Publication: The Lancet Psychiatry
Varun Warrier, Alex S F Kwong, Mannan Luo, Shareefa Dalvie, Jazz Croft, Hannah M Sallis, et al.
16 March 2021
Childhood maltreatment is associated with poor mental and physical health. However, the mechanisms of gene–environment correlations and the potential causal effects of childhood maltreatment on health are unknown. Using genetics, the researchers aimed to delineate the sources of gene–environment correlation for childhood maltreatment and the causal relationship between childhood maltreatment and health.
They did a genome-wide association study meta-analysis of childhood maltreatment using data from the UK Biobank, Psychiatric Genomics Consortium, Avon Longitudinal Study of Parents and Children, Adolescent Brain Cognitive Development Study and Generation R.
Family-based and population-based polygenic score analyses were done to elucidate gene–environment correlation mechanisms. The team used genetic correlation and Mendelian randomisation analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions.
This meta-analysis of genome-wide association studies identified 14 independent loci associated with childhood maltreatment. The researchers identified high genetic overlap among different maltreatment operationalisations, subtypes, and reporting methods.
Within-family analyses provided some support for active and reactive gene–environment correlation but did not show the absence of passive gene–environment correlation. Robust Mendelian randomisation suggested a potential causal role of childhood maltreatment in depression (unidirectional), as well as both schizophrenia and ADHD (bidirectional), but not in physical health conditions (coronary artery disease, type 2 diabetes) or inflammation (C-reactive protein concentration).
Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalisations, subtypes, and retrospective and prospective reports of childhood maltreatment.
Family-based analyses point to a role of active and reactive gene–environment correlation, with equivocal support for passive correlation. Mendelian randomisation supports a (primarily bidirectional) causal role of childhood maltreatment on mental health, but not on physical health conditions. This study identifies research avenues to inform the prevention of childhood maltreatment and its long-term effects.View publication
Publication: International Journal of Epidemiology
Aurora Perez-Cornago , Francesca L Crowe, Paul N Appleby, Kathryn E Bradbury, Angela M Wood, Marianne Uhre Jakobsen, Laura Johnson, Carlotta Sacerdote, Marinka Steur, Elisabete Weiderpass, Anne Mette L Würtz, Tilman Kühn, Verena Katzke, Antonia Trichopoulou, Anna Karakatsani, Carlo La Vecchia, Giovanna Masala, Rosario Tumino, Salvatore Panico, Ivonne Sluijs, Guri Skeie, Liher Imaz, Dafina Petrova, J Ramón Quirós, Sandra Milena Colorado Yohar, Paula Jakszyn, Olle Melander, Emily Sonestedt, Jonas Andersson, Maria Wennberg, Dagfinn Aune, Elio Riboli, Matthias B Schulze, Emanuele di Angelantonio, Nicholas J Wareham, John Danesh, Nita G Forouhi, Adam S Butterworth, Timothy J Key
3 March 2021
Epidemiological evidence indicates that diets rich in plant foods are associated with a moderately lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre.
This study found that higher intakes of fruit and vegetables combined, total fruit, bananas, nuts and seeds, total fibre, fruit and vegetable combined fibre and fruit fibre are associated with a lower risk of IHD, of small magnitude.
To the best of the researchers’ knowledge, this is the largest prospective study looking at major plant foods, their subtype, and dietary fibre in relation to IHD risk including incident IHD cases and death from IHD.
As with other observational studies, the associations reported may be subject to residual confounding, and whether these small associations are causal remains unclear.View publication
Publication: European Journal of Epidemiology
Stephen Burgess, Sonja A Swanson & Jeremy A Labrecque
21 February 2021
Mendelian randomization uses genetic variants as instrumental variables to make causal inferences about the effect of a risk factor on an outcome. If a genetic variant satisfies the instrumental variable assumptions for the given risk factor and outcome, then an association between the genetic variant and the outcome implies the risk factor affects the outcome in some individuals at some point in the life-course.
Combining the instrumental variable assumptions with further assumptions and precise specification of the outcome (including specifying a time period for the outcome) allows valid testing of a more specific causal hypothesis and/or valid estimation of global or local, and point or period average causal effects.
In this short manuscript, the researchers discuss three ways in which Mendelian randomization analyses may be susceptible to bias due to reverse causation. They conclude that while the analyses offer some protection against biases, they are not totally immune from the phenomenon; and that researchers should consider carefully whether their findings could be explained by genetic variants having a primary association with the outcome, and how previous versions of an outcome can impact the stated risk factor.View publication
Publication: Stroke AHA
Eric L. Harshfield, Marios K. Georgakis, Rainer Malik, Martin Dichgans, Hugh S. Markus
4 February 2021
Assessing whether modifiable risk factors are causally associated with stroke risk is important in planning public health measures, but determining causality can be difficult in epidemiological data.
Here the research team evaluated whether modifiable lifestyle factors including educational attainment, smoking, and body mass index are causal risk factors for ischemic stroke and its subtypes and hemorrhagic stroke.
They performed 2-sample and multivariable Mendelian randomization to assess the causal effect of 12 lifestyle factors on risk of stroke and whether these effects are independent.
Genetically predicted years of education was inversely associated with ischemic, large artery, and small vessel stroke, and intracerebral hemorrhage.
Genetically predicted smoking, body mass index, and waist-hip ratio were associated with ischemic and large artery stroke. The effects of education, body mass index, and smoking on ischemic stroke were independent.
These findings support the hypothesis that reduced education and increased smoking and obesity increase risk of ischemic, large artery, and small vessel stroke, suggesting that lifestyle modifications addressing these risk factors will reduce stroke risk.View publication
Publication: Communications Biology
E Allara, S Kaptoge, AM Wood, AS Butterworth, J Danesh, E Di Angelantonio et al
3 February 2021
Iron is essential for many biological functions and iron deficiency and overload have major health implications.
Here the researchers performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin, total iron binding capacity, iron and transferrin saturation.
They identified 46 novel loci affecting iron homeostasis and showed an association of five of these loci with IDA, a major clinical entity that hitherto has not been studied thoroughly from a genetic point of view.
This study reveals a substantial catalog of possible iron regulatory genes, awaiting further inquiry to fully elucidate their functional role.View publication
Marios K. Georgakis, Eric L. Harshfield, Rainer Malik, Nora Franceschini, Claudia Langenberg, Nicholas J. Wareham, Hugh S. Markus, Martin Dichgans
25 January 2021
The researchers employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.
This study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. Genetically predicted insulin resistance and β-cell dysfunction are associated with large artery and small vessel stroke; this may have implications for antidiabetic treatments targeting these mechanisms.View publication
Publication: BJPsych Open
Bhardwaj A, Moore A, Cardinal RN, Bradley C, Cross L, Ford TJ
13 January 2021
The Covid-19 crisis necessitated rapid adoption of remote consultations across National Health Service (NHS) child and adolescent mental health services (CAMHS).
This study aimed to understand practitioners’ experiences of rapid implementation of remote consultations across CAMHS in one NHS trust in the east of England.
Data were collected through a brief questionnaire documenting clinicians’ experiences following remote delivery of services. The questionnaire began before ‘lockdown’ and focused on 102 assessment consultations as part of a planned move to virtual assessment.
As the roll-out of remote consultations was extended at lockdown, the researchers extended the questionnaire to include all remote clinical contacts (n = 202).
Despite high levels of initial concern, clinicians’ reports were positive overall; importantly, however, their experiences varied by team. When restrictions on face-to-face working are lifted, a blended approach of remote and face-to-face service delivery is recommended to optimise access and capacity while retaining effective and safe care.View publication
Publication: International Journal of Cancer
Olga E. Titova, Karl Michaëlsson, Mathew Vithayathil, Amy M. Mason, Siddhartha Kar, Stephen Burgess, Susanna C. Larsson
7 September 2020
Studies of sleep duration in relation to the risk of site‐specific cancers other than breast cancer are scarce. Furthermore, the available results are inconclusive and the causality remains unclear. In this study researchers aimed to investigate the potential causal associations of sleep duration with overall and site‐specific cancers using the Mendelian randomization (MR) design.
