ORCID Profile
0000-0002-7725-7520
Current Organisations
Health Data Research UK
,
NHS Lothian
,
The University of Edinburgh
,
UK Biobank
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Publisher: Springer Science and Business Media LLC
Date: 30-11-2011
Publisher: SAGE Publications
Date: 27-07-2016
Abstract: The Mindful Attention Awareness Scale was developed to measure in idual differences in the tendency to be mindful. The current study examined the psychometric properties of the Mindful Attention Awareness Scale in a heterogeneous s le of 565 nonmeditators and 612 meditators using the polytomous Rasch model. The results showed that some items did not function the same way for these two groups. Overall, meditators had higher mean estimates than nonmeditators. The analysis identified a group of items as highly discriminating. Using a different model, Van Dam, Earleywine, and Borders in 2010 identified the same group of items as highly discriminating, and concluded that they were the items with the most information. Multiple pieces of evidence from the Rasch analysis showed that these items discriminate highly because of local dependence, hence do not supply independent information. We discussed how these different conclusions, based on similar findings, result from two very different paradigms in measurement.
Publisher: Royal College of Psychiatrists
Date: 03-04-2018
DOI: 10.1192/BJO.2018.12
Abstract: UK Biobank is a well-characterised cohort of over 500 000 participants that offers unique opportunities to investigate multiple diseases and risk factors. An online mental health questionnaire completed by UK Biobank participants was expected to expand the potential for research into mental disorders. An expert working group designed the questionnaire, using established measures where possible, and consulting with a patient group regarding acceptability. Case definitions were defined using operational criteria for lifetime depression, mania, anxiety disorder, psychotic-like experiences and self-harm, as well as current post-traumatic stress and alcohol use disorders. 157 366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status than the general population across a range of indicators. Thirty-five per cent (55 750) of participants had at least one defined syndrome, of which lifetime depression was the most common at 24% (37 434). There was extensive comorbidity among the syndromes. Mental disorders were associated with high neuroticism score, adverse life events and long-term illness addiction and bipolar affective disorder in particular were associated with measures of deprivation. The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed owing to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health. G.B. received grants from the National Institute for Health Research during the study and support from Illumina Ltd. and the European Commission outside the submitted work. B.C. received grants from the Scottish Executive Chief Scientist Office and from The Dr Mortimer and Theresa Sackler Foundation during the study. C.S. received grants from the Medical Research Council and Wellcome Trust during the study, and is the Chief Scientist for UK Biobank. M.H. received grants from the Innovative Medicines Initiative via the RADAR-CNS programme and personal fees as an expert witness outside the submitted work.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-01-2019
DOI: 10.1212/WNL.0000000000006851
Abstract: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 −8 and LINC00539/ZDHHC20, p = 5.82 × 10 −9 . Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up s le or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 −25 p [SSBI] = 5.23 × 10 −14 for hypertension), smoking ( p [BI] = 4.4 × 10 −10 p [SSBI] = 1.2 × 10 −4 ), diabetes ( p [BI] = 1.7 × 10 −8 p [SSBI] = 2.8 × 10 −3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 −18 p [SSBI] = 2.3 × 10 −7 ), stroke ( p [BI] = 3.9 × 10 −69 p [SSBI] = 3.2 × 10 −24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 −157 p [SSBI] = 3.16 × 10 −106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ≤ 0.0022), without indication of directional pleiotropy. In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2013
DOI: 10.1161/STROKEAHA.113.679936
Abstract: Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free in iduals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 ( P =0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.
