Indigenous Australian genomes show deep structure and rich novel variation.

The Indigenous peoples of Australia have a rich linguistic and cultural history. How this relates to genetic diversity remains largely unknown because of their limited engagement with genomic studies. Here we analyse the genomes of 159 individuals from four remote Indigenous communities, including people who speak a language (Tiwi) not from the most widespread family (Pama-Nyungan). This large collection of Indigenous Australian genomes was made possible by careful community engagement and consultation. We observe exceptionally strong population structure across Australia, driven by divergence times between communities of 26,000-35,000 years ago and long-term low but stable effective population sizes. This demographic history, including early divergence from Papua New Guinean (47,000 years ago) and Eurasian groups1, has generated the highest proportion of previously undescribed genetic variation seen outside Africa and the most extended homozygosity compared with global samples. A substantial proportion of this variation is not observed in global reference panels or clinical datasets, and variation with predicted functional consequence is more likely to be homozygous than in other populations, with consequent implications for medical genomics2. Our results show that Indigenous Australians are not a single homogeneous genetic group and their genetic relationship with the peoples of New Guinea is not uniform. These patterns imply that the full breadth of Indigenous Australian genetic diversity remains uncharacterized, potentially limiting genomic medicine and equitable healthcare for Indigenous Australians.

2022 William Allan Award introduction: Peter Donnelly.

This article is based on the address given by the author at the 2022 meeting of The American Society of Human Genetics (ASHG) in Los Angeles, California. The video of the original address can be found at the ASHG website.

The UK Biobank resource with deep phenotyping and genomic data.

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

A 20-year population study of peripartum cardiomyopathy.

BACKGROUND AND AIMS: The epidemiology of peripartum cardiomyopathy (PPCM) in Europe is poorly understood and data on long-term outcomes are lacking. A retrospective, observational, population-level study of validated cases of PPCM in Scotland from 1998 to 2017 was conducted. METHODS: Women hospitalized with presumed de novo left ventricular systolic dysfunction around the time of pregnancy and no clear alternative cause were included. Each case was matched to 10 controls. Incidence and risk factors were identified. Morbidity and mortality were examined in mothers and children. RESULTS: The incidence of PPCM was 1 in 4950 deliveries. Among 225 women with PPCM, obesity, gestational hypertensive disorders, and multi-gestation were found to be associated with having the condition. Over a median of 8.3 years (9.7 years for echocardiographic outcomes), 8% of women with PPCM died and 75% were rehospitalized for any cause at least once. Mortality and rehospitalization rates in women with PPCM were ∼12- and ∼3-times that of controls, respectively. The composite of all-cause death, mechanical circulatory support, or cardiac transplantation occurred in 14%. LV recovery occurred in 76% and, of those who recovered, 13% went on to have a decline in LV systolic function despite initial recovery. The mortality rate for children born to women with PPCM was ∼5-times that of children born to controls and they had an ∼3-times greater incidence of cardiovascular disease over a median of 8.8 years. CONCLUSIONS: PPCM affected 1 in 4950 women around the time of pregnancy. The condition is associated with considerable morbidity and mortality for the mother and child. There should be a low threshold for investigating at-risk women. Long term follow-up, despite apparent recovery, should be considered.

Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data.

Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government's Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government's objectives and its commitment "to leveraging the benefits of genomics in the health system for all Australians." They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged.

What do we mean by complex percutaneous coronary intervention? An assessment of agreement amongst interventional cardiologists for defining complexity.

BACKGROUND: In the last decade, percutaneous coronary intervention (PCI) has evolved toward the treatment of complex disease in patients with multiple comorbidities. Whilst there are several definitions of complexity, it is unclear whether there is agreement between cardiologists in classifying complexity of cases. Inconsistent identification of complex PCI can lead to significant variation in clinical decision-making. AIM: This study aimed to determine the inter-rater agreement in rating the complexity and risk of PCI procedures. METHOD: An online survey was designed and disseminated amongst interventional cardiologists by the European Association of Percutaneous Cardiovascular Intervention (EAPCI) board. The survey presented four patient vignettes, with study participants assessing these cases to classify their complexity. RESULTS: From 215 respondents, there was poor inter-rater agreement in classifying the complexity level (k = 0.1) and a fair agreement (k = 0.31) in classifying the risk level. The experience level of participants did not show any significant impact on the inter-rater agreement of rating the complexity level and the risk level. There was good level of agreement between participants in terms of rating 26 factors for classifying complex PCI. The top five factors were (1) impaired left ventricular function, (2) concomitant severe aortic stenosis, (3) last remaining vessel PCI, (4) requirement fort calcium modification and (5) significant renal impairment. CONCLUSION: Agreement among cardiologists in classifying complexity of PCI is poor, which may lead to suboptimal clinical decision-making, procedural planning as well as long-term management. Consensus is needed to define complex PCI, and this requires clear criteria incorporating both lesion and patient characteristics.

Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1.

Highly polymorphic interaction of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of immunotherapies, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data. We designed the model to represent a substantial component of human genetic diversity. Our Global imputation model is effective at genotyping KIR3DL1/S1 alleles with an accuracy ranging from 88% in Africans to 97% in East Asians, with mean specificity of 99% and sensitivity of 95% for alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 with HLA-A and -B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable.

Epistatic interactions between killer immunoglobulin-like receptors and human leukocyte antigen ligands are associated with ankylosing spondylitis.

The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.

The Effect of ACTN3 Gene Doping on Skeletal Muscle Performance.

Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Our general meta-analysis using a Bayesian random effects model in elite sprint/power athlete cohorts demonstrated a consistent homozygous-group effect across studies (per allele OR = 1.4, 95% CI 1.3-1.6) but substantial heterogeneity in heterozygotes. In mouse muscle, rAAV-mediated gene transfer overexpressed and rescued α-actinin-3 expression. Contrary to expectation, in vivo "doping" of ACTN3 at low to moderate doses demonstrated an absence of any change in function. At high doses, ACTN3 is toxic and detrimental to force generation, to demonstrate gene doping with supposedly performance-enhancing isoforms of sarcomeric proteins can be detrimental for muscle function. Restoration of α-actinin-3 did not enhance muscle mass but highlighted the primary role of α-actinin-3 in modulating muscle metabolism with altered fatiguability. This is the first study to express a Z-disk protein in healthy skeletal muscle and measure the in vivo effect. The sensitive balance of the sarcomeric proteins and muscle function has relevant implications in areas of gene doping in performance and therapy for neuromuscular disease.

The fine-scale genetic structure of the British population.

Fine-scale genetic variation between human populations is interesting as a signature of historical demographic events and because of its potential for confounding disease studies. We use haplotype-based statistical methods to analyse genome-wide single nucleotide polymorphism (SNP) data from a carefully chosen geographically diverse sample of 2,039 individuals from the United Kingdom. This reveals a rich and detailed pattern of genetic differentiation with remarkable concordance between genetic clusters and geography. The regional genetic differentiation and differing patterns of shared ancestry with 6,209 individuals from across Europe carry clear signals of historical demographic events. We estimate the genetic contribution to southeastern England from Anglo-Saxon migrations to be under half, and identify the regions not carrying genetic material from these migrations. We suggest significant pre-Roman but post-Mesolithic movement into southeastern England from continental Europe, and show that in non-Saxon parts of the United Kingdom, there exist genetically differentiated subgroups rather than a general 'Celtic' population.

A rapid review of the impact of COVID-19 on the mental health of healthcare workers: implications for supporting psychological well-being.

