopting amoxicillin. The panel voted strongly against amoxicillin for severe pneumonia over benzyl penicillin despite moderate quality evidence suggesting clinical equivalence between the two and additional factors favoring amoxicillin. Very low quality evidence suggesting ceftriaxone was as effective as the standard benzyl penicillin plus gentamicin for very severe pneumonia received a strong recommendation supporting the standard treatment.Although this exercise may have fallen short of the rigorous requirements recommended by the developers of GRADE, it was arguably an improvement on previous attempts at guideline development in low-income countries and offers valuable lessons for future similar exercises where resources and locally-generated evidence are scarce. The approach to developing clinical practice guidelines has become increasingly formal over the last two decades. Requirements now span rigor in evidence appraisal to incorporation of user preferences. As a result developed countries have invested substantially in national institutes to develop guidelines  that spanned all guideline topics under review. This approach was used to help standardize procedures and in anticipation of presentation and discussion with a national recommendations panel likely to have limited experience considering research evidence. PICO  formatted questions  had experience conducting systematic reviews and limited, prior exposure to the GRADE approach. However, supported by one key team member (NO), software developed by the GRADE Working Group was utilized to classify the quality of available evidence into four categories   can be aWe searched online databases, PubMed and The Cochrane Library using a common search strategy displayed in Table For the policy question "should cotrimoxazole be replaced by amoxicillin in Kenyan children aged 2 - 59 months fulfilling the WHO criteria for non-severe pneumonia?" our search (see Table Among children with severe pneumonia we sought to address the following questions:1) Should injectable benzyl penicillin be replaced by oral amoxicillin?2) Should injectable benzyl penicillin monotherapy be replaced by benzyl penicillin plus gentamicin?We identified 8 articles including 2 Cochrane systematic reviews that addressed the two questions.Three trials compared oral versus parenteral treatment for severe pneumonia: Addo-Yobo et al ,20,25,26Only one small trial was found comparing costs and clinical outcomes enrolling 40 children with severe pneumonia in Malaysia in 1999/2000 after randomization to either benzyl penicillin/ampicillin monotherapy or combination therapy with gentamicin ,29. The Two policy questions were addressed relating to antibiotic treatment of children with very severe pneumonia:1) Should chloramphenicol be abandoned as an alternative treatment to benzyl penicillin plus gentamicin?2) Should benzyl penicillin plus gentamicin/chloramphenicol be replaced by ceftriaxone?Two trials reviewed addressed each of the two questions. The studies were also summarized in a Cochrane review .Two trials compared the effectiveness of benzyl penicillin/ampicillin combined with gentamicin versus chloramphenicol for very severe pneumonia. Duke et al 2002) studied 1116 children in Papua New Guinea ,20,30 wh02 studieWe found no experimental data directly comparing outcomes following treatment of very severe childhood pneumonia using the recommended antibiotics against ceftriaxone, a common regimen used by clinicians in Kenya. One small trial (n = 97) from Turkey compared benzyl penicillin combined with chloramphenicol and ceftriaxone at day 10 of treatment for radiologically-confirmed severe and very severe pneumonia ,32 whileThe primary evidence retrieved was from randomized controlled trials and therefore might initially be considered high in quality. However, after subjecting the studies to the GRADE quality assessment process, all the studies were graded downwards leaving no high quality evidence for any of our 5 Kenyan policy questions. Although the GRADE system provides for the inclusion of data from observational studies, we found none that addressed our clinical questions. Our reasons for downgrading evidence, and any challenges with this are highlighted below.Limitations that might result in downgrading are reasonably clearly defined in GRADE and include lack of allocation concealment, absence of blinding and large losses to follow up. For pneumonia two trials failed to report allocation concealment ,32 and bInconsistency refers to large and unexplained variability in magnitude of effects across studies. Hidden inconsistency becomes more apparent as the number of studies compared increases. With only a few studies available apparent inconsistency was only detected in one instance, in trials comparing cotrimoxazole and amoxicillin for non-severe pneumonia. Straus et al  reportedIndirectness refers to differences between the evidence under review and the clinical question of interest in relation to the PICO elements. We downgraded all the studies reviewed by one level for indirectness of population based on geographic location since they included little or no data from African children. This subjective decision was based on studies suggesting higher risks of treatment failure and mortality in African children with pneumonia ,35,36. IIn studies where sample size is small and number of events few, estimated effects are associated with wide confidence intervals and therefore regarded as imprecise. This was relatively common with three trials which recruited less than 100 patients graded downwards by one level for imprecision ,32,33.Our ability to conduct meta-analysis incorporating data from all of the studies reviewed was frustrated by differences in reported outcomes  or an inReliance only on published studies may cause bias if there is a preference for reporting only 'positive' outcomes. Our resources and we suspect those of many in low income settings, precluded detailed searches of grey literature making such a bias likely, particularly where there are already very few published trials. In the case of pneumonia the similarity of studies to those identified in a subsequently published Cochrane review  are reasin vitro resistance and the clinical effectiveness of antibiotic treatments were either limited or completely lacking respectively.We did not find any studies reporting on cost-effectiveness of alternative pneumonia treatments. We considered that evidence from observational studies suggesting no clinical difference following treatment of pneumonia in children with beta-lactam antibiotics in the presence of penicillin-resistant or penicillin-sensitive pneumococci  to be ofThe GRADE approach indicates that contextual factors including cost, local values and preferences, feasibility, undesired effects and benefits should be taken into account in making a recommendation based on evidence. There is no explicitly defined preferred method for taking these factors into account. Our pragmatic approach was to engage a national guideline development forum attended by a panel of 70 people from academic and policy backgrounds and routine clinical settings. After presenting and discussing the evidence we invited discussion on these contextual considerations Figure  amongst Most notable was a strong recommendation against the proposal to adopt oral