Publisher: Wiley
Date: 2013
DOI: 10.1002/ANA.23838
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-07-2014
Publisher: Public Library of Science (PLoS)
Date: 22-05-2015
Publisher: Elsevier BV
Date: 04-2016
Publisher: Springer Science and Business Media LLC
Date: 05-03-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-03-2016
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.IJCARD.2015.03.075
Abstract: Electronic health records (EHRs) offer the opportunity to ascertain clinical outcomes at large scale and low cost, thus facilitating cohort studies, quality of care research and clinical trials. For acute myocardial infarction (AMI) the extent to which different EHR sources are accessible and accurate remains uncertain. Using MEDLINE and EMBASE we identified thirty three studies, reporting a total of 128658 patients, published between January 2000 and July 2014 that permitted assessment of the validity of AMI diagnosis drawn from EHR sources against a reference such as manual chart review. In contrast to clinical practice, only one study used EHR-derived markers of myocardial necrosis to identify possible AMI cases, none used electrocardiogram findings and one used symptoms in the form of free text combined with coded diagnosis. The remaining studies relied mostly on coded diagnosis. Thirty one studies reported positive predictive value (PPV)≥ 70% between AMI diagnosis from both secondary care and primary care EHRs and the reference. Among fifteen studies reporting EHR-derived AMI phenotypes, three cross-referenced ST-segment elevation AMI diagnosis (PPV range 71-100%), two non-ST-segment elevation AMI (PPV 91.0, 92.1%), three non-fatal AMI (PPV range 82-92.2%) and six fatal AMI (PPV range 64-91.7%). Clinical coding of EHR-derived AMI diagnosis in primary care and secondary care was found to be accurate in different clinical settings and for different phenotypes. However, markers of myocardial necrosis, ECG and symptoms, the cornerstones of a clinical diagnosis, are underutilised and remain a challenge to retrieve from EHRs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/STROKEAHA.114.007362
Abstract: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. The distribution of pathogenic categories varied by study, age, sex, and race ( P .001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72 95% confidence interval, 0.69–0.75) and phenotypic classifications (κ 0.73 95% confidence interval, 0.70–0.75). This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2009
DOI: 10.1161/STROKEAHA.108.526996
Abstract: Background and Purpose— If the diagnostic and prognostic significance of brain microbleeds (BMBs) are to be investigated and used for these purposes in clinical practice, observer variation in BMB assessment must be minimized. Methods— Two doctors used a pilot rating scale to describe the number and distribution of BMBs (round, low-signal lesions, mm diameter on gradient echo MRI) among 264 adults with stroke or TIA. They were blinded to clinical data and their counterpart’s ratings. Disagreements were adjudicated by a third observer, who informed the development of a new Brain Observer MicroBleed Scale (BOMBS), which was tested in a separate cohort of 156 adults with stroke. Results— In the pilot study, agreement about the presence of ≥1 BMB in any location was moderate (κ=0.44 95% CI, 0.32–0.56), but agreement was worse in lobar locations (κ=0.44 95% CI, 0.30–0.58) than in deep (κ=0.62 95% CI, 0.48–0.76) or posterior fossa locations (κ=0.66 95% CI, 0.47–0.84). Using BOMBS, agreement about the presence of ≥1 BMB improved in any location (κ=0.68 95% CI, 0.49–0.86) and in lobar locations (κ=0.78 95% CI, 0.60–0.97). Conclusion— Interrater reliability concerning the presence of BMBs was moderate to good, and could be improved with the use of the BOMBS rating scale, which takes into account the main sources of interrater disagreement identified by our pilot scale.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2014
DOI: 10.1161/STROKEAHA.113.002707
Abstract: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance ( P .01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 in iduals with the ischemic large artery stroke (LAS) subtype. Common variants associated with CAD at P .01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance ( P ×10 −8 ) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 ( P IS =1.62×10 −7 ) and ABO ( P IS =2.6×10 −4 ), as well as at HDAC9 ( P LAS =2.32×10 −12 ), 9p21 ( P LAS =3.70×10 −6 ), RAI1-PEMT-RASD1 ( P LAS =2.69×10 −5 ), EDNRA ( P LAS =7.29×10 −4 ), and CYP17A1-CNNM2-NT5C2 ( P LAS =4.9×10 −4 ). Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2000
Abstract: Background and Purpose —Aspirin is the most widely studied and prescribed antiplatelet drug for patients at high risk of vascular disease. We aimed to establish how the thienopyridines (ticlopidine and clopidogrel) compare with aspirin in terms of effectiveness and safety. Methods —We did a systematic review of all unconfounded randomized trials comparing either ticlopidine or clopidogrel with aspirin for patients at high risk of vascular disease. The primary outcome was vascular events (stroke, myocardial infarction, or vascular death). Adverse outcomes were intracranial and extracranial hemorrhage, upper and lower gastrointestinal disturbances, neutropenia, thrombocytopenia, and skin rash. Results —In 4 trials among 22 656 patients (including 9840 presenting with a transient ischemic attack/ischemic stroke), the thienopyridines reduced the odds of a vascular event by 9% (odds ratio 0.91, 95% CI 0.84 to 0.98 2 P =0.01), preventing 11 (95% CI 2 to 19) events per 1000 patients treated for ≈2 years. The thienopyridines produced significantly less gastrointestinal hemorrhage and upper gastrointestinal upset (indigestion/nausea/vomiting) than did aspirin. Both thienopyridines increased the odds of skin rash and of diarrhea (ticlopidine by ≈2-fold and clopidogrel by approximately one third). Only ticlopidine increased the odds of neutropenia. Conclusions —The thienopyridines appear modestly more effective than aspirin in preventing serious vascular events in high-risk patients. Clopidogrel appears to be safer than ticlopidine and as safe as aspirin, making it an appropriate, but more expensive, alternative antiplatelet drug for patients unable to tolerate aspirin. However, there is insufficient information to determine which particular types of patients would benefit most, and which least, from clopidogrel instead of aspirin.
