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| 2. |
- Bassford, Chris, et al.
(author)
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Developing an intervention around referral and admissions to intensive care : a mixed-methods study
- 2019
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Reports (other academic/artistic)abstract
- Background: Intensive care treatment can be life-saving, but it is invasive and distressing for patients receiving it and it is not always successful. Deciding whether or not a patient will benefit from intensive care is a difficult clinical and ethical challenge.Objectives: To explore the decision-making process for referral and admission to the intensive care unit and to develop and test an intervention to improve it.Methods: A mixed-methods study comprising (1) two systematic reviews investigating the factors associated with decisions to admit patients to the intensive care unit and the experiences of clinicians, patients and families; (2) observation of decisions and interviews with intensive care unit doctors, referring doctors, and patients and families in six NHS trusts in the Midlands, UK; (3) a choice experiment survey distributed to UKintensive care unit consultants and critical care outreach nurses, eliciting their preferences for factors used in decision-making for intensive care unit admission; (4) development of a decision-support intervention informed by the previous work streams, including an ethical framework for decision-making and supporting referral and decision-support forms and patient and family information leaflets. Implementation feasibility was tested in three NHS trusts; (5) development and testing of a tool to evaluate the ethical quality of decision-making related to intensive care unit admission, based on the assessment of patient records The tool was tested for inter-rater and intersite reliability in 120 patient records.Results: Influences on decision-making identified in the systematic review and ethnographic study included age, presence of chronic illness, functional status, presence of a do not attempt cardiopulmonary resuscitation order, referring specialty, referrer seniority and intensive care unit bed availability. Intensive care unit doctors used a gestalt assessment of the patient when making decisions. The choice experiment showed that age was the most important factor in consultants’ and critical care outreach nurses’ preferences for admission. The ethnographic study illuminated the complexity of the decision-making process, and the importanceof interprofessional relationships and good communication between teams and with patients and families. Doctors found it difficult to articulate and balance the benefits and burdens of intensive care unit treatment for a patient. There was low uptake of the decision-support intervention, although doctors who used it noted that it improved articulation of reasons for decisions and communication with patients.Limitations: Limitations existed in each of the component studies; for example, we had difficulty recruiting patients and families in our qualitative work. However, the project benefited from a mixed-method approachthat mitigated the potential limitations of the component studies. Conclusions: Decision-making surrounding referral and admission to the intensive care unit is complex. This study has provided evidence and resources to help clinicians and organisations aiming to improve thedecision-making for and, ultimately, the care of critically ill patients.Future work: Further research is needed into decision-making practices, particularly in how best to engage with patients and families during the decision process. The development and evaluation of trainingfor clinicians involved in these decisions should be a priority for future work.
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| 3. |
- Butler, Eadaoin M., et al.
(author)
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A prediction model for childhood obesity in New Zealand
- 2021
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11
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Journal article (peer-reviewed)abstract
- Several early childhood obesity prediction models have been developed, but none for New Zealand's diverse population. We aimed to develop and validate a model for predicting obesity in 4-5-year-old New Zealand children, using parental and infant data from the Growing Up in New Zealand (GUiNZ) cohort. Obesity was defined as body mass index (BMI) for age and sex >= 95th percentile. Data on GUiNZ children were used for derivation (n=1731) and internal validation (n=713). External validation was performed using data from the Prevention of Overweight in Infancy Study (POI, n=383) and Pacific Islands Families Study (PIF, n=135) cohorts. The final model included: birth weight, maternal smoking during pregnancy, maternal pre-pregnancy BMI, paternal BMI, and infant weight gain. Discrimination accuracy was adequate [AUROC=0.74 (0.71-0.77)], remained so when validated internally [AUROC=0.73 (0.68-0.78)] and externally on PIF [AUROC=0.74 [0.66-0.82)] and POI [AUROC=0.80 (0.71-0.90)]. Positive predictive values were variable but low across the risk threshold range (GUiNZ derivation 19-54%; GUiNZ validation 19-48%; and POI 8-24%), although more consistent in the PIF cohort (52-61%), all indicating high rates of false positives. Although this early childhood obesity prediction model could inform early obesity prevention, high rates of false positives might create unwarranted anxiety for families.
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| 4. |
- Danaei, Goodarz, et al.
