149 research outputs found
Genetic risk factors for stroke-related quantitative traits and their associated ischaemic stroke subtypes
No full textStroke is the 2nd leading cause of death in the UK and worldwide. 150,000 people have a stroke each year in the UK (ischaemic stroke being the most common) and a significant proportion of NHS resources go towards the treatment of these individuals (~£2.8 billion). Twin and family history studies have shown that having affected relatives makes you between 30 and 76% more likely to suffer a stroke, suggesting that there is a genetic component to the disease. So far, no genes have been convincingly associated with stroke. Intermediate traits may be useful tools for identifying genetic factors in complex disease. For stroke, two commonly used intermediate traits are carotid intima-media thickness (CIMT) and white matter hyperintensities (WMHs), which both show high heritabilities. These traits have both been studied widely for associations with many candidate gene polymorphisms.
In this thesis I systematically reviewed the literature for all genetic association studies of these two traits. Where particular associations have been studied in large numbers I meta-analysed the available data, developing novel methods for meta-analysis of genetic association data. I found there was substantial heterogeneity and small study bias in the literature and most polymorphisms have still been studied in too small numbers to make accurate conclusions. Apolipoprotein E (APOE) ε is the only polymorphism which shows a consistent association with CIMT, even when only the largest studies are analysed (MD 8μm (95% CI 6 to 11) between E4 and E3, and E3 and E2). No polymorphism has shown a convincing association with WMHs and interestingly APOE appears unlikely to be associated with this trait. This is consistent with previous work that shows that APOE is associated with large artery but not small artery stroke.
Taking this hypothesis I attempted to investigate the association of APOE comparing patients who have had a large artery stroke with those who have had a small artery stroke in the Edinburgh Stroke Study cohort. However, genotyping of this polymorphism failed and I present investigatory analyses of problems from the genotyping laboratory
Epidemiology of ischaemic stroke subtypes: do differences in epidemiology provide evidence for a distinct lacunar arterial pathology?
No full textBackground Lacunar ischaemic stroke accounts for around one quarter of all
strokes, and is presumed to result from the occlusion of a single perforating artery
supplying the deep subcortical areas of the brain. The underlying arterial pathology
is poorly understood, but is thought to differ from the atherothrombotic processes
that occlude larger intra- and extracranial arteries causing most other ischaemic
stroke subtypes. Progress in understanding the aetiology of lacunar stroke has been
limited by the lack of informative autopsy studies, and the difficulties in studying
small blood vessels using brain imaging. One alternative approach is to compare the
epidemiology of ischaemic stroke subtypes, since differences in the epidemiology
may reflect and inform about different underlying pathologies.
Methods I performed two systematic literature reviews to identify studies presenting
data on (1) the risk factors for, and (2) the outcome of, different ischaemic stroke
subtypes. I extracted relevant data from included studies and performed a series of
meta-analyses comparing risk factor profiles, and risks of death, recurrent stroke and
myocardial infarction (MI) in patients with lacunar versus non-lacunar ischaemic
stroke. To address some of the unanswered questions and controversies surrounding
the causes of ischaemic stroke we set up the Edinburgh Stroke Study (ESS), which I
co-ordinated. We recruited patients with stroke and transient ischaemic attack seen
at our hospital between 2002 and 2005, and followed them for 1-4 years for death,
recurrent stroke and MI. To overcome the methodological limitations of the studies
included in my reviews and of my meta-analyses, I carried out a large collaborative
individual patient data analysis in which I combined data from five stroke registries -
including the ESS - that had used similar robust methodology, and performed a series of analyses comparing the risk factor profiles of patients with lacunar versus nonlacunar
ischaemic stroke. In an updated meta-analysis, I combined this data with
existing published studies that had used an unbiased method of classifying ischaemic
stroke subtypes. Using the ESS data, I compared the risks of recurrent stroke and
MI, and patterns of recurrent stroke subtypes in patients with lacunar versus nonlacunar
stroke.
Results In my systematic review of risk factors I found evidence of classification
bias in many studies, where systematic error was introduced through the use of
classification methods that included risk factors in the definitions of stroke subtypes.
