Evaluation of polygenic scoring methods in five biobanks shows larger variation between biobanks than methods and finds benefits of ensemble learning.

Methods of estimating polygenic scores (PGSs) from genome-wide association studies are increasingly utilized. However, independent method evaluation is lacking, and method comparisons are often limited. Here, we evaluate polygenic scores derived via seven methods in five biobank studies (totaling about 1.2 million participants) across 16 diseases and quantitative traits, building on a reference-standardized framework. We conducted meta-analyses to quantify the effects of method choice, hyperparameter tuning, method ensembling, and the target biobank on PGS performance. We found that no single method consistently outperformed all others. PGS effect sizes were more variable between biobanks than between methods within biobanks when methods were well tuned. Differences between methods were largest for the two investigated autoimmune diseases, seropositive rheumatoid arthritis and type 1 diabetes. For most methods, cross-validation was more reliable for tuning hyperparameters than automatic tuning (without the use of target data). For a given target phenotype, elastic net models combining PGS across methods (ensemble PGS) tuned in the UK Biobank provided consistent, high, and cross-biobank transferable performance, increasing PGS effect sizes (ß coefficients) by a median of 5.0% relative to LDpred2 and MegaPRS (the two best-performing single methods when tuned with cross-validation). Our interactively browsable online-results and open-source workflow prspipe provide a rich resource and reference for the analysis of polygenic scoring methods across biobanks.

The Polygenic Score Catalog: new functionality and tools to enable FAIR research.

Polygenic scores (PGS) have transformed human genetic research and have multiple potential clinical applications, including risk stratification for disease prevention and prediction of treatment response. Here, we present a series of recent enhancements to the PGS Catalog (www.PGSCatalog.org), the largest findable, accessible, interoperable, and reusable (FAIR) repository of PGS. These include expansions in data content and ancestral diversity as well as the addition of new features. We further present the PGS Catalog Calculator (pgsc_calc, https://github.com/PGScatalog/pgsc_calc), an open-source, scalable and portable pipeline to reproducibly calculate PGS that securely democratizes equitable PGS applications by implementing genetic ancestry estimation and score normalization using reference data. With the PGS Catalog & calculator users can now quantify an individual's genetic predisposition for hundreds of common diseases and clinically relevant traits. Taken together, these updates and tools facilitate the next generation of PGS, thus lowering barriers to the clinical studies necessary to identify where PGS may be integrated into clinical practice.

Genomic, Proteomic, and Phenotypic Biomarkers of COVID-19 Severity: Protocol for a Retrospective Observational Study.

BACKGROUND: Health organizations and countries around the world have found it difficult to control the spread of COVID-19. To minimize the future impact on the UK National Health Service and improve patient care, there is a pressing need to identify individuals who are at a higher risk of being hospitalized because of severe COVID-19. Early targeted work was successful in identifying angiotensin-converting enzyme-2 receptors and type II transmembrane serine protease dependency as drivers of severe infection. Although a targeted approach highlights key pathways, a multiomics approach will provide a clearer and more comprehensive picture of severe COVID-19 etiology and progression. OBJECTIVE: The COVID-19 Response Study aims to carry out an integrated multiomics analysis to identify biomarkers in blood and saliva that could contribute to host susceptibility to SARS-CoV-2 and the development of severe COVID-19. METHODS: The COVID-19 Response Study aims to recruit 1000 people who recovered from SARS-CoV-2 infection in both community and hospital settings on the island of Ireland. This protocol describes the retrospective observational study component carried out in Northern Ireland (NI; Cohort A); the Republic of Ireland cohort will be described separately. For all NI participants (n=519), SARS-CoV-2 infection has been confirmed by reverse transcription-quantitative polymerase chain reaction. A prospective Cohort B of 40 patients is also being followed up at 1, 3, 6, and 12 months postinfection to assess longitudinal symptom frequency and immune response. Data will be sourced from whole blood, saliva samples, and clinical data from the electronic care records, the general health questionnaire, and a 12-item general health questionnaire mental health survey. Saliva and blood samples were processed to extract DNA and RNA before whole-genome sequencing, RNA sequencing, DNA methylation analysis, microbiome analysis, 16S ribosomal RNA gene sequencing, and proteomic analysis were performed on the plasma. Multiomics data will be combined with clinical data to produce sensitive and specific prognostic models for severity risk. RESULTS: An initial demographic and clinical profile of the NI Cohort A has been completed. A total of 249 hospitalized patients and 270 nonhospitalized patients were recruited, of whom 184 (64.3%) were female, and the mean age was 45.4 (SD 13) years. High levels of comorbidity were evident in the hospitalized cohort, with cardiovascular disease and metabolic and respiratory disorders being the most significant (P<.001), grouped according to the International Classification of Diseases 10 codes. CONCLUSIONS: This study will provide a comprehensive opportunity to study the mechanisms of COVID-19 severity in recontactable participants. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50733.

