Staphylococcus aureus (MRSA) increasingly causes disease worldwide. USA300 has emerged as the predominant clone causing superficial and invasive infections in children and adults in the USA. Epidemiological studies suggest that USA300 is more virulent than other CA-MRSA. The genetic determinants that render virulence and dominance to USA300 remain unclear.Community acquired (CA) methicillin-resistant S. epidermidis. The USA300 sequence was aligned with other sequenced S. aureus genomes and regions unique to USA300 MRSA were identified.We sequenced the genomes of two pediatric USA300 isolates: one CA-MRSA and one CA-methicillin susceptible (MSSA), isolated at Texas Children's Hospital in Houston. DNA sequencing was performed by Sanger dideoxy whole genome shotgun (WGS) and 454 Life Sciences pyrosequencing strategies. The sequence of the USA300 MRSA strain was rigorously annotated. In USA300-MRSA 2658 chromosomal open reading frames were predicted and 3.1 and 27 kilobase (kb) plasmids were identified. USA300-MSSA contained a 20 kb plasmid with some homology to the 27 kb plasmid found in USA300-MRSA. Two regions found in US300-MRSA were absent in USA300-MSSA. One of these carried the arginine deiminase operon that appears to have been acquired from USA300-MRSA is highly similar to other MRSA strains based on whole genome alignments and gene content, indicating that the differences in pathogenesis are due to subtle changes rather than to large-scale acquisition of virulence factor genes. The USA300 Houston isolate differs from another sequenced USA300 strain isolate, derived from a patient in San Francisco, in plasmid content and a number of sequence polymorphisms. Such differences will provide new insights into the evolution of pathogens. Staphylococcus aureus (CA-MRSA) infections are increasing worldwide [S. aureus infections, predominantly CA-MRSA, in a prospective surveillance study initiated in 2001 [e.g. complicated pneumonia, osteomyelitis, pyomyositis, myositis and severe sepsis syndrome associated with the predominance of clone USA300 [Community acquired methicillin-resistant orldwide ,2. Althoorldwide -6. In thorldwide . Howeverorldwide -12. At T in 2001 . Skin ane USA300 ,14-18. Se USA300 . Recent e USA300 ,20,21. Ue USA300 ,23.S. aureus strains at TCH are MRSA; 95% of these are USA300. In contrast to the homogeneity of CA-MRSA, CA methicillin-susceptible S. aureus (MSSA) from the same population are more heterogeneous; USA300 represented approximately 25% of these strains between 2000–2002 [Approximately 75% of the CA-S. aureus strain have been deposited in the GenBank database. Recently, the genome sequence of a multi-resistant USA300-MR isolate (FPR3757) from an abscess of an HIV-positive intravenous drug user was reported [S. aureus clones circulating in Houston.At the time of this writing, the complete genomes of eleven MRSA and MSSA clinical strains, of both community and hospital origin, plus a bovine reported . We presmec (SCCmec) type IVa methicillin resistance cassette. In addition to SCCmec IVa, the strain also contains a ca. 31 kb region of DNA from 57860 to 88845 that is unique only to USA300-HOU-MR, USA300-FPR3757 and to S. epidermidis ATCC12228  is flanked by an IS431mec transposase gene and a possible transposase gene. The region downstream of SCCmec carries genes encoding an arginine deiminase operon, a Crp family transcriptional regulator, an APC family arginine/ornithine antiporter, and an arginine repressor. In USA300-FPR3757, this region is called ACME, for arginine catabolic mobile element [mec-ACME region encodes four non-classically secreted proteins and three other extracellular proteins. The region also encodes a possible endonuclease, possible tRNA ligases, RNA polymerases and a primase. We also identified a number of ORFs that were not annotated in USA300-FPR3757; these were hypothetical or conserved hypothetical proteins.The USA300-HOU-MR genome is 2,872,915 bp in length and was annotated to encode 2658 proteins, 59 tRNAs (plus one pseudogene), 5 ribosomal RNA operons and 21 non-coding RNAs Table . USA300- element . Downstr element . ClustalS. aureus genomes [S. aureus toxin or virulence factor genes, and while strains contain different combinations of the islands, no strain appears to carry more than one copy of each type [vSaα, vSaβ, and vSaγ. These encode enterotoxins, extotoxins and serine proteases as well as leukotoxin, hemolysin, exfoliatin, and epidermin  [geh lipase gene, which is disrupted in strains carrying the L54α-like prophage, is intact and presumed to be expressed.USA300-HOU-MR carries two complete prophage sequences, φSLT-USA300 and φβC-USA300. Prophage remnants also occur within pathogenicity island SaPI5. The φSLT-USA300 sequence is 98% identical to the 46139 bp φSLT sequence , excepti(phiSLT)   ,29. The S. aureus N315; pSR1 from S. aureus strain 01A103; and pSERP from S. epidermidis RP62A. The plasmid carries two recombinase genes and three IS431 transposase genes that may have played a role in fusion of the three elements. The replication region appears to be derived from pNF315B. pUSA300-HOU-MRSA encodes resistance to beta-lactam, macrolide, aminoglycoside, streptothricin (nourseothricin) and bacitracin antibiotics, consistent with the resistance pattern observed for USA300-HOU-MR  flank these genes. The repeats are most similar to the inverted repeats found in IS257 from S. epidermidis strain SK76 (Genbank SEU40386) though similar repeats are found on a number of plasmids from both S. aureus and S. epidermidis. Thus, it appears that this region constitutes a compound transposon that could also be part of a larger element carrying the bacitracin transporter genes. A ca. 400 nt repeat (which is a subset of the ca 700 bp repeat) also occurs within the IS431 transpose genes at ca. 12.5 and 21 kb on the map. pUSA300-HOU-MR also encodes a cadmium transporter CadD and regulator CadX, and at least three additional predicted transcriptional regulators including BlaI and BlaR.Two plasmids were detected in USA300-HOU-MR Figure  and 6b. accB, and the elongation factor P gene efp. In USA300-HOU-MR, this same 13 kb segment of DNA is inserted at nt 680,375 within the snoA gene at the beginning of the staphylococcal nuo-like operon, which encodes an NADH dehydrogenase [SA1 transposase. The frameshift occurs in a poly adenine tract so sequence variation through slipped-strand mispairing is possible. Six of the proteins encoded by the 13 kb segment may be non-classically secreted proteins. Also encoded are a possible lipoprotein, a peptidoglycan hydrolase, a cell division protein, a GTP-binding protein, a replication protein and a possible actin-binding protein.We identified 14 insertions/deletions (indels) of greater than four bp between USA300- FPR3757 and USA300-HOU-MR  not reported in the annotation of FP3757.An insertion of 159 bp in USA300-HOU-MR but not in USA300-FPR3757 occurs within a staphylococcal conserved hypothetical protein between 1857878 and 1858036. This insertion is a duplication of flanking sequence and maintains the reading frame of the protein. Another difference identified is a 47 bp region in USA300-FPR3757, within the repeated region of the IgG binding protein gene; again, these are absent from USA300-HOU. Additional short deletions in USA300-HOU-MR also occur within intergenic regions. Also of note is a frameshift in the gene encoding an AraC family transcriptional regulator in USA300 (742860–745009). This frameshift is not observed in any of the other sequenced gyrA gene causes a leucine to serine change at amino acid 84. The serine-containing GyrA protein confers resistance to ciprofloxacin (FPR357), while leucine confers the wild-type, susceptible phenotype  and two four bp. deletions  to the nickel transporter were found in all staphylococcal genomes but this is likely due to generalized matches to other ABC transporter subunits. In contrast, the nickel transporter proteins are most homologous to proteins encoded by Staphylococcus haemolyticus. The proteins encoded by the region between 680132 and 694219 are also encoded by the genomes of two nosocomial MRSA strains, COL and MRSA252. These were not found in the CA isolate MW2.We surveyed other sequenced staphylococcal genomes using TBLASTX for the presence of ORFs that were homologous to proteins encoded by the regions of USA300-HOU-MR that were missing in the MSSA strain. These are shown in Additional file 552 invertase and recombinase. In addition, this same region on pUSA300-HOU-MS is 96% identical to nts. 7615–13573 on pUS300-HOU-MR. Thus, pUSA300-HOU-MS also appears to be mosaic. We also identified sequences homologous to pUSA01 on two contigs that were 1212 and 1278 bp in length, respectively. Since pUSA01 has now been sequenced twice, we did not attempt to complete the pUSA01 sequence in the MS strain.USA300-HOU-MS does not carry plasmid pUSA300-HOU-MR but it does carry a 21 kb plasmid (pUSA300-HOU-MS) that encodes resistance to beta-lactams and to cadmium Figure . It alsoWe used Mauve  to alignet al. [Because of the rapid and continuing increase of the prevalence of CA USA300 strains at TCH, we initiated the sequencing of two typical isolates from pediatric patients. During this time, Diep et al.  reportedsnoABCDEFG) that has been implicated in susceptibility to thrombin-induced platelet microbicidal protein 1 (tPMP-1). Bayer et al. [S. aureus to tPMP-1 in vitro. Resistance to tPMP-1 may allow US300-HOU-MR to cause more serious disease by evasion of platelet-mediated killing in the blood stream. USA300-FPR3757 has an additional repeat within the gene encoding the IgG binding protein A, so it is possible that IgG binding protein is subject to structural variation. We also identified nine SNPs within this gene. This may suggest that the IgG binding protein undergoes significant variation, possibly in response to the host.Several indels between USA300-HOU-MR and USA300-FPR3757 were identified. The majority of the indels were within repeat regions or rRNAs, though a 13 kb segment was located in different regions of the two genomes. In USA300-FPR3757, the region is inserted between two genes. In USA300-HOU-MR, the segment interrupts an operon  by recombination to become USA300-HOU-MR. We propose that USA300-HOU-MS first acquired the arginine deiminase region plus the cassette chromosome recombinase genes (ccrAB) from a strain similar to S. epidermidis ATCC12228. This is based on the observation that the ccrAB genes in USA300-HOU-MR are 95–100% identical to those found near the arginine deiminase region in S. epidermidis ATCC12228. The SCCmec was likely acquired in a separate event from another MRSA, or from a MR-S. epidermidis strain, via ccrAB recombination within the repeats flanking the arginine deiminase region [Listeria monocytogenes [To further our understanding of the evolution of the USA300-HOU-MR strain, we created a draft sequence of an MS isolate from TCH. This revealed two regions of the MR strain not found in the MS strain. It is likely that the progenitor MS strain acquired these regions  pattern .Clinical isolate TCH1516 (USA300-HOU-MR) was obtained from an adolescent patient with severe sepsis syndrome [n Figure  observeds aureus . The strAntimicrobial susceptibilities were obtained by microbroth dilution assays using Clinical Laboratory Standards Institute (CLSI) guidelines  Table 33. UnlikeGenomic DNA was purified from CsCl gradients  and DNA Glimmer  and GeneDNA comparisons were performed with BLASTN and BLASTZ. Protein sequences were analyzed by BLASTP and BLASTX and by the use of the predictive tools InterProScan , PFP 5050, PSORTSKH performed much of the post-annotation analysis and wrote the draft of the manuscript. SKH, KGH, EOM, RMF, YL, OI, SY, JP, MT, AU, GEF annotated the genome. XQ and HJ contributed bioinformatics support. YS, TMW and AMC performed the SNP verification. DMM, LH, YD, SD, PRB, CJB, HHD, ACH, MH, CLK, SLL, WL, LVN, QW and JZ composed the sequencing and finishing team. KGH, RMF, EOM, SLK and GMW assisted critical review of the manuscript. All authors read and approved the final manuscript.DNA regions present in USA300-HOU-MR but missing in USA300-HOU-MS and their presence in other sequenced staphylococcal genomes.Click here for fileS. aureus strains are also listed.Single nucleotide polymorphisms and short insertions/deletions between USA300-MR, USA300-MS and FPR3757. Alleles in other sequenced Click here for filePredicted non-classically secreted proteins.Click here for file


This article is part of a series written for people responsible for making decisions about health policies and programmes and for those who support these decision makers.In this article, we address the use of evidence to inform judgements about the balance between the pros and cons of policy and programme options. We suggest five questions that can be considered when making these judgements. These are: 1. What are the options that are being compared? 2. What are the most important potential outcomes of the options being compared? 3. What is the best estimate of the impact of the options being compared for each important outcome? 4. How confident can policymakers and others be in the estimated impacts? 5. Is a formal economic model likely to facilitate decision making? This article is part of a series written for people responsible for making decisions about health policies and programmes and for those who support these decision makers. The series is intended to help such people ensure that their decisions are well informed by the best available research evidence. The SUPPORT tools and the ways in which they can be used are described in more detail in the Introduction to this series [A glossary for the entire series is attached to each article . Links to Spanish, Portuguese, French and Chinese translations of this series can be found on the SUPPORT website http://www.support-collaboration.org. Feedback about how to improve the tools in this series is welcome and should be sent to: STP@nokc.no.s series . A glossYou work in the Ministry of Health. The Minister of Health has asked you to present a summary of the expected benefits, harms and costs of an important change in health policy that is being considered.In this article, we suggest five questions that policymakers and those who support them can ask when considering how to ensure that judgements about the pros and cons of health policy and programme options are well-informed by research evidence. Such questions can be asked, for instance, in scenarios, such as the one described above.Research alone does not make decisions . JudgemeIt would be simple to make a decision if an option was expected to have large benefits with few downsides and little cost, if we were confident about the evidence and the importance of the benefits, and if the option was a clear priority. Unfortunately, this is rarely the case. More often the expected impacts and costs are uncertain, and complex and difficult judgements must be made.The questions we propose here do not reduce the need for judgements. However, more systematic considerations and discussions of these questions could help to ensure that important considerations are not overlooked and that judgements are well informed. These could also help to resolve disagreements or at least help to provide clarification. If these judgements are made transparently they could help others to understand the reasoning behind health policy decisions.Preparing and using a balance sheet  should be constructed by researchers or technical support staff together with policymakers. They should also be based on systematic reviews for the same reasons described elsewhere that highlight the importance of systematic reviews in general . We willand the comparative option. Typically, the comparison is the status quo. However, the status quo is likely to vary from setting to setting. Decisions need to be made, therefore, about which characteristics of the status quo are:When using a balance sheet such as the one shown in Table • Crucial - such that research with a comparison without those same characteristics would be excluded• Important but not crucial - such that research with a comparison without those same characteristics would be included, but with less confidence that the results would be the same in the chosen setting, and• Unimportant - such that we would be confident that the results are likely be the same in the chosen settingThese same judgements also need to be made about the options being considered: which of their characteristics are crucial, important or unimportant in terms of affecting the likely impacts?Policymakers, in general, are motivated by the desire to serve the people they represent and should be interested primarily in the impacts of policy and programme options on outcomes that are important to those affected , decisions should be based on the impacts of these options on important outcomes (cardiovascular disease). Evidence of impacts on blood pressure alone is only a form of indirect evidence of the impacts on cardiovascular disease.Being explicit about which outcomes are important can help to ensure that the important consequences of an option are not overlooked. It can also help to ensure that unimportant consequences are not given undue weight. This is particularly important for surrogate outcomes - i.e. outcomes that are not important in and of themselves. They are considered important because they are believed to reflect important outcomes. For example, people do not typically regard their blood pressure as an important concern. What makes the issue of blood pressure important is its association with strokes, heart attacks and death, all of which were to be implemented, and what could be expected if it were not - or what could be expected if a different option were implemented instead (see Table Deciding whether the desirable impacts of an option are worth the undesirable impacts requires an estimate of how large these different impacts (and their economic consequences) will be. Ideally, this should take the form of a comparison between what could be expected for every important outcome if an option relative effects, and those that are presented as absolute effects. Patients, health professionals, and people making decisions about health policies and programmes are more likely to decide to use an intervention if its effects are reported as a relative effect than if they are reported as an absolute effect [It is important that decision makers recognise the difference between estimates of effect that are presented as e effect . For exae effect . Both ese effect ).Six factors can lower our confidence in estimates of the impacts of a policy or programme :• A weak study design• Other study limitations• Imprecision• Inconsistent results• Indirectness of the evidence• Publication biasAn assessment of these factors is inevitably technical. Policymakers do not need to have a detailed understanding of these factors or how they are assessed. But both policymakers and their technical support staff can still benefit from understanding why it is important to consider these factors.Studies in which a programme is randomly assigned reduce the risk of unknown or unmeasured differences between the groups being compared. This gives greater confidence that impacts are attributable to the programme and not some other factor -15. StudOther study limitations can affect both randomised and non-randomised impact evaluations. Incomplete data or the unreliable measurement of outcomes, for instance, may increase the risk of an estimate being biased, and therefore lower confidence in the derived estimates.Imprecision  also lowers the confidence with which chance can be ruled out as a factor shaping any observed differences in outcomes between compared groups, and consequently our confidence in an estimated effect.  and studies of a different option compared to a control. Other ways in which evidence can be indirect include differences between a study and the setting of interest in:There are several ways in which studies might not be directly relevant to a particular question, and therefore result in less confidence in the results. As noted above, if an indirectly relevant outcome (such as blood pressure) is measured in place of an important outcome (cardiovascular disease), there will be less confidence in the impacts on the important outcome (for which the indirect outcome is a surrogate). If only • The characteristics of the population• The option being considered, or• The status quo or comparison optionStudies that find statistically significant effects are often more likely to be published than those that do not . When suall of the factors noted above. Although there are no fixed rules for assessing these factors, judgements related to the quality of evidence that explicitly address each factor help to reduce the likelihood of important factors being overlooked. They also help to reduce the probability of biased assessments of the evidence  is large in relation to the costs, we are more confident about a decision. When the net benefit is small in relation to the costs, we are less confident.Generally, the less confident we are about the likely impacts of an option, the less confident we will be when deciding what to do. There are exceptions to this: firstly, we may have so little confidence about the impacts of something that it is easy to decide not to do it.cannot do harm [Secondly, even if there is little confidence in the benefits of a particular option it may be easy to decide to do something simply because there is little or no risk of harm, it doesn't cost much, and it might do some good. Many types of health information could be categorised as such. Policymakers, though, should be cautious about assuming that seemingly harmless polices and programmes  do harm . Even so do harm . This is do harm .Finally, despite important uncertainty about the likely impacts of a policy or programme, it may be easy to come to a decision that something that is promising should only be done in the context of a well-designed evaluation of its impacts .Even when we are confident about the impacts of a policy or programme, it may not be a priority to implement it. The extent to which we are confident is a critical factor for deciding on what to do and the extent to which doing something is a priority. Other additional factors  Working Group has developed an approach to grading the quality of evidence and the strength of healthcare recommendations.- GRADE Working Group: The authors declare that they have no competing interests.ADO prepared the first draft of this article. JNL, AF and SL contributed to drafting and revising it.GlossaryClick here for file


Clinical Evidence, called ECCE. Doctors have access to an electronic version and related clinical vignettes. Correct answers to the interactive vignettes provide Continuing Medical Education credits. The aims of this trial are to establish whether the e-learning program (ECCE) increases physicians' basic knowledge about common clinical scenarios, and whether ECCE is superior to the passive diffusion of information through the printed version of Clinical Evidence.In an effort to ensure that all physicians have access to valid and reliable evidence on drug effectiveness, the Italian Drug Agency sponsored a free-access e-learning system, based on Clinical Evidence chapters and vignettes lot A and will provide control data for Clinical Evidence chapters and vignettes lot B; group two vice versa; group three will receive the concise printed version of Clinical Evidence. There are in fact two designs: a before and after pragmatic trial utilising a two by two incomplete block design (group one versus group two) and a classical design (group one and two versus group three). The primary outcome will be the retention of Clinical Evidence contents assessed from the scores for clinical vignettes selected from ECCE at least six months after the intervention. To avoid test-retest effects, we will randomly select vignettes out of lot A and lot B, avoiding repetitions. In order to preserve the comparability of lots, we will select vignettes with similar, optimal psychometric characteristics.All Italian doctors naïve to ECCE will be randomised to three groups. Group one will have access to ECCE for ISRCTN27453314 In the last decade many countries have legislated within their health systems the revalidation and recertification of medical practitioners . Two prii.e., one hour of education is worth one credit, but there is a weighting towards activities that present evidence-based (EB) information and are free of commercial interests. The traditional form of acquiring CME credits is to attend lectures and conferences; it is more rare for doctors to be exposed to small group interactive events. Between 2004 and 2005, the committee approved and evaluated the provision of distant learning programmes: 136,208 health professionals  earned 737,603 credits, a result welcomed as a large success  repeated-measures ANOVA having: 1) one between-subjects factor (ECCE lot A and ECCE lot B) and one within-subject factor  for the incomplete block design trial; 2) one between-subjects factor (ECCE set and control) and one within-subject factor  for the classical trial. Tests of Sidak-adjusted simple main effects will be used for post-hoc mean comparisons as needed. Orthogonal planned contrasts will be formulated for the knowledge test data to verify knowledge retention. We do not expect the data sets to follow normal distributions and assumptions completely. If this is the case, we will do nonparametric and robust analyses to explore differences in medians or distributional shapes. If nonparametric analysis yields similar interpretations and conclusions, we will focus on the parametric results.e.g., general internal medicine versus general surgery); preferred CME format; computer skills; ease using the internet; familiarity with and readiness to use EB information; study drop-out; satisfaction with learning experience, and frequency of attending residential and distant CME activities. For these analyses, we will use parametric methods ) and nonparametric methods  as needed, based on the data. Holm's modified Bonferroni corrections will be applied to check experimental error . Analyses will be done based on an intention-to-treat basis, whether or not doctors logged and took credits. We will restrict the explanatory analysis to those doctors who took credits. All the analyses will consider p = 0.05 as significant (two-sided).Additional analyses will include examination of the relationship between knowledge test outcomes and potential moderator variables including sex, age, and years of practice, speciality  will be used.Clinical Evidence.The study has been approved by the Research Ethics Board Azienda Sanitaria Locale "Città di Milano", Milano (file number 43-06 SO) and the participating institutions . This study is funded by a grant from the Italian Drug Agency, a government agency that aims to provide credible, impartial advice, and EB information about the effectiveness of drugs. The Italian Drug Agency approved the design and the methods but had no role in its conduct, analysis, interpretation, or reporting, and will not have access to the data. This trial is completely independent from the BMJ Publishing Group, which publishes the original version of Clinical Evidence. The educational intervention, ECCE, comprises of:Clinical Evidence, the source of the content; clinical vignettes as the educational model; the e-learning tool as information and test vehicle. Our implementation of these elements may reduce the generalizability of this intervention. In addition, differences in the CME system regulation, the availability CME programmes, and access to EB health care information are likely to increase the differences in many industrialized countries. However, other elements favour the transferability of ECCE: the worldwide diffusion and appreciation of Clinical Evidence, including the standardization of its contents and of the clinical vignettes, its basic computer requirements, and the low cost for each credit provided.This protocol of an incomplete block design randomised control trial aims to determine the effect of a large-scale online educational intervention using vignettes based on Clinical Evidence chapter. It is clearly easier to measure an educational intervention designed to change a single behaviour than one targeting general management of conditions or patients. In particular, without evidence of prior efficacy or knowledge, it may be injudicious and precipitous to consider behavioural outcomes. Indeed, our trial's positive results may reflect physicians' competence more than appropriate clinical practice. The teaching properties of case histories are known [Clinical Evidence was boredom. If our intervention is effective, the written case simulation will turn the passive reading into a more interactive experience in which doctors search for the right information for specific situations, increasing their knowledge.A recent randomised controlled trial tested an internet-based CME program compared with a live course . A cholere known -29, and re known . FurtherThe Italian Cochrane Centre (ICC) was the recipient of grants from the Italian Drug Agency (AIFA) for the translations of Clinical Evidence. Zadig developed and managed the ECCE platform and its contents and AIFA supported these activities. The ICC and Zadig closely collaborated in the two projects. The ICC was the recipient of a grant to design and carry out this trial independently from AIFA and the BMJ Publishing Group. Both the ICC and Zadig have scientific and cultural interests in the success of the dissemination of Clinical Evidence and ECCE and this may have influenced the conduct of this study.LM and IM specified null hypotheses and lead on study design, with contributions from MC, PD, AL, PD and JMG. LM, IM, MC, VS, AC, LC, CD and PD managed clinical vignettes' data and surveys. MC lead the statistical analyses, with contributions from LM, IM and PD. IM, PD, LC and CD managed the clinical vignettes' platform. PD, AL, RS and AA supervised the CME program. LM drafted the paper, with contribution from all authors.CONSORT checklist. CONSORT checklist as provided by investigators to improve the reporting of the RCT.Click here for file


In this issue, Professor Karen Facey and colleagues publish an important Commentary (p 224) on the use of positron emission tomography (PET) imaging in cancer management. As they point out, any novel health technology tends to generate calls for immediate implementation by clinical enthusiasts, but the case for investment should be based on a clear evidence of benefit to patients (rather than to doctors) as well as cost benefit. PET using fluorine-18 deoxyglucose has given oncologists insight into tumour metabolism in addition to imaging, and it is a superb clinical research tool. But should PET imaging become routine?The Commentary, based on a recent Health Technology Assessment report, is timely for the UK because the Royal Colleges Intercollegiate Standing Committee on Nuclear Medicine earlier this year recommended the development and expansion of PET imaging. This Committee's conclusions are almost entirely devoted to the logistics of implementation, essentially following American assumptions, without critical appraisal of their utility. That is why the Health Technology Assessment on PET is so important.The authors make two salient points. First, they show that evidence of accuracy is not directly translatable into cost benefit, and therefore patient benefit should be recognised as a more important end point than potential cost saving. Indeed, it is surprising that although PET imaging was introduced some 20 years ago and has accrued more than 1000 research publications, patient outcome has not been adequately addressed. Second, the novel decision modelling scheme developed by these investigators, which includes the handling of uncertainty, may in this type of situation provide more useful evidence for policy making than a randomised controlled clinical trial. No doubt, oncologists will initially be reluctant to acknowledge this paradigm shift.


Disorders related to pregnancy and childbirth are a major health issue in South East Asia. They represent one of the biggest health risk differentials between the developed and developing world. Our broad research question is: Can the health of mothers and babies in Thailand, Indonesia, the Philippines and Malaysia be improved by increasing the local capacity for the synthesis of research, implementation of effective interventions, and identification of gaps in knowledge needing further research?The project is a before-after study which planned to benefit from and extend existing regional and international networks. Over five years the project was designed to comprise five phases; pre-study, pre-intervention, intervention, outcome assessment and reporting/dissemination. The study was proposed to be conducted across seven project nodes: four in South East Asia and three in Australia. Each South East Asian study node was planned to be established within an existing department of obstetrics and gynaecology or neonatology and was intended to form the project coordinating centre and focus for evidence-based practice activities within that region. Nine hospitals in South East Asia planned to participate, representing a range of clinical settings. The three project nodes in Australia were intended to provide project support.The intervention was planned to consist of capacity-strengthening activities targeted at three groups: generators of evidence, users of evidence and teachers of evidence. The primary outcome was established as changes in adherence to recommended clinical practices from baseline to completion of the project and impact on health outcomes.The SEA-ORCHID project was intended to improve care during pregnancy and the perinatal period of mothers and their babies in South East Asia. The possible benefits extend beyond this however, as at the end of this project there is hoped to be an existing network of South East Asian researchers and health care providers with the capacity to generalise this model to other health priority areas. It is anticipated that this project facilitate ongoing development of evidence-based practice and policy in South East Asia through attracting long-term funding, expansion into other hospitals and community-based care and the establishment of nodes in other countries. Each year there are over half a million maternal deaths worldwide and 98 percent of these occur in the developing world. This represents a tragic and striking health risk differential between the developed and developing world. For women in Asia the lifetime risk of maternal death is one in 65 compared with one in 1,800 for women in developed countries [The main causes of mortality directly related to pregnancy and childbirth are unsafe abortions, bleeding, infection, hypertension (including eclampsia) and obstructed labour . The majPerinatal and early infant deaths are also high in developing countries. Each year there are almost eight million stillbirths and early neonatal deaths. These arise because of poor maternal health and pregnancy care. Associated morbidity manifests as low birth weight, asphyxia and infection .The high rate of maternal, infant and child mortality in SE Asian countries has been associated with poverty, reduced education and literacy, lack of remunerative employment, low social status, and limited access to health services and family planning . SE AsiaAccess to scientifically valid and up-to-date information is a prerequisite for allocation of resources according to evidence and need. Most health workers and policy-makers in developing countries do not have easy access to the latest reliable information on effective care or may not have the skills to evaluate and implement such evidence .A variety of problems arise when clinical practices that are not based on sound scientific evidence are incorporated into established healthcare practice. Valuable resources continue to be used in some developing countries to fund practices of unknown effectiveness, for example electronic fetal monitoring during labour . On the Clearly a mechanism is needed to provide healthcare practitioners in the developing world with access to relevant evidence, a means of determining their own evidence requirements and the infrastructure to disseminate and implement clinical practice change based on that evidence. The effects of this provision then need to be evaluated to inform future initiatives aiming to improve health care.The Cochrane Collaboration is an international organisation of healthcare practitioners, researchers and consumers that prepares and disseminates systematic reviews of high quality evidence about the effects of healthcare interventions . The groHowever, this growth has been predominantly in the developed world, and a key objective of the Cochrane Collaboration is to ensure growth of this research activity in the developing world. The Cochrane Developing Countries Network has been established to pursue strategies for encouraging the involvement of contributors from low- and middle-income countries, both in producing reviews and in implementing their findings. In 2004, the level of developing country involvement in the Cochrane Pregnancy and Childbirth Group was modest, with 59 review authors from 11 developing countries and only eight review authors from SE Asia. In the Cochrane Neonatal Group there were 11 review authors from seven developing countries and only three of these were from SE Asia.WHO Reproductive Health Library [The Cochrane Library, was made available and practitioners trained in its use within South Africa [The Cochrane Library, has the potential to contribute to addressing the issues surrounding maternal mortality and morbidity.In a joint project between WHO, UNDP/UNFPA/WHO/World Bank Special Programme of Research Development and Research Training in Human Reproduction (HRP), South African Cochrane Centre and WHO Regional Office for Africa, the  Library  derived h Africa . IntroduOur project, which began in 2004, planned to build on these previous strategies and go beyond the implementation of evidence alone to assess the effect of a more far-reaching intervention of identifying evidence needs; training and support in evidence generation, synthesis and use; and provision of research infrastructure to facilitate these evidence-based practice activities.It has been stated that providing access to reliable health information for workers in developing countries is potentially the single most cost effective and achievable strategy for sustainable improvement in health care . InformaIn order to increase the uptake of effective treatments and stop the use of harmful ones, it is essential that healthcare communities within SE Asia are the drivers of the project. This includes promoting interventions that are locally appropriate, identifying important research questions, conducting relevant research and evidence synthesis, and training local practitioners in the implementation of research findings. It has been demonstrated that a sense of local ownership of projects and processes aiming to improve practice, including evidence generation, contributes to the success of implementing evidence .In 2001, the Thai Cochrane Network, based at Khon Kaen University, became the first registered group of the Cochrane Collaboration in SE Asia and provides the ideal platform from which to launch this current initiative. To maximise the potential of this intervention we plan to build upon existing partnerships and organisations to extend current capacity .The project was designed to address the following broad scientific question: Can the health of mothers and babies in Thailand, Indonesia, the Philippines and Malaysia be improved by increasing capacity for the synthesis of research, implementation of effective interventions, and identification of gaps in knowledge needing further research in those countries? The objectives of the project were intended to answer the following questions as components of the broad question:1. What is the current teaching and practice related to pregnancy and childbirth in SE Asia?2. What are the local barriers to the use of research in SE Asia and how can these barriers be overcome?3. Will targeted interventions to build capacity for the generation, evaluation, synthesis and implementation of relevant evidence lead to improved research output, research implementation and better health outcomes for women and babies in SE Asia?The SEA-ORCHID project was designed as a before-after study, using action research to design and implement the intervention. It set out to extend and benefit from existing networks. The project was planned to be conducted across seven nodes, four in SE Asia and three in Australia Table . Each SEActivities and timelines for each project phase are outlined in the following sections and summarised in Table  that includes information about the project; a library of project materials, resources and presentations; and a secure data-entry system.During this phase of the study, we planned to establish three Australian support nodes and a project node within each of the four SE Asian participating countries. Under the supervision of the local SEA-ORCHID investigator, each node put in place the infrastructure to support and sustain the project. This involved purchasing equipment, employing and training staff, and seeking local ethics approval. As part of efforts to promote the project we set up a dedicated website The investigators planned to meet in Malaysia before the start of the pre-intervention phase to ensure all nodes were functioning smoothly, and to plan the development of the data collection assessment tools, the training of local fieldworkers in web-based data entry and finalise project procedures.The principal activities during this phase were the collection of baseline data and the recruitment and training of staff who were delivering the intervention. Three categories of information were planned to be collected at baseline and post-intervention:We planned to assess whether current clinical practice during pregnancy and childbirth follows best-practice recommendations, and assess the impact of some these practices on the health of mothers and babies. Adherence to 12 areas of current recommended clinical practice and 13 health outcomes of mothers and babies in the four SE Asian centres were the primary outcome. The various practices and their associated health outcomes were selected on the basis of clear evidence from Cochrane systematic reviews - identifying local clinical practice guidelines related to pregnancy, childbirth and infant care - assessing the amount of undergraduate medical teaching related to evidence-based practice The Cochrane Library).In addition, we planned to assess the contribution of SE Asians to the Cochrane Collaboration with respect to numbers of reviews and contributors  and dichotomous variables presented as numbers and frequencies of events.A customised, secure database was designed to be housed on the project website to allow fieldworkers to enter the extracted information on data collection forms directly into the database Twelve educational training lecturers (educators), nine from the SE Asian participating hospitals and one at each of the Australian support nodes were recruited and trained, and materials developed for use in the training components of the intervention. A fellowships program was planned to enable health professionals and researchers from SE Asia to visit Australia to receive advanced training in the skills of evidence-based practice, guideline development, critical appraisal and systematic reviewing. These fellowships were advertised in the four SE Asian countries, and the recipients selected by the SE Asian investigators.The investigators and educational training lecturers planned to meet in the Philippines towards the end of the pre-intervention phase to review baseline findings and to finalise the intervention, taking into consideration the barriers to practice change identified by the baseline questionnaires and interviews. Following this meeting, the Australian-based educational trainers planned to carry out the first SE Asia teaching tour, conducting training events with the local training lecturer. This was the beginning of the intervention phase.The planned intervention can be divided into the following categories with the timing of delivery according to the project schema in Table The provision of training to support various evidence-based practice initiatives is a major component of the intervention being tested. Local researchers and clinicians planned to conduct training with the support of the Australian-based project members through the provision of materials and teaching assistance. Training will comprise of a fellowships program, teaching tours of all four SE Asian nodes by the Australian-based trainers in partnership with local trainers, and five project meetings. Activities will focus around three core groups:The emphasis is on setting up training programs in critical appraisal, systematic reviewing and guideline development. The Cochrane Collaboration takes great pride in the quality and relevance of its training programs, and the Australian investigators have all been involved in the development and delivery of training in evidence-based practice for many years. We have access to an array of training methods and tools that have been tried and tested cross-culturally and in a variety of formats.The Cochrane Library