This led to overestimation of some risk factor-stroke subtype associations and, in
particular, to apparently stronger associations between hypertension and diabetes and
lacunar compared with non-lacunar ischaemic stroke. When I included only
unbiased studies, I found a significantly reduced prevalence of atrial fibrillation (AF)
and severe carotid stenosis and a trend towards a reduced prevalence of ischaemic
heart disease (IHD) in lacunar patients. I found a very slight excess of hypertension
among lacunar patients, but no difference in the prevalence of diabetes, or any other
risk factor studied. In my collaborative individual patient data analysis, I confirmed
a significantly lower prevalence of severe carotid stenosis, AF and previous IHD in
patients with lacunar ischaemic stroke, but found no difference in the prevalence of
hypertension, diabetes, or any other risk factor studied, even after adjusting for
confounding factors. These results were largely confirmed in my updated metaanalysis,
although there was a slight excess of hypertension among lacunar compared
with non-lacunar ischaemic strokes. In my systematic review of outcome after
lacunar versus non-lacunar ischaemic stroke, I found a lower risk of death following lacunar compared with non-lacunar stroke which attenuated but persisted long-term;
a higher recurrent stroke risk in non-lacunar patients during the first month only; and
limited data on recurrent stroke subtypes suggesting that ischaemic stroke subtypes
may breed true to type. Data on MI risk were extremely sparse. My analyses of data
from the ESS showed no difference overall in risk of recurrent stroke between
patients with lacunar versus non-lacunar ischaemic stroke, but some evidence for a
lower very early recurrence risk among lacunar patients. There was evidence that
recurrent stroke subtypes breed true, since patients with a lacunar stroke at baseline
were much more likely to have a lacunar than a non-lacunar recurrence. We
identified five times as many MI events following stroke than have been previously
reported in the published literature, and found a non-significantly reduced risk of MI
in patients with lacunar compared with non-lacunar ischaemic stroke.
Conclusions My comparisons of the epidemiology of lacunar versus non-lacunar
ischaemic stroke subtypes revealed differences in the risk factor profiles and risks of
recurrent stroke and myocardial infarction which suggest that a distinct, nonatherothrombotic
arteriopathy underlies many lacunar ischaemic strokes. My
analyses of recurrent stroke subtype patterns suggest that recurrent ischaemic strokes
subtypes tend to breed true, providing further support for a distinct lacunar
arteriopathy. Contrary to widespread belief, hypertension and diabetes do not appear
to be more important in the aetiology of lacunar stroke than in other types of
ischaemic stroke.
These findings support other lines of evidence for a distinct lacunar arteriopathy, and
highlight the need for further research into the aetiology of lacunar ischaemic stroke
Magnetic resonance imaging versus computed tomography for detection of acute vascular lesions in patients presenting with stroke symptoms
No full textBackground Magnetic resonance imaging (MRI) is increasingly used for the diagnosis of acute ischaemic stroke but its sensitivity for the early detection of intracerebral haemorrhage has been debated. Computed tomography (CT) is extensively used in the clinical management of acute stroke, especially for the rapid exclusion of intracerebral haemorrhage. Objectives To compare the diagnostic accuracy of diffusion-weighted MRI (DWI) and CT for acute ischaemic stroke, and to estimate the diagnostic accuracy of MRI for acute haemorrhagic stroke. Search strategy We searched MEDLINE and EMBASE (January 1995 to March 2009) and perused bibliographies of relevant studies for additional references. Selection criteria We selected studies that either compared DWI and CT in the same patients for detection of ischaemic stroke or examined the utility of MRI for detection of haemorrhagic stroke, had imaging performed within 12 hours of stroke onset, and presented sufficient data to allow construction of contingency tables. Data collection and analysis Three authors independently extracted data on study characteristics and measures of accuracy. We assessed data on ischaemic stroke using random-effects and fixed-effect meta-analyses. Main results Eight studies with a total of 308 participants met our inclusion criteria. Seven studies contributed to the assessment of ischaemic stroke and two studies to the assessment of haemorrhagic stroke. The spectrum of patients was relatively narrow in all studies, sample