The researchers concluded that this MR study does not provide strong evidence to support causal associations of sleep duration with risk of overall and site‐specific cancers. The suggestive associations of short‐ or long‐sleep duration with certain cancers merit further investigation in other large MR studies.View publication
Publication: Journal of Internal Medicine
S. van Oort, J. W. J. Beulens, A. J. van Ballegooijen, S. Burges,s S. C. Larsson
26 October 2020
The American Heart Association introduced the Life’s Simple 7 initiative to improve cardiovascular health by modifying cardiovascular risk factors and lifestyle behaviours. It is unclear whether these risk factors are causally associated with longevity.
This study aimed to investigate causal associations of Life’s Simple 7 modifiable risk factors, as well as sleep and education, with longevity using the two‐sample Mendelian randomization design.
Risk factors associated with a lower odds of longevity included the following: genetic liability to type 2 diabetes, genetically predicted systolic and diastolic blood pressure, body mass index, low‐density lipoprotein cholesterol and smoking initiation. Genetically increased high‐density lipoprotein cholesterol and educational level were associated with a higher odds of longevity. Fasting glucose and other lifestyle factors were not significantly associated with longevity.
Most of the Life’s Simple 7 modifiable risk factors are causally related to longevity. Prevention strategies should focus on modifying these risk factors and reducing education inequalities to improve cardiovascular health and longevity.View publication
Publication: Science Direct
Michael J. Sweeting, John Marshall, Matthew Glover, Akhtar Nasim, Matthew J. Bown
25 December 2020
The National Health Service Abdominal Aortic Aneurysm Screening Programme has been shown to be highly cost-effective. Recently, the prevalence of screen-detected abdominal aortic aneurysm (AAA) has fallen. If this trend continues, the cost-effectiveness of AAA screening is threatened.
One option to improve program cost-effectiveness is to extend the length of time between surveillance scans for men who are found to have AAA at screening. The potential safety and cost savings associated with such a change are unknown.
Extending the length of time between surveillance scans for men with screen-detected AAA in the Abdominal Aortic Aneurysm Screening Programme, especially for those with smaller AAAs, reduces the incremental cost per quality-adjusted life-year of the program. This is associated with a small increase in the number of adverse clinical events in the overall population of men invited for screening.
It is unclear whether the benefit of cost saving from refining surveillance strategies justifies the increased harms associated with such a change in clinical practice. Furthermore, realizing the benefits of minimized surveillance strategies for individual screening units may be difficult owing to the regional structure of the AAA screening workforce.
This study aimed to investigate the safety and cost-effectiveness of lengthening the time between surveillance ultrasound scans in the UK Abdominal Aortic Aneurysm (AAA) Screening Programme.
A discrete event simulation model was used to evaluate the cost-effectiveness of AAA screening for men aged 65, comparing current surveillance intervals to 6 alternative surveillance interval strategies that lengthened the time between surveillance scans for 1 or more AAA size categories. The model considered clinical events and costs incurred over a 30-year time horizon and the cost per quality-adjusted life year (QALY). The model adopted the National Health Service perspective and discounted future costs and benefits at 3.5%.
Compared with current practice, alternative surveillance strategies resulted in up to a 4% reduction in the number of elective AAA repairs but with an increase of up to 1.6% in the number of AAA ruptures and AAA-related deaths. Alternative strategies resulted in a small reduction in QALYs compared to current practice but with reduced costs. Two strategies that lengthened surveillance intervals in only very small AAAs (3.0-3.9 cm) provided, at a cost-effectiveness threshold of £20 000 per QALY, the highest positive incremental net benefit. There was negligible chance that current practice is the most cost-effective strategy at any threshold below £40,000 per QALY.
Lengthening surveillance intervals in the UK Abdominal Aortic Aneurysm Screening Programme, especially for small AAA, can marginally reduce the incremental cost per QALY of the program. Nevertheless, whether the cost savings from refining surveillance strategies justifies a change in clinical practice is unclear.View publication
Publication: ACL Anthology
Wang Z, Ive J, Moylett S, Mueller C, Cardinal RN, Velupillai S, O’Brien J, Stewart R
1 November 2020
While Dementia with Lewy Bodies (DLB) is the second most common type of neurodegenerative dementia following Alzheimer’s Disease (AD), it is difficult to distinguish from AD.
Here the researchers propose a method for DLB detection by using mental health record (MHR) documents from a (3-month) period before a patient has been diagnosed with DLB or AD. The objective is to develop a model that could be clinically useful to differentiate between DLB and AD across datasets from different healthcare institutions.
The researchers cast this as a classification task using Convolutional Neural Network (CNN), an efficient neural model for text classification. They experiment with different representation models, and explore the features that contribute to model performances.
In addition, they apply temperature scaling, a simple but efficient model calibration method, to produce more reliable predictions. They believe the proposed method has important potential for clinical applications using routine healthcare records, and for generalising to other relevant clinical record datasets.
To the best of the team’s knowledge, this is the first attempt to distinguish DLB from AD using mental health records, and to improve the reliability of DLB predictions.View publication
Publication: Frontiers in Psychiatry
Chen S, She R, Qin P, Kershenbaum A, Fernández-Egea E, Nelder JR, Ma C, Lewis JR, Wang C, Cardinal RN
26 November 2020
To date, there is a paucity of information regarding the effect of COVID-19 or lockdown on mental disorders.
In this study researchers aimed to quantify the medium-term impact of lockdown on referrals to secondary care mental health clinical services.
They conducted a controlled interrupted time series study using data from Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), UK (catchment population ~0.86 million).
The UK lockdown resulted in an instantaneous drop in mental health referrals but then a longer-term acceleration in the referral rate. This acceleration was primarily for urgent or emergency referrals, including referrals to liaison psychiatry and mental health crisis teams. The acceleration was significant for females, males, working-age adults, people of White ethnicity, those living alone, and those who had pre-existing depression, severe mental illness, hypertension / cardiovascular / cerebrovascular disease, personality disorders, asthma / chronic obstructive pulmonary disease, dyslipidemia, anxiety, substance misuse or reactions to severe stress.
No significant post-lockdown acceleration was observed for children / adolescents, older adults, people of ethnic minorities, married / cohabiting people, and those who had previous / pre-existing dementia, diabetes, cancer, eating disorder, a history of self-harm or intellectual disability. This evidence may help service planning and policy-making, including preparation for any future lockdown in response to outbreaks.View publication
Publication: International Journal of Geriatric Psychiatry
Kershenbaum A, Cardinal RN, Chen S, Underwood B, Seyedsalehi A, Lewis JR, Rubinsztein JS
4 November 2020
Previous studies have shown increased rates of death and dementia in older people in specific serious mental illnesses (SMI) such as bipolar disorder or depression.
In this study researchers examined the rates of death and dementia in older people referred into a secondary care psychiatric service across a range of SMIs, using an anonymised dataset across 6 consecutive years with 28,340 patients aged 65 years and older from a single secondary care psychiatric trust in the United Kingdom.
They identified deaths and incident dementia in patients with bipolar disorder/mania, schizophrenia, recurrent depression and anxiety disorders. They compared mortality and dementia rates between these diagnostic groups and in different treatment settings, and also examined mortality rates and dementia rates compared with general population rates.
Patients with schizophrenia showed the highest hazard rate for death compared to other groups with SMIs. Survival was reduced in patients referred to liaison psychiatry services. There were no significant differences between the SMI groups in terms of rates of dementia. However, risks of death and dementia were significantly increased compared to the general population; and older adults referred into an old age psychiatry service showed higher rates of dementia and death than those reported for the general population.View publication
Publication: Journal of Psychiatric Research
Chen S, Jones PB, Underwood BR, Moore A, Bullmore ET, Banerjee S, Osimo EF, Deakin JB, Hatfield CF, Thompson FJ, Artingstall JD, Slann MP, Lewis JR, Cardinal RN
22 September 2020
COVID-19 has affected social interaction and healthcare worldwide.
Here researchers examined changes in presentations and referrals to the primary provider of mental health and community health services in Cambridgeshire and Peterborough, UK (population ~0·86 million), plus service activity and deaths.
