Acceptability of a Mobile App (iMPAKT) for Measurement and Implementation of Person-Centredness: Mixed-Methods Study.

This study tested the acceptability of the iMPAKT App with end users. Cognitive task analysis and semi-structured interviews were used. Twelve participants took part. The majority of tasks were found to be easy to complete but issues were identified with a section of the app that provides Speech-To-Text transcription of patients speaking about their experience of care. Artificial Intelligence (AI) based systems may be needed to address these limitations. Overall views on acceptability of the app were positive and participants valued how it could be used to support practice improvement initiatives and large scale collection of person-centred measures.

Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

Pharmacogenomics for Prader-Willi syndrome: caregiver interest and planned utilization.

Aim: The study aim was to determine caregiver interest and planned utilization of pharmacogenomic (PGx) results for their child with Prader-Willi syndrome. Methods: Caregivers consented to PGx testing for their child and completed a survey before receiving results. Results: Of all caregivers (n = 48), 93.8% were highly interested in their child's upcoming PGx results. Most (97.9%) planned to share results with their child's medical providers. However, only 47.9% of caregivers were confident providers would utilize the PGx results. Conclusion: Caregivers are interested in utilizing PGx but are uncertain providers will use these results in their child's care. More information about provider comfort with PGx utilization is needed to understand how PGx education would benefit providers and ultimately patients with PGx results.

Vitamin D status and variable responses to supplements depend in part on genetic factors in adults with cystic fibrosis.

Vitamin D sufficiency has been difficult to achieve consistently in patients with cystic fibrosis (CF), even with robust oral supplements. To assess vitamin D status and resistance to supplementation, we studied 80 adults using 25-hydroxyvitamin D (25OHD) determinations and whole genome sequencing to construct polygenic risk scores (PRS) that aggregate variants associated with vitamin D status. The results revealed that 30 % of patients were below the threshold of 30 ng/mL and thus should be regarded as insufficient despite normal vitamin E status, a reflection of adherence to fat soluble vitamin supplementation. The PRS values were significantly correlated with 25OHD concentrations, confirming our results in children with CF, and indicating that genetic factors play a role and have implications for therapy.

Impact of intrinsic and extrinsic risk factors on early-onset lung disease in cystic fibrosis.

BACKGROUND: Although respiratory pathology is known to develop in young children with cystic fibrosis (CF), the determinants of early-onset lung disease have not been elucidated. OBJECTIVE: We aimed to determine the impact of potential intrinsic and extrinsic risk factors during the first 3 years of life, testing the hypothesis that both contribute significantly to early-onset CF lung disease. DESIGN: We studied 104 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and evaluated comprehensively to 36 months of age. Lung disease manifestations were quantified with a new scoring system known as CFELD for Cystic Fibrosis Early-onset Lung Disease. The variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were determined and categorized. Whole genome sequencing was performed on each subject and the data transformed to polygenic risk scores (PRS) that aggregate variants associated with lung function. Extrinsic factors included socioeconomic status (SES) indicators and environmental experiences such as exposures to smoking, pets, and daycare. RESULTS: We found by univariate analysis that CFTR genotype and genetic modifiers aggregated by the PRS method were significantly associated with early-onset CF lung disease. Ordinal logistic regression analysis demonstrated that high and stable SES (maternal education ≥community college, stable 2-parent home, and not receiving Medicaid) and better growth (weight-for-age and height-for-age z-scores) reduced risks, while exposure to smoking and daycare ≥20 h/week increased the risk of CFELD severity. CONCLUSIONS: Extrinsic, modifiable determinants are influential early and potentially as important as the intrinsic risk factors in the onset of CF lung disease.

Exploring the contribution and impact of master's education for leadership development in adult general nursing: A scoping review.

