Meta-analysis, Group Sequential Study Designs, Centralized Endpoint Adjudication, and Composite Endpoints

Abstract Background An adequate sample size calculation is essential for designing a successful clinical trial. One way to tackle planning difficulties regarding parameter assumptions required for sample size calculation is to adapt the sample size during the ongoing trial.This can be attained by adaptive group sequential study designs. At a predefined timepoint, the interim effect is tested for significance. Based on the interim test result, the trial is either stopped or continued with the possibility of a sample size recalculation. Objectives Sample size recalculation rules have different limitations in application like a high variability of the recalculated sample size. Hence, the goal is to provide a tool to counteract this performance limitation. Methods Sample size recalculation rules can be interpreted as functions of the observed interim effect. Often, a “jump” from the first stage's sample size to the maximal sample size at a rather arbitrarily chosen interim effect size is implemented and the curve decreases monotonically afterwards. This jump is one reason for a high variability of the sample size. In this work, we investigate how the shape of the recalculation function can be improved by implementing a smoother increase of the sample size. The design options are evaluated by means of Monte Carlo simulations. Evaluation criteria are univariate performance measures such as the conditional power and sample size as well as a conditional performance score which combines these components. Results We demonstrate that smoothing corrections can reduce variability in conditional power and sample size as well as they increase the performance with respect to a recently published conditional performance score for medium and large standardized effect sizes. Conclusion Based on the simulation study, we present a tool that is easily implemented to improve sample size recalculation rules. The approach can be combined with existing sample size recalculation rules described in the literature.

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On the Use of Group Sequential Study Designs for the Test of Bioequivalence for Complicated Products

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2017.05.015 ◽

2017 ◽

Vol 106 (10) ◽

pp. 3167-3170

Author(s):

Rajesh Krishna ◽

Wen-Lin Luo ◽

Patrick J. Larson ◽

Paul H. Fackler

Keyword(s):

Group Sequential ◽

Sequential Study ◽

Study Designs

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A historical cohort of temporal lobe surgery for medically refractory epilepsy: a systematic review and meta-analysis to guide future nonrandomized controlled trial studies

Journal of Neurosurgery ◽

10.3171/2019.4.jns183235 ◽

2020 ◽

Vol 133 (1) ◽

pp. 71-78 ◽

Cited By ~ 2

Author(s):

Anthony T. Lee ◽

John F. Burke ◽

Pranathi Chunduru ◽

Annette M. Molinaro ◽

Robert Knowlton ◽

...

Keyword(s):

Systematic Review ◽

Temporal Lobe ◽

Epilepsy Surgery ◽

Refractory Epilepsy ◽

Meta Analysis ◽

Small Sample ◽

Seizure Freedom ◽

Level I ◽

Study Designs ◽

Medically Refractory Epilepsy

OBJECTIVERecent trials for temporal lobe epilepsy (TLE) highlight the challenges of investigating surgical outcomes using randomized controlled trials (RCTs). Although several reviews have examined seizure-freedom outcomes from existing data, there is a need for an overall seizure-freedom rate estimated from level I data as investigators consider other methods besides RCTs to study outcomes related to new surgical interventions.METHODSThe authors performed a systematic review and meta-analysis of the 3 RCTs of TLE in adults and report an overall surgical seizure-freedom rate (Engel class I) composed of level I data. An overall seizure-freedom rate was also collected from level II data (prospective cohort studies) for validation. Eligible studies were identified by filtering a published Cochrane meta-analysis of epilepsy surgery for RCTs and prospective studies, and supplemented by searching indexed terms in MEDLINE (January 1, 2012–April 1, 2018). Retrospective studies were excluded to minimize heterogeneity in patient selection and reporting bias. Data extraction was independently reverified and pooled using a fixed-effects model. The primary outcome was overall seizure freedom following surgery. The historical benchmark was applied in a noninferiority study design to compare its power to a single-study cohort.RESULTSThe overall rate of seizure freedom from level I data was 72.4% (55/76 patients, 3 RCTs), which was nearly identical to the overall seizure-freedom rate of 71.7% (1325/1849 patients, 18 studies) from prospective cohorts (z = 0.134, p = 0.89; z-test). Seizure-freedom rates from level I and II studies were consistent over the years of publication (R2< 0.01, p = 0.73). Surgery resulted in markedly improved seizure-free outcomes compared to medical management (RR 10.82, 95% CI 3.93–29.84, p < 0.01; 2 RCTs). Noninferiority study designs in which the historical benchmark was used had significantly higher power at all difference margins compared to using a single cohort alone (p < 0.001, Bonferroni’s multiple comparison test).CONCLUSIONSThe overall rate of seizure freedom for temporal lobe surgery is approximately 70% for medically refractory epilepsy. The small sample size of the RCT cohort underscores the need to move beyond standard RCTs for epilepsy surgery. This historical seizure-freedom rate may serve as a useful benchmark to guide future study designs for new surgical treatments for refractory TLE.

