109 research outputs found
Inclusion of a priori information in genome‐wide association analysis
No full textGenome-wide association studies (GWAS) continue to gain in popularity To utilize the wealth of data created more effectively, a variety of methods have recently been proposed to include a priori information (e.g., biologically interpretable sets of genes, candidate gene information, or gene expression) in GWAS analysis. Six contributions to Genetic Analysis Workshop 16 Group 11 applied novel or recently proposed methods to GWAS of rheumatoid arthritis and heart disease related phenotypes. The results of these analyses were a variety of novel candidate genes and sets of genes, in addition to the validation of well-known genotype-phenotype associations. However, because many methods are relatively new, they would benefit from further methodological research to ensure that they maintain type I error rates while increasing power to find additional associations. When methods have been adapted from other study types (e.g., gene expression data analysis or linkage analysis), the lessons learned there should be used to guide implementation of techniques. Lastly, many open research questions exist concerning the logistic details of the origin of the a priori information and the way to incorporate it. Overall, our group has demonstrated a strong potential for identifying novel genotype-phenotype relationships by including a priori data in the analysis of GWAS, while also uncovering a series of questions requiring further research
Indigenous Peoples and Litigation:Strategies for Legal Empowerment
No full textAcross the globe indigenous peoples are increasingly using litigation to seek remedies for violation of their fundamental human rights. The rise of litigation is to be placed in the larger issue of increased land grabbing, natural resources exploitation and the general lack of recognition of their rights at the national level. This lack of legal rights is usually coupled with a lack of political will to address the issues faced by indigenous peoples, often leading to serious human rights violations, leaving indigenous advocates with few options but to turn to courts as a last resort to seek remedies. This article examines some of the issues faced by indigenous peoples and their advocates when engaging in human rights litigation. The goal is to offer a practice-based reflection on the encounter between courts and indigenous peoples with a specific focus on analysing strategies to ensure their legal empowerment. This is particularly important knowing the technicality, externalities and complexities of the process of litigation, and the fact that many decisions do not get implemented. In this context this article explores how the process of litigation in itself can support legal empowerment and the wider fight for justice. © 2020, The Author(s). The attached document (embargoed until 10/10/2022) is an author produced version of a paper published in JOURNAL OF HUMAN RIGHTS PRACTICE uploaded in accordance with the publisher’s self-archiving policy. The final published version (version of record) is available online at the link. Some minor differences between this version and the final published version may remain. We suggest you refer to the final published version should you wish to cite from it.<br/
Response to the comment on: "Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): A post-hoc analysis of the AWARD-2, -4 and -5 trials"
No full textTo the Editor
The paper by Jones et al. in which they studied the response of a
cohort of 19 patients with adult-onset diabetes who were glutamic
acid decarboxylase autoantibodies (GADA) positive, most with very
low levels of C peptide and multiple autoantibodies, is consistent with
published results studying GLP-1 agonists in patients with established
type 1 diabetes who show little by way of a beneficial response.1,2
Importantly, they note that those with GADA, who were not on insulin
therapy from diagnosis, had a similar response to a GLP-1 agonist
to those who were GADA negative and by implication had type 2 diabetes.
This point is important as the implication is that patients with
GADA, the usual diabetes-associated autoantibodies screening test in
adults, could benefit from GLP-1 agonists as long as they have limited
insulin deficiency, that is, as long as they are not on multiple
insulin injections. By inference, GLP-1 agonists are a reasonable
option in the management of adult-onset autoimmune diabetes
patients who are not on multiple insulin therapy.
Jones and McDonald have misread the assay specificity of our
GADA assay; their assay specificity is 97.5% and ours, based on the
international workshop (DASP), is 99%; therefore, our assay is more
specific than theirs.3 In addition, the positive predictive value of an
assay increases as the population under test is enriched, as with the
adult-onset diabetes cases we studied.4 We found a rate of GADA
positive cases in our cohort (7.6%, 188 GADA+ out of 2466 patients)
comparable to the rate they found with their assay, despite theirs having
only a slightly lower assay specificity: “Eight percent of insulintreated
participants” compared with a lower rate and longer disease
duration at “0.9% of non–insulin-treated participants.”1
Finally, the high titre cut-off is arbitrary in this cohort in order to
make it comparable with other studies in which it was not arbitrary.
Those previous studies used inflections in the Quartile-Quartile plot
to define a second population with a high GADA titre different from
those with a lower GADA titre.