Publisher: American Medical Association (AMA)
Date: 04-2019
Publisher: Springer Science and Business Media LLC
Date: 28-08-2015
DOI: 10.1038/EYE.2015.157
Publisher: Wiley
Date: 07-10-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-09-2014
Publisher: Springer Science and Business Media LLC
Date: 03-12-2018
DOI: 10.1038/S41467-018-07340-5
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 in iduals for cIMT, and 48,434 in iduals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4 . LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/STROKEAHA.114.006609
Abstract: Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes. Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73 998), eGFR using cystatin C (eGFRcys: n=22 937), and urinary albumin to creatinine ratio (n=31 580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease. Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P .05 (peak P =0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P =0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio–based score also associated with small vessel disease ( P =0.03). The global pattern of results was unlikely to have occurred by chance ( P =0.02). This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2010
DOI: 10.1161/STROKEAHA.109.572594
Abstract: Background and Purpose— Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA). Methods— We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH (2) antithrombotic users vs nonusers with IS/TIA and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB. Results— In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio range, 2.3–3.5) in nonantithrombotic users to 5.7 (range, 3.4–9.7) in antiplatelet users and 8.0 (range, 3.5–17.8) in warfarin users ( P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7 95% CI, 1.6–4.4 P .001) but none in warfarin users with IS/TIA (OR, 1.3 95% CI, 0.9–1.7 P =0.33 P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7 95% CI, 1.3–2.3 P .001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4 95% CI, 1.2–1.7 P .001 P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1 95% CI, 3.4–42.5 P .001). Conclusions— The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.
Publisher: Royal College of Psychiatrists
Date: 15-08-2018
DOI: 10.1192/BJO.2018.47
Publisher: BMJ
Date: 02-2019
DOI: 10.1136/BMJOPEN-2018-025077
Abstract: To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank. UK Biobank is a large, multisite, prospective cohort study. Extensive lifestyle and health questionnaires, a range of physical measures and collection of biological specimens are collected. The scope of UK Biobank was extended midway through data collection to include assessments of other measures of health, including eyes and vision. The eye assessment at baseline included questionnaires detailing past ophthalmic and family history, measurement of visual acuity, refractive error and keratometry, intraocular pressure (IOP), corneal biomechanics, spectral domain optical coherence tomography (OCT) of the macula and a disc–macula fundus photograph. Since recruitment, UK Biobank has collected accelerometer data and begun multimodal imaging data (including brain, heart and abdominal MRI) in 100 000 participants. Dense genotypic data and a panel of 20 biochemistry measures are available, and linkage to medical health records for the full cohort has begun. A total of 502 665 people aged between 40 and 69 were recruited to participate in UK Biobank. Of these, 117 175 took part in baseline assessment of vision, IOP, refraction and keratometry. A subgroup of 67 321 underwent OCT and retinal photography. The introduction of eye and vision measures in UK Biobank was accompanied by intensive training, support and a data monitoring quality control process. UK Biobank is one of the largest prospective cohorts worldwide with extensive data on ophthalmic diseases and conditions. Data collection is an ongoing process and a repeat of the baseline assessment including the questionnaires, measurements and s le collection will be performed in subsets of 25 000 participants every 2–3 years. The depth and breadth of this dataset, coupled with its open-access policy, will create a powerful resource for all researchers to investigate the eye diseases in later life.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
DOI: 10.1161/STROKEAHA.113.001857
Abstract: Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10 296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14 549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research–generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
Publisher: Public Library of Science (PLoS)
Date: 11-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
DOI: 10.1161/STROKEAHA.113.002186
Abstract: Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 in iduals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 ( P =1.4×10 −8 ). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02 95% CI, 0.97–1.07 P =0.52) or its subtypes: cardioembolic (odds ratio, 1.07 95% CI, 0.97–1.16 P =0.17), large vessel disease (odds ratio, 0.98 95% CI, 0.89–1.07 P =0.60), and small vessel disease (odds ratio, 1.07 95% CI, 0.97–1.17 P =0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants ( P =0.18). We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2019
DOI: 10.1101/19001214
Abstract: This paper corrects and updates a paper published in BJPsych Open 2018 “Mental Health in UK Biobank” ( 0.1192/bjo.2018.12 ) that was voluntarily retracted following the finding of errors in the coding of the variable for alcohol use disorder. Notably, the percentage of participants reaching threshold for alcohol use disorder on the Alcohol Use Disorder Identification Tool increased from 7% to 21%. UK Biobank is a well-characterised cohort of over 500,000 participants that offers unique opportunities to investigate multiple diseases and risk factors. An online mental health questionnaire completed by UK Biobank participants expands the potential for research into mental disorders. An expert working group designed the questionnaire, using established measures where possible, and consulting with a service user group regarding acceptability. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and alcohol use disorders. 157,366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was the most common finding in 24% of participants (37,434), with current alcohol use disorder criteria met by 21% (32,602), while other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness addiction and bipolar affective disorder in particular were associated with measures of deprivation. The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed due to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2015
DOI: 10.1161/STROKEAHA.114.007930
Abstract: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has h ered gene discovery, motivating analyses of diagnostic subtypes with reduced s le sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, in idual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA–SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. High genetic correlation was identified between LAA and SVD using linear mixed models ( r g =0.96, SE=0.47, P =9×10 −4 ) and profile scores ( r g =0.72 95% confidence interval, 0.52–0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association ( P =1×10 −7 ) for single nucleotide polymorphisms near the opioid receptor μ1 ( OPRM1 ) gene. Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-12-2015
Publisher: Proceedings of the National Academy of Sciences
Date: 06-03-2017
Abstract: Common single-amino acid variations of proteins are traditionally regarded as functionally neutral polymorphisms because these substitutions are mostly located outside functionally relevant surfaces. In this study, we present an ex le of a functionally relevant coding sequence variation, which, as we show here, confers risk for large artery atherosclerotic stroke. The single-residue variation M1(A213V) in serpin family A member 1 ( SERPINA1 ) [encoding alpha-1 antitrypsin (AAT)] is situated outside the protease-reactive inhibitory loop and is found in a β-turn on the protein surface. We show that the Ala-to-Val exchange in the gate region of AAT alters its functional dynamics toward neutrophil elastase in the presence of complex lipid-containing plasma and also affects the overall structural flexibility of the protein.
