Publications by authors named "Lesley A Stewart"

44 Publications

Intensive behavioural interventions based on applied behaviour analysis for young children with autism: An international collaborative individual participant data meta-analysis.

Autism 2021 Jan 22:1362361320985680. Epub 2021 Jan 22.

Newcastle University, UK.

Lay Abstract: Early intensive applied behaviour analysis-based interventions are designed to support young autistic children's learning and development. Unfortunately, the available evidence about the effectiveness of these interventions remains unclear. Several reviews have focused on the published findings rather than contacting the authors to collect and analyse data about the individual participants in the original studies. Also, most of the studies were carried out by groups involved in delivering the interventions leading to the potential bias in interpreting the results. Our research team (supported by an international advisory group) carried out an independent individual patient data review by collecting the original participant data from the authors of the studies, to examine the effectiveness of these interventions. The results suggested that early intensive applied behaviour analysis-based interventions might lead to some changes in children's cognitive ability (intelligence quotient) and everyday life skills after 2 years, compared with standard treatments. However, all the studies had problems with the way they were designed. Also, few of the studies looked at outcomes that have been described as most important to autistic people or followed children beyond 2 years. We think that further systematic reviews of the existing evidence are unlikely to add to the findings of our review. Furthermore, we recommend that future research should investigate which types of supports and interventions are most effective for children and families, prioritising outcomes measures that are meaningful for the autism community and include, wherever possible, longer-term follow-up.
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http://dx.doi.org/10.1177/1362361320985680DOI Listing
January 2021

Influence and management of conflicts of interest in randomised clinical trials: qualitative interview study.

BMJ 2020 10 27;371:m3764. Epub 2020 Oct 27.

Centre for Evidence-Based Medicine Odense (CEBMO), Odense University Hospital, Kløvervænget 10, 13th floor, 5000 Odense C, Denmark.

Objective: To characterise and analyse the experiences of trial researchers of if and how conflicts of interest had unduly influenced clinical trials they had worked on, what management strategies they had used to minimise any potential influence, and their experiences and views on conflicts of interest more generally.

Design: Qualitative interview study.

Participants: Trial researchers who had participated in at least 10 clinical trials with methodological or statistical expertise. Researchers differed by geographical location, educational background, and experience with different types of funders. Interviewees were identified by searches on Web of Science and snowball sampling. 52 trial researchers were approached by email; 20 agreed to be interviewed.

Setting: Interviews conducted by telephone, recorded, transcribed verbatim, imported to NVivo 12, and analysed by systematic text condensation. Semistructured interviews focused on financial and non-financial conflicts of interest.

Results: The interviewees had participated in a median of 37.5 trials and were mainly male physicians who had experience with commercial and non-commercial trial funders. Two predefined themes (influence of conflicts of interest and management strategies) and two additional themes (definition and reporting of conflicts of interest) emerged. Examples of perceived influence of conflicts of interest were: choice of inferior comparator, manipulation of the randomisation process, prematurely stopping the trials, fabrication of data, blocking access to data, and spin (eg, overly favourable interpretation of the results). Examples of strategies to manage conflicts of interest were: disclosure procedures, exclusion of the funder from design and analysis, independent committees, contracts ensuring complete access to the data, and no restriction by the funder on analysis and reporting. Interviewees used different definitions or thresholds for what they considered to be conflicts of interest, and they described different criteria for when to report them. Some interviewees considered non-commercial financial conflicts of interest (eg, funding of trials by governmental health agencies with a political agenda) to be equally or more important than commercial financial conflicts of interest (eg, funding by drug and device companies), but more challenging to report and manage.

Conclusion: This study described how trial researchers perceive conflicts of interest unduly influencing clinical trials they had worked on, and the management strategies they used to prevent these influences. The results indicated considerable variability in researchers' understanding of what conflicts of interest are and when they should be reported.
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http://dx.doi.org/10.1136/bmj.m3764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590918PMC
October 2020

Assessing the format and content of journal published and non-journal published rapid review reports: A comparative study.

PLoS One 2020 26;15(8):e0238025. Epub 2020 Aug 26.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.

Background: As production of rapid reviews (RRs) increases in healthcare, knowing how to efficiently convey RR evidence to various end-users is important given they are often intended to directly inform decision-making. Little is known about how often RRs are produced in the published or unpublished domains, and what and how information is structured.

Objectives: To compare and contrast report format and content features of journal-published (JP) and non-journal published (NJP) RRs.

Methods: JP RRs were identified from key databases, and NJP RRs were identified from a grey literature search of 148 RR producing organizations and were sampled proportionate to cluster size by organization and product type to match the JP RR group. We extracted and formally compared 'how' (i.e., visual arrangement) and 'what' information was presented.

