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Privacy regulations and the physical distribution of heterogeneous data are often primary concerns for the development of deep learning models in a medical context. This paper evaluates the feasibility of differentially private federated learning for chest X-ray classification as a defense against data privacy attacks. To the best of our knowledge, we are the first to directly compare the impact of differentially private training on two different neural network architectures, DenseNet121 and ResNet50. Extending the federated learning environments previously analyzed in terms of privacy, we simulated a heterogeneous and imbalanced federated setting by distributing images from the public CheXpert and Mendeley chest X-ray datasets unevenly among 36 clients. Both non-private baseline models achieved an area under the receiver operating characteristic curve (AUC) of 0.940.94 on the binary classification task of detecting the presence of a medical finding. We demonstrate that both model architectures are vulnerable to privacy violation by applying image reconstruction attacks to local model updates from individual clients. The attack was particularly successful during later training stages. To mitigate the risk of a privacy breach, we integrated Rényi differential privacy with a Gaussian noise mechanism into local model training. We evaluate model performance and attack vulnerability for privacy budgets ε∈{1,3,6,10}�∈{1,3,6,10}. The DenseNet121 achieved the best utility-privacy trade-off with an AUC of 0.940.94 for ε=6�=6. Model performance deteriorated slightly for individual clients compared to the non-private baseline. The ResNet50 only reached an AUC of 0.760.76 in the same privacy setting. Its performance was inferior to that of the DenseNet121 for all considered privacy constraints, suggesting that the DenseNet121 architecture is more robust to differentially private training.
Privacy regulations and the physical distribution of heterogeneous data are often primary concerns for the development of deep learning models in a medical context. This paper evaluates the feasibility of differentially private federated learning for chest X-ray classification as a defense against data privacy attacks. To the best of our knowledge, we are the first to directly compare the impact of differentially private training on two different neural network architectures, DenseNet121 and ResNet50. Extending the federated learning environments previously analyzed in terms of privacy, we simulated a heterogeneous and imbalanced federated setting by distributing images from the public CheXpert and Mendeley chest X-ray datasets unevenly among 36 clients. Both non-private baseline models achieved an area under the receiver operating characteristic curve (AUC) of 0.940.94 on the binary classification task of detecting the presence of a medical finding. We demonstrate that both model architectures are vulnerable to privacy violation by applying image reconstruction attacks to local model updates from individual clients. The attack was particularly successful during later training stages. To mitigate the risk of a privacy breach, we integrated Rényi differential privacy with a Gaussian noise mechanism into local model training. We evaluate model performance and attack vulnerability for privacy budgets ε∈{1,3,6,10}�∈{1,3,6,10}. The DenseNet121 achieved the best utility-privacy trade-off with an AUC of 0.940.94 for ε=6�=6. Model performance deteriorated slightly for individual clients compared to the non-private baseline. The ResNet50 only reached an AUC of 0.760.76 in the same privacy setting. Its performance was inferior to that of the DenseNet121 for all considered privacy constraints, suggesting that the DenseNet121 architecture is more robust to differentially private training.
StudyMe
(2022)
N-of-1 trials are multi-crossover self-experiments that allow individuals to systematically evaluate the effect of interventions on their personal health goals. Although several tools for N-of-1 trials exist, there is a gap in supporting non-experts in conducting their own user-centric trials. In this study, we present StudyMe, an open-source mobile application that is freely available from https://play.google.com/store/apps/details?id=health.studyu.me and offers users flexibility and guidance in configuring every component of their trials. We also present research that informed the development of StudyMe, focusing on trial creation. Through an initial survey with 272 participants, we learned that individuals are interested in a variety of personal health aspects and have unique ideas on how to improve them. In an iterative, user-centered development process with intermediate user tests, we developed StudyMe that features an educational part to communicate N-of-1 trial concepts. A final empirical evaluation of StudyMe showed that all participants were able to create their own trials successfully using StudyMe and the app achieved a very good usability rating. Our findings suggest that StudyMe provides a significant step towards enabling individuals to apply a systematic science-oriented approach to personalize health-related interventions and behavior modifications in their everyday lives.
