Welcome to The Royal Devon Research Repository
The Royal Devon Research Repository contains research outputs from staff at the Royal Devon University Healthcare NHS Foundation Trust.
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The repository contains details of published, peer-reviewed journal articles, reviews, book chapters, conference abstracts and posters. Full-text of journal articles have been included where publisher's permissions allow.
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Recent Submissions
Item The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification(BMJ, 2024-09-03)BACKGROUND: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity. METHODS: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1). RESULTS: PS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation. CONCLUSION: PS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework.Item A simple technique for checking nipple height in breast reduction and mastopexy(Royal College of Surgeons, 2024-07-31)Item A scoping review of stroke services within the Philippines(BioMed Central, 2024-08-30)BACKGROUND: Stroke is a leading cause of mortality and disability. In higher-income countries, mortality and disability have been reduced with advances in stroke care and early access to rehabilitation services. However, access to such services and the subsequent impact on stroke outcomes in the Philippines, which is a lower- and middle-income countries (LMIC), is unclear. Understanding gaps in service delivery and underpinning research from acute to chronic stages post-stroke will allow future targeting of resources. AIMS: This scoping review aimed to map available literature on stroke services in the Philippines, based on Arksey and O'Malley's five-stage-process. A targeted strategy was used to search relevant databases (Focused: MEDLINE (ovid), EMBASE (ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO (ebsco); broad-based: Scopus; review-based: Cochrane Library, International Prospective Register of Systematic Reviews (PROSPERO), JBI (formerly Joanna Briggs Institute) as well as grey literature (Open Grey, Google scholar). The searches were conducted between 12/2022-01/2023 and repeated 12/2023. Literature describing adults with stroke in the Philippines and stroke services that aimed to maximize well-being, participation and function were searched. Studies were selected if they included one or more of: (a) patient numbers and stroke characteristics (b) staff numbers, qualifications and role (c) service resources (e.g., access to a rehabilitation unit) (d) cost of services and methods of payment) (e) content of stroke care (f) duration of stroke care/rehabilitation and interventions undertaken (g) outcome measures used in clinical practice. A total of 70 papers were included. Articles were assessed, data extracted and classified according to structure, process, or outcome related information. Advances in stroke services, including stroke ready hospitals providing early access to acute care such as thrombectomy and thrombolysis and early referral to rehabilitation coupled with rehabilitation guidelines have been developed. Gaps exist in stroke services structure (e.g., low number of neurologists and neuroimaging, lack of stroke protocols and pathways, inequity of stroke care across urban and rural locations), processes (e.g., delayed arrival to hospital, lack of stroke training among health workers, low awareness of stroke among public and non-stroke care workers, inequitable access to rehabilitation both hospital and community) and outcomes (e.g., low government insurance coverage resulting in high out-of-pocket expenses, limited data on caregiver burden, absence of unified national stroke registry to determine prevalence, incidence and burden of stroke). Potential solutions such as increasing stroke knowledge and awareness, use of mobile stroke units, TeleMedicine, TeleRehab, improving access to rehabilitation, upgrading PhilHealth and a unified national long-term stroke registry representing the real situation across urban and rural were identified. CONCLUSION: This scoping review describes the existing evidence-base relating to structure, processes and outcomes of stroke services for adults within the Philippines. Developments in stroke services have been identified however, a wide gap exists between the availability of stroke services and the high burden of stroke in the Philippines. Strategies are critical to address the identified gaps as a precursor to improving stroke outcomes and reducing burden. Potential solutions identified within the review will require healthcare government and policymakers to focus on stroke awareness programs, primary and secondary stroke prevention, establishing and monitoring of stroke protocols and pathways, sustainable national stroke registry, and improve access to and availability of rehabilitation both hospital and community. WHAT IS ALREADY KNOWN?: Stroke services in the Philippines are inequitable, for example, urban versus rural due to the geography of the Philippines, location of acute stroke ready hospitals and stroke rehabilitation units, limited transport options, and low government healthcare insurance coverage resulting in high out-of-pocket costs for stroke survivors and their families. WHAT ARE THE NEW FINDINGS?: The Philippines have a higher incidence of stroke in younger adults than other LMICs, which impacts the available workforce and the country's economy. There is a lack of data on community stroke rehabilitation provision, the content and intensity of stroke rehabilitation being delivered and the role and knowledge/skills of those delivering stroke rehabilitation, unmet needs of stroke survivors and caregiver burden and strain, WHAT DO THE NEW FINDINGS IMPLY?: A wide gap exists between the availability of stroke services and the high burden of stroke. The impact of this is unclear due to the lack of a compulsory national stroke registry as well as published data on community or home-based stroke services that are not captured/published. WHAT DOES THIS REVIEW OFFER?: This review provides a broad overview of existing evidence-base of stroke services in the Philippines. It provides a catalyst for a) healthcare government to address stroke inequities and burden; b) development of future evidence-based interventions such as community-based rehabilitation; c) task-shifting e.g., training non-neurologists, barangay workers and caregivers; d) use of digital technologies and innovations e.g., stroke TeleRehab, TeleMedicine, mobile stroke units.Item Non-coding variants are a rare cause of recessive developmental disorders in trans with coding variants(Nature, 2024-09-03)PURPOSE: Identifying pathogenic non-coding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic non-coding 'second hits' in trans with these is unknown. METHODS: In 4,073 genetically undiagnosed rare disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare non-coding variants on the other haplotype in introns, untranslated regions (UTRs), promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit, and performed functional testing where possible. RESULTS: We identified 3,761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2,430 probands. For 1,366 (36.3%) of these, we identified at least one rare non-coding variant in trans. Bioinformatic filtering and clinical review, revealed seven to be a good clinical fit. After detailed characterisation, we identified likely diagnoses for three probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further three (PAH, LAMA2, IGHMBP2). CONCLUSION: We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/non-coding variants and conclude that this mechanism is likely to be a rare cause of DDs.Item Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing(Oxford University Press, 2024-10-01)BACKGROUND: Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with 'population-type' breast cancer in mainstream oncology clinics, with wide variation in the genes included. PATIENTS AND METHODS: Weighted meta-analysis was carried out for three population-based case-control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, 'population-type' breast cancer cases and their association with breast cancer and its subtypes. RESULTS: Meta-analysed odds ratios (ORs) and frequencies of PVs in 'population-type' breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in 'population-type' breast cancer cases was very low for 'syndromic' BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11. CONCLUSIONS: These metrics reflecting 'population-type' breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases.
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