Results: We identified 103 RRs (52 JP and 51 NJP) from 2016. A higher percentage of certain features were observed in JP RRs compared to NJP RRs (e.g., reporting authors; use of a traditional journal article structure; section headers including abstract, methods, discussion, conclusions, acknowledgments, conflict of interests, and author contributions; and use of figures (e.g., Study Flow Diagram) in the main document). For NJP RRs, a higher percentage of features were observed (e.g., use non-traditional report structures; bannering of executive summary sections and appendices; use of typographic cues; and including outcome tables). NJP RRs were more than double in length versus JP RRs. Including key messages was uncommon in both groups.

Conclusions: This comparative study highlights differences between JP and NJP RRs. Both groups may benefit from better use of plain language, and more clear and concise design. Alternative innovative formats and end-user preferences for content and layout should be studied further with thought given to other considerations to ensure better packaging of RR results to facilitate uptake into policy and practice.

Study Registration: The full protocol is available at: https://osf.io/29xvk/.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238025PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449464PMC
October 2020

Sharing Roles and Control in Pediatric Low Risk Febrile Neutropenia: A Multicenter Focus Group Discussion Study Involving Patients, Parents, and Health Care Professionals.

J Pediatr Hematol Oncol 2020 07;42(5):337-344

Department of Health Sciences, University of York, York.

Introduction: Reducing treatment intensity for pediatric low risk febrile neutropenia may improve quality of life, and reduce hospital-acquired infections and costs. Key stakeholders' attitudes toward early discharge regimens are unknown. This study explored perceptions of reduced therapy regimens in the United Kingdom.

Materials And Methods: Three study sites were purposively selected for their approaches to risk stratification, treatment protocols, shared care networks, and geographical spread of patients. Patients aged 13 to 18 years, parents of children of all ages and health care professionals participated in focus group discussions. A constant comparison analysis was used.

Results: Thirty-two participants spoke of their different roles in managing febrile neutropenia and how these would change if reduced therapy regimens were implemented, how mutual trust would need to be strengthened and responsibility redistributed. Having identified a need for discretion and a desire for individualized care, negotiation within a spectrum of control allows achievement of the potential for realized discretion. Nonattendance exemplifies when control is different and families use their assessments of risk and sense of mutual trust, along with previous experiences, to make decisions.

Conclusions: The significance of shared decision making in improving patient experience through sharing risks, developing mutual trust, and negotiating control to achieve individualized treatment cannot be underestimated.
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http://dx.doi.org/10.1097/MPH.0000000000001827DOI Listing
July 2020

Comparison of aggregate and individual participant data approaches to meta-analysis of randomised trials: An observational study.

PLoS Med 2020 01 31;17(1):e1003019. Epub 2020 Jan 31.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom.

Background: It remains unclear when standard systematic reviews and meta-analyses that rely on published aggregate data (AD) can provide robust clinical conclusions. We aimed to compare the results from a large cohort of systematic reviews and meta-analyses based on individual participant data (IPD) with meta-analyses of published AD, to establish when the latter are most likely to be reliable and when the IPD approach might be required.

Methods And Findings: We used 18 cancer systematic reviews that included IPD meta-analyses: all of those completed and published by the Meta-analysis Group of the MRC Clinical Trials Unit from 1991 to 2010. We extracted or estimated hazard ratios (HRs) and standard errors (SEs) for survival from trial reports and compared these with IPD equivalents at both the trial and meta-analysis level. We also extracted or estimated the number of events. We used paired t tests to assess whether HRs and SEs from published AD differed on average from those from IPD. We assessed agreement, and whether this was associated with trial or meta-analysis characteristics, using the approach of Bland and Altman. The 18 systematic reviews comprised 238 unique trials or trial comparisons, including 37,082 participants. A HR and SE could be generated for 127 trials, representing 53% of the trials and approximately 79% of eligible participants. On average, trial HRs derived from published AD were slightly more in favour of the research interventions than those from IPD (HRAD to HRIPD ratio = 0.95, p = 0.007), but the limits of agreement show that for individual trials, the HRs could deviate substantially. These limits narrowed with an increasing number of participants (p < 0.001) or a greater number (p < 0.001) or proportion (p < 0.001) of events in the AD. On average, meta-analysis HRs from published AD slightly tended to favour the research interventions whether based on fixed-effect (HRAD to HRIPD ratio = 0.97, p = 0.088) or random-effects (HRAD to HRIPD ratio = 0.96, p = 0.044) models, but the limits of agreement show that for individual meta-analyses, agreement was much more variable. These limits tended to narrow with an increasing number (p = 0.077) or proportion of events (p = 0.11) in the AD. However, even when the information size of the AD was large, individual meta-analysis HRs could still differ from their IPD equivalents by a relative 10% in favour of the research intervention to 5% in favour of control. We utilised the results to construct a decision tree for assessing whether an AD meta-analysis includes sufficient information, and when estimates of effects are most likely to be reliable. A lack of power at the meta-analysis level may have prevented us identifying additional factors associated with the reliability of AD meta-analyses, and we cannot be sure that our results are generalisable to all outcomes and effect measures.