amoxicillin in place of or even as an alternative to benzyl penicillin/ampicillin for severe pneumonia. This was despite evidence from three large trials suggesting equivalence between the treatments and several additional factors apparently favoring oral amoxicillin including lower cost, more convenient twice daily dosing and reduction in the use of injections in children. In this case the panel essentially discounted moderate quality evidence and felt that such a change in policy should only be informed by locally-generated data. Such an absolute rejection of evidence gathered from trials involving almost 5000 children, something of a surprise to those summarizing it, was also observed for other guideline topics. In this particular case one could speculate that the absence of patient views, children who might receive either multiple injections or oral therapy, might have been an important omission.Interestingly, strong recommendations were also made against proposals to adopt penicillin plus gentamicin for severe pneumonia and ceftriaxone for very severe pneumonia. Although evidence was largely absent, and thus did not support these proposals, such regimens were admitted to be common local practice. Here a major reason given for strongly rejecting what was already being practiced, in support of existing recommendations, was the perceived need to preserve the alternative treatments as second line regimens in the absence of viable alternatives. It is thus possible that here discussions on the absence of evidence supporting superiority of non-guideline regimens being used in practice may have helped to rebuild confidence in existing guidelines. In line with the evidence presented, the panel made a strong recommendation to abandon chloramphenicol as an alternative treatment to benzyl penicillin/ampicillin and gentamicin for very severe pneumonia. In this case, although the decision was consistent with the moderate quality evidence, much of the data summarized was from non-African children. This contrasts with rejection of similar quality evidence, also from non-African children, referred to above in the case of amoxicillin in severe pneumonia. In this case we speculate that abandoning chloramphenicol may have resonated with existing views that the drug was no longer suitable, having been abandoned by western countries many years ago on the grounds of safety.We used the GRADE system to review and contextualize the evidence on a number of topics as part of an effort to revise Kenyan national guidelines. We have used the antibiotic treatment of community-acquired pneumonia in Kenyan children to illustrate the approach and some of the challenges encountered. Perhaps one of the most striking findings is the limited availability of high quality evidence generalizable to the population of interest, Kenyan or African children. Whereas it is not feasible for all policies to have supporting data from large randomized controlled trials, we noted a serious shortage of good evidence on a number of other important guideline related questions in pediatric and neonatal care. This contrasts with the situation for a topic such as outpatient malaria, where a recent systematic review managed to include fifty randomized trials , reflectWhere studies are few limitations of the evidence are likely to be greatest. It is hard to detect publication bias, inconsistency is clearly hard to evaluate, imprecision is likely and indirectness related to study site will be common. With low quality data recommendations should generally be weak if the GRADE system is adhered to. We employed a voting system based on an adaptation of the GRADE grid  that it Grading the evidence when resources are limited may depend, to a considerable degree, on the subjective decisions of a small number of people. In our case evidence was summarized and graded by only two to three people. In an attempt to engage the local pediatric establishment review teams included people with very limited prior training or experience in this field. While the GRADE approach and software appeared relatively intuitive to use after limited introductory training, decisions on how to grade the quality of evidence, for example down-grading for indirectness, might have influenced subsequent recommendations and inexperience resulting in inappropriate decisions may have been important. The alternative of engaging a team of experienced methodologists in an effort to minimize the potential limitations referred to above would have been associated with substantial increases in the cost of the process challenging the feasibility of this exercise in low income settings . InsteadThe GRADE approach promotes a more transparent contextualization of evidence to produce final recommendations. The degree to which it is reasonable to 'abandon' evidence in favor of context is perhaps debatable. It appeared to us that moderate quality evidence was on occasions influential and on others ignored. Thus in the absence of likely significant additional contextual factors (such as costs or feasibility) decisions appeared to be based largely on the preferences of the people assembled and their views on patient preferences. The dynamics of the group process, the choice of the discussion moderator and his interaction with the recommendations panel, the composition of this panel, the mode of presentation of the evidence and other factors may all have contributed to the direction and strength of final recommendations -44. We wAlthough our application of the GRADE system may have implications for the validity of our final recommendations, it can be argued that our approach was in fact an improvement on previous exercises in national guideline development that lacked transparency . PreviouThe authors declare that they have no competing interests.AA supported by ME and NO was primarily responsible for the systematic review of pneumonia case management. AA produced the first draft of the report on use of GRADE that was further developed with input from ME and NO. All authors reviewed and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/12/1/prepub


Annals, I described the medical technologies evaluation programme that was established in 2009 and which has matured since that time.1 This NICE programme selects and evaluates devices and diagnostics notified by manufacturers and produces guidance on them, based on claims of advantages to patients and/or to the health service. Evaluation demands clear value propositions but it is often done on the basis of rather limited published clinical evidence.2–3 The advice and opinions of clinical experts is a very important part of the evidence used by the advisory committee.In a previous issue of the Medical technologies guidance relates to specific products but it may help to steer clinicians and the NHS towards adopting general types of technology, provided that the evidence base for other similar devices is adequate. Published medical technologies guidance relevant to surgical practice includes the following.4 There may be circumstances in which the two types of warming are used together. The evidence supports the claim by the manufacturers that the Inditherm mattress is as effective as forced air warming in maintaining core body temperature above 360 degrees but Inditherm may have practical advantages. Cost modelling, including