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      Olfactory Ensheathing Cell Transplantation in Experimental Spinal Cord Injury: Effect size and Reporting Bias of 62 Experimental Treatments: A Systematic Review and Meta-Analysis

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          Abstract

          Olfactory ensheathing cell (OEC) transplantation is a candidate cellular treatment approach for human spinal cord injury (SCI) due to their unique regenerative potential and autologous origin. The objective of this study was, through a meta-epidemiologic approach, (i) to assess the efficacy of OEC transplantation on locomotor recovery after traumatic experimental SCI and (ii) to estimate the likelihood of reporting bias and/or missing data. A study protocol was finalized before data collection. Embedded into a systematic review and meta-analysis, we conducted a literature research of databases including PubMed, EMBASE, and ISI Web of Science from 1949/01 to 2014/10 with no language restrictions, screened by two independent investigators. Studies were included if they assessed neurobehavioral improvement after traumatic experimental SCI, administrated no combined interventions, and reported the number of animals in the treatment and control group. Individual effect sizes were pooled using a random effects model. Details regarding the study design were extracted and impact of these on locomotor outcome was assessed by meta-regression. Missing data (reporting bias) was determined by Egger regression and Funnel-plotting. The primary study outcome assessed was improvement in locomotor function at the final time point of measurement. We included 49 studies (62 experiments, 1,164 animals) in the final analysis. The overall improvement in locomotor function after OEC transplantation, measured using the Basso, Beattie, and Bresnahan (BBB) score, was 20.3% (95% CI 17.8–29.5). One missing study was imputed by trim and fill analysis, suggesting only slight publication bias and reducing the overall effect to a 19.2% improvement of locomotor activity. Dose-response ratio supports neurobiological plausibility. Studies were assessed using a 9-point item quality score, resulting in a median score of 5 (interquartile range [IQR] 3–5). In conclusion, OEC transplantation exerts considerable beneficial effects on neurobehavioral recovery after traumatic experimental SCI. Publication bias was minimal and affirms the translational potential of efficacy, but safety cannot be adequately assessed. The data justify OECs as a cellular substrate to develop and optimize minimally invasive and safe cellular transplantation paradigms for the lesioned spinal cord embedded into state-of-the-art Phase I/II clinical trial design studies for human SCI.

          Abstract

          This meta-analysis study examines the effects of transplanting olfactory ensheathing cells in rodents with experimental spinal cord injury, finding evidence for significant recovery and identifying aspects of the procedure that influence the effect size.

          Author Summary

          Spinal cord injury converts into a debilitating disease affecting millions of chronic patients worldwide. Despite increased molecular knowledge over the last decades, no causal pharmacological or cellular therapy has proven effective so far. Due to their unique regenerative capabilities and their autologous origin, olfactory ensheathing cells (OECs) constitute an appealing candidate for topical cell transplantation. In contrast to few and heterogeneous experimental reports of OEC transplantation after spinal cord injury in humans, a considerable number of preclinical studies have been conducted applying OEC transplantation in rodent models. We set out to conduct a systematic review and meta-analysis to assess preclinical efficacy of OEC transplantation. We detected a significant overall increase of functional neurological recovery in animals after OEC transplantation compared to the control group. This effect was not distorted by publication bias. We identified several specific hallmarks of the cell transplantation procedure that determine the effect size of the transplantation. Our findings delineate conditions for optimized OEC transplantation into lesioned spinal cords and its relevance for effective translation to human trials.

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          Most cited references27

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          p-Curve and Effect Size: Correcting for Publication Bias Using Only Significant Results.

          Journals tend to publish only statistically significant evidence, creating a scientific record that markedly overstates the size of effects. We provide a new tool that corrects for this bias without requiring access to nonsignificant results. It capitalizes on the fact that the distribution of significant p values, p-curve, is a function of the true underlying effect. Researchers armed only with sample sizes and test results of the published findings can correct for publication bias. We validate the technique with simulations and by reanalyzing data from the Many-Labs Replication project. We demonstrate that p-curve can arrive at conclusions opposite that of existing tools by reanalyzing the meta-analysis of the "choice overload" literature.
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            Meta-analysis of data from animal studies: a practical guide.