and WHO Reproductive Health Library; implementing and using guidelines; and accessing and interpreting evidence. Training will be open to all disciplines involved in the management of the mothers and babies unit . For policy makers we plan to conduct tailored training workshops around understanding and interpreting evidence. These will be adapted from a series of workshops for policy makers developed by the Australasian Cochrane Centre and will be taught in partnership with SE Asian contributors.We planned to conduct training for clinicians in using To build capacity and to ensure the outcomes from this project are sustained and extended to other clinical areas, we planned to conduct training events targeting future clinical trainers and potential opinion leaders in SE Asia. In addition, to facilitate practice change through investment in our future clinicians, we plan to provide material and training on the principles of evidence-based practice to those involved in undergraduate programs for doctors, nurses and allied health workers. We will achieve this through existing networks linking the investigators and medical educators in SE Asia.The Cochrane Library, and the results actively disseminated to clinicians through guidelines, training events and other publications.We planned to work with those providing care to women and babies in SE Asia to identify important questions for which systematic review evidence is lacking. Interventions appraised in systematic reviews were clinically relevant and culturally acceptable for the management of pregnancy and childbirth in SE Asia. These reviews were intended to be prepared with support from investigators and educators and published in Based on experience with developing guidelines for the Australian National Health and Medical Research Council, we planned to co-ordinate and facilitate locally relevant evidence-based guideline development and implementation.Health care based on evidence requires not only trained personnel, but also physical infrastructure, for example, computers and access to information and support. This project was designed to improve research infrastructure and capacity within SE Asia to address locally relevant and culturally specific questions by providing a central focus for research activity and skills.Over the course of this project there were numerous opportunities for academic exchange. Fellowships in Australia were offered to researchers and clinicians from SE Asia, and the Australian-based educators will travel to all the nodes to conduct workshops and partner the SE Asian educational trainers in the development of materials.The five project meetings were planned to be held to coincide with local clinical meetings and events. This allowed access to the SE Asian and Australian investigators as speakers at these events and assist in the promotion of evidence-based practice, the SEA-ORCHID project and the results of the research conducted. In addition, the work resulting from the project was intended to be published in the academic literature and presented at local, national and international perinatal meetings and Cochrane Colloquia.We planned to facilitate teaching of evidence-based practice skills in medical, nursing and allied health schools by sharing knowledge, skills and materials from Australia together with content relevant to SE Asia. This was intended to be facilitated based on the audit of evidence-based practice learning gathered as part of the baseline data collection.A larger meeting involving the investigators, educational trainers and SEA-ORCHID fellows was planned to be held in Thailand. This meeting intended to review progress with the intervention, identify potential future research projects based on identified research needs, and consider opportunities for funding beyond the project to sustain the SE Asian nodes and evidence-based practice activity. Again, immediately following the meeting, Australian educational trainers planned to undertake a tour to support local educators in training events.The methodology of outcome assessment was designed to duplicate that of the baseline data collection, with SE Asian fieldworkers recruited and trained to carry out the tasks overseen by the local investigators, and facilitated through a web-based data collection system.The primary indication of the value of the intervention was planned as changes in the process of care during pregnancy and childbirth and any associated impact on health outcomes for mothers and babies. Adherence to recommended practice and maternal/neonatal outcomes Table  were recThe following activities were planned to be re-assessed in a similar way as at baseline and compared:a) Involvement in evidence-based practice activityb) Knowledge and beliefs and the potential barriers to practice changec) SE Asian contribution to the work of the Cochrane CollaborationIn addition, sustainability of activities beyond the project through procurement of future research funding was intended to form a measure of the impact of the intervention.The investigators and trainers planned to meet in Indonesia to review the intervention phase and ensure the project teams are prepared for the post-intervention data collection. There was also planned to be a focus on sustaining the activities initiated during the SEA-ORCHID project once funding ends, and planning for future intra- and inter-regional collaborations and partnerships.Dissemination of results will be an integral feature of the project and we anticipate the following publications:- management of pregnancy and childbirth in SE Asia prior to the intervention- perceived barriers to clinical practice change in SE Asia- several systematic reviews and clinical practice guidelines relevant to the management of pregnancy and childbirth in SE Asia and other resource poor settings- experiences of training in partnership across cultures- final report and publications regarding the effect of the interventionThe final conference will be attended by the investigators and will focus on interpretation of the analysed results, planning final reports and associated publications, and planning future work in SE Asia.Basing healthcare practice and policy on evidence ensures the maximal benefit for investment. This is important in all communities but particularly when resources are low and the threats to health are large. This project has the potential to impact significantly on the health of mothers and babies in SE Asia by improving care during pregnancy and birth. Resulting from this project, we anticipate that within SE Asia there will be enhanced capacity to:• train existing and future clinicians to interpret and implement evidence• ensure locally relevant evidence is available and accessible• identify important questions yet to be answered and so take a cost effective and high impact approach to future research funding• base policy decisions on research findings• develop and implement local clinical practice guidelines• contribute more relevant systematic reviews for Cochrane LibraryThe possible benefits, however, extend beyond maternal and newborn care as at the end of this project there will be an existing network of SE Asian researchers and clinicians with the capacity to generalise this model to other health priority areas. It is anticipated that this project will facilitate the ongoing development of evidence-based practice and policy in SE Asia through attracting additional long term funding, expansion into community-based care and the establishment of nodes in other countries in the region.SE Asia – South East AsiaSEA-ORCHID – South East Asia Optimising Reproductive and Child Health in Developing CountriesUNDP – United Nations Development ProgrammeUNFPA – United Nations Population FundUNICEF – United Nations Children's FundWHO – World Health OrganizationThe author(s) declare that they have no competing interests.DH-S, PL, SG and CC conceived the study and participated in the project design. All authors were involved in the development of the design of the project, drafting of the manuscript and revising it critically for important intellectual content and have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:


ABSTRACT Good guidelines will help us to take evidence into practice. In a survey among Dutch orthopedic surgeons, development and use of evidence-based guidelines was perceived as one of the best ways of moving from opinion-based to evidence-based orthopedic practice. The increasing number of guidelines means that knowing how to make a critical appraisal of guidelines is now a key part of every surgeon’s life. This is particularly true because guidelines use varying systems to judge the quality of evidence and the strength of recommendations. In this manuscript we discuss what a guideline is, where we can find guidelines, how to evaluate the quality of guidelines, and finally provide an example on the different steps of guideline development. Thus, we show that good guidelines are a summary of the best available evidence and that they provide a graded recommendation to help surgeons in evidence-based practice. In the post-Second World War era, surgeons used a wide variety of treatment modalities for comparable conditions. The decisions for or against a certain treatment option were primarily based on the origin of the doctor’s training, and less frequently based on sound research findings . This inGood guidelines will help us to take evidence into practice. In a survey among Dutch orthopedic surgeons, the development and use of evidence-based guidelines was perceived as one of the best ways to move from opinion-based to evidence-based orthopedic practice . HoweverIn this article, we provide principles of guideline development, and databases of guidelines, and we give a case example of the development of a recently developed set of guidelines.Guidelines are devised to help doctors in the clinical decision process. They should include a clear recommendation for action . In contIn past centuries, consensus in medical decision making was reached through eminence-based strategies. Decision making was highly influenced by the simple fact that if an eminent professor stated something as a golden rule or a good idea, or guideline, then it was considered a guideline. The modern guideline-based approach to healthcare originated in the 1990s. In the Netherlands, guidelines are produced at the national level by medical associations. Two bodies, CBO  and NHG  publish specialist and primary care guidelines, respectively.Internationally, there has been progress in the development of guideline. Modern medical guidelines are documents designed to guide decisions and criteria in specific medical areas, as defined by the best research evidence available . ClinicaYou can find many guideline resources on the internet. We suggest that one should start by searching for guidelines developed in one’s own country, as they are most suitable for local circumstances. Institutional guidelines are adjusted to the local situation, and are usually adapted from a professional organization’s guidelines or national guidelines. The National Guideline Clearinghouse (NGC) is a public resource for evidence-based clinical practice guidelines (http://www.guideline.gov/). It provides guidelines from several institutions, professional societies, and government agencies worldwide. A helpful feature is side-by-side comparison of guidelines. Another useful source is http://www.guidelines-international.net/. Furthermore, the TRIP database can be searched for EBM guidelines (http://www.tripdatabase.com/). In the UK, the National Institute for Health and Clinical Excellence (NICE) is the independent organization dedicated to guideline development (http://www.nice.org.uk/). Finally, the G-I-N  created the International Guideline Library, which includes the International Guideline Database with over 5,000 guidelines. G-I-N is a global non-profit association of organizations and individuals involved in the development and use of clinical practice guidelines. It aims to improve the quality of healthcare by endorsing the systematic development of clinical practice guidelines and their application in practice, through worldwide collaboration (http://www.g-i-n.net).The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach is used by an increasing number of other organizations internationally . In inteThe AGREE  collaboration (http://www.agreecollaboration.org/) endeavors to establish a shared framework for guideline development, reporting, and assessment. An instrument for the appraisal of clinical guidelines was developed through this collaboration . The AGRThe Conference on Guideline Standardization (COGS) used a 2-stage modified Delphi process to develop standards for reporting clinical practice guidelines, which resulted in the COGS checklist  Shiffma see htt.In the Netherlands, the organization facilitating the development of medical guidelines is CBO , which is financed by the Order of Medical Specialists in collaboration with the Dutch College of General Practitioners. Since it was founded in 1979, more than 125 national guidelines have been published. The understanding is that every guideline should be revised after 5 years. The last Dutch guidelines “Deep Venous Thrombosis and Pulmonary Embolism” were published in 1999 and are due for revision, entitled “Diagnosis, Prevention and Treatment of Venous Thromboembolism and secondary prevention of Arterial Thrombosis”.For the development of evidence-based