GSuite HyperBrowser: integrative analysis of dataset collections across the genome and epigenome

Background: Recent large-scale undertakings such as ENCODE and Roadmap Epigenomics have generated experimental data mapped to the human reference genome (as genomic tracks) representing a variety of functional elements across a large number of cell types. Despite the high potential value of these publicly available data for a broad variety of investigations, little attention has been given to the analytical methodology necessary for their widespread utilisation. Findings: We here present a first principled treatment of the analysis of collections of genomic tracks. We have developed novel computational and statistical methodology to permit comparative and confirmatory analyses across multiple and disparate data sources. We delineate a set of generic questions that are useful across a broad range of investigations and discuss the implications of choosing different statistical measures and null models. Examples include contrasting analyses across different tissues or diseases. The methodology has been implemented in a comprehensive open-source software system, the GSuite HyperBrowser. To make the functionality accessible to biologists, and to facilitate reproducible analysis, we have also developed a web-based interface providing an expertly guided and customizable way of utilizing the methodology. With this system, many novel biological questions can flexibly be posed and rapidly answered. Conclusions: Through a combination of streamlined data acquisition, interoperable representation of dataset collections, and customizable statistical analysis with guided setup and interpretation, the GSuite HyperBrowser represents a first comprehensive solution for integrative analysis of track collections across the genome and epigenome. The software is available at: https://hyperbrowser.uio.no.This work was supported by the Research Council of Norway (under grant agreements 221580, 218241, and 231217/F20), by the Norwegian Cancer Society (under grant agreements 71220’PR-2006-0433 and 3485238-2013), and by the South-Eastern Norway Regional Health Authority (under grant agreement 2014041).Peer Reviewe

Game Theory and Cancer : Using Game Theory to Model Host-Tumor Interactions

Cancer can be seen as an evolutionary disease, where natural selection works on the cells in an organism to promote traits that are detrimental to the organism. Evolutionary game theory (EGT) is a field using the methods of game theory, which is usually concerned with the behaviour of rational agents, to model adaptive systems. The basis for EGT is that the stable rest points of the adaptive system correspond to stable equilibrium solutions to related games. EGT has been used to model the cellular evolution in cancer with focus on the interactions between different cancer cells, and between cancer cells and normal cells. This thesis is an attempt to model the relationship between the host and the cancer cells using game theory. Simplified systems of differential equations simultaneously describing the cellular evolution within organisms as well as organismal evolution are presented, and a correspondence between stable rest points of these systems and stable equilibrium solutions to a class of extensive games are shown. The game theoretical models are applied to modified versions of cell- cell interaction games from the literature. The results show that it is evolutionarily plausible for multicellular organisms to develop tactical elements in their anti-cancer strategies

Time trade-off with someone to live for: impact of having significant others on time trade-off valuations of hypothetical health states

Abstract Background The TTO task involves giving up life years, i.e. living a shorter life, to avoid an undesirable health state. Despite being a hypothetical task, some respondents take other life factors into account when completing the task. This study explored the effect of having children and/or a partner on TTO valuations of hypothetical EQ-5D-5L health states in a valuation study of the general population. Methods The study used TTO data collected in a Norwegian EQ-5D-5L valuation study in 2019–2020, by one-to-one pc-assisted interviews following the EQ-VT protocol. We used regression modelling to determine the effect of significant others (having children or a partner) on disutility per health state from the TTO valuations. Results 430 respondents were included [mean age 43.8 (SD 15.9) years, 58% female, 48% with children, 68% with a partner, 25% with neither children nor partner]. Having children and/or a partner was associated with lowered willingness to trade life years translating to higher elicited health state utilities ( p  < 0.01). Conclusion Having significant others, or the lack of having significant others, was associated with respondents’ valuation of hypothetical health states using TTO, more so than traditional sampling variables such as age and sex. Inadequate representativeness in terms of having significant others could bias health state preference values in valuation studies

KAGE: fast alignment-free graph-based genotyping of SNPs and short indels

Genotyping is a core application of high-throughput sequencing. We present KAGE, a genotyper for SNPs and short indels that is inspired by recent developments within graph-based genome representations and alignment-free methods. KAGE uses a pan-genome representation of the population to efficiently and accurately predict genotypes. Two novel ideas improve both the speed and accuracy: a Bayesian model incorporates genotypes from thousands of individuals to improve prediction accuracy, and a computationally efficient method leverages correlation between variants. We show that the accuracy of KAGE is at par with the best existing alignment-free genotypers, while being an order of magnitude faster

General population norms for the EQ-5D-3 L in Norway: comparison of postal and web surveys