They conducted interrupted time series analyses with respect to the time of UK “lockdown”, which was shortly before the peak of COVID-19 infections in this area, and examined changes in standardized mortality ratio for those with and without severe mental illness (SMI).
Referrals and presentations to nearly all mental and physical health services dropped at lockdown, with evidence for changes in both supply (service provision) and demand (help-seeking).
This was followed by an increase in demand for some services. This pattern was seen for all major forms of presentation to liaison psychiatry services, except for eating disorders, for which there was no evidence of change.
Inpatient numbers fell, but new detentions under the Mental Health Act were unchanged. Many services shifted from face-to-face to remote contacts. Excess mortality was primarily in the over-70s. There was a much greater increase in mortality for patients with SMI, which was not explained by ethnicity.
In conclusion, the research showed that COVID-19 has been associated with a system-wide drop in the use of mental health services, with some subsequent return in activity. “Supply” changes may have reduced access to mental health services for some. “Demand” changes may reflect a genuine reduction of need or a lack of help-seeking with pent-up demand. There has been a disproportionate increase in death among those with SMI during the pandemic.View publication
Publication: Transfusion Medicine
Steven Bell, Michael Sweeting, Anna Ramond, Ryan Chung, Stephen Kaptoge, Matthew Walker, Thomas Bolton, Jennifer Sambrook, Carmel Moore, Amy McMahon, Sarah Fahle
20 December 2020
To safeguard donors, blood services measure haemoglobin concentration in advance of each donation. NHS Blood and Transplant’s (NHSBT) customary method have been capillary gravimetry (copper sulphate), followed by venous spectrophotometry (HemoCue) for donors failing gravimetry. However, NHSBT’s customary method results in 10% of donors being inappropriately bled (ie, with haemoglobin values below the regulatory threshold).
Here the researchers compared the following four methods in 21 840 blood donors (aged ≥18 years) recruited from 10 NHSBT centres in England, with the Sysmex XN‐2000 haematology analyser, the reference standard: (1) NHSBT’s customary method; (2) “post donation” approach, that is, estimating current haemoglobin concentration from that measured by a haematology analyser at a donor’s most recent prior donation; (3) “portable haemoglobinometry” (using capillary HemoCue); (4) non‐invasive spectrometry (using MBR Haemospect or Orsense NMB200). The team assessed sensitivity; specificity; proportion who would have been inappropriately bled, or rejected from donation (“deferred”) incorrectly; and test preference.
Compared with the reference standard, the methods ranged in test sensitivity from 17.0% (MBR Haemospect) to 79.0% (portable haemoglobinometry) in men, and from 19.0% (MBR Haemospect) to 82.8% (portable haemoglobinometry) in women.
For specificity, the methods ranged from 87.2% (MBR Haemospect) to 99.9% (NHSBT’s customary method) in men, and from 74.1% (Orsense NMB200) to 99.8% (NHSBT’s customary method) in women. The proportion of donors who would have been inappropriately bled ranged from 2.2% in men for portable haemoglobinometry to 18.9% in women for MBR Haemospect. The proportion of donors who would have been deferred incorrectly with haemoglobin concentration above the minimum threshold ranged from 0.1% in men for NHSBT’s customary method to 20.3% in women for OrSense. Most donors preferred non‐invasive spectrometry.
In the largest study reporting head‐to‐head comparisons of four methods to measure haemoglobin prior to blood donation, the results support replacement of NHSBT’s customary method with portable haemoglobinometry.View publication
Publication: European Neuropsychopharmacology
Rose E, Chen S, Turrion C, Jenkins C, Cardinal RN, Fernández-Egea E
17 September 2020
Approximately one-third of patients presenting with a first episode of psychosis need long-term support, but there is a limited understanding of the sociodemographic or biological factors that predict this outcome. ]
Researchers used electronic health records from a naturalistic cohort of consecutive patients referred to an early intervention in psychosis service to address this question.
They extracted data on demographic (age, sex, ethnicity and marital status), immune and metabolic factors at baseline, and subsequent need for long-term secondary (specialist) psychiatric care.
Of 749 patients with outcome data available, 447 (60%) had a good outcome and were discharged to primary care, while 302 (40%) required follow-up by secondary mental health services indicating a worse outcome.
The need for ongoing secondary mental healthcare was associated with high triglyceride levels, a low basophil:lymphocyte ratio, and a high monocyte count at baseline.
In conclusion, the research provides evidence that triglyceride levels and several blood cell counts measured at presentation may be clinically useful markers of long-term prognosis for first episode psychosis in clinical settings. These findings will require replication.View publication
Publication: Journal of Psychopharmacology
Kanen JW, Arntz FE, Yellowlees R, Cardinal RN, Price A, Christmas DM, Sahakian BJ, Apergis-Schoute AM, Robbins TW
18 February 2020
The involvement of serotonin in responses to negative feedback is well established. Acute serotonin reuptake inhibition has enhanced sensitivity to negative feedback (SNF), modelled by behaviour in probabilistic reversal learning (PRL) paradigms. Whilst experiments employing acute tryptophan depletion (ATD) in humans, to reduce serotonin synthesis, have shown no clear effect on SNF, sample sizes have been small.
The researchers studied a large sample of healthy volunteers, male and female, and found ATD had no effect on core behavioural measures in PRL.
These results indicate that ATD effects can differ from other manipulations of serotonin expected to have a parallel or opposing action.View publication
Publication: BMJ Open Diabetes Research & Care
Fernández-Egea E, Walker R, Ziauddeen H, Cardinal RN, Bullmore ET
28 January 2020
The prevalence of diabetes in schizophrenia is twice that in the general population, but there are few reliable predictors of which individuals will develop glucose dysregulation.
This research tested if abnormal birth weight (either too low or too high) and parental diabetes, both variables that can be ascertained in the clinic, can predict diabetes onset in patients with schizophrenia.
Researchers looked at electronic records of a cohort of 190 clozapine-treated patients (37% treated for more than 20 years) and Cox regression survival analysis (with any type of glucose dysregulation as the event) to account for differences in length of treatment before the event and age at clozapine treatment initiation.
Age at clozapine initiation, family history of diabetes and birth weight were significant predictors of glucose dysregulation onset, while gender was not.
Among individuals with 10 years of follow-up, 80% of those with both abnormal birth weight and a family history of diabetes developed diabetes compared with 56% with only abnormal birth weight, 40% with only a family history of diabetes and 20% in those with neither.
Since 48% of cases had at least one risk factor and 6% had both risk factors, there is a substantial proportion of patients for whom preventive strategies could be implemented.View publication
Lim TV, Cardinal RN, Savulich GJ, Moustafa AA, Robbins TW, Ersche KD
1 August 2019
Drug addiction has been suggested to develop through drug-induced changes in learning and memory processes. Whilst the initiation of drug use is typically goal-directed and hedonically motivated, over time, drug-taking may develop into a stimulus-driven habit, characterised by persistent use of the drug irrespective of the consequences.
Converging lines of evidence suggest that stimulant drugs facilitate the transition of goal-directed into habitual drug-taking, but their contribution to goal-directed learning is less clear.
Computational modelling may provide an elegant means for elucidating changes during instrumental learning that may explain enhanced habit formation.
The research team used formal reinforcement learning algorithms to deconstruct the process of appetitive instrumental learning and to explore potential associations between goal-directed and habitual actions in patients with cocaine use disorder (CUD).
They re-analysed appetitive instrumental learning data in 55 healthy control volunteers and 70 CUD patients by applying a reinforcement learning model within a hierarchical Bayesian framework. They used a regression model to determine the influence of learning parameters and variations in brain structure on subsequent habit formation.
The research showed that poor instrumental learning performance in CUD patients was largely determined by difficulties with learning from feedback, as reflected by a significantly reduced learning rate.
Subsequent formation of habitual response patterns was partly explained by group status and individual variation in reinforcement sensitivity. White matter integrity within goal-directed networks was only associated with performance parameters in controls but not in CUD patients.