StudyMe
(2022)
N-of-1 trials are multi-crossover self-experiments that allow individuals to systematically evaluate the effect of interventions on their personal health goals. Although several tools for N-of-1 trials exist, there is a gap in supporting non-experts in conducting their own user-centric trials. In this study, we present StudyMe, an open-source mobile application that is freely available from https://play.google.com/store/apps/details?id=health.studyu.me and offers users flexibility and guidance in configuring every component of their trials. We also present research that informed the development of StudyMe, focusing on trial creation. Through an initial survey with 272 participants, we learned that individuals are interested in a variety of personal health aspects and have unique ideas on how to improve them. In an iterative, user-centered development process with intermediate user tests, we developed StudyMe that features an educational part to communicate N-of-1 trial concepts. A final empirical evaluation of StudyMe showed that all participants were able to create their own trials successfully using StudyMe and the app achieved a very good usability rating. Our findings suggest that StudyMe provides a significant step towards enabling individuals to apply a systematic science-oriented approach to personalize health-related interventions and behavior modifications in their everyday lives.
CovRadar
(2022)
The ongoing pandemic caused by SARS-CoV-2 emphasizes the importance of genomic surveillance to understand the evolution of the virus, to monitor the viral population, and plan epidemiological responses. Detailed analysis, easy visualization and intuitive filtering of the latest viral sequences are powerful for this purpose. We present CovRadar, a tool for genomic surveillance of the SARS-CoV-2 Spike protein. CovRadar consists of an analytical pipeline and a web application that enable the analysis and visualization of hundreds of thousand sequences. First, CovRadar extracts the regions of interest using local alignment, then builds a multiple sequence alignment, infers variants and consensus and finally presents the results in an interactive app, making accessing and reporting simple, flexible and fast.
ReadBouncer
(2022)
Motivation:
Nanopore sequencers allow targeted sequencing of interesting nucleotide sequences by rejecting other sequences from individual pores. This feature facilitates the enrichment of low-abundant sequences by depleting overrepresented ones in-silico. Existing tools for adaptive sampling either apply signal alignment, which cannot handle human-sized reference sequences, or apply read mapping in sequence space relying on fast graphical processing units (GPU) base callers for real-time read rejection. Using nanopore long-read mapping tools is also not optimal when mapping shorter reads as usually analyzed in adaptive sampling applications.
Results:
Here, we present a new approach for nanopore adaptive sampling that combines fast CPU and GPU base calling with read classification based on Interleaved Bloom Filters. ReadBouncer improves the potential enrichment of low abundance sequences by its high read classification sensitivity and specificity, outperforming existing tools in the field. It robustly removes even reads belonging to large reference sequences while running on commodity hardware without GPUs, making adaptive sampling accessible for in-field researchers. Readbouncer also provides a user-friendly interface and installer files for end-users without a bioinformatics background.
With the fast rise of cloud computing adoption in the past few years, more companies are migrating their confidential files from their private data center to the cloud to help enterprise's digital transformation process. Enterprise file synchronization and share (EFSS) is one of the solutions offered for enterprises to store their files in the cloud with secure and easy file sharing and collaboration between its employees. However, the rapidly increasing number of cyberattacks on the cloud might target company's files on the cloud to be stolen or leaked to the public. It is then the responsibility of the EFSS system to ensure the company's confidential files to only be accessible by authorized employees.
CloudRAID is a secure personal cloud storage research collaboration project that provides data availability and confidentiality in the cloud. It combines erasure and cryptographic techniques to securely store files as multiple encrypted file chunks in various cloud service providers (CSPs). However, several aspects of CloudRAID's concept are unsuitable for secure and scalable enterprise cloud storage solutions, particularly key management system, location-based access control, multi-cloud storage management, and cloud file access monitoring.
This Ph.D. thesis focuses on CloudRAID for Business (CfB) as it resolves four main challenges of CloudRAID's concept for a secure and scalable EFSS system. First, the key management system is implemented using the attribute-based encryption scheme to provide secure and scalable intra-company and inter-company file-sharing functionalities. Second, an Internet-based location file access control functionality is introduced to ensure files could only be accessed at pre-determined trusted locations. Third, a unified multi-cloud storage resource management framework is utilized to securely manage cloud storage resources available in various CSPs for authorized CfB stakeholders. Lastly, a multi-cloud storage monitoring system is introduced to monitor the activities of files in the cloud using the generated cloud storage log files from multiple CSPs.
