Resampling procedures to identify important SNPs using a consensus approach

Our goal is to identify common single-nucleotide polymorphisms (SNPs) (minor allele frequency > 1%) that add predictive accuracy above that gained by knowledge of easily measured clinical variables. We take an algorithmic approach to predict each phenotypic variable using a combination of phenotypic and genotypic predictors. We perform our procedure on the first simulated replicate and then validate against the others. Our procedure performs well when predicting Q1 but is less successful for the other outcomes. We use resampling procedures where possible to guard against false positives and to improve generalizability. The approach is based on finding a consensus regarding important SNPs by applying random forests and the least absolute shrinkage and selection operator (LASSO) on multiple subsamples. Random forests are used first to discard unimportant predictors, narrowing our focus to roughly 100 important SNPs. A cross-validation LASSO is then used to further select variables. We combine these procedures to guarantee that cross-validation can be used to choose a shrinkage parameter for the LASSO. If the clinical variables were unavailable, this prefiltering step would be essential. We perform the SNP-based analyses simultaneously rather than one at a time to estimate SNP effects in the presence of other causal variants. We analyzed the first simulated replicate of Genetic Analysis Workshop 17 without knowledge of the true model. Post-conference knowledge of the simulation parameters allowed us to investigate the limitations of our approach. We found that many of the false positives we identified were substantially correlated with genuine causal SNPs

Creating a Scenic Design Studio

Creating A Scenic Design Studio documents an IQP for the WPI Drama/Theatre division of the Department of Humanities and Arts, and Masque. The work involved transforming the old scene shop in the Alden Hall sub-basement into a Studio equipped with the tools to create a wide range of high quality scenic elements. Our portfolio provides the academic theatre performance program with instructions and resources to enhance the theory and practice of the art of theatre at WPI

Fine-Grain Parallelism

Computer hardware is at the beginning of the multi-core revolution. While hardware at the commodity level is capable of running concurrent software, most software does not take advantage of this fact because parallel software development is difficult. This project addressed potential remedies to these difficulties by investigating graphical programming and fine-grain parallelism. A prototype system taking advantage of both of these concepts was implemented and evaluated in terms of real-world applications

Ontology-based Navigation of Bibliographic Metadata

This paper describes the work done within the Food and Agriculture Organization of the United Nations (FAO) on providing an ontology-based navigation for the Food, Nutrition and Agriculture (FNA) Journal. The aim of the revised navigation was to provide more efficient and effective browsing of the Food and Nutrition Publications using a knowledge model to guide the user with concepts and relationships relevant to a specific subject area. With this approach, data from two different bibliographical databases was merged, unified and presented to the user with improved services. A preliminary metadata merge was needed to combine all the information into one system in order to produce a metadata-ontology. Resource Description Framework Schema (RDFS) was chosen to exploit semantic relationships, e.g. the possibilities of browsing the data in different ways (by keywords, categories, authors, etc.), and the creation of a multilingual concept-based advanced search

Impact of metabolic syndrome and its components on cardiovascular disease event rates in 4900 patients with type 2 diabetes assigned to placebo in the field randomised trial