The data indicate that impairments in reinforcement learning are insufficient to account for enhanced habitual responding in CUD.View publication
Kanen JW, Ersche KD, Fineberg NA, Robbins TW, Cardinal RN
20 July 2019
Disorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms.
This study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses.
The researchers applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design.
The researchers compared seven models using a bridge sampling estimate of the marginal likelihood.
The results showed that stimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo).
Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward).
Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects.
The research showed how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD.
D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects.View publication
Robbins TW, Cardinal RN
4 April 2019
Psychopharmacology needs novel quantitative measures and theoretical approaches based on computational modelling that can be used to help translate behavioural findings from experimental animals to humans, including patients with neuropsychiatric disorders.
Here, researchers carried out a brief review which exemplifies this approach when applied to recent published studies of the effects of manipulating central dopaminergic and serotoninergic systems in rodents and marmoset monkeys, and possible comparisons with healthy human volunteers receiving systemic agents or patients with depression and schizophrenia.
Behavioural effects of central depletions of dopamine or serotonin in monkeys in probabilistic learning paradigms are characterised further by computational modelling methods and related to rodent and human data.
Several examples are provided of the power of computational modelling to derive new measures and reappraise conventional explanations of regional neurotransmitter depletion and other drug effects, whilst enhancing construct validation in patient groups. Specifically, effects are shown on such parameters as ‘stimulus stickiness’ and ‘side stickiness’, which occur over and above effects on standard parameters of reinforcement learning, reminiscent of some early innovations in data analysis in psychopharmacology.
Computational modelling provides a useful methodology for further detailed analysis of behavioural mechanisms that are affected by pharmacological manipulations across species and will aid the translation of experimental findings to understand the therapeutic effects of medications in neuropsychiatric disorders, as well as facilitating future drug discovery.View publication
Alsiö J, Phillips BU, Sala Bayo J, Nilsson SRO, Calafat-Pla TC, Rizwand A, Plumbridge J, López-Cruz L, Dalley JW, Cardinal RN, Mar AC, Robbins TW
19 June 2019
Dopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson’s disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear.
Here researchers tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback.
Male Lister Hooded rats were trained on a novel visual reversal learning task. Performance on “probe trials”, during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback.
The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism.
Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors.
The team found that D2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials. They concluded that D2R stimulation impairs reversal learning by blocking the impact of negative feedback.View publication
Publication: BMJ Open
Price A, Farooq R, Yuan J-M, Menon VB, Cardinal RN, O’Brien JT
3 November 2017
The researchers here aimed to use routine clinical data to investigate survival in dementia with Lewy bodies (DLB) compared with Alzheimer’s dementia (AD).
DLB is the second most common dementia subtype after AD, accounting for around 7% of dementia diagnoses in secondary care, though studies suggest that it is underdiagnosed by up to 50%.
Most previous studies of DLB have been based on select research cohorts, so little is known about the outcome of the disease in routine healthcare settings.
Working with Cambridgeshire & Peterborough NHS Foundation Trust, a mental health trust providing secondary mental health care in England, the researchers used samples from 251 DLB and 222 AD identified from an anonymised database, derived from electronic clinical case records across an 8-year period (2005-2012), with mortality data updated to May 2015.
Raw (uncorrected) median survival was 3.72 years for DLB and 6.95 years for AD. Controlling for age at diagnosis, comorbidity and antipsychotic prescribing the model predicted median survival for DLB was 3.3 years for males and 4.0 years for females, while median survival for AD was 6.7 years for males and 7.0 years for females.
The researchers concluded that survival from first presentation with cognitive impairment was markedly shorter in DLB compared with AD, independent of age, sex, physical comorbidity or antipsychotic prescribing.
This finding, in one of the largest clinical cohorts of DLB cases assembled to date, adds to existing evidence for poorer survival for DLB versus AD. There is an urgent need for further research to understand possible mechanisms accounting for this finding.View publication
Publication: BMC Medical Informatics and Decision Making
Rudolf N Cardinal
26 April 2017
Electronic medical records contain information of value for research, but contain identifiable and often highly sensitive confidential information.
Patient-identifiable information cannot in general be shared outside clinical care teams without explicit consent, but anonymisation/de-identification allows research uses of clinical data without explicit consent.
This article presents CRATE (Clinical Records Anonymisation and Text Extraction), an open-source software system with separable functions: (1) it anonymises or de-identifies arbitrary relational databases, with sensitivity and precision similar to previous comparable systems; (2) it uses public secure cryptographic methods to map patient identifiers to research identifiers (pseudonyms); (3) it connects relational databases to external tools for natural language processing; (4) it provides a web front end for research and administrative functions; and (5) it supports a specific model through which patients may consent to be contacted about research.
Creation and management of a research database from sensitive clinical records with secure pseudonym generation, full-text indexing, and a consent-to-contact process is possible and practical using entirely free and open-source software.View publication
Publication: npj Schizophrenia
Cardinal RN, Savulich G, Mann LM, Fernández-Egea E
21 October 2015
The impact of psychotropic drug choice upon admissions for schizophrenia is not well understood. This study aimed to examine the association between antipsychotic / antidepressant use and time in hospital for patients with schizophrenia.
The researchers conducted an observational study, using 8 years’ admission records and electronically generated drug histories from an institution providing secondary mental health care in Cambridgeshire, UK, covering the period 2005-2012 inclusive.
Patients with a coded ICD-10 diagnosis of schizophrenia were selected. The primary outcome measure was the time spent as an inpatient in a psychiatric unit. Antipsychotic and antidepressant drugs used by at least 5% of patients overall were examined for associations with admissions. Periods before and after drug commencement were compared for patients having pre-drug admissions, in mirror-image analyses correcting for overall admission rates.
Drug use in one 6-month calendar period was used to predict admissions in the next period, across all patients, in a regression analysis accounting for the effects of all other drugs studied and for time.
In mirror-image analyses, sulpiride, aripiprazole, clozapine, and olanzapine were associated with fewer subsequent admission days. In regression analyses, sulpiride, mirtazapine, venlafaxine, and clozapine-aripiprazole and clozapine-amisulpride combinations were associated with fewer subsequent admission days.
Use of these drugs was associated with fewer days in hospital. Causation is not implied and these findings require confirmation by randomized controlled trials.View publication
Publication: Journal of Medical EthicsView publication
Publication: Nature Medicine
Liam Gaziano, Claudia Giambartolomei, Alexandre C. Pereira, Anna Gaulton, Daniel C. Posner, Sonja A. Swanson, Yuk-Lam Ho, Sudha K. Iyengar, Nicole M. Kosik, Marijana Vujkovic, David R. Gagnon, A. Patrícia Bento, Inigo Barrio-Hernandez, Lars Rönnblom, Niklas Hagberg, Christian Lundtoft, Claudia Langenberg, Maik Pietzner, Dennis Valentine, Stefano Gustincich, Gian Gaetano Tartaglia, Elias Allara, Praveen Surendran, Stephen Burgess, Jing Hua Zhao, James E. Peters, Bram P. Prins, Emanuele Di Angelantonio, Poornima Devineni, Yunling Shi, Kristine E. Lynch, Scott L. DuVall, Helene Garcon, Lauren O. Thomann, Jin J. Zhou, Bryan R. Gorman, Jennifer E. Huffman, Christopher J. O’Donnell, Philip S. Tsao, Jean C. Beckham, Saiju Pyarajan, Sumitra Muralidhar, Grant D. Huang, Rachel Ramoni, Pedro Beltrao, John Danesh, Adriana M. Hung, Kyong-Mi Chang, Yan V. Sun, Jacob Joseph, Andrew R. Leach, Todd L. Edwards, Kelly Cho, J. Michael Gaziano, Adam S. Butterworth, Juan P. Casas & VA Million Veteran Program COVID-19 Science Initiative
9 April 2021
Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, researchers conducted Mendelian randomization (MR) analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development.View publication
Hannah Wand, Samuel A. Lambert, Cecelia Tamburro, Michael A. Iacocca, Jack W. O’Sullivan, Catherine Sillari, Iftikhar J. Kullo, Robb Rowley, Jacqueline S. Dron, Deanna Brockman, Eric Venner, Mark I. McCarthy, Antonis C. Antoniou, Douglas F. Easton, Robert A. Hegele, Amit V. Khera, Nilanjan Chatterjee, Charles Kooperberg, Karen Edwards, Katherine Vlessis, Kim Kinnear, John N. Danesh, et al
10 March 2021
This research is a perspective piece that provides a framework to promote the validity, transparency, and reproducibility of polygenic risk scores (PRS) by encouraging authors to detail the study population, statistical methods, and potential clinical utility of a published score.
Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics.
However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, the researchers present the Polygenic Risk Score Reporting Standards (PRS-RS), in which they update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field.
Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications.
The researchers encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.View publication
Publication: Nature Genetics
Samuel A. Lambert, Laurent Gil, Simon Jupp, Scott C. Ritchie, Yu Xu, Annalisa Buniello, Aoife McMahon, Gad Abraham, Michael Chapman, Helen Parkinson, John Danesh, Jacqueline A. L. MacArthur & Michael Inouye
10 March 2021
Researchers have led a report describing an important new set of reporting guidelines and an international open science database for polygenic risk scores, which are powerful genomic tools being increasingly used to predict disease outcomes and traits.
The Polygenic Score (PGS) Catalog is an open resource of published scores (including variants, alleles and weights) and consistently curated metadata required for reproducibility and independent applications.
The PGS Catalog has capabilities for user deposition, expert curation and programmatic access, thus providing the community with a platform for PGS dissemination, research and translation.
It promotes PGS reproducibility by providing a venue to annotate and distribute scores according to current exemplar reporting standards. As such, it allows users to reuse and evaluate PGSs, to firmly establish their predictive ability and facilitate further investigations of clinical utility.
- Visit the PGS Catalog website: https://www.PGSCatalog.org
Angela Wood, Rachel Denholm, Sam Hollings, Jennifer Cooper, Samantha Ip, Venexia Walker, Spiros Denaxas, Ashley Akbari, Jonathan Sterne, Cathie Sudlow, Rachel Denholm, Sam Hollings, Jennifer Cooper, Samantha Ip, Venexia Walker, Spiros Denaxas, Amitava Banerjee, William Whiteley, Alvina Lai, Rouven Priedon, Cathie Sudlow, Lynn Morrice, Debbie Ringham, Suzannah Power, Lynn Laidlaw, Michael Molete, John Walsh, Garry Coleman, Cath Day, Elizabeth Gaffney, Tim Gentry, Lisa Gray, Sam Hollings, Richard Irvine, Brian Roberts, Estelle Spence, Janet Waterhouse
23 February 2021
A new population-wide health data resource to accelerate research on COVID-19 and cardiovascular disease in England.
This work has been led by the CVD-COVID-UK consortium in partnership with NHS Digital. The CVD-COVID-UK consortium is a collaborative group of more than 130 members across 40 institutions working to understand the relationship between COVID-19 and cardiovascular diseases. The consortium is managed by the British Heart Foundation (BHF) Data Science Centre, led by Health Data Research UK.View publication
Christopher N. Osuafor, Catriona Davidson, Alistair J. Mackett, Marie Goujon, Lelane Van Der Poel, Vince Taylor, Jacobus Preller, Robert J. B. Goudie and Victoria L. Keevil
1 February 2021
In an observational study, researchers in Cambridge investigated the clinical features and inpatient trajectories of older adults hospitalised with COVID-19 and explore relationships with frailty.View publication
Publication: AHA Journals - Hypertension
Dipender Gill, Alan C. Cameron, Stephen Burgess, Xue Li, Daniel J. Doherty, Ville Karhunen, Azmil H. Abdul-Rahim, Martin Taylor-Rowan, Verena Zuber, Philip S. Tsao, Derek Klarin, Evangelos Evangelou, Paul Elliott, Scott M. Damrauer, Terence J. Quinn, Abbas Dehghan, Evropi Theodoratou, Jesse Dawson, Ioanna Tzoulaki
28 December 2020
Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, researchers performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials.View publication
Eric L. Harshfield, Lisa Pennells, Joseph, Schwartz, Peter Willeit, Stephen Kaptoge, Steven Bell, Jonathan A. Shaffer, Thomas Bolton, Sarah Spackman, Sylvia Wassertheil-Smoller, Frank Kee, Philippe Amouyel, Steven J. Shea, Lewis H. Kuller, Jussi Kauhanen, E. M. van Zutphen, Dan G. Blazer, Harlan Krumholz, Paul J. Nietert, Daan Kromhout, MD19; Gail Laughlin, Lisa Berkman, Robert B. Wallace, Leon A. Simons, Elaine M. Dennison, Elizabeth L. M. Barr, Haakon E. Meyer, Angela M. Wood, John Danesh, Emanuele Di Angelantonio, Karina W. Davidson
15 December 2020
People who experience symptoms of depression are more likely to go on to develop heart disease or suffer a stroke than those who report good mental health.
Researchers analysed the health records of over half a million people, with no prior history of heart and circulatory disease, who were enrolled to two different studies.
Upon joining the studies, participants were given a score based on questionnaires assessing their mood and any symptoms of depression that they had experienced over the previous one to two weeks.
Over 10, researchers have found that those in the highest scoring group, and with most severe symptoms of depression, were more likely to have since developed heart disease or to have had a stroke, compared to people with the lowest scores.View publication
Publication: Nature Genetics
Praveen Surendran, Joanna M. M. Howson et al
23 November 2020
Increased blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and related disability worldwide. Identifying biological pathways associated with blood pressure is important to understand the aetiology of CVD.
In this study involving collaborators from across the globe, and participants from diverse ancestries, researchers investigated whether genetic variants that a small proportion of people carry have an impact on blood pressure regulation and more readily implicate the genes underlying blood pressure regulation.
They identified 87 such genetic variants influencing blood pressure regulation that only a small proportion of people carry. In addition to identifying novel candidate genes associated with blood pressure, they showed a potential link between foetal development and an inverse relationship between systolic and diastolic blood pressure with stroke.
As shown in this study, a complex outcome like blood pressure requires large sample sizes to detect genetic variation associated with blood pressure that are rare in humans; studies to date have mainly looked at genetic variants that are carried by many people and therefore have very small effects on blood pressure regulation.
This study contributes to a significant improvement in researchers’ understanding of key genes controlling a risk factor like BP so they can better understand complex diseases like CVD and help identify new blood pressure therapies.View publication
Publication: Journal of Magnetic Resonance Imaging
Dimitri A. Kessler, James W. MacKay, Scott McDonald, Stephen McDonnell, Andrew J. Grainger, Alexandra R. Roberts, Robert L. Janiczek, Martin J. Graves, Joshua D. Kaggie, Fiona J. Gilbert
The researchers wanted to further understanding of the biomechanical properties of articular cartilage in our knee joints. By combining quantitative magnetic resonance imaging (MRI) and sophisticated 3D surface analysis methods of articular cartilage they were able to determine changes in cartilage microstructure following a mild, 5-minute stepping exercise in young, healthy individuals.
The team determined that our quantitative MRI methods are sensitive to changes of different compositional characteristics of articular cartilage such as changes in its water content or macromolecular structure following the stepping exercise. While previous studies have shown that changes in cartilage morphology (thickness, volume) recovers almost fully in about 45–90 minutes, they showed that the compositional changes induced by the exercise do not recover within an hour following cessation.
