| 1. |
- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Ekker, Merel, et al.
(author)
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Global Outcome Assessment Life-long after stroke in young adults initiative-the GOAL initiative: study protocol and rationale of a multicentre retrospective individual patient data meta-analysis.
- 2019
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In: BMJ open. - : BMJ. - 2044-6055. ; 9:11
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Journal article (peer-reviewed)abstract
- Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients.The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence.Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.
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| 3. |
- Moy, Linda, et al.
(author)
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Improving specificity of breast MRI using prone PET and fused MRI and PET 3D volume datasets
- 2007
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In: Journal of Nuclear Medicine. - Reston, Virginia, USA : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667. ; 48:4, s. 528-537
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Journal article (peer-reviewed)abstract
- MRI is a sensitive method for detecting invasive breast cancer, but it lacks specificity. To examine the effect of combining PET with MRI on breast lesion characterization, a prototype positioning device was fabricated to allow PET scans to be acquired in the same position as MRI scans-that is, prone. Methods: To test the hypothesis that fusion of 18F-FDG PET and MRI scans improves detection of breast cancer, 23 patients with suspected recurrent or new breast cancer underwent a routine whole-body PET scan, a prone PET scan of the chest, and a routine breast MRJ scan. The attenuation-corrected prone PET and MRI clatasets were registered twice by different operators. The fusion results were judged for quality by visual inspection and statistical analysis. A joint reading of the MRI and PET scans side by side and integrated images was performed by a nuclear medicine physician and a radiologist. Sensitivity and specificity of MRI and combined MRI and PET scans were calculated on the basis of pathology reports or at least 1 y of clinical and radiologic follow-up. Results: All fusions were verified to be well matched using specific anatomic criteria. A total of 45 lesions was assessed. Lesion size range was 0.6 to 10.0 cm. Of the 44 breasts examined, 29 were suspicious for cancer, of which 15 were found to be positive on surgical excision. In lesion-by-lesion analysis, sensitivity and specificity of MRI alone were 92% and 52%, respectively; after MRI and PETfusion, they were 63% and 95%, respectively. The positive predictive value and the negative predictive value for MRI alone were 69% and 85%, respectively; after MRI and PET fusion, they were 94% and 69%, respectively. Conclusion: Acquisition of prone PET scans using the new positioning device permitted acquisition of prone scans suitable for fusion with breast MRI scans. Fused PET and MRI scans increased the specificity of MRI but decreased the sensitivity in this small group of patients. Additional data are needed to confirm the statistical significance of these preliminary findings.
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