sizes were small, there was substantial incorporation bias, and blinding procedures were often incomplete. Amongst the patients subsequently confirmed to have acute ischaemic stroke (161/226), the summary estimates for DWI were: sensitivity 0.99 (95% CI 0.23 to 1.00), specificity 0.92 (95% CI 0.83 to 0.97). The summary estimates for CT were: sensitivity 0.39 (95% CI 0.16 to 0.69), specificity 1.00 (95% CI 0.94 to 1.00). The two studies on haemorrhagic stroke reported high estimates for diffusion-weighted and gradient-echo sequences but had inconsistent reference standards. We did not calculate overall estimates for these two studies. We were not able to assess practicality or cost-effectiveness issues. Authors' conclusions DWI appears to be more sensitive than CT for the early detection of ischaemic stroke in highly selected patients. However, the variability in the quality of included studies and the presence of spectrum and incorporation biases render the reliability and generalisability of observed results questionable. Further well-designed studies without methodological biases, in more representative patient samples, with practicality and cost estimates are now needed to determine which patients should undergo MRI and which CT in suspected acute stroke
P164 Utility of LCI2.5 as an outcome measure for people with cystic fibrosis of all ages – Experience from a pilot feasibility trial spanning adult and paediatric care
No full textLung clearance index (LCI2.5), measured by nitrogen-multiple breath washout (N2-MBW), is a measure of ventilation inhomogeneity and a promising endpoint for clinical trials in cystic fibrosis (CF). The utility of LCI2.5 in adult lung disease has been questioned, due to long test times. LCI2.5 was included as a key safety outcome in the ‘Exercise as an Airway Clearance Technique in CF (ExACT-CF)’ study – a randomised, pilot feasibility trial comparing daily ExACT with usual care (chest physiotherapy). We report utility of LCI2.5 as an outcome measure in this 28-day trial which spanned adult and paediatric age groups
Early computed tomography coronary angiography in patients with suspected acute coronary syndrome: randomised controlled trial
No full textObjectives To establish if the use of early computed tomography (CT) coronary angiography improves one year clinical outcomes in patients presenting to the emergency department with acute chest pain and at intermediate risk of acute coronary syndrome and subsequent clinical events.
Design Randomised controlled trial.
Setting 37 hospitals in the UK.
Participants Adults with suspected or a provisional diagnosis of acute coronary syndrome and one or more of previous coronary heart disease, raised levels of cardiac troponin, or abnormal electrocardiogram.
Interventions Early CT coronary angiography and standard of care compared with standard of care only.
Main outcome measures Primary endpoint was all cause death or subsequent type 1 or 4b myocardial infarction at one year.
Results Between 23 March 2015 and 27 June 2019, 1748 participants (mean age 62 years (standard deviation 13), 64% men, mean global registry of acute coronary events (GRACE) score 115 (standard deviation 35)) were randomised to receive early CT coronary angiography (n=877) or standard of care only (n=871). Median time from randomisation to CT coronary angiography was 4.2 (interquartile range 1.6-21.6) hours. The primary endpoint occurred in 51 (5.8%) participants randomised to CT coronary angiography and 53 (6.1%) participants who received standard of care only (adjusted hazard ratio 0.91 (95% confidence interval 0.62 to 1.35), P=0.65). Invasive coronary angiography was performed in 474 (54.0%) participants randomised to CT coronary angiography and 530 (60.8%) participants who received standard of care only (adjusted hazard ratio 0.81 (0.72 to 0.92), P=0.001). There were no overall differences in coronary revascularisation, use of drug treatment for acute coronary syndrome, or subsequent preventive treatments between the two groups. Early CT coronary angiography was associated with a slightly longer time in hospital (median increase 0.21 (95% confidence interval 0.05 to 0.40) days from a median hospital stay of 2.0 to 2.2 days).
Conclusions In intermediate risk patients with acute chest pain and suspected acute coronary syndrome, early CT coronary angiography did not alter overall coronary therapeutic interventions or one year clinical outcomes, but reduced rates of invasive angiography while modestly increasing length of hospital stay. These findings do not support the routine use of early CT coronary angiography in intermediate risk patients with acute chest pain and suspected acute coronary syndrome.
