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The active global SARS-CoV-2 pandemic caused more than 426 million cases and 5.8 million deaths worldwide. The development of completely new drugs for such a novel disease is a challenging, time intensive process. Despite researchers around the world working on this task, no effective treatments have been developed yet. This emphasizes the importance of drug repurposing, where treatments are found among existing drugs that are meant for different diseases. A common approach to this is based on knowledge graphs, that condense relationships between entities like drugs, diseases and genes. Graph neural networks (GNNs) can then be used for the task at hand by predicting links in such knowledge graphs. Expanding on state-of-the-art GNN research, Doshi et al. recently developed the Dr-COVID model. We further extend their work using additional output interpretation strategies. The best aggregation strategy derives a top-100 ranking of 8,070 candidate drugs, 32 of which are currently being tested in COVID-19-related clinical trials. Moreover, we present an alternative application for the model, the generation of additional candidates based on a given pre-selection of drug candidates using collaborative filtering. In addition, we improved the implementation of the Dr-COVID model by significantly shortening the inference and pre-processing time by exploiting data-parallelism. As drug repurposing is a task that requires high computation and memory resources, we further accelerate the post-processing phase using a new emerging hardware-we propose a new approach to leverage the use of high-capacity Non-Volatile Memory for aggregate drug ranking.
Background:
Contamination detection is a important step that should be carefully considered in early stages when designing and performing microbiome studies to avoid biased outcomes. Detecting and removing true contaminants is challenging, especially in low-biomass samples or in studies lacking proper controls. Interactive visualizations and analysis platforms are crucial to better guide this step, to help to identify and detect noisy patterns that could potentially be contamination. Additionally, external evidence, like aggregation of several contamination detection methods and the use of common contaminants reported in the literature, could help to discover and mitigate contamination.
Results:
We propose GRIMER, a tool that performs automated analyses and generates a portable and interactive dashboard integrating annotation, taxonomy, and metadata. It unifies several sources of evidence to help detect contamination. GRIMER is independent of quantification methods and directly analyzes contingency tables to create an interactive and offline report. Reports can be created in seconds and are accessible for nonspecialists, providing an intuitive set of charts to explore data distribution among observations and samples and its connections with external sources. Further, we compiled and used an extensive list of possible external contaminant taxa and common contaminants with 210 genera and 627 species reported in 22 published articles.
Conclusion:
GRIMER enables visual data exploration and analysis, supporting contamination detection in microbiome studies. The tool and data presented are open source and available at https://gitlab.com/dacs-hpi/grimer.
Background
The aggregation of a series of N-of-1 trials presents an innovative and efficient study design, as an alternative to traditional randomized clinical trials. Challenges for the statistical analysis arise when there is carry-over or complex dependencies of the treatment effect of interest.
Methods
In this study, we evaluate and compare methods for the analysis of aggregated N-of-1 trials in different scenarios with carry-over and complex dependencies of treatment effects on covariates. For this, we simulate data of a series of N-of-1 trials for Chronic Nonspecific Low Back Pain based on assumed causal relationships parameterized by directed acyclic graphs. In addition to existing statistical methods such as regression models, Bayesian Networks, and G-estimation, we introduce a carry-over adjusted parametric model (COAPM).
Results
The results show that all evaluated existing models have a good performance when there is no carry-over and no treatment dependence. When there is carry-over, COAPM yields unbiased and more efficient estimates while all other methods show some bias in the estimation. When there is known treatment dependence, all approaches that are capable to model it yield unbiased estimates. Finally, the efficiency of all methods decreases slightly when there are missing values, and the bias in the estimates can also increase.
Conclusions
This study presents a systematic evaluation of existing and novel approaches for the statistical analysis of a series of N-of-1 trials. We derive practical recommendations which methods may be best in which scenarios.
Economic evaluation of digital therapeutic care apps for unsupervised treatment of low back pain
(2023)
Background:
Digital therapeutic care (DTC) programs are unsupervised app-based treatments that provide video exercises and educational material to patients with nonspecific low back pain during episodes of pain and functional disability. German statutory health insurance can reimburse DTC programs since 2019, but evidence on efficacy and reasonable pricing remains scarce. This paper presents a probabilistic sensitivity analysis (PSA) to evaluate the efficacy and cost-utility of a DTC app against treatment as usual (TAU) in Germany.
Objective:
The aim of this study was to perform a PSA in the form of a Monte Carlo simulation based on the deterministic base case analysis to account for model assumptions and parameter uncertainty. We also intend to explore to what extent the results in this probabilistic analysis differ from the results in the base case analysis and to what extent a shortage of outcome data concerning quality-of-life (QoL) metrics impacts the overall results.
Methods:
The PSA builds upon a state-transition Markov chain with a 4-week cycle length over a model time horizon of 3 years from a recently published deterministic cost-utility analysis. A Monte Carlo simulation with 10,000 iterations and a cohort size of 10,000 was employed to evaluate the cost-utility from a societal perspective. Quality-adjusted life years (QALYs) were derived from Veterans RAND 6-Dimension (VR-6D) and Short-Form 6-Dimension (SF-6D) single utility scores. Finally, we also simulated reducing the price for a 3-month app prescription to analyze at which price threshold DTC would result in being the dominant strategy over TAU in Germany.
Results:
The Monte Carlo simulation yielded on average a euro135.97 (a currency exchange rate of EUR euro1=US $1.069 is applicable) incremental cost and 0.004 incremental QALYs per person and year for the unsupervised DTC app strategy compared to in-person physiotherapy in Germany. The corresponding incremental cost-utility ratio (ICUR) amounts to an additional euro34,315.19 per additional QALY. DTC yielded more QALYs in 54.96% of the iterations. DTC dominates TAU in 24.04% of the iterations for QALYs. Reducing the app price in the simulation from currently euro239.96 to euro164.61 for a 3-month prescription could yield a negative ICUR and thus make DTC the dominant strategy, even though the estimated probability of DTC being more effective than TAU is only 54.96%.
Conclusions:
Decision-makers should be cautious when considering the reimbursement of DTC apps since no significant treatment effect was found, and the probability of cost-effectiveness remains below 60% even for an infinite willingness-to-pay threshold. More app-based studies involving the utilization of QoL outcome parameters are urgently needed to account for the low and limited precision of the available QoL input parameters, which are crucial to making profound recommendations concerning the cost-utility of novel apps.
Giving emotional intelligence to machines can facilitate the early detection and prediction of mental diseases and symptoms. Electroencephalography (EEG)-based emotion recognition is widely applied because it measures electrical correlates directly from the brain rather than indirect measurement of other physiological responses initiated by the brain. Therefore, we used non-invasive and portable EEG sensors to develop a real-time emotion classification pipeline. The pipeline trains different binary classifiers for Valence and Arousal dimensions from an incoming EEG data stream achieving a 23.9% (Arousal) and 25.8% (Valence) higher F1-Score on the state-of-art AMIGOS dataset than previous work. Afterward, the pipeline was applied to the curated dataset from 15 participants using two consumer-grade EEG devices while watching 16 short emotional videos in a controlled environment. Mean F1-Scores of 87% (Arousal) and 82% (Valence) were achieved for an immediate label setting. Additionally, the pipeline proved to be fast enough to achieve predictions in real-time in a live scenario with delayed labels while continuously being updated. The significant discrepancy from the readily available labels on the classification scores leads to future work to include more data. Thereