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1.  Commercial Serological Antibody Detection Tests for the Diagnosis of Pulmonary Tuberculosis: A Systematic Review 
PLoS Medicine  2007;4(6):e202.
The global tuberculosis epidemic results in nearly 2 million deaths and 9 million new cases of the disease a year. The vast majority of tuberculosis patients live in developing countries, where the diagnosis of tuberculosis relies on the identification of acid-fast bacilli on unprocessed sputum smears using conventional light microscopy. Microscopy has high specificity in tuberculosis-endemic countries, but modest sensitivity which varies among laboratories (range 20% to 80%). Moreover, the sensitivity is poor for paucibacillary disease (e.g., pediatric and HIV-associated tuberculosis). Thus, the development of rapid and accurate new diagnostic tools is imperative. Immune-based tests are potentially suitable for use in low-income countries as some test formats can be performed at the point of care without laboratory equipment. Currently, dozens of distinct commercial antibody detection tests are sold in developing countries. The question is “do they work?”
Methods and Findings
We conducted a systematic review to assess the accuracy of commercial antibody detection tests for the diagnosis of pulmonary tuberculosis. Studies from all countries using culture and/or microscopy smear for confirmation of pulmonary tuberculosis were eligible. Studies with fewer than 50 participants (25 patients and 25 control participants) were excluded. In a comprehensive search, we identified 68 studies. The results demonstrate that (1) overall, commercial tests vary widely in performance; (2) sensitivity is higher in smear-positive than smear-negative samples; (3) in studies of smear-positive patients, Anda-TB IgG by enzyme-linked immunosorbent assay shows limited sensitivity (range 63% to 85%) and inconsistent specificity (range 73% to 100%); (4) specificity is higher in healthy volunteers than in patients in whom tuberculosis disease is initially suspected and subsequently ruled out; and (5) there are insufficient data to determine the accuracy of most commercial tests in smear microscopy–negative patients, as well as their performance in children or persons with HIV infection.
None of the commercial tests evaluated perform well enough to replace sputum smear microscopy. Thus, these tests have little or no role in the diagnosis of pulmonary tuberculosis. Lack of methodological rigor in these studies was identified as a concern. It will be important to review the basic science literature evaluating serological tests for the diagnosis of pulmonary tuberculosis to determine whether useful antigens have been described but their potential has not been fully exploited. Activities leading to the discovery of new antigens with immunodiagnostic potential need to be intensified.
Based on a systematic review, Madhukar Pai and colleagues conclude that none of the commercial immune-based tests for pulmonary tuberculosis so far evaluated perform well enough to replace sputum smear microscopy.
Editors' Summary
Tuberculosis (TB) is, globally, one of the most important infectious diseases. It is thought that in 2005 around 1.6 million people died as a result of TB. Controlling TB requires that the disease is correctly diagnosed so that it can then be promptly treated, which will reduce the risk of infection being passed on to other individuals. The method normally used for diagnosing TB disease in poor countries (where most people with TB disease live) involves taking a sample of mucus coughed up from the lungs; this mucus is then spread thinly onto a glass slide, dyed, and viewed under the microscope. The bacteria responsible for TB take up the dye in a particular pattern and can be clearly seen under the microscope. Although this test (sputum smear) is relatively straightforward to carry out even where facilities are basic, it is not particularly good at identifying TB disease in children or amongst individuals who are HIV-positive. Finally, the sputum smear test is also not very sensitive; that is, many people who have TB disease may not give a positive reading. Therefore, there is an urgent need to develop and evaluate new tests that are suitable for use in poor countries, which will accurately diagnose TB disease, especially amongst children and people who are HIV-positive.
Why Was This Study Done?
New tests for TB have become available which detect whether an individual has raised antibodies against particular proteins and other substances present on the surface of the TB bacterium. These tests are carried out on blood samples, once blood cells and other factors have been taken out. These antibody tests are often quite simple to carry out, so in principle they could be suitable for use in developing countries. Since the tests are available on the market and can be freely used in some developing countries without any need for government regulatory bodies to approve them, it is important to know how good these tests are at diagnosing TB disease. The researchers here wanted, therefore, to evaluate all of the available data relating to the accuracy of antibody detection tests for diagnosis of TB disease.
What Did the Researchers Do and Find?
In order to evaluate all of the information available on commercial antibody detection tests for diagnosis of TB disease of the lungs, the researchers carried out a systematic review. First, they searched biomedical literature databases using specific terms to identify studies for inclusion. A study was included in their analysis if the commercial test was compared against one of two other standard tests (sputum smear microscopy, or growth of TB bacteria in culture). One researcher from the team then pulled out specific pieces of information from each published study: these included the type of study design; information on study participants; the type of test; what the test was compared against; and finally the results of evaluation of the test. A second researcher pulled out pieces of information from several of the same studies. The researchers then compared the information to ensure that it was recorded correctly. Each study was also assigned a quality rating, based on four distinct criteria. For each type of test, the researchers used the data in the published studies to work out the test's accuracy, both in terms of its ability to give a positive reading for people who have TB disease as well as its ability to give a negative reading for people who do not have TB disease.
The researchers found 27 papers meeting their criteria. These papers reported the results of 68 original studies. Nine different commercial tests were examined in the studies. Overall, the studies seemed to be of relatively poor quality, with only 25% of them meeting all four of the researchers' criteria for a good-quality study. The different studies appeared to produce varying results for the accuracy of these commercial tests. In particular, the tests seemed to be less accurate at detecting TB disease amongst people who had a negative sputum smear than amongst people with a positive sputum smear. When all the data for these different studies were combined, the statistics indicated that the commercial tests, overall, were only modestly accurate for diagnosis of TB disease. None of the studies had been carried out in children or in HIV-positive people.
What Do These Findings Mean?
The results of this systematic review suggest that the commercial antibody detection tests considered here are not particularly useful in diagnosis of TB disease as compared to other tests, such as sputum smear and bacterial culture. Some people are concerned that there is pressure in certain developing countries to start using these tests, but the current data do not support greater use. This systematic review also highlights the fact that many studies evaluating commercial TB tests are of poor quality, and that further research needs to be done to evaluate the accuracy of different TB tests amongst children and HIV-positive patients.
Additional Information.
Please access these Web sites via the online version of this summary at
World Health Organization Stop TB Department website. Information about the current Stop TB strategy, data and factsheets about TB, and other resources are available
Questions and Answers about Tuberculosis provided by the US Centers for Disease Control and Prevention
Information about TB tests from Médicins sans Frontières (MSF). Links to MSF reports on new diagnostic tests are also available
Wikipedia entry on Systematic Reviews (Note: Wikipedia is an internet encyclopedia anyone can edit)
PMCID: PMC1891320  PMID: 17564490
2.  Rating the Quality of Trials in Systematic Reviews of Physical Therapy Interventions 
Physical therapists seeking to use evidence to guide their practice may have limited time to read research reports. One way to reduce the time required to identify and read about the research that is relevant to a particular clinical question is to read a systematic review that summarizes multiple studies. This paper explains the process that is used to conduct systematic reviews, which includes the establishment of a protocol, comprehensive searching, appraisal of the quality of the included studies, data extraction and metaanalysis, and consideration of the clinical and research implications of the findings. We also consider how the reader of a systematic review can determine whether the review is likely to provide an unbiased (believable) estimate of the treatment effect. A systematic review of randomized trials of a cardiopulmonary physical therapy intervention is used as an example. The issue of appraisal of quality is then discussed further, with a demonstration of how one validated tool for quality appraisal–the PEDro scale–can be used to evaluate a randomized trial in cardiopulmonary physical therapy.
PMCID: PMC2941354  PMID: 20957075
systematic review; physical therapy
3.  Towards evidence based medicine for paediatricians 
In order to give the best care to patients and families, paediatricians need to integrate the highest quality scientific evidence with clinical expertise and the opinions of the family.1Archimedes seeks to assist practising clinicians by providing “evidence based” answers to common questions which are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format which has been successfully developed by Kevin Macaway‐Jones and the group at the Emergency Medicine Journal—“BestBets”.
A word of warning. The topic summaries are not systematic reviews, through they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor search the grey, unpublished literature. What Archimedes offers are practical, best evidence based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching,2 and gaining answers.3) A brief report of the search used follows—this has been performed in a hierarchical way, to search for the best quality evidence to answer the question.4 A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal, and the measures of effect (such as number needed to treat, NNT) books by Sackett5 and Moyer6 may help. To pull the information together, a commentary is provided. But to make it all much more accessible, a box provides the clinical bottom lines.
Readers wishing to submit their own questions—with best evidence answers—are encouraged to review those already proposed at If your question still hasn't been answered, feel free to submit your summary according to the Instructions for Authors at Three topics are covered in this issue of the journal:
Does neonatal BCG vaccination protect against tuberculous meningitis?
Does dexamethasone reduce the risk of extubation failure in ventilated children?
Should metformin be prescribed to overweight adolescents in whom dietary/behavioural modifications have not helped?
1. Moyer VA, Ellior EJ. Preface. In: Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
2. Richardson WS, Wilson MC, Nishikawa J, et al. The well‐built clinical question: a key to evidence‐based decisions. ACP J Club 1995;123:A12–13.
3. Bergus GR, Randall CS, Sinift SD, et al. Does the structure of clinical questions affect the outcome of curbside consultations with specialty colleagues? Arch Fam Med 2000;9:541–7.
4. (accessed July 2002).
5. Sackett DL, Starus S, Richardson WS, et al. Evidence‐based medicine. How to practice and teach EBM. San Diego: Harcourt‐Brace, 2000.
6. Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
How to read your journals
Most people have their journals land, monthly, weekly, or quarterly, on their desk, courtesy of their professional associations. Then they sit, gathering dust and guilt, for a period of time. When the layer of either is too great for comfort (or the desk space is needed for some proper work), the wrapper is removed and the journal scanned. But does how people read reflect their information needs or their entertainment requirements?
It is not uncommon to find people straying from the editorial introduction to the value added sections (like obituaries, Lucina‐like summary pages, and end‐of‐article fillers) rather than face the impenetrable science that sits between them. I think that this is probably unhelpful, and would urge readers to do one more thing before placing the journal in the recycling. Scan the table of contents; if it mentions a systematic review or a randomised trial, then read at least the title and the abstract's conclusions. If you agree, pat yourself warmly on the back for being evidence based and up‐to‐date. If you disagree, ask if it will make any impact on your clinical (or personal) life. If it might, run through the methods and quickly appraise them. Does it supply higher quality evidence than that you already possess? If it does, it's worth reading. If it doesn't, don't bother too much.