Trial registration ISRCTN19102565, NCT02284191
Are anonymised datasets from clinical trials truly anonymous?
No full textBACKGROUND:
Funders, regulators and publishers are increasingly requesting that clinical trial researchers share their research data with others, once the primary analysis has been completed. Existing clinical trial data could significantly contribute to expanding medical and scientific knowledge by investigating questions beyond the original study scope, facilitating individual participant data (IPD) meta-analysis, verifying results, and exploring novel methodologies for data analysis. Anonymisation of IPD before sharing can offer a way to safeguard participants' privacy. While there are several recommendations and guidance available for attempting data anonymisation prior to sharing, completely anonymising data while keeping it usable remains challenging. Moreover, many anonymised datasets are already publicly available for secondary research. However, it remains unclear whether study participants could potentially be at risk of re-identification, and under what circumstances re-identification is more likely to occur.
METHODS:
In the first phase of this PhD research, a systematic scoping review was conducted to gather publications that reported recommendations on anonymisation for enabling data sharing from clinical trials, to understand what guidance was available to researchers and how publicly available anonymised datasets from clinical trials might have been compiled. Two reviewers, Aryelly Rodriguez with Chris Tuck or Alastair Murray independently assessed titles, abstracts, and full texts for eligibility. One reviewer extracted data from selected papers using thematic synthesis, which was then reviewed by a second reviewer for accuracy. Results were summarised through narrative analysis. Moving on to the second phase, I collected a broad selection of publicly available anonymised datasets that have been made available for research purposes extending beyond their original scope, to explore the characteristics of these anonymised datasets, assess the feasibility of applying re-identification risk scores to them, and determine how these scores could be useful. I estimated their re-identification risk scores with three equations designed for calculation of such scores based on the information in the entire dataset. These equations are commonly applied to routinely collected health records and only generate numerical values ranging from 0 (lowest risk) to 1 (maximum risk), without attempting to re-identify individuals within the datasets. Subsequently, I calculated the re-identification risk scores for each dataset, using the three equations. This analysis explored the characteristics of the datasets associated with increased or decreased risk scores, and compared the risk scores to evaluate their practicality for implementation. In the third and final phase of this PhD research, I used an online exploratory cross-sectional descriptive survey that consisted of both open-ended and closed questions to gather the UK researchers’ views regarding their experiences with the de-identification, anonymisation, release methods and re-identification risk estimation for clinical trials datasets.
RESULTS:
The systematic scoping review identified 59 eligible articles (from 43 studies) for inclusion. From these articles, three distinct themes emerged: anonymisation, de-identification and pseudonymisation. The articles also showed that the most commonly recommended anonymisation techniques are removal of direct participant identifiers, and the careful evaluation and modification of indirect identifiers to minimise the risk of identification. Anonymisation of datasets in conjunction with controlled access was the most recommended method for data sharing.
For the next phase, I contacted data holders and followed their local procedures to access the anonymised datasets. I identified 86 potentially eligible datasets from 18 repositories and successfully secured 76 of them. After full evaluation, 70 datasets met the inclusion criteria and were included in the analysis, representing 14 out of the 18 repositories. Thirty-one datasets were shared with minimal restrictions (open access), while 39 were shared with varying levels of restrictions before access was granted (controlled access). Datasets had, on average, four identifiers and mean risk scores ranging from 0.47 to 0.91. The most common pieces of information present in the datasets that, when combined, may indirectly identify a participant were sex (80%) and age (72.9%). For the final phase, the exploratory survey had 38 responses to invitation from June 2022 to October 2022. Thirty-five participants (92%) used internal documentation, institutional standard operating procedures and/or published guidance to de-identify/anonymise clinical trials datasets. De-identification followed by anonymisation and then fulfilling data holders’ requirements before access was granted (controlled access) was the most common process for releasing the datasets as reported by 18 (47%) participants. Eleven participants (29%) had previous knowledge of re-identification risk estimation but had not used this. Experiences in the process of de-identifying/anonymising the datasets and maintaining such datasets were mostly negative, the main reported issues were lack of resources, guidance, and training.