AIM: The aim of this scoping review was to explore the evidence relating to master's education for leadership development in adult/general nurses who are not in advanced practice or leadership roles and its impact on practice. BACKGROUND: The importance of effective, clinical leadership in nursing and health care, has been highlighted following failings reported by Public Inquiries both nationally and internationally. While initiatives have been implemented to address these, the provision of safe, quality care remains problematic. Complex care requires highly skilled professionals to challenge and lead improvements in practice. Master's education results in graduates with the skills and confidence to make these changes and to become the clinical leaders of the future. METHODS: An a priori scoping review protocol was developed by the review team. This was used to undertake searches across CINAHL Ultimate; Medline (Ovid), Scopus and ProQuest Complete databases, chosen due to their relevance to the subject area. Articles were limited to those in the English Language, peer reviewed and published since 2009. Citation chaining via the reference lists of frequently identified articles were also searched. A further search for relevant grey material using the same relevant keywords and phrases was performed using the limited, Trip Database and Google Scholar. RESULTS: Eight articles were selected for data extraction, and these were published between 2011 and 2019. The articles were predominantly from the UK and Europe, with a focus either on master's education or on aspects of leadership in nursing and healthcare. Themes identified: a) The need for clinical leadership; b) master's education for clinical leadership skills; and c) master's education for professional and organisational outcomes. CONCLUSIONS: The scoping review identified that there is a need for strong clinical leadership in the practice setting. Evidence shows that effective nursing leadership can improve patient outcomes as well as enhancing workplace culture and staff retention. The review has shown that the skills required for clinical leadership are those produced by master's education. Studies of the impact of master's education are often self reported and tend to focus on nurses in advanced practice roles. More research is required into master's education for adult/general nurses not in advanced roles and in examining the link between master's education and improved patient, professional and organisational outcomes.

APPLICATION OF A NOVEL ASPERGILLUS LATERAL-FLOW DEVICE IN THE DIAGNOSIS OF ASPERGILLOSIS IN CAPTIVE GENTOO PENGUINS (PYGOSCELIS PAPUA PAPUA).

Aspergillosis is the primary fungal disease affecting captive penguins globally. Its diagnosis remains challenging, and currently no tests are both sensitive and specific for the detection of early infection. The present study evaluated a recently developed Aspergillus lateral-flow device (AspLFD) for the detection of Aspergillus spp. antigen in plasma and glottis mucus from captive penguins. In a pilot retrospective study, banked frozen plasma samples from captive penguins were reviewed: samples from 11 gentoo penguins (Pygoscelis papua papua) and 4 king penguins (Aptenodytes patagonicus) fulfilled the inclusion criteria and were used in the analysis. Positive plasma AspLFD test results were found in 80% (four of five) of the aspergillosis-positive cases tested. All of the aspergillosis-negative cases tested negative (10 of 10) on the AspLFD test. In a cohort prospective study, paired plasma and glottis swab samples were opportunistically and nonrandomly collected from captive gentoo penguins. In total, 26 penguins were tested. In the negative control group, AspLFD test was negative on plasma and swab in 100% of birds (14 of 14). In the aspergillosis-positive group, AspLFD test was positive on plasma samples from 33% (4 of 12) of birds, on swab samples from 50% (6 of 12) of birds, and on either plasma or swab samples from 75% (9 of 12) of birds. The AspLFD is currently used for the diagnosis of aspergillosis in humans and also shows promise for use in penguins. Larger prospective studies are recommended.

The epidemiology of strabismus and cataracts within a pediatric population in Saint Vincent and the Grenadines: an analysis of 201 consecutive cases.

PURPOSE: Childhood cataracts and strabismus are among the most common causes of visual impairment in children worldwide, and prompt diagnosis and correction can significantly reduce disease burden. In certain regions, including the Eastern Caribbean, access to adequate treatment can be limited and epidemiological data scarce. This study aims to analyze the epidemiological data of pediatric strabismus and cataract cases in St. Vincent and the Grenadines. METHODS: The setting of the study is a clinical practice including 201 patients between the age of 0 to 19 who received care with World Pediatric Project (WPP). Factors analyzed include patient age, sex, and type of cataract or strabismus. The findings were compared to publicly available demographic information. RESULTS: The cases were divided into cataract (n=51), strabismus (n=134), and both strabismus and cataract (n=16). Mean ages (years) were 5.96, 5.54, and 4.50, respectively. The most frequent type of cataract and strabismus were congenital (n=25) and esotropia (n=95), respectively. The highest annual cumulative incidence was 31 and 49 cases per 100,000 people for cataracts and strabismus, respectively. CONCLUSION: This study provides regional epidemiological data on pediatric strabismus and cataracts. Further studies can expand the patient population by increasing collaboration with local providers. Ultimately, these findings can offer a basis for which additional epidemiological studies can be performed and help guide public health efforts to prevent visual impairment in St. Vincent and the Grenadines.