There are new innovations which might aid the tedious task of consuming research effort. The on‐line Précis section of the Archives provides a highly readable version of the contents page to whet one's appetite. Finally, it's worth mentioning that evidence based summary materials (like Archimedes, or Journal Watch) are always worth reading—and if you didn't think that you wouldn't be here, would you?
PMCID: PMC2082933
Archimedes; evidence based medicine
4.  Patient Adherence to Tuberculosis Treatment: A Systematic Review of Qualitative Research 
PLoS Medicine  2007;4(7):e238.
Tuberculosis (TB) is a major contributor to the global burden of disease and has received considerable attention in recent years, particularly in low- and middle-income countries where it is closely associated with HIV/AIDS. Poor adherence to treatment is common despite various interventions aimed at improving treatment completion. Lack of a comprehensive and holistic understanding of barriers to and facilitators of, treatment adherence is currently a major obstacle to finding effective solutions. The aim of this systematic review of qualitative studies was to understand the factors considered important by patients, caregivers and health care providers in contributing to TB medication adherence.
Methods and Findings
We searched 19 electronic databases (1966–February 2005) for qualitative studies on patients', caregivers', or health care providers' perceptions of adherence to preventive or curative TB treatment with the free text terms “Tuberculosis AND (adherence OR compliance OR concordance)”. We supplemented our search with citation searches and by consulting experts. For included studies, study quality was assessed using a predetermined checklist and data were extracted independently onto a standard form. We then followed Noblit and Hare's method of meta-ethnography to synthesize the findings, using both reciprocal translation and line-of-argument synthesis. We screened 7,814 citations and selected 44 articles that met the prespecified inclusion criteria. The synthesis offers an overview of qualitative evidence derived from these multiple international studies. We identified eight major themes across the studies: organisation of treatment and care; interpretations of illness and wellness; the financial burden of treatment; knowledge, attitudes, and beliefs about treatment; law and immigration; personal characteristics and adherence behaviour; side effects; and family, community, and household support. Our interpretation of the themes across all studies produced a line-of-argument synthesis describing how four major factors interact to affect adherence to TB treatment: structural factors, including poverty and gender discrimination; the social context; health service factors; and personal factors. The findings of this study are limited by the quality and foci of the included studies.
Adherence to the long course of TB treatment is a complex, dynamic phenomenon with a wide range of factors impacting on treatment-taking behaviour. Patients' adherence to their medication regimens was influenced by the interaction of a number of these factors. The findings of our review could help inform the development of patient-centred interventions and of interventions to address structural barriers to treatment adherence.
From a systematic review of qualitative research, Munro and coauthors found that a range of interacting factors can lead to patients deciding not to complete their course of tuberculosis treatment.
Editors' Summary
Every year nearly nine million people develop tuberculosis—a contagious infection, usually of the lungs—and about two million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with active tuberculosis sneeze or cough. Tuberculosis can be cured by taking several strong antibiotics daily for at least six months but many patients fail to complete this treatment because the drugs have unpleasant side-effects and the treatment is complicated. In addition, people often feel better soon after starting treatment so they stop taking their tablets before all the bacteria in their body are dead. Poor treatment adherence (poor compliance) means that people remain infectious for longer and are more likely to relapse and die. It also contributes to the emergence of drug-resistant tuberculosis. To help people complete their treatment, the World Health Organization recommends a strategy known as DOTS (directly observed treatment, short course). As part of this strategy, a health worker or a tuberculosis treatment supporter—a person nominated by the health worker and the patient—watches the patient take his/her antibiotics.
Why Was This Study Done?
Although DOTS has contributed to improved tuberculosis control, better patient compliance is needed to halt the global tuberculosis epidemic. Treatment adherence is a complex behavioral issue and improving treatment outcomes for tuberculosis (and for other diseases) requires a full understanding of the factors that prevent people taking medicines correctly and those that help them complete their treatment. In this study, the researchers have done a systematic review (a study in which the medical literature is surveyed and appraised using defined methods to reach a consensus view on a specific question) of qualitative studies that asked patients, carers, and health workers which factors contributed to adherence to tuberculosis treatment. Qualitative studies collect non-quantitative data so, for example, a qualitative study on tuberculosis treatment might ask people how the treatment made them feel whereas a quantitative study might count bacteria in patient samples.
What Did the Researchers Do and Find?
The researchers searched electronic databases and reference lists for qualitative studies on adherence to tuberculosis treatments and also consulted experts on tuberculosis treatment. They carefully read the 44 published papers that met their predefined inclusion criteria and then used a method called “meta-ethnography” to compare the factors (themes) associated with good or bad adherence in the different studies and to synthesize (reach) a consensus view of which factors influence adherence to tuberculosis treatment. The researchers identified eight major factors associated with adherence to treatment. These included: health service factors such as the organization of treatment and care; social context (family, community and household influences); and the financial burden of treatment. Finally, the researchers interpreted the themes that emerged from the studies to build a simple model that proposes that adherence to tuberculosis treatment is influenced by four interacting sets of factors—structural factors (including poverty and gender discrimination), social context factors, health service factors, and personal factors (including attitudes towards treatment and illness).
What Do These Findings Mean?
The findings of this systematic review of qualitative research on patient adherence to tuberculosis treatment are inevitably limited by the quality and scope of the original research. Consequently, further studies into patients' understanding of tuberculosis and its treatment are needed. Nevertheless, the findings and the model proposed by the researchers indicate that patients often take their tuberculosis medications under very difficult conditions and that they cannot control many of the factors that prevent them taking their drugs. So, although current efforts to improve adherence to tuberculosis treatments emphasize instilling a willingness to take their medications into patients, this systematic review suggests that more must be done to address how factors such as poverty and gender affect treatment adherence and to tailor support systems to patients' needs. Most importantly, it indicates that future interventions should involve patients more in the decisions made about their treatment.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus has an encyclopedia page on tuberculosis (in English and Spanish)
See the US National Institute of Allergy and Infectious Disease fact sheet on tuberculosis
US Centers for Disease Control and Prevention provide a variety of fact sheets and other information resources on tuberculosis
World Health Organization has produced the 2007 Global Tuberculosis Control report (in English with key findings in French and Spanish), information on DOTS (in English, Spanish, French, Russian, Arabic and Chinese), and A Guide for Tuberculosis Treatment Supporters
See the brief guide to systematic reviews, published by the British Medical Journal
PMCID: PMC1925126  PMID: 17676945
5.  Reviewing evidence on complex social interventions: appraising implementation in systematic reviews of the health effects of organisational-level workplace interventions 
The reporting of intervention implementation in studies included in systematic reviews of organisational-level workplace interventions was appraised. Implementation is taken to include such factors as intervention setting, resources, planning, collaborations, delivery and macro-level socioeconomic contexts. Understanding how implementation affects intervention outcomes may help prevent erroneous conclusions and misleading assumptions about generalisability, but implementation must be adequately reported if it is to be taken into account.
Data on implementation were obtained from four systematic reviews of complex interventions in workplace settings. Implementation was appraised using a specially developed checklist and by means of an unstructured reading of the text.
103 studies were identified and appraised, evaluating four types of organisational-level workplace intervention (employee participation, changing job tasks, shift changes and compressed working weeks). Many studies referred to implementation, but reporting was generally poor and anecdotal in form. This poor quality of reporting did not vary greatly by type or date of publication. A minority of studies described how implementation may have influenced outcomes. These descriptions were more usefully explored through an unstructured reading of the text, rather than by means of the checklist.
Evaluations of complex interventions should include more detailed reporting of implementation and consider how to measure quality of implementation. The checklist helped us explore the poor reporting of implementation in a more systematic fashion. In terms of interpreting study findings and their transferability, however, the more qualitative appraisals appeared to offer greater potential for exploring how implementation may influence the findings of specific evaluations. Implementation appraisal techniques for systematic reviews of complex interventions require further development and testing.
PMCID: PMC2596297  PMID: 18718981
6.  A qualitative study into the difficulties experienced by healthcare decision makers when reading a Cochrane diagnostic test accuracy review 
Systematic Reviews  2013;2:32.
Cochrane reviews are one of the best known and most trusted sources of evidence-based information in health care. While steps have been taken to make Cochrane intervention reviews accessible to a diverse readership, little is known about the accessibility of the newcomer to the Cochrane library: diagnostic test accuracy reviews (DTARs). The current qualitative study explored how healthcare decision makers, who varied in their knowledge and experience with test accuracy research and systematic reviews, read and made sense of DTARs.
A purposive sample of clinicians, researchers and policy makers (n = 21) took part in a series of think-aloud interviews, using as interview material the first three DTARs published in the Cochrane library. Thematic qualitative analysis of the transcripts was carried out to identify patterns in participants’ ‘reading’ and interpretation of the reviews and the difficulties they encountered.
Participants unfamiliar with the design and methodology of DTARs found the reviews largely inaccessible and experienced a range of difficulties stemming mainly from the mismatch between background knowledge and level of explanation provided in the text. Experience with systematic reviews of interventions did not guarantee better understanding and, in some cases, led to confusion and misinterpretation. These difficulties were further exacerbated by poor layout and presentation, which affected even those with relatively good knowledge of DTARs and had a negative impact not only on their understanding of the reviews but also on their motivation to engage with the text. Comparison between the readings of the three reviews showed that more accessible presentation, such as presenting the results as natural frequencies, significantly increased participants’ understanding.
The study demonstrates that authors and editors should pay more attention to the presentation as well as the content of Cochrane DTARs, especially if the reports are aimed at readers with various levels of background knowledge and experience. It also raises the question as to the anticipated target audience of the reports and suggests that different groups of healthcare decision-makers may require different modes of presentation.
