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Quantifying neurological disorders from voice is a rapidly growing field of research and holds promise for unobtrusive and large-scale disorder monitoring. The data recording setup and data analysis pipelines are both crucial aspects to effectively obtain relevant information from participants. Therefore, we performed a systematic review to provide a high-level overview of practices across various neurological disorders and highlight emerging trends. PRISMA-based literature searches were conducted through PubMed, Web of Science, and IEEE Xplore to identify publications in which original (i.e., newly recorded) datasets were collected. Disorders of interest were psychiatric as well as neurodegenerative disorders, such as bipolar disorder, depression, and stress, as well as amyotrophic lateral sclerosis amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease, and speech impairments (aphasia, dysarthria, and dysphonia). Of the 43 retrieved studies, Parkinson's disease is represented most prominently with 19 discovered datasets. Free speech and read speech tasks are most commonly used across disorders. Besides popular feature extraction toolkits, many studies utilise custom-built feature sets. Correlations of acoustic features with psychiatric and neurodegenerative disorders are presented. In terms of analysis, statistical analysis for significance of individual features is commonly used, as well as predictive modeling approaches, especially with support vector machines and a small number of artificial neural networks. An emerging trend and recommendation for future studies is to collect data in everyday life to facilitate longitudinal data collection and to capture the behavior of participants more naturally. Another emerging trend is to record additional modalities to voice, which can potentially increase analytical performance.
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.
Piloting a Survey-Based Assessment of Transparency and Trustworthiness with Three Medical AI Tools
(2022)
Artificial intelligence (AI) offers the potential to support healthcare delivery, but poorly trained or validated algorithms bear risks of harm. Ethical guidelines stated transparency about model development and validation as a requirement for trustworthy AI. Abundant guidance exists to provide transparency through reporting, but poorly reported medical AI tools are common. To close this transparency gap, we developed and piloted a framework to quantify the transparency of medical AI tools with three use cases. Our framework comprises a survey to report on the intended use, training and validation data and processes, ethical considerations, and deployment recommendations. The transparency of each response was scored with either 0, 0.5, or 1 to reflect if the requested information was not, partially, or fully provided. Additionally, we assessed on an analogous three-point scale if the provided responses fulfilled the transparency requirement for a set of trustworthiness criteria from ethical guidelines. The degree of transparency and trustworthiness was calculated on a scale from 0% to 100%. Our assessment of three medical AI use cases pin-pointed reporting gaps and resulted in transparency scores of 67% for two use cases and one with 59%. We report anecdotal evidence that business constraints and limited information from external datasets were major obstacles to providing transparency for the three use cases. The observed transparency gaps also lowered the degree of trustworthiness, indicating compliance gaps with ethical guidelines. All three pilot use cases faced challenges to provide transparency about medical AI tools, but more studies are needed to investigate those in the wider medical AI sector. Applying this framework for an external assessment of transparency may be infeasible if business constraints prevent the disclosure of information. New strategies may be necessary to enable audits of medical AI tools while preserving business secrets.
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.
It is estimated that data scientists spend up to 80% of the time exploring, cleaning, and transforming their data. A major reason for that expenditure is the lack of knowledge about the used data, which are often from different sources and have heterogeneous structures. As a means to describe various properties of data, metadata can help data scientists understand and prepare their data, saving time for innovative and valuable data analytics. However, metadata do not always exist: some data file formats are not capable of storing them; metadata were deleted for privacy concerns; legacy data may have been produced by systems that were not designed to store and handle meta- data. As data are being produced at an unprecedentedly fast pace and stored in diverse formats, manually creating metadata is not only impractical but also error-prone, demanding automatic approaches for metadata detection.
In this thesis, we are focused on detecting metadata in CSV files – a type of plain-text file that, similar to spreadsheets, may contain different types of content at arbitrary positions. We propose a taxonomy of metadata in CSV files and specifically address the discovery of three different metadata: line and cell type, aggregations, and primary keys and foreign keys.