BACKGROUND: Health and social care workers (HSCWs) have carried a heavy burden during the COVID-19 crisis and, in the challenge to control the virus, have directly faced its consequences. Supporting their psychological wellbeing continues, therefore, to be a priority. This rapid review was carried out to establish whether there are any identifiable risk factors for adverse mental health outcomes amongst HSCWs during the COVID-19 crisis. METHODS: We undertook a rapid review of the literature following guidelines by the WHO and the Cochrane Collaboration's recommendations. We searched across 14 databases, executing the search at two different time points. We included published, observational and experimental studies that reported the psychological effects on HSCWs during the COVID-19 pandemic. RESULTS: The 24 studies included in this review reported data predominantly from China (18 out of 24 included studies) and most sampled urban hospital staff. Our study indicates that COVID-19 has a considerable impact on the psychological wellbeing of front-line hospital staff. Results suggest that nurses may be at higher risk of adverse mental health outcomes during this pandemic, but no studies compare this group with the primary care workforce. Furthermore, no studies investigated the psychological impact of the COVID-19 pandemic on social care staff. Other risk factors identified were underlying organic illness, gender (female), concern about family, fear of infection, lack of personal protective equipment (PPE) and close contact with COVID-19. Systemic support, adequate knowledge and resilience were identified as factors protecting against adverse mental health outcomes. CONCLUSIONS: The evidence to date suggests that female nurses with close contact with COVID-19 patients may have the most to gain from efforts aimed at supporting psychological well-being. However, inconsistencies in findings and a lack of data collected outside of hospital settings, suggest that we should not exclude any groups when addressing psychological well-being in health and social care workers. Whilst psychological interventions aimed at enhancing resilience in the individual may be of benefit, it is evident that to build a resilient workforce, occupational and environmental factors must be addressed. Further research including social care workers and analysis of wider societal structural factors is recommended.

Longitudinal evaluation of the effects of illness perceptions and beliefs about cardiac rehabilitation on quality of life of patients with coronary artery disease and their caregivers.

BACKGROUND: Patients' negative illness perceptions and beliefs about cardiac rehabilitation (CR) can influence uptake and adherence to CR. Little is known about the interpartner influence of these antecedent variables on quality of life of patients with coronary artery disease (CAD) and their family caregivers. The aims of the study were: 1) to assess differences in illness perceptions, beliefs about CR and quality of life between patients with CAD and their family caregivers upon entry to a CR programme and at 6 months follow-up; and 2) to examine whether patients' and caregivers' perceptions of the patient's illness and beliefs about CR at baseline predict their own and their partner's quality of life at 6 months. METHODS: In this longitudinal study of 40 patient-caregiver dyads from one CR service, patients completed the Brief Illness Perception Questionnaire and Beliefs about Cardiac Rehabilitation Questionnaire at baseline and 6 months; and caregivers completed these questionnaires based on their views about the patient's illness and CR. The Short-Form 12 Health Survey was used to assess patients' and caregivers' perceived health status. Dyadic data were analysed using the Actor-Partner Interdependence Model. RESULTS: Most patients (70%) were men, mean age 62.45 years; and most caregivers (70%) were women, mean age 59.55 years. Caregivers were more concerned about the patient's illness than the patients themselves; although they had similar scores for beliefs about CR. Patients had poorer physical health than caregivers, but their level of mental health was similar. Caregivers' poorer mental health at 6 months was predicted by the patient's perceptions of timeline and illness concern (i.e. partner effects). Patient's and caregiver's illness perceptions and beliefs about CR were associated with their own physical and mental health at 6 months (i.e. actor effects). CONCLUSIONS: Overall, the patients and caregivers had similar scores for illness perceptions and beliefs about CR. The actor and partner effect results indicate a need to focus on specific illness perceptions and beliefs about CR, targeting both the individual and the dyad, early in the rehabilitation process to help improve patients and caregivers physical and mental health (outcomes).

Longitudinal study of the relationship between patients' medication adherence and quality of life outcomes and illness perceptions and beliefs about cardiac rehabilitation.