PMCID: PMC3663697  PMID: 23680077
Cochrane reviews; Diagnostic accuracy; Sensitivity and specificity; Qualitative research; Think -aloud interview
7.  Triage systems for pre-hospital emergency medical services - a systematic review 
The emergency medical services (EMS) cover initiatives and services established to provide essential medical assistance in situations of acute illness. Triage-methods for systematic prioritizing of patients according to how urgent patients need care, including triage of requests of acute medical treatment, are adopted in hospitals as well as in the pre-hospital settings. This systematic review searched to identify available research on the effects of validated triage systems for use in the pre-hospital EMS on health outcomes, patient safety, patient satisfaction, user-friendliness, resource use, goal achievement, and the quality on the information exchange between the different settings of the EMS (for example the quality of documentation). The specific research questions were: 1) are pre-hospital triage systems effective, 2) is one triage system more effective than others, and 3) is it effective to use the same triage system in two or more settings of the EMS-chain? We conducted a systematic literature search in nine databases up to June 2012. We searched for systematic reviews (SRs), randomized controlled trials (RCTs), non-randomized controlled trials (non-RCTs), controlled before and after studies (CBAs) and interrupted time series analyses (ITSs). Two persons independently reviewed titles and abstracts, and the same persons read all possibly relevant full text articles and rated the methodological quality where relevant. The literature search identified 11011 unique references. A total of 120 publications were read in full text. None of the identified articles fulfilled our inclusion criteria, thus our question on the effects of pre-hospital triage systems, if one system is better than other systems, and the question on effects of using the same triage system in two or more settings of the EMS, remain unanswered. We conclude that there is an evidence gap regarding the effects of pre-hospital triage systems and the effects of using the same triage system in two or more settings of the EMS. The finding does not mean that pre-hospital triage systems are ineffective, but that we lack knowledge about potential effects. When introducing a new assessment tool in the EMS, it is timely to conduct well-planned studies aimed to assess the effect.
PMCID: PMC3641954  PMID: 23587133
Triage; Triage system; Pre-hospital; Emergency medical services; Controlled trials; Emergencies; Effect
8.  Improving the use of research evidence in guideline development: 8. Synthesis and presentation of evidence 
The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the eighth of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this.
We reviewed the literature on the synthesis and presentation of research evidence, focusing on four key questions.
We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments.
Key questions and answers
We found two reviews of instruments for critically appraising systematic reviews, several studies of the importance of using extensive searches for reviews and determining when it is important to update reviews, and consensus statements about the reporting of reviews that informed our answers to the following questions.
How should existing systematic reviews be critically appraised?
• Because preparing systematic reviews can take over a year and require capacity and resources, existing reviews should be used when possible and updated, if needed.
• Standard criteria, such as A MeaSurement Tool to Assess Reviews (AMSTAR), should be used to critically appraise existing systematic reviews, together with an assessment of the relevance of the review to the questions being asked.
When and how should WHO undertake or commission new reviews?
• Consideration should be given to undertaking or commissioning a new review whenever a relevant, up-to-date review of good quality is not available.
• When time or resources are limited it may be necessary to undertake rapid assessments. The methods that are used to do these assessments should be reported, including important limitations and uncertainties and explicit consideration of the need and urgency of undertaking a full systematic review.
• Because WHO has limited capacity for undertaking systematic reviews, reviews will often need to be commissioned when a new review is needed. Consideration should be given to establishing collaborating centres to undertake or support this work, similar to what some national organisations have done.
How should the findings of systematic reviews be summarised and presented to committees responsible for making recommendations?
• Concise summaries (evidence tables) of the best available evidence for each important outcome, including benefits, harms and costs, should be presented to the groups responsible for making recommendations. These should include an assessment of the quality of the evidence and a summary of the findings for each outcome.
• The full systematic reviews, on which the summaries are based, should also be available to both those making recommendations and users of the recommendations.
What additional information is needed to inform recommendations and how should this information be synthesised with information about effects and presented to committees?
• Additional information that is needed to inform recommendations includes factors that might modify the expected effects, need (prevalence, baseline risk or status), values (the relative importance of key outcomes), costs and the availability of resources.
• Any assumptions that are made about values or other factors that may vary from setting to setting should be made explicit.
• For global guidelines that are intended to inform decisions in different settings, consideration should be given to using a template to assist the synthesis of information specific to a setting with the global evidence of the effects of the relevant interventions.
PMCID: PMC1702353  PMID: 17147809
9.  Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature 
PLoS Medicine  2011;8(5):e1000434.
A systematic search of the literature reveals limited evidence to support use of aripiprazole, a second-generation antipsychotic medication, in maintenance therapy of bipolar disorder, despite widespread use.
Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.
Methods and Findings
We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations.
A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature.
Please see later in the article for the Editors' Summary
Editors' Summary
Bipolar disorder (manic depression) is a serious, long-term mental illness that affects about 1% of adults at some time during their life. It usually develops in late adolescence or early adulthood and affects men and women from all backgrounds. People with bipolar disorder experience wild mood swings that interfere with daily life and damage relationships. During “manic” episodes, which can last several months if untreated, they may feel euphoric (“high”), energetic, or irritable. They may be full of ambitious plans, feel creative, and spend money recklessly. They can also have psychotic symptoms—they may see or hear things that are not there. During depressive episodes, affected individuals may feel helpless, worthless, and suicidal. Treatments for bipolar disorder include drugs to stabilize mood swings (for example, lithium and anticonvulsant medications), antidepressants to treat depressive episodes, and antipsychotic drugs to treat manic episodes. Psychotherapy can also help and patients can be taught to recognize the signs of approaching manic or depressive episodes and the triggers for these episodes.
Why Was This Study Done?
Treatment of bipolar disorder is divided into three phases: acute treatment lasting about 2 months to achieve remission, continuance treatment lasting from months 2 through 6 to prevent relapse, and long-term maintenance treatment to prevent recurrence. Second-generation (atypical) antipsychotics are widely used for acute treatment of manic episodes but are also used for maintenance treatment. For example, the atypical antipsychotic aripiprazole, which gained US approval for this indication in 2005, is now a popular choice among clinicians for treating bipolar disorder. But how much evidence is there to support aripiprazole's use in the maintenance treatment of bipolar disorder? Here, the researchers systematically search the published literature for double-blind randomized controlled trials of aripiprazole for this indication, critically analyze the quality of these trials, and undertake a citation search to investigate how the results of these trials have been disseminated in the scientific literature. In double-blind randomized controlled trials, patients are randomly assigned to receive a test drug or a control (generally, placebo), and the effects of these drugs compared; patients in the trial, and physicians administering treatments, would not know who is receiving the test drug or control until the trial is completed.
What Did the Researchers Do and Find?
The researchers' search for reports of double-blind randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder using predefined criteria identified only two publications, both describing a single trial—the Keck trial. Critical review of this trial identified four issues that limit its interpretation for supporting aripiprazole as a maintenance therapy: the trial was too short to demonstrate maintenance efficacy; all the trial participants had responded well to aripiprazole as an acute treatment so the generalizability of the trial's results was limited; the trial design meant that some of the apparent beneficial treatment results could have reflected the adverse effects of abrupt medication discontinuation in the control group; and the trial had a low completion rate. The researchers' citation search identified 80 publications that cited the Keck trial in discussions of the use of aripiprazole for maintenance treatment of bipolar disorder. Only a quarter of these papers presented any numerical data from the trial, only a third mentioned any of the reported adverse events, and only four papers mentioned the trial's limitations.
What Do These Findings Mean?
This evaluation of the evidence base supporting the use of aripiprazole for the maintenance treatment of bipolar disorder shows that the justification for this practice relies on the results of one published trial. Moreover, the methodology and reporting of this trial mean that its results cannot easily be generalized to inform the treatment of most patients with bipolar disorder. Worryingly, the researchers' citation search indicates that the Keck trial has been cited uncritically in the ensuing scientific literature. Although the unique features of bipolar disorder make it hard to undertake controlled studies of treatment options, the researchers express concern that “the publication and apparently uncritical acceptance of this trial may be diverting patients away from more effective treatments”.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute of Mental Health has detailed information on bipolar disorder, including an Easy to Read booklet (in English and Spanish)
The UK National Health Service Choices website provides information on all aspects of bipolar disorder
The UK charity Mind has information on bipolar disorder and provides links to other useful organizations
MedlinePlus has links to further information on bipolar disorder (in English and Spanish)
PMCID: PMC3086871  PMID: 21559324
10.  The Influence of Health Systems on Hypertension Awareness, Treatment, and Control: A Systematic Literature Review 
PLoS Medicine  2013;10(7):e1001490.
Will Maimaris and colleagues systematically review the evidence that national or regional health systems, including place of care and medication co-pays, influence hypertension awareness, treatment, and control.
Please see later in the article for the Editors' Summary
Hypertension (HT) affects an estimated one billion people worldwide, nearly three-quarters of whom live in low- or middle-income countries (LMICs). In both developed and developing countries, only a minority of individuals with HT are adequately treated. The reasons are many but, as with other chronic diseases, they include weaknesses in health systems. We conducted a systematic review of the influence of national or regional health systems on HT awareness, treatment, and control.
Methods and Findings
Eligible studies were those that analyzed the impact of health systems arrangements at the regional or national level on HT awareness, treatment, control, or antihypertensive medication adherence. The following databases were searched on 13th May 2013: Medline, Embase, Global Health, LILACS, Africa-Wide Information, IMSEAR, IMEMR, and WPRIM. There were no date or language restrictions. Two authors independently assessed papers for inclusion, extracted data, and assessed risk of bias. A narrative synthesis of the findings was conducted. Meta-analysis was not conducted due to substantial methodological heterogeneity in included studies. 53 studies were included, 11 of which were carried out in LMICs. Most studies evaluated health system financing and only four evaluated the effect of either human, physical, social, or intellectual resources on HT outcomes. Reduced medication co-payments were associated with improved HT control and treatment adherence, mainly evaluated in US settings. On balance, health insurance coverage was associated with improved outcomes of HT care in US settings. Having a routine place of care or physician was associated with improved HT care.
This review supports the minimization of medication co-payments in health insurance plans, and although studies were largely conducted in the US, the principle is likely to apply more generally. Studies that identify and analyze complexities and links between health systems arrangements and their effects on HT management are required, particularly in LMICs.
Please see later in the article for the Editors' Summary
Editors' Summary
In 2008, one billion people, three-quarters of whom were living in low- and middle-income countries, had high blood pressure (hypertension). Worldwide, hypertension, which rarely has any symptoms, leads to about 7.5 million deaths annually from heart attacks, stroke, other cardiovascular diseases, and kidney disease. Hypertension, selected by the World Health Organization as the theme for World Health Day 2013, is diagnosed by measuring blood pressure, the force that blood circulating in the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is contracts to pump blood out (systolic blood pressure) and lowest when the heart relaxes and refills (diastolic blood pressure). Normal adult blood pressure is defined as a systolic blood pressure of less than 120 millimeters of mercury (mmHg) and a diastolic blood pressure of less than 80 mmHg (a blood pressure of less than 120/80 mmHg). A blood pressure reading of more than 140/90 mmHg indicates hypertension. Many factors affect blood pressure, but overweight people and individuals who eat fatty or salty foods are at high risk of developing hypertension.