Genetic factors help explain the variable responses of young children with cystic fibrosis to vitamin D supplements.

BACKGROUND & AIMS: Children with cystic fibrosis (CF) are susceptible to fat-soluble vitamin deficiencies unless supplemented, but even large doses of vitamin D may not prevent low 25-hydroxyvitamin D (25OHD) concentrations. The explanation for these vitamin D non-responders has been elusive. We utilized data from whole genome sequencing (WGS) to test the hypothesis that genetic variations predict responsiveness to vitamin D supplementation in a prospective cohort study of children with CF in the first 3 years of life. METHODS: One hundred and one infants born during 2012-2017 and diagnosed with CF through newborn screening were studied. Serum 25OHD concentrations and vitamin D supplement doses were assessed during early infancy and annually thereafter. WGS was performed, the resultant variant calling files processed, and the summary statistics from a recent genome-wide association study were utilized to construct a polygenic risk score (PRS) for each subject. RESULTS: Overall, the prevalence of vitamin D insufficiency (<30 ng/mL) was 21% in the first 3 years of life. Among the 70 subjects who always adhered to vitamin D supplement doses recommended by the US CF Foundation guidelines, 89% were responders (achieved vitamin D sufficiency) by 3 years of age, while 11% were transient or non-responders. Multiple regression analysis revealed that PRS was a significant predictor of 25OHD concentrations (p < 0.001) and the likelihood of being an earlier responder in the first 3 years of life (p < 0.01). A limited SNP analysis revealed variants in four important genes (GC, LIPC, CYP24A1, and PDE3B) that were shown to be associated with 25OHD concentrations and vitamin D responder status. Other determinants included vitamin D supplement dose, season at 25OHD measurement, and pancreatic functional status. CONCLUSIONS: Applying WGS in conjunction with utilizing a PRS approach revealed genetic variations that partially explain the unresponsiveness of some children with CF to vitamin D supplementation. Our findings suggest that a nutrigenomics strategy could help promote personalized treatment in CF.

International, multi-disciplinary, cross-section study of pain knowledge and attitudes in nursing, midwifery and allied health professions students.

BACKGROUND: Persistent pain is a highly prevalent, global cause of disability. Research suggests that many healthcare professionals are not well equipped to manage pain, and this may be attributable at least in part to undergraduate education. The primary aim of this study was to quantify and compare first and final year nursing, midwifery and allied health professional (NMAHP) students' pain related knowledge and attitudes. The secondary aim was to explore what factors influence students' pain related knowledge and attitudes. METHODS: In this cross-sectional study, 1154 first and final year healthcare students, from 12 universities in five different countries completed the Revised Neurophysiology of Pain Quiz (RNPQ) [knowledge] and the Health Care Providers Pain and Impairment Relationship Scale (HC-PAIRS) [attitudes]. RESULTS: Physiotherapy was the only student group with statistically and clinically improved pain related knowledge [mean difference, 95% CI] (3.4, 3.0 to 3.9, p = 0.01) and attitudes (-17.2, -19.2 to 15.2, p = 0.01) between first and final year. Pain education teaching varied considerably from course to course (0 to 40 h), with greater levels of pain related knowledge and attitudes associated with higher volumes of pain specific teaching. CONCLUSIONS: There was little difference in pain knowledge and attitudes between all first and final year NMAHP students other than physiotherapy. This suggests that for most NMAHP disciplines, undergraduate teaching has little or no impact on students' understanding of pain. There is an urgent need to enhance pain education provision at the undergraduate level in NMAHPs. TRIAL REGISTRATION: The study protocol was prospectively registered at ClinicalTrials.Gov NCT03522857 .