the costs of equipment, disposables and projections of likely reduction of postoperative infections as a result of avoiding hypothermia, predicted a potential annual cost saving of £9,800 per operating theatre if Inditherm is routinely adopted instead of forced air warming.This is a pressure-relieving system of mattresses and blankets, which incorporates a uniform direct heating surface, with safety features to prevent overheating. The mattress can be left on the operating table and cleaned between patients, just like a normal theatre table mattress. Guidance recommends that the Inditherm system should be considered as an alternative to forced air warming, which is one component of the current standard of care for preventing perioperative hypothermia.4 Medical technologies guidance may offer recommendations on new, alternative technologies, with explicit information about their potential advantages and likely cost consequences. It introduces considerations, based on novel and bespoke evaluation methods, which are new and additional to any clinical guideline: the latter may be updated to incorporate the more recent evidence and recommendations made for medical technologies.It is worth clarifying the relationship between medical technologies guidance and NICE clinical guidelines .This is a Doppler ultrasound system, incorporating reusable sterile probes, for measuring flow in bypass grafts. It was clear to the Committee that practices vary and opinions differ about techniques for checking graft flow during CABG operations. However, thorough examination of the evidence presented did support the claim that using VeriQ  would prompt revision of imperfections in a small proportion of CABGs, which could otherwise lead to occlusion. Although the numbers of patients who might suffer serious clinical deterioration as a result would be small, the damage to them and the costs of their care supported the case for adopting VeriQ, with an expectation of saving £115 per patient, assuming its widespread and regular use.This device is an adjunct to experienced clinical evaluation of the depth of burns and the need for skin grafting. There was evidence that this device can usefully guide treatment decisions when there is uncertainty about burn depth: it allows earlier planning and avoidance of needless skin grafting in some patients. Cost modelling suggested savings per patient scanned of around £1,240, based on a 17% reduction in the number of skin grafting operations.This system comprises a silicone catheter and 1-litre vacuum bottle with associated kit that can be used in patients’ homes instead of traditional inpatient paracentesis for distressing recurrent malignant ascites. There is good evidence that the system is effective and has a low complication rate. It has the potential to allow earlier treatment in the community when ascites starts to cause distress, instead of waiting for large-volume paracentesis in hospital, associated with an average inpatient stay of almost three days. Using the PleurX® system offers not only the opportunity to improve quality of life for patients with advanced malignant disease but it is also associated with a likely cost saving to the NHS of some £679 per patient.This technology involves the delivery of ultrasound energy through a saline mist. It is claimed to enhance healing of chronic ‘hard-to-heal’ wounds. Based on the evidence available, MIST appeared to have real promise but there was insufficient evidence about just how effective it is in clinical practice. An explicit recommendation was therefore made for research and NICE used new capacity that it has created to facilitate the setting up of collaborative research between manufacturers and the NHS to answer the outstanding questions. That research has now been commissioned and MIST will be reviewed for updated medical technologies guidance when the results of that research are available.


The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to helpclinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-knownexamples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPICguideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypesand assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to helpclinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews thedevelopment process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing TrustworthyClinical Practice Guidelines. At the time of this writing, CPIC has published nine gene-drug guidelines [http://www.pharmgkb.org/page/cpicGeneDrugPairs). An important CPIC activity has been the development of consensus guidelines that emphasize clinical relevance and applicability. The purpose of this manuscript is to review the CPIC guideline development process. We also compare this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines [The Clinical Pharmacogenetics Implementation Consortium (CPIC), a shared project between The Pharmacogenomics Knowledgebase  and an extensive pre- and post-submission peer review approval process. The CPIC Steering Committee and the CPIC Coordinator provide oversight for the guideline development process. CPIC guidelines are developed using established methods, including a rigorous review and grading of the relevant scientific literature, input of a writing committee composed of clinicians and basic researchers with expertise in the subject, a standard format  with evidence in favor of their use, such that treatment could be improved for a patient whose genotype is known. The potential consequences of ignoring genetic test results versus using them to change therapy based on the probability of both the desired therapeutic effects and the undesired adverse effects are considered. Additional gene-drug pairs are considered after nomination by CPIC members or by external experts (who are then invited to join CPIC) and are identified by regular review of FDA recommendations and PharmGKB clinical annotations [In 2009 and 2010 CPIC conducted two surveys, one among CPIC members and the other among members of the American Society for Clinical Pharmacology and Therapeutics (ASCPT). Responders were asked to rank 29 gene-drug pairs according to the perceived importance for using a genetic test to inform prescribing of the drug [otations  of gene-e.g., pharmacists and physicians). Authors will have a track record of publication and/or expertise in the specific topic area of the guideline. PharmGKB assigns at least one Scientific Curator to each CPIC guideline writing committee who has expertise in searching, compiling and evaluating the evidence for gene-drug associations, and making it computable and available on the PharmGKB website. Furthermore, PharmGKB curators often take primary responsibility for completing background gene and drug summaries, assigning likely phenotypes based on genotypes (i.e. “Table 1” in guidelines), literature review, as well as preparing supplementary material provided in each guideline (i.e. genotypes that constitute the star (*) alleles or haplotypes, frequencies of alleles in major race/ethnic groups, genetic test interpretation and availability, and evidence linking genotype with phenotype).Once a guideline topic has been approved by CPIC members and the Steering Committee, a senior author is identified through self-nomination or by request of the CPIC Steering Committee. The