In summary, this thesis helps CfB system to provide holistic security for company's confidential files on the cloud-level, system-level, and file-level to ensure only authorized company and its employees could access the files.
Many participants in Massive Open Online Courses are full-time employees seeking greater flexibility in their time commitment and the available learning paths. We recently addressed these requirements by splitting up our 6-week courses into three 2-week modules followed by a separate exam. Modularizing courses offers many advantages: Shorter modules are more sustainable and can be combined, reused, and incorporated into learning paths more easily. Time flexibility for learners is also improved as exams can now be offered multiple times per year, while the learning content is available independently. In this article, we answer the question of which impact this modularization has on key learning metrics, such as course completion rates, learning success, and no-show rates. Furthermore, we investigate the influence of longer breaks between modules on these metrics. According to our analysis, course modules facilitate more selective learning behaviors that encourage learners to focus on topics they are the most interested in. At the same time, participation in overarching exams across all modules seems to be less appealing compared to an integrated exam of a 6-week course. While breaks between the modules increase the distinctive appearance of individual modules, a break before the final exam further reduces initial interest in the exams. We further reveal that participation in self-paced courses as a preparation for the final exam is unlikely to attract new learners to the course offerings, even though learners' performance is comparable to instructor-paced courses. The results of our long-term study on course modularization provide a solid foundation for future research and enable educators to make informed decisions about the design of their courses.
Many participants in Massive Open Online Courses are full-time employees seeking greater flexibility in their time commitment and the available learning paths. We recently addressed these requirements by splitting up our 6-week courses into three 2-week modules followed by a separate exam. Modularizing courses offers many advantages: Shorter modules are more sustainable and can be combined, reused, and incorporated into learning paths more easily. Time flexibility for learners is also improved as exams can now be offered multiple times per year, while the learning content is available independently. In this article, we answer the question of which impact this modularization has on key learning metrics, such as course completion rates, learning success, and no-show rates. Furthermore, we investigate the influence of longer breaks between modules on these metrics. According to our analysis, course modules facilitate more selective learning behaviors that encourage learners to focus on topics they are the most interested in. At the same time, participation in overarching exams across all modules seems to be less appealing compared to an integrated exam of a 6-week course. While breaks between the modules increase the distinctive appearance of individual modules, a break before the final exam further reduces initial interest in the exams. We further reveal that participation in self-paced courses as a preparation for the final exam is unlikely to attract new learners to the course offerings, even though learners' performance is comparable to instructor-paced courses. The results of our long-term study on course modularization provide a solid foundation for future research and enable educators to make informed decisions about the design of their courses.
The analysis of behavioral models such as Graph Transformation Systems (GTSs) is of central importance in model-driven engineering. However, GTSs often result in intractably large or even infinite state spaces and may be equipped with multiple or even infinitely many start graphs. To mitigate these problems, static analysis techniques based on finite symbolic representations of sets of states or paths thereof have been devised. We focus on the technique of k-induction for establishing invariants specified using graph conditions. To this end, k-induction generates symbolic paths backwards from a symbolic state representing a violation of a candidate invariant to gather information on how that violation could have been reached possibly obtaining contradictions to assumed invariants. However, GTSs where multiple agents regularly perform actions independently from each other cannot be analyzed using this technique as of now as the independence among backward steps may prevent the gathering of relevant knowledge altogether.
In this paper, we extend k-induction to GTSs with multiple agents thereby supporting a wide range of additional GTSs. As a running example, we consider an unbounded number of shuttles driving on a large-scale track topology, which adjust their velocity to speed limits to avoid derailing. As central contribution, we develop pruning techniques based on causality and independence among backward steps and verify that k-induction remains sound under this adaptation as well as terminates in cases where it did not terminate before.
