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2.  Individual Participant Data (IPD) Meta-analyses of Randomised Controlled Trials: Guidance on Their Use 
PLoS Medicine  2015;12(7):e1001855.
Jayne Tierney and colleagues offer guidance on how to spot a well-designed and well-conducted individual participant data meta-analysis.
PMCID: PMC4510878  PMID: 26196287
3.  Uptake of systematic reviews and meta-analyses based on individual participant data in clinical practice guidelines: descriptive study 
Objective To establish the extent to which systematic reviews and meta-analyses of individual participant data (IPD) are being used to inform the recommendations included in published clinical guidelines.
Design Descriptive study.
Setting Database maintained by the Cochrane IPD Meta-analysis Methods Group, supplemented by records of published IPD meta-analyses held in a separate database.
Population A test sample of systematic reviews of randomised controlled trials that included a meta-analysis of IPD, and a separate sample of clinical guidelines, matched to the IPD meta-analyses according to medical condition, interventions, populations, and dates of publication.
Data extraction Descriptive information on each guideline was extracted along with evidence showing use or critical appraisal, or both, of the IPD meta-analysis within the guideline; recommendations based directly on its findings and the use of other systematic reviews in the guideline.
Results Based on 33 IPD meta-analyses and 177 eligible, matched clinical guidelines there was evidence that IPD meta-analyses were being under-utilised. Only 66 guidelines (37%) cited a matched IPD meta-analysis. Around a third of these (n=22, 34%) had critically appraised the IPD meta-analysis. Recommendations based directly on the matched IPD meta-analyses were identified for only 18 of the 66 guidelines (27%). For the guidelines that did not cite a matched IPD meta-analysis (n=111, 63%), search dates had preceded the publication of the IPD meta-analysis in 23 cases (21%); however, for the remainder, there was no obvious reasons why the IPD meta-analysis had not been cited.
Conclusions Our results indicate that systematic reviews and meta-analyses based on IPD are being under-utilised. Guideline developers should routinely seek good quality and up to date IPD meta-analyses to inform guidelines. Increased use of IPD meta-analyses could lead to improved guidelines ensuring that routine patient care is based on the most reliable evidence available.
PMCID: PMC4353308  PMID: 25747860
4.  Thanks to all those who reviewed for Systematic Reviews in 2014 
Systematic Reviews  2015;4:14.
Contributing reviewers
A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized. Although final decisions are always editorial, they are greatly facilitated by the deeper technical knowledge, scientific insights, understanding of social consequences, and passion that reviewers bring to our deliberations. For these reasons, the Editors-in-Chief and staff of the journal warmly thank the 219 reviewers whose comments helped to shape Systematic Reviews, for their invaluable assistance with review of manuscripts for the journal in Volume 3 (2014).
PMCID: PMC4335375
5.  Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement 
Systematic Reviews  2015;4(1):1.
Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
PMCID: PMC4320440  PMID: 25554246
6.  Protocol for a systematic review of reductions in therapy for children with low-risk febrile neutropenia 
Systematic Reviews  2014;3:119.
Febrile neutropenia is a common complication of therapy in children with cancer. Some patients are at low risk of complications, and research has considered reduction in therapy for these patients. A previous systematic review broadly considered whether outpatient treatment and oral antibiotics were safe in this context and concluded that this was likely to be the case. Since that review, there has been further research in this area. Therefore, we aim to provide a more robust answer to these questions and to additionally explore whether the exact timing of discharge, including entirely outpatient treatment, has an impact on outcomes.
The search will cover MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CDSR, CENTRAL, LILACS, HTA and DARE. A full search strategy is provided. Key conference proceedings and reference lists of included papers will be hand searched. Prominent authors/clinicians in the field will be contacted. We will include randomised and quasi-randomised controlled trials along with prospective single-arm studies that examine the location of therapy and/or the route of administration of antibiotics in children or young adults (aged less than 18 years) who attend paediatric services with fever and neutropenia due to treatment for cancer and are assessed to be at low risk of medical complications. Studies will be screened and data extracted by one researcher and independently checked by a second. All studies will be critically appraised using tools appropriate to the study design. Data from randomised controlled trials (RCTs) will be combined to provide comparative estimates of treatment failure, safety and adequacy. Information from quasi-randomised trials and single-arm studies will provide further data on the safety and adequacy of regimes. Random effects meta-analysis will be used to combine studies. A detailed analysis plan, including assessment of heterogeneity and publication bias, is provided.
This study will aim to specifically define the features of a low-risk strategy that will maintain levels of safety and adequacy equivalent to those of traditional treatments. This will both inform the development of services and provide patients and families with data to help them make an informed decision about care.