Publisher: Wiley
Date: 30-03-2016
DOI: 10.1002/ANA.24621
Publisher: Springer Science and Business Media LLC
Date: 26-01-2016
DOI: 10.1038/MP.2015.225
Publisher: Elsevier BV
Date: 09-2010
Publisher: Elsevier BV
Date: 12-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2016
DOI: 10.1161/STROKEAHA.115.011328
Abstract: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset years. The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P ×10 −6 and performed in silico association analyses in an independent s le of ≤1003 cases and 7745 controls. One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all s les from the discovery and follow-up stages (rs11196288 odds ratio =1.41 P =9.5×10 −9 ). The associated locus is in an intergenic region between TCF7L2 and HABP2 . In a further analysis in an independent s le, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII–activating protease levels, a product of HABP2 . HABP2 , which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
Publisher: Wiley
Date: 19-10-2016
DOI: 10.1002/ANA.24780
Abstract: In observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein ( CETP ) gene activity increase plasma HDL‐C as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH. We performed 2 candidate‐gene analyses of CETP . First, we tested in idual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk. Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10 −4 ) with no heterogeneity across studies ( I 2 = 0%). This association was replicated in patients of European ancestry ( p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10 −6 ). Genetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016 :730–740
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.OPHTHA.2015.11.009
Abstract: To derive macular thickness measures and their associations by performing rapid, automated segmentation of spectral-domain optical coherence tomography (SD OCT) images collected and stored as part of the UK Biobank (UKBB) study. Large, multisite cohort study in the United Kingdom. Analysis of cross-sectional data. Adults from the United Kingdom aged 40 to 69 years. Participants had nonmydriatic SD OCT (Topcon 3D OCT-1000 Mark II Topcon GB, Newberry, Berkshire, UK) performed as part of the ocular assessment module. Rapid, remote, automated segmentation of the images was performed using custom optical coherence tomography (OCT) image analysis software (Topcon Advanced Boundary Segmentation [TABS] Topcon GB) to generate macular thickness values. We excluded people with a history of ocular or systemic disease (diabetes or neurodegenerative diseases) and eyes with reduced vision (<0.1 logarithm of the minimum angle of resolution) or with low SD OCT signal-to-noise ratio and low segmentation success certainty. Macular thickness values across 9 Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields. The SD OCT scans of 67 321 subjects were available for analysis, with 32 062 people with at least 1 eye meeting the inclusion criteria. There were 17 274 women and 14 788 men, with a mean (standard deviation [SD]) age of 55.2 (8.2) years. The mean (SD) logarithm of the minimum angle of resolution visual acuity was -0.075 (0.087), and the refractive error was -0.071 (+1.91) diopters (D). The mean (SD) central macular thickness (CMT) in the central 1-mm ETDRS subfield was 264.5 (22.9) μm, with 95% confidence limits of 220.8 and 311.5 μm. After adjusting for covariates, CMT was positively correlated with older age, female gender, greater myopia, smoking, body mass index (BMI), and white ethnicity (all P < 0.001). Of note, macular thickness in other subfields was negatively correlated with older age and greater myopia. We report macular thickness data derived from SD OCT images collected as part of the UKBB study and found novel associations among older age, ethnicity, BMI, smoking, and macular thickness.
Publisher: Springer Science and Business Media LLC
Date: 02-09-2012
DOI: 10.1038/NG.2397
Publisher: Public Library of Science (PLoS)
Date: 24-08-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2015
DOI: 10.1161/STROKEAHA.114.008540
Abstract: The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly. We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency .01 were included in the analysis. A significance level of P .0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method. We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association. Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease.