This is important because measuring the responses of cartilage to dynamic joint loading may present a way of determining cartilage health state as well as differences in healthy and diseased cartilage. With the exercise performed in this study being short and of limited duration, it could be extended for use in patients with early‐stage knee joint disease and minimal accompanying pain. As exercise is recommended as a form of conservative management of joint disease-related symptoms, the study provides an initial interpretation of short-term changes that occur in cartilage microstructure in response to exercise.View publication
Ranya Mulchandani, Hayley E Jones, Sian Taylor-Phillips, Justin Shute, Keith Perry, Shabnam Jamarani, Tim Brooks, Andre Charlett, Matthew Hickman, Isabel Oliver, Stephen Kaptoge, John Danesh, Emanuele Di Angelantonio, Anthony E Ades, David H Wyllie,
11 November 2020
The accuracy of a COVID-19 test is lower than previously believed. Testing nearly 5,000 samples found some results were giving false positives.View publication
Publication: European Heart Journal
Tammy Y N Tong, Paul N Appleby, Timothy J Key, Christina C Dahm, Kim Overvad, Anja Olsen, Anne Tjønneland, Verena Katzke, Tilman Kühn, Heiner Boeing, Anna Karakatsani, Eleni Peppa, Antonia Trichopoulou, Elisabete Weiderpass, Giovanna Masala, Sara Grioni, Salvatore Panico, Rosario Tumino, Jolanda M A Boer, W M Monique Verschuren, J Ramón Quirós, Antonio Agudo, Miguel Rodríguez-Barranco, Liher Imaz, María-Dolores Chirlaque, Conchi Moreno-Iribas, Gunnar Engström, Emily Sonestedt, Marcus Lind, Julia Otten, Kay-Tee Khaw, Dagfinn Aune, Elio Riboli, Nicholas J Wareham, Fumiaki Imamura, Nita G Forouhi, Emanuele di Angelantonio, Angela M Wood, Adam S Butterworth, Aurora Perez-Cornago
24 February 2020
This research looked at more than 418,000 people in nine European countries who were recruited to the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1992 and 2000. Researchers found that while higher intakes of fruit, vegetables, fibre, milk, cheese or yoghurt were each linked to a lower risk of ischaemic stroke, there was no significant association with a lower risk of haemorrhagic stroke.
As the study is observational, it cannot show that the foods studied cause an increase or decrease in risk of ischaemic or haemorrhagic stroke, only that they are associated with different risks.View publication
Publication: The Lancet
Michael J Sweeting, Katya L Masconi, PhD, Edmund Jones, PhD, Pinar Ulug, PhD, Matthew J Glover, MSc, Prof Jonathan A Michaels, MChir, Prof Matthew J Bown, MD, Prof Janet T Powell, MD, Prof Simon G Thompson, DSc
26 July 2018
The NHS introduced ultrasound screening in men aged 65 and over in 2009 to detect and treat the condition – which arises when the main blood vessel swells in the abdomen, and is symptomless until the point of rupture. Since the launch, the programme has been successfully screening and identifying men at risk of an AAA.
Researchers wanted to see if UK women – who are less likely to have AAAs – could also benefit from a similar screening programme. Read the full press release hereView publication
Publication: Diabetes Care
Vissers LET, Sluijs I, van der Schouw YT, Forouhi NG, Imamura F, Burgess S, et al.
6 February 2019View publication
Publication: Nature Genetics
Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, et al.
25 February 2019View publication
Linda M. O’Keeffe, PhD; Anna Ramond, DPharm; Clare Oliver-Williams, PhD; Peter Willeit, MD; Ellie Paige, PhD; Patrick Trotter, MBChB; Jonathan Evans, MBChB; Jonas Wadström, MD; Michael Nicholson, MD; Dave Collett, PhD; Emanuele Di Angelantonio, MD
30 January 2018
Living kidney donors are not at increased risk for some health outcomes previously of concern, but do seem at risk for worse blood pressure and kidney function than nondonors. In addition, female donors seem to be at increased risk for preeclampsia.
A team lead by researchers reviewed 52 published studies comprising more than 100,000 living kidney donors and more than 110,000 nondonors to assess the mid- and long-term health risks associated with living kidney donation in adults.
The data showed that kidney donors had higher diastolic blood pressure, poorer renal function, and higher risk for ESRD than nondonors. Female donors had an almost two-fold higher risk than nondonors for pregnancy-related complications, such as preeclampsia.
There was no evidence that living kidney donors had higher risk for mortality, cardiovascular disease, or type 2 diabetes, or reduced quality of life.View publication
Sun YQ, Burgess S, Staley JR, Wood AM, Bell S, Kaptoge SK, et al.
26 March 2019View publication
Publication: European Respiratory Journal
Sofianopoulou E, Kaptoge S, Graf S, Hadinnapola C, Treacy CM, Church C, et al.
30 May 2019View publication
Publication: Circulation: Genomic and Precision Medicine.
Larsson SC, Allara E, Mason AM, Michaelsson K, Burgess S.
31 January 2019View publication
Publication: The New England Journal of Medicine
Ference BA, Ray KK, Catapano AL, Ference TB, Burgess S, Neff DR, et al.
14 March 2019View publication
Luo S, Au Yeung SL, Zhao JV, Burgess S, Schooling CM.
6 March 2019View publication
Publication: Nature Communications
Wittemans LBL, Lotta LA, Oliver-Williams C, Stewart ID, Surendran P, Karthikeyan S, et al.
5 March 2019View publication
Publication: Genomic and Precision Medicine
Paige E, Clement M, Lareyre F, Sweeting M, Raffort J, Grenier C, et al.
18 January 2019View publication
Publication: Nature Communications
Emdin CA, Khera AV, Chaffin M, Klarin D, Natarajan P, Aragam K, et al.
24 April 2018View publication
Publication: Nature Communications
Yao C, Chen G, Song C, Keefe J, Mendelson M, Huan T, et al. .
15 August 2018View publication
Publication: Nature Genetics
Mahajan A, Wessel J, Willems SM, Zhao W, Robertson NR, Chu AY, et al.
9 April 2018View publication
Publication: Journal of the American College of Cardiology
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8 October 2018
Genetic factors have long been known to be major contributors of someone’s risk of developing coronary heart disease – the leading cause of heart attacks. Currently to identify those at risk doctors use scores based on lifestyle and clinical conditions associated with coronary heart disease such as cholesterol level, blood pressure, diabetes and smoking. But these scores are imprecise, age-dependent and miss a large proportion of people who appear ‘healthy’, but will still develop the disease.
The ‘big-data’ GRS technique takes into account 1.7 million genetic variants in a person’s DNA to calculate their underlying genetic risk for coronary heart disease.
The team analysed genomic data of nearly half a million people from the UK Biobank research project aged between 40-69 years. This included over 22,000 people who had coronary heart disease.
The GRS was better at predicting someone’s risk of developing heart disease than each of the classic risk factors for coronary heart disease alone. The ability of the GRS to predict coronary heart disease was also largely independent of these known risk factors. This showed that the genes which increase the risk of coronary heart disease don’t simply work by elevating blood pressure or cholesterol, for example.
People with a genomic risk score in the top 20 per cent of the population were over four-times more likely to develop coronary heart disease than someone with a genomic risk score in the bottom 20 per cent. Read the full press releaseView publication
Publication: Nature Genetics
Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, et al.
12 March 2018View publication
Publication: Nature Communications
Iglesias AI, Mishra A, Vitart V, Bykhovskaya Y, Hohn R, Springelkamp H, et al.