snpQT: flexible, reproducible, and comprehensive quality control and imputation of genomic data.

Quality control of genomic data is an essential but complicated multi-step procedure, often requiring separate installation and expert familiarity with a combination of different bioinformatics tools. Software incompatibilities, and inconsistencies across computing environments, are recurrent challenges, leading to poor reproducibility. Existing semi-automated or automated solutions lack comprehensive quality checks, flexible workflow architecture, and user control. To address these challenges, we have developed snpQT: a scalable, stand-alone software pipeline using nextflow and BioContainers, for comprehensive, reproducible and interactive quality control of human genomic data. snpQT offers some 36 discrete quality filters or correction steps in a complete standardised pipeline, producing graphical reports to demonstrate the state of data before and after each quality control procedure. This includes human genome build conversion, population stratification against data from the 1,000 Genomes Project, automated population outlier removal, and built-in imputation with its own pre- and post- quality controls. Common input formats are used, and a synthetic dataset and comprehensive online tutorial are provided for testing, educational purposes, and demonstration. The snpQT pipeline is designed to run with minimal user input and coding experience; quality control steps are implemented with numerous user-modifiable thresholds, and workflows can be flexibly combined in custom combinations. snpQT is open source and freely available at https://github.com/nebfield/snpQT. A comprehensive online tutorial and installation guide is provided through to GWAS (https://snpqt.readthedocs.io/en/latest/), introducing snpQT using a synthetic demonstration dataset and a real-world Amyotrophic Lateral Sclerosis SNP-array dataset.

Exploring variation in ambulance calls and conveyance rates for adults with diabetes mellitus who contact the Northern Ireland Ambulance Service: a retrospective database analysis.

BACKGROUND: People with diabetes frequently contact the ambulance service about acute problems. Overall, treating diabetes and its associated complications costs the NHS 10% of the annual budget. Reducing unnecessary hospital admissions and ambulance attendances is a high priority policy for the NHS across the UK. This study aimed to determine the characteristics of emergency calls for people with diabetes who contact the ambulance service and are subsequently conveyed to hospital by the Northern Ireland Ambulance Service (NIAS). METHODS: A retrospective dataset from the NIAS was obtained from the NIAS Trust's Command and Control system relating to calls where the final complaint group was 'Diabetes' for the period 1 January 2017 to 23 November 2019. RESULTS: Of a total 11,396 calls related to diabetes, 63.2% of callers to the NIAS were conveyed to hospital. Over half of the calls related to males, with 35.5% of callers aged 60-79. The more deprived areas had a higher frequency of calls and conveyance to hospital, with this decreasing as deprivation decreased. Calls were evenly distributed across the week, with the majority of calls originating outside of GP working hours, although callers were more likely to be conveyed to hospital during working hours. Calls from healthcare professionals were significantly more likely to be conveyed to hospital, despite accounting for the minority of calls. CONCLUSION: This research found that older males were more likely to contact the ambulance service but older females were more likely to be conveyed to hospital. The likelihood of conveyance increased if the call originated from an HCP or occurred during GP working hours. The availability of alternative care pathways has the potential to reduce conveyance to hospital, which has been particularly important during the COVID-19 pandemic. Integration of data is vitally important to produce high quality research and improve policy and practice in this area.

