scholarly journals Behavioral Phenotyping in a Murine Model of GBA1-Associated Parkinson Disease

2021 ◽  
Vol 22 (13) ◽  
pp. 6826
Author(s):  
Jenny Do ◽  
Gani Perez ◽  
Bahafta Berhe ◽  
Nahid Tayebi ◽  
Ellen Sidransky
Keyword(s):  
Parkinson Disease ◽  
Statistical Significance ◽  
Small Sample ◽  
Motor Deficits ◽  
Disease Course ◽  
Prodromal Stage ◽  
Object Recognition Test ◽  
Gene Encoding ◽  
Small Sample Sizes ◽  
Symptom Progression

Mutations in GBA1, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with GBA1-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled GBA1-associated PD by crossing gba haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (SNCAA53T), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether gba+/−//SNCAA53T mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of gba+/−//SNCAA53T (n = 8), SNCAA53T (n = 9), gba+/− (n = 10) and wildtype (n = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old gba+/−//SNCAA53T mice showed more olfactory and motor deficits than wildtype mice. However, differences between gba+/−//SNCAA53T and SNCAA53T mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while gba haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course.

Characterization of microsatellite instability (dMMR/MSI-H) and mutational landscape in a large contemporary cohort of upper tract urothelial cancer (UTUC) patients.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 465-465
Author(s):  
Arpit Rao ◽  
Julie Elaine McGrath ◽  
Joanne Xiu ◽  
Andre Luiz De Souza ◽  
Shuchi Gulati ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Chromatin Remodeling ◽  
Statistical Significance ◽  
Small Sample ◽  
Biological Pathways ◽  
High Rate ◽  
Chi Square ◽  
Mutational Landscape ◽  
Comparison Results ◽  
Small Sample Sizes

465 Background: UTUC is a rare genitourinary malignancy and a number of studies, limited by small sample sizes, have attempted to characterize its mutational landscape. Because immunotherapy is commonly used for this disease type, we evaluated the prevalence of microsatellite instability and characterized the mutational landscapes of UTUC in a large contemporary patient cohort. Methods: UTUC tumor samples were analyzed using next generation sequencing (NGS) (NextSeq, 592 gene panel) or whole exome sequencing (WES) (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Mismatch repair status (deficient [dMMR] or proficient [pMMR]) and microsatellite instability status (MSI-high or stable [MSS]) were detected by immunohistochemistry (IHC), fragment analysis, and NGS. Tumor mutational burden (TMB) was measured by counting all somatic mutations found per tumor (high cutoff ≥ 10 mutations per MB). PD-L1 expression was tested by IHC using PD-L1 antibody clones 22c3 (Agilent; positive cutoff CPS ≥ 10) and SP142 (Ventana; positive cutoff ≥ 5% IC). Pathogenic fusion events were detected using whole transcriptome sequencing (NovaSeq). Statistical significance was determined using the Chi-square test and adjusted for multiple comparison. Results: 538 patients with included – median (range) age 71.5 (30-89) years and 37.5% female/62.5% male. Prevalence of dMMR/MSI-H was 3.9% (21/538) and TMB-high was 22.7% (96/423). Significant molecular differences were not detected in primary vs metastatic disease or in male vs female cases. dMMR/MSI-H tumors had higher frequency of TMB-high compared to MSS tumors (100% vs. 19%, p = 0.00003). dMMR/MSI-H tumors also had a higher frequency than MSS tumors for mutations in genes involved in chromatin remodeling (ASXL 82.4%, CREBBP 60%, SMARCA4 40%, KMT2D 95%, ARIDIA 100%, KMT2A 20%, KMT2C 35.3%, NSD1 20%), DNA-damage repair (FANCG 10%, ATM 45%, ATRX 40%) and other biological pathways (RNF43 10%, PTCH1 21.4%, ERBB3 30%, CDKN2A 25%, TSC2 15%, FLNC 15%, HNF1A 20%, CIC 15%, DNMT3A 17.6%); all adjusted p < 0.05. Pathogenic fusions were detected in 3.8% (17/443) cases, with FGFR3 fusion being the most common, occurring in 2.7% (12/443) cases. PD-L1 positivity was identified in 33.2% (133/400) cases tested by 22c3 antibody and 28.4% (89/313) cases tested by SP142 antibody. No difference was seen in PD-L1 positivity between MSI-H/dMMR vs. MSS tumors. Conclusions: In the largest analysis to date, we found a 3.9% prevalence of dMMR/MSI-high rate in UTUC. All dMMR/MSI-H tumors displayed TMB-high. PD-L1 positivity was comparable between dMMR/MSI-H and MSS tumors. dMMR/MSI-H tumors had a significantly higher rate of mutations in genes involved in chromatin remodeling and DDR biological pathways. These results could inform design of targeted therapy trials in UTUC.