guidelines, a sequence of steps were taken as illustrated in the Figure.Certain topics of the subject were ambiguous in the last guidelines because of lack of high-quality evidence or confusing recommendations. One example was the use of pharmacological thromboprophylaxis in daycare surgery (knee arthroscopy) or during plaster immobilization. Also, relevant questions from the professionals in the field had to be addressed.When evidence is of low quality, recommendations will be weak. To make recommendations, a consensus will always have to be reached. Well-known methods for reaching a consensus are the Nominal Group Technique (NGT), the Delphi Method, and Consensus Conferences .Listings of major questions and dilemmas on the subject derived from the analysis of impediments were assembled. Also, a short set-up with planned chapters was proposed.Guidelines can be helpful in clinical decision making, provided that they have been developed following rigorous methodology and provided that they address clinically and patient-important endpoints . Thus, aThe main databases to be used were Medline/PubMed and Embase. The National Guidelines Clearinghouse and the Guidelines International Network were checked for existing guidelines on the subject. Furthermore, the Cochrane Database and the Database of Abstracts of Reviews of Effectiveness (DARE) were reviewed. With the AGREE instrument  developed for the assessment of clinical practice guidelines, current guidelines were evaluated . Upon thThe actual searches with relevant search terms resulted altogether in thousands of hits. Selection factors were, for example, language , no case reports nor letters, meta-analysis, and systematic review. From the records selected, abstracts were evaluated. For records that were relevant, the corresponding papers were retrieved.Assessment of the quality of the literature selected concerned the internal validity, where a judgment was made on selection bias, information bias and confounding. Then an evidence table was constructed for groups of studies concerning one subject, in which following parameters were scored: year of publication, randomization, blinding, set-up, number of patients, duration of treatment, lost to follow-up , outcomes, efficacy, safety, and grading of level of evidence. Grading was done according to Grades of Recommendation Assessment, Development, and Evaluation (GRADE) .Grading quality of evidence was directly related, but only one factor when determining the strength of recommendations . Each meA key element of reporting guidelines is the use of a structured format. Quality of evidence and strength of recommendations should be reported clearly using a standard approach .The concept text is now presented to the various users. Depending on the subject, it is possible to invite selected experts to comment, choose a cross-sectional panel, or address all users. The Dutch Orthopaedic Association placed the text on its website and communicated to all its members that they were invited to make comments by e-mail. At the next national assembly, the guideline was approved. This authorization is a formality where generally content and procedure are not discussed but important for its acceptance in clinical practice. There is evidence that wide representation of stakeholders in guideline panels leads to more balanced recommendations. While we have not evaluated this for the example described in this article, we believe that the generalization from studies to our guideline effort is secure. We achieve this wide representation through participation of 23 organizations (250 delegates).Strategies of implementation should be tailored to the intended users, who are health professionals and their organizations. Several models are available for planning and achievement of desired improvements, depending on the type of guideline. Dissemination of the guideline plays a key role in its implementation . The disIn order to determine quality in healthcare, there is a need for indicators. Evidence-based guidelines are particularly suited to development of indicators. The requirements for these indicators are:Relevant to clinical practiceRelated to patientcareResult(s) in improvementSufficiently specific and sensitiveReadily availableWide applicabilityRelevant to societyStrong recommendations, or documentation that a decision-making process has taken place for weak recommendations.The evaluation of the last 1999 Dutch guideline of the section prevention VTE orthopedic surgery was evaluated through a questionnaire send to all orthopedics departments . This is


An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated. © 2001 Cancer Research Campaign


While the potential of clinical practice guidelines (CPGs) to support implementation of evidence has been demonstrated, it is not currently being achieved. CPGs are both poorly developed and ineffectively implemented. To improve clinical practice and health outcomes, both well-developed CPGs and effective methods of CPG implementation are needed. We sought to establish whether there is agreement on the fundamental characteristics of an evidence-based CPG development process and to explore whether the level of guidance provided in CPG development handbooks is sufficient for people using these handbooks to be able to apply it.CPG development handbooks were identified through a broad search of published and grey literature. Documents published in English produced by national or international organisations purporting to support development of evidence-based CPGs were included. A list of 14 key elements of a CPG development process was developed. Two authors read each handbook. For each handbook a judgement was made as to how it addressed each element; assigned as: 'mentioned and clear guidance provided', 'mentioned but limited practical detail provided ', or 'not mentioned'.Six CPG development handbooks were included. These were produced by the Council of Europe, the National Health and Medical Research Council of Australia, the National Institute for Health and Clinical Excellence in the UK, the New Zealand Guidelines Group, the Scottish Intercollegiate Guideline Network, and the World Health Organization (WHO).There was strong concordance between the handbooks on the key elements of an evidence-based CPG development process. All six of the handbooks require and provide guidance on establishment of a multidisciplinary guideline development group, involvement of consumers, identification of clinical questions or problems, systematic searches for and appraisal of research evidence, a process for drafting recommendations, consultation with others beyond the guideline development group, and ongoing review and updating of the CPG.The key elements of an evidence-based CPG development process are addressed with strong concordance by existing CPG development handbooks. Further research is required to determine why these key elements are often not addressed by CPG developers. Clinicians want to give their patients the best possible care. To do this, they need to keep up to date with the evolving body of scientific research, and combine this scientific knowledge with their own clinical experience and each individual patient's circumstances and preferences. This is evidence-based practice .While there is a growing acceptance of the importance of taking an evidence-based approach to clinical decision-making, in many areas across the spectrums of speciality and location, clinical practice is still not evidence-based . Given tOne way of supporting implementation of evidence is through evidence-based clinical practice guidelines (CPGs) ,4. CPGs While the potential of CPGs to support implementation of evidence has been demonstrated, it is not currently being achieved . To imprCPGs are increasingly being developed at local, regional, and national levels ,7. The iIn parallel with the increasing interest in CPGs, several groups responsible for producing evidence-based CPGs have published handbooks outlining the development methodology -13. ThesHowever, in spite of the massive increase of interest in CPGs, and the availability of CPG development handbooks, several studies in a number of countries including Australia, Canada, the United Kingdom, and Finland have demonstrated that few CPGs meet quality criteria, such as those outlined by AGREE, and that the link between research and recommendations is an area of particular weakness -24. ThisIf the available handbooks provide differing guidance, then perhaps it is reasonable that CPG developers are unclear as to the components of a CPG development process, and this might explain some of the weaknesses observed in CPG development. If this is the case, it is imperative to ascertain what the differences in guidance are, whether these differences are gaps or contradictions in guidance, and, importantly, why these differences occur. On the other hand, if all the handbooks provide consistent advice, then perhaps this duplication represents wasted effort, and one handbook that synthesises the best of each and is regularly updated, supplemented by additional materials to meet the needs of each particular organisation, would be a better use of resources.As part of a wider study investigating methods of evidence-based CPG development in hospital settings, we sought to compare the advice of CPG development handbooks produced by major national or international organisations that have a role in developing standards for evidence-based CPGs. We aimed to establish whether there was agreement on the fundamental characteristics of an evidence-based CPG development process. Further, we were interested to explore whether the level of guidance provided in these handbooks was sufficient for people using these handbooks to be able to apply it and develop evidence-based CPGs. and the Guidelines International Network , websites of known CPG development bodies, and the internet using Google. We also asked members of the evidence-based health care email list "evidence-based-health@jiscmail.ac.uk" to suggest potentially relevant documents.We identified CPG development handbooks through a broad search of MEDLINE using search terms including 'guideline* and evidence and (method* or develop*)'. We searched CPG websites such as the US National Guidelines Clearinghouse We included documents published in English produced by national or international organisations responsible for CPG development. We only included those documents purporting to support development of evidence-based CPGs, not consensus-only or non-evidence-based CPGs. We excluded documents produced by professional colleges or peak bodies for specific conditions, as we were aiming to identify documents that were used widely beyond the organisation in which they were developed.We initially planned to use the AGREE instrument  to compaTo establish face validity, a draft list of evidence-based CPG development elements was circulated to the evidence-based health care email list, and to leaders in evidence-based CPG methods for their comments. As a result, the list was reordered and the wording of some elements was refined to reduce opportunity for misinterpretation.Fourteen key elements of the development process were identified Table . These kTwo authors  independently read each handbook to identify whether it addressed each of the key elements. We were interested in whether the handbooks mentioned each element and, if so, whether they provided enough practical information for a CPG developer to understand not only what was required for each element of the process but also how to complete that element. For each key element, evidence was extracted in the form of direct quotations for illustration where possible, and a judgement of whether the handbook addressed each element then assigned of either 'not mentioned', 'mentioned but limited practical detail provided', or 'mentioned and clear practical guidance provided'. Disagreements were resolved through discussion. During the data extraction process, we also sought to identify any other key elements of the CPG development process that we had not included in our list 14 key elements. As no human participants were involved, ethics approval was not required.Our search did not yield any handbooks of which we were not already aware. Six handbooks for developing CPGs were included. The six handbooks were produced by the Council of Europe, the National Health and Medical Research Council of Australia (NHMRC), the National Institute for Health and Clinical Excellence in the UK (NICE), the New Zealand Guidelines Group (NZGG), the Scottish Intercollegiate Guideline Network (SIGN), and the WHO. Table 'Guideline topics... are chosen on the basis of the burden of disease, the existence of variation in practice, and the potential to improve outcome.' The NICE handbook is the only handbook which does not address this aspect, the reason being that for NICE 'Guideline topics are selected by the Department of Health'.Five of the six handbooks provide clear guidance on the way in which CPG topics are or should be selected. For example the SIGN handbooks states: Two of the handbooks  make no mention of defining the scope of the CPG in terms of patient population, clinical condition, context or target audience. SIGN provides some mention and NICE, NZGG, and the NHMRC have very clear guidance and specific processes with the NHMRC stating: 'Before proceeding, the panel should clarify the purpose of and target audience for the guidelines. This will