Why Was This Study Done?
Most individuals can achieve good hypertension control, which reduces death and disability from cardiovascular and kidney disease, by making lifestyle changes (mild hypertension) and/or by taking antihypertensive drugs. Yet, in both developed and developing countries, many people with hypertension are not aware of their condition and are not adequately treated. As with other chronic diseases, weaknesses in health care systems probably contribute to the inadequate treatment of hypertension. A health care system comprises all the organizations, institutions, and resources whose primary purpose is to improve health. Weaknesses in health care systems can exist at the national, regional, district, community, and household level. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers investigate how national and regional health care system arrangements influence hypertension awareness, treatment, and control. Actions that might influence hypertension care at this level of health care systems include providing treatment for hypertension at no or reduced cost, the introduction of financial incentives to healthcare practitioners for the diagnosis and treatment of hypertension, and enhanced insurance coverage in countries such as the US where people pay for health care through insurance policies.
What Did the Researchers Do and Find?
The researchers identified 53 studies that analyzed whether regional or national health care systems arrangements were associated with patient awareness of hypertension, treatment of hypertension, adherence to antihypertensive medication treatment, and control of hypertension. The researchers used an established conceptual framework for health care systems and an approach called narrative synthesis to analyze the results of these studies, most of which were conducted in the US (36 studies) and other high-income countries (eight studies). Nearly all the studies evaluated the effects of health system financing on hypertension outcomes, although several looked at the effects of delivery and governance of health systems on these outcomes. The researchers' analysis revealed an association between reduced medication co-payments (drug costs that are not covered by health insurance and that are paid by patients in countries without universal free healthcare) and improved hypertension control and treatment adherence, mainly in US settings. In addition, in US settings, health insurance coverage was associated with improved hypertension outcomes, as was having a routine physician or place of care.
What Do These Findings Mean?
These findings suggest that minimizing co-payments for health care and expansion of health insurance coverage in countries without universal free health care may improve the awareness, treatment, and control of hypertension. Although these findings are based mainly on US studies, they are likely to apply more generally but, importantly, these findings indicate that additional, high-quality studies are needed to unravel the impact of health systems arrangements on the management of hypertension. In particular, they reveal few studies in low- and middle-income countries where most of the global burden of hypertension lies and where weaknesses in health systems often result in deficiencies in the care of chronic diseases. Moreover, they highlight a need for studies that evaluate how aspects of health care systems other than financing (for example, delivery and governance mechanisms) and interactions between health care system arrangements affect hypertension outcomes. Without the results of such studies, governments and national and international organizations will not know the best ways to deal effectively with the global public-health crisis posed by hypertension.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Heart Lung and Blood Institute has patient information about high blood pressure (in English and Spanish)
The American Heart Association provides information on high blood pressure (in several languages) and personal stories about dealing with high blood pressure
The UK National Health Service (NHS) Choices website provides detailed information for patients about hypertension and a personal story about hypertension
The World Health Organization provides information on controlling blood pressure and on health systems (in several languages); its "A Global Brief on Hypertension" was published on World Health Day 2013
MedlinePlus provides links to further information about high blood pressure (in English and Spanish)
PMCID: PMC3728036  PMID: 23935461
11.  Integration of existing systematic reviews into new reviews: identification of guidance needs 
Systematic Reviews  2014;3:60.
An exponential increase in the number of systematic reviews published, and constrained resources for new reviews, means that there is an urgent need for guidance on explicitly and transparently integrating existing reviews into new systematic reviews. The objectives of this paper are: 1) to identify areas where existing guidance may be adopted or adapted, and 2) to suggest areas for future guidance development.
We searched documents and websites from healthcare focused systematic review organizations to identify and, where available, to summarize relevant guidance on the use of existing systematic reviews. We conducted informational interviews with members of Evidence-based Practice Centers (EPCs) to gather experiences in integrating existing systematic reviews, including common issues and challenges, as well as potential solutions.
There was consensus among systematic review organizations and the EPCs about some aspects of incorporating existing systematic reviews into new reviews. Current guidance may be used in assessing the relevance of prior reviews and in scanning references of prior reviews to identify studies for a new review. However, areas of challenge remain. Areas in need of guidance include how to synthesize, grade the strength of, and present bodies of evidence composed of primary studies and existing systematic reviews. For instance, empiric evidence is needed regarding how to quality check data abstraction and when and how to use study-level risk of bias assessments from prior reviews.
There remain areas of uncertainty for how to integrate existing systematic reviews into new reviews. Methods research and consensus processes among systematic review organizations are needed to develop guidance to address these challenges.
PMCID: PMC4066698  PMID: 24956937
systematic review methods; evidence-based practice centers; using existing reviews
12.  The use of systematic reviews in the planning, design and conduct of randomised trials: a retrospective cohort of NIHR HTA funded trials 
A systematic review, with or without a meta-analysis, should be undertaken to determine if the research question of interest has already been answered before a new trial begins. There has been limited research on how systematic reviews are used within the design of new trials, the aims of this study were to investigate how systematic reviews of earlier trials are used in the planning and design of new randomised trials.
Documentation from the application process for all randomised trials funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) between 2006 and 2008 were obtained. This included the: commissioning brief (if appropriate), outline application, minutes of the Board meeting in which the outline application was discussed, full application, detailed project description, referee comments, investigator response to referee comments, Board minutes on the full application and the trial protocol. Data were extracted on references to systematic reviews and how any such reviews had been used in the planning and design of the trial.
50 randomised trials were funded by NIHR HTA during this period and documentation was available for 48 of these. The cohort was predominately individually randomised parallel trials aiming to detect superiority between two treatments for a single primary outcome. 37 trials (77.1%) referenced a systematic review within the application and 20 of these (i.e. 41.7% of the total) used information contained in the systematic review in the design or planning of the new trial. The main areas in which systematic reviews were used were in the selection or definition of an outcome to be measured in the trial (7 of 37, 18.9%), the sample size calculation (7, 18.9%), the duration of follow up (8, 21.6%) and the approach to describing adverse events (9, 24.3%). Boards did not comment on the presence/absence or use of systematic reviews in any application.
Systematic reviews were referenced in most funded applications but just over half of these used the review to inform the design. There is an expectation from funders that applicants will use a systematic review to justify the need for a new trial but no expectation regarding further use of a systematic review to aid planning and design of the trial. Guidelines for applicants and funders should be developed to promote the use of systematic reviews in the design and planning of randomised trials, to optimise delivery of new studies informed by the most up-to-date evidence base and to minimise waste in research.
PMCID: PMC3621166  PMID: 23530582
Systematic review; Meta-analysis; Randomised controlled trial; Planning; Design
13.  Epidemiology and Reporting Characteristics of Systematic Reviews 
PLoS Medicine  2007;4(3):e78.
Systematic reviews (SRs) have become increasingly popular to a wide range of stakeholders. We set out to capture a representative cross-sectional sample of published SRs and examine them in terms of a broad range of epidemiological, descriptive, and reporting characteristics, including emerging aspects not previously examined.
Methods and Findings
We searched Medline for SRs indexed during November 2004 and written in English. Citations were screened and those meeting our inclusion criteria were retained. Data were collected using a 51-item data collection form designed to assess the epidemiological and reporting details and the bias-related aspects of the reviews. The data were analyzed descriptively. In total 300 SRs were identified, suggesting a current annual publication rate of about 2,500, involving more than 33,700 separate studies including one-third of a million participants. The majority (272 [90.7%]) of SRs were reported in specialty journals. Most reviews (213 [71.0%]) were categorized as therapeutic, and included a median of 16 studies involving 1,112 participants. Funding sources were not reported in more than one-third (122 [40.7%]) of the reviews. Reviews typically searched a median of three electronic databases and two other sources, although only about two-thirds (208 [69.3%]) of them reported the years searched. Most (197/295 [66.8%]) reviews reported information about quality assessment, while few (68/294 [23.1%]) reported assessing for publication bias. A little over half (161/300 [53.7%]) of the SRs reported combining their results statistically, of which most (147/161 [91.3%]) assessed for consistency across studies. Few (53 [17.7%]) SRs reported being updates of previously completed reviews. No review had a registration number. Only half (150 [50.0%]) of the reviews used the term “systematic review” or “meta-analysis” in the title or abstract. There were large differences between Cochrane reviews and non-Cochrane reviews in the quality of reporting several characteristics.
SRs are now produced in large numbers, and our data suggest that the quality of their reporting is inconsistent. This situation might be improved if more widely agreed upon evidence-based reporting guidelines were endorsed and adhered to by authors and journals. These results substantiate the view that readers should not accept SRs uncritically.
Data were collected on the epidemiological, descriptive, and reporting characteristics of recent systematic reviews. A descriptive analysis found inconsistencies in the quality of reporting.
Editors' Summary
In health care it is important to assess all the evidence available about what causes a disease or the best way to prevent, diagnose, or treat it. Decisions should not be made simply on the basis of—for example—the latest or biggest research study, but after a full consideration of the findings from all the research of good quality that has so far been conducted on the issue in question. This approach is known as “evidence-based medicine” (EBM). A report that is based on a search for studies addressing a clearly defined question, a quality assessment of the studies found, and a synthesis of the research findings, is known as a systematic review (SR). Conducting an SR is itself regarded as a research project and the methods involved can be quite complex. In particular, as with other forms of research, it is important to do everything possible to reduce bias. The leading role in developing the SR concept and the methods that should be used has been played by an international network called the Cochrane Collaboration (see “Additional Information” below), which was launched in 1992. However, SRs are now becoming commonplace. Many articles published in journals and elsewhere are described as being systematic reviews.
Why Was This Study Done?
Since systematic reviews are claimed to be the best source of evidence, it is important that they should be well conducted and that bias should not have influenced the conclusions drawn in the review. Just because the authors of a paper that discusses evidence on a particular topic claim that they have done their review “systematically,” it does not guarantee that their methods have been sound and that their report is of good quality. However, if they have reported details of their methods, then it can help users of the review decide whether they are looking at a review with conclusions they can rely on. The authors of this PLoS Medicine article wanted to find out how many SRs are now being published, where they are being published, and what questions they are addressing. They also wanted to see how well the methods of SRs are being reported.
What Did the Researchers Do and Find?
They picked one month and looked for all the SRs added to the main list of medical literature in that month. They found 300, on a range of topics and in a variety of medical journals. They estimate that about 20% of reviews appearing each year are published by the Cochrane Collaboration. They found many cases in which important aspects of the methods used were not reported. For example, about a third of the SRs did not report how (if at all) the quality of the studies found in the search had been assessed. An important assessment, which analyzes for “publication bias,” was reported as having been done in only about a quarter of the cases. Most of the reporting failures were in the “non-Cochrane” reviews.