Data are organized in an ad-hoc manner in CSV files, and do not follow a fixed structure, which is assumed by common data processing tools. Detecting the structure of such files is a prerequisite of extracting information from them, which can be addressed by detecting the semantic type, such as header, data, derived, or footnote, of each line or each cell. We propose the supervised- learning approach Strudel to detect the type of lines and cells. CSV files may also include aggregations. An aggregation represents the arithmetic relationship between a numeric cell and a set of other numeric cells. Our proposed AggreCol algorithm is capable of detecting aggregations of five arithmetic functions in CSV files. Note that stylistic features, such as font style and cell background color, do not exist in CSV files. Our proposed algorithms address the respective problems by using only content, contextual, and computational features.
Storing a relational table is also a common usage of CSV files. Primary keys and foreign keys are important metadata for relational databases, which are usually not present for database instances dumped as plain-text files. We propose the HoPF algorithm to holistically detect both constraints in relational databases. Our approach is capable of distinguishing true primary and foreign keys from a great amount of spurious unique column combinations and inclusion dependencies, which can be detected by state-of-the-art data profiling algorithms.
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.
Duplicate detection describes the process of finding multiple representations of the same real-world entity in the absence of a unique identifier, and has many application areas, such as customer relationship management, genealogy and social sciences, or online shopping. Due to the increasing amount of data in recent years, the problem has become even more challenging on the one hand, but has led to a renaissance in duplicate detection research on the other hand.
This thesis examines the effects and opportunities of transitive relationships on the duplicate detection process. Transitivity implies that if record pairs ⟨ri,rj⟩ and ⟨rj,rk⟩ are classified as duplicates, then also record pair ⟨ri,rk⟩ has to be a duplicate. However, this reasoning might contradict with the pairwise classification, which is usually based on the similarity of objects. An essential property of similarity, in contrast to equivalence, is that similarity is not necessarily transitive.
First, we experimentally evaluate the effect of an increasing data volume on the threshold selection to classify whether a record pair is a duplicate or non-duplicate. Our experiments show that independently of the pair selection algorithm and the used similarity measure, selecting a suitable threshold becomes more difficult with an increasing number of records due to an increased probability of adding a false duplicate to an existing cluster. Thus, the best threshold changes with the dataset size, and a good threshold for a small (possibly sampled) dataset is not necessarily a good threshold for a larger (possibly complete) dataset. As data grows over time, earlier selected thresholds are no longer a suitable choice, and the problem becomes worse for datasets with larger clusters.
Second, we present with the Duplicate Count Strategy (DCS) and its enhancement DCS++ two alternatives to the standard Sorted Neighborhood Method (SNM) for the selection of candidate record pairs. DCS adapts SNMs window size based on the number of detected duplicates and DCS++ uses transitive dependencies to save complex comparisons for finding duplicates in larger clusters. We prove that with a proper (domain- and data-independent!) threshold, DCS++ is more efficient than SNM without loss of effectiveness.
Third, we tackle the problem of contradicting pairwise classifications. Usually, the transitive closure is used for pairwise classifications to obtain a transitively closed result set. However, the transitive closure disregards negative classifications. We present three new and several existing clustering algorithms and experimentally evaluate them on various datasets and under various algorithm configurations. The results show that the commonly used transitive closure is inferior to most other clustering algorithms, especially for the precision of results. In scenarios with larger clusters, our proposed EMCC algorithm is, together with Markov Clustering, the best performing clustering approach for duplicate detection, although its runtime is longer than Markov Clustering due to the subexponential time complexity. EMCC especially outperforms Markov Clustering regarding the precision of the results and additionally has the advantage that it can also be used in scenarios where edge weights are not available.
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.
