The Impact of Excluding Nonrandomized Studies From Systematic Reviews in Rare Diseases: “The Example of Meta-Analyses Evaluating the Efficacy and Safety of Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis”

Nonrandomized studies are usually excluded from systematic reviews. This could lead to loss of a considerable amount of information on rare diseases. In this article, we explore the impact of excluding nonrandomized studies on the generalizability of meta-analyses results on mucopolysaccharidosis (MPS) disease. A comprehensive search of systematic reviews on MPS patients up to May 2020 was carried out (CRD42020191217). The primary endpoint was the rate of patients excluded from systematic reviews if only randomized studies were considered. Secondary outcomes included the differences in patient and study characteristics between randomized and nonrandomized studies, the methods used to combine data from studies with different designs, and the number of patients excluded from systematic reviews if case reports were not considered. More than 50% of the patients analyzed have been recruited in nonrandomized studies. Patient characteristics, duration of follow-up, and the clinical outcomes evaluated differ between the randomized and nonrandomized studies. There are feasible strategies to combine the data from different randomized and nonrandomized designs. The analyses suggest the relevance of including case reports in the systematic reviews, since the smaller the number of patients in the reference population, the larger the selection bias associated to excluding case reports. Our results recommend including nonrandomized studies in the systematic reviews of MPS to increase the representativeness of the results and to avoid a selection bias. The recommendations obtained from this study should be considered when conducting systematic reviews on rare diseases.

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The Value of Case Reports in Systematic Reviews from Rare Diseases. The Example of Enzyme Replacement Therapy (ERT) in Patients with Mucopolysaccharidosis Type II (MPS-II)

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17186590 ◽

2020 ◽

Vol 17 (18) ◽

pp. 6590

Author(s):

Miguel Sampayo-Cordero ◽

Bernat Miguel-Huguet ◽

Andrea Malfettone ◽

José Manuel Pérez-García ◽

Antonio Llombart-Cussac ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Systematic Reviews ◽

Rare Diseases ◽

Clinical Studies ◽

Case Reports ◽

Mucopolysaccharidosis Type ◽

Type Ii ◽

Mucopolysaccharidosis Type Ii ◽

Enzyme Replacement ◽

Mps Ii

Background: Case reports are usually excluded from systematic reviews. Patients with rare diseases are more dependent on novel individualized strategies than patients with common diseases. We reviewed and summarized the novelties reported by case reports in mucopolysaccharidosis type II (MPS-II) patients treated with enzyme replacement therapy (ERT). Methods: We selected the case reports included in a previous meta-analysis of patients with MPS-II treated with ERT. Later clinical studies evaluating the same topic of those case reports were reported. Our primary aim was to summarize novelties reported in previous case reports. Secondary objectives analyzed the number of novelties evaluated in subsequent clinical studies and the time elapsed between the publication of the case report to the publication of the clinical study. Results: We identified 11 innovative proposals in case reports that had not been previously considered in clinical studies. Only two (18.2%) were analyzed in subsequent nonrandomized cohort studies. The other nine novelties (81.8%) were analyzed in later case reports (five) or were not included in ulterior studies (four) after more than five years from their first publication. Conclusions: Case reports should be included in systematic reviews of rare disease to obtain a comprehensive summary of the state of research and offer valuable information for healthcare practitioners.

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The Involvement of Hypothalamus–Pituitary–Adrenal (HPA) Axis in Suicide Risk

Brain Sciences ◽

10.3390/brainsci10090653 ◽

2020 ◽

Vol 10 (9) ◽

pp. 653 ◽

Cited By ~ 3

Author(s):

Isabella Berardelli ◽

Gianluca Serafini ◽

Natalia Cortese ◽

Federica Fiaschè ◽

Rory C O’Connor ◽

...

Keyword(s):