Cyber-physical systems often encompass complex concurrent behavior with timing constraints and probabilistic failures on demand. The analysis whether such systems with probabilistic timed behavior adhere to a given specification is essential. When the states of the system can be represented by graphs, the rule-based formalism of Probabilistic Timed Graph Transformation Systems (PTGTSs) can be used to suitably capture structure dynamics as well as probabilistic and timed behavior of the system. The model checking support for PTGTSs w.r.t. properties specified using Probabilistic Timed Computation Tree Logic (PTCTL) has been already presented. Moreover, for timed graph-based runtime monitoring, Metric Temporal Graph Logic (MTGL) has been developed for stating metric temporal properties on identified subgraphs and their structural changes over time.
In this paper, we (a) extend MTGL to the Probabilistic Metric Temporal Graph Logic (PMTGL) by allowing for the specification of probabilistic properties, (b) adapt our MTGL satisfaction checking approach to PTGTSs, and (c) combine the approaches for PTCTL model checking and MTGL satisfaction checking to obtain a Bounded Model Checking (BMC) approach for PMTGL. In our evaluation, we apply an implementation of our BMC approach in AutoGraph to a running example.
Data profiling is the extraction of metadata from relational databases. An important class of metadata are multi-column dependencies. They come associated with two computational tasks. The detection problem is to decide whether a dependency of a given type and size holds in a database. The discovery problem instead asks to enumerate all valid dependencies of that type. We investigate the two problems for three types of dependencies: unique column combinations (UCCs), functional dependencies (FDs), and inclusion dependencies (INDs).
We first treat the parameterized complexity of the detection variants. We prove that the detection of UCCs and FDs, respectively, is W[2]-complete when parameterized by the size of the dependency. The detection of INDs is shown to be one of the first natural W[3]-complete problems. We further settle the enumeration complexity of the three discovery problems by presenting parsimonious equivalences with well-known enumeration problems. Namely, the discovery of UCCs is equivalent to the famous transversal hypergraph problem of enumerating the hitting sets of a hypergraph. The discovery of FDs is equivalent to the simultaneous enumeration of the hitting sets of multiple input hypergraphs. Finally, the discovery of INDs is shown to be equivalent to enumerating the satisfying assignments of antimonotone, 3-normalized Boolean formulas.
In the remainder of the thesis, we design and analyze discovery algorithms for unique column combinations. Since this is as hard as the general transversal hypergraph problem, it is an open question whether the UCCs of a database can be computed in output-polynomial time in the worst case. For the analysis, we therefore focus on instances that are structurally close to databases in practice, most notably, inputs that have small solutions. The equivalence between UCCs and hitting sets transfers the computational hardness, but also allows us to apply ideas from hypergraph theory to data profiling. We devise an discovery algorithm that runs in polynomial space on arbitrary inputs and achieves polynomial delay whenever the maximum size of any minimal UCC is bounded. Central to our approach is the extension problem for minimal hitting sets, that is, to decide for
a set of vertices whether they are contained in any minimal solution. We prove that this is yet another problem that is complete for the complexity class W[3], when parameterized by the size of the set that is to be extended. We also give several conditional lower bounds under popular hardness conjectures such as the Strong Exponential Time Hypothesis (SETH). The lower bounds suggest that the running time of our algorithm for the extension problem is close to optimal.
We further conduct an empirical analysis of our discovery algorithm on real-world databases to confirm that the hitting set perspective on data profiling has merits also in practice. We show that the resulting enumeration times undercut their theoretical worst-case bounds on practical data, and that the memory consumption of our method is much smaller than that of previous solutions. During the analysis we make two observations about the connection between databases and their corresponding hypergraphs. On the one hand, the hypergraph representations containing all relevant information are usually significantly smaller than the original inputs. On the other hand, obtaining those hypergraphs is the actual bottleneck of any practical application. The latter often takes much longer than enumerating the solutions, which is in stark contrast to the fact that the preprocessing is guaranteed to be polynomial while the enumeration may take exponential time.