Peripheral T cell lymphoma.

1987 ◽  
Vol 5 (5) ◽  
pp. 750-755 ◽  
Author(s):  
R Liang ◽  
D Todd ◽  
T K Chan ◽  
K L Wong ◽  
F Ho ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Statistical Significance ◽  
Disease Free Survival ◽  
Complete Response ◽  
Small Sample ◽  
T Cell Lymphoma ◽  
Chinese Patients ◽  
Peripheral T Cell Lymphoma ◽  
Small Sample Sizes

Thirty-one Chinese patients with peripheral T cell lymphoma (PTCL) were reviewed. Using the modified Japanese Lymphoma Group classification, there were nine (29%) of the pleomorphic type, 16 (52%) immunoblastic lymphadenopathy (IBL)-like, two (7%) T-zone lymphoma, and one (3%) Lennert's lymphoepithelioid type. Three (9%) were not classifiable. All were positive for T11 (E rosette receptor antigen). Fifty-four percent (15 of 28) were positive predominantly for T4 (helper T cell) and 46% (13/28) for T8 (suppressor T cell). The median age of the patients was 57 years. They usually presented with advanced disease, and while extranodal involvement was common, CNS disease was not seen. The IBL-like type was associated with a positive Coombs' test and polyclonal hypergammaglobulinemia. Five of the nine pleomorphic type were checked for antibody to HTLV-I virus and all were negative. PTCL was associated with poor prognosis, which was not influenced by the histologic subtypes and the T4/T8 phenotypes. The complete response rate of 13 consecutive patients who received the BACOP (bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone) L17M regimen was significantly better than the 16 historic controls who received other less-intensive regiments, 84% v 19% (P less than .01). The relapse rate was also significantly lower, 9% v 100% (P less than .001). There appeared to be an improvement in the disease-free survival (DFS) (80% v 0% at 18 months), as well as the overall survival (60% v 36% at 18 months), but the differences did not reach statistical significance due to small sample sizes.

The Predicament of Large Numbers of Observations and How We Got There: Critical Review

2020 ◽  
Author(s):  
Stanley S Levinson
Keyword(s):  
Statistical Significance ◽  
Roc Curves ◽  
Small Sample ◽  
Computational Techniques ◽  
Number Needed To Treat ◽  
Clinical Effects ◽  
Statistical Parameters ◽  
Large Numbers ◽  
Classical Statistics ◽  
Small Sample Sizes

Abstract Background Classical statistics were developed in a time when small sample sizes were the norm; thus, statistical significance typically ensured large clinical effects. Over the past 10–20 years, computational techniques have allowed studies with modest effects to reach statistical significance (usually P &lt; 0.05) by analyzing very large numbers of patients. In this review, I discuss how this came about and provide an intuitive understanding of the strengths and weaknesses of various statistical parameters that provide insight into clinical effect sizes. Content In this review of the literature, a simple web-based program was used for calculations. Examples are shown. Odds and risk ratios are compared with ROC curves to allow better understanding of their predictive value. Summary In these complex times, an intuitive understanding of statistical procedures is increasingly important. This review will attempt to advance the reader’s knowledge so that one can calculate the number needed to treat and its confidence interval, understand the meaning of a modest association, and determine when a study is likely to be accurate but with questionable clinical utility.

scholarly journals Comparative Evaluation of a Novel Concept Design Method

2013 ◽  
Author(s):  
Damian Rogers ◽  
Filippo A. Salustri
Keyword(s):  
Design Method ◽  
Statistical Significance ◽  
Small Sample ◽  
Design Methods ◽  
Concept Design ◽  
Sample Sizes ◽  
Pilot Experiment ◽  
Small Sample Sizes ◽  
Novel Concept ◽  
Future Work