involve a careful specification of the following: the conditions and clinical problems that are at issue; the type of care providers for whom the guidelines are intended; the type of consumers for whom the guidelines are intended; a description of consumers not covered by the guidelines (where it might otherwise be assumed that the guidelines are relevant to these consumers); the types of settings in which the guidelines will be employed; and the interventions to be evaluated.'Adaptation of existing CPGs is addressed in all except the WHO handbook. Varying levels of support for and details of the process are provided. The NZGG handbook states: 'If there is already a guideline in existence that addresses the same issue or problem, another guideline may not be needed. An evaluation and/or adaptation of that guideline may be more appropriate than developing a new guideline.' The NICE handbook differentiates between adaptation of NICE CPGs and adaptation of CPGs developed by other organisations. For NICE CPGs, the handbook suggests that the evidence summaries should be used in the form that they are found, and the wording of recommendations adapted as necessary. The handbook suggests that existing non-NICE CPGs can be used as evidence, but new evidence summaries should be created and new recommendations written.The requirement for a multidisciplinary guideline development group is mentioned by all six handbooks, with all providing clear guidance, though the detail of the suggested makeup of the group varies, as does the emphasis on specific aspects of this process such as identification and management of conflicts of interest.Consumer involvement is mentioned by all six handbooks. The degree to which consumer involvement is required, and the nature and level of detail in the advice on how this involvement should be facilitated vary widely. NHMRC, NICE, NZGG, and SIGN provide clear guidance, and WHO and The Council of Europe provide less detailed advice. The SIGN handbooks states: 'The involvement of patients, carers or their representatives in guideline development is therefore important to help ensure that guidelines reflect their needs and concerns.'Formulation of clinical questions is only addressed in detail in the NICE, NZGG, and SIGN handbooks, though the other handbooks all mention the importance of defining the clinical problems to be addressed and provide limited guidance on how this should be done. While the NICE and NZGG handbooks provide useful guidance, for example, on how to format questions within a PICO  framework, none of the handbooks address how to ascertain the clinical questions to be addressed by the CPG.All six handbooks mention that systematic searches should be undertaken, and the NICE and NZGG handbooks provide clear guidance on how to do this, with practical details about which information sources to search and when to use filters or limits. Some handbooks seem to suggest that one systematic search may be enough for an entire CPG, others are clear that a systematic search should be undertaken for each clinical question addressed by the CPG. For example, the Council of Europe handbook states: 'At present, the preferred guideline development method is to search explicitly and systematically for pertinent evidence to answer each central question being addressed in the guideline.'The NICE and SIGN handbooks provide clear guidance on processes for inclusion or exclusion of potentially relevant research evidence. The other handbooks provide more limited information.All six handbooks address appraisal of evidence in some way, with NICE, NZGG and SIGN providing clear processes and templates.Methods for drafting recommendations are at least mentioned by all six handbooks, with the Council of Europe providing more limited advice than the NHMRC, NICE, NZGG, WHO, and SIGN handbooks. NICE in particular provides detailed advice describing how to word recommendations including instructions that they should be 'standalone' and 'action-oriented'.Similarly, all six handbooks mention the importance of facilitating consultation on the draft CPGs, for example, the WHO handbook states: 'Ensure peer review – Circulate widely to experts, professional organizations, regional offices, countries'. NICE, NHMRC, and SIGN have clear, well-defined consultation processes.Writing of summaries is mentioned in all but the Council of Europe and WHO handbooks. The NZGG asserts that 'The majority of readers and users of CPGs will not have the time to read the whole document and it is essential that a summary of the guideline with recommendations is produced. Algorithms are also useful tools that can improve guideline utilisation.'A process for developing an implementation strategy for inclusion in the CPG is addressed in all but the SIGN and NICE handbooks. Implementation is beyond the scope of the SIGN mandate, and the NICE handbook refers CPG developers to the NICE website for implementation materials. The Council of Europe, NHMRC, and NZGG handbooks provide particularly detailed practical guidance in this area.Evaluation, review, and updating of CPGs is addressed by all of the handbooks, with the NHMRC pointedly stating: 'Evaluation of CPGs is essential. How will we know if guidelines are worth developing, disseminating and implementing if we do not know whether they make a difference to clinical practice and health outcomes?' The amount of practical detail available to enable guideline developers to carry out these processes varies between handbooks, and often discussion is quite limited. were also excluded, as they did not meet our criteria, but may be relevant to this discussion. These restrictions were pragmatic, chosen a priori, and allowed application of objective criteria for inclusion, but we acknowledge that this is a limitation of our study. Another potential limitation of this study was the assessment of the degree to which a key element was addressed by each of the handbooks. By its nature, this type of assessment is subjective, and what constitutes sufficient practical detail to undertaken a particular step of the CPG development process will vary from one CPG author to another. In almost every case, however, the assessment of the handbooks by our two reviewers was very similar.This study has a number of limitations. Resource restrictions meant that we were only able to search for and include handbooks that were published in English. Our requirement that handbooks be developed by national or international organisations responsible for CPG development may mean that well-developed handbooks for guideline development were excluded, particularly in North America where several handbooks are produced by professional groups. Related resources such as the manual for the U.S. Preventive Services Task Force This review of six 'guidelines for developing guidelines' has highlighted a strong concordance on the central elements of an evidence-based CPG development process. All six of the handbooks require establishment of a multidisciplinary guideline development group, involvement of consumers, identification of clinical questions or problems, systematic searches for and appraisal of research evidence, a process for drafting recommendations, consultation with others beyond the guideline development group, and ongoing review and updating of the CPG. While the handbooks vary in the amount of detail they provide to CPG developers in these areas, fundamentally they agree that these are the key components of an acceptable CPG development process.It is unlikely that these handbooks were developed independently of each other, though ironically, this is hard to assess as few of the handbooks explicitly detail the methods by which they were developed. For example the NHMRC, NICE, NZGG, and Council of Europe handbooks all mention the SIGN handbook, though none describe how it was used in their handbook development.The degree of concordance between handbooks is interesting given the range of publication dates. The handbooks have been produced over an eight year period, with the earliest, the NHMRC 'Guide to the development, implementation and evaluation of CPGs' published in 1999, and the most recent, the NICE 'Guidelines Manual' released in April 2007. Eight years is a long time in any field, and in evidence-based practice a great deal has changed over the past eight years. The strong similarities between the processes recommended by these two handbooks, and the others published in the intervening period, may be viewed either positively, suggesting that the process of evidence-based CPG development is well established and widely accepted in CPG development organisations; or negatively, suggesting that development CPG processes are not progressing with changes in the field of evidence-based practice.The concordance between handbooks on what constitutes evidence-based CPG development is particularly interesting given that research shows that many CPG developers are not following this approach -24. If t, and are sometimes referred to by CPG development handbooks, these have not been written with CPG developers in mind, and may not meet their specific needs.While the handbooks provide information on the steps that make up the CPG development process, they often lack detail on how to carry out these steps in practice. A good example is the development of clinical questions. While all handbooks mention clinical questions and some provide a great deal of useful information on what constitutes a good clinical question, the PICO  framework, the importance of ensuring clinical questions cover the whole scope of the guideline, etc., none of the handbooks provide advice on how to actually generate the clinical questions. This lack of practical detail is found in most aspects of the CPG development process and may explain some the variation seen in the quality of CPGs. On the basis of reading these handbooks, CPG developers may be aware of what is required in an evidence-based CPG development process but may not know how to do it. While detailed handbooks have been produced in related areas, such as the Cochrane Handbook of Systematic Reviews Given the general agreement between handbooks and the increasing collaboration of CPG developers through organisations such as the Guidelines International Network, a question is also raised about the appropriateness of each of the CPG development organisations continuing to invest in updating, revising, and refining the content of these handbooks. This surely represents a duplication of effort. Perhaps the limited available resources might be better spent on a collection of shared materials which could be enriched in terms of practical detail, providing thorough guidance on how to complete each step in the process as well as the currently available guidance on 'what to do'. These shared materials could then be supplemented by smaller documents describing organisation specific processes or requirements.This review also highlights some differences between the methods of evidence-based CPG development proposed by the handbooks, and the criteria used to assess the quality of CPGs. AGREE, a widely used method of CPG appraisal, does not include criteria addressing how the CPG topic was selected or how the CPG will be implemented. Perhaps more importantly, it also does not assess whether systematic methods were used to appraise the research evidence used to support CPG recommendations, which was considered a key step in a CPG development process by the handbooks reviewed in this study. The reason for these discrepancies is unclear, and they seem quite odd given that each of these three areas was addressed in the instrument from which AGREE was developed . If a coThere has been a rapid increase in the rates of development of CPGs. In the evidence-based CPG development handbooks reviewed in this study, there is strong concordance as to the key elements in this process: establishment of a multidisciplinary guideline development group, involvement of consumers, clear identification of clinical issues, systematic searches for and appraisal of research evidence, a process for drafting CPG recommendations and consultation with others beyond the GDG. While it seems that the key elements of an evidence-based CPG development process are well established, given that they are often not followed by developers, research is needed to determine the barriers to implementing the recommended CPG development methods; and perhaps more practical detail or a simpler approach to developing CPGs may be required.TT, CH, SG and MM have all been involved in evidence-based CPG development using methods adapted from the NHMRC, SIGN and NICE handbooks. MM and SG are staff of the Australasian Cochrane Centre, funded by the Australian Department of Health and Ageing and supported by Monash University. Sally Green is a member of the Cochrane Collaboration Steering Group. SG is an editor of the Cochrane Handbook of Systematic Reviews of Interventions which informs the methodology for Cochrane systematic reviews. The views expressed in this paper represent those of the authors and are not necessarily the views or the official policy of the Cochrane Collaboration (unless otherwise stated and referenced).TT conceived of this project and developed the methodology and data extraction approach, which TT, SG and CH refined. TT and MM undertook the data extraction. TT prepared the first draft of this article which CH, SG, MM and TT then revised. TT is guarantor for the content of this article.