To make the first observation rigorous, we introduce a maximum-entropy model for non-uniform random hypergraphs and prove that their expected number of minimal hyperedges undergoes a phase transition with respect to the total number of edges. The result also explains why larger databases may have smaller hypergraphs. Motivated by the second observation, we present a new kind of UCC discovery algorithm called Hitting Set Enumeration with Partial Information and Validation (HPIValid). It utilizes the fast enumeration times in practice in order to speed up the computation of the corresponding hypergraph. This way, we sidestep the bottleneck while maintaining the advantages of the hitting set perspective. An exhaustive empirical evaluation shows that HPIValid outperforms the current state of the art in UCC discovery. It is capable of processing databases that were previously out of reach for data profiling.
Boolean Satisfiability (SAT) is one of the problems at the core of theoretical computer science. It was the first problem proven to be NP-complete by Cook and, independently, by Levin. Nowadays it is conjectured that SAT cannot be solved in sub-exponential time. Thus, it is generally assumed that SAT and its restricted version k-SAT are hard to solve. However, state-of-the-art SAT solvers can solve even huge practical instances of these problems in a reasonable amount of time.
Why is SAT hard in theory, but easy in practice? One approach to answering this question is investigating the average runtime of SAT. In order to analyze this average runtime the random k-SAT model was introduced. The model generates all k-SAT instances with n variables and m clauses with uniform probability. Researching random k-SAT led to a multitude of insights and tools for analyzing random structures in general. One major observation was the emergence of the so-called satisfiability threshold: A phase transition point in the number of clauses at which the generated formulas go from asymptotically almost surely satisfiable to asymptotically almost surely unsatisfiable. Additionally, instances around the threshold seem to be particularly hard to solve.
In this thesis we analyze a more general model of random k-SAT that we call non-uniform random k-SAT. In contrast to the classical model each of the n Boolean variables now has a distinct probability of being drawn. For each of the m clauses we draw k variables according to the variable distribution and choose their signs uniformly at random. Non-uniform random k-SAT gives us more control over the distribution of Boolean variables in the resulting formulas. This allows us to tailor distributions to the ones observed in practice. Notably, non-uniform random k-SAT contains the previously proposed models random k-SAT, power-law random k-SAT and geometric random k-SAT as special cases.
We analyze the satisfiability threshold in non-uniform random k-SAT depending on the variable probability distribution. Our goal is to derive conditions on this distribution under which an equivalent of the satisfiability threshold conjecture holds. We start with the arguably simpler case of non-uniform random 2-SAT. For this model we show under which conditions a threshold exists, if it is sharp or coarse, and what the leading constant of the threshold function is. These are exactly the three ingredients one needs in order to prove or disprove the satisfiability threshold conjecture. For non-uniform random k-SAT with k=3 we only prove sufficient conditions under which a threshold exists. We also show some properties of the variable probabilities under which the threshold is sharp in this case. These are the first results on the threshold behavior of non-uniform random k-SAT.
Based on the performance requirements of modern spatio-temporal data mining applications, in-memory database systems are often used to store and process the data. To efficiently utilize the scarce DRAM capacities, modern database systems support various tuning possibilities to reduce the memory footprint (e.g., data compression) or increase performance (e.g., additional indexes). However, the selection of cost and performance balancing configurations is challenging due to the vast number of possible setups consisting of mutually dependent individual decisions. In this paper, we introduce a novel approach to jointly optimize the compression, sorting, indexing, and tiering configuration for spatio-temporal workloads. Further, we consider horizontal data partitioning, which enables the independent application of different tuning options on a fine-grained level. We propose different linear programming (LP) models addressing cost dependencies at different levels of accuracy to compute optimized tuning configurations for a given workload and memory budgets. To yield maintainable and robust configurations, we extend our LP-based approach to incorporate reconfiguration costs as well as a worst-case optimization for potential workload scenarios. Further, we demonstrate on a real-world dataset that our models allow to significantly reduce the memory footprint with equal performance or increase the performance with equal memory size compared to existing tuning heuristics.