Conclusions: In this study we found that HRs from published AD were most likely to agree with those from IPD when the information size was large. Based on these findings, we provide guidance for determining systematically when standard AD meta-analysis will likely generate robust clinical conclusions, and when the IPD approach will add considerable value.
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http://dx.doi.org/10.1371/journal.pmed.1003019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993967PMC
January 2020

Systematic review finds that appraisal tools for medical research studies address conflicts of interest superficially.

J Clin Epidemiol 2020 04 3;120:104-115. Epub 2019 Dec 3.

Centre for Evidence-Based Medicine Odense (CEBMO), Odense University Hospital, Odense, Denmark; Open Patient data Exploratory Network (OPEN), Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

Objectives: The objective of this study was to identify and summarize 1) appraisal tools and other guides which address conflicts of interest in medical research studies; and 2) top journals with policies on managing conflicts of interest in journal papers.

Study Design And Setting: We searched bibliographic databases, other sources, and websites of 30 top medical journals. Two authors selected documents and extracted data.

Results: We included 27 appraisal tools. None were designed specifically for addressing conflicts of interest and they included only 1-2 short items on conflicts of interest. We also included eight other types of guides. Of 27 appraisal tools, 23 addressed study funding, and 19 authors' conflicts of interest. Nine tools addressed availability of conflicts of interest information, 13 reported conflicts of interest, and five influence from conflicts of interest. Twelve of 30 top journals had conflicts of interest managing policies (beyond disclosure). One journal restricted nonresearch papers (e.g., editorials) to authors without financial conflicts of interest and ten only restricted under certain circumstances.

Conclusion: Appraisal tools that address conflicts of interest typically do so superficially and rarely address how conflicts of interest may influence studies. Less than half of top medical journals have explicit policies on managing conflicts of interest.
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http://dx.doi.org/10.1016/j.jclinepi.2019.12.005DOI Listing
April 2020

Retrieval of individual patient data depended on study characteristics: a randomized controlled trial.

J Clin Epidemiol 2019 09 30;113:176-188. Epub 2019 May 30.

Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Objectives: The aim of the study was to examine the effect of providing a financial incentive to authors of randomized clinical trials (RCTs) to obtain individual patient data (IPD).

Study Design And Setting: Parallel-group RCT with authors identified in the RCTs eligible for two systematic reviews. The authors were randomly allocated to the intervention (financial incentive with several contact approaches) or control group (using the same contact approaches). Studied outcomes are proportion of authors who provided IPD, time to obtain IPD, and completeness of IPD received.

Results: Of the 129 authors contacted, 37 authors suggested or contacted a person or funder providing relevant details or showed interest to collaborate, whereas 45 authors directed us to contact a person or funder, lacked resources or time, did not have ownership or approval to share the IPD, or claimed IPD was too old. None of the authors shared their IPD. We contacted 17 sponsors and received two complete IPD datasets from one sponsor. The time to obtain IPD was >1 year after a sponsor's positive response. Common barriers included study identification, data ownership, limited data access, and required IPD licenses.

Conclusion: IPD sharing may depend on study characteristics, including funding type, study size, study risk of bias, and treatment effect, but not on providing a financial incentive.
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http://dx.doi.org/10.1016/j.jclinepi.2019.05.031DOI Listing
September 2019

When to include clinical study reports and regulatory documents in systematic reviews.

BMJ Evid Based Med 2018 Dec 11;23(6):210-217. Epub 2018 Oct 11.

Centre for Reviews and Dissemination, University of York, York, UK.

Reporting bias is a major threat to the validity and credibility of systematic reviews. This article outlines the rationale for accessing clinical study reports and other regulatory documents (regulatory data) as a means of addressing reporting bias and identifies factors that may help decide whether (or not) to include regulatory data in systematic reviews. The article also describes the origins and current state of regulatory data access and summarises a survey of current systematic reviewers' practices in considering regulatory data for inclusion in systematic reviews. How to access and extract regulatory data is not addressed. Organisations and other stakeholders such as Cochrane should encourage the use of data from clinical study reports as an important source of data in reviews of pharmaceutical interventions particularly when the intervention in question is of high importance and the risk of reporting bias is great.
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http://dx.doi.org/10.1136/bmjebm-2018-110963DOI Listing
December 2018

Reflections and aspirations: the journal after 5 years.

Syst Rev 2018 06 20;7(1):87. Epub 2018 Jun 20.

West Los Angeles VA Medical Center, Los Angeles, CA, USA.

The journal recently celebrated its fifth anniversary. Like systematic reviews themselves, the journal is thriving and publishing a variety of protocols, reviews, and methods papers. We have also had success in publishing-themed series.
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http://dx.doi.org/10.1186/s13643-018-0753-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011401PMC
June 2018

Quest for certainty regarding early discharge in paediatric low-risk febrile neutropenia: a multicentre qualitative focus group discussion study involving patients, parents and healthcare professionals in the UK.

BMJ Open 2018 05 14;8(5):e020324. Epub 2018 May 14.

Department of Health Sciences, University of York, York, UK.

