Fast marginal likelihood estimation of penalties for group-adaptive elastic net

Nowadays, clinical research routinely uses omics data, such as gene expression, for predicting clinical outcomes or selecting markers. Additionally, so-called co-data are often available, providing complementary information on the covariates, like p-values from previously published studies or groups of genes corresponding to pathways. Elastic net penalisation is widely used for prediction and covariate selection. Group-adaptive elastic net penalisation learns from co-data to improve the prediction and covariate selection, by penalising important groups of covariates less than other groups. Existing methods are, however, computationally expensive. Here we present a fast method for marginal likelihood estimation of group-adaptive elastic net penalties for generalised linear models. We first derive a low-dimensional representation of the Taylor approximation of the marginal likelihood and its first derivative for group-adaptive ridge penalties, to efficiently estimate these penalties. Then we show by using asymptotic normality of the linear predictors that the marginal likelihood for elastic net models may be approximated well by the marginal likelihood for ridge models. The ridge group penalties are then transformed to elastic net group penalties by using the variance function. The method allows for overlapping groups and unpenalised variables. We demonstrate the method in a model-based simulation study and an application to cancer genomics. The method substantially decreases computation time and outperforms or matches other methods by learning from co-data.Comment: 16 pages, 6 figures, 1 tabl

Low grade mosaic for a complex supernumerary ring chromosome 18 in an adult patient with multiple congenital anomalies

Background. Several cases have been reported of patients with a ring chromosome 18 replacing one of the normal chromosomes 18. Less common are patients with a supernumerary ring chromosomes 18. High resolution whole genome examination in patients with multiple congenital abnormalities might reveal cytogenetic abnormalities of an unexpected complexity. Results. We report a 24 years old male patient with lower spinal anomalies, hypospadia, bifid scrotum, cryptorchism, anal atresia, kidney stones, urethra anomalies, radial dysplasia, and a hypoplastic thumb. Some of the anomalies overlap with the VACTERL association. Chromosome analysis of cultured peripheral blood lymphocytes revealed an additional ring chromosome in 13% of the metaphases. Both parents had a normal karyotype, demonstrating the de novo origin of this ring chromosome. FISH analysis using whole chromosome paints showed that the additional chromosomal material was derived from chromosome 18. Chromosome analysis of cultured fibroblasts revealed only one cell with the supernumerary ring chromosome in the 400 analyzed. To characterize the ring chromosome in more detail peripheral blood derived DNA was analyzed using SNP-arrays. The array results indicated a 5 Mb gain of the pericentromeric region of chromosome 18q10-q11.2. FISH analysis using BAC-probes located in the region indicated the presence of 6 signals on the r(18) chromosome. In addition, microsatellite analysis demonstrated that the unique supernumerary ring chromosome was paternally derived and both normal copies showed biparental disomy. Conclusions. We report on an adult patient with multiple congenital abnormalities who had in 13% of his cells a unique supernumerary ring chromosome 18 that was composed of 6 copies of the 5 Mb gene rich region of 18q11

Circuit topology approach for the comparative analysis of intrinsically disordered proteins

Intrinsically disordered proteins (IDPs) lack a stable native conformation, making it challenging to characterize their structure and dynamics. Key topological motifs with fundamental biological relevance are often hidden in the conformational noise, eluding detection. Here, we develop a circuit topology toolbox to extract conformational patterns, critical contacts, and timescales from simulated dynamics of intrinsically disordered proteins. We follow the dynamics of IDPs by providing a smart low-dimensionality representation of their three-dimensional (3D) configuration in the topology space. Such an approach allows us to quantify topological similarity in dynamic systems, therefore providing a pipeline for structural comparison of IDPs.Pharmacolog

¹⁸F-FDG PET baseline radiomics features improve the prediction of treatment outcome in diffuse large B-cell lymphoma