senior author takes responsibility for forming the writing committee and completing the guideline. The writing committee is multidisciplinary, comprising a variety of scientists, pharmacologists, and clinicians (2) in the proposed guideline will contain specific recommendations for changing dose or choice of drug based on genotype. Without specific, actionable recommendations, the need for a CPIC guideline is reconsidered. If a guideline is not deemed appropriate, a new category of pharmacogenetic summary  can instead be considered (see sub-section “Development of Therapeutic Recommendation and Assignment of Strength of Recommendation” for further explanation).The writing committee first determines whether it is likely that, based on available evidence, the therapeutic recommendation table  OR (gene symbol) OR (dbSNP rs number) OR (gene common names) AND (drug name OR drug class name). Furthermore, papers listed on PharmGKB are cross-checked as there may be annotations for the papers and/or additional publications. Examples of types of evidence reviewed include, but are not limited to, randomized clinical trials with pharmacogenetic-based prescribing versus dosing not based on genetics, pre-clinical and clinical studies demonstrating that drug effects or concentration are linked to functional pharmacogenetic loci, case studies associating rare variants with drug effects, et al. [high, evidence includes consistent results from well-designed, well-conducted studies; moderate, evidence is sufficient to determine effects, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence; weak, evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information. Primary publications are summarized in the Evidence Table which is published in the manuscript supplemental material. It is the writing committee’s evaluation of this evidence that provides the basis for the therapeutic recommendation(s).Publications supporting a major finding are usually considered as a group and scored by members of the writing committee based on the totality of the evidence supporting that major finding. Thus, it is possible for an evidentiary conclusion based on many papers, each of which may be relatively weak, to be graded as “moderate” or even “strong,” if there are multiple small case reports or studies that are all supportive with no contradictory studies. The rating scheme uses a scale modified slightly from Valdes et al. : high, e2 of each guideline and occasionally in an algorithm. The writing committee discusses the evaluation of the literature and develops a draft recommendation via web conferences and email communication. CPIC’s therapeutic recommendations are based on weighing the evidence summarized in the supplementary Evidence Table from a combination of preclinical functional and clinical data, as well as on any existing consensus guidelines . Evidenchttp://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf). Therapeutic recommendations are graded as: strong, where “the evidence is high quality and the desirable effects clearly outweigh the undesirable effects”; moderate, in which “there is a close or uncertain balance” as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects; and optional, in which the desirable effects of pharmacogenetic-based dosing are closely balanced with undesirable effects and there is room for differences in opinion as to the need for the recommended course of action. Each recommendation also includes an assessment of its usefulness in pediatric patients. To assign strength to a recommendation, CPIC uses a transparent three category system for rating recommendations that was adopted with slight modification from the rating scale for evidence-based recommendations on the use of antiretroviral agents . For these and many other gene-drug pairs, PharmGKB also contains clinical annotations that are genotype-based summaries of the association between a drug and a particular variant. Each clinical annotation is assigned a level of evidence depending on population, replication, effect size and statistical significance (reviewed in [CPIC guidelines currently focus on gene-drug pairs for which at least one of the prescribing recommendations is actionable (iewed in ).CPIC is considering developing gene-drug pair “evaluations,” as opposed to guidelines, for cases in which the evidence is weak, the prescribing recommendations are optional, or the weight of the evidence does not support altering prescribing based on genetics. As more and more preemptive genotyping is performed, providing guidance to clinicians linking gene variation to drug response and how or whether to use genetic test results, even when recommendations are not strong, becomes more relevant to practice.e.g., CYP2D6 poor metabolizer) or drug prescribing groups . The therapeutic recommendations are based on these predicted phenotypes or groupings. As such, assignment of phenotype based on genotype is an important step in the CPIC guideline development process, especially because phenotype assignment is variable in the literature. Each guideline contains a table that assigns likely function to relevant alleles and phenotypes based on possible genotypes . Another potential risk discussed in CPIC guidelines is a possible error in genotyping, as these errors could stay in the medical record for the life of the patient.Each guideline also contains a section on potential benefits and harm for the patient. This section discusses the consequences, toxicities or adverse drug reactions that may be avoided by pharmacogenetic-based dosing as well as any potential risks from incidental findings or use of alternative drugs or dosing strategies  and announced to the pharmacogenetic community via a blog posting. Each gene-drug pair has its own page with interactive therapeutic recommendations, enabling the user to select a particular genotype or diplotype to view the specific therapeutic recommendation. A summary table is included that provides phenotype assignments based on genotypes, implications for use of the drug based on phenotype/genotype, and the gene-drug based recommendations. The full published article and supplements are also available for download on PharmGKB. CPIC pharmacogenetic guidelines are fully integrated into the PharmGKB database and are available as a JSON (Java Script Object Notation) download for integration with other systems, as well as linking to gene and drug pages with further relevant pharmacogenetic information such as FDA drug labels. CPIC guidelines are listed on PharmGKB along with guidelines from other professional societies, enabling comparison with other known existing guidelines. Once published online, each CPIC guideline is also incorporated online at PharmGKB . Authors of CPIC guidelines have often been involved in SRs for their gene/drug topic, but there is no concerted effort to involve the same team of authors. The updated American College of Chest Physicians (ACCP) Antithrombotic Therapy Guideline (2012) provides an example for operationalizing this standard [a priori to use research methodologists to conduct all evidence review and grading rather than clinicians or experts in antithrombotic therapy research. Of note, the research methodologists involved were aided by existence of many published clinical trials (for many of the recommendations) used similar methods