Text collections, such as corpora of books, research articles, news, or business documents are an important resource for knowledge discovery. Exploring large document collections by hand is a cumbersome but necessary task to gain new insights and find relevant information. Our digitised society allows us to utilise algorithms to support the information seeking process, for example with the help of retrieval or recommender systems. However, these systems only provide selective views of the data and require some prior knowledge to issue meaningful queries and asses a system’s response. The advancements of machine learning allow us to reduce this gap and better assist the information seeking process. For example, instead of sighting countless business documents by hand, journalists and investigator scan employ natural language processing techniques, such as named entity recognition. Al-though this greatly improves the capabilities of a data exploration platform, the wealth of information is still overwhelming. An overview of the entirety of a dataset in the form of a two-dimensional map-like visualisation may help to circumvent this issue. Such overviews enable novel interaction paradigms for users, which are similar to the exploration of digital geographical maps. In particular, they can provide valuable context by indicating how apiece of information fits into the bigger picture.This thesis proposes algorithms that appropriately pre-process heterogeneous documents and compute the layout for datasets of all kinds. Traditionally, given high-dimensional semantic representations of the data, so-called dimensionality reduction algorithms are usedto compute a layout of the data on a two-dimensional canvas. In this thesis, we focus on text corpora and go beyond only projecting the inherent semantic structure itself. Therefore,we propose three dimensionality reduction approaches that incorporate additional information into the layout process: (1) a multi-objective dimensionality reduction algorithm to jointly visualise semantic information with inherent network information derived from the underlying data; (2) a comparison of initialisation strategies for different dimensionality reduction algorithms to generate a series of layouts for corpora that grow and evolve overtime; (3) and an algorithm that updates existing layouts by incorporating user feedback provided by pointwise drag-and-drop edits. This thesis also contains system prototypes to demonstrate the proposed technologies, including pre-processing and layout of the data and presentation in interactive user interfaces.
The “HPI Future SOC Lab” is a cooperation of the Hasso Plattner Institute (HPI) and industry partners. Its mission is to enable and promote exchange and interaction between the research community and the industry partners.
The HPI Future SOC Lab provides researchers with free of charge access to a complete infrastructure of state of the art hard and software. This infrastructure includes components, which might be too expensive for an ordinary research environment, such as servers with up to 64 cores and 2 TB main memory. The offerings address researchers particularly from but not limited to the areas of computer science and business information systems. Main areas of research include cloud computing, parallelization, and In-Memory technologies.
This technical report presents results of research projects executed in 2018. Selected projects have presented their results on April 17th and November 14th 2017 at the Future SOC Lab Day events.
Omics and male infertility
(2022)
Male infertility is a multifaceted disorder affecting approximately 50% of male partners in infertile couples.
Over the years, male infertility has been diagnosed mainly through semen analysis, hormone evaluations, medical records and physical examinations, which of course are fundamental, but yet inefficient, because 30% of male infertility cases remain idiopathic. This dilemmatic status of the unknown needs to be addressed with more sophisticated and result-driven technologies and/or techniques.
Genetic alterations have been linked with male infertility, thereby unveiling the practicality of investigating this disorder from the "omics" perspective.
Omics aims at analyzing the structure and functions of a whole constituent of a given biological function at different levels, including the molecular gene level (genomics), transcript level (transcriptomics), protein level (proteomics) and metabolites level (metabolomics). In the current study, an overview of the four branches of omics and their roles in male infertility are briefly discussed; the potential usefulness of assessing transcriptomic data to understand this pathology is also elucidated.
After assessing the publicly obtainable transcriptomic data for datasets on male infertility, a total of 1385 datasets were retrieved, of which 10 datasets met the inclusion criteria and were used for further analysis.
These datasets were classified into groups according to the disease or cause of male infertility.
The groups include non-obstructive azoospermia (NOA), obstructive azoospermia (OA), non-obstructive and obstructive azoospermia (NOA and OA), spermatogenic dysfunction, sperm dysfunction, and Y chromosome microdeletion.
Findings revealed that 8 genes (LDHC, PDHA2, TNP1, TNP2, ODF1, ODF2, SPINK2, PCDHB3) were commonly differentially expressed between all disease groups.