BACKGROUND: Adherence to medication regimens is essential for preventing and reducing adverse outcomes among patients with coronary artery disease (CAD). Greater understanding of the relation between negative illness perceptions, beliefs about cardiac rehabilitation (CR) and medication adherence may help inform future approaches to improving medication adherence and quality of life (QoL) outcomes. The aims of the study are: 1) to compare changes in illness perceptions, beliefs about CR, medication adherence and QoL on entry to a CR programme and 6 months later; 2) to examine associations between patients' illness perceptions and beliefs about CR at baseline and medication adherence and QoL at 6 months. METHODS: A longitudinal study of 40 patients with CAD recruited from one CR service in Scotland. Patients completed the Medication Adherence Report Scale, Brief Illness Perception Questionnaire, Beliefs about CR questionnaire and the Short-Form 12 Health Survey. Data were analysed using the Wilcoxon Signed Ranks test, Pearson Product Moment correlation and Bayesian multiple logistic regression. RESULTS: Most patients were men (70%), aged 62.3 mean (SD 7.84) years. Small improvements in 'perceived suitability' of CR at baseline increased the odds of being fully adherent to medication by approximately 60% at 6 months. Being fully adherent at baseline increased the odds of staying so at 6 months by 13.5 times. 'Perceived necessity, concerns for exercise and practical barriers' were negatively associated with reductions in the probability of full medication adherence of 50, 10, and 50%. Small increases in concerns about exercise decreased the odds of better physical health at 6 months by about 50%; and increases in practical barriers decreased the odds of better physical health by about 60%. Patients perceived fewer consequences of their cardiac disease at 6 months. CONCLUSIONS: Patients' beliefs on entry to a CR programme are especially important to medication adherence at 6 months. Negative beliefs about CR should be identified early in CR to counteract any negative effects on QoL. Interventions to improve medication adherence and QoL outcomes should focus on improving patients' negative beliefs about CR and increasing understanding of the role of medication adherence in preventing a future cardiac event.

Establishing the efficacy of interventions to improve health literacy and health behaviours: a systematic review.

BACKGROUND: The primary aim of this review was to establish whether health literacy interventions, in adults, are effective for improving health literacy. Two secondary aims assessed the impact of health literacy interventions on health behaviours and whether health literacy interventions have been conducted in cardiovascular patients. METHODS: A systematic review (Prospero registration: CRD42018110772) with no start date running through until April 2020. Eligible studies were conducted in adults and included a pre/post measure of health literacy. Medline, Embase, Eric, PsychINFO, CINAHL, Psychology and Behavioural Science, HMIC, Web of Science, Scopus, Social Care Online, NHS Scotland Journals, Social Policy and Practice, and Global Health were searched. Two thousand one hundred twenty-seven papers were assessed, and 57 full text papers screened to give 22 unique datasets from 23 papers. Risk of bias was assessed regarding randomisation, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting and other biases. Intervention reporting quality was assessed using the TIDieR checklist. RESULTS: Twenty-two studies were included reporting on 10,997 participants in nine countries. The majority of studies (14/22) were published in 2018 or later. Eight studies (n = 1268 participants) also reported on behavioural outcomes. Health literacy interventions resulted in improvements in at least some aspect of health literacy in 15/22 studies (n = 10,180 participants) and improved behavioural outcomes in 7/8 studies (n = 1209 participants). Only two studies were conducted with cardiovascular patients. All studies were at risk of bias with 18 judged as high risk. In addition, there was poor reporting of intervention content with little explication of the theoretical basis for the interventions. CONCLUSIONS: Health literacy interventions can improve health literacy and can also lead to changes in health behaviours. Health literacy interventions offer a way to improve outcomes for populations most at risk of health inequalities. Health literacy is a developing field with very few interventions using clear theoretical frameworks. Closer links between health literacy and behaviour change theories and frameworks could result in higher quality and more effective interventions. PROSPERO REGISTRATION: Prospero registration: CRD42018110772.