Exploring ways to enhance pain management for older people with dementia in acute care settings using a Participatory Action Research approach.

BACKGROUND: Dementia is a progressive condition that leads to reduced cognition, deteriorating communication and is a risk factor for other acute and chronic health problems. The rise in the prevalence of dementia means untreated pain is becoming increasingly common with healthcare staff being challenged to provide optimal pain management. This negatively impacts the person living with dementia and their carers. There is minimal evidence that explores the pain management experience of patients as they move through acute care settings. OBJECTIVE: To understand the complexities of managing the pain of older people with dementia as they progress through acute care settings, with the view of assisting staff to improve practice. METHOD: A Participatory Action Research approach, guided by the Promoting Action Research in Health Services framework, was used. Three Action Cycles were completed comprising of an exploratory audit and two case studies (Action Cycle One), three focus groups with a total of 14 participants (Action Cycle Two) and the development and implementation of immediate and long-term actions (Action Cycle Three). RESULTS: Thematic analysis identified four themes that affected pain management practices. These were not knowing the patient; balancing competing priorities; knowledge and understanding of pain and dementia and not assimilating available information. CONCLUSION: Pain management practices for patient living with dementia, across acute care settings, was influenced by shared ways of thinking and working. Not knowing the patient, fragmentation of information and having insufficient knowledge of the subtleties of dementia led participants to deliver task-focused, target and policy-driven care that was not person-centred in its approach. Facilitated reflection enabled acute care teams to actively participate in identifying problems and finding solutions to enhance practice.

DOCKopathies: A systematic review of the clinical pathologies associated with human DOCK pathogenic variants.

The Dedicator of Cytokinesis (DOCK) family (DOCK1-11) of genes are essential mediators of cellular migration, growth, and fusion in a variety of cell types and tissues. Recent advances in whole-genome sequencing of patients with undiagnosed genetic disorders have identified several rare pathogenic variants in DOCK genes. We conducted a systematic review and performed a patient database and literature search of reported DOCK pathogenic variants that have been identified in association with clinical pathologies such as global developmental delay, immune cell dysfunction, muscle hypotonia, and muscle ataxia among other categories. We then categorized these pathogenic DOCK variants and their associated clinical phenotypes under several unique categories: developmental, cardiovascular, metabolic, cognitive, or neuromuscular. Our systematic review of DOCK variants aims to identify and analyze potential DOCK-regulated networks associated with neuromuscular diseases and other disease pathologies, which may identify novel therapeutic strategies and targets. This systematic analysis and categorization of human-associated pathologies with DOCK pathogenic variants is the first report to the best of our knowledge for a unique class in this understudied gene family that has important implications in furthering personalized genomic medicine, clinical diagnoses, and improve targeted therapeutic outcomes across many clinical pathologies.

'Owning the space'-person-centred practice in a 100% single-room acute-care environment: an ethnographic study.

AIMS AND OBJECTIVES: Exploring the influence of the 100% single-room environment on staff and patient experience of person-centred practice in an acute-care setting. BACKGROUND: Current building guidance for the NHS advocates increasing the single-room inpatient environment. There is little evidence of the impact of this design in adult acute-care settings on the experience and delivery of person-centred care. DESIGN: Ethnography, underpinned by McCormack and McCance's Person-centred Practice Framework. METHODS: Data collection took place between March and June 2018. Staff and patients in a National Health Service hospital in the United Kingdom took part in observations of practice (n = 108 hours); face to face inpatient interviews (n = 9); and participatory reflective staff groups (n = 3). A reflexive journal was kept by the researcher throughout the study. Reporting adhered to the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. RESULTS: Themes relating to care delivery and interactions were identified. Staff and patients' views converged around visibility and isolation. Patients appreciated the privacy afforded by the single rooms, while staff experienced a psychological shift, being viewed (and viewing themselves) as 'visitors'. There was space for more sympathetic presencing, encouraging patients to speak more openly, to facilitate knowing and authentic engagement. However, time remained an issue resulting in more task-focused care. CONCLUSION: Changes to the physical environment have an impact on the delivery and experience of person-centred practice. While the facilities enhance patient experience, the interweaving of engagement, emotional support and the development of therapeutic relationships remain challenging.