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Smartphone Applications for Encouraging Asthma Self-Management in Adolescents: A Systematic Review

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph15112403 ◽

2018 ◽

Vol 15 (11) ◽

pp. 2403 ◽

Cited By ~ 23

Author(s):

Alaa Alquran ◽

Katrina Lambert ◽

Ambereen Farouque ◽

Anne Holland ◽

Janet Davies ◽

...

Keyword(s):

Systematic Review ◽

Asthma Control ◽

Meta Analysis ◽

Review Literature ◽

Self Management ◽

Bibliographic Databases ◽

Smartphone Apps ◽

Study Designs ◽

Positive Effect ◽

Control Medication

Adolescent asthma is still a major problem with poor adherence to treatment. Globally, adolescents are devoted users of smartphone technologies and app use in asthma self-management may improve adherence. The objective of this systematic review is to assess the feasibility and efficacy of mobile technology in improving asthma outcomes in adolescents. We conducted an extensive review of the peer-review literature of studies with populations consisting of children and adolescents under 18 years in seven bibliographic databases and Google Scholar. All study designs were considered. Quality assessment of included studies were independently assessed and reported. The search identified 291 articles; of the 16 eligible full-text papers, 8 met the review criteria, reporting two interventional, two qualitative and four observational studies. Samples ranged from 12 to 21 participants. Heterogeneity related to study design and the methods of the included studies prevented meta-analysis. Nevertheless, the intervention studies reported a positive effect of smartphone apps on asthma control, medication adherence and self-efficacy. Smartphone apps may be an effective asthma control tool especially among adolescents who are major users of smartphones; however, conclusions are limited by a lack of controlled trials and adequate sample sizes.

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Erythritol-Enriched Air-Polishing Powder for the Surgical Treatment of Peri-Implantitis

The Scientific World JOURNAL ◽

10.1155/2015/802310 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Silvio Taschieri ◽

Roberto Weinstein ◽

Massimo Del Fabbro ◽

Stefano Corbella

Keyword(s):

Surgical Treatment ◽

Scientific Literature ◽

Meta Analysis ◽

Major Complication ◽

Review Of The Literature ◽

Implant Surface ◽

Treatment Protocols ◽

Air Polishing ◽

Study Designs ◽

Viable Treatment

Peri-implantitis represents a major complication that can compromise the success and survival of implant-supported rehabilitations. Both surgical and nonsurgical treatment protocols were proposed to improve clinical parameters and to treat implants affected by peri-implantitis. A systematic review of the literature was performed on electronic databases. The use of air-polishing powder in surgical treatment of peri-implantitis was investigated. A total of five articles, of different study designs, were included in the review. A meta-analysis could not be performed. The data from included studies reported a substantial benefit of the use of air-polishing powders for the decontamination of implant surface in surgical protocols. A case report of guided bone regeneration in sites with implants affected by peri-implantitis was presented. Surgical treatment of peri-implantitis, though demanding and not supported by a wide scientific literature, could be considered a viable treatment option if an adequate decontamination of infected surfaces could be obtained.