Machine learning techniques for detecting electrode misplacement and interchanges when recording ECGs: A systematic review and meta-analysis.

INTRODUCTION: Electrode misplacement and interchange errors are known problems when recording the 12­lead electrocardiogram (ECG). Automatic detection of these errors could play an important role for improving clinical decision making and outcomes in cardiac care. The objectives of this systematic review and meta-analysis is to 1) study the impact of electrode misplacement on ECG signals and ECG interpretation, 2) to determine the most challenging electrode misplacements to detect using machine learning (ML), 3) to analyse the ML performance of algorithms that detect electrode misplacement or interchange according to sensitivity and specificity and 4) to identify the most commonly used ML technique for detecting electrode misplacement/interchange. This review analysed the current literature regarding electrode misplacement/interchange recognition accuracy using machine learning techniques. METHOD: A search of three online databases including IEEE, PubMed and ScienceDirect identified 228 articles, while 3 articles were included from additional sources from co-authors. According to the eligibility criteria, 14 articles were selected. The selected articles were considered for qualitative analysis and meta-analysis. RESULTS: The articles showed the effect of lead interchange on ECG morphology and as a consequence on patient diagnoses. Statistical analysis of the included articles found that machine learning performance is high in detecting electrode misplacement/interchange except left arm/left leg interchange. CONCLUSION: This review emphasises the importance of detecting electrode misplacement detection in ECG diagnosis and the effects on decision making. Machine learning shows promise in detecting lead misplacement/interchange and highlights an opportunity for developing and operationalising deep learning algorithms such as convolutional neural network (CNN) to detect electrode misplacement/interchange.

Percutaneous treatment of a massive saphenous vein graft aneurysm.

Saphenous vein graft (SVG) aneurysms are a rare, frequently late presenting, potentially fatal complication of coronary artery bypass graft (CABG) surgery. They are often discovered incidentally during radiological tasks such as chest x-ray or CT but can present clinically with symptoms such as worsening angina and breathlessness as well as complications such as rupture or myocardial infarction. Given the risks if left untreated, consideration should be given to treatment either through percutaneous routes or open surgery. However, because of a lack of strong evidence, there are no definitive guidelines on the treatment of SVG aneurysms. We describe a patient with an extensive cardiac surgical history who presented with angina and breathlessness and was found to have a large SVG aneurysm, subsequently successfully treated with percutaneous coronary intervention with covered stents.

Prescribers' views and experiences of using direct acting oral anticoagulants in the management of nonvalvular atrial fibrillation: A survey in remote and rural Scotland.

AIMS: A recent systematic review highlighted the lack of robust studies on prescribers' perspectives of direct-acting oral anticoagulants (DOACs) for nonvalvular atrial fibrillation. The aim was to determine prescribers' views and experiences of prescribing DOACs. METHODS: A cross-sectional survey of prescribers in a remote and rural area of Scotland. Survey items were: demographics; prescribing of DOACs; views of potential influences on DOAC prescribing; knowledge of prescribing guidelines; and experiences. Items on potential influences were based on the Theoretical Domains Framework. Data were analysed using descriptive and inferential statistics, and content analysis of responses to open questions. Principal component analysis was performed on the items of potential influences. RESULTS: In total, 154 responses were received, 120 (77.9%) from doctors, 18 (11.7%) from nurse prescribers and 10 (6.4%) from pharmacist prescribers (6 missing). Principal component analysis of the Theoretical Domains Framework items of potential influences gave 4 components. Component scores for (i) role of professionals, their knowledge and skills and (ii) influences on prescribing were positive. Those for (iii) consequences of prescribing and (iv) monitoring for safety and effectiveness were more neutral. There were low levels of agreement for statements relating to DOACs being more effective, safer and cost-effective than warfarin. There were similar responses around the complexity of bleeding management and detection of over and under-anticoagulation. CONCLUSION: This study has identified several key issues of DOAC prescribing (e.g. bleeding management) hence further emphasis is required in continuing professional development and during guideline implementation and evaluation.