CONCLUSIONS:
There is no single standardised set of recommendations on how to anonymise clinical trial datasets for sharing. However, the systematic scoping review showed a developing consensus on techniques used to achieve anonymisation. Researchers in clinical trials still consider that anonymisation techniques by themselves are insufficient to protect participant privacy, and they need to be paired with controlled access. The second phase of this research confirmed that clinical trial datasets are very rich in personal details and using re-identification risk scores as a measure of this richness is feasible. These scores could inform the anonymisation process of clinical trials datasets to release them for secondary research. We proposed a strategy for incorporating these scores into the decision-making process for releasing clinical trials datasets. Finally, the majority of responders to the survey reported using documented processes for de-identification and anonymisation. However, our survey results clearly indicate that there are still gaps in the areas of guidance, resources and training to fulfil sharing requests of de-identified/anonymised datasets, and that re-identification risk estimation is an underdeveloped area. This work will be of interest to the clinical trials research community, funders and publishers seeking to improve the process of anonymisation and foster data sharing
Staff-led interventions for improving oral hygiene in patients following stroke
No full textBackground For people with limitations due to neurological conditions such as stroke, the routine practice of oral care may become a challenge. Evidence-based supported oral care intervention is essential for this patient group. Objectives To compare the effectiveness of staff-led oral care interventions with standard care for ensuring oral hygiene for individuals after a stroke. Search strategy We searched the trials registers of the Cochrane Stroke Group and Oral Health Group (August 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to February 2006), CINAHL (1982 to February 2006), Research Findings Electronic Register (February 2006), National Research Register (Issue 1, 2006), ISI Science and Technology Proceedings (August 2005), Dissertation Abstracts and Conference Papers Index (August 2005). We scanned reference lists from relevant papers and contacted authors and researchers in the field. Selection criteria We identified randomised controlled trials that evaluated one or more interventions designed to improve oral hygiene. Trials based on a mixed population were included, provided it was possible to extract the data specific to the individuals post stroke. Data collection and analysis Two review authors independently classified identified trials according to the inclusion and exclusion criteria, assessed the trial quality and extracted data. Clarification was sought from study authors when required. Main results Eight eligible randomised controlled trials were identified but only one provided stroke-specific information. It compared an oral health care education training programme (OHCE) delivered to nursing home care assistants to delayed training intervention in the control group. Comparisons were made at one and six months after the intervention, using the primary outcome measures dental plaque and denture plaque, and three secondary outcomes. The data available for the 67 individuals with a stroke (obtained from the larger cluster randomised controlled trial) showed that denture plaque scores were significantly reduced up to six months (P < 0.00001) after the intervention. Staff knowledge (P = 0.0008) and attitudes (P = 0.0001) towards oral care also improved significantly. Authors' conclusions Based on one study with a small number of stroke survivors, providing oral care training for carers in a nursing home setting improves their knowledge of and attitudes towards the provision of oral care. In turn, residents' dentures were cleaner, though other oral hygiene measures did not change. Further evidence relating to oral care interventions is severely lacking, in particular with reference to care in hospital for those following stroke. This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 2011, Issue 7. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.</p
Prophylactic zoledronic acid therapy to prevent or modify Paget’s disease of bone progression in adults with SQSTM1 mutations: the ZiPP RCT
