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Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis

The possible presence of pathological changes in cholinergic synaptic inputs [cholinergic boutons (C-boutons)] is a contentious topic within the ALS field. Conflicting data reported on this issue makes it difficult to assess the roles of these synaptic inputs in ALS. Our objective was to determine w...

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Autores principales: Dukkipati, S. Shekar, Chihi, Aouatef, Wang, Yiwen, Elbasiouny, Sherif M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241941/
https://www.ncbi.nlm.nih.gov/pubmed/28101533
http://dx.doi.org/10.1523/ENEURO.0281-16.2016
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author Dukkipati, S. Shekar
Chihi, Aouatef
Wang, Yiwen
Elbasiouny, Sherif M.
author_facet Dukkipati, S. Shekar
Chihi, Aouatef
Wang, Yiwen
Elbasiouny, Sherif M.
author_sort Dukkipati, S. Shekar
collection PubMed
description The possible presence of pathological changes in cholinergic synaptic inputs [cholinergic boutons (C-boutons)] is a contentious topic within the ALS field. Conflicting data reported on this issue makes it difficult to assess the roles of these synaptic inputs in ALS. Our objective was to determine whether the reported changes are truly statistically and biologically significant and why replication is problematic. This is an urgent question, as C-boutons are an important regulator of spinal motoneuron excitability, and pathological changes in motoneuron excitability are present throughout disease progression. Using male mice of the SOD1-G93A high-expresser transgenic (G93A) mouse model of ALS, we examined C-boutons on spinal motoneurons. We performed histological analysis at high statistical power, which showed no difference in C-bouton size in G93A versus wild-type motoneurons throughout disease progression. In an attempt to examine the underlying reasons for our failure to replicate reported changes, we performed further histological analyses using several variations on experimental design and data analysis that were reported in the ALS literature. This analysis showed that factors related to experimental design, such as grouping unit, sampling strategy, and blinding status, potentially contribute to the discrepancy in published data on C-bouton size changes. Next, we systematically analyzed the impact of study design variability and potential bias on reported results from experimental and preclinical studies of ALS. Strikingly, we found that practices such as blinding and power analysis are not systematically reported in the ALS field. Protocols to standardize experimental design and minimize bias are thus critical to advancing the ALS field.
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spelling pubmed-52419412017-01-18 Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis Dukkipati, S. Shekar Chihi, Aouatef Wang, Yiwen Elbasiouny, Sherif M. eNeuro Failure to Replicate The possible presence of pathological changes in cholinergic synaptic inputs [cholinergic boutons (C-boutons)] is a contentious topic within the ALS field. Conflicting data reported on this issue makes it difficult to assess the roles of these synaptic inputs in ALS. Our objective was to determine whether the reported changes are truly statistically and biologically significant and why replication is problematic. This is an urgent question, as C-boutons are an important regulator of spinal motoneuron excitability, and pathological changes in motoneuron excitability are present throughout disease progression. Using male mice of the SOD1-G93A high-expresser transgenic (G93A) mouse model of ALS, we examined C-boutons on spinal motoneurons. We performed histological analysis at high statistical power, which showed no difference in C-bouton size in G93A versus wild-type motoneurons throughout disease progression. In an attempt to examine the underlying reasons for our failure to replicate reported changes, we performed further histological analyses using several variations on experimental design and data analysis that were reported in the ALS literature. This analysis showed that factors related to experimental design, such as grouping unit, sampling strategy, and blinding status, potentially contribute to the discrepancy in published data on C-bouton size changes. Next, we systematically analyzed the impact of study design variability and potential bias on reported results from experimental and preclinical studies of ALS. Strikingly, we found that practices such as blinding and power analysis are not systematically reported in the ALS field. Protocols to standardize experimental design and minimize bias are thus critical to advancing the ALS field. Society for Neuroscience 2017-01-18 /pmc/articles/PMC5241941/ /pubmed/28101533 http://dx.doi.org/10.1523/ENEURO.0281-16.2016 Text en Copyright © 2017 Dukkipati et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Failure to Replicate
Dukkipati, S. Shekar
Chihi, Aouatef
Wang, Yiwen
Elbasiouny, Sherif M.
Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis
title Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis
title_full Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis
title_fullStr Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis
title_full_unstemmed Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis
title_short Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis
title_sort experimental design and data analysis issues contribute to inconsistent results of c-bouton changes in amyotrophic lateral sclerosis
topic Failure to Replicate
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241941/
https://www.ncbi.nlm.nih.gov/pubmed/28101533
http://dx.doi.org/10.1523/ENEURO.0281-16.2016
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