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Second-hand smoke and the risk of tuberculosis: a systematic review and a meta-analysis

Epidemiology and Infection ◽

10.1017/s0950268815001235 ◽

2015 ◽

Vol 143 (15) ◽

pp. 3158-3172 ◽

Cited By ~ 14

Author(s):

O. F. DOGAR ◽

N. PILLAI ◽

N. SAFDAR ◽

S. K. SHAH ◽

R. ZAHID ◽

...

Keyword(s):

Meta Analysis ◽

Statistical Significance ◽

Epidemiological Studies ◽

Second Hand Smoke ◽

Significant Heterogeneity ◽

Inclusion Criteria ◽

Tb Treatment ◽

Marked Variability ◽

Shs Exposure ◽

Study Designs

SUMMARYThere is limited evidence and lack of consensus whether second-hand smoke (SHS) increases risk of tuberculosis (TB), which has substantial implications for unrestricted smoking indoors and TB control policies. We aimed to establish the association between SHS and the risk of acquiring and worsening of TB in non-smokers. We identified 428 articles in the initial search and 12 comparative epidemiological studies met our inclusion criteria. Exposure to SHS was found to have a higher risk of TB infection [risk ratio (RR) 1·19, 95% confidence interval (CI) 0·90–1·57] compared to non-exposure; however, this did not reach statistical significance. There was marked variability (I2 = 74%, P = 0·0008) between studies’ results, which could be explained by the differences in the diagnostic criteria used. Exposure to SHS was found to be statistically significantly associated (RR 1·59, 95% CI 1·11–2·27) with the risk of TB disease. There was significant heterogeneity (I2 = 77%, P = 0·0006) between studies’ results, which was sourced to the internal characteristics of the studies rather than combining different study designs. We did not find any studies for SHS and TB treatment-related outcomes. Thus, we conclude that SHS exposure may increase the risk of acquiring TB infection and progression to TB disease; however, the evidence remains scanty and weak.

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Maternal and Neonatal Polyunsaturated Fatty Acid Intake and Risk of Neurodevelopmental Impairment in Premature Infants

International Journal of Molecular Sciences ◽

10.3390/ijms23020700 ◽

2022 ◽

Vol 23 (2) ◽

pp. 700

Author(s):

Rory J. Heath ◽

Susanna Klevebro ◽

Thomas R. Wood

Keyword(s):

Fatty Acids ◽

Premature Infants ◽

Placental Transfer ◽

Meta Analysis ◽

Narrative Review ◽

Neurodevelopmental Outcomes ◽

Infant Neurodevelopment ◽

Pubmed Search ◽

Study Designs ◽

Prematurely Born Infants

The N3 and N6 long chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are essential for proper neurodevelopment in early life. These fatty acids are passed from mother to infant via the placenta, accreting into fetal tissues such as brain and adipose tissue. Placental transfer of LCPUFA is highest in the final trimester, but this transfer is abruptly severed with premature birth. As such, efforts have been made to supplement the post-natal feed of premature infants with LCPUFA to improve neurodevelopmental outcomes. This narrative review analyzes the current body of evidence pertinent to neurodevelopmental outcomes after LCPUFA supplementation in prematurely born infants, which was identified via the reference lists of systematic and narrative reviews and PubMed search engine results. This review finds that, while the evidence is weakened by heterogeneity, it may be seen that feed comprising 0.3% DHA and 0.6% AA is associated with more positive neurodevelopmental outcomes than LCPUFA-deplete feed. While no new RCTs have been performed since the most recent Cochrane meta-analysis in 2016, this narrative review provides a wider commentary; the wider effects of LCPUFA supplementation in prematurely born infants, the physiology of LCPUFA accretion into preterm tissues, and the physiological effects of LCPUFA that affect neurodevelopment. We also discuss the roles of maternal LCPUFA status as a modifiable factor affecting the risk of preterm birth and infant neurodevelopmental outcomes. To better understand the role of LCPUFAs in infant neurodevelopment, future study designs must consider absolute and relative availabilities of all LCPUFA species and incorporate the LCPUFA status of both mother and infant in pre- and postnatal periods.

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