Likewise, 56 genes were common between NOA versus NOA and OA (ADAD1, BANF2, BCL2L14, C12orf50, C20orf173, C22orf23, C6orf99, C9orf131, C9orf24, CABS1, CAPZA3, CCDC187, CCDC54, CDKN3, CEP170, CFAP206, CRISP2, CT83, CXorf65, FAM209A, FAM71F1, FAM81B, GALNTL5, GTSF1, H1FNT, HEMGN, HMGB4, KIF2B, LDHC, LOC441601, LYZL2, ODF1, ODF2, PCDHB3, PDHA2, PGK2, PIH1D2, PLCZ1, PROCA1, RIMBP3, ROPN1L, SHCBP1L, SMCP, SPATA16, SPATA19, SPINK2, TEX33, TKTL2, TMCO2, TMCO5A, TNP1, TNP2, TSPAN16, TSSK1B, TTLL2, UBQLN3).
These genes, particularly the above-mentioned 8 genes, are involved in diverse biological processes such as germ cell development, spermatid development, spermatid differentiation, regulation of proteolysis, spermatogenesis and metabolic processes.
Owing to the stage-specific expression of these genes, any mal-expression can ultimately lead to male infertility.
Therefore, currently available data on all branches of omics relating to male fertility can be used to identify biomarkers for diagnosing male infertility, which can potentially help in unravelling some idiopathic cases.
Polyglot programming allows developers to use multiple programming languages within the same software project. While it is common to use more than one language in certain programming domains, developers also apply polyglot programming for other purposes such as to re-use software written in other languages. Although established approaches to polyglot programming come with significant limitations, for example, in terms of performance and tool support, developers still use them to be able to combine languages.
Polyglot virtual machines (VMs) such as GraalVM provide a new level of polyglot programming, allowing languages to directly interact with each other. This reduces the amount of glue code needed to combine languages, results in better performance, and enables tools such as debuggers to work across languages. However, only a little research has focused on novel tools that are designed to support developers in building software with polyglot VMs. One reason is that tool-building is often an expensive activity, another one is that polyglot VMs are still a moving target as their use cases and requirements are not yet well understood.
In this thesis, we present an approach that builds on existing self-sustaining programming systems such as Squeak/Smalltalk to enable exploratory programming, a practice for exploring and gathering software requirements, and re-use their extensive tool-building capabilities in the context of polyglot VMs. Based on TruffleSqueak, our implementation for the GraalVM, we further present five case studies that demonstrate how our approach helps tool developers to design and build tools for polyglot programming. We further show that TruffleSqueak can also be used by application developers to build and evolve polyglot applications at run-time and by language and runtime developers to understand the dynamic behavior of GraalVM languages and internals. Since our platform allows all these developers to apply polyglot programming, it can further help to better understand the advantages, use cases, requirements, and challenges of polyglot VMs. Moreover, we demonstrate that our approach can also be applied to other polyglot VMs and that insights gained through it are transferable to other programming systems.
We conclude that our research on tools for polyglot programming is an important step toward making polyglot VMs more approachable for developers in practice. With good tool support, we believe polyglot VMs can make it much more common for developers to take advantage of multiple languages and their ecosystems when building software.
Here we present an exome-wide rare genetic variant association study for 30 blood biomarkers in 191,971 individuals in the UK Biobank. We compare gene- based association tests for separate functional variant categories to increase interpretability and identify 193 significant gene-biomarker associations. Genes associated with biomarkers were ~ 4.5-fold enriched for conferring Mendelian disorders. In addition to performing weighted gene-based variant collapsing tests, we design and apply variant-category-specific kernel-based tests that integrate quantitative functional variant effect predictions for mis- sense variants, splicing and the binding of RNA-binding proteins. For these tests, we present a computationally efficient combination of the likelihood- ratio and score tests that found 36% more associations than the score test alone while also controlling the type-1 error. Kernel-based tests identified 13% more associations than their gene-based collapsing counterparts and had advantages in the presence of gain of function missense variants. We introduce local collapsing by amino acid position for missense variants and use it to interpret associations and identify potential novel gain of function variants in PIEZO1. Our results show the benefits of investigating different functional mechanisms when performing rare-variant association tests, and demonstrate pervasive rare-variant contribution to biomarker variability.