Institute of Computer Science

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

The issue of controlling values of various parameters of an evolutionary algorithm is one of the most important and promising areas of research in evolutionary computation: it has a potential of adjusting the algorithm to the problem while solving the problem. In the paper we: 1) revise the terminology, which is unclear and confusing, thereby providing a classification of such control mechanisms, and 2) survey various forms of control which have been studied by the evolutionary computation community in recent years. Our classification covers the major forms of parameter control in evolutionary computation and suggests some directions for further research.

Evolutionary computation techniques have received a great deal of attention regarding their potential as optimization techniques for complex numerical functions. However, they have not produced a significant breakthrough in the area of nonlinear programming due to the fact that they have not addressed the issue of constraints in a systematic way. Only recently have several methods been proposed for handling nonlinear constraints by evolutionary algorithms for numerical optimization problems; however, these methods have several drawbacks, and the experimental results on many test cases have been disappointing. In this paper we (1) discuss difficulties connected with solving the general nonlinear programming problem; (2) survey several approaches that have emerged in the evolutionary computation community; and (3) provide a set of 11 interesting test cases that may serve as a handy reference for future methods.

Abstract Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

Abstract A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

We generalize the notion of an approximation space introduced in [8]. In tolerance approximation spaces we define the lower and upper set approximations. We investigate some attribute reduction problems for tolerance approximation spaces determined b

Medical care has become one of the most indispensable parts of human lives, leading to a dramatic increase in medical big data. To streamline the diagnosis and treatment process, healthcare professionals are now adopting Internet of Things (IoT)-based wearable technology. Recent years have witnessed billions of sensors, devices, and vehicles being connected through the Internet. One such technology-remote patient monitoring-is common nowadays for the treatment and care of patients. However, these technologies also pose grave privacy risks and security concerns about the data transfer and the logging of data transactions. These security and privacy problems of medical data could result from a delay in treatment progress, even endangering the patient's life. We propose the use of a blockchain to provide secure management and analysis of healthcare big data. However, blockchains are computationally expensive, demand high bandwidth and extra computational power, and are therefore not completely suitable for most resource-constrained IoT devices meant for smart cities. In this work, we try to resolve the above-mentioned issues of using blockchain with IoT devices. We propose a novel framework of modified blockchain models suitable for IoT devices that rely on their distributed nature and other additional privacy and security properties of the network. These additional privacy and security properties in our model are based on advanced cryptographic primitives. The solutions given here make IoT application data and transactions more secure and anonymous over a blockchain-based network.

People supported by AI-powered decision support tools frequently overrely on the AI: they accept an AI's suggestion even when that suggestion is wrong. Adding explanations to the AI decisions does not appear to reduce the overreliance and some studies suggest that it might even increase it. Informed by the dual-process theory of cognition, we posit that people rarely engage analytically with each individual AI recommendation and explanation, and instead develop general heuristics about whether and when to follow the AI suggestions. Building on prior research on medical decision-making, we designed three cognitive forcing interventions to compel people to engage more thoughtfully with the AI-generated explanations. We conducted an experiment (N=199), in which we compared our three cognitive forcing designs to two simple explainable AI approaches and to a no-AI baseline. The results demonstrate that cognitive forcing significantly reduced overreliance compared to the simple explainable AI approaches. However, there was a trade-off: people assigned the least favorable subjective ratings to the designs that reduced the overreliance the most. To audit our work for intervention-generated inequalities, we investigated whether our interventions benefited equally people with different levels of Need for Cognition (i.e., motivation to engage in effortful mental activities). Our results show that, on average, cognitive forcing interventions benefited participants higher in Need for Cognition more. Our research suggests that human cognitive motivation moderates the effectiveness of explainable AI solutions.

With prevalent attacks in communication, sharing a secret between communicating parties is an ongoing challenge. Moreover, it is important to integrate quantum solutions with classical secret sharing schemes with low computational cost for the real world use. This paper proposes a novel hybrid threshold adaptable quantum secret sharing scheme, using an m-bonacci orbital angular momentum (OAM) pump, Lagrange interpolation polynomials, and reverse Huffman-Fibonacci-tree coding. To be exact, we employ entangled states prepared by m-bonacci sequences to detect eavesdropping. Meanwhile, we encode m-bonacci sequences in Lagrange interpolation polynomials to generate the shares of a secret with reverse Huffman-Fibonacci-tree coding. The advantages of the proposed scheme is that it can detect eavesdropping without joint quantum operations, and permits secret sharing for an arbitrary but no less than threshold-value number of classical participants with much lower bandwidth. Also, in comparison with existing quantum secret sharing schemes, it still works when there are dynamic changes, such as the unavailability of some quantum channel, the arrival of new participants and the departure of participants. Finally, we provide security analysis of the new hybrid quantum secret sharing scheme and discuss its useful features for modern applications.