and outcome measures. Evidence review was systematically conducted using an established framework, and studies were assessed and summarized using criteria from the Cochrane Collaboration. When evidence grading was completed, the writing group voted to approve or not approve recommendation statements drafted from the graded evidence. In comparison, because of the nature of pharmacogenomic studies, the CPIC guideline development process often relies on published results of pharmacogenomics studies, observational cohort studies providing post-hoc analysis of clinical trials, and preclinical experimental work, some of which can vary with respect to methodological rigor and study outcomes [Table standard . The ACCoutcomes . This vaper se which further limits the potential impact of conflict of interest. Other differences between the CPIC guideline process and IOM standards are worth noting. CPIC requires full disclosure of all workgroup members’ potential conflict of interest. While current policies do not explicitly require those with conflict of interest to divest interests or ensure that those with conflict of interest are in the minority of the workgroup, a review of the extant guidelines shows that in most cases the majority of guideline authors declare no conflict of interest. All proposed guidelines are reviewed by CPIC members and an independent peer review managed by journal editors, which act to ameliorate concerns about undue influence of conflict of interest. Another unique aspect of the CPIC guidelines that may mitigate concerns regarding conflict of interest is that CPIC guidelines focus on how to use pharmacogenomic information available to the clinician, not whether to order a genetic test. In this way the guidelines do not recommend a test CPIC guidelines are all posted in draft form on CPIC’s website for comment by CPIC members prior to submission of the guideline for publication. At present, CPIC does not actively include a mechanism for comment by the general public either through representation on the guideline workgroup or through a public comment period prior to publication, a feature that is recommended by the IOM. The selection and prioritization of guideline topics incorporates the patient perspective indirectly through the surrogate of the FDA black box warning, but this does not meet the letter of the IOM recommendations. Personal communication and experience from several authors involved in other professional society guideline efforts indicate that CPIC is not alone in evaluating how to meet this IOM standard. CPIC will continue to discuss and evaluate the best approach to expand opportunities for public comment.e.g., JSON format).An ultimate goal for CPIC guidelines is to guide clinicians to make patient care decisions for specific drugs when genetic results are available. Electronic health records (EHRs) and clinical decision support (CDS) are essential to implementation of pharmacogenomics , 15, 22,CYP2D6, CYP2C19, and TPMT (http://www.pharmgkb.org/page/tppTables), and processes to develop and maintain each table as part of the CPIC guideline update process are being developed. Other informatics priorities for CPIC include encouraging vendors that produce clinical electronic references and EHRs to include CPIC guidelines and developing recommendations for CDS based on the guidelines. Long term opportunities include working with standards development organizations to create content that supports the CPIC guidelines and pharmacogenetics, such as terms that properly define metabolizer status and other pharmacogenetic phenotypes, and generating computable representations of the CPIC guidelines using formal knowledge representation and standard terminologies. Ultimately, these efforts will position the CPIC guidelines to work effectively in our increasingly electronic health care system. To address the growing interest in the informatics aspects of CPIC guidelines and clinical implementation of pharmacogenetics, CPIC created an informatics working group in 2013. The working group’s goal is to support the adoption of the CPIC guidelines by identifying, and resolving where possible, potential technical barriers to the implementation of the guidelines within a clinical electronic environment. Because detailed information that translates each result from genotype to phenotype to clinical recommendation is needed to implement pharmacogenetics into patient care, the informatics working group’s initial focus is creating translation tables, which complement similar data gathered by the Translational Pharmacogenetics Project (TPP), a network wide PGRN venture . Initial® repository. Moreover, the NIH’s Genetic Testing Registry, which provides a central location for voluntary submission of genetic test information by providers, provides links to CPIC guidelines based on condition/phenotype . Recently, CPIC guidelines have been accepted for inclusion to the AHRQ-sponsored National Guideline Clearinghouse (www.guidelines.gov) and summaries of the guidelines, including the prescribing recommendation, are freely available to the public from this site as well. A number of methods are used to distribute and support uptake of CPIC guidelines after publication. As discussed above, all guidelines are posted on the PharmGKB website, linked to pages for the gene and the drug that also provide other relevant information. Furthermore, all guidelines are cited in PubMed and classified as a “practice guideline,” a method used to organize and index published clinical practice guidelines in PubMed. The final published full text guidelines are also freely available in the NIH’s PubMed CentralCYP2C19/clopidogrel and CYP2D6/codeine CPIC guidelines (http://www.ashp.org/menu/PracticePolicy/PolicyPositionsGuidelinesBestPractices/BrowsebyDocumentType/EndorsedDocuments.aspx). Other professional organizations have also indicated an interest in formally endorsing CPIC guidelines.Indicators for the growing uptake of CPIC guidelines are emerging. The first eight CPIC guidelines and the first guideline update -9, 11 haAdoption of pharmacogenetic tests in routine clinical practice has been sparse. One major barrier to clinical implementation is the lack of clear, curated, peer-reviewed pharmacogenetic guidelines. CPIC guidelines represent a critical step enabling the translation of clinical genetic test results into actionable prescribing decisions. All CPIC guidelines adhere to a standard format and contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug prescribing groups. Our experiences indicate that key factors for successful development and adoption of these guidelines include: (1) adhering to standard systems for grading levels of evidence and for assigning strength to each prescribing recommendation;(2) close collaboration among clinicians, scientists, pharmacologists, and informatics experts; (3) provision of clear and specific recommendations for prescribing and (4) converting the guidelines into machine readable formats for incorporation into electronic medical records and linking to clinical decision support tools. The underlying principle, that CPIC guidelines provide recommendations on how to use but not whether to order genetic tests, has allowed the guideline development process to focus on practical aspects of implementing pharmacogenomics into clinical care.