Objectives: A systematic review of paediatric low-risk febrile neutropenia found that outpatient care is safe, with low rates of treatment failure. However, this review, and a subsequent meta-ethnography, suggested that early discharge of these patients may not be acceptable to key stakeholders. This study aimed to explore experiences and perceptions of patients, parents and healthcare professionals involved in paediatric febrile neutropenia care in the UK.

Setting: Three different centres within the UK, purposively selected from a national survey on the basis of differences in their service structure and febrile neutropenia management.

Participants: Thirty-two participants were included in eight focus group discussions.

Primary Outcomes: Experiences and perceptions of paediatric febrile neutropenia care, including possible future reductions in therapy.

Results: Participants described a quest for certainty, in which they attempted to balance the uncertainty involved in understanding, expressing and negotiating risk with the illusion of certainty provided by strict protocols. Participants assessed risk using both formal and informal stratification tools, overlaid with emotional reactions to risk and experiences of risk within other situations. The benefits of certainty provided by protocols were counterbalanced by frustration at their strict constraints. The perceived benefits and harms of previous inpatient care informed participants' appraisals of future treatment strategies.

Conclusions: This study highlighted the previously underestimated harms of admission for febrile neutropenia and the paternalistic nature of decision making, along with the frustrations and challenges for all parties involved in febrile neutropenia care. It demonstrates how the same statistics, generated by systematic reviews, can be used by key stakeholders to interpret risk differently, and how families in particular can view the harms of therapeutic options as different from the outcomes used within the literature. It justifies a reassessment of current treatment strategies for these children and further exploration of the potential to introduce shared decision making.
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http://dx.doi.org/10.1136/bmjopen-2017-020324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961608PMC
May 2018

Meta-ethnography of experiences of early discharge, with a focus on paediatric febrile neutropenia.

Support Care Cancer 2018 Apr 29;26(4):1039-1050. Epub 2017 Dec 29.

Department of Health Sciences, University of York, York, UK.

Purpose (stating The Main Purposes And Research Question): Many children have no significant sequelae of febrile neutropenia. A systematic review of clinical studies demonstrated patients at low risk of septic complications can be safely treated as outpatients using oral antibiotics with low rates of treatment failure. Introducing earlier discharge may improve quality of life, reduce hospital acquired infection and reduce healthcare service pressures. However, the review raised concerns that this might not be acceptable to patients, families and healthcare professionals.

Methods: This qualitative synthesis explored experiences of early discharge in paediatric febrile neutropenia, including reports from studies of adult febrile neutropenia and from other paediatric conditions. Systematic literature searching preceded meta-ethnographic analysis, including reading the studies and determining relationships between studies, translation of studies and synthesis of these translations.

Results: Nine papers were included. The overarching experience of early discharge is that decision-making is complex and difficult and influenced by fear, timing and resources. From this background, we identified two distinct themes. First, participants struggled with practical consequences of treatment regimens, namely childcare, finances and follow-up. A second theme identified social and emotional issues, including isolation, relational and environmental challenges. Linking these, participants considered continuity of care and the need for information important.

Conclusions: Trust and confidence appeared interdependent with resources available to families-both are required to manage early discharge. Socially informed resilience is relevant to facilitating successful discharge strategies. Interventions which foster resilience may mediate the ability and inclination of families to accept early discharge. Services have an important role in recognising and enhancing resilience.
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http://dx.doi.org/10.1007/s00520-017-3983-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847030PMC
April 2018

Evaluating progestogens for prevention of preterm birth international collaborative (EPPPIC) individual participant data (IPD) meta-analysis: protocol.

Syst Rev 2017 Nov 28;6(1):235. Epub 2017 Nov 28.

Centre for Reviews and Dissemination, University of York, Heslington, York, YO10 5DD, UK.

Background: Preterm birth is the most common cause of death and harm to newborn babies. Babies that are born early may have difficulties at birth and experience health problems during early childhood. Despite extensive study, there is still uncertainty about the effectiveness of progestogen (medications that are similar to the natural hormone progesterone) in preventing or delaying preterm birth, and in improving birth outcomes. The Evaluating Progestogen for Prevention of Preterm birth International Collaborative (EPPPIC) project aims to reduce uncertainty about the specific conditions in which progestogen may (or may not) be effective in preventing or delaying preterm birth and improving birth outcomes.

Methods: The design of the study involves international collaborative individual participant data meta-analysis comprising systematic review, re-analysis, and synthesis of trial datasets. Inclusion criteria are as follows: randomized controlled trials comparing progestogen versus placebo or non-intervention, or comparing different types of progestogen, in asymptomatic women at risk of preterm birth. Main outcomes are as follows; fetal/infant death, preterm birth or fetal death (<=37 weeks, <=34 weeks, <= 28 weeks), serious neonatal complications or fetal/infant death, neurosensory disability (measured at 18 months or later) or infant/child death, important maternal morbidity, or maternal death. In statistical methods, IPD will be synthesized across trials using meta-analysis. Both 'two-stage' models (where effect estimates are calculated for each trial and subsequently pooled in a meta-analysis) and 'one-stage' models (where all IPD from all trials are analyzed in one step, while accounting for the clustering of participants within trials) will be used. If sufficient suitable data are available, a network meta-analysis will compare all types of progesterone and routes of administration extending the one-stage models to include multiple treatment arms.