What Do These Findings Mean?
The authors concluded that the standards of reporting of SRs vary widely and that readers should, therefore, not accept the conclusions of SRs uncritically. To improve this situation, they urge that guidelines be drawn up regarding how SRs are reported. The writers of SRs and also the journals that publish them should follow these guidelines.
Additional Information.
Please access these Web sites via the online version of this summary at
An editorial discussing this research article and its relevance to medical publishing appears in the same issue of PLoS Medicine
A good source of information on the evidence-based approach to medicine is the James Lind Library
The Web site of the Cochrane Collaboration is a good source of information on systematic reviews. In particular there is a newcomers' guide and information for health care “consumers”. From this Web site, it is also possible to see summaries of the SRs published by the Cochrane Collaboration (readers in some countries can also view the complete SRs free of charge)
Information on the practice of evidence-based medicine is available from the US Agency for Healthcare Research and Quality and the Canadian Agency for Drugs and Technologies in Health
PMCID: PMC1831728  PMID: 17388659
14.  Use of Automated External Defibrillators in Cardiac Arrest 
Executive Summary
The objectives were to identify the components of a program to deliver early defibrillation that optimizes the effectiveness of automated external defibrillators (AEDs) in out-of-hospital and hospital settings, to determine whether AEDs are cost-effective, and if cost-effectiveness was determined, to advise on how they should be distributed in Ontario.
Clinical Need
Survival in people who have had a cardiac arrest is low, especially in out-of-hospital settings. With each minute delay in defibrillation from the onset of cardiac arrest, the probability of survival decreases by 10%. (1) Early defibrillation (within 8 minutes of a cardiac arrest) has been shown to improve survival outcomes in these patients. However, in out-of-hospital settings and in certain areas within a hospital, trained personnel and their equipment may not be available within 8 minutes. This implies that “first responders” should take up the responsibility of delivering shock. The first responders in out-of-hospital settings are usually bystanders, firefighters, police, and community volunteers. In hospital settings, they are usually nurses. These first responders are not trained in reading electrocardiograms and identifying abnormal heart rhythms restorable by defibrillation.
The Technology
An AED is a device that can analyze a heart rhythm and deliver a shock if needed. Thus, AEDs can be used by first responders to deliver early defibrillation in out-of-hospital and hospital settings. However, simply providing an AED would not likely improve survival outcomes. Rather, AEDs have a role in strengthening the “chain of survival,” which includes prompt activation of the 911 telephone system, early cardiopulmonary resuscitation (CPR), rapid defibrillation, and timely advanced life support.
In the chain of survival, the first step for a witness of a cardiac arrest in an out-of-hospital setting is to call 911. Second, the witness initiates CPR (if she or he is trained in CPR). If the witness cannot initiate CPR, or the first responders of the 911 system (e.g., firefighters/police) have arrived, the first responders initiate CPR. Third, the witness or first responders apply an AED to the patient. The device reads the patient’s heart rhythm and prompts for shock when indicated. Fourth, the patient is handed over to the advanced life-support team with subsequent admission to an intensive care unit in a hospital.
The use of AEDs requires developing and implementing a program at sites where the cardiac arrest rate is high, where a number of potential first responders are trained and retained, and where patients are transferred to an advanced care facility after initiating resuscitation. Obviously, placing an AED at a site where no cardiac arrests are likely to occur would be futile, as would placing an AED at a site where no one knows how to use it. Moreover, abandoning patients after initial resuscitation by not transferring them to an advanced care facility would negate all earlier efforts. Thus, it is important to identify the essential components of an AED program that might also optimize the effectiveness of AED use.
There is a large body of literature on the use of AEDs in various settings ranging from closed environments such as hospitals, airlines, and casinos to open places such as sports fields and highways. There is little doubt regarding the effectiveness and safety of AEDs to treat people in cardiac arrest. It is intuitive that these devices should be provided in hospitals in areas that are not readily accessible to the traditional responders, the “code blue team.” Similarly, it is intuitive to provide AEDs in out-of-hospital settings where the risk of cardiac arrest is high and a response plan involving trained first responders in the use of AEDs is in place.
Thus, the Medical Advisory Secretariat reviewed the literature and focused on the components of an AED program in out-of-hospital settings that maximize the effectiveness and cost-effectiveness of the program in the management of cardiac arrest. Search engines included MEDLINE, EMBASE, EconLit and Web sites of other agencies that assess health technologies. Any study that reported results of an AED program in an out-of-hospital setting was included. Studies that did not use AEDs, had a physician-assisted emergency response plan, did not have a program for the use of AEDs, or did not include cardiac arrest as an outcome were excluded.
Summary of Findings
A total of 133 articles were identified; 62 were excluded after reviewing titles and abstracts. Of the 71 articles reviewed, 8 reported findings of 2 large studies, the Ontario Prehospital Advanced Life Support (OPALS) study and the Public Access Defibrillation (PAD) trial. These studies examined the effect of a community program to respond to cardiac arrest with and without the use of AEDs. Their authors had reported a significant reduction in overall mortality from cardiac arrest with the use of AEDs.
Factors That Improve the Effectiveness of an AED Program
The PAD trial investigators reported a significant improvement in survival (P = .03) after providing AEDs in public access areas and training volunteers in CPR compared with training volunteers in CPR only. The OPALS study investigators reported odds ratios (ORs) and 95% confidence intervals (CIs) for significant predictors of survival, which were age (OR [age per 10 year], 0.8; CI, 0.8–0.9), arrest witnessed by bystander (OR, 3.9; CI, 2.7–5.5), CPR initiated by bystander (OR, 3.7; CI, 2.6–5.1), CPR initiated by first responder (OR, 1.6; CI, 1.1–2.3), and emergency medical service response within 8 minutes (OR, 3.0; CI, 1.8–5.1). The last 3 variables are modifiable and thus may improve the effectiveness of an AED program. For example, the rate of bystander-initiated CPR was only 14% in the OPALS study, but it was 100% in the PAD trial. This was because PAD trial investigators trained community volunteers whereas the OPALS study investigators did not.
A systematic review of the literature suggests that cost-effectiveness varies from setting to setting. Most of the studies have estimated cost-effectiveness in American settings from a societal perspective; therefore, the results are not applicable to this report. However, results from this review suggest that the incidence of cardiac arrest in out-of-hospital setting in Ontario is 59 per 100,000 people. The mean age of cardiac arrest patients is 69 years. Eighty-five percent of these cardiac arrests occur in homes. Of all the cardiac arrests, 37% have heart rhythm abnormalities (ventricular tachycardia or ventricular fibrillation) that are correctable by delivering shock through an AED. Thus, in an out-of-hospital setting, general use of AEDs by laypersons would not be cost-effective. Special programs are needed in the out-of-hospital setting for cost-effective use of AEDs.
One model for the use of AEDs in out-of-hospital settings was examined in the OPALS study. Firefighters and police were trained and provided with AEDs. The total initial cost (in US dollars) of this program was estimated to be $980,000. The survival rate was 3.9% before implementing the AED program and 5.2% after its implementation (OR, 1.33; 95% CI, 1.03–1.7; P = .03). Applying these estimates to cardiac arrest rates in Ontario in 2002, one would expect 54 patients of the total 1,395 cardiac arrests to survive without AEDs compared with 73 patients with AEDs; thus, 19 additional lives might be saved each year with an AED program. It would initially cost $51,579 to save each additional life. In subsequent years, however, total cost would be lower (about $50,000 per year), when it would cost $2,632 to save each additional life per year. One limitation of the OPALS study was that the authors combined emergency medical service response time and application of an AED into a single variable. Thus, it was not possible to tease out the independent effects of reduction in response time and application of an AED on the small improvement in survival. Nevertheless, the PAD study found that when response time was fixed, the application of AED improved survival.
There are other delivery models for AEDs in casinos, sports arenas, and airports. The proportion of cardiac arrest at these sites out of the total cardiac arrests in Ontario is between 0.05% and 0.4%. Thus, an AED placed at these sites would likely not be used at all.
Of the 85% cardiac arrests that occur in homes, 56% occur in single residential dwellings (houses), 23% occur in multi-residential dwellings (apartments/condominiums), and 6% occur in nursing homes. There is no program in place except the 911 system to reach these patients.
Accordingly, the Medical Advisory Secretariat examined the cost-effectiveness of providing AEDs in hospitals, office buildings, apartments/condominiums, and houses. The results suggested that deployment of AEDs in hospitals would be cost-effective in terms of cost per quality adjusted life year gained. Conversely, deployment of AEDs in office buildings, apartments, and houses was not cost-effective. An exception, however, was noted for people at high risk of sudden cardiac arrest; these were patients with a left ventricular ejection fraction less than or equal to 0.35.
The OPALS study model appears cost-effective, and effectiveness can be further enhanced by training community volunteers to improve the bystander-initiated CPR rates. Deployment of AEDs in all public access areas and in houses and apartments is not cost-effective. Further research is needed to examine the benefit of in-home use of AEDs in patients at high risk of cardiac arrest.
PMCID: PMC3382296  PMID: 23074470
15.  Impact of missing participant data for dichotomous outcomes on pooled effect estimates in systematic reviews: a protocol for a methodological study 
Systematic Reviews  2014;3:137.
There is no consensus on how authors conducting meta-analysis should deal with trial participants with missing outcome data. The objectives of this study are to assess in Cochrane and non-Cochrane systematic reviews: (1) which categories of trial participants the systematic review authors consider as having missing participant data (MPD), (2) how trialists reported on participants with missing outcome data in trials, (3) whether systematic reviewer authors actually dealt with MPD in their meta-analyses of dichotomous outcomes consistently with their reported methods, and (4) the impact of different methods of dealing with MPD on pooled effect estimates in meta-analyses of dichotomous outcomes.
We will conduct a methodological study of Cochrane and non-Cochrane systematic reviews. Eligible systematic reviews will include a group-level meta-analysis of a patient-important dichotomous efficacy outcome, with a statistically significant effect estimate. Teams of two reviewers will determine eligibility and subsequently extract information from each eligible systematic review in duplicate and independently, using standardized, pre-piloted forms. The teams will then use a similar process to extract information from the trials included in the meta-analyses of interest. We will assess first which categories of trial participants the systematic reviewers consider as having MPD. Second, we will assess how trialists reported on participants with missing outcome data in trials. Third, we will compare what systematic reviewers report having done, and what they actually did, in dealing with MPD in their meta-analysis. Fourth, we will conduct imputation studies to assess the effects of different methods of dealing with MPD on the pooled effect estimates of meta-analyses. We will specifically calculate for each method (1) the percentage of systematic reviews that lose statistical significance and (2) the mean change of effect estimates across systematic reviews.