14 May 2018View publication
Publication: The Lancet
Angela M Wood PhD, P, Stephen Kaptoge, PhD, Adam S Butterworth, PhD, Peter Willeit, MD, Samantha Warnakula, PhD, Thomas Bolton, MMath, Ellie Paige, PhD, Dirk S Paul, PhD, Michael Sweeting, PhD, Stephen Burgess, PhD, Steven Bell, PhD, William Astle, PhD, David Stevens, MSc, Albert Koulman, PhD, Randi M Selmer, PhD, Prof W M Monique Verschuren, PhD, Prof Shinichi Sato, MD, Prof Inger Njølstad, MD, Prof Mark Woodward, PhD, Prof Veikko Salomaa, MD, Prof Børge G Nordestgaard, MD, Prof Bu B Yeap, MBBS, Prof Astrid Fletcher, PhD, Prof Olle Melander, MD, Prof Lewis H Kuller, MD, Beverley Balkau, PhD, Prof Michael Marmot, FMedSci, Prof Wolfgang Koenig, MD, Prof Edoardo Casiglia, MD, Prof Cyrus Cooper, FMedSci, Volker Arndt, MD, Prof Oscar H Franco, MD, Patrik Wennberg, MD, Prof John Gallacher, PhD, Agustín Gómez de la Cámara, MD, Prof Henry Völzke, MD, Christina C Dahm, PhD, Caroline E Dale, PhD, Manuela M Bergmann, PhD, Carlos J Crespo, PhD, Prof Yvonne T van der Schouw, PhD, Prof Rudolf Kaaks, MD, Leon A Simons, MD, Pagona Lagiou, MD, Josje D Schoufour, PhD, Jolanda M A Boer, PhD, Prof Timothy J Key, DPhil, Beatriz Rodriguez, MD, Conchi Moreno-Iribas, PhD, Karina W Davidson, PhD, James O Taylor, MD, Carlotta Sacerdote, PhD, Prof Robert B Wallace, MD, J Ramon Quiros, MD, Prof Rosario Tumino, MD, Dan G Blazer II, MD, Prof Allan Linneberg, MD, Makoto Daimon, MD, Salvatore Panico, MD, Barbara Howard, PhD, Guri Skeie, PhD, Prof Timo Strandberg, MD, Prof Elisabete Weiderpass, PhD, Prof Paul J Nietert, PhD, Prof Bruce M Psaty, MD, Prof Daan Kromhout, PhD, Elena Salamanca-Fernandez, MSc, Prof Stefan Kiechl, MD, Prof Harlan M Krumholz, MD, Sara Grioni, BSc, Domenico Palli, MD, José M Huerta, PhD, Prof Jackie Price, MD, Prof Johan Sundström, MD, Larraitz Arriola, MD, Prof Hisatomi Arima, MD, Ruth C Travis, DPhil, Prof Demosthenes B Panagiotakos, PhD, Anna Karakatsani, MD, Prof Antonia Trichopoulou, MD, Tilman Kühn, PhD, Prof Diederick E Grobbee, MD, Elizabeth Barrett-Connor, MD, Natasja van Schoor, MD, Prof Heiner Boeing, PhD, Prof Kim Overvad, MD, Prof Jussi Kauhanen, MD, Prof Nick Wareham, MD, Claudia Langenberg, MD, Prof Nita Forouhi, PhD, Maria Wennberg, PhD, Prof Jean-Pierre Després, DPhil, Prof Mary Cushman, MD, Jackie A Cooper, MSc, Prof Carlos J Rodriguez, MD, Masaru Sakurai, MD, Jonathan E Shaw, PhD, Prof Matthew Knuiman, PhD, Trudy Voortman, PhD, Prof Christa Meisinger, MD, Anne Tjønneland, MD, Prof Hermann Brenner, MD, Luigi Palmieri, PhD, Jean Dallongeville, MD, Prof Eric J Brunner, PhD, Prof Gerd Assmann, MD, Maurizio Trevisan, MD, Richard F Gillum, MD, Prof Ian Ford, PhD, Prof Naveed Sattar, FMedSci, Mariana Lazo, MD, Prof Simon G Thompson, FMedSci, Pietro Ferrari, PhD, Prof David A Leon, PhD, Prof George Davey Smith, MD, Prof Richard Peto, FRS, Prof Rod Jackson, PhD, Prof Emily Banks, PhD, Emanuele Di Angelantonio, MD, Prof John Danesh
14 April 2018
Regularly drinking more than the recommended UK guidelines for alcohol could take years off your life, according to new research from the University of Cambridge. The study shows that drinking more alcohol is associated with a higher risk of stroke, fatal aneurysm, heart failure and death.
The authors say their findings challenge the widely held belief that moderate drinking is beneficial to cardiovascular health, and support the UK’s recently lowered guidelines. The study compared the health and drinking habits of over 600,000 people in 19 countries worldwide and controlled for age, smoking, history of diabetes, level of education and occupation.
Publication: The Lancet Haemotology
Lane WJ, Westhoff CM, Gleadall NS, Aguad M, Smeland-Wagman R, Vege S, et al.
1 June 2018View publication
Publication: Oxford Academic
Lisa Pennells, Stephen Kaptoge, AngelaWood, Mike Sweeting , Xiaohui Zhao, Ian White, Stephen Burgess, Peter Willeit, Thomas Bolton, Karel G.M. Moons, Yvonne T. van der Schouw, Randi Selmer, Kay-Tee Khaw, Vilmundur Gudnason, Gerd Assmann, Philippe Amouyel, Veikko Salomaa, Mika Kivimaki, Børge G. Nordestgaard, Michael J. Blaha, Lewis H. Kuller, Hermann Brenner, Richard F. Gillum, Christa Meisinger, Ian Ford, MatthewW. Knuiman, Annika Rosengren, Debbie A. Lawlor, Henry Vo¨ lzke, Cyrus Cooper, Alejandro Marı´n Iba~nez, Edoardo Casiglia, Jussi Kauhanen, Jackie A. Cooper, Beatriz Rodriguez, Johan Sundstro¨m, Elizabeth Barrett-Connor, Rachel Dankner, Paul J. Nietert, KarinaW. Davidson, Robert B.Wallace, Dan G. Blazer, Cecilia Bjo¨ rkelund, Chiara Donfrancesco, Harlan M. Krumholz, Aulikki Nissinen, Barry R. Davis, Sean Coady, Peter H.Whincup, Torben Jørgensen, Pierre Ducimetiere, Maurizio Trevisan, Gunnar Engstro¨m, Carlos J. Crespo, TomW. Meade, Marjolein Visser, Daan Kromhout, Stefan Kiechl, Makoto Daimon, Jackie F. Price, Agustin Go´mez de la Ca´mara, JWouter Jukema, Benoıˆt Lamarche, Altan Onat, Leon A. Simons, Maryam Kavousi, Yoav Ben-Shlomo, John Gallacher, Jacqueline M. Dekker, Hisatomi Arima, Nawar Shara, RobertW. Tipping, Ronan Roussel, Eric J Brunner, Wolfgang Koenig, Masaru Sakurai, Jelena Pavlovic, Ron T. Gansevoort, Dorothea Nagel, Uri Goldbourt, Elizabeth L.M. Barr, Luigi Palmieri, Inger Njølstad, Shinichi Sato,W.M. Monique Verschuren, Cherian V. Varghese, Ian Graham, Oyere Onuma, Philip Greenland, MarkWoodward, Majid Ezzati, Bruce M. Psaty, Naveed Sattar, Rod Jackson, Paul M. Ridker, Nancy R. Cook, Ralph B. D’Agostino,
22 November 2018View publication
Publication: The Lancet
Emanuele Di Angelantonio, Prof Simon G Thompson, Stephen Kaptoge, Carmel Moore, Matthew Walker, Prof Jane Armitage, Prof Willem H Ouwehand, Prof David J Roberts, Prof John Danesh
20 September 2017View publication
Danish Saleheen, Pradeep Natarajan, Irina M. Armean, Wei Zhao, Asif Rasheed, Sumeet A. Khetarpal, Hong-Hee Won, Konrad J. Karczewski, Anne H. O’Donnell-Luria, Kaitlin E. Samocha, Benjamin Weisburd, Namrata Gupta, Mozzam Zaidi, Maria Samuel, Atif Imran, Shahid Abbas, Faisal Majeed, Madiha Ishaq, Saba Akhtar, Kevin Trindade, Megan Mucksavage, Nadeem Qamar, Khan Shah Zaman, Zia Yaqoob, Tahir Saghir, Syed Nadeem Hasan Rizvi, Anis Memon, Nadeem Hayyat Mallick, Mohammad Ishaq, Syed Zahed Rasheed, Fazal-ur-Rehman Memon, Khalid Mahmood, Naveeduddin Ahmed, Ron Do, Ronald M. Krauss, Daniel G. MacArthur, Stacey Gabriel, Eric S. Lander, Mark J. Daly, Philippe Frossard, John Danesh, Daniel J. Rader & Sekar Kathiresan
12 April 2017View publication
Astle WJ, Elding H, Jiang T, Allen D, Ruklisa D, Mann AL, Mead D, Bouman H, Riveros-Mckay F, Kostadima MA, Lambourne JJ, Sivapalaratnam S, Downes K, Kundu K, Bomba L, Berentsen K, Bradley JR, Daugherty LC, Delaneau O, Freson K, Garner SF, Grassi L, Guerrero J, Haimel M, Janssen-Megens EM, Kaan A, Kamat M, Kim B, Mandoli A, Marchini J, Martens JH, Meacham S, Megy K, O’Connell J, Petersen R, Sharifi N, Sheard SM, Staley JR, Tuna S, van der Ent M, Walter K, Wang SY, Wheeler E, Wilder SP, Iotchkova V, Moore C, Sambrook J, Stunnenberg HG, Di Angelantonio E, Kaptoge S, Kuijpers TW, Carrillo-de-Santa-Pau E, Juan D, Rico D, Valencia A, Chen L, Ge B, Vasquez L, Kwan T, Garrido-Martín D, Watt S, Yang Y, Guigo R, Beck S, Paul DS, Pastinen T, Bujold D, Bourque G, Frontini M, Danesh J, Roberts DJ, Ouwehand WH, Butterworth AS, Soranzo N.