Discussion: EPPPIC is an international collaborative project being conducted by the forming EPPPIC group, which includes trial investigators, an international secretariat, and the research project team. Results, which are intended to contribute to improvements in maternal and child health, are expected to be publicly available in mid 2018.

Systematic Review Registration: PROSPERO CRD42017068299.
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http://dx.doi.org/10.1186/s13643-017-0600-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706301PMC
November 2017

Comparison of two independent systematic reviews of trials of recombinant human bone morphogenetic protein-2 (rhBMP-2): the Yale Open Data Access Medtronic Project.

Syst Rev 2017 02 15;6(1):28. Epub 2017 Feb 15.

Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, 1 Church Street, Suite 200, New Haven, CT, 06510, USA.

Background: It is uncertain whether the replication of systematic reviews, particularly those with the same objectives and resources, would employ similar methods and/or arrive at identical findings. We compared the results and conclusions of two concurrent systematic reviews undertaken by two independent research teams provided with the same objectives, resources, and individual participant-level data.

Methods: Two centers in the USA and UK were each provided with participant-level data on 17 multi-site clinical trials of recombinant human bone morphogenetic protein-2 (rhBMP-2). The teams were blinded to each other's methods and findings until after publication. We conducted a retrospective structured comparison of the results of the two systematic reviews. The main outcome measures included (1) trial inclusion criteria; (2) statistical methods; (3) summary efficacy and risk estimates; and (4) conclusions.

Results: The two research teams' meta-analyses inclusion criteria were broadly similar but differed slightly in trial inclusion and research methodology. They obtained similar results in summary estimates of most clinical outcomes and adverse events. Center A incorporated all trials into summary estimates of efficacy and harms, while Center B concentrated on analyses stratified by surgical approach. Center A found a statistically significant, but small, benefit whereas Center B reported no advantage. In the analysis of harms, neither showed an increased cancer risk at 48 months, although Center B reported a significant increase at 24 months. Conclusions reflected these differences in summary estimates of benefit balanced with small but potentially important risk of harm.

Conclusions: Two independent groups given the same research objectives, data, resources, funding, and time produced broad general agreement but differed in several areas. These differences, the importance of which is debatable, indicate the value of the availability of data to allow for more than a single approach and a single interpretation of the data.

Systematic Review Registration: PROSPERO CRD42012002040 and CRD42012001907 .
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http://dx.doi.org/10.1186/s13643-017-0422-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310069PMC
February 2017

Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab).

Int J Cancer 2016 Nov 28;139(10):2370-80. Epub 2016 Jul 28.

Centre for Reviews and Dissemination, University of York, York, United Kingdom.

Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165.
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http://dx.doi.org/10.1002/ijc.30280DOI Listing
November 2016

Risk stratification in febrile neutropenic episodes in adolescent/young adult patients with cancer.

Eur J Cancer 2016 09 5;64:101-6. Epub 2016 Jul 5.

Centre for Reviews and Dissemination, University of York, York, UK.

Background: Risk-stratified management of febrile neutropenia (FN) allows intensive management of high-risk cases and early discharge of low-risk cases. Most risk stratification systems predicting severe infection from admission variables have been derived from childhood or adult populations and consequently their value in adolescents/young adults (AYA) may vary. Our objective was to determine their value in this population.

Methods: Data from the 'predicting infectious complications in children with cancer' (PICNICC) individual participant data collaboration were used to evaluate six previously described risk stratification schema in the AYA population. Complete case analyses were undertaken for five 'paediatric' rules, with imputation for specific missing variables of the 'adult' rule. The predictive performance of the rules or the outcome microbiologically defined infection (sensitivity, specificity and predictive values) were compared.

Results: Among the 5,127 episodes of FN in 3,504 patients in the PICNICC collaboration data set, 603 episodes of FN from 478 patients in 20 studies were of patients 16-25 years old. The six rules demonstrated variable sensitivity (33-96%) and specificity (13-83%). Their overall discriminatory ability was poor (area under the receiver operator curve estimates 0.514-0.593).

Conclusions: Both paediatric and adult FN risk stratification schema perform poorly in AYA with cancer. An alternative rule or clinical recognition of their limitations is required.
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http://dx.doi.org/10.1016/j.ejca.2016.05.027DOI Listing
September 2016

A third of systematic reviews changed or did not specify the primary outcome: a PROSPERO register study.

J Clin Epidemiol 2016 11 11;79:46-54. Epub 2016 Apr 11.

Ottawa Methods Centre, Ottawa Hospital Research Institute, The Ottawa Hospital, 501 Smyth Road, PO Box 201B, Ottawa, Ontario K1H 8L6, Canada.