Piloting a Survey-Based Assessment of Transparency and Trustworthiness with Three Medical AI Tools
(2022)
Artificial intelligence (AI) offers the potential to support healthcare delivery, but poorly trained or validated algorithms bear risks of harm. Ethical guidelines stated transparency about model development and validation as a requirement for trustworthy AI. Abundant guidance exists to provide transparency through reporting, but poorly reported medical AI tools are common. To close this transparency gap, we developed and piloted a framework to quantify the transparency of medical AI tools with three use cases. Our framework comprises a survey to report on the intended use, training and validation data and processes, ethical considerations, and deployment recommendations. The transparency of each response was scored with either 0, 0.5, or 1 to reflect if the requested information was not, partially, or fully provided. Additionally, we assessed on an analogous three-point scale if the provided responses fulfilled the transparency requirement for a set of trustworthiness criteria from ethical guidelines. The degree of transparency and trustworthiness was calculated on a scale from 0% to 100%. Our assessment of three medical AI use cases pin-pointed reporting gaps and resulted in transparency scores of 67% for two use cases and one with 59%. We report anecdotal evidence that business constraints and limited information from external datasets were major obstacles to providing transparency for the three use cases. The observed transparency gaps also lowered the degree of trustworthiness, indicating compliance gaps with ethical guidelines. All three pilot use cases faced challenges to provide transparency about medical AI tools, but more studies are needed to investigate those in the wider medical AI sector. Applying this framework for an external assessment of transparency may be infeasible if business constraints prevent the disclosure of information. New strategies may be necessary to enable audits of medical AI tools while preserving business secrets.
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.
In discrete manufacturing, the knowledge about causal relationships makes it possible to avoid unforeseen production downtimes by identifying their root causes. Learning causal structures from real-world settings remains challenging due to high-dimensional data, a mix of discrete and continuous variables, and requirements for preprocessing log data under the causal perspective. In our work, we address these challenges proposing a process for causal reasoning based on raw machine log data from production monitoring. Within this process, we define a set of transformation rules to extract independent and identically distributed observations. Further, we incorporate a variable selection step to handle high-dimensionality and a discretization step to include continuous variables. We enrich a commonly used causal structure learning algorithm with domain-related orientation rules, which provides a basis for causal reasoning. We demonstrate the process on a real-world dataset from a globally operating precision mechanical engineering company. The dataset contains over 40 million log data entries from production monitoring of a single machine. In this context, we determine the causal structures embedded in operational processes. Further, we examine causal effects to support machine operators in avoiding unforeseen production stops, i.e., by detaining machine operators from drawing false conclusions on impacting factors of unforeseen production stops based on experience.
Knowledge graphs are structured repositories of knowledge that store facts
about the general world or a particular domain in terms of entities and
their relationships. Owing to the heterogeneity of use cases that are served
by them, there arises a need for the automated construction of domain-
specific knowledge graphs from texts. While there have been many research
efforts towards open information extraction for automated knowledge graph
construction, these techniques do not perform well in domain-specific settings.
Furthermore, regardless of whether they are constructed automatically from
specific texts or based on real-world facts that are constantly evolving, all
knowledge graphs inherently suffer from incompleteness as well as errors in
the information they hold.
This thesis investigates the challenges encountered during knowledge graph
construction and proposes techniques for their curation (a.k.a. refinement)
including the correction of semantic ambiguities and the completion of missing
facts. Firstly, we leverage existing approaches for the automatic construction
of a knowledge graph in the art domain with open information extraction
techniques and analyse their limitations. In particular, we focus on the
challenging task of named entity recognition for artwork titles and show
empirical evidence of performance improvement with our proposed solution
for the generation of annotated training data.
Towards the curation of existing knowledge graphs, we identify the issue of
polysemous relations that represent different semantics based on the context.
Having concrete semantics for relations is important for downstream appli-
cations (e.g. question answering) that are supported by knowledge graphs.
Therefore, we define the novel task of finding fine-grained relation semantics
in knowledge graphs and propose FineGReS, a data-driven technique that
discovers potential sub-relations with fine-grained meaning from existing pol-
ysemous relations. We leverage knowledge representation learning methods
that generate low-dimensional vectors (or embeddings) for knowledge graphs
to capture their semantics and structure. The efficacy and utility of the
proposed technique are demonstrated by comparing it with several baselines
on the entity classification use case.
Further, we explore the semantic representations in knowledge graph embed-
ding models. In the past decade, these models have shown state-of-the-art
results for the task of link prediction in the context of knowledge graph comple-
tion. In view of the popularity and widespread application of the embedding
techniques not only for link prediction but also for different semantic tasks,
this thesis presents a critical analysis of the embeddings by quantitatively
measuring their semantic capabilities. We investigate and discuss the reasons
for the shortcomings of embeddings in terms of the characteristics of the
underlying knowledge graph datasets and the training techniques used by
popular models.