Systematic review registration
PROSPERO CRD42014005817
PMCID: PMC4234526  PMID: 25336249
Fever; Neutropenia; Cancer; Children; Outpatient
9.  Happy birthday: we are one year old 
Systematic Reviews  2013;2:61.
PMCID: PMC3751830
10.  PROSPERO at one year: an evaluation of its utility 
Systematic Reviews  2013;2:4.
PROSPERO, an international prospective register of systematic review protocols in health and social care, was launched in February 2011. After one year of operation we describe access and use, explore user experience and identify areas for future improvement.
We collated administrative data and web statistics and conducted an online survey of users’ experiences.
On 21 February 2012, there were 1,076 registered users and 359 registration records published on PROSPERO. The database usage statistics demonstrate the international interest in PROSPERO with high access around the clock and around the world. Based on 232 responses from PROSPERO users (response rate 22%), almost all respondents found joining and navigation was easy or very easy (99%); turn round time was good or excellent (96%); and supporting materials provided were helpful or very helpful (80%). The registration fields were found by 80% to be relevant to their review; 99% rated their overall experience of registering with PROSPERO as good or excellent. Most respondents (81%) had a written protocol before completing the registration form and 19% did not. The majority, 136 (79%), indicated they completed the registration form in 60 minutes or less. Of those who expressed an opinion, 167 (87%) considered the time taken to be about right.
The first year of PROSPERO has shown that registration of systematic review protocols is feasible and not overly burdensome for those registering their reviews. The evaluation has demonstrated that, on the whole, survey respondents are satisfied and the system allows registration of protocol details in a straightforward and acceptable way. The findings have prompted some changes to improve user experience and identified some issues for future consideration.
PMCID: PMC3563608  PMID: 23320413
Systematic review protocol; Register; Prospero; Evaluation
12.  Statistical Analysis of Individual Participant Data Meta-Analyses: A Comparison of Methods and Recommendations for Practice 
PLoS ONE  2012;7(10):e46042.
Individual participant data (IPD) meta-analyses that obtain “raw” data from studies rather than summary data typically adopt a “two-stage” approach to analysis whereby IPD within trials generate summary measures, which are combined using standard meta-analytical methods. Recently, a range of “one-stage” approaches which combine all individual participant data in a single meta-analysis have been suggested as providing a more powerful and flexible approach. However, they are more complex to implement and require statistical support. This study uses a dataset to compare “two-stage” and “one-stage” models of varying complexity, to ascertain whether results obtained from the approaches differ in a clinically meaningful way.
Methods and Findings
We included data from 24 randomised controlled trials, evaluating antiplatelet agents, for the prevention of pre-eclampsia in pregnancy. We performed two-stage and one-stage IPD meta-analyses to estimate overall treatment effect and to explore potential treatment interactions whereby particular types of women and their babies might benefit differentially from receiving antiplatelets. Two-stage and one-stage approaches gave similar results, showing a benefit of using anti-platelets (Relative risk 0.90, 95% CI 0.84 to 0.97). Neither approach suggested that any particular type of women benefited more or less from antiplatelets. There were no material differences in results between different types of one-stage model.
For these data, two-stage and one-stage approaches to analysis produce similar results. Although one-stage models offer a flexible environment for exploring model structure and are useful where across study patterns relating to types of participant, intervention and outcome mask similar relationships within trials, the additional insights provided by their usage may not outweigh the costs of statistical support for routine application in syntheses of randomised controlled trials. Researchers considering undertaking an IPD meta-analysis should not necessarily be deterred by a perceived need for sophisticated statistical methods when combining information from large randomised trials.
PMCID: PMC3463584  PMID: 23056232
13.  Establishing a new journal for systematic review products 
Systematic Reviews  2012;1:1.
Welcome to a new age in publishing systematic reviews. We hope the launch of Systematic Reviews will resonate with a broad spectrum of readers interested in using them in a variety of ways, such as providing comprehensive and up to date evidence for patient management, informing health policy, and developing rigorous practice guidelines. Systematic reviews are increasingly popular. Our journal is committed to publishing a wide variety of well conducted and transparently reported systematic reviews and associated research. We are open access and electronic and not confined by space and so offer scope for publishing reviews in detail and providing a modern and innovative approach to publishing. We look forward to participating in the voyage with all of our readers.
PMCID: PMC3348672  PMID: 22587946
new journal; systematic reviews; open access
14.  The nuts and bolts of PROSPERO: an international prospective register of systematic reviews 
Systematic Reviews  2012;1:2.