Based on their previous work in creating a new method of design, termed the “Design by DNA” method, the authors are now experimentally validating the method against other, known methods. The goal of the experiment is to determine if Design by DNA promotes creative designs. Specifically, the authors are seeking to measure and compare creativity resulting from the use of Design by DNA and from other, known design methods. However, few have conducted empirical experiments in the past, and further, the literature on comparatively evaluating creativity of different design methods is relatively sparse. Therefore, the authors are developing a framework for defining and executing meaningful experiments that can accommodate various design methods, including Design by DNA, and also provide meaningful data to comparatively evaluate those methods, with the goal of determining whether Design by DNA impacts creativity in design. The experimental framework is described, and results of a pilot experiment are given. In that framework, creativity was characterized by novelty, usefulness, and cohesion. Due to small sample sizes, confidence in the results is not particularly high. Even so, some results do indicate several points of interest. An analysis of the results suggests that Design by DNA can offer advantages in engineering design, ranking higher in both the ‘usefulness’ and ‘cohesion’ categories of the creativity assessment. Hypotheses are given to explain why the experimental results show the slightly lower score in the ‘novelty’ category. Experiment participants were also evaluated on the NASA Task Loading Index (TLX) to evaluate how taxed they were using the different design methods and results are shown. Here, the Design by DNA method accrues better scores in 5 of the 6 NASA TLX categories, suggesting that it was less strenuous on the participants than the other methods. Statistical analysis of both the creativity scores and the TLX document shows confidence levels of between 65% and 96%, which is acceptable for very low populations. As this was a pilot experiment, the authors foresee future work to improve the results presented here. First, larger sample sizes are needed to improve statistical significance of our conclusions. Secondly, the authors wish to set out a series of experiments whereby each test is run by pitting one specific design method against the Design by DNA method, to better show a 1-on-1 comparison between the methods and highlight the strengths and weaknesses of each.

Abstract 14: Effects of Lesion Laterality on Post-Stroke Motor Performance: An ENIGMA Stroke Recovery Analysis

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Sook-Lei Liew ◽  
Neda Jahanshad ◽  
Lisa Aziz-Zadeh ◽  
Niels Birbaumer ◽  
Michael Borich ◽  
...  
Keyword(s):  
Motor Performance ◽  
Statistical Significance ◽  
Motor Recovery ◽  
Small Sample ◽  
Stroke Recovery ◽  
Intracranial Volume ◽  
Brain Volumes ◽  
Post Stroke ◽  
Small Sample Sizes ◽  
Cortical Regions

The laterality of the lesioned hemisphere is often overlooked in stroke recovery research due to small sample sizes. Here, we used a well-powered dataset from ENIGMA Stroke Recovery (a consortium that harmonizes post-stroke MRIs and behavioral data worldwide; http://enigma.usc.edu) to analyze the effects of left (LHL) versus right (RHL) hemisphere lesions on motor performance. Given the different functional roles of each hemisphere, we hypothesized that the LHL group should show better motor performance, and, consequently, different brain-behavior relationships, compared to the RHL group. Data from over 2000 stroke patients across 20 sites worldwide has been committed. To date, structural T1-weighted MRIs from n=343 (10 sites) have been analyzed (LHL n=174; RHL n=169). ENIGMA protocols extracted volumes of subcortical regions of interest and provided quality control. Regression analyses examined brain volumes as predictors of motor outcomes. Motor scores were combined across scales/sites, with each score expressed as a percentage of the maximum score. Covariates (e.g., age, sex, intracranial volume) and manually marked lesion effects were also modeled. Statistical significance was assessed nonparametrically by permutation. As anticipated, the LHL group had better motor performance compared to the RHL group (t(1,341)=3.07, p=0.0023). In addition, while the combined LHL+RHL analyses showed significant associations between motor scores and volumes of the basal ganglia/lateral ventricles, separate group analyses showed strong associations for the LHL group, but only one association for the RHL group (Table 1). This may suggest that motor recovery following RH lesions is more heterogeneous or relies more on cortical regions/networks that were not assessed here. While further research is needed, these results suggest that laterality of the lesioned hemisphere affects neural patterns related to motor recovery and should be carefully examined.