No full textBackground:Paget’s disease of bone is characterised by focal abnormalities of bone turnover resulting in various complications. It often presents at an advanced stage with irreversible bone damage. At this point, the symptomatic benefits of treatment are blunted. Paget’s disease of bone has a strong genetic component and the most important susceptibility gene is SQSTM1. Carriers of SQSTM1 mutations have more severe disease with an earlier age of onset than non-carriers and about 80% develop Paget’s disease of bone by the seventh decade.Objectives:The primary objective was to determine if zoledronic acid could prevent new Paget’s disease of bone-like bone lesions in SQSTM1 mutation carriers. Secondary objectives were to assess if zoledronic acid could: modify existing Paget’s disease of bone lesions, markers of bone turnover, quality of life, bone pain, anxiety, depression or the risk of complications.Design:This was a multicentre, double-blind placebo-controlled trial. Genetic screening of the SQSTM1 gene was offered to people with a family history of Paget’s disease of bone, identifying 222 mutation carriers who consented to participate. At baseline, a radionuclide bone scan was performed; biochemical markers of bone turnover were measured and questionnaires on pain, quality of life and mental health were completed. Participants completed annual biochemical markers measurements and questionnaires. Adverse events were recorded on a continuous basis. At the end of study, the bone scan was repeated, along with biochemical markers and questionnaires.Setting:This was a multicentre trial that was conducted at 27 secondary care referral centres for bone disease in 7 countries. All the visits were conducted within a secondary healthcare setting.Participants Interventions:Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo.Main outcome measures:The study’s primary outcome measure was defined as the total number of participants who developed new bone lesions on radionuclide bone scans with the characteristics of PDB between the baseline visit and the final end-of-study visit. The secondary outcomes included the number of new PDB bone lesions on radionuclide bone scans, change in the activity of existing PDB bone lesions at the end of study assessed by radionuclide scans; changes in plasma type I collagen C-telopeptides (CTX); plasma procollagen type I amino-terminal propeptide (PINP); serum bone-specific alkaline phosphatase (BAP); quality of life assessed by SF-36, BPI, HADS questionnaires; the presence and severity of localized bone pain assessed by the BPI pain manikin; and the development of PDB-related skeletal events (PDRSE) in SQSTM1 mutation carriers including new lesions, complications (fractures, deformity), or the need for treatment of PDB.Methods:This was a multicentre, double-blind placebo-controlled trial. Genetic screening of the SQSTM1 gene was offered to people with a family history of Paget’s disease of bone, identifying 222 mutation carriers who consented to participate. At baseline, a radionuclide bone scan was performed; biochemical markers of bone turnover were measured and questionnaires on pain, quality of life and mental health were completed. Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo. Participants completed annual biochemical markers measurements and questionnaires. Adverse events were recorded on a continuous basis. At the end of study, the bone scan was repeated, along with biochemical markers and questionnaires.Results:At baseline, 21/222 individuals (9.5%) had evidence of Paget’s disease of bone on bone scans. In the placebo group, 2/90 individuals (2.2%) developed new bone lesions compared with 0/90 (0%) in the zoledronic acid group (odds ratio 0.41, 95% confidence interval 0.00 to 3.43; p = 0.25). Eight participants in the placebo group had a poor outcome (new/unchanged/progressing lesions) compared with none in the zoledronic acid group (odds ratio 0.08, 95% confidence interval 0.00 to 0.42; p = 0.003). With placebo, 1/29 (3.4%) lesions disappeared compared with 13/15 (86.6%) with zoledronic acid (p < 0.0001). One participant allocated to placebo required treatment with zoledronic acid due to a complication of Paget’s disease of bone. Significant reductions were observed for serum C-terminal telopeptide (p < 0.0001), bone-specific alkaline phosphatase (p = 0.0003) and N-terminal propeptide of type I procollagen (p < 0.0001) in the zoledronic acid group compared with placebo. There was no significant difference between groups in quality of life, pain, anxiety or depression.Conclusion:Genetic testing for SQSTM1 mutations coupled with bone scan examination can detect early Paget’s disease of bone in those with a family history of the disorder and zoledronic acid treatment can favourably modify its evolution.The study had some limitations. First, 9.5% of participants already had Paget’s disease of bone, reducing power. Second, only two participants developed new lesions compared to the 15% expected. The small number of events meant the study was underpowered for the primary outcome and we were unable to adjust analyses for co-variates or family clustering.An extended follow-up in the zoledronic acid in the prevention of Paget’s disease – long-term extension study is in progress and will provide valuable information on the duration of effects of a single zoledronic acid infusion. It will be important to consider a health economic analysis to model the effects of genetic testing, scanning and zoledronic acid treatment, to evaluate long-term clinical and symptomatic benefits.<br/
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