The impact of different methods of dealing with MPD on pooled effect estimates will help judge the associated risk of bias in systematic reviews. Our findings will inform recommendations regarding what assumptions for MPD should be used to test the robustness of meta-analytical results.
Electronic supplementary material
The online version of this article (doi:10.1186/2046-4053-3-137) contains supplementary material, which is available to authorized users.
PMCID: PMC4285551  PMID: 25423894
Missing participant data; Imputation; Risk of bias; Trials; Systematic reviews; Meta-analysis
16.  Can you believe what you read in the papers? 
Trials  2009;10:55.
The number of reports of clinical trials grows by hundreds every week. However, this does not mean that people making decisions about healthcare are finding it easier to obtain reliable knowledge for these decisions. Some of the information is unreliable. Systematic reviews are helping to resolve this by bringing together the research on a topic, appraising and summarising it. But the quality of these reviews depends greatly on the quality of the studies, and this usually means the quality of their reports. If there are fundamental flaws within a study, such as the use of inappropriate 'randomisation' techniques in the context of reviews of the effects of interventions, the reviewers will not be able to fix these. Worse still, if they are not aware of underlying flaws, they might make incorrect judgements about the quality of the research in their review. A study by Wu and colleagues of 'randomised trials' from China provides a reminder of the cautious approach needed by users of scientific articles. They contacted the authors of more than 2000 research articles, which purported to be reports of randomised trials; and concluded that ten of every 11 studies claiming to be a randomised trial probably did not use random allocation. Better education of researchers, peer reviewers and editors about what is, and is not, a properly randomised trial is needed; along with better reporting of the details for how participants were allocated to the different interventions. Systematic reviewers must be cautious in making assumptions about the conduct of trials based on simple phrases about the trial methodology, rather than a full description of the methods actually used. It's not that you can't believe anything that you read in the papers, just that you cannot believe everything.
PMCID: PMC2720956  PMID: 19607671
17.  The challenges of including sex/gender analysis in systematic reviews: a qualitative survey 
Systematic Reviews  2014;3:33.
Systematic review methodology includes the rigorous collection, selection, and evaluation of data in order to synthesize the best available evidence for health practice, health technology assessments, and health policy. Despite evidence that sex and gender matter to health outcomes, data and analysis related to sex and gender are frequently absent in systematic reviews, raising concerns about the quality and applicability of reviews. Few studies have focused on challenges to implementing sex/gender analysis within systematic reviews.
A multidisciplinary group of systematic reviewers, methodologists, biomedical and social science researchers, health practitioners, and other health sector professionals completed an open-ended survey prior to a two-day workshop focused on sex/gender, equity, and bias in systematic reviews. Respondents were asked to identify challenging or ‘thorny’ issues associated with integrating sex and gender in systematic reviews and indicate how they address these in their work. Data were analysed using interpretive description. A summary of the findings was presented and discussed with workshop participants.
Respondents identified conceptual challenges, such as defining sex and gender, methodological challenges in measuring and analysing sex and gender, challenges related to availability of data and data quality, and practical and policy challenges. No respondents discussed how they addressed these challenges, but all proposed ways to address sex/gender analysis in the future.
Respondents identified a wide range of interrelated challenges to implementing sex/gender considerations within systematic reviews. To our knowledge, this paper is the first to identify these challenges from the perspectives of those conducting and using systematic reviews. A framework and methods to integrate sex/gender analysis in systematic reviews are in the early stages of development. A number of priority items and collaborative initiatives to guide systematic reviewers in sex/gender analysis are provided, based on the survey results and subsequent workshop discussions. An emerging ‘community of practice’ is committed to enhancing the quality and applicability of systematic reviews by integrating considerations of sex/gender into the review process, with the goals of improving health outcomes and ensuring health equity for all persons.
PMCID: PMC3990268  PMID: 24720875
Gender; Qualitative methods; Sex; Sex/gender analysis; Systematic review methods
18.  10 years of mindlines: a systematic review and commentary 
In 2004, Gabbay and le May showed that clinicians generally base their decisions on mindlines—internalised and collectively reinforced tacit guidelines—rather than consulting written clinical guidelines. We considered how the concept of mindlines has been taken forward since.
We searched databases from 2004 to 2014 for the term ‘mindline(s)’ and tracked all sources citing Gabbay and le May’s 2004 article. We read and re-read papers to gain familiarity and developed an interpretive analysis and taxonomy by drawing on the principles of meta-narrative systematic review.
In our synthesis of 340 papers, distinguished between authors who used mindlines purely in name (‘nominal’ view) sometimes dismissing them as a harmful phenomenon, and authors who appeared to have understood the term’s philosophical foundations. The latter took an ‘in-practice’ view (studying how mindlines emerge and spread in real-world settings), a ‘theoretical and philosophical’ view (extending theory) or a ‘solution focused’ view (exploring how to promote and support mindline development). We found that it is not just clinicians who develop mindlines: so do patients, in face-to-face and (potentially) online communities.
Theoretical publications on mindlines have continued to challenge the rationalist assumptions of evidence-based medicine (EBM). Conventional EBM assumes a single, knowable reality and seeks to strip away context to generate universal predictive rules. In contrast, mindlines are predicated on a more fluid, embodied and intersubjective view of knowledge; they accommodate context and acknowledge multiple realities. When considering how knowledge spreads, the concept of mindlines requires us to go beyond the constraining notions of ‘dissemination’ and ‘translation’ to study tacit knowledge and the interactive human processes by which such knowledge is created, enacted and shared. Solution-focused publications described mindline-promoting initiatives such as relationship-building, collaborative learning and thought leadership.
The concept of mindlines challenges the naïve rationalist view of knowledge implicit in some EBM publications, but the term appears to have been misunderstood (and prematurely dismissed) by some authors. By further studying mindlines empirically and theoretically, there is potential to expand EBM’s conceptual toolkit to produce richer forms of ‘evidence-based’ knowledge. We outline a suggested research agenda for achieving this goal.
Electronic supplementary material
The online version of this article (doi:10.1186/s13012-015-0229-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4399748  PMID: 25890280
Mindlines; Tacit knowledge; Knowledge in practice; Knowledge translation; Knowledge creation; guidelines; EBM; Evidence-based medicine; Meta-narrative review; Systematic review
19.  Incorporating evidence review into quality improvement: meeting the needs of innovators 
BMJ Quality & Safety  2013;22(11):931-939.
Achieving quality improvement (QI) aims often requires local innovation. Without objective evidence review, innovators may miss previously tested approaches, rely on biased information, or use personal preferences in designing and implementing local QI programmes.
To develop a practical, responsive approach to evidence review for QI innovations aimed at both achieving the goals of the Patient Centered Medical Home (PCMH) and developing an evidence-based QI culture.
Descriptive organisational case report.
As part of a QI initiative to develop and spread innovations for achieving the Veterans Affairs (VA) PCMH (termed Patient Aligned Care Team, or PACT), we involved a professional evidence review team (consisting of review experts, an experienced librarian, and administrative support) in responding to the evidence needs of front-line primary care innovators. The review team developed a systematic approach to responsive innovation evidence review (RIER) that focused on innovator needs in terms of time frame, type of evidence and method of communicating results. To assess uptake and usefulness of the RIERs, and to learn how the content and process could be improved, we surveyed innovation leaders.
In the first 16 months of the QI initiative, we produced 13 RIERs on a variety of topics. These were presented as 6–15-page summaries and as slides at a QI collaborative. The RIERs focused on innovator needs (eg, topic overviews, how innovations are carried out, or contextual factors relevant to implementation). All 17 innovators who responded to the survey had read at least one RIER; 50% rated the reviews as very useful and 31%, as probably useful.
These responsive evidence reviews appear to be a promising approach to integrating evidence review into QI processes.
PMCID: PMC3812883  PMID: 23832925
Quality improvement; Evidence-based medicine; Medical homes
20.  Annual Research Review: The nature and classification of reading disorders – a commentary on proposals for DSM-5 
This article reviews our understanding of reading disorders in children and relates it to current proposals for their classification in DSM-5. There are two different, commonly occurring, forms of reading disorder in children which arise from different underlying language difficulties. Dyslexia (as defined in DSM-5), or decoding difficulty, refers to children who have difficulty in mastering the relationships between the spelling patterns of words and their pronunciations. These children typically read aloud inaccurately and slowly, and experience additional problems with spelling. Dyslexia appears to arise principally from a weakness in phonological (speech sound) skills, and there is good evidence that it can be ameliorated by systematic phonic teaching combined with phonological awareness training. The other major form of reading difficulty is reading comprehension impairment. These children read aloud accurately and fluently, but have difficulty understanding what they have read. Reading comprehension impairment appears to arise from weaknesses in a range of oral language skills including poor vocabulary knowledge, weak grammatical skills and difficulties in oral language comprehension. We suggest that the omission of reading comprehension impairment from DSM-5 is a serious one that should be remedied. Both dyslexia and reading comprehension impairment are dimensional in nature, and show strong continuities with other disorders of language. We argue that recognizing the continuities between reading and language disorders has important implications for assessment and treatment, and we note that the high rates of comorbidity between reading disorders and other seemingly disparate disorders (including ADHD and motor disorders) raises important challenges for understanding these disorders.
PMCID: PMC3492851  PMID: 22141434
Reading disorders; language disorders; dyslexia; reading comprehension impairment; intervention
21.  Financial Conflicts of Interest and Reporting Bias Regarding the Association between Sugar-Sweetened Beverages and Weight Gain: A Systematic Review of Systematic Reviews 
PLoS Medicine  2013;10(12):e1001578.
Maira Bes-Rastrollo and colleagues examine whether financial conflicts of interest are likely to bias conclusions from systematic reviews that investigate the relationship between sugar-sweetened beverages and weight gain or obesity.
Please see later in the article for the Editors' Summary
Industry sponsors' financial interests might bias the conclusions of scientific research. We examined whether financial industry funding or the disclosure of potential conflicts of interest influenced the results of published systematic reviews (SRs) conducted in the field of sugar-sweetened beverages (SSBs) and weight gain or obesity.