(author)
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Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331288 participants
- 2015
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In: The Lancet Diabetes & Endocrinology. - 2213-8595 .- 2213-8587. ; 3:8, s. 624-637
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Journal article (peer-reviewed)abstract
- Background Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA(1c). We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. Methods We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA(1c) (HbA(1c) >= 6 . 5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG >= 7 . 0 mmol/L or 2hOGTT >= 11 . 1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. Findings Population prevalence of diabetes based on FPG- or-2hOGTT was correlated with prevalence based on FPG alone (r= 0 . 98), but was higher by 2-6 percentage points at different prevalence levels. Prevalence based on HbA(1c) was lower than prevalence based on FPG in 42 . 8% of age-sex-survey groups and higher in another 41 . 6%; in the other 15 . 6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA(1c)-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA(1c) 6 . 5% or more had a pooled sensitivity of 52 . 8% (95% CI 51 . 3-54 . 3%) and a pooled specificity of 99 . 74% (99 . 71-99 . 78%) compared with FPG 7 . 0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30 . 5% (28 . 7-32 . 3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA(1c) versus FPG. Interpretation Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA(1c)-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test.
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| 6. |
- Docherty, Anna R, et al.
(author)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Journal article (peer-reviewed)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 7. |
- Evangelou, Evangelos, et al.
(author)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Journal article (peer-reviewed)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 8. |
- Matthews, Blake, et al.
(author)
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Toward an integration of evolutionary biology and ecosystem science
- 2011
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In: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 14:7, s. 690-701
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Research review (peer-reviewed)abstract
- At present, the disciplines of evolutionary biology and ecosystem science are weakly integrated. As a result, we have a poor understanding of how the ecological and evolutionary processes that create, maintain, and change biological diversity affect the flux of energy and materials in global biogeochemical cycles. The goal of this article was to review several research fields at the interfaces between ecosystem science, community ecology and evolutionary biology, and suggest new ways to integrate evolutionary biology and ecosystem science. In particular, we focus on how phenotypic evolution by natural selection can influence ecosystem functions by affecting processes at the environmental, population and community scale of ecosystem organization. We develop an eco-evolutionary model to illustrate linkages between evolutionary change (e. g. phenotypic evolution of producer), ecological interactions (e. g. consumer grazing) and ecosystem processes (e. g. nutrient cycling). We conclude by proposing experiments to test the ecosystem consequences of evolutionary changes.
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| 9. |
- Mullins, Niamh, et al.
(author)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Journal article (peer-reviewed)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 10. |
- Wain, Louise V, et al.
(author)
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Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
- 2017
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:3, s. 416-425
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Journal article (peer-reviewed)abstract
- Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
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| 11. |
- Wain, Louise V., et al.
(author)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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In: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Journal article (peer-reviewed)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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| 12. |
- Welti, André, et al.
(author)
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Ship-based measurements of ice nuclei concentrations over the Arctic, Atlantic, Pacific and Southern oceans
- 2020
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In: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 20:23, s. 15191-15206
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Journal article (peer-reviewed)abstract
- Ambient concentrations of ice-forming particles measured during ship expeditions are collected and summarised with the aim of determining the spatial distribution and variability in ice nuclei in oceanic regions. The presented data from literature and previously unpublished data from over 23 months of ship-based measurements stretch from the Arctic to the Southern Ocean and include a circumnavigation of Antarctica. In comparison to continental observations, ship-based measurements of ambient ice nuclei show 1 to 2 orders of magnitude lower mean concentrations. To quantify the geographical variability in oceanic areas, the concentration range of potential ice nuclei in different climate zones is analysed by meridionally dividing the expedition tracks into tropical, temperate and polar climate zones. We find that concentrations of ice nuclei in these meridional zones follow temperature spectra with similar slopes but vary in absolute concentration. Typically, the frequency with which specific concentrations of ice nuclei are observed at a certain temperature follows a log-normal distribution. A consequence of the log-normal distribution is that the mean concentration is higher than the most frequently measured concentration. Finally, the potential contribution of ship exhaust to the measured ice nuclei concentration on board research vessels is analysed as function of temperature. We find a sharp onset of the influence at approximately -36 degrees C but none at warmer temperatures that could bias ship-based measurements.
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