Despite being well visualized by different cross-sectional imaging techniques, the spleen is many times overlooked during the abdominal examination. The major reason is the low frequency of splenic abnormalities, the majority consisting of incidental findings. There has been a steady increase in the number of performed abdominal magnetic resonance imaging (MRI) studies; therefore, it is important to be familiar to the major MRI characteristics of disease processes involving the spleen, in order to interpret the findings correctly, reaching whenever possible the appropriate diagnosis. The spleen may be involved in several pathologic conditions like congenital diseases, trauma, inflammation, vascular disorders and hematologic disorders, benign and malignant tumors, and other disease processes that focally or diffusely affect the spleen. This paper presents a description and representative MRI images for many of these disorders. Splenic disease has always been a challenge to the radiologist. Despite of being well visualized by different cross sectional imaging techniques, the spleen is many times overlooked during the abdominal examination. The major reason is the low frequency of splenic abnormalities, the majority consisting of incidental findings.There has been a steady increase in the number of performed abdominal magnetic resonance imaging (MRI) studies; therefore, it is important to be familiar to the major MR imaging characteristics of disease processes involving the spleen, in order to interpret the findings correctly, reaching whenever possible the appropriate diagnosis. Nowadays, MRI permits the characterization of the most common splenic lesions, such as cysts, small hemangiomas, and hamartomas, and improvement in the detection of malignant diseases such as lymphoma and metastases .The spleen may be involved by several pathologic conditions including congenital diseases, trauma, inflammation, vascular disorders and hematologic disorders, benign and malignant tumors, and other disease processes that focally or diffusely affects the spleen. This article presents a description and representative MRI images for many of these disorders.The spleen is located in the left hypogastric quadrant of the abdomen and is fixed in its intraperitoneal position beneath the 9th to 11th intercostal spaces by the splenorenal, splenocolic, splenogastric, and phrenicosplenic ligaments. The configuration of the spleen is variable , as well as the size, which is related with the patient's morphological type and age . The orgOn T1-weighted MR images, the normal signal intensity of the spleen is lower than that of hepatic tissue. Conversely, on T2-weighted images, the spleen shows higher signal intensity, appearing brighter than the liver  Figure . The disThe spleen demonstrates a heterogeneous serpentine or arciform pattern enhancement immediately after contrast material administration, secondary to differences in flow between the red and white pulps, becoming homogeneous in venous and interstitial phases  Figure . Any hetThe congenital absence of spleen is known as asplenia and the presence of one or more spleens is known as polysplenia. Both are very rare and usually associated with other congenital abnormalities.The accessory spleens may be found in 10% of the population , more frSplenosis develops when splenic tissue is seeded within the abdomen or pelvis  followinThe “upside-down spleen” is a normal variant due to an abnormal splenic rotation where the hilum is superiorly located and the convex border is medial and adjacent to the left kidney  Figure .All these normal variants and congenital abnormalities are usually easy to recognize.Splenic abscess is an uncommon lesion with high mortality rates, because of delayed detection and treatment , 15. TheSplenic abscesses are hypointense on T1-weighted images and have a moderate to high signal intensity on T2-weighted images, with irregular and undefined margins , 16. GasCandidiasis is the opportunistic infection that most frequently affects the liver and the spleen in immunocompromised patients. MRI is superior to CT for the detection and characterization of splenic microabscesses (<1 cm), most commonly secondary to candidiasis and appear as multiple hyperintense lesions in T2-weighted images with peripheral ring enhancement on gadolinium-enhanced images , 8 Figu.Although it might be seen in patients with competent immune systems, the prevalence of histoplasmosis is greater in immunocompromised patients. MR imaging demonstrates the acute and subacute phases of this disease as scattered hypointense lesions on both T1- and T2-weighted images. Old granulomas can be calcified, causing with the characteristic signal intensity changes with blooming artifacts on MR images .Sarcoidosis is a granulomatous systemic disease of unknown etiology that may involve several organs and not infrequently the spleen. Of patients with systemic sarcoidosis, 24 to 59% have biopsy-documented splenic sarcoidosis .Nodular sarcoidosis has been reported to demonstrate low signal intensity in all MR sequences. The lesions are most conspicuous on T2-weighted fat-suppressed or early phase contrast-enhanced images. Sarcoid lesions enhance minimally on delayed images .Splenic infarcts may result from venous or arterial blood supply interruption. The vascular occlusions can be the result of a tromboembolic process caused by any type of hemolytic anemia, endocartitis or chronic valvular diseases, Gaucher disease, portal hypertension, or vascular collagen diseases , 18.The typical MR appearance of a splenic infarct is a triangular wedge-shaped area, at the periphery of the spleen, with varying signal intensity according to the age of the infarct. It shows no enhancement after gadolinium injection and it is better depicted in late vascular phases, when the spleen is homogeneously enhanced , 8 Figu.Splenic hematoma is usually secondary to trauma . Like spCysts are the most common benign focal splenic masses. They may be separated into epithelial or true cysts (approximately 25% of splenic cysts), which are lined with epithelium, and pseudocysts that can be posttraumatic or secondary to pancreatitis, in which the wall is fibrotic and lacks a true cellular lining (account for approximately 75% of splenic cysts) , 19. Posttraumatic pseudocysts are thought to represent the final stage in evolution of a splenic hematoma, although some have suggested that they might also be secondary to infarct or infection , 18. PanMRI shows the characteristic findings