PURPOSE: Accurate prognostic markers are urgently needed to identify diffuse large B-Cell lymphoma (DLBCL) patients at high risk of progression or relapse. Our purpose was to investigate the potential added value of baseline radiomics features to the international prognostic index (IPI) in predicting outcome after first-line treatment. METHODS: Three hundred seventeen newly diagnosed DLBCL patients were included. Lesions were delineated using a semi-automated segmentation method (standardized uptake value ≥ 4.0), and 490 radiomics features were extracted. We used logistic regression with backward feature selection to predict 2-year time to progression (TTP). The area under the curve (AUC) of the receiver operator characteristic curve was calculated to assess model performance. High-risk groups were defined based on prevalence of events; diagnostic performance was assessed using positive and negative predictive values. RESULTS: The IPI model yielded an AUC of 0.68. The optimal radiomics model comprised the natural logarithms of metabolic tumor volume (MTV) and of SUV(peak) and the maximal distance between the largest lesion and any other lesion (Dmax(bulk), AUC 0.76). Combining radiomics and clinical features showed that a combination of tumor- (MTV, SUV(peak) and Dmax(bulk)) and patient-related parameters (WHO performance status and age > 60 years) performed best (AUC 0.79). Adding radiomics features to clinical predictors increased PPV with 15%, with more accurate selection of high-risk patients compared to the IPI model (progression at 2-year TTP, 44% vs 28%, respectively). CONCLUSION: Prediction models using baseline radiomics combined with currently used clinical predictors identify patients at risk of relapse at baseline and significantly improved model performance. TRIAL REGISTRATION NUMBER AND DATE: EudraCT: 2006–005,174-42, 01–08-2008. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05480-3

Design and evaluation protocol of "FATaintPHAT", a computer-tailored intervention to prevent excessive weight gain in adolescents

<p>Abstract</p> <p>Background</p> <p>Computer tailoring may be a promising technique for prevention of overweight in adolescents. However, very few well-developed, evidence-based computer-tailored interventions are available for this target group. We developed and evaluated a computer-tailored intervention for adolescents targeting energy balance-related behaviours: i.e. consumption of snacks, sugar-sweetened beverages, fruit, vegetables, and fibre, physical activity, and sedentary behaviours. This paper describes the planned development of a school-based computer-tailored intervention aimed at improving energy balance-related behaviours in order to prevent excessive weight gain in adolescents, and the protocol for evaluating this intervention.</p> <p>Methods/design</p> <p>Intervention development: Informed by the Precaution Adoption Process Model and the Theory of Planned Behaviour, the computer-tailored intervention provided feedback on personal behaviour and suggestions on how to modify it. The intervention (VETisnietVET translated as 'FATaintPHAT') has been developed for use in the first year of secondary school during eight lessons.</p> <p>Evaluation design: The intervention will be evaluated in a cluster-randomised trial including 20 schools with a 4-months and a 2-years follow-up. Outcome measures are BMI, waist circumference, energy balance-related behaviours, and potential determinants of these behaviours. Process measures are appreciation of and satisfaction with the program, exposure to the program's content, and implementation facilitators and barriers measured among students and teachers.</p> <p>Discussion</p> <p>This project resulted in a theory and evidence-based intervention that can be implemented in a school setting. A large-scale randomised controlled trial with a short and long-term follow-up will provide sound statements about the effectiveness of this computer-tailored intervention in adolescents.</p> <p>Trial Registration</p> <p>ISRCTN15743786</p

EuropeaN Energy balance Research to prevent excessive weight Gain among Youth (ENERGY) project: Design and methodology of the ENERGY cross-sectional survey