An exploratory analysis investigating blood protein biomarkers to augment ECG diagnosis of ACS.

BACKGROUND: Acute Coronary Syndrome (ACS) is currently diagnosed using a 12­lead Electrocardiogram (ECG). Our recent work however has shown that interpretation of the 12­lead ECG is complex and that clinicians can be sub-optimal in their interpretation. Additionally, ECG does not always identify acute total occlusions in certain patients. PURPOSE: The aim of the present study was to undertake an exploratory analysis to compare protein expression profiles of ACS patients that may in the future augment ECG diagnosis. METHODS: Patients were recruited consecutively at the cardiac catheterization laboratory at Altnagelvin Hospital over a period of 6 months. A low risk control group was recruited by advertisement. Blood samples were analysed using the multiplex proximity extension assays by OLINK proteomics. Support vector machine (SVM) learning was used as a classifier to distinguish between patient groups on training data. The ST segment elevation level was extracted from each ECG for a subset of patients and combined with the protein markers. Quadratic SVM (QSVM) learning was then used as a classifier to distinguish STEMI from NSTEMI on training and test data. RESULTS: Of the 344 participants recruited, 77 were initially diagnosed with NSTEMI, 7 with STEMI, and 81 were low risk controls. The other participants were those diagnosed with angina (stable and unstable) or non-cardiac patients. Of the 368 proteins analysed, 20 proteins together could significantly differentiate between patients with ACS and patients with stable angina (ROC-AUC = 0.96). Six proteins discriminated significantly between the stable angina and the low risk control groups (ROC-AUC = 1.0). Additionally, 16 proteins together perfectly discriminated between the STEMI and NSTEMI patients (ROC-AUC = 1). ECG comparisons with the protein biomarker data for a subset of patients (STEMI n = 6 and NSTEMI n = 6), demonstrated that 21 features (20 proteins + ST elevation) resulted in the highest classification accuracy 91.7% (ROC-AUC = 0.94). The 20 proteins without the ST elevation feature gave an accuracy of 80.6% (ROC-AUC 0.91), while the ST elevation feature without the protein biomarkers resulted in an accuracy of 69.3% (ROC-AUC = 0.81). CONCLUSIONS: This preliminary study identifies panels of proteins that should be further explored in prospective studies as potential biomarkers that may augment ECG diagnosis and stratification of ACS. This work also highlights the importance for future studies to be designed to allow a comparison of blood biomarkers not only with ECG's but also with cardio angiograms.

Data driven feature selection and machine learning to detect misplaced V1 and V2 chest electrodes when recording the 12­lead electrocardiogram.

BACKGROUND: Electrocardiogram (ECG) lead misplacement can adversely affect ECG diagnosis and subsequent clinical decisions. V1 and V2 are commonly placed superior of their correct position. The aim of the current study was to use machine learning approaches to detect V1 and V2 lead misplacement to enhance ECG data quality. METHOD: ECGs for 453 patients, (normal n = 151, Left Ventricular Hypertrophy (LVH) n = 151, Myocardial Infarction n = 151) were extracted from body surface potential maps. These were used to extract both the correct and incorrectly placed V1 and V2 leads. The prevalence for correct and incorrect leads were 50%. Sixteen features were extracted in three different domains: time-based, statistical and time-frequency features using a wavelet transform. A hybrid feature selection approach was applied to select an optimal set of features. To ensure optimal model selection, five classifiers were used and compared. The aforementioned feature selection approach and classifiers were applied for V1 and V2 misplacement in three different positions: first, second and third intercostal spaces (ICS). RESULTS: The accuracy for V1 misplacement detection was 93.9%, 89.3%, 72.8% in the first, second and third ICS respectively. In V2, the accuracy was 93.6%, 86.6% and 68.1% in the first, second and third ICS respectively. There is a noticeable decline in accuracy when detecting misplacement in the third ICS which is expected.