Publisher: Elsevier BV
Date: 07-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-05-2017
Abstract: Some investigators have reported an excess risk of venous thromboembolism ( VTE ) associated with depression and with use of antidepressant drugs. We explored these associations in a large prospective study of UK women. The Million Women Study recruited 1.3 million women through the National Health Service Breast Screening Programme in England and Scotland. Three years after recruitment, women were sent a second questionnaire that enquired about depression and regular use of medications in the previous 4 weeks. The present analysis included those who responded and did not have prior VTE , cancer, or recent surgery. Follow‐up for VTE was through linkage to routinely collected National Health Service statistics. Cox regression analyses yielded adjusted hazard ratios and 95% CI s. A total of 734 092 women (mean age 59.9 years) were included in the analysis 6.9% reported use of antidepressants, 2.7% reported use of other psychotropic drugs, and 1.8% reported being treated for depression or anxiety but not use of psychotropic drugs. During follow‐up for an average of 7.3 years , 3922 women were hospitalized for and/or died from VTE . Women who reported antidepressant use had a significantly higher risk of VTE than women who reported neither depression nor use of psychotropic drugs (hazard ratio, 1.39 95% CI , 1.23–1.56). VTE risk was not significantly increased in women who reported being treated for depression or anxiety but no use of antidepressants or other psychotropic drugs (hazard ratio, 1.19 95% CI, 0.95–1.49). Use of antidepressants is common in UK women and is associated with an increased risk of VTE .
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-05-2010
Abstract: Lombardi et al . (Reports, 23 October 2009, p. 585) reported an association between the human gammaretrovirus XMRV and chronic fatigue syndrome. However, their results may be misleading because of various potential sources of bias and confounding. If real, the association may lack generalizability because of the specific characteristics of the cases studied and could be due to reverse causality.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2014
DOI: 10.1161/STROKEAHA.113.002938
Abstract: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based s les and to establish its external validity in prospective population-based cohorts. Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication s le. The validation s le consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case–control s les and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had -fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based s les but not in the population-based studies, and there was no significant improvement in net reclassification. A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based s les and in the general population. However, the improvement in clinical risk prediction was found to be small.
Publisher: BMJ
Date: 02-03-2013
Abstract: Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic associations with CAA to better understand its pathogenesis. We comprehensively sought and critically appraised published studies of associations between any genetic polymorphism and histopathologically confirmed CAA. We assessed the effects of genotype by calculating study specific and pooled odds ratios (ORs) in meta-analyses, and assessed small study bias. 58 studies (6855 participants) investigated apolipoprotein E (APOE) genotype and sporadic CAA. Meta-analysis of 24 (3520 participants) of these showed an association of APOE ε4 with CAA (ε4 present vs absent, pooled OR 2.7, 95% CI 2.3 to 3.1, p<0.00001), which was dose dependent, robust to potential small study biases and occurred irrespective of dementia status. There was no significant association between APOE ε2 and CAA. Among 24 studies (4703 participants) of other genetic polymorphisms, there was preliminary evidence of an association with CAA of polymorphisms in the transforming growth factor β1 gene (two studies, 449 participants), translocase of outer mitochondrial membrane 40 gene (one study, 723 participants) and the complement component receptor 1 gene (one study, 544 participants). There were insufficient data to draw conclusions from 24 studies (∼200 participants) of APOE and hereditary CAA or familial Alzheimer's disease. There is convincing evidence for a dose dependent association between APOE ε4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA.
Publisher: Elsevier BV
Date: 05-2017
Publisher: American Medical Association (AMA)
Date: 12-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-12-2015
Publisher: Public Library of Science (PLoS)
Date: 10-09-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2015
DOI: 10.1161/STROKEAHA.115.009816
Abstract: Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups ided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. We found that genetic factors influence age at stroke onset ( h 2 [SE]=18.0 [6.8] P =0.0038), with a trend toward a stronger influence in women (women: h 2 [SE]=21.6 [3.5] Men: h 2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes ( rG [SE]=0.68 [0.16]) and between younger and older cases ( rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex ( P =0.037) and to younger or older groups ( P =0.056), particularly for women ( P =0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men ( P =0.084). Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-01-2019
DOI: 10.1212/WNL.0000000000006952
Abstract: To identify novel genetic associations with white matter hyperintensities (WMH). We performed a genome-wide association meta-analysis of WMH volumes in 11,226 in iduals, including 8,429 population-based in iduals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 in iduals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels. We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013] p = 1.6 × 10 −8 ), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent s le (overall p value, 2.4 × 10 −9 ). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03–1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00–1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020 β [SE] = 0.106 [0.016] p = 1.2 × 10 −11 and rs7596872 β [SE] = 0.143 [0.021] p = 3.4 × 10 −12 ). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability. Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.