Following publication of the PRISMA statement, the UK Centre for Reviews and Dissemination (CRD) at the University of York in England began to develop an international prospective register of systematic reviews with health-related outcomes. The objectives were to reduce unplanned duplication of reviews and provide transparency in the review process, with the aim of minimizing reporting bias.
An international advisory group was formed and a consultation undertaken to establish the key items necessary for inclusion in the register and to gather views on various aspects of functionality. This article describes the development of the register, now called PROSPERO, and the process of registration.
PROSPERO offers free registration and free public access to a unique prospective register of systematic reviews across all areas of health from all around the world. The dedicated web-based interface is electronically searchable and available to all prospective registrants. At the moment, inclusion in PROSPERO is restricted to systematic reviews of the effects of interventions and strategies to prevent, diagnose, treat, and monitor health conditions, for which there is a health-related outcome.
Ideally, registration should take place before the researchers have started formal screening against inclusion criteria but reviews are eligible as long as they have not progressed beyond the point of completing data extraction.
The required dataset captures the key attributes of review design as well as the administrative details necessary for registration.
Submitted registration forms are checked against the scope for inclusion in PROSPERO and for clarity of content before being made publicly available on the register, rejected, or returned to the applicant for clarification.
The public records include an audit trail of major changes to planned methods, details of when the review has been completed, and links to resulting publications when provided by the authors.
There has been international support and an enthusiastic response to the principle of prospective registration of protocols for systematic reviews and to the development of PROSPERO.
In October 2011, PROSPERO contained 200 records of systematic reviews being undertaken in 26 countries around the world on a diverse range of interventions.
PMCID: PMC3348673  PMID: 22587842
Systematic review protocol; register; PROSPERO
15.  Predicting infectious complications in neutropenic children and young people with cancer (IPD protocol) 
Systematic Reviews  2012;1:8.
A common and potentially life-threatening complication of the treatment of childhood cancer is infection, which frequently presents as fever with neutropenia. The standard management of such episodes is the extensive use of intravenous antibiotics, and though it produces excellent survival rates of over 95%, it greatly inconveniences the three-fourths of patients who do not require such aggressive treatment. There have been a number of studies which have aimed to develop risk prediction models to stratify treatment. Individual participant data (IPD) meta-analysis in therapeutic studies has been developed to improve the precision and reliability of answers to questions of treatment effect and recently have been suggested to be used to answer questions regarding prognosis and diagnosis to gain greater power from the frequently small individual studies.
In the IPD protocol, we will collect and synthesise IPD from multiple studies and examine the outcomes of episodes of febrile neutropenia as a consequence of their treatment for malignant disease. We will develop and evaluate a risk stratification model using hierarchical regression models to stratify patients by their risk of experiencing adverse outcomes during an episode. We will also explore specific practical and methodological issues regarding adaptation of established techniques of IPD meta-analysis of interventions for use in synthesising evidence derived from IPD from multiple studies for use in predictive modelling contexts.
Our aim in using this model is to define a group of individuals at low risk for febrile neutropenia who might be treated with reduced intensity or duration of antibiotic therapy and so reduce the inconvenience and cost of these episodes, as well as to define a group of patients at very high risk of complications who could be subject to more intensive therapies. The project will also help develop methods of IPD predictive modelling for use in future studies of risk prediction.
PMCID: PMC3351734  PMID: 22588015
individual participant data meta-analysis; predictive modelling; paediatric oncology; febrile neutropenia; collaborative studies
16.  Why prospective registration of systematic reviews makes sense 
Systematic Reviews  2012;1:7.
Prospective registration of systematic reviews promotes transparency, helps reduce potential for bias and serves to avoid unintended duplication of reviews. Registration offers advantages to many stakeholders in return for modest additional effort from the researchers registering their reviews.
PMCID: PMC3369816  PMID: 22588008
17.  Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer 
BMC Medicine  2012;10:6.
Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people.
This review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485.
We found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules.
The limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study.
PMCID: PMC3331823  PMID: 22257704
18.  Establishing a Minimum Dataset for Prospective Registration of Systematic Reviews: An International Consultation 
PLoS ONE  2011;6(11):e27319.
In response to growing recognition of the value of prospective registration of systematic review protocols, we planned to develop a web-based open access international register. In order for the register to fulfil its aims of reducing unplanned duplication, reducing publication bias, and providing greater transparency, it was important to ensure the appropriate data were collected. We therefore undertook a consultation process with experts in the field to identify a minimum dataset for registration.
Methods and Findings
A two-round electronic modified Delphi survey design was used. The international panel surveyed included experts from areas relevant to systematic review including commissioners, clinical and academic researchers, methodologists, statisticians, information specialists, journal editors and users of systematic reviews. Direct invitations to participate were sent out to 315 people in the first round and 322 in the second round. Responses to an open invitation to participate were collected separately. There were 194 (143 invited and 51 open) respondents with a 100% completion rate in the first round and 209 (169 invited and 40 open) respondents with a 91% completion rate in the second round. In the second round, 113 (54%) of the participants reported having previously taken part in the first round. Participants were asked to indicate whether a series of potential items should be designated as optional or required registration items, or should not be included in the register. After the second round, a 70% or greater agreement was reached on the designation of 30 of 36 items.
The results of the Delphi exercise have established a dataset of 22 required items for the prospective registration of systematic reviews, and 18 optional items. The dataset captures the key attributes of review design as well as the administrative details necessary for registration.
PMCID: PMC3217945  PMID: 22110625
20.  Systematic review and meta-analysis of the discriminatory performance of risk prediction rules in febrile neutropaenic episodes in children and young people 
European Journal of Cancer  2010;46(16):2950-2964.
Febrile neutropaenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer, yet many children are aggressively over-treated. We aimed to undertake a systematic review and meta-analysis to summarise evidence on the discriminatory ability and predictive accuracy of clinical decision rules (CDR) of risk stratification in febrile neutropaenic episodes.
The review was conducted in accordance with Centre for Reviews and Dissemination methods, using random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100453.
We found 20 studies describing 16 different CDR assessed in 8388 episodes of FNP. No study compared different approaches and only one CDR had been subject to testing across multiple datasets. This review cannot conclude that any system is more effective or reliable than any other.
To maximise the value of the information already collected by these and other cohorts of children with febrile neutropaenia, an individual-patient-data (IPD) meta-analysis is required to develop and test new and existing CDR to improve stratification and optimise therapy.
PMCID: PMC2981857  PMID: 20621468
Systematic review; Meta-analysis; Neutropaenic sepsis; Clinical decision rules; Diagnosis
21.  The Hypothalamic-Pituitary-Adrenal Axis Response to Stress in Mice Lacking Functional Vasopressin V1b Receptors 
Endocrinology  2006;148(2):849-856.
The role of arginine vasopressin (Avp) as an adrenocorticotropin (ACTH) secretagogue is mediated by the Avp 1b receptor (Avpr1b) found on anterior pituitary corticotropes. Avp also potentiates the actions of corticotropin-releasing hormone (Crh) and appears to be an important mediator of the hypothalamic-pituitary-adrenal (HPA) axis response to chronic stress. To investigate the role of Avp in the HPA axis response to stress, we measured plasma ACTH and corticosterone (CORT) levels in Avpr1b knockout (KO) mice and wild-type controls in response to two acute (restraint and insulin administration) and one form of chronic (daily restraint for 14 days) stress. No significant difference was found in the basal plasma levels of ACTH and CORT between the two genotypes. Acute restraint (30 min) increased plasma ACTH and CORT to a similar level in both the Avpr1b mutant and wild-type mice. In contrast, plasma ACTH and CORT levels induced by hypoglycemia were significantly decreased in the Avpr1b KO mice when compared to wild-type littermates. There was no difference in the ACTH response to acute and chronic restraint in wild-type mice. In the Avpr1b KO group subjected to 14 sessions of daily restraint, plasma ACTH was decreased when compared to wild-type mice. On the other hand, the CORT elevations induced by restraint did not adapt in the Avpr1b KO or wild-type mice. The data suggests that the Avpr1b is required for the normal pituitary and adrenal response to some acute stressful stimuli, and is necessary only for a normal ACTH response during chronic stress.
PMCID: PMC2040022  PMID: 17122081
Avp 1b receptor; adrenocorticotropic hormone; corticosterone; hypoglycemia; restraint stress
22.  Attenuated stress response to acute lipopolysaccharide challenge and ethanol administration in vasopressin V1b receptor knockout mice 
Journal of neuroendocrinology  2007;19(7):543-551.
The arginine vasopressin (Avp) 1b receptor (Avpr1b) present on anterior pituitary corticotrophs is involved in the stimulation of adrenocorticotrophin (ACTH) secretion, especially during times of stress. Corticotrophin-releasing hormone (Crh) is considered the major ACTH secretagogue during acute stress while Avp appears to be the more dominant mediator of the hypothalamic-pituitary-adrenal (HPA) axis response during chronic stress situations. To investigate the role of the Avpr1b in the HPA axis response to acute stress, we measured ACTH and corticosterone (CORT) plasma levels in Avpr1b knockout (KO) mice and wild-type controls in response to bacterial lipopolysaccharide (LPS) challenge and ethanol (EtOH) administration. Mice deficient in Avpr1b had markedly compromised plasma ACTH and CORT responses to acute (30 min) LPS, but normal ACTH and CORT response to more extended exposure (4 h) to the immune system activator. The plasma ACTH and CORT levels stimulated by intoxicating, sedative doses of EtOH (3.2 and 4g/kg) were significantly decreased in the Avpr1b KO mice, as compared to wild-type littermates. Significantly higher EtOH-induced plasma ACTH and CORT secretion was measured in female than in male Avpr1b wild-type mice. There was no difference in the blood alcohol levels (BALs) following acute EtOH administration in Avpr1b KO or wild-type mice of either gender. Our results clearly suggest that the Avpr1b plays a significant role in the HPA axis response to acute immune stress and EtOH intoxication.
PMCID: PMC1892245  PMID: 17561882
Avp 1b receptor; hypothalamic-pituitary-adrenal axis; lipopolysaccharide; ethanol
23.  Practical methods for incorporating summary time-to-event data into meta-analysis 
Trials  2007;8:16.
In systematic reviews and meta-analyses, time-to-event outcomes are most appropriately analysed using hazard ratios (HRs). In the absence of individual patient data (IPD), methods are available to obtain HRs and/or associated statistics by carefully manipulating published or other summary data. Awareness and adoption of these methods is somewhat limited, perhaps because they are published in the statistical literature using statistical notation.
This paper aims to 'translate' the methods for estimating a HR and associated statistics from published time-to-event-analyses into less statistical and more practical guidance and provide a corresponding, easy-to-use calculations spreadsheet, to facilitate the computational aspects.
A wider audience should be able to understand published time-to-event data in individual trial reports and use it more appropriately in meta-analysis. When faced with particular circumstances, readers can refer to the relevant sections of the paper. The spreadsheet can be used to assist them in carrying out the calculations.
The methods cannot circumvent the potential biases associated with relying on published data for systematic reviews and meta-analysis. However, this practical guide should improve the quality of the analysis and subsequent interpretation of systematic reviews and meta-analyses that include time-to-event outcomes.
PMCID: PMC1920534  PMID: 17555582
25.  Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion 
Objective To investigate whether published results of industry funded trials of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion match underlying trial data by comparing three different data sources: individual participant data, internal industry reports, and publicly available journal publications and conference abstracts.
Data collection and synthesis The manufacturer of rhBMP-2 products (Medtronic; Minneapolis, MN) provided complete individual participant data and internal reports for all its studies of rhMBP-2 in spinal fusion. We identified publications and conference abstracts through comprehensive literature searches. We compared outcomes provided in the individual participant data against outcomes reported in publications. For effectiveness outcomes, we compared meta-analyses of randomised controlled trials based on each of the three data sources. For adverse events, meta-analysis of the published aggregate data was not possible and we compared the number and type of adverse events reported between data sources.
Results 32 publications reported outcomes from 11 of the 17 existing manufacturer sponsored studies. For individual randomised controlled trials, 56% (9/16) to 88% (15/17) of effectiveness outcomes known to have been collected were reported in the published literature. Meta-analyses of effectiveness data were almost identical for pain outcomes and similar for fusion across the three data sources. A minority of adverse event data known to have been collected were reported in the published literature. Several journal articles reported only “serious,” “related,” or “unanticipated” adverse events, without defining these terms. Others reported a small proportion of the collected adverse event categories. Around 23% (533/2302) of the total adverse events collected in published randomised controlled trials have been reported in the literature, with randomised controlled trials evaluating the licensed preparation (Infuse) reporting around 11% (122/1108) of collected adverse events.
Conclusions The published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. This did not lead to substantially different results for meta-analysis of effectiveness outcomes. In contrast, reporting of adverse event data in trial publications was inadequate and inconsistent to the extent that any systematic review based solely on the publicly available data would not be able to properly evaluate the safety of rhBMP-2. Analysis of individual participant data enabled the most complete, detailed, and in-depth analysis and was not more resource intensive than extracting, collating, and analysing aggregate data from multiple trial publications and conference abstracts. Confidential internal reports presented considerably more adverse event data than publications, and in the absence of individual participant data access to these reports would support more accurate and reliable investigation, with less time and effort than relying on incomplete published data.
PMCID: PMC3687771  PMID: 23788229

Results 1-25 (25)