scholarly journals Changing the logic of replication: A case from infant studies

2019 ◽  
Author(s):  
Francesco Margoni ◽  
Martin Shepperd
Keyword(s):  
Statistical Power ◽  
Sampling Error ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Small Sample ◽  
Infant Research ◽  
Replication Studies ◽  
Wide Range ◽  
Small Sample Sizes ◽  
Meta Analyses

Infant research is making considerable progresses. However, among infant researchers there is growing concern regarding the widespread habit of undertaking studies that have small sample sizes and employ tests with low statistical power (to detect a wide range of possible effects). For many researchers, issues of confidence may be partially resolved by relying on replications. Here, we bring further evidence that the classical logic of confirmation, according to which the result of a replication study confirms the original finding when it reaches statistical significance, could be usefully abandoned. With real examples taken from the infant literature and Monte Carlo simulations, we show that a very wide range of possible replication results would in a formal statistical sense constitute confirmation as they can be explained simply due to sampling error. Thus, often no useful conclusion can be derived from a single or small number of replication studies. We suggest that, in order to accumulate and generate new knowledge, the dichotomous view of replication as confirmatory/disconfirmatory can be replaced by an approach that emphasizes the estimation of effect sizes via meta-analysis. Moreover, we discuss possible solutions for reducing problems affecting the validity of conclusions drawn from meta-analyses in infant research.

Pharmacological treatment of refugees with trauma-related disorders: What do we know today?

2016 ◽  
Vol 54 (2) ◽  
pp. 260-280 ◽  
Author(s):  
Charlotte Sonne ◽  
Jessica Carlsson ◽  
Per Bech ◽  
Erik Lykke Mortensen
Keyword(s):  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Pharmacological Treatment ◽  
Statistical Power ◽  
Statistical Significance ◽  
Small Sample ◽  
Post Traumatic Stress ◽  
Post Traumatic ◽  
The Subject ◽  
Small Sample Sizes

There is a dearth of evidence on the effectiveness of pharmacological treatment for refugees with trauma-related disorders. The present paper provides an overview of available literature on the subject and discusses the transferability of results from studies on other groups of patients with post traumatic stress disorder (PTSD). We conducted a systematic review of published treatment outcome studies on PTSD and depression among refugees. Fifteen studies were identified and reviewed. Most studies focused on the use of antidepressants. Included studies differed widely in method and quality. The majority were observational studies and case studies. Small sample sizes limited the statistical power. Few studies reported effect sizes, confidence intervals, and statistical significance of findings. No specific pharmacological treatment for PTSD among refugees can be recommended on the basis of the available literature. There is a need for well-designed clinical trials, especially with newer antidepressants and antipsychotics. Until such studies are available, clinical practice and design of trials can be guided by results from studies of other groups of PTSD patients, although differences in pharmacogenetics, compliance, and trauma reactions may affect the direct transferability of results from studies on nonrefugee populations.

Integrating Visual and Bayesian Statistical Analyses in Single Case Experimental Research to Evaluate the Effectiveness and Magnitude of a Comprehensive Behavioral Intervention

2018 ◽  
Author(s):  
Prathiba Natesan ◽  
Smita Mehta
Keyword(s):  
Behavioral Intervention ◽  
Effect Size ◽  
Rate Ratio ◽  
Visual Analysis ◽  
Single Case ◽  
Small Sample ◽  
Statistical Analyses ◽  
Data Types ◽  
Ratio Effect ◽  
Small Sample Sizes

Single case experimental designs (SCEDs) have become an indispensable methodology where randomized control trials may be impossible or even inappropriate. However, the nature of SCED data presents challenges for both visual and statistical analyses. Small sample sizes, autocorrelations, data types, and design types render many parametric statistical analyses and maximum likelihood approaches ineffective. The presence of autocorrelation decreases interrater reliability in visual analysis. The purpose of the present study is to demonstrate a newly developed model called the Bayesian unknown change-point (BUCP) model which overcomes all the above-mentioned data analytic challenges. This is the first study to formulate and demonstrate rate ratio effect size for autocorrelated data, which has remained an open question in SCED research until now. This expository study also compares and contrasts the results from BUCP model with visual analysis, and rate ratio effect size with nonoverlap of all pairs (NAP) effect size. Data from a comprehensive behavioral intervention are used for the demonstration.

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