Methods and Findings
We conducted a search of the PubMed, Cochrane Library, and Scopus databases to identify published SRs from the inception of the databases to August 31, 2013, on the association between SSB consumption and weight gain or obesity. SR conclusions were independently classified by two researchers into two groups: those that found a positive association and those that did not. These two reviewers were blinded with respect to the stated source of funding and the disclosure of conflicts of interest.
We identified 17 SRs (with 18 conclusions). In six of the SRs a financial conflict of interest with some food industry was disclosed. Among those reviews without any reported conflict of interest, 83.3% of the conclusions (10/12) were that SSB consumption could be a potential risk factor for weight gain. In contrast, the same percentage of conclusions, 83.3% (5/6), of those SRs disclosing some financial conflict of interest with the food industry were that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain or obesity. Those reviews with conflicts of interest were five times more likely to present a conclusion of no positive association than those without them (relative risk: 5.0, 95% CI: 1.3–19.3).
An important limitation of this study is the impossibility of ruling out the existence of publication bias among those studies not declaring any conflict of interest. However, the best large randomized trials also support a direct association between SSB consumption and weight gain or obesity.
Financial conflicts of interest may bias conclusions from SRs on SSB consumption and weight gain or obesity.
Please see later in the article for the Editors' Summary
Editors' Summary
In our daily lives, we frequently rely on the results of scientific research to make decisions about our health. If we are healthy, we may seek out scientific advice about how much exercise to do to reduce our risk of a heart attack, and we may follow dietary advice issued by public health bodies to help us maintain a healthy weight. If we are ill, we expect our treatment to be based on the results of clinical trials and other studies. We assume that the scientific research that underlies our decisions about health-related issues is unbiased and accurate. However, there is increasing evidence that the conclusions of industry-sponsored scientific research are sometimes biased. So, for example, reports of drug trials sponsored by pharmaceutical companies sometimes emphasize the positive results of trials and “hide” unwanted side effects deep within the report or omit them altogether.
Why Was This Study Done?
Although the effects of company sponsors on the conclusions of pharmaceutical research have been extensively examined, little is known about the effects of industry sponsorship on nutrition research, even though large commercial entities are increasingly involved in global food and drink production. It is important to know whether the scientific evidence about nutrition is free of bias because biased information might negatively affect the health of entire populations. Moreover, scientific evidence from nutrition research underlies the formulation of governmental dietary guidelines and food-related public health interventions. In this systematic review, the researchers investigate whether the disclosure of potential financial conflicts of interest (for example, research funding by a beverage company) has influenced the results of systematic reviews undertaken to examine the association between the consumption of highly lucrative sugar-sweetened beverages (SSBs) and weight gain or obesity. Systematic reviews identify all the research on a given topic using predefined criteria. In an ideal world, systematic reviews provide access to all the available evidence on specific exposure–disease associations, but publication bias related to authors' conflicts of interest may affect the reliability of the conclusions of such studies.
What Did the Researchers Do and Find?
The researchers identified 18 conclusions from 17 systematic reviews that had investigated the association between SSB consumption and weight gain or obesity. In six of these reviews, a financial conflict of interest with a food industry was disclosed. Among the reviews that reported having no conflict of interest, 83.3% of the conclusions were that SSB consumption could be a potential risk factor for weight gain. By contrast, the same percentage of reviews in which a potential financial conflict of interest was disclosed concluded that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain, or reported contradictory results and did not state any definitive conclusion about the association between SSB consumption and weight gain. Reviews in which a potential conflict of interest was disclosed were five times more likely to present a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no financial conflict of interest.
What Do These Findings Mean?
These findings indicate that systematic reviews that reported financial conflicts of interest or sponsorship from food or drink companies were more likely to reach a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no conflicts of interest. A major limitation of this study is that it cannot assess which interpretation of the available evidence is truly accurate. For example, the scientists involved in the systematic reviews that reported having no conflict of interest may have had preexisting prejudices that affected their interpretation of their findings. However, the interests of the food industry (increased sales of their products) are very different from those of most researchers (the honest pursuit of knowledge), and recent randomized trials support a positive association between SSB consumption and overweight/obesity. Thus, these findings draw attention to possible inaccuracies in scientific evidence from research funded by the food and drink industry. They do not imply that industry sponsorship of nutrition research should be avoided entirely. Rather, as in other research areas, clear guidelines and principles (for example, sponsors should sign contracts that state that they will not be involved in the interpretation of results) need to be established to avoid dangerous conflicts of interest.
Additional Information
Please access these websites via the online version of this summary at
The Research Ethics Program at the University of California, San Diego provides an overview of conflicts of interest for researchers and details of US regulations and guidelines
The PLOS Medicine series on Big Food examines the activities and influence of the food industry in global health
A PLOS Medicine Research Article by Basu et al. uses mathematical modeling to investigate whether SSB taxation would avert obesity and diabetes in India
A 2012 policy brief from the Yale Rudd Center for Food Policy and Obesity discusses current evidence regarding SSB taxes
The US National Institutes of Health has regulations on financial conflicts of interest for institutions applying to receive funding
Wikipedia has pages on conflict of interest, reporting bias, systematic review, and SSBs (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC3876974  PMID: 24391479
22.  Converting systematic reviews to Cochrane format: a cross-sectional survey of Australian authors of systematic reviews 
Despite the growing reputation and subject coverage of the Cochrane Database of Systematic Reviews, many systematic reviews continue to be published solely in paper-based health care journals. This study was designed to determine why authors choose to publish their systematic reviews outside of the Cochrane Collaboration and if they might be interested in converting their reviews to Cochrane format for publication in the Cochrane Database of Systematic Reviews.
Cross-sectional survey of Australian primary authors of systematic reviews not published on the Cochrane Database of Systematic Reviews identified from the Database of Abstracts of Reviews of Effectiveness.
We identified 88 systematic reviews from the Database of Abstracts of Reviews of Effectiveness with an Australian as the primary author. We surveyed 52 authors for whom valid contact information was available. The response rate was 88 per cent (46/52). Ten authors replied without completing the survey, leaving 36 valid surveys for analysis. The most frequently cited reasons for not undertaking a Cochrane review were: lack of time (78%), the need to undergo specific Cochrane training (46%), unwillingness to update reviews (36%), difficulties with the Cochrane process (26%) and the review topic already registered with the Cochrane Collaboration (21%). (Percentages based on completed responses to individual questions.) Nearly half the respondents would consider converting their review to Cochrane format. Dedicated time emerged as the most important factor in facilitating the potential conversion process. Other factors included navigating the Cochrane system, assistance with updating and financial support. Eighty-six per cent were willing to have their review converted to Cochrane format by another author.
Time required to complete a Cochrane review and the need for specific training are the primary reasons why some authors publish systematic reviews outside of the Cochrane Collaboration. Encouragingly, almost half of the authors would consider converting their review to Cochrane format. Based on the current number of reviews in the Database of Abstracts of Reviews of Effectiveness, this could result in more than 700 additional Cochrane reviews. Ways of supporting these authors and how to provide dedicated time to convert systematic reviews needs further consideration.
PMCID: PMC149345  PMID: 12533194
23.  Reading, writing and systematic review 
Journal of advanced nursing  2008;64(1):104-110.
This paper offers a discussion of the reading and writing practices that define systematic review.
Although increasingly popular, systematic review has engendered a critique of the claims made for it as a more objective method for summing up research findings than other kinds of reviews.
An alternative understanding of systematic review is as a highly subjective, albeit disciplined, engagement between resisting readers and resistant texts. Reviewers of research exemplify the resisting reader when they exclude reports on grounds of relevance, quality, or methodological difference. Research reports exemplify resistant texts as they do not simply yield their findings, but rather must be made docile to review. These acts of resistance make systematic review possible, but challenge claims of its greater capacity to control bias.
An understanding of the reading and writing practices that define systematic review still holds truth and objectivity as regulative ideals, but is aware of the reading and writing practices that both enable and challenge those ideals.
PMCID: PMC2569151  PMID: 18721156
bias; qualitative research; quantitative research; research methods; resisting reader; systematic review; textual practices
24.  Collagen Cross-Linking Using Riboflavin and Ultraviolet-A for Corneal Thinning Disorders 
Executive Summary
The main objectives for this evidence-based analysis were to determine the safety and effectiveness of photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A radiation, referred to as CXL, for the management of corneal thinning disease conditions. The comparative safety and effectiveness of corneal cross-linking with other minimally invasive treatments such as intrastromal corneal rings was also reviewed. The Medical Advisory Secretariat (MAS) evidence-based analysis was performed to support public financing decisions.
Subject of the Evidence-Based Analysis
The primary treatment objective for corneal cross-linking is to increase the strength of the corneal stroma, thereby stabilizing the underlying disease process. At the present time, it is the only procedure that treats the underlying disease condition. The proposed advantages for corneal cross-linking are that the procedure is minimally invasive, safe and effective, and it can potentially delay or defer the need for a corneal transplant. In addition, corneal cross-linking does not adversely affect subsequent surgical approaches, if they are necessary, or interfere with corneal transplants. The evidence for these claims for corneal cross-linking in the management of corneal thinning disorders such as keratoconus will be the focus of this review.
The specific research questions for the evidence review were as follows:
Technical: How technically demanding is corneal cross-linking and what are the operative risks?
Safety: What is known about the broader safety profile of corneal cross-linking?
Effectiveness - Corneal Surface Topographic Affects:
What are the corneal surface remodeling effects of corneal cross-linking?
Do these changes interfere with subsequent interventions, particularly corneal transplant known as penetrating keratoplasty (PKP)?
Effectiveness -Visual Acuity:
What impacts does the remodeling have on visual acuity?
Are these impacts predictable, stable, adjustable and durable?
Effectiveness - Refractive Outcomes: What impact does remodeling have on refractive outcomes?
Effectiveness - Visual Quality (Symptoms): What impact does corneal cross-linking have on vision quality such as contrast vision, and decreased visual symptoms (halos, fluctuating vision)?
Effectiveness - Contact lens tolerance: To what extent does contact lens intolerance improve after corneal cross-linking?
Vision-Related QOL: What is the impact of corneal cross-linking on functional visual rehabilitation and quality of life?
Patient satisfaction: Are patients satisfied with their vision following the procedure?
Disease Process:
What impact does corneal cross-linking have on the underling corneal thinning disease process?
Does corneal cross-linking delay or defer the need for a corneal transplant?
What is the comparative safety and effectiveness of corneal cross-linking compared with other minimally invasive treatments for corneal ectasia such as intrastromal corneal rings?