Publisher: Springer Science and Business Media LLC
Date: 12-03-2018
Publisher: BMJ
Date: 22-11-2018
DOI: 10.1136/BMJ.K4577
Abstract: To determine prevalence and types of potentially serious incidental findings on magnetic resonance imaging (MRI) in apparently asymptomatic adults, describe factors associated with potentially serious incidental findings, and summarise information on follow-up and final diagnoses. Systematic review and meta-analyses. Citation searches of relevant articles and authors’ files in Medline and Embase (from inception to 25 April 2017). Eligible studies included prevalence and types of incidental findings detected among apparently asymptomatic adults undergoing MRI of the brain, thorax, abdomen, or brain and body. Data on study population and methods, prevalence and types of incidental findings, and final diagnoses were extracted. Pooled prevalence was estimated by random effects meta-analysis, and heterogeneity by τ 2 statistics. Prevalence of potentially serious incidental findings on MRI of the brain, thorax, abdomen, and brain and body. Of 5905 retrieved studies, 32 (0.5%) met the inclusion criteria (n=27 643 participants). Pooled prevalence of potentially serious incidental findings was 3.9% (95% confidence interval 0.4% to 27.1%) on brain and body MRI, 1.4% (1.0% to 2.1%) on brain MRI, 1.3% (0.2% to 8.1%) on thoracic MRI, and 1.9% (0.3% to 12.0%) on abdominal MRI. Pooled prevalence rose after including incidental findings of uncertain potential seriousness (12.8% (3.9% to 34.3%), 1.7% (1.1% to 2.6%), 3.0% (0.8% to 11.3%), and 4.5% (1.5% to 12.9%), respectively). There was generally substantial heterogeneity among included studies. About half the potentially serious incidental findings were suspected malignancies (brain, 0.6% (95% confidence interval 0.4% to 0.9%) thorax, 0.6% (0.1% to 3.1%) abdomen, 1.3% (0.2% to 9.3%) brain and body, 2.3% (0.3% to 15.4%)). There were few informative data on potential sources of between-study variation or factors associated with potentially serious incidental findings. Limited data suggested that relatively few potentially serious incidental findings had serious final diagnoses (48/234, 20.5%). A substantial proportion of apparently asymptomatic adults will have potentially serious incidental findings on MRI, but little is known of their health consequences. Systematic, long term follow-up studies are needed to better inform on these consequences and the implications for policies on feedback of potentially serious incidental findings. Prospero CRD42016029472.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2015
Publisher: John Wiley & Sons, Ltd
Date: 24-01-2000
Publisher: American Medical Association (AMA)
Date: 23-04-2014
Abstract: Whether conservative management is superior to interventional treatment for unruptured brain arteriovenous malformations (bAVMs) is uncertain because of the shortage of long-term comparative data. To compare the long-term outcomes of conservative management vs intervention for unruptured bAVM. Population-based inception cohort study of 204 residents of Scotland aged 16 years or older who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed up prospectively for 12 years. Conservative management (no intervention) vs intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination). Cox regression analyses, with multivariable adjustment for prognostic factors and baseline imbalances if hazards were proportional, to compare rates of the primary outcome (death or sustained morbidity of any cause by Oxford Handicap Scale [OHS] score ≥2 for ≥2 successive years [0 = no symptoms and 6 = death]) and the secondary outcome (nonfatal symptomatic stroke or death due to bAVM, associated arterial aneurysm, or intervention). Of 204 patients, 103 underwent intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median follow-up of 6.9 years (94% completeness), the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 vs 39 events 9.5 vs 9.8 per 100 person-years adjusted hazard ratio, 0.59 95% CI, 0.35-0.99), but rates were similar thereafter. The rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 vs 38 events 1.6 vs 3.3 per 100 person-years adjusted hazard ratio, 0.37 95% CI, 0.19-0.72). Among patients aged 16 years or older diagnosed as having unruptured bAVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. Longer follow-up is required to understand whether this association persists.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Springer Science and Business Media LLC
Date: 13-10-2201
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2017
DOI: 10.1212/WNL.0000000000004560
Abstract: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. We meta-analyzed genotype data from in iduals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes ( COL4A1 , COL4A2 , NOTCH3 , HTRA1 , TREX1 , and CECR1 ) with intracerebral hemorrhage (ICH) (deep, lobar, all 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. A locus in COL4A2 was associated (significance threshold p 3.5 × 10 −4 ) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 × 10 −8 ) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 × 10 −5 ). A SNP in HTRA1 was associated (significance threshold p 5.5 × 10 −4 ) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 × 10 −4 ) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype. These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-10-2022
DOI: 10.1212/WNL.0000000000201006
Abstract: Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18–59 years, using in idual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. We observed genome-wide significant associations of EOS with 2 variants in ABO , a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85–0.91) in EOS vs 0.96 (95% CI: 0.92–1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11–1.21) for EOS vs 1.05 (0.99–1.11) in LOS p -values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS ( p = 0.008). The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-01-0015
DOI: 10.1161/CIRCRESAHA.118.313533
Abstract: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P =1.70×10 −9 ). Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-10-2020
Abstract: Conventional epidemiology associates increased body mass index (BMI) with higher risk of CKD. Diabetes and high BP explain half of the association. However, residual confounding factors preclude causal inferences and impede mediation assessments. A genetic approach (Mendelian randomization) may overcome these limitations. Analyses of 281,228 genotyped UK Biobank participants identified positive independent genetic associations between central and general adiposity with CKD, suggesting both are causal risk factors. Conventional approaches underestimate the role of known mediators. Diabetes and BP (and correlates) explain % of genetic associations between waist-to-hip ratio and CKD and two-thirds between BMI and CKD. In people without diabetes, obesity appeared to cause CKD. BP accounted for about half of the BMI-CKD associations. The size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown. Data from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR). Evidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m 2 increase in BMI were associated with 69% (odds ratio, 1.69 95% CI, 1.64 to 1.74) and 58% (1.58 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06–genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29 1.20 to 1.38) increased odds of CKD, and each 5-kg/m 2 genetically-predicted higher BMI was associated with a 49% (1.49 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively. Genetic analyses suggest that conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP, and their correlates. Genetic approaches suggest these mediators explain most of adiposity-CKD–associated risk.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-12-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2023
DOI: 10.1161/STROKEAHA.122.040529
Abstract: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from in idual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9–17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4–14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10–1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05–1.32]), per unit increase log e IL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09–1.29] recurrent stroke RR, 1.12 [95% CI, 1.04–1.21], per unit increase log e hsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04–1.21] hsCRP, RR, 1.09 [95% CI, 1.04–1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00–1.19] hsCRP, RR, 1.05 [95% CI, 1.00–1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09–1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07–1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08–1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93–1.43]). Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.