Hpa Axis ◽

Systematic Reviews ◽

Suicidal Behavior ◽

Suicide Risk ◽

Case Reports ◽

Number Of Patients ◽

Hpa Axis Dysregulation ◽

New Treatment ◽

Meta Analyses ◽

Hpa Axis Activity

Stress and Hypothalamic–Pituitary–Adrenal (HPA) axis dysregulation play a major role in various pathophysiological processes associated with both mood disorders and suicidal behavior. We conducted a systematic review with the primary aim of clarifying the nature and extent of HPA axis activity and suicidal behavior. The second aim of this review was to investigate whether potential biomarkers related to HPA axis abnormalities act as individual susceptibility factors for suicide. The PRISMA statement for reporting systematic reviews was used. Only articles published in English peer-reviewed journals were considered for possible inclusion; we excluded case reports, meta-analyses, and systematic reviews, and studies that did not clearly report statistical analysis, diagnostic criteria, or the number of patients included. Overall, 36 articles on HPA axis and suicide risk met inclusion criteria and were reviewed. Studies that investigated tests detecting biomarkers and the role of early life stressors in suicide risk were also included. We found that HPA axis activity is involved in suicide risk, regardless of the presence or absence of psychiatric conditions. The HPA axis abnormalities, mainly characterized by hyperactivity of the HPA axis, may exert an important modulatory influence on suicide risk. Impaired stress response mechanisms contribute to suicide risk. Targeting HPA axis dysregulation might represent a fruitful strategy for identifying new treatment targets and improving suicide risk prediction.

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Impact of heterogeneity and effect size on the estimation of the optimal information size: analysis of recently published meta-analyses

BMJ Open ◽

10.1136/bmjopen-2017-015888 ◽

2017 ◽

Vol 7 (11) ◽

pp. e015888 ◽

Cited By ~ 7

Author(s):

Josep M Garcia-Alamino ◽

Clare Bankhead ◽

Carl Heneghan ◽

Nicola Pidduck ◽

Rafael Perera

Keyword(s):

Systematic Reviews ◽

Effect Size ◽

Sequential Analysis ◽

Trial Sequential Analysis ◽

Size Analysis ◽

Cochrane Reviews ◽

Number Of Patients ◽

Optimal Information ◽

Meta Analyses ◽

The Impact

ObjectiveTo estimate the proportion of systematic reviews that meet the optimal information size (OIS) and assess the impact heterogeneity and effect size have on the OIS estimate by type of outcome (eg, mortality, semiobjective or subjective).MethodsWe carried out searches of Medline and Cochrane to retrieve meta-analyses published in systematic reviews from 2010 to 2012. We estimated the OIS usingTrial Sequential Analysissoftware (TSA V.0.9) and based on several heterogeneity and effect size scenarios, stratifying by type of outcome (mortality/semiobjective/subjective) and by Cochrane/non-Cochrane reviews.ResultsWe included 137 meta-analyses out of 218 (63%) potential systematic reviews (one meta-analysis from each systematic review). Of these reviews, 83 (61%) were Cochrane and 54 (39%) non-Cochrane. The Cochrane reviews included a mean of 6.5 (SD 6.1) studies and the non-Cochrane included a mean of 13.2 (SD 10.2) studies. The mean number of patients was 2619.1 (SD 6245.8 or median 586.0) for the Cochrane and 19 888.5 (SD 32 925.7 or median 6566.5) patients for the non-Cochrane reviews. The percentage of systematic reviews that achieved the OIS for all-cause mortality outcome were 0% Cochrane and 25% for non-Cochrane reviews; for semiobjective outcome 17% for Cochrane and 46% for non-Cochrane reviews and for subjective outcome 45% for Cochrane and 72% for non-Cochrane reviews.ConclusionsThe number of systematic reviews that meet an optimal information size is low and varies depending on the type of outcome and the type of publication. Less than half of primary outcomes synthesised in systematic reviews achieve the OIS, and therefore the conclusions are subject to substantial uncertainty.

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Susceptibility to Fraud in Systematic Reviews

Anesthesiology ◽

10.1097/aln.0b013e3181c14c3d ◽

2009 ◽

Vol 111 (6) ◽

pp. 1279-1289 ◽

Cited By ~ 32

Author(s):

Emmanuel Marret ◽

Nadia Elia ◽

Jørgen B. Dahl ◽

Henry J. McQuay ◽

Steen Møiniche ◽

...

Keyword(s):