Objectives: To examine outcome reporting bias of systematic reviews registered in PROSPERO.

Study Design And Setting: Retrospective cohort study. The primary outcomes from systematic review publications were compared with those reported in the corresponding PROSPERO records; discrepancies in the primary outcomes were assessed as upgrades, additions, omissions, or downgrades. Relative risks (RRs) and 95% confidence intervals (CI) were calculated to determine the likelihood of having a change in primary outcome when the meta-analysis result was favorable and statistically significant.

Results: Ninety-six systematic reviews were published. A discrepancy in the primary outcome occurred in 32% of the included reviews and 39% of the reviews did not explicitly specify a primary outcome(s); 6% of the primary outcomes were omitted. There was no significant increased risk of adding/upgrading (RR, 2.14; 95% CI: 0.53, 8.63) or decreased risk of downgrading (RR, 0.76; 95% CI: 0.27, 2.17) an outcome when the meta-analysis result was favorable and statistically significant. As well, there was no significant increased risk of adding/upgrading (RR, 0.89; 95% CI: 0.31, 2.53) or decreased risk of downgrading (RR, 0.56; 95% CI: 0.29, 1.08) an outcome when the conclusion was positive.

Conclusions: We recommend review authors carefully consider primary outcome selection, and journals are encouraged to focus acceptance on registered systematic reviews.
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http://dx.doi.org/10.1016/j.jclinepi.2016.03.025DOI Listing
November 2016

Contacting authors to retrieve individual patient data: study protocol for a randomized controlled trial.

Trials 2016 Mar 15;17(1):138. Epub 2016 Mar 15.

Li Ka Shing Knowledge Institute of St. Michael's Hospital, 209 Victoria Street, East Building, Toronto, ON, M5B 1T8, Canada.

Background: Individual patient data (IPD) meta-analysis is considered the "gold standard" for exploring the effectiveness of interventions in different subgroups of patients. However, obtaining IPD is time-consuming and contact with the researchers responsible for the original trials is usually required. To date, there are no studies evaluating different strategies to optimize the process for retrieval of IPD from such researchers. Our aim is to examine the impact of providing incentives to the researchers responsible for the trials eligible for a meta-analysis to submit their IPD.

Methods/design: We updated our previously published systematic reviews for type 1 diabetes mellitus comparing long- and intermediate-acting insulin regimens (from January 2013 to June 2015) and for Alzheimer's dementia comparing cognitive enhancers (from January 2015 to May 2015). Eligible were randomized controlled trials (RCTs) fulfilling the eligibility criteria of the systematic reviews. We will randomly allocate authors of the reports of these RCTs into an intervention or control group. Those allocated to the intervention group will be contacted by email, mail, and phone, and will be asked to provide the IPD from their RCT and will be given a financial incentive. Those allocated to the control group will be contacted by email, mail, and phone, but will not receive a financial incentive. Our primary outcome will be the proportion of authors who provide the IPD. The secondary outcomes will be the time to return the dataset (defined as the period between the information request and the authors' response with the dataset), and completeness of data. We will compare the response rates in the two groups using the odds ratio and the corresponding 95 % confidence interval. We will also use binary logistic regression and cox regression analyses to examine whether different RCT characteristics, such as study size and sponsor information, influence the probability of providing IPD and the time needed to share the data.

Discussion: This study will determine whether a financial incentive affects response rates when seeking IPD from the original researchers. We will disseminate our findings in an open access scientific journal and present results at national and international conferences.

Trial Registration: This trial is registered in Clinical Trials.gov, ID number NCT02569411 . Date of registration 5 October 2015.
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http://dx.doi.org/10.1186/s13063-016-1238-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791799PMC
March 2016

Predicting microbiologically defined infection in febrile neutropenic episodes in children: global individual participant data multivariable meta-analysis.

Br J Cancer 2016 03 8;114(6):623-30. Epub 2016 Mar 8.

Centre for Reviews and Dissemination, University of York, York, UK.

Background: Risk-stratified management of fever with neutropenia (FN), allows intensive management of high-risk cases and early discharge of low-risk cases. No single, internationally validated, prediction model of the risk of adverse outcomes exists for children and young people. An individual patient data (IPD) meta-analysis was undertaken to devise one.

Methods: The 'Predicting Infectious Complications in Children with Cancer' (PICNICC) collaboration was formed by parent representatives, international clinical and methodological experts. Univariable and multivariable analyses, using random effects logistic regression, were undertaken to derive and internally validate a risk-prediction model for outcomes of episodes of FN based on clinical and laboratory data at presentation.

