33 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
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
A High-resolution depth model for the North West Shelf and Outer Browse Basin (20210025C)
No full textMaintenance and Update Frequency: asNeededStatement: This dataset was produced using Python 2.7 and ArcGIS 10.5
The vertical datum is MSL while the horizontal datum is WGS84 UTM-50S.
For additional metadata questions, please download the Metadata.txt file and the lineage shapefile located with the dataset.
Processing methodology:
The detailed methodology is presented in the journal article located with the dataset<b>Purpose</b><br/>Client RequestThis resource contains a bathymetry compilation prepared by the University of Western Australia for the North West Shelf of Australia, between the Cape Range and the Dampier Peninsula. <br/><br/>The compilation includes, by decreasing resolution:<br/>- Publicly available MBES datasets, made available by Geoscience Australia by December 2019.<br/>- Satellite derived bathymetry produced using 1000+ images acquired between January 2017 and December 2019.<br/>- Seismic derived bathymetry extracted from 100+ surveys acquired between 1981 and 2015.<br/>- SRTM topography, reprocessed by Galant et al, 2011: https://pid.geoscience.gov.au/dataset/ga/72759<br/>- 2009 Australian Bathymetry and Topography grid: https://pid.geoscience.gov.au/dataset/ga/67703<br/><br/>The Seismic and Satellite derived bathymetry grids are also available as individual layers.<br/><br/>The vertical and spatial accuracy of the datasets have been thoroughly assessed using high-resolution datasets including publicly available MBES and LADS surveys. The assessment indicates that the seismic derived bathymetry has a depth accuracy better than 1 m + 2% of the absolute water depths while the satellites derived bathymetry has a depth accuracy better than 1 m + 5% of the absolute water depths. <br/><br/>A detailed methodology is provided in: Lebrec et al, 2021. Towards a regional high-resolution bathymetry of the North West Shelf of Australia based on Sentinel-2 satellite images, 3D seismic surveys and historical datasets. (https://doi.org/10.5194/essd-13-5191-2021)<br/><br/>This dataset is published with the permission of the CEO, Geoscience Australia.<br/><br/>AUTHOR’S NOTICE: <br/>This dataset should not be used, under any circumstances, for navigation.<br/>When used, the dataset should be referenced as follow:<br/>Lebrec, U., Paumard, V., O'Leary, M. J., and Lang, S. C.: Towards a regional high-resolution bathymetry of the North West Shelf of Australia based on Sentinel-2 satellite images, 3D seismic surveys and historical datasets, Earth Syst. Sci. Data Discuss. [preprint], https://doi.org/10.5194/essd-2021-128, in review, 2021
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
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.
GLP-1 RA Treatment and Dosing Patterns Among Type 2 Diabetes Patients in Six Countries: A Retrospective Analysis of Pharmacy Claims Data
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Treatment persistence in patients with type 2 diabetes treated with glucagon‐like peptide‐1 receptor agonists in clinical practice in Sweden
No full text- To compare treatment persistence in patients with type 2 diabetes mellitus initiating the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) dulaglutide, exenatide once-weekly (QW), liraglutide, or lixisenatide in routine clinical practice in Sweden and assess clinical outcomes.We performed a retrospective study using data from several nationwide Swedish health registries, including the National Diabetes Register and other mandatory and population-based registries. Individual level data were collected from 17,361 patients who initiated GLP-1 RA treatment between the 23 May 2015 and the 15 Oct 2017, up to 2.5years post-index (treatment start date). Treatment persistence and modification, predictors of discontinuation, glycated hemoglobin A1c (HbA1c), and body weight were recorded. Non-persistence was defined as a treatment gap of >45days. Treatment modification included switching and augmentation. Confounding was addressed through the use of propensity scores.Treatment persistence was higher and treatment modifications were lower in patients initiating dulaglutide, compared with those on exenatide QW, liraglutide, and lixisenatide. Patients who remained on the same treatment for 1-year post-index experienced greater HbA1c reductions and a steadier decrease in body weight, compared with those who switched treatment.Our study suggests that in clinical practice in Sweden, there is a greater persistence of treatment among patients initiating dulaglutide, compared with those on exenatide QW, liraglutide, and lixisenatide. Persistence with the index GLP-1 RA was closely correlated with positive clinical outcomes and should thus be considered a critical factor of patient-centric treatment in Sweden. This article is protected by copyright. All rights reserved