Variations in the oral microbiome are associated with depression in young adults.

A growing body of evidence supports an important role for alterations in the brain-gut-microbiome axis in the aetiology of depression and other psychiatric disorders. The potential role of the oral microbiome in mental health has received little attention, even though it is one of the most diverse microbiomes in the body and oral dysbiosis has been linked to systemic diseases with an underlying inflammatory aetiology. This study examines the structure and composition of the salivary microbiome for the first time in young adults who met the DSM-IV criteria for depression (n = 40) and matched controls (n = 43) using 16S rRNA gene-based next generation sequencing. Subtle but significant differences in alpha and beta diversity of the salivary microbiome were observed, with clear separation of depressed and healthy control cohorts into distinct clusters. A total of 21 bacterial taxa were found to be differentially abundant in the depressed cohort, including increased Neisseria spp. and Prevotella nigrescens, while 19 taxa had a decreased abundance. In this preliminary study we have shown that the composition of the oral microbiome is associated with depression in young adults. Further studies are now warranted, particuarly investigations into whether such shifts play any role in the underling aetiology of depression.

A predictive model for paediatric autism screening.

Autism spectrum disorder is an umbrella term for a group of neurodevelopmental disorders that is associated with impairments to social interaction, communication, and behaviour. Typically, autism spectrum disorder is first detected with a screening tool (e.g. modified checklist for autism in toddlers). However, the interpretation of autism spectrum disorder behavioural symptoms varies across cultures: the sensitivity of modified checklist for autism in toddlers is as low as 25 per cent in Sri Lanka. A culturally sensitive screening tool called pictorial autism assessment schedule has overcome this problem. Low- and middle-income countries have a shortage of mental health specialists, which is a key barrier for obtaining an early autism spectrum disorder diagnosis. Early identification of autism spectrum disorder enables intervention before atypical patterns of behaviour and brain function become established. This article proposes a culturally sensitive autism spectrum disorder screening mobile application. The proposed application embeds an intelligent machine learning model and uses a clinically validated symptom checklist to monitor and detect autism spectrum disorder in low- and middle-income countries for the first time. Machine learning models were trained on clinical pictorial autism assessment schedule data and their predictive performance was evaluated, which demonstrated that the random forest was the optimal classifier (area under the receiver operating characteristic (0.98)) for embedding into the mobile screening tool. In addition, feature selection demonstrated that many pictorial autism assessment schedule questions are redundant and can be removed to optimise the screening process.

Robust Microbial Markers for Non-Invasive Inflammatory Bowel Disease Identification.

Inflammatory Bowel Disease (IBD) is an umbrella term for a group of inflammatory diseases of the gastrointestinal tract, including Crohn's Disease and ulcerative colitis. Changes to the intestinal microbiome, the community of micro-organisms that resides in the human gut, have been shown to contribute to the pathogenesis of IBD. IBD diagnosis is often delayed due to its non-specific symptoms and because an invasive colonoscopy is required for confirmation, which leads to poor growth in children and worse treatment outcomes. Feature selection algorithms are often applied to microbial communities to identify bacterial groups that drive disease. It has been shown that aggregating Ensemble Feature Selection (EFS) can improve the robustness of feature selection algorithms, which is defined as the variation of feature selector output caused by small changes to the dataset. In this work, we apply a two-step filter and an EFS process to generate robust feature subsets that can non-invasively predict IBD subtypes from high-resolution microbiome data. The predictive power of the robust feature subsets is the highest reported in literature to date. Furthermore, we identify five biologically plausible bacterial species that have not previously been implicated in IBD aetiology.