Exploring how key performance indicators influence nursing and midwifery practice: A mixed-methods study.

AIMS: To scope the key performance indicators (KPIs) used in nursing and midwifery across the United Kingdom and Republic of Ireland and explore how they influence practice in healthcare organizations. DESIGN: The study adopted a sequential, exploratory mixed-methods design. METHODS: Phase 1 incorporated a multiple-choice questionnaire completed by 77 Directors of Nursing recruited using voluntary response sampling. In phase 2, 35 nurses and midwives who were working at executive, senior manager and clinical levels, participated in semi-structured interviews. Data collection of both phases was conducted from January 2016 to October 2016. FINDINGS: Quantitative data revealed over 100 nursing and midwifery-specific KPIs. National requirements were a deciding factor in KPI selection, while clinical involvement was mainly through data collection. Respondents stated that they used patient experience KPIs, but only one was assessed as valid. Thematic analysis identified two themes: The leadership challenge (including 'voiceless in the national conversation', 'aligning KPIs in the practice context' and 'listening to those who matter'); and taking action (including 'establishing ownership and engaging staff', 'checks and balances' and 'closing the loop'). CONCLUSION: The large volume of KPI measurement taking place makes meaningful evaluation of performance and quality of care difficult, both in and across organizations. Nurses and midwives require enhanced knowledge of the nature and purpose of KPIs, as evidence gained from KPI data collection is insufficient to lead to improvements in practice. A practice context that encourages collective leadership, where multiple sources of evidence are gathered and everyone is included in KPI evaluation and subsequent decision-making, is key. IMPACT: This study adds to the body of evidence on KPI understanding. It informs the future effective management of indicators that will facilitate the delivery of meaningful care and reduce the cost, time and effort invested in the implementation of KPIs and data management.

Eurasian beaver (Castor fiber) health surveillance in Britain: Assessing a disjunctive reintroduced population.

BACKGROUND: Numerous translocations of Eurasian beavers have occurred with little implementation of standardised health screening. Pre-release health screening enables the selection of individuals with the best survival prospects and reduces potential health risks, but this is by-passed during unofficial releases. Beaver reintroduction to Britain has been haphazard and currently disjunctive populations of varying status exist. METHODS: This observational cross section study investigated the health status of three beaver populations, with 90 live beavers tested for a range of pathogens comprising 56 from Tayside (unofficially released Scotland), nine from Knapdale (officially released Scotland) and 25 from Devon (unofficially released England). In addition, a further 32 cadavers were screened (25 from Tayside and seven from Knapdale). RESULTS: All beavers were in good physical condition, did not harbour any non-native disease or parasites of concern and demonstrated remarkably low levels of any disease or parasite exposure. CONCLUSION: Beavers are establishing and adapting well to British landscapes and are not acting as reservoirs of significant zoonotic diseases. Official, licensed reintroduction programmes may appear overly convoluted; however, reputational damage of unofficial releases should be considered, along with the health and welfare of the animals involved and collateral damage to other wildlife, domestic animals and humans.

Implementing and measuring person-centredness using an APP for knowledge transfer: the iMPAKT app.

OBJECTIVE: The aim of the study was to evaluate a technological solution in the form of an App to implement and measure person-centredness in nursing. The focus was to enhance the knowledge transfer of a set of person-centred key performance indicators and the corresponding measurement framework used to inform improvements in the experience of care. DESIGN: The study used an evaluation approach derived from the work of the Medical Research Council to assess the feasibility of the App and establish the degree to which the App was meeting the aims set out in the development phase. Evaluation data were collected using focus groups (n = 7) and semi-structured interviews (n = 7) to capture the impact of processes experienced by participating sites. SETTING: The study was conducted in the UK and Australia in two organizations, across 11 participating sites. PARTICIPANTS: 22 nurses from 11 sites in two large health care organizations were recruited on a voluntary basis. INTERVENTION: Implementing the KPIs and measurement framework via the APP through two cycles of data collection. MAIN OUTCOME MEASURES: The main outcome was to establish feasibility in the use of the App. RESULTS: The majority of nurse/midwife participants found the App easy to use. There was broad consensus that the App was an effective method to measure the patient experience and generated clear, concise reports in real time. CONCLUSIONS: The implementation of the person-centred key performance indicators using the App enhanced the generation of meaningful data to evidence patient experience across a range of different clinical settings.