Results: Data came from 22 different study groups from 15 countries, of 5127 episodes of FN in 3504 patients. There were 1070 episodes in 616 patients from seven studies available for multivariable analysis. Univariable analyses showed associations with microbiologically defined infection (MDI) in many items, including higher temperature, lower white cell counts and acute myeloid leukaemia, but not age. Patients with osteosarcoma/Ewings sarcoma and those with more severe mucositis were associated with a decreased risk of MDI. The predictive model included: malignancy type, temperature, clinically 'severely unwell', haemoglobin, white cell count and absolute monocyte count. It showed moderate discrimination (AUROC 0.723, 95% confidence interval 0.711-0.759) and good calibration (calibration slope 0.95). The model was robust to bootstrap and cross-validation sensitivity analyses.

Conclusions: This new prediction model for risk of MDI appears accurate. It requires prospective studies assessing implementation to assist clinicians and parents/patients in individualised decision making.
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http://dx.doi.org/10.1038/bjc.2016.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800297PMC
March 2016

Systematic review of reduced therapy regimens for children with low risk febrile neutropenia.

Support Care Cancer 2016 06 13;24(6):2651-60. Epub 2016 Jan 13.

Centre for Reviews and Dissemination, University of York, Heslington, York, YO10 5DD, UK.

Purpose: Reduced intensity therapy for children with low-risk febrile neutropenia may provide benefits to both patients and the health service. We have explored the safety of these regimens and the effect of timing of discharge.

Methods: Multiple electronic databases, conference abstracts and reference lists were searched. Randomised controlled trials (RCT) and prospective observational cohorts examining the location of therapy and/or the route of administration of antibiotics in people younger than 18 years who developed low-risk febrile neutropenia following treatment for cancer were included. Meta-analysis using a random effects model was conducted. I (2) assessed statistical heterogeneity not due to chance.

Registration: PROSPERO (CRD42014005817).

Results: Thirty-seven studies involving 3205 episodes of febrile neutropenia were included; 13 RCTs and 24 prospective observational cohorts. Four safety events (two deaths, two intensive care admissions) occurred. In the RCTs, the odds ratio for treatment failure (persistence, worsening or recurrence of fever/infecting organisms, antibiotic modification, new infections, re-admission, admission to critical care or death) with outpatient treatment was 0.98 (95% confidence interval (95%CI) 0.44-2.19, I (2) = 0 %) and with oral treatment was 1.05 (95%CI 0.74-1.48, I (2) = 0 %). The estimated risk of failure using outpatient therapy from all prospective data pooled was 11.2 % (95%CI 9.7-12.8 %, I (2) = 77.2 %) and using oral antibiotics was 10.5 % (95%CI 8.9-12.3 %, I (2) = 78.3 %). The risk of failure was higher when reduced intensity therapies were used immediately after assessment, with lower rates when these were introduced after 48 hours.

Conclusions: Reduced intensity therapy for specified groups is safe with low rates of treatment failure. Services should consider how these can be acceptably implemented.
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http://dx.doi.org/10.1007/s00520-016-3074-9DOI Listing
June 2016

Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement.

JAMA 2015 Apr;313(16):1657-65

MRC Clinical Trials Unit at UCL, London, United Kingdom.

Importance: Systematic reviews and meta-analyses of individual participant data (IPD) aim to collect, check, and reanalyze individual-level data from all studies addressing a particular research question and are therefore considered a gold standard approach to evidence synthesis. They are likely to be used with increasing frequency as current initiatives to share clinical trial data gain momentum and may be particularly important in reviewing controversial therapeutic areas.

Objective: To develop PRISMA-IPD as a stand-alone extension to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement, tailored to the specific requirements of reporting systematic reviews and meta-analyses of IPD. Although developed primarily for reviews of randomized trials, many items will apply in other contexts, including reviews of diagnosis and prognosis.

Design: Development of PRISMA-IPD followed the EQUATOR Network framework guidance and used the existing standard PRISMA Statement as a starting point to draft additional relevant material. A web-based survey informed discussion at an international workshop that included researchers, clinicians, methodologists experienced in conducting systematic reviews and meta-analyses of IPD, and journal editors. The statement was drafted and iterative refinements were made by the project, advisory, and development groups. The PRISMA-IPD Development Group reached agreement on the PRISMA-IPD checklist and flow diagram by consensus.

Findings: Compared with standard PRISMA, the PRISMA-IPD checklist includes 3 new items that address (1) methods of checking the integrity of the IPD (such as pattern of randomization, data consistency, baseline imbalance, and missing data), (2) reporting any important issues that emerge, and (3) exploring variation (such as whether certain types of individual benefit more from the intervention than others). A further additional item was created by reorganization of standard PRISMA items relating to interpreting results. Wording was modified in 23 items to reflect the IPD approach.

Conclusions And Relevance: PRISMA-IPD provides guidelines for reporting systematic reviews and meta-analyses of IPD.
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http://dx.doi.org/10.1001/jama.2015.3656DOI Listing
April 2015

Uptake of systematic reviews and meta-analyses based on individual participant data in clinical practice guidelines: descriptive study.

BMJ 2015 Mar 6;350:h1088. Epub 2015 Mar 6.

Centre for Reviews and Dissemination, A/B Block Alcuin College, University of York, York, UK.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353308PMC
http://dx.doi.org/10.1136/bmj.h1088DOI Listing
March 2015

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.