Clinical Need: Target Population and Condition
Corneal ectasia (thinning) disorders represent a range of disorders involving either primary disease conditions, such as keratoconus (KC) and pellucid marginal corneal degeneration, or secondary iatrogenic conditions, such as corneal thinning occurring after laser in situ keratomileusis (LASIK) refractive surgery.
Corneal thinning is a disease that occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. The thinning occurs primarily in the stroma layers and is believed to be a breakdown in the collagen process. This bulging can lead to irregular astigmatism or shape of the cornea. Because the anterior part of the cornea is responsible for most of the focusing of the light on the retina, this can then result in loss of visual acuity. The reduced visual acuity can make even simple daily tasks, such as driving, watching television or reading, difficult to perform.
Keratoconus is the most common form of corneal thinning disorder and involves a noninflammatory chronic disease process of progressive corneal thinning. Although the specific cause for the biomechanical alterations in the corneal stroma is unknown, there is a growing body of evidence suggesting that genetic factors may play an important role. Keratoconus is a rare disease (< 0.05% of the population) and is unique among chronic eye diseases because it has an early onset, with a median age of 25 years. Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. Patients are referred for corneal transplants as a last option when they can no longer tolerate contact lenses or when lenses no longer provide adequate vision.
Keratoconus is one of the leading indications for corneal transplants and has been so for the last 3 decades. Despite the high success rate of corneal transplants (up to 20 years) there are reasons to defer it as long as possible. Patients with keratoconus are generally young and a longer-term graft survival of at least 30 or 40 years may be necessary. The surgery itself involves lengthy time off work and postsurgery, while potential complications include long-term steroid use, secondary cataracts, and glaucoma. After a corneal transplant, keratoconus may recur resulting in a need for subsequent interventions. Residual refractive errors and astigmatism can remain challenges after transplantation, and high refractive surgery and regraft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients.
Description of Technology/Therapy
Corneal cross-linking involves the use of riboflavin (vitamin B2) and ultraviolet-A (UVA) radiation. A UVA irradiation device known as the CXL® device (license number 77989) by ACCUTECH Medical Technologies Inc. has been licensed by Health Canada as a Class II device since September 19, 2008. An illumination device that emits homogeneous UVA, in combination with any generic form of riboflavin, is licensed by Health Canada for the indication to slow or stop the progression of corneal thinning caused by progressive keratectasia, iatrogenic keratectasia after laser-assisted in situ keratomileusis (LASIK) and pellucid marginal degeneration. The same device is named the UV-X® device by IROCMedical, with approvals in Argentina, the European Union and Australia.
UVA devices all use light emitting diodes to generate UVA at a wavelength of 360-380 microns but vary in the number of diodes (5 to 25), focusing systems, working distance, beam diameter, beam uniformity and extent to which the operator can vary the parameters. In Ontario, CXL is currently offered at over 15 private eye clinics by refractive surgeons and ophthalmologists.
The treatment is an outpatient procedure generally performed with topical anesthesia. The treatment consists of several well defined procedures. The epithelial cell layer is first removed, often using a blunt spatula in a 9.0 mm diameter under sterile conditions. This step is followed by the application of topical 0.1% riboflavin (vitamin B2) solution every 3 to 5 minutes for 25 minutes to ensure that the corneal stroma is fully penetrated. A solid-state UVA light source with a wavelength of 370 nm (maximum absorption of riboflavin) and an irradiance of 3 mW/cm2 is used to irradiate the central cornea. Following treatment, a soft bandage lens is applied and prescriptions are given for oral pain medications, preservative-free tears, anti-inflammatory drops (preferably not nonsteroidal anti-inflammatory drugs, or NSAIDs) and antibiotic eye drops. Patients are recalled 1 week following the procedure to evaluate re-epithelialization and they are followed-up subsequently.
Evidence-Based Analysis Methods
A literature search was conducted on photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A for the management of corneal thinning disorders using a search strategy with appropriate keywords and subject headings for CXL for literature published up until April 17, 2011. The literature search for this Health Technology Assessment (HTA) review was performed using the Cochrane Library, the Emergency Care Research Institute (ECRI) and the Centre for Reviews and Dissemination. The websites of several other health technology agencies were also reviewed, including the Canadian Agency for Drugs and Technologies in Health (CADTH) and the United Kingdom’s National Institute for Clinical Excellence (NICE). The databases searched included OVID MEDLINE, MEDLINE IN-Process and other Non-Indexed Citations such as EMBASE.
As the evidence review included an intervention for a rare condition, case series and case reports, particularly for complications and adverse events, were reviewed. A total of 316 citations were identified and all abstracts were reviewed by a single reviewer for eligibility. For those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
English-language reports and human studies
patients with any corneal thinning disorder
reports with CXL procedures used alone or in conjunction with other interventions
original reports with defined study methodology
reports including standardized measurements on outcome events such as technical success, safety effectiveness, durability, vision quality of life or patient satisfaction
systematic reviews, meta-analyses, randomized controlled trials, observational studies, retrospective analyses, case series, or case reports for complications and adverse events
Exclusion Criteria
nonsystematic reviews, letters, comments and editorials
reports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implants
reports not involving corneal thinning disorders and an intervention involving CXL
Summary of Evidence Findings
In the Medical Advisory Secretariat evidence review on corneal cross-linking, 65 reports (16 case reports) involving 1403 patients were identified on the use of CXL for managing corneal thinning disorders. The reports were summarized according to their primary clinical indication, whether or not secondary interventions were used in conjunction with CXL (referred to as CXL-Plus) and whether or not it was a safety-related report.
The safety review was based on information from the cohort studies evaluating effectiveness, clinical studies evaluating safety, treatment response or recovery, and published case reports of complications. Complications, such as infection and noninfectious keratitis (inflammatory response), reported in case reports, generally occurred in the first week and were successfully treated with topical antibiotics and steroids. Other complications, such as the cytotoxic effects on the targeted corneal stroma, occurred as side effects of the photo-oxidative process generated by riboflavin and ultraviolet-A and were usually reversible.
The reports on treatment effectiveness involved 15 pre-post longitudinal cohort follow-up studies ranging from follow-up of patients’ treated eye only, follow-up in both the treated and untreated fellow-eye; and follow-up in the treated eye only and a control group not receiving treatment. One study was a 3-arm randomized control study (RCT) involving 2 comparators: one comparator was a sham treatment in which one eye was treated with riboflavin only; and the other comparator was the untreated fellow-eye. The outcomes reported across the studies involved statistically significant and clinically relevant improvements in corneal topography and refraction after CXL. In addition, improvements in treated eyes were accompanied by worsening outcomes in the untreated fellow-eyes. Improvements in corneal topography reported at 6 months were maintained at 1- and 2-year follow-up. Visual acuity, although not always improved, was infrequently reported as vision loss. Additional procedures such as the use of intrastromal corneal ring segments, intraocular lenses and refractive surgical practices were reported to result in additional improvements in topography and visual acuity after CXL.
Considerations for Ontario Health System
The total costs of providing CXL therapy to keratoconus patients in Ontario was calculated based on estimated physician, clinic, and medication costs. The total cost per patient was approximately $1,036 for the treatment of one eye, and $1,751 for the treatment of both eyes. The prevalence of keratoconus was estimated at 4,047 patients in FY2011, with an anticipated annual incidence (new cases) of about 148 cases. After distributing the costs of CXL therapy for the FY2011 prevalent keratoconus population over the next 3 years, the estimated average annual cost was approximately $2.1 million, of which about $1.3 million would be physician costs specifically.
Corneal cross-linking effectively stabilizes the underlying disease, and in some cases reverses disease progression as measured by key corneal topographic measures. The affects of CXL on visual acuity are less predictable and the use of adjunct interventions with CXL, such as intrastromal corneal ring segments, refractive surgery, and intraocular lens implants are increasingly employed to both stabilize disease and restore visual acuity. Although the use of adjunct interventions have been shown to result in additional clinical benefit, the order, timing, and risks of performing adjunctive interventions have not been well established.
Although there is potential for serious adverse events with corneal UVA irradiation and photochemical reactions, there have been few reported complications. Those that have occurred tended to be related to side effects of the induced photochemical reactions and were generally reversible. However, to ensure that there are minimal complications with the use of CXL and irradiation, strict adherence to defined CXL procedural protocols is essential.
Keratoconus, corneal cross-linking, corneal topography, corneal transplant, visual acuity, refractive error.
PMCID: PMC3377552  PMID: 23074417
25.  The use of older studies in meta-analyses of medical interventions: a survey 
Open Medicine  2009;3(2):e62-e68.
Evidence for medical interventions sometimes derives from data that are no longer up to date. These data can influence the outcomes of meta-analyses, yet do not always reflect current clinical practice. We examined the age of the data used in meta-analyses contained within systematic reviews of medical interventions, and investigated whether authors consider the age of these data in their interpretations.
From Issue 4, 2005, of the Cochrane Database of Systematic Reviews we randomly selected 10% of systematic reviews containing at least 1 meta-analysis. From this sample we extracted 1 meta-analysis per primary outcome. We calculated the number of years between the study’s publication and 2005 (the year that the systematic review was published), as well as the number of years between the study’s publication and the year of the literature search conducted in the study. We assessed whether authors discussed the implications of including less recent data, and, for systematic reviews containing meta-analyses of studies published before 1996, we calculated whether excluding the findings of those studies changed the significance of the outcomes. We repeated these calculations and assessments for 22 systematic reviews containing meta-analyses published in 6 high-impact general medical journals in 2005.
For 157 meta-analyses (n = 1149 trials) published in 2005, the median year of the most recent literature search was 2003 (interquartile range [IQR] 2002-04). Two-thirds of these meta-analyses (103/157, 66%) involved no trials published in the preceding 5 years (2001-05). Forty-seven meta-analyses (30%) included no trials published in the preceding 10 years (1996-2005). In another 16 (10%), the statistical significance of the outcomes would have been different had the studies been limited to those published between 1996 and 2005, although in some cases this change in significance would have been due to loss of power. Only 12 (8%) of the meta-analyses discussed the potential implications of including older studies. Among the 22 meta-analyses considered in high-impact general medical journals, 2 included no studies published in the 5 years prior to the reference year (2005), and 18 included at least 1 study published before 1996. Only 4 meta-analyses discussed the implications of including older studies.
In most systematic reviews containing meta-analyses of evidence for health care interventions, very recent studies are rare. Researchers who conduct systematic reviews with meta-analyses, and clinicians who read the outcomes of these studies, should be made aware of the potential implications of including less recent data.
PMCID: PMC2765773  PMID: 19946395

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