Systematic Reviews ◽

Surgical Patients ◽

Relevant Difference ◽

Number Of Patients ◽

Subgroup Analyses ◽

Current Article ◽

Web Of Knowledge ◽

Meta Analyses ◽

The Impact

Background Dr. Scott Reuben allegedly fabricated data. The authors of the current article examined the impact of Reuben reports on conclusions of systematic reviews. Methods The authors searched in ISI Web of Knowledge systematic reviews citing Reuben reports. Systematic reviews were grouped into one of three categories: I, only cited but did not include Reuben reports; II, retrieved and considered, but eventually excluded Reuben reports; III, included Reuben reports. For quantitative systematic reviews (i.e., meta-analyses), a relevant difference was defined as a significant result becoming nonsignificant (or vice versa) by excluding Reuben reports. For qualitative systematic reviews, each author decided independently whether noninclusion of Reuben reports would have changed conclusions. Results Twenty-five systematic reviews (5 category I, 6 category II, 14 category III) cited 27 Reuben reports (published 1994-2007). Most tested analgesics in surgical patients. One of 6 quantitative category III reviews would have reached different conclusions without Reuben reports. In all 6 (30 subgroup analyses involving Reuben reports), exclusion of Reuben reports never made any difference when the number of patients from Reuben reports was less than 30% of all patients included in the analysis. Of 8 qualitative category III reviews, all authors agreed that one would certainly have reached different conclusions without Reuben reports. For another 4, the authors' judgment was not unanimous. Conclusions Carefully performed systematic reviews proved robust against the impact of Reuben reports. Quantitative systematic reviews were vulnerable if the fraudulent data were more than 30% of the total. Qualitative systematic reviews seemed at greater risk than quantitative.

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Efficacy and safety of aliskiren combination therapy: a protocol for an umbrella review

BMJ Open ◽

10.1136/bmjopen-2020-043807 ◽

2021 ◽

Vol 11 (3) ◽

pp. e043807

Author(s):

Jiantong Shen ◽

Wenming Feng ◽

Yike Wang ◽

Qiyuan Zhao ◽

Billong Laura Flavorta ◽

...

Keyword(s):

Combination Therapy ◽

Systematic Reviews ◽

Cochrane Library ◽

Umbrella Review ◽

Quality Of Reporting ◽

Ethical Approval ◽

Registration Number ◽

Third Person ◽

Meta Analyses ◽

The Impact

IntroductionEfficacy of aliskiren combination therapy with other antihypertensive has been evaluated in the treatment of patients with hypertension in recent systematic reviews. However, most previous reviews only focused on one single health outcome or one setting, none of them made a full summary that assessed the impact of aliskiren combination treatment comprehensively. As such, this umbrella review based on systematic reviews and meta-analyses is aimed to synthesise the evidences on efficacy, safety and tolerability of aliskiren-based therapy for hypertension and related comorbid patients.Methods and analysisA comprehensive search of PubMed, EMBASE, Cochrane Library, CNKI published from inception to August 2020 will be conducted. The selected articles are systematic reviews which evaluated efficacy, safety and tolerability of aliskiren combination therapy. Two reviewers will screen eligible articles, extract data and evaluate quality independently. Any disputes will be resolved by discussion or the arbitration of a third person. The quality of reporting evidence will be assessed using the Assessment of Multiple Systematic Reviews V.2 tool tool. We will take a mixed-methods approach to synthesising the review literatures, reporting summary of findings tables and iteratively mapping the results.Ethics and disseminationEthical approval is not required for the study, as we would only collect data from available published materials. This umbrella review will be also submitted to a peer-reviewed journal for publication after completion.PROSPERO registration numberCRD42020192131.

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Consequences of the COVID-19 Syndemic for Nutritional Health: A Systematic Review

Nutrients ◽

10.3390/nu13041168 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1168

Author(s):

Cristian Neira ◽

Rejane Godinho ◽

Fabio Rincón ◽

Rodrigo Mardones ◽

Janari Pedroso

Keyword(s):

Systematic Review ◽

Systematic Reviews ◽

Preventive Measures ◽

Physical Contact ◽

Current Evidence ◽

Study Objective ◽

Eating Style ◽

Healthy Nutrition ◽

Meta Analyses ◽

The Impact

Confinement at home, quarantine, and social distancing are some measures adopted worldwide to prevent the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2), which has been generating an important alteration in the routines and qualities of life of people. The impact on health is still being evaluated, and consequences in the nutritional field are not entirely clear. The study objective was to evaluate the current evidence about the impact that preventive measures of physical contact restriction causes in healthy nutrition. A systematic review was carried out according to the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” PRISMA Group and Cochrane method for rapid systematic reviews. Searching was performed in six electronic databases and evaluated articles published between 2010 and 2020, including among their participants adult subjects who had been exposed to the preventive measures of physical contact restriction. Seven studies met the selection criteria and reported an overall increase in food consumption, weight, Body Mass Index (BMI), and a change in eating style. Findings suggest that healthy nutrition is affected by preventive measures to restrict physical contact as a result of the COVID-19 syndemic.