Publisher: Wiley
Date: 02-04-2018
Publisher: SAGE Publications
Date: 05-2007
DOI: 10.1111/J.1747-4949.2007.00111.X
Abstract: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke, dementia and depression. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B 12 and vitamin B 6 , it is not known whether lowering tHcy, by means of B vitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. To determine whether the addition of B-vitamin supplements (folic acid 2 mg, B 6 25 mg, B 12 500 μg) to best medical and surgical management will reduce the combined incidence of stroke, myocardial infarction (MI) and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. A prospective, international, multicentre, randomised, double blind, placebo-controlled clinical trial. One hundred and four medical centres in 20 countries on five continents. Eight thousand (6600 recruited as of 5 January, 2006) patients with recent (7 months) stroke (ischaemic or haemorrhagic) or TIA (brain or eye). Randomisation and data collection are performed by means of a central telephone service or secure internet site. One tablet daily of either placebo or B vitamins (folic acid 2mg, B 6 25 mg, B 12 500 μg). The composite of stroke, MI or death from any vascular cause, whichever occurs first. Outcome and serious adverse events are adjudicated blinded to treatment allocation. TIA, unstable angina, revascularisation procedures, dementia, depression. With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8% among patients assigned placebo, the study will have at least 80% power to detect a relative reduction of 15% in the incidence of the primary outcome among patients assigned B vitamins (to 6·8%/year), applying a two-tailed level of significance of 5%. VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008, and provide a reliable estimate of the safety and effectiveness of folic acid, vitamin B 12 , and vitamin B 6 supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
DOI: 10.1161/CIRCOUTCOMES.108.808469
Abstract: Background— Statins reduce the rates of heart attacks, strokes, and revascularization procedures (ie, major vascular events) in a wide range of circumstances. Randomized controlled trial data from 20 536 adults have been used to estimate the cost-effectiveness of prescribing statin therapy in the United States for people at different levels of vascular disease risk and to explore whether wider use of generic statins beyond the populations currently recommended for treatment in clinical guidelines is indicated. Methods and Results— Randomized controlled trial data, an internally validated vascular disease model, and US costs of statin therapy and other medical care were used to project lifetime risks of vascular events and evaluate the cost-effectiveness of 40 mg simvastatin daily. For an average of 5 years, allocation to simvastatin reduced the estimated US costs of hospitalizations for vascular events by ≈20% (95% CI, 15 to 24) in the different subcategories of participants studied. At a daily cost of $1 for 40 mg generic simvastatin, the estimated costs of preventing a vascular death within the 5-year study period ranged from a net saving of $1300 (95% CI, $15 600 saving to $13 200 cost) among participants with a 42% 5-year major vascular event risk to a net cost of $216 500 ($123 700 to $460 000 cost) among those with a 12% 5-year risk. The costs per life year gained with lifetime simvastatin treatment ranged from $2500 (−$40 to $3820) in people aged 40 to 49 years with a 42% 5-year major vascular event risk to $10 990 ($9430 to $14 700) in people aged 70 years and older with a 12% 5-year risk. Conclusions— Treatment with generic simvastatin appears to be cost-effective for a much wider population in the United States than that recommended by current guidelines.