            Meta-analyses of data from human studies are invaluable resources in the life sciences and the methods to conduct these are well documented. Similarly there are a number of benefits in conducting meta-analyses on data from animal studies; they can be used to inform clinical trial design, or to try and explain discrepancies between preclinical and clinical trial results. However there are inherit differences between animal and human studies and so applying the same techniques for the meta-analysis of preclinical data is not straightforward. For example preclinical studies are frequently small and there is often substantial heterogeneity between studies. This may have an impact on both the method of calculating an effect size and the method of pooling data. Here we describe a practical guide for the meta-analysis of data from animal studies including methods used to explore sources of heterogeneity. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.
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              A systematic review of cellular transplantation therapies for spinal cord injury.

              Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem/progenitor cells, fate-restricted neural/glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same "type" exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, CA USA )
                1544-9173
                1545-7885
                31 May 2016
                May 2016
                31 May 2016
                : 14
                : 5
                : e1002468
                Affiliations
                [1 ]Department of Neurology and Experimental Neurology, Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory (Neuroparaplegiology), Charité–Universitätsmedizin Berlin, Berlin, Germany
                [2 ]Department of Neurosurgery, University Medical Center Freiburg, Freiburg, Germany
                [3 ]Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
                [4 ]Stroke Division, Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
                [5 ]F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, United States of America
                [6 ]Center for Stroke Research Berlin, Charité–Universitätsmedizin, Berlin, Germany
                [7 ]German Center for Neurodegenerative Diseases (DZNE) Berlin site, Berlin, Germany
                [8 ]University of Tasmania, School of Medicine, Faculty of Health, Medical Sciences Precinct, Hobart, Tasmania, Australia
                [9 ]Department of Neurology, Spinal Cord Injury Division, The Neurological Institute, The Ohio State University, Wexner Medical Center, Columbus, United States of America
                [10 ]Department of Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical Center, Columbus, United States of America
                University of California San Francisco, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RW ESS UD MRM DWH JMS. Analyzed the data: RW JR ESS. Contributed reagents/materials/analysis tools: ESS BB TZ MAK MRM DWH JMS. Wrote the paper: RW JR UD MRM DWH JMS.

                Author information
                http://orcid.org/0000-0001-7886-3314
                http://orcid.org/0000-0001-6456-7135
                http://orcid.org/0000-0003-3362-9780
                http://orcid.org/0000-0001-8059-0677
                http://orcid.org/0000-0001-6832-9599
                http://orcid.org/0000-0001-9187-9839
                Article
                PBIOLOGY-D-15-03405
                10.1371/journal.pbio.1002468
                4886956
                27244556
                d606c9b9-07f0-4a0a-83ed-f19d9c6d5bc1
                © 2016 Watzlawick et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 December 2015
                : 25 April 2016
                Page count
                Figures: 4, Tables: 0, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003042, Else Kröner-Fresenius-Stiftung;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100008191, Wings for Life;
                Award ID: 60-2012
                Award Recipient :
                RW was sponsored by the "Studienstiftung des deutschen Volkes" (#186392). JMS received funding support from the Else-Kroehner-Fresenius Foundation, the Wings-for-Life Spinal Cord Research Foundation (#60-2012), and the W.E. Hunt & C.M. Curtis Endowment. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Neurology
                Spinal Cord Injury
                Medicine and Health Sciences
                Critical Care and Emergency Medicine
                Trauma Medicine
                Traumatic Injury
                Spinal Cord Injury
                Biology and Life Sciences
                Anatomy
                Brain
                Olfactory Bulb
                Medicine and Health Sciences
                Anatomy
                Brain
                Olfactory Bulb
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Cell Transplantation
                Biology and Life Sciences
                Biomechanics
                Biological Locomotion
                Biology and Life Sciences
                Physiology
                Biological Locomotion
                Medicine and Health Sciences
                Physiology
                Biological Locomotion
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Glial Cells
                Macroglial Cells
                Schwann Cells
                Biology and Life Sciences
                Anatomy
                Nervous System
                Neuroanatomy
                Spinal Cord
                Medicine and Health Sciences
                Anatomy
                Nervous System
                Neuroanatomy
                Spinal Cord
                Biology and Life Sciences
                Neuroscience
                Neuroanatomy
                Spinal Cord
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Surgical Resection
                Custom metadata
                Data are fully available and stored in the CAMARADES database, hosted at the University of Edinburgh. Institutional Data Access will be granted on demand for researchers who meet the criteria for access.

                Life sciences
                Life sciences

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