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Polyphenols and Cognition In Humans: An Overview of Current Evidence from Recent Systematic Reviews and Meta-Analyses

Brain Plasticity ◽

10.3233/bpl-200111 ◽

2020 ◽

pp. 1-15

Author(s):

Daniel Joseph Lamport ◽

Claire Michelle Williams

Keyword(s):

Systematic Reviews ◽

Evidence Base ◽

Epidemiological Studies ◽

Cognitive Outcome ◽

Current Evidence ◽

Duration Of Treatment ◽

Current Evidence Base ◽

Cognitive Benefits ◽

Meta Analyses ◽

The Impact

There is increasing interest in the impact of dietary influences on the brain throughout the lifespan, ranging from improving cognitive development in children through to attenuating ageing related cognitive decline and reducing risk of neurodegenerative diseases. Polyphenols, phytochemicals naturally present in a host of fruits, vegetables, tea, cocoa and other foods, have received particular attention in this regard, and there is now a substantial body of evidence from experimental and epidemiological studies examining whether their consumption is associated with cognitive benefits. The purpose of this overview is to synthesise and evaluate the best available evidence from two sources, namely meta-analyses and systematic reviews, in order to give an accurate reflection of the current evidence base for an association between polyphenols and cognitive benefits. Four meta-analyses and thirteen systematic reviews published between 2017–2020 were included, and were categorised according to whether they reviewed specific polyphenol-rich foods and classes or all polyphenols. A requirement for inclusion was assessment of a behavioural cognitive outcome in humans. A clear and consistent theme emerged that whilst there is support for an association between polyphenol consumption and cognitive benefits, this conclusion is tentative, and by no means definitive. Considerable methodological heterogeneity was repeatedly highlighted as problematic such that the current evidence base does not support reliable conclusions relating to efficacy of specific doses, duration of treatment, or sensitivity in specific populations or certain cognitive domains. The complexity of multiple interactions between a range of direct and indirect mechanisms of action is discussed. Further research is required to strengthen the reliability of the evidence base.

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2033. A Systematic Review of Systematic Reviews: Procalcitonin in the ICU to Guide Antibiotic Therapy

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1713 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S683-S683

Author(s):

Joshua York ◽

Maithili Varadarajan ◽

James Wilson ◽

Gavin Barlow

Keyword(s):

Antimicrobial Resistance ◽

Systematic Reviews ◽

A Priori ◽

Study Groups ◽

Health Crisis ◽

Consistent Finding ◽

Number Of Patients ◽

Antibiotic Duration ◽

Course Length ◽

The Impact

Abstract Background Antimicrobial resistance is an emerging global health crisis with overall antimicrobial use a key contributor. Strategies to safely reduce antibiotic course length are important. Procalcitonin (PCT) is a serum biomarker produced in the presence of bacterial infection. There have been many systematic reviews (SRs) evaluating PCT in various populations but its use remains controversial. The aim of this SR of SRs was to evaluate the extent to which PCT in critical care (ICU) impacts antibiotic duration and other reported outcomes. Methods A systematic search of major databases using an “a priori” strategy and protocol was performed. SRs were included if one of the reported outcomes related to antibiotic duration or initiation in the ICU. Data were extracted by an author, checked and corrected independently by another author. The quality of SRs was assessed by 2 authors independently using AMSTAR II. Disagreements were resolved by consensus with a third author. Results are presented narratively and in tabular format (Table 1). Results Figure 1 shows the PRISMA diagram. 19 SRs were included. The number of patients included ranged from 308 to 6,037 (median = 1,316) across SRs. Overall, there was a consistent finding of a statistically significant (sf) reduction in antibiotic duration in study groups using PCT cessation protocols (all studies in Table 1). 3 SRs did not contain suitable statistics for inclusion in Table 1. SRs that presented the antibiotic duration outcome as a mean or median difference in exposure days (N = 16) showed a median reduction of 2.10 days (range −1.19 to -5) with PCT use. 1 SR found an sf decrease in mortality with PCT use. 4 SRs included antibiotic initiation as an outcome: 2 found an sf decrease in antibiotic prescription rate with PCT; 2 found no difference. Conclusion SRs have found that PCT use in ICU leads to an sf reduction in antibiotic duration without impacting mortality. There are no data presented in the SRs about the impact of this on antimicrobial resistance. Few SRs detail the infections included; thus the applicability of these findings to a single ICU remains challenging. Other outcomes, such as length of stay, are not affected by PCT use in ICU. Disclosures All authors: No reported disclosures.

