Knut Dagestad Rand

• Bope, Christian Domilongo; Kalyanasundaram, Sumana; Rand, Knut Dagestad; Nakken, Sigve; Lingjærde, Ole Christian & Hovig, Eivind (2025). StarSignDNA: Mutation-to-signature attribution for accurate representation of mutational processes in low-mutation contexts. NAR Genomics and Bioinformatics. 7(4). doi: 10.1093/nargab/lqaf181. Full text in Research Archive Show summary

  All cell lineages accumulate mutations over time, increasing the probability that some lineages eventually become malignant. Many of the processes responsible for generating mutations leave a characteristic footprint in the genome that allows their presence to be detected. However, the mutational pattern in a tumour is usually the combined result of multiple mutational processes being at work simultaneously, and the problem of disentangling the different footprints and their relative impact then becomes a deconvolution problem. Several algorithms have been developed for this purpose, most of them involving a factorisation of the mutation count matrix into two non-negative matrices, representing, respectively, the underlying mutational signatures and the relative exposure to these signatures. Here, we introduce the StarSignDNA algorithm for mutational signature analysis, which offers efficient re-fitting and de novo mutational signature extraction. StarSignDNA performs mutation-to-signature attribution, assigning each mutation to its most probable causative mutational signature(s) based on the mutation’s trinucleotide context and the signature profiles. StarSignDNA demonstrates robust and clinically relevant performance in low-mutation contexts, with particular strengths in re-fitting analysis and balanced performance in de novo signature discovery. The package offers a command-line-based interface and data visualisation routines. The package is available at https://github.com/uio-bmi/StarSignDNA and can be installed via PyPI.

• Hajj, Ghadi al; Hubin, Aliaksandr; Kanduri, Chakravarthi; Pavlovic, Milena; Rand, Knut Dagestad & Widrich, Michael [Show all 11 contributors for this article] (2024). Incorporating probabilistic domain knowledge into deep multiple instance learning. Proceedings of Machine Learning Research (PMLR). 235, p. 17279–17297. Full text in Research Archive Show summary

  Deep learning methods, including deep multiple instance learning methods, have been criticized for their limited ability to incorporate domain knowledge. A reason that knowledge incorporation is challenging in deep learning is that the models usually lack a mapping between their model components and the entities of the domain, making it a non-trivial task to incorporate probabilistic prior information. In this work, we show that such a mapping between domain entities and model components can be defined for a multiple instance learning setting and propose a framework DeeMILIP that encompasses multiple strategies to exploit this mapping for prior knowledge incorporation. We motivate and formalize these strategies from a probabilistic perspective. Experiments on an immune-based diagnostics case show that our proposed strategies allow to learn generalizable models even in settings with weak signals, limited dataset size, and limited compute.

• Kanduri, Chakravarthi; Scheffer, Lonneke; Pavlović, Milena; Rand, Knut Dagestad; Chernigovskaia, Maria & Pirvandy, Oz [Show all 9 contributors for this article] (2023). simAIRR: simulation of adaptive immune repertoires with realistic receptor sequence sharing for benchmarking of immune state prediction methods. GigaScience. 12, p. 1–16. doi: 10.1093/gigascience/giad074. Full text in Research Archive Show summary

  Abstract Background Machine learning (ML) has gained significant attention for classifying immune states in adaptive immune receptor repertoires (AIRRs) to support the advancement of immunodiagnostics and therapeutics. Simulated data are crucial for the rigorous benchmarking of AIRR-ML methods. Existing approaches to generating synthetic benchmarking datasets result in the generation of naive repertoires missing the key feature of many shared receptor sequences (selected for common antigens) found in antigen-experienced repertoires. Results We demonstrate that a common approach to generating simulated AIRR benchmark datasets can introduce biases, which may be exploited for undesired shortcut learning by certain ML methods. To mitigate undesirable access to true signals in simulated AIRR datasets, we devised a simulation strategy (simAIRR) that constructs antigen-experienced-like repertoires with a realistic overlap of receptor sequences. simAIRR can be used for constructing AIRR-level benchmarks based on a range of assumptions (or experimental data sources) for what constitutes receptor-level immune signals. This includes the possibility of making or not making any prior assumptions regarding the similarity or commonality of immune state–associated sequences that will be used as true signals. We demonstrate the real-world realism of our proposed simulation approach by showing that basic ML strategies perform similarly on simAIRR-generated and real-world experimental AIRR datasets. Conclusions This study sheds light on the potential shortcut learning opportunities for ML methods that can arise with the state-of-the-art way of simulating AIRR datasets. simAIRR is available as a Python package: https://github.com/KanduriC/simAIRR.

• Grytten, Ivar; Rand, Knut Dagestad & Sandve, Geir Kjetil Ferkingstad (2022). KAGE: fast alignment-free graph-based genotyping of SNPs and short indels. Genome Biology. ISSN 1465-6906. 23(1). doi: 10.1186/s13059-022-02771-2. Full text in Research Archive Show summary

  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.