Abstract Background The EQ-5D-3 L instrument is a standardized questionnaire which was developed as a simple, generic measure of health for clinical and economic appraisal. To aid in the interpretation, scores are often compared with a normative group. The objectives of this study were 1) to provide population norms for the EQ-5D-3 L for Norway, and 2) to compare scores from postal and web surveys. Methods We conducted two surveys in samples that were aimed to be representative of the Norwegian general population: 1) a postal survey (n = 5000) and 2) a panel study with electronic data collection (n = 1936). For scoring the EQ-5D Index, we used the UK tariff. EQ-5D items were compared using multivariable ordinal logistic regression analysis and EQ-5D Index and EQ VAS scores using multivariable linear regression, adjusting for age, sex and education. Results In total 1131 (22.6%) responded to the postal survey and 977 (50.5%) to the web survey. The odds ratio (OR) for being in a higher score category on the Pain/Discomfort scale in the web survey was 1.25 (95%CI 1.04 to 1.50, p = 0.019) relative to the postal survey. The odds were similar in the other four dimensions. The EQ-5D Index and EQ VAS scores were similar in the postal and web surveys in the various strata according to age, sex and education, except for lower unadjusted and adjusted score for web respondents aged 41–50 years and for those with higher education (≥14 years) than postal respondents. Conclusions The distribution of scores for the EQ-5D descriptive system and its derived utility scores were rather similar in a postal survey and a panel web survey. Hence, these values were combined into a norm set for Norway

General population norms for the EQ-5D-3 L in Norway: comparison of postal and web surveys

Background The EQ-5D-3 L instrument is a standardized questionnaire which was developed as a simple, generic measure of health for clinical and economic appraisal. To aid in the interpretation, scores are often compared with a normative group. The objectives of this study were 1) to provide population norms for the EQ-5D-3 L for Norway, and 2) to compare scores from postal and web surveys. Methods We conducted two surveys in samples that were aimed to be representative of the Norwegian general population: 1) a postal survey (n = 5000) and 2) a panel study with electronic data collection (n = 1936). For scoring the EQ-5D Index, we used the UK tariff. EQ-5D items were compared using multivariable ordinal logistic regression analysis and EQ-5D Index and EQ VAS scores using multivariable linear regression, adjusting for age, sex and education. Results In total 1131 (22.6%) responded to the postal survey and 977 (50.5%) to the web survey. The odds ratio (OR) for being in a higher score category on the Pain/Discomfort scale in the web survey was 1.25 (95%CI 1.04 to 1.50, p = 0.019) relative to the postal survey. The odds were similar in the other four dimensions. The EQ-5D Index and EQ VAS scores were similar in the postal and web surveys in the various strata according to age, sex and education, except for lower unadjusted and adjusted score for web respondents aged 41–50 years and for those with higher education (≥14 years) than postal respondents. Conclusions The distribution of scores for the EQ-5D descriptive system and its derived utility scores were rather similar in a postal survey and a panel web survey. Hence, these values were combined into a norm set for Norway

Assessing graph-based read mappers against a baseline approach highlights strengths and weaknesses of current methods

Background Graph-based reference genomes have become popular as they allow read mapping and follow-up analyses in settings where the exact haplotypes underlying a high-throughput sequencing experiment are not precisely known. Two recent papers show that mapping to graph-based reference genomes can improve accuracy as compared to methods using linear references. Both of these methods index the sequences for most paths up to a certain length in the graph in order to enable direct mapping of reads containing common variants. However, the combinatorial explosion of possible paths through nearby variants also leads to a huge search space and an increased chance of false positive alignments to highly variable regions. Results We here assess three prominent graph-based read mappers against a hybrid baseline approach that combines an initial path determination with a tuned linear read mapping method. We show, using a previously proposed benchmark, that this simple approach is able to improve overall accuracy of read-mapping to graph-based reference genomes. Conclusions Our method is implemented in a tool Two-step Graph Mapper, which is available at https://github.com/uio-bmi/two_step_graph_mapperalong with data and scripts for reproducing the experiments. Our method highlights characteristics of the current generation of graph-based read mappers and shows potential for improvement for future graph-based read mappers

Norwegian population norms for the EQ-5D-5L: results from a general population survey

Abstract Purpose To provide the first Norwegian EQ-5D-5L and EQ VAS population norms for the adult general population. Methods Postal survey of a random sample of 12,790 Norwegians identified through the National Registry of the Norwegian Tax Administration. Norms, weighted for Norwegian general population characteristics, are shown for the five EQ-5D-5L dimensions, EQ-5D index, and EQ VAS scores for seven age categories, females, males, and education level. Results There were 3200 (25.9%) respondents to 12,263 correctly addressed questionnaires. The EQ-5D-5L dimensions, EQ VAS, and background questions were completed by 3120 (24.6%) respondents. The mean age (SD) was 50.9 (21.7) and range was 18–97 years. The youngest age group of 18–29 years and oldest of 80 years and over had the highest ( n  = 691) and lowest ( n  = 239) number of respondents, respectively. Compared to the general population, the respondents comprised a greater number of females, younger and older ages, and had a higher education level. 32% of respondents reported no health problems on the EQ-5D-5L. From the youngest to oldest age groups, there was a general decline in health as assessed by the EQ-5D-5L. The exception was for anxiety/depression, where the youngest age groups had the poorest health. Apart from self-care, women reported poorer health than men, as assessed by the EQ-5D-5L; EQ VAS scores were similar for men and women. Higher levels of health (EQ-5D index, EQ VAS scores) were found with increasing levels of education. Conclusion The population norms will improve interpretation of EQ-5D-5L and EQ VAS scores in Norwegian applications including clinical practice, clinical and health services research, and national quality registers where EQ-5D-5L is the most widely used patient-reported instrument