We accept that our study has limitations, despite it comprising
tenfold the number of cases than their analysis. In addition, this is the
first study of a once-weekly as compared to a once-daily GLP-1 agonist
regime, which could be relevant to differences in responses. Large case-controlled cases are awaited, but the data we presented on our
large cohort is compelling, while the combined results from their study
and the study by Jones et al. indicate that GLP-1 agonists are likely to
have a limited role in patients with severe insulin deficiency and frank
clinical type 1 diabetes
Disease Progression in Mild Dementia due to Alzheimer Disease in an 18-Month Observational Study (GERAS): The Impact on Costs and Caregiver Outcomes
No full textBackground/Aims: We assessed whether cognitive and functional decline in community-dwelling patients with mild Alzheimer disease (AD) dementia were associated with increased societal costs and caregiver burden and time outcomes. Methods: Cognitive decline was defined as a ≥3-point reduction in the Mini-Mental State Examination and functional decline as a decrease in the ability to perform one or more basic items of the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) or ≥20% of instrumental ADL items. Total societal costs were estimated from resource use and caregiver hours using 2010 costs. Caregiver burden was assessed using the Zarit Burden Interview (ZBI); caregiver supervision and total hours were collected. Results: Of 566 patients with mild AD enrolled in the GERAS study, 494 were suitable for the current analysis. Mean monthly total societal costs were greater for patients showing functional (+61%) or cognitive decline (+27%) compared with those without decline. In relation to a typical mean monthly cost of approximately EUR 1,400 at baseline, this translated into increases over 18 months to EUR 2,254 and 1,778 for patients with functional and cognitive decline, respectively. The number of patients requiring supervision doubled among patients showing functional or cognitive decline compared with those not showing decline, while caregiver total time increased by 70 and 33%, respectively and ZBI total score by 5.3 and 3.4 points, respectively. Conclusion: Cognitive and, more notably, functional decline were associated with increases in costs and caregiver outcomes in patients with mild AD dementia
Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): A post-hoc analysis of the AWARD-2, -4 and -5 Trials
No full textAIMS:
Patients with a type-2-diabetes (T2D) phenotype positive for glutamic acid decarboxylase antibodies (GADA) represent the majority of cases of latent autoimmune diabetes of the adult (LADA). The GLP-1 receptor agonist dulaglutide, recently introduced for treatment of T2D, has yet to be evaluated in LADA patients. Our primary objective was to evaluate the effect of dulaglutide on glycaemic control (HbA1c) in GADA-positive LADA vs GADA-negative T2D patients.
METHODS:
A post-hoc analysis was performed using data from 3 randomized phase 3 trials (AWARD-2,-4,-5; patients with GADA assessment) which were part of the dulaglutide clinical development programme in T2D. LADA patients were identified by GADA ≥5 IU/mL (ELISA). Changes in HbA1c during 12 months of treatment with dulaglutide or comparator were analysed using mixed-effect model repeated measures.
RESULTS:
Of 2466 adults tested for GADA (dulaglutide, 1710; glargine, 298; sitagliptin, 294; placebo, 164), 2278 (92.4%) were GADA-negative and 188 (7.6%) were GADA-positive, including 58 GADA-high patients (> 200 IU/mL) and 130 GADA-low patients (≤200 and ≥5 IU/mL). Overall, baseline parameters were comparable between the groups. Dulaglutide resulted in comparable HbA1c reductions in GADA-negative (LS mean change [95%CI], -1.09% [-1.15, -1.03]) and GADA-positive patients (-0.94% [-1.15, -0.72]) at 12 months. HbA1c reductions were numerically, but not statistically, significantly larger in GADA-low patients (-1.02% [-1.26, -0.78]) vs GADA-high patients (-0.72% [-1.21,-0.24]) at 12 months. Similar outcomes were observed at 3 and 6 months.
CONCLUSIONS:
These data are the first to indicate that dulaglutide was effective in reducing HbA1c in LADA patients
How useful is the EQ-5D in assessing the impact of caring for people with Alzheimer's disease?
No full textBACKGROUND: The impact on informal caregivers of caring for people with Alzheimer's disease (AD) dementia can be substantial, but it remains unclear which measures(s) best assess such impact. Our objective was to use data from the GERAS study to assess the ability of the EuroQol 5-dimension questionnaire (EQ-5D) to measure the impact on caregivers of caring for people with AD dementia and to examine correlations between EQ-5D and caregiver burden. METHODS: GERAS was a prospective, non-interventional cohort study in community-dwelling patients with AD dementia and their informal caregivers. The EQ-5D and Zarit Burden Interview (ZBI) were used to measure health-related quality of life and caregiver burden, respectively. Resource-use data collected included caregiver time spent with the patient on activities of daily living (ADL). Spearman correlations were computed between EQ-5D scores, ZBI scores, and time spent on instrumental ADL (T-IADL) at baseline, 18 months, and for 18-month change scores. T-IADL and ZBI change scores were summarized by EQ-5D domain change category (better/stable/worse). RESULTS: At baseline, 1495 caregivers had mean EQ-5D index scores of 0.86, 0.85, and 0.82, and ZBI total scores of 24.6, 29.4, and 34.1 for patients with mild, moderate, and moderately severe/severe AD dementia, respectively. Change in T-IADL showed a stronger correlation with change in ZBI (0.12; P < 0.001) than with change in EQ-5D index score (0.02; P = 0.546) although both correlations were very weak. Worsening within EQ-5D domains was associated with increases in ZBI scores, although 68%-90% of caregivers remained stable within each EQ-5D domain. There was no clear pattern for change in T-IADL by change in EQ-5D domain. CONCLUSIONS: EQ-5D may not be the optimum measure of the impact of caring for people with AD dementia due to its focus on physical health. Alternative measures need further investigation
3-D geological and petrophysical models with synthetic geophysics based on data from the Hamersley region (Western Australia)
No full text3-D geological and petrophysical models with synthetic geophysics based on data from the Hamersley region (Western Australia)
M. Jessell 1,2, J. Giraud 1,2, M. Lindsay 1,2
1 Centre for Exploration Targeting (School of Earth Sciences), University of Western Australia, 35 Stirling Highway, 6009 Crawley, Australia
2 Mineral Exploration Cooperative Research Centre, School of Earth Sciences, University of Western Australia, 35 Stirling Highway, WA Crawley 6009, Australia
Contact author: Jeremie Giraud ([email protected])
Companion dataset to the paper:
Structural, petrophysical and geological constraints in potential field inversion using the Tomofast-x open-source code, J. Giraud, V. Ogarko, R. Martin, M. Lindsay, M. Jessell, Geoscientific Model Development Discussions.