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.

Abstract The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

Abstract Transcript alterations often result from somatic changes in cancer genomes 1 . Various forms of RNA alterations have been described in cancer, including overexpression 2 , altered splicing 3 and gene fusions 4 ; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 5 . Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis , of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed ‘bridged’ fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.

The increasing integration of technology into our lives has created unprecedented volumes of data on society’s everyday behaviour. Such data opens up exciting new opportunities to work towards a quantitative understanding of our complex social systems, within the realms of a new discipline known as Computational Social Science. Against a background of financial crises, riots and international epidemics, the urgent need for a greater comprehension of the complexity of our interconnected global society and an ability to apply such insights in policy decisions is clear. This manifesto outlines the objectives of this new scientific direction, considering the challenges involved in it, and the extensive impact on science, technology and society that the success of this endeavour is likely to bring about. Graphical abstract

Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.

Based on evolutionary computation (EC) concepts, we developed an adaptive evolutionary planner/navigator (EP/N) as a novel approach to path planning and navigation. The EP/N is characterized by generality, flexibility, and adaptability. It unifies off-line planning and online planning/navigation processes in the same evolutionary algorithm which 1) accommodates different optimization criteria and changes in these criteria, 2) incorporates various types of problem-specific domain knowledge, and 3) enables good tradeoffs among near-optimality of paths, high planning efficiency, and effective handling of unknown obstacles. More importantly, the EP/N can self-tune its performance for different task environments and changes in such environments, mostly through adapting probabilities of its operators and adjusting paths constantly, even during a robot's motion toward the goal.

A large number of papers are appearing in the biomedical engineering literature that describe the use of machine learning techniques to develop classifiers for detection or diagnosis of disease. However, the usefulness of this approach in developing clinically validated diagnostic techniques so far has been limited and the methods are prone to overfitting and other problems which may not be immediately apparent to the investigators. This commentary is intended to help sensitize investigators as well as readers and reviewers of papers to some potential pitfalls in the development of classifiers, and suggests steps that researchers can take to help avoid these problems. Building classifiers should be viewed not simply as an add-on statistical analysis, but as part and parcel of the experimental process. Validation of classifiers for diagnostic applications should be considered as part of a much larger process of establishing the clinical validity of the diagnostic technique.

Emerging bacterial antibiotic resistance draws attention to bacteriophages as a therapeutic alternative to treat bacterial infection. Examples of phage that combat bacteria abound. However, despite careful testing of antibacterial activity in vitro, failures nevertheless commonly occur. We investigated immunological response of phage antibacterial potency in vivo. Anti-phage activity of phagocytes, antibodies, and serum complement were identified by direct testing and by high-resolution fluorescent microscopy. We accommodated the experimental data into a mathematical model. We propose a universal schema of innate and adaptive immunity impact on phage pharmacokinetics, based on the results of our numerical simulations. We found that the mammalian-host response to infecting bacteria causes the concomitant removal of phage from the system. We propose the notion that this effect as an indirect pathway of phage inhibition by bacteria with significant relevance for the clinical outcome of phage therapy.

This paper presents preliminary results of a representative survey of the German population focusing on perceptions of risk and ways of coping with COVID-19. Results show that older people estimate the risk of COVID-19 as being less than younger people. Women are more concerned about COVID-19 than men. People especially worry about being infected in places with high public traffic such as public transport and shops or restaurants. Coping strategies are highly problem-focused and most respondents listen to experts’ advice and try to behave calmly and appropriately. People accept that measures to tackle COVID-19 will take time to be effective. Bulk buying and storing of food is mainly justified by a combination of convenience and a perceived need to be prepared for potential quarantine.

Adaptation of parameters and operators is one of the most important and promising areas of research in evolutionary computation; it tunes the algorithm to the problem while solving the problem. In this paper we develop a classification of adaptation on the basis of the mechanisms used, and the level at which adaptation operates within the evolutionary algorithm. The classification covers all forms of adaptation in evolutionary computation and suggests further research.