Background: Obesity treatment is by large ineffective long term, and more emphasis on the prevention of excessive weight gain in childhood and adolescence is warranted. To inform energy balance related behaviour (EBRB) change interventions, insight in the potential personal, family and school environmental correlates of these behaviours is needed. Studies on such multilevel correlates of EBRB among schoolchildren in Europe are lacking. The ENERGY survey aims to (1) provide up-to-date prevalence rates of measured overweight, obesity, self-reported engagement in EBRBs, and objective accelerometer-based assessment of physical activity and sedentary behaviour and blood-sample biomarkers of metabolic function in countries in different regions of Europe, (2) to identify personal, family and school environmental correlates of these EBRBs. This paper describes the design, methodology and protocol of the survey. Method/Design: A school-based cross-sectional survey was carried out in 2010 in seven different European countries; Belgium, Greece, Hungary, the Netherlands, Norway, Slovenia, and Spain. The survey included measurements of anthropometrics, child, parent and school-staff questionnaires, and school observations to measure and assess outcomes (i.e. height, weight, and waist circumference), EBRBs and potential personal, family and school environmental correlates of these behaviours including the social-cultural, physical, political, and economic environmental factors. In addition, a selection of countries conducted accelerometer measurements to objectively assess physical activity and sedentary behaviour, and collected blood samples to assess several biomarkers of metabolic function. Discussion: The ENERGY survey is a comprehensive cross-sectional study measuring anthropometrics and biomarkers as well as assessing a range of EBRBs and their potential correlates at the personal, family and school level, among 10-12 year old children in seven European countries. This study will result in a unique dataset, enabling cross country comparisons in overweight, obesity, risk behaviours for these conditions as well as the correlates of engagement in these risk behaviours

Direct and indirect associations between the family physical activity environment and sports participation among 10-12 year-old European children: testing the EnRG framework in the ENERGY project

BACKGROUND: Sport participation makes an important contribution to children’s overall physical activity. Understanding influences on sports participation is important and the family environment is considered key, however few studies have explored the mechanisms by which the family environment influences children’s sport participation. The purpose of this study was to examine whether attitude, perceived behavioural control, health belief and enjoyment mediate associations between the family environment and 10–12 year-old children’s sports participation. METHODS: Children aged 10–12 years ( = 7234) and one of their parents (n = 6002) were recruited from 175 schools in seven European countries in 2010. Children self-reported their weekly duration of sports participation, physical activity equipment items at home and the four potential mediator variables. Parents responded to items on financial, logistic and emotional support, reinforcement, modelling and co-participation in physical activity. Cross-sectional single and multiple mediation analyses were performed for 4952 children with complete data using multi-level regression analyses. RESULTS: Availability of equipment (OR = 1.16), financial (OR = 1.53), logistic (OR = 1.47) and emotional (OR = 1.51) support, and parental modelling (OR = 1.07) were positively associated with participation in ≥ 30mins/wk of sport. Attitude, beliefs, perceived behavioural control and enjoyment mediated and explained between 21-34% of these associations. Perceived behavioural control contributed the most to the mediated effect for each aspect of the family environment. CONCLUSIONS: Both direct (unmediated) and indirect (mediated) associations were found between most family environment variables and children’s sports participation. Thus, family-based physical activity interventions that focus on enhancing the family environment to support children’s sport participation are warranted

Optimizing diffusion of an online computer tailored lifestyle program: a study protocol

ABSTRACT: Background Although the Internet is a promising medium to offer lifestyle interventions to large amounts of people at relatively low costs and effort, actual exposure rates of these interventions fail to meet the high expectations. Since public health impact of interventions is determined by intervention efficacy and level of exposure to the intervention, it is imperative to put effort in optimal dissemination. The present project attempts to optimize the dissemination process of a new online computer tailored generic lifestyle program by carefully studying the adoption process and developing a strategy to achieve sustained use of the program. Methods/Design A prospective study will be conducted to yield relevant information concerning the adoption process by studying the level of adoption of the program, determinants involved in adoption and characteristics of adopters and non-adopters as well as satisfied and unsatisfied users. Furthermore, a randomized control trial will be conducted to the test the effectiveness of a proactive strategy using periodic e-mail prompts in optimizing sustained use of the new program. Discussion Closely mapping the adoption process will gain insight in characteristics of adopters and non-adopters and satisfied and unsatisfied users. This insight can be used to further optimize the program by making it more suitable for a wider range of users, or to develop adjusted interventions to attract subgroups of users that are not reached or satisfied with the initial intervention. Furthermore, by studying the effect of a proactive strategy using period prompts compared to a reactive strategy to stimulate sustained use of the intervention and, possibly, behaviour change, specific recommendations on the use and the application of prompts in online lifestyle interventions can be developed. Trial registration Dutch Trial Register (NTR1786) and Medical Ethics Committee of Maastricht University and the University Hospital Maastricht (NL2723506809/MEC0903016)