This dataset contains models and data shown in the paper, in both 2D and 3D:
1. Geological model
Reference lithology voxet:
The reference geological model was obtained using public data from the Geological Survey of Western Australia and modified subsequently (stretched vertically and flattened at surface level) for the purpose of this study.
Probability voxet
The lithology probability voxet was derived using Monte Carlo simulations for uncertainty estimation as mentioned in the paper.
2. True and inverted models for density and magnetic susceptibility
Derivation is detailed in the paper; it uses fictitious density and magnetic susceptibility values.
3. Bouguer and total magnetic field anomaly
Calculation is detailed in the paper.
The authors are supported, in part, by Loop – Enabling Stochastic 3D Geological Modelling (LP170100985) and the Mineral Exploration Cooperative Research Centre (MinEx CRC) whose activities are funded by the Australian Government's Cooperative Research Centre Program. This is MinEx CRC Document 2021/3. Mark Lindsay acknowledges funding from the ARC and DECRA DE190100431.
It is a companion dataset to:
Vitaliy Ogarko, Jeremie Giraud, & Roland. (2021, February 5). Tomofast-x v1.0 source code (Version 1.0). Zenodo. http://doi.org/10.5281/zenodo.445262
A parametric study of vestibular stimulation during centrifugation
No full textThesis (S.M.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 2006.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections."February 2006."Includes bibliographical references (p. 155-160).Artificial Gravity (AG) provided by short-radius centrifugation is a promising countermeasure to the health problems associated with long duration human spaceflight. Head-turns performed during centrifugation, however, trigger a disturbing vestibular response that is only qualitatively understood. In order to design an efficient incremental adaptation procedure, the present study investigates the quantitative aspect of the vestibular side effects associated with AG, in particular, the relationship among crosscoupled stimulation, vestibular response, and adaptation. We tested 20 young adults with supine right-quadrant yaw head-turns performed in a dark environment during short-radius centrifugation. We studied the changes in vestibular response and adaptation to head-turns at different levels of cross-coupled stimulation. Nine combinations of head-turn angle (20°, 40° or 80°) with centrifugevelocity (12, 19 or 30 rpm) were tested over two consecutive days.(cont.) There were four key findings: 1. All measures, except the slow-phase velocity (SPV) peak amplitude of the vestibulo-ocular reflex, decrease significantly between the two experimental days, which demonstrates that significant adaptation is achieved. 2. Large head-angles lead to longer vertical vestibulo-ocular reflex time-constants than smaller angles do, but do not lead to greater adaptation. 3. In the nose-up position, the perceived body-tilt is highly correlated with the true tilt of the gravito-inertial force at mid-chest level. 4. The SPV-peak amplitude and all subjective ratings except body-tilt show significant correlation with the intensity of the cross-coupled stimulus (CCS): the larger the CCS, the stronger the vestibular response.by Jeremie M. Pouly.S.M
Dealing with Heterogeneity between Cohorts in Genomewide SNP Association Studies
No full textIn Genomewide association (GWA) studies investigating thousands of SNPs, large sample sizes are needed to obtain a reasonable power after correction for multiple testing. To obtain the necessary sample sizes, data from different populations/cohorts are combined. The problem of pooling evidence across cohorts bears some resemblance with meta-analysis of clinical trials, and in fact classical meta-analytic methodologies from that field are typically used in GWAs. However, in genetics, it can be expected that the cohorts show some amount of heterogeneity in the association measures that are used for significance testing. In this paper, we demonstrate how it is possible to exploit this heterogeneity to improve our ability to detect influential genetic variants. We also discuss how pathway analysis based on summary data can help resolve heterogeneity. The current standard method for testing SNPs across cohorts in GWAs will miss heterogeneous but important genetic variants affecting complex diseases. Our new testing strategy has the potential to detect them while maintaining sensitivity to variants with homogeneous effects.
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