<p>Abstract</p> <p>Background</p> <p>Patients with the metabolic syndrome are more likely to develop type 2 diabetes and may have an increased risk of cardiovascular disease (CVD) events.We aimed to establish whether CVD event rates were influenced by the metabolic syndrome as defined by the World Health Organisation (WHO), the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and the International Diabetes Federation (IDF) and to determine which component(s) of the metabolic syndrome (MS) conferred the highest cardiovascular risk in in 4900 patients with type 2 diabetes allocated to placebo in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.</p> <p>Research design and methods</p> <p>We determined the influence of MS variables, as defined by NCEP ATPIII, IDF and WHO, on CVD risk over 5 years, after adjustment for CVD, sex, HbA_1c, creatinine, and age, and interactions between the MS variables in a Cox proportional-hazards model.</p> <p>Results</p> <p>About 80% had hypertension, and about half had other features of the metabolic syndrome (IDF, ATPIII). There was no difference in the prevalence of metabolic syndrome variables between those with and without CVD at study entry. The WHO definition identified those at higher CVD risk across both sexes, all ages, and in those without prior CVD, while the ATPIII definition predicted risk only in those aged over 65 years and in men but not in women. Patients meeting the IDF definition did not have higher risk than those without IDF MS.</p> <p>CVD risk was strongly influenced by prior CVD, sex, age (particularly in women), baseline HbA1_c, renal dysfunction, hypertension, and dyslipidemia (low HDL-c, triglycerides > 1.7 mmol/L). The combination of low HDL-c and marked hypertriglyceridemia (> 2.3 mmol/L) increased CVD risk by 41%. Baseline systolic blood pressure increased risk by 16% per 10 mmHg in those with no prior CVD, but had no effect in those with CVD. In those without prior CVD, increasing numbers of metabolic syndrome variables (excluding waist) escalated risk.</p> <p>Conclusion</p> <p>Absence of the metabolic syndrome (by the WHO definition) identifies diabetes patients without prior CVD, who have a lower risk of future CVD events. Hypertension and dyslipidemia increase risk.</p

A Novel Method to Adjust Efficacy Estimates for Uptake of Other Active Treatments in Long-Term Clinical Trials

BACKGROUND: When rates of uptake of other drugs differ between treatment arms in long-term trials, the true benefit or harm of the treatment may be underestimated. Methods to allow for such contamination have often been limited by failing to preserve the randomization comparisons. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, patients were randomized to fenofibrate or placebo, but during the trial many started additional drugs, particularly statins, more so in the placebo group. The effects of fenofibrate estimated by intention-to-treat were likely to have been attenuated. We aimed to quantify this effect and to develop a method for use in other long-term trials. METHODOLOGY/PRINCIPAL FINDINGS: We applied efficacies of statins and other cardiovascular drugs from meta-analyses of randomized trials to adjust the effect of fenofibrate in a penalized Cox model. We assumed that future cardiovascular disease events were reduced by an average of 24% by statins, and 20% by a first other major cardiovascular drug. We applied these estimates to each patient who took these drugs for the period they were on them. We also adjusted the analysis by the rate of discontinuing fenofibrate. Among 4,900 placebo patients, average statin use was 16% over five years. Among 4,895 assigned fenofibrate, statin use was 8% and nonuse of fenofibrate was 10%. In placebo patients, use of cardiovascular drugs was 1% to 3% higher. Before adjustment, fenofibrate was associated with an 11% reduction in coronary events (coronary heart disease death or myocardial infarction) (P = 0.16) and an 11% reduction in cardiovascular disease events (P = 0.04). After adjustment, the effects of fenofibrate on coronary events and cardiovascular disease events were 16% (P = 0.06) and 15% (P = 0.008), respectively. CONCLUSIONS/SIGNIFICANCE: This novel application of a penalized Cox model for adjustment of a trial estimate of treatment efficacy incorporates evidence-based estimates for other therapies, preserves comparisons between the randomized groups, and is applicable to other long-term trials. In the FIELD study example, the effects of fenofibrate on the risks of coronary heart disease and cardiovascular disease events were underestimated by up to one-third in the original analysis. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN64783481

Serotonin Reduction in Post-acute Sequelae of Viral Infection

Post-acute sequelae of COVID-19 (PASC, Long COVID ) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Ontology-based navigation of bibliographic metadata: example of the Food, Nutrition and Agriculture Journal

This paper describes the work done within the Food and Agriculture Organization of the United Nations (FAO) on providing an ontology-based navigation for the Food, Nutrition and Agriculture (FNA) Journal. The aim of the revised navigation was to provide more efficient and effective browsing of the Food and Nutrition Publications using a knowledge model to guide the user with concepts and relationships relevant to a specific subject area. With this approach, data from two different bibliographical databases was merged, unified and presented to the user with improved services. A preliminary metadata merge was needed to combine all the information into one system in order to produce a metadata-ontology. Resource Description Framework Schema (RDFS) was chosen to exploit semantic relationships, e.g. the possibilities of browsing the data in different ways (by keywords, categories, authors, etc.), and the creation of a multilingual concept-based advanced search