Following up on this, we propose ReasonKGE, a novel method for generating
semantically enriched knowledge graph embeddings by taking into account the
semantics of the facts that are encapsulated by an ontology accompanying the
knowledge graph. With a targeted, reasoning-based method for generating
negative samples during the training of the models, ReasonKGE is able to
not only enhance the link prediction performance, but also reduce the number
of semantically inconsistent predictions made by the resultant embeddings,
thus improving the quality of knowledge graphs.
We present fully polynomial time approximation schemes for a broad class of Holant problems with complex edge weights, which we call Holant polynomials. We transform these problems into partition functions of abstract combinatorial structures known as polymers in statistical physics. Our method involves establishing zero-free regions for the partition functions of polymer models and using the most significant terms of the cluster expansion to approximate them. Results of our technique include new approximation and sampling algorithms for a diverse class of Holant polynomials in the low-temperature regime (i.e. small external field) and approximation algorithms for general Holant problems with small signature weights. Additionally, we give randomised approximation and sampling algorithms with faster running times for more restrictive classes. Finally, we improve the known zero-free regions for a perfect matching polynomial.
Quantifying neurological disorders from voice is a rapidly growing field of research and holds promise for unobtrusive and large-scale disorder monitoring. The data recording setup and data analysis pipelines are both crucial aspects to effectively obtain relevant information from participants. Therefore, we performed a systematic review to provide a high-level overview of practices across various neurological disorders and highlight emerging trends. PRISMA-based literature searches were conducted through PubMed, Web of Science, and IEEE Xplore to identify publications in which original (i.e., newly recorded) datasets were collected. Disorders of interest were psychiatric as well as neurodegenerative disorders, such as bipolar disorder, depression, and stress, as well as amyotrophic lateral sclerosis amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease, and speech impairments (aphasia, dysarthria, and dysphonia). Of the 43 retrieved studies, Parkinson's disease is represented most prominently with 19 discovered datasets. Free speech and read speech tasks are most commonly used across disorders. Besides popular feature extraction toolkits, many studies utilise custom-built feature sets. Correlations of acoustic features with psychiatric and neurodegenerative disorders are presented. In terms of analysis, statistical analysis for significance of individual features is commonly used, as well as predictive modeling approaches, especially with support vector machines and a small number of artificial neural networks. An emerging trend and recommendation for future studies is to collect data in everyday life to facilitate longitudinal data collection and to capture the behavior of participants more naturally. Another emerging trend is to record additional modalities to voice, which can potentially increase analytical performance.
The availability of commercial 3D printers and matching 3D design software has allowed a wide range of users to create physical prototypes – as long as these objects are not larger than hand size. However, when attempting to create larger, "human-scale" objects, such as furniture, not only are these machines too small, but also the commonly used 3D design software is not equipped to design with forces in mind — since forces increase disproportionately with scale.
In this thesis, we present a series of end-to-end fabrication software systems that support users in creating human-scale objects. They achieve this by providing three main functions that regular "small-scale" 3D printing software does not offer: (1) subdivision of the object into small printable components combined with ready-made objects, (2) editing based on predefined elements sturdy enough for larger scale, i.e., trusses, and (3) functionality for analyzing, detecting, and fixing structural weaknesses. The presented software systems also assist the fabrication process based on either 3D printing or steel welding technology.
The presented systems focus on three levels of engineering challenges: (1) fabricating static load-bearing objects, (2) creating mechanisms that involve motion, such as kinematic installations, and finally (3) designing mechanisms with dynamic repetitive movement where power and energy play an important role.
We demonstrate and verify the versatility of our systems by building and testing human-scale prototypes, ranging from furniture pieces, pavilions, to animatronic installations and playground equipment. We have also shared our system with schools, fablabs, and fabrication enthusiasts, who have successfully created human-scale objects that can withstand with human-scale forces.
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.
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.
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.
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.
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.