17 November 2016View publication
Publication: Nat Genet 2016
Surendran P, Drenos F, Young R, Warren H, Cook JP, Manning AK, Grarup N, Sim X, Barnes DR, Witkowska K, Staley JR, Tragante V, Tukiainen T, Yaghootkar H, Masca N, Freitag DF, Ferreira T, Giannakopoulou O, Tinker A, Harakalova M, Mihailov E, Liu C, Kraja AT, Nielsen SF, Rasheed A, Samuel M, Zhao W, Bonnycastle LL, Jackson AU, Narisu N, Swift AJ, Southam L, Marten J, Huyghe JR, Stančáková A, Fava C, Ohlsson T, Matchan A, Stirrups KE, Bork-Jensen J, Gjesing AP, Kontto J, Perola M, Shaw-Hawkins S, Havulinna AS, Zhang H, Donnelly LA, Groves CJ, Rayner NW, Neville MJ, Robertson NR, Yiorkas AM, Herzig KH, Kajantie E, Zhang W, Willems SM, Lannfelt L, Malerba G, Soranzo N, Trabetti E, Verweij N, Evangelou E, Moayyeri A, Vergnaud AC, Nelson CP, Poveda A, Varga TV, Caslake M, de Craen AJ, Trompet S, Luan J, Scott RA, Harris SE, Liewald DC, Marioni R, Menni C, Farmaki AE, Hallmans G, Renström F, Huffman JE, Hassinen M, Burgess S, Vasan RS, Felix JF; CHARGE-Heart Failure Consortium, Uria-Nickelsen M, Malarstig A, Reilly DF, Hoek M, Vogt TF, Lin H, Lieb W; EchoGen Consortium, Traylor M, Markus HS; METASTROKE Consortium, Highland HM, Justice AE, Marouli E; GIANT Consortium, Lindström J, Uusitupa M, Komulainen P, Lakka TA, Rauramaa R, Polasek O, Rudan I, Rolandsson O, Franks PW, Dedoussis G, Spector TD; EPIC-InterAct Consortium, Jousilahti P, Männistö S, Deary IJ, Starr JM, Langenberg C, Wareham NJ, Brown MJ, Dominiczak AF, Connell JM, Jukema JW, Sattar N, Ford I, Packard CJ, Esko T, Mägi R, Metspalu A, de Boer RA, van der Meer P, van der Harst P; Lifelines Cohort Study, Gambaro G, Ingelsson E, Lind L, de Bakker PI, Numans ME, Brandslund I, Christensen C, Petersen ER, Korpi-Hyövälti E, Oksa H, Chambers JC, Kooner JS, Blakemore AI, Franks S, Jarvelin MR, Husemoen LL, Linneberg A, Skaaby T, Thuesen B, Karpe F, Tuomilehto J, Doney AS, Morris AD, Palmer CN, Holmen OL, Hveem K, Willer CJ, Tuomi T, Groop L, Käräjämäki A, Palotie A, Ripatti S, Salomaa V, Alam DS, Majumder AA, Di Angelantonio E, Chowdhury R, McCarthy MI, Poulter N, Stanton AV, Sever P, Amouyel P, Arveiler D, Blankenberg S, Ferrières J, Kee F, Kuulasmaa K, Müller-Nurasyid M, Veronesi G, Virtamo J, Deloukas P; Wellcome Trust Case Control Consortium, Elliott P; Understanding Society Scientific Group, Zeggini E, Kathiresan S, Melander O, Kuusisto J, Laakso M, Padmanabhan S, Porteous DJ, Hayward C, Scotland G, Collins FS, Mohlke KL, Hansen T, Pedersen O, Boehnke M, Stringham HM; EPIC-CVD Consortium, Frossard P, Newton-Cheh C; CHARGE+ Exome Chip Blood Pressure Consortium, Tobin MD, Nordestgaard BG; T2D-GENES Consortium; GoT2DGenes Consortium; ExomeBP Consortium; CHD Exome+ Consortium, Caulfield MJ, Mahajan A, Morris AP, Tomaszewski M, Samani NJ, Saleheen D, Asselbergs FW, Lindgren CM, Danesh J, Wain LV, Butterworth AS, Howson JM, Munroe PB.
12 September 2016View publication
Publication: Lancet Diabetes Endocrinol
Willeit P, Kaptoge S, Welsh P, Butterworth AS, Chowdury R, Spackman S, Pennells L,Gao P, Burgess S, Freitag DF, Sweeting M, Wood AM, Cook NR, Judd S, Trompet S, Nambi V, Hecht Olsen M, Everett BM, Kee F, Ärnlöv J, Salomaa V, Levy D, Kauhanen J, Laukkanen JA, Kavousi M, Ninomiya T, Casas J-P, Daniels LB, Lind L, Kistorp CN, Rosenberg J, Mueller T, Rubattu S, Panagiotakos DB, Franco OH, de Lemos JA, Luchner A, St Marien K, Kizer JR, Kiechl S, Salonen JT, Wannamethee SG, Nordestgaard BG, Anderson J, Jørgensen T, Melander O, Ballantyne CM, DeFilippi C, Ridker PM, Cushman M, Rosamond WD, Thompson SG, Gudnason V, Sattar N, Danesh J, Di Angelantonio E.
3 September 2016View publication
Di Angelantonio E, Bhupathiraji SN, Wormser D, Gao P, Kaptoget S, Berrington de Gonzalez A, Cairns BJ, Huxley R, Jackson CL, Joshy G, Lewington S, Manson JE, Murphy N, Patel AV, Samet JM, Woodward M, Zheng W, Zhou M, Bansal N, Barricarte A, Carter B, Cerhan JR, Collins R, Davey Smith G, Franco OH, Green J, Halsey J, Hildebrand JS, Jung KJ, Korda RJ, McLerran DF, Moore SC, O’Keeffe LM, Paige E, Ramond A, Reeves GK, Rolland B, Sacerdote C, Sattar N, Sofanopoulou E,Stevens J, Thun M, Ueshima H, Yang L, Duk Yun Y, Willeit P, Banks E, Beral V, Chen Z, Gapstur SM, Gunter MJ, Hartge P, Jee SH, Lam T-H, Peto R, Potter JD, Willet WC, Thompson SG, Danesh J, Hu FB
13 July 2016View publication
Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, Jukema JW, De Craen A, Deloukas P, Sattar N, Ford I, Packard C, Majumder Aa, Alam DS, Di Angelantonio E, Abecasis G, Chowdhury R, Erdmann J, Nordestgaard BG, Nielsen SF, Tybjærg-Hansen A, Schmidt RF, Kuulasmaa K, Liu DJ, Perola M, Blankenberg S, Salomaa V, Männistö S, Amouyel P, Arveiler D, Ferrieres J, Müller-Nurasyid M, Ferrario M, Kee F, Willer CJ, Samani N, Schunkert H, Butterworth AS, Howson JM, Peloso GM, Stitziel NO, Danesh J, Kathiresan S, Rader DJ; CHD Exome+ Consortium; CARDIoGRAM Exome Consortium; Global Lipids Genetics Consortium.
11 March 2016View publication