of a cyst, that is, a well-defined round mass, with thin or imperceptible wall, homogeneous hypointense on T1-weighted images, and hyperintense on T2-weighted images, with no enhancement on postcontrast images  Figure .It is often impossible to distinguish between true and false cysts; the clinical presentation and patient history may help to narrow the differential diagnoses. Cyst wall trabeculation or peripheral septations are much more commonly found in true cysts .Usually involves the liver or lungs but occasionally may also involve the spleen. Splenic hydatid cysts are very rare even in endemic regions (less than 2%) . On MRI Splenic hemangiomas are the most common benign solid tumor of the spleen. Their frequency in large autopsy series is 0.03%–14%, and they are more frequently found in males (1.4 versus 1.0) , 21. TheDiffuse hemangiomatosis of the spleen is a rare benign vascular condition occurring as a manifestation of systemic angiomatosis  or, less commonly, confined to the spleen .Most hemangiomas are well-defined homogeneous, hypo- to isointense on T1-weighted images and most commonly hyperintense on T2-weighted images compared with splenic parenchyma  Figure . On dynaHamartoma is an infrequently benign, usually asymptomatic tumor of the spleen, with an autopsy incidence of 0.13% and no gender predilection. Approximately, one-sixth of hamartomas are found in children (<16 years). They are nonneoplastic tumors composed of a mixture of normal elements of splenic red and white pulp components , 23. TheHamartomas are a sharply defined, rounded, single solid lesion that sometimes may be multiple . On MRI,Littoral cell angioma is a relatively new clinicopathological entity of a rare benign tumor of the spleen that develops from the lining cells of the red-pulp sinuses, the so-called “littoral cells”, giving rise to littoral cell angioma . It has Lesions are of variable size and commonly multinodular. They are composed of anastomosing vascular channels with irregular lumina featuring cyst-like spaces and lined by tall endothelial cells. On MRI, lesions are inhomogeneously hyperintense on T2-weighted images, with signal intensity similar to that of hemangiomas and slightly hypointense on unenhanced T1-weighted images. Littoral cell angiomas may show low signal intensity on all sequences due to hemosiderin accumulation within neoplastic littoral cells . DynamicLymphangioma is a rare vascular benign lesion filled with lymph instead of red blood cells as seen in hemangioma . UsuallyCystic lymphangioma is the most frequent type and is characterized by a honeycomb of large and small thin-walled cysts containing lymph-like clear fluid. On MRI, lymphangiomas usually present as well-defined multilocular cystic lesions, with thin septations and hyperintensity on T2-weighted sequences. However, some of the cysts may be hyperintense on T1-weighted images, due to protein or hemorrhagic content , 19.Lymphoma is the most common splenic malignancy. Both Hodgkin's and non-Hodgkin's lymphoma may present in the spleen as the primary site (less than 1%) or as part of systemic involvement ..28].Angiosarcoma is exceedingly rare, yet it is the most common primary malignant nonlymphoid tumor of the spleen . These tAngiosarcoma typically appears as multiple nodular heterogeneous masses, with variable signal intensity on T1-weighted and T2-weighted images, due to the presence of hemorrhage with different ages, siderotic nodules, and areas of necrosis. Following the intravenous administration of gadolinium, the lesion demonstrates heterogeneous enhancement. MRI seems to be more precise than CT in the overall assessment and staging of this type of tumor and is of particular value for timely diagnosis .There are other extremely rare primary malignant splenic tumors including malignant fibrous histiocytoma, leiomyosarcoma, fibrosarcoma, malignant teratoma, and Kaposi sarcoma, all of which are with nonspecific appearance.Splenomegaly is a radiologic and clinical sign, classically described when the craniocaudal splenic length is more than 12 cm . This maFoci of hemosiderin deposition are seen in about 9%–12% of patients with portal hypertension and are the so-called Gamma-Gandy bodies . These fGaucher disease is an autosomal recessive lysosomal disorder secondary to lack of the enzyme glucocerebrosidase, leading to the accumulation of glucocerebrosides in the cells of the reticuloendothelial system, causing hepatosplenomegaly. Splenic infarcts and fibrosis associated with Gaucher disease may exhibit a multifocal pattern .Hemosiderosis, with splenic involvement, shows diffuse diminished signal intensity of the organ on both T1- and T2-weighted images relative to musculature as a result of hemosiderin deposition [Sickle cell disease is common in the Afro-descendent population with a prevalence of 0.2% (homozygous form) and 8%–10% (heterozygous form). The spleen is the most commonly organ involved. In patients with sickle cell disease, the spleen appears as a nearly signal void area due to iron deposition from blood transfusion. Autosplenectomy is often found in patients with homozygous sickle cell disease , 8 Figu.Extramedullary hematopoiesis is a compensatory response to failure of the bone marrow cells. A focal mass-like involvement of the liver and spleen, which are the main affected organs, may be present. On MRI, the appearance of the nodular lesions depends on the evolution of the hematopoiesis. Active lesions reveal intermediate signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and moderate enhancement after administration of intravenous gadolinium. Older lesions are hypointense on T1- and T2-weighted images and do not show any enhancement. These lesions usually demonstrate low signal intensity on in-phase T1-weighted GRE images compared with that on out-of phase images due to the presence of iron .Focal and diffuse lesions of the spleen are uncommon and usually discovered incidentally on cross-sectional imaging studies. Due to the widespread of MRI there has been an increase in the detection of diseases involving the spleen. By virtue of its excellent contrast resolution and the possibility of tissue characterization through the use of different sequences, MRI provides an excellent tool for the evaluation and characterization of various splenic lesions. Awareness of the MRI appearance of the most common splenic disease processes is important for the radiologist to interpret the findings correctly, reaching whenever possible the appropriate diagnosis.