• Pavlović, Milena; Scheffer, Lonneke; Motwani, Keshav; Kanduri, Chakravarthi; Kompova, Radmila & Vazov, Nikolay Aleksandrov [Show all 42 contributors for this article] (2021). The immuneML ecosystem for machine learning analysis of adaptive immune receptor repertoires. Nature Machine Intelligence. 3(11), p. 936–944. doi: 10.1038/s42256-021-00413-z. Full text in Research Archive
• Grytten, Ivar; Rand, Knut Dagestad; Nederbragt, Alexander Johan & Sandve, Geir Kjetil (2020). Assessing graph-based read mappers against a baseline approach highlights strengths and weaknesses of current methods. BMC Genomics. 21. doi: 10.1186/s12864-020-6685-y. Full text in Research Archive Show summary

  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.

• Salvatore, Stefania; Rand, Knut Dagestad; Grytten, Ivar; Ferkingstad, Egil; Domanska, Diana & Holden, Lars [Show all 10 contributors for this article] (2019). Beware the Jaccard: the choice of similarity measure is important and non-trivial in genomic colocalisation analysis. Briefings in Bioinformatics. ISSN 1467-5463. p. 1–8. doi: 10.1093/bib/bbz083. Full text in Research Archive
• Grytten, Ivar; Rand, Knut Dagestad; Nederbragt, Alexander Johan; Storvik, Geir Olve; Glad, Ingrid Kristine & Sandve, Geir Kjetil (2019). Graph Peak Caller: Calling ChIP-seq peaks on graph-based reference genomes. PLoS Computational Biology. ISSN 1553-734X. 15(2), p. 1–13. doi: 10.1371/journal.pcbi.1006731. Full text in Research Archive Show summary

  Graph-based representations are considered to be the future for reference genomes, as they allow integrated representation of the steadily increasing data on individual variation. Currently available tools allow de novo assembly of graph-based reference genomes, alignment of new read sets to the graph representation as well as certain analyses like variant calling and haplotyping. We here present a first method for calling ChIP-Seq peaks on read data aligned to a graph-based reference genome. The method is a graph generalization of the peak caller MACS2, and is implemented in an open source tool, Graph Peak Caller. By using the existing tool vg to build a pan-genome of Arabidopsis thaliana, we validate our approach by showing that Graph Peak Caller with a pan-genome reference graph can trace variants within peaks that are not part of the linear reference genome, and find peaks that in general are more motif-enriched than those found by MACS2.

• Simovski, Boris; Vodak, Daniel; Gundersen, Sveinung; Domanska, Diana Ewa; Azab, Abdulrahman & Holden, Lars [Show all 25 contributors for this article] (2017). GSuite HyperBrowser: integrative analysis of dataset collections across the genome and epigenome. GigaScience. 6(7), p. 1–12. doi: 10.1093/gigascience/gix032. Full text in Research Archive Show summary

  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

• Rand, Knut Dagestad; Grytten, Ivar; Nederbragt, Alexander Johan; Storvik, Geir Olve; Glad, Ingrid Kristine & Sandve, Geir Kjetil (2017). Coordinates and intervals in graph-based reference genomes. BMC Bioinformatics. 18:263, p. 1–8. doi: 10.1186/s12859-017-1678-9. Full text in Research Archive Show summary

  Background It has been proposed that future reference genomes should be graph structures in order to better represent the sequence diversity present in a species. However, there is currently no standard method to represent genomic intervals, such as the positions of genes or transcription factor binding sites, on graph-based reference genomes. Results We formalize offset-based coordinate systems on graph-based reference genomes and introduce methods for representing intervals on these reference structures. We show the advantage of our methods by representing genes on a graph-based representation of the newest assembly of the human genome (GRCh38) and its alternative loci for regions that are highly variable. Conclusion More complex reference genomes, containing alternative loci, require methods to represent genomic data on these structures. Our proposed notation for genomic intervals makes it possible to fully utilize the alternative loci of the GRCh38 assembly and potential future graph-based reference genomes. We have made a Python package for representing such intervals on offset-based coordinate systems, available at https://github.com/uio-cels/offsetbasedgraph . An interactive web-tool using this Python package to visualize genes on a graph created from GRCh38 is available at https://github.com/uio-cels/genomicgraphcoords .

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• Rand, Knut Dagestad; Grytten, Ivar; Pavlović, Milena; Kanduri, Chakravarthi & Sandve, Geir Kjetil Ferkingstad (2024). BioNumPy: array programming for biology. Nature Methods. ISSN 1548-7091. doi: 10.1038/s41592-024-02483-4. Full text in Research Archive
• Torgersen, Eivind; Rand, Knut Dagestad; Grytten, Ivar & Sandve, Geir Kjetil Ferkingstad (2024). Nå blir det enklere å kode for forskere som jobber med biologiske data. [Journal]. Digi.no. Full text in Research Archive
• Balaban, Gabriel; Grytten, Ivar; Rand, Knut Dagestad; Scheffer, Lonneke & Sandve, Geir Kjetil (2021). Ten simple rules for quick and dirty scientific programming. PLoS Computational Biology. ISSN 1553-734X. 17:e1008549(3), p. 1–15. doi: 10.1371/journal.pcbi.1008549. Full text in Research Archive

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