Corrado Barbui and colleagues describe their use and adaptation of the GRADE approach in developing the guidelines for the WHO mental health Gap Action Programme (mhGAP). The World Health Organization (WHO) has been criticized recently for not consistently making recommendations based on systematic reviews of the best available evidence and for the quality of some of its guidelines GRADE is an approach for creating clinical practice guidelines based on an explicit assessment of the evidence base.http://www.cc-ims.net/revman).GRADE is not a system for performing systematic reviews and meta-analyses  summarizing the evidence extracted from systematic reviews and meta-analyses into “Summary of Findings (SoF) tables”; (b) grading the quality of evidence summarized in SoF tables; and (c) grading the strength of treatment recommendations.GRADE separates the judgment on quality of evidence from strength of recommendations.http://www.gradeworkinggroup.org/toolbox/index.htm.An application called GRADE Profiler (GRADEpro) has been developed to summarize the evidence and grade its quality. GRADEpro can be freely downloaded at http://www.gradeworkinggroup.org/index.htm.Additional information on the GRADE methodology and on the GRADE working group can be found at WHO is in the process of developing a model intervention guide within its mental health Gap Action Programme (mhGAP) Mental, neurological, and substance use (MNS) disorders are prevalent throughout the world and are major contributors to morbidity and premature mortality. The treatment gap for these disorders is more than 75% in many low- and lower-middle income countries. Substantial initiatives have been made by in the last decade to bring mental health onto public health agenda The pathway describing the process of recommendation development is presented in We report here some challenges encountered during the process of evidence review and developing recommendations. Developing recommendations in the context of these disorders is complex, as evidence directly from low- and middle-income settings is still limited, and values, preferences, and feasibility issues tend to play a large role in informing recommendations.The pathway from defining scoping questions to developing evidence profiles is described in Identification of critical and important outcomes was a crucial process, as outcomes guided the subsequent phases of evidence retrieval, synthesis, and making recommendations. Based on the GRADE methodology, outcomes were grouped into three categories: critical, important, and not important. Very often, clinical trials report those outcomes  that can be easily measured, while omitting other key outcomes  that are more difficult to quantify. During the outcome rating process, the GDG members explicitly considered the value of choosing and rating outcomes that should be measured rather than those that have been measured.For each scoping question, the experts and WHO focal points formed review teams that as a first step searched for systematic reviews from databases and existing evidence-based guidelines that have tried to answer a similar scoping question. In case no synthesized evidence was available, new systematic reviews were commissioned. The review teams summarized the evidence base using the GRADE profiler software, a tool developed to help transparently summarize the evidence and grade its quality see . The GRAIn our process, to increase transparency and consistency between raters, explicit instructions were developed to help reviewers use the same background logic in making the choice , althougOne of the key challenges in evaluating the quality of evidence with GRADE is that some factors  imply a judgement on the quality of a group of trials, while other factors  imply a judgement on the meta-analytic process of data aggregation  across studies.Indirectness: The question being addressed by the guideline panel is different from the available evidence regarding the population, intervention, comparator, or outcome.Imprecision: Results are imprecise when studies include relatively few patients and few events and thus have wide confidence intervals around the estimate of the effect.Publication bias: Systematic underestimate or overestimate of the underlying beneficial or harmful effect due to the selective publication (or reporting) of studies.Problems with reliability in GRADE are particularly problematic when several raters are involved in the development of recommendations, which is often the case for development of guidelines covering a broad range of conditions. We therefore reasoned that raters should follow the same background logic in assessing the evidence and developed pragmatic instructions to guide the process of grading the quality of the evidence , to incrWe note that our instructions are inevitably based on rules of thumb in many cases, and may not be automatically extrapolated from one guideline to another, because criteria are based on the perspective that the guideline developers assume and are tuned to the relevant clinical area.According to the GRADE methodology, raters should assess the possibility of publication bias. We note that the instruments for making such a judgment are inadequate. We tried to rely on the funnel plot, although its use is controversial For many clinical questions, more often than not, evidence in the form of randomized trials is not available. Epidemiological studies and qualitative studies cannot easily be described in GRADE tables, and a risk exists of omitting the contribution of non-randomized research in the development of the evidence profiles. For example, the value of asking about suicide ideation of individuals with specific mental disorders has never been investigated through clinical trials, but still there is indirect epidemiological evidence suggesting that asking increases detection with no major drawbacks, and increased detection is associated with increased treatment and better outcomes. Although this issue was addressed by requiring the inclusion of additional evidence in a narrative section of the evidence profiles, this remains a weak aspect of the whole process. Even for observational studies that investigate the beneficial or harmful effects of interventions, grading is rarely straightforward, as systematic reviews of these studies are typically not available, and the meta-analytical process of pooling their results may often be methodologically inappropriate.We note that the systematic omission of some non-randomized evidence from GRADE inevitably creates an imbalance between low- and high-level quality of evidence, with low value and consideration given to what is kept out from GRADE tables. This may represent a serious bias in the process of guideline development, considering that each research question requires a proper research design, and clinical trials cannot provide an answer to all health-related questions The pathway from aggregating and grading the quality of evidence to developing recommendations is described in Inclusion in the WHO list of essential medicines and likely availability of medication in LAMICAcquisition costCurrent treatment skills availability in LAMIC for this interventionSpecific training requirements (comment if >1.0 day just for this specific intervention)Number of sessions, number of minutes per sessions requiredSpecific laboratory requirementsOther equipment requirementsContinuous supply of medication Specific supervision requirements (comment if more than one supervisory discussion is needed per 3 months)Any other feasibility issuesPromotion of social inclusionProtection of human rights and dignity Prevention of discrimination (and stigma)Prevention of medicalization of social problemsPromotion of individual and family members' capacity and skillsAny other valuesNOTE: Many of these aspects are not absolute concepts, and their relevance may vary according to local context characteristics.This approach allows for the transparent reporting of how recommendations derived from the scientific evidence may then be modified due to the weight given to other factors . For exaFor certain key areas, the conventional way of evaluating the quality of evidence revealed no or very poor quality evidence that was not sufficient to make any recommendation. In such instances we relied on the consensus of GDG consisting of international experts, who applied their professional experience and their tacit knowledge. Value-based decisions in mental health are unavoidable, as violation of human rights of people with mental disorders is common. For example, for the strategies aimed at improving community attitudes towards people with mental, neurological, and substance use conditions, the evidence base is very poor and indirect. Nevertheless, because of strong values and the importance of improving community attitudes, the GDG made a recommendation to consider planning and implementation of activities such as anti-stigma campaigns. We note that the added value of GRADE in these circumstances is that it is required to transparently report that some recommendations are based on strong values and weak evidence. The GDG was also requested to make specific statements for recommending research in areas where there is a paucity of evidence .While the main focus of WHO's mental health work was to develop recommendations for health care providers in low- and middle-income settings, most of the evidence comes from specialist settings of high-income countries. We tried to address this concern as follows. First, the GRADE assessment of directness was used to downgrade the quality of evidence if there were concerns about generalisability of population, intervention comparator, or outcome. Additionally, we included a judgment on the extent to which the characteristics of those who would deliver the intervention in the real world (including context characteristics) match with the characteristics of those who actually delivered the intervention under experimental conditions . A further aspect was the availability of implementation studies conducted in low- and middle-income countries. For example, the applicability of some brief psychological treatments in low-income settings has been documented in research projects carried out in Uganda and Pakistan Our experience suggests that GRADE may be applied as a useful technical framework for synthesizing and presenting evidence on the effectiveness of clinical interventions. It is a helpful tool to uncover implicit subjectivity, since it requires a systematic, explicit, and judicious approach to interpreting evidence Text S1Appendix(0.30 MB DOC)Click here for additional data file.