As the use of eHealth grows and diversifies globally, the concept of eHealth literacy – a foundational skill set that underpins the use of information and communication technologies (ICT) for health – becomes more important than ever to understand and advance. EHealth literacy draws our collective attention to the knowledge and complex skill set that is often taken for granted when people interact with technology to address information, focusing our attention on learning and usability issues from the clinical through to population health level. Just as the field of eHealth is dynamic and evolving, so too is the context where eHealth literacy is applied and understood. The original Lily Model of eHealth literacy and scale used to assess it were developed at a time when the first generation of web tools gained prominence before the rise of social media. The rapid shifts in the informational landscape created by Web 2.0 tools and environments suggests it might be time to revisit the concept of eHealth Literacy and consider what a second release might look like. As the use of eHealth grows and diversifies globally, the concept of eHealth literacy – a foundational skill set that underpins the use of information and communication technologies (ICT) for health – becomes more important than ever to understand and advance . eHealthJournal of Medical Internet Research (JMIR) provides examples of the diverse means in which the concept of eHealth Literacy has been applied, introducing challenges and presenting opportunities for understanding the evolution of the concept in the age of eHealth and mHealth. These challenges and opportunities will now be discussed in light of four papers published in this issue of JMIR [This issue of the  of JMIR -6.The eHealth literacy concept, model and related measurement scale, the eHealth Literacy Scale (eHEALS) , 2, origThe theory and measurement of eHealth literacy is not without challenges and the papers in this issue highlight some of them, while presenting opportunities for further learning.The work by Stellefson and colleagues  looked aThe study by Chan and Kaufman  illustraXie  took a dContext is also an issue with the eHEALS itself, as the work by van der Vaart and colleagues  (perhapsThe research by van der Vaart and colleagues  questionSuch questions may be less about validity in a specific sense and more about the validity in a more generalized sense of Internet usage. Indeed, the positive coherence of the eHEALS in other studies and its psychometric robustness might suggest adding a social media interactive subscale rather than a change to the existing items, which would have significant consequences for the psychometric integrity of the instrument. Items could be developed that consider skills and tasks like:confidence in expressing oneself clearly in social interactions onlineability to synthesize professional and non-professional advicecomfort and skill in navigating through information obtained through a mobile deviceability to use apomediaries to filter relevant and trustworthy information .The fundamental collection of skills that comprise eHealth Literacy have not likely changed, but the contexts in which they are expressed in the dynamic realm introduced by social media have. This presents an opportunity for research and practice to consider the ways in which eHealth literacy can be understood and fostered. The papers presented in this issue of JMIR provide important additions to the growing field of study in eHealth literacy and offer a glimpse as to where the concept may evolve to as more evidence unfolds.


Many aspects of a trial may be incompletely reported, including the outcomes collected and the full set of analyses undertaken. Selective reporting bias occurs when the inclusion of outcomes or analyses in the report is based on the results. We review and summarise the empirical evidence from studies that have assessed the selective reporting of outcomes and analyses and provide guidance to trialists to help reduce this problem.outcomes and ii) evidence for selective reporting of analyses. An international collaboration of experts will be brought together in July to discuss the available evidence alongside current reporting guidance for trials. Recommendations are being produced with regards to raising the awareness and safeguarding trial publications against selective reporting.Two systematic reviews of studies that have examined randomised trials for i) evidence for publication bias or selective reporting of From twenty studies, of which four were newly identified, the evidence in the first systematic review demonstrated an association between statistically significant results and publication. Statistically significant outcomes had a higher odds of being fully reported compared to non-significant outcomes (range of odds ratios: 2.2 to 4.7). A further seventeen studies consider aspects of selective reporting such as statistical analyses; subgroup analyses and composite outcomes.This work highlights the evidence of selective reporting and demonstrates the importance of pre-specifying outcomes, analyses and reporting strategies during the planning and design of a clinical trial, for the purposes of minimising bias when findings are reported.