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Clinical Considerations for Return to Driving a Car following a Total Knee or Hip Arthroplasty: A Systematic Review

BioMed Research International ◽

10.1155/2020/8921892 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Annalisa Na ◽

Kacy Richburg ◽

Zbigniew Gugala

Keyword(s):

Systematic Reviews ◽

Hip Arthroplasty ◽

Response Times ◽

Meta Analysis ◽

Patient Characteristics ◽

Postoperative Management ◽

Cochrane Library ◽

Clinical Factors ◽

Study Results ◽

Meta Analyses

Aim. The purpose of this study is to systematically review patient characteristics and clinical determinants that may influence return to driving status and time frames following a primary TKA or THA and provide an update of the current literature. Methods. This review was completed per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Final electronic database searches were completed in October 2019 in Medline/PubMed, Medline/OVID, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Library using preselected search terms. Manuscripts of prospective and nonrandomized studies that examined the return to driving a car after a primary knee or hip arthroplasty patients were included. The Methodological Index for Non-Randomized Studies was used to measure study quality. Two authors selected studies and assessed their qualities. All disagreements were resolved through discussion and, as needed, a third reviewer. Data on study title, author(s), country, year, study design, sample size, inclusion and exclusion criteria, age, BMI, gender, statistical analyses, driving measure, follow-up time, surgical approach, laterality, and postoperative management were extracted from each study. Results. A total of 23 studies were eligible, including 12 TKA studies (n=654) with mean ages between 43 and 82 years, 9 THA studies (n=922) with mean ages between 34 and 85 years, and 2 combined TKA and THA (TKA, n=815; THA, n=685), yielded MINORS scores between 6 and 12. Most patients achieved or exceeded preoperative response times between 1 and 8 weeks following a TKA and 2 days to 8 weeks following a THA, and/or self-reported return to driving between 1 week and 6 months. Influences on return to driving time included laterality and pain, but gender was mixed. Discussion/Conclusions. Study results were consistent with previous systematic reviews in that return to driving a car after a primary TKA or THA is highly variable, and most commonly occurs around 4 weeks, but can range between 2 and 8 weeks. While various patient and clinical factors can influence return to driving for a TKA or THA, the most common contributing facts were pain and laterality. The heterogeneous nature of the studies prevented a meta-analysis for determining contributions of return to driving following a primary TKA or THA. Regardless, this study updates previous systematic reviews and presents insight on patient and clinical factors beyond generalized timeframes for return to driving a car. This information and results from future studies are essential to guide clinical recommendations and patient and clinician expectations for return to driving a car after a primary TKA or THA.

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Management of haemorrhoids: protocol of an umbrella review of systematic reviews and meta-analyses

BMJ Open ◽

10.1136/bmjopen-2019-035287 ◽

2020 ◽

Vol 10 (3) ◽

pp. e035287

Author(s):

Min Chen ◽

Tai-Chun Tang ◽

Tao-Hong He ◽

Yong-Jun Du ◽

Di Qin ◽

...

Keyword(s):

Systematic Reviews ◽

Meta Analysis ◽

Random Effect Model ◽

Current Evidence ◽

Cochrane Library ◽

Final Report ◽

Umbrella Review ◽

Effect Model ◽

Meta Analyses ◽

The Impact

IntroductionThe prevalence of haemorrhoidal diseases was high in general population, and many treatments are proposed for the management of haemorrhoids. The treatments include conservative and surgical interventions; the credibility and strength of current evidence of their effectiveness are not comprehensively evaluated. We aim to evaluate the credibility of systematic reviews and meta-analyses that assess the effectiveness of the treatments for haemorrhoidal diseases through an umbrella review.Methods and analysisWe will search Ovid Medline, Embase, Cochrane library and Web of Science from inception to March 2020 without any language restriction. We will include meta-analyses that examine the effectiveness of treatments in the management of haemorrhoids. Two reviewers will independently screen the titles and abstracts of retrieved articles, and they will extract data from the included meta-analyses. For each meta-analysis, we will estimate the effect size of a treatment through the random-effect model and the fixed-effect model, and we will evaluate between-study heterogeneity (Cochrane’s Q and I2statistics) and small-study effect (Egger’s test); we will also estimate the evidence of excess significance bias. Evidence of each treatment will be graded according to prespecified criteria. Methodological quality of each meta-analysis will be evaluated by using Assessment of Multiple Systematic Reviews 2. The corrected cover area method will be used to assess the impact of overlap in reviews on the findings of the umbrella review.Ethics and disseminationWe will present the results of the umbrella review at conferences and publish the final report in a peer-reviewed journal. The umbrella review does not require ethical approval.PROSPERO registration numberCRD42019140702.

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