Publisher: Elsevier BV
Date: 06-2012
Publisher: SAGE Publications
Date: 09-07-2016
Abstract: Accurately distinguishing non-traumatic intracerebral hemorrhage (ICH) subtypes is important since they may have different risk factors, causal pathways, management, and prognosis. We systematically assessed the inter- and intra-rater reliability of ICH classification systems. We sought all available reliability assessments of anatomical and mechanistic ICH classification systems from electronic databases and personal contacts until October 2014. We assessed included studies’ characteristics, reporting quality and potential for bias summarized reliability with kappa value forest plots and performed meta-analyses of the proportion of cases classified into each subtype. We included 8 of 2152 studies identified. Inter- and intra-rater reliabilities were substantial to perfect for anatomical and mechanistic systems (inter-rater kappa values: anatomical 0.78–0.97 [six studies, 518 cases], mechanistic 0.89–0.93 [three studies, 510 cases] intra-rater kappas: anatomical 0.80–1 [three studies, 137 cases], mechanistic 0.92–0.93 [two studies, 368 cases]). Reporting quality varied but no study fulfilled all criteria and none was free from potential bias. All reliability studies were performed with experienced raters in specialist centers. Proportions of ICH subtypes were largely consistent with previous reports suggesting that included studies are appropriately representative. Reliability of existing classification systems appears excellent but is unknown outside specialist centers with experienced raters. Future reliability comparisons should be facilitated by studies following recently published reporting guidelines.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Springer Science and Business Media LLC
Date: 05-02-2012
DOI: 10.1038/NG.1081
Publisher: Royal College of Psychiatrists
Date: 19-04-2018
DOI: 10.1192/BJO.2018.19
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-07-2011
Publisher: BMJ
Date: 25-10-2013
Publisher: Wiley
Date: 03-2017
DOI: 10.1002/ANA.24840
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Publisher: Wiley
Date: 08-2016
Publisher: Elsevier BV
Date: 06-2016
Publisher: Elsevier BV
Date: 02-2016
Publisher: Public Library of Science (PLoS)
Date: 02-10-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2016
DOI: 10.1161/STROKEAHA.115.011545
Abstract: Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels–associated genetic variant MTHFR C677T for association with magnetic resonance imaging–confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. We included 1359 magnetic resonance imaging–confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. MTHFR C677T was associated with lacunar stroke ( P =0.0003) and white matter hyperintensity volume ( P =0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive in iduals ( P =0.0002), but not in normotensive in iduals ( P =0.30). MTHFR C677T was associated with magnetic resonance imaging–confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2010
DOI: 10.1161/STROKEAHA.109.558809
Abstract: Background and Purpose— Differences in risk factor profiles between lacunar and other ischemic stroke subtypes may provide evidence for a distinct lacunar arteriopathy, but existing studies have limitations. We overcame these by pooling in idual data on 2875 patients with first-ever ischemic stroke from 5 collaborating prospective stroke registers that used similar, unbiased methods to define risk factors and classify stroke subtypes. Methods— We compared risk factors between lacunar and nonlacunar ischemic strokes, altering the comparison groups in sensitivity analyses, and incorporated these data into a meta-analysis of published studies. Results— Unadjusted and adjusted analyses gave similar results. We found a lower prevalence of cardioembolic source (adjusted odds ratio, 0.33 95% CI, 0.24 to 0.46), ipsilateral carotid stenosis (odds ratio, 0.21 95% CI, 0.14 to 0.30), and ischemic heart disease (odds ratio, 0.75 95% CI, 0.58 to 0.97) in lacunar compared with nonlacunar patients but no difference for hypertension, diabetes, or any other risk factor studied. Results were robust to sensitivity analyses and largely confirmed in our meta-analysis. Conclusions— Hypertension and diabetes appear equally common in lacunar and nonlacunar ischemic stroke, but lacunar stroke is less likely to be caused by embolism from the heart or proximal arteries, and the lower prevalence of ischemic heart disease in lacunar stroke provides additional support for a nonatherosclerotic arteriopathy causing many lacunar ischemic strokes. Our findings have implications for how clinicians classify ischemic stroke subtypes and highlight the need for additional research into the specific causes of and treatments for lacunar stroke.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
DOI: 10.1161/STROKEAHA.115.011625
Abstract: White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging–confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR 95% confidence interval [CI]]=1.14 [1.06–1.22] P =0.0003), in patients both with and without WMH (WMH: OR [95% CI]=1.15 [1.05–1.26] P =0.003 and no WMH: OR [95% CI]=1.11 [1.02–1.21] P =0.019). Conversely, the risk score was not associated with cardioembolic stroke (OR [95% CI]=1.03 [0.97–1.09] P =0.63) or large vessel stroke (OR [95% CI]=0.99 [0.93,1.04] P =0.39). However, none of the WMH-associated single nucleotide polymorphisms passed Bonferroni-corrected significance for association with lacunar stroke. Genetic variants that influence WMH are associated with an increased risk of lacunar stroke but not cardioembolic or large vessel stroke. Some genetic susceptibility factors seem to be shared across different radiological manifestations of small vessel disease.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2014
End Date: 2015
Funder: Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2019
Funder: Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: Medical Research Council
View Funded Activity