USE OF CLINDAMYCIN IN PALLAS' CATS [OTOCOLOBUS (FELIS) MANUL] TO REDUCE JUVENILE TOXOPLASMOSIS-ASSOCIATED MORTALITY RATES.

Pallas' cat [Otocolobus (Felis) manul] experiences a high mortality rate from toxoplasmosis. During the period 2006-2016, the overall mortality rate for this species from all causes during the first year of life was 71.59% in European Association of Zoos and Aquaria institutions, with the most significant infectious cause from systemic toxoplasmosis (20.6%) as confirmed by postmortem examination and histopathology. Clindamycin was used starting in 2014 in two collections that had previously experienced 100% mortality rates by toxoplasmosis in kittens less than one year of age, covering key Toxoplasma gondii exposure periods for kittens (n = 17) as a prophylactic measure. This protocol resulted in a 67.03% (95% confidence interval 41.76-78.61%) reduction in the first year mortality rate over a two-year period to 5.88% in those animals treated.

Applying whole-genome sequencing in relation to phenotype and outcomes in siblings with cystic fibrosis.

Variations in disease onset and/or severity have often been observed in siblings with cystic fibrosis (CF), despite the same CFTR genotype and environment. We postulated that genomic variation (modifier and/or pharmacogenomic variants) might explain these clinical discordances. From a cohort of patients included in the Wisconsin randomized clinical trial (RCT) of newborn screening (NBS) for CF, we identified two brothers who showed discordant lung disease courses as children, with one milder and the other more severe than average, and a third, eldest brother, who also has severe lung disease. Leukocytes were harvested as the source of DNA, and whole-genome sequencing (WGS) was performed. Variants were identified and analyzed using in-house-developed informatics tools. Lung disease onset and severity were quantitatively different between brothers during childhood. The youngest, less severely affected brother is homozygous for HFE p.H63D. He also has a very rare PLG p.D238N variant that may influence host-pathogen interaction during chronic lung infection. Other variants of interest were found differentially between the siblings. Pharmacogenomics findings were consistent with the middle, most severely affected brother having poor outcomes to common CF treatments. We conclude that genomic variation between siblings with CF is expected. Variable lung disease severity may be associated with differences acting as genetic modifiers and/or pharmacogenomic factors, but large cohort studies are needed to assess this hypothesis.

Implementing person-centred key performance indicators to strengthen leadership in community nursing: A feasibility study.

AIMS: To explore the utility and feasibility of implementing eight person-centred nursing key performance indicators in supporting community nurses to lead the development of person-centred practice. BACKGROUND: Policy advocates person-centred health care, but few quality indicators exist that explicitly focus on evaluating person-centred practice in community nursing. Current quality measurement frameworks in the community focus on incidences of poor or missed opportunities for care, with few mechanisms to measure how clients perceive the care they receive. METHODS: An evaluation approach derived from work of the Medical Research Council was used, and the study was underpinned by the Person-centred Practice Framework. Participatory methods were used, consistent with person-centred research. RESULTS: Data were thematically analysed, revealing five themes: giving voice to experience; talking the language of person-centredness; leading for cultural change; proud to be a nurse; and facilitating engagement. CONCLUSIONS: The findings suggest that implementing the eight person-centred nursing key performance indicators (KPIs) and the measurement framework is feasible and offers a means of evidencing person-centredness in community nursing. IMPLICATIONS FOR NURSING MANAGEMENT: Person-centred KPI data, used alongside existing quality indicators, will enable nurse managers to evidence a high standard of care delivery and assist in the development of person-centred practice.

VarSight: prioritizing clinically reported variants with binary classification algorithms.

BACKGROUND: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. METHODS: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. RESULTS: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. CONCLUSIONS: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.