BMJ 2015 01 2;350:g7647. Epub 2015 Jan 2.

Centre for Reviews and Dissemination, University of York, UK.

Protocols of systematic reviews and meta-analyses allow for planning and documentation of review methods, act as a guard against arbitrary decision making during review conduct, enable readers to assess for the presence of selective reporting against completed reviews, and, when made publicly available, reduce duplication of efforts and potentially prompt collaboration. Evidence documenting the existence of selective reporting and excessive duplication of reviews on the same or similar topics is accumulating and many calls have been made in support of the documentation and public availability of review protocols. Several efforts have emerged in recent years to rectify these problems, including development of an international register for prospective reviews (PROSPERO) and launch of the first open access journal dedicated to the exclusive publication of systematic review products, including protocols (BioMed Central's Systematic Reviews). Furthering these efforts and building on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, an international group of experts has created a guideline to improve the transparency, accuracy, completeness, and frequency of documented systematic review and meta-analysis protocols--PRISMA-P (for protocols) 2015. The PRISMA-P checklist contains 17 items considered to be essential and minimum components of a systematic review or meta-analysis protocol.This PRISMA-P 2015 Explanation and Elaboration paper provides readers with a full understanding of and evidence about the necessity of each item as well as a model example from an existing published protocol. This paper should be read together with the PRISMA-P 2015 statement. Systematic review authors and assessors are strongly encouraged to make use of PRISMA-P when drafting and appraising review protocols.
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http://dx.doi.org/10.1136/bmj.g7647DOI Listing
January 2015

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.

Syst Rev 2015 Jan 1;4. Epub 2015 Jan 1.

Ottawa Hospital Research Institute and University of Ottawa, Ottawa, Canada.

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.
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http://dx.doi.org/10.1186/2046-4053-4-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320440PMC
January 2015

Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion.

BMJ 2013 Jun 20;346:f3981. Epub 2013 Jun 20.

Centre for Reviews and Dissemination, University of York, UK.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687771PMC
http://dx.doi.org/10.1136/bmj.f3981DOI Listing
June 2013

Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data.

Ann Intern Med 2013 Jun;158(12):877-89

Centre for Reviews and Dissemination, University of York, York, United Kingdom.

Background: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used to promote fusion in spinal surgery, but its safety has been questioned.

Purpose: To evaluate the effectiveness and safety of rhBMP-2.

Data Sources: Individual-participant data obtained from the sponsor or investigators and data extracted from study publications identified by systematic bibliographic searches through June 2012.

Study Selection: Randomized, controlled trials of rhBMP-2 versus iliac crest bone graft (ICBG) in spinal fusion surgery for degenerative disc disease and related conditions and observational studies in similar populations for investigation of adverse events.

Data Extraction: Individual-participant data from 11 eligible of 17 provided trials sponsored by Medtronic (Minneapolis, Minnesota) (n = 1302) and 1 of 2 other eligible trials (n = 106) were included. Additional aggregate adverse event data were extracted from 35 published observational studies.

Data Synthesis: Primary outcomes were pain (assessed with the Oswestry Disability Index [ODI] or Short Form-36), fusion, and adverse events. At 24 months, ODI scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% to 6.5%) and radiographic fusion was 12% higher (CI, 2% to 23%). At or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [CI, 1.06 to 2.95]). Cancer was more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 to 4.54]), but the small number of events precluded definite conclusions.

Limitation: The observational studies were diverse and at risk of bias.

Conclusion: At 24 months, rhBMP-2 increases fusion rates, reduces pain by a clinically insignificant amount, and increases early postsurgical pain compared with ICBG. Evidence of increased cancer incidence is inconclusive.

Primary Funding Source: Yale University Open Data Access Project.
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http://dx.doi.org/10.7326/0003-4819-158-12-201306180-00005DOI Listing
June 2013

Random-effects meta-analysis of time-to-event data using the expectation-maximisation algorithm and shrinkage estimators.

Res Synth Methods 2013 Jun 22;4(2):144-55. Epub 2012 Nov 22.

Centre for Reviews and Dissemination, University of York, York, UK.

Meta-analysis of time-to-event data has proved difficult in the past because consistent summary statistics often cannot be extracted from published results. The use of individual patient data allows for the re-analysis of each study in a consistent fashion and thus makes meta-analysis of time-to-event data feasible. Time-to-event data can be analysed using proportional hazards models, but incorporating random effects into these models is not straightforward in standard software. This paper fits random-effects proportional hazards models by treating the random effects as missing data and applying the expectation-maximisation algorithm. This approach has been used before by using Markov chain Monte Carlo methods to perform the expectation step of the algorithm. In this paper, the expectation step is simplified, without sacrificing accuracy, by approximating the expected values of the random effects using simple shrinkage estimators. This provides a robust method for fitting random-effects models that can be implemented in standard statistical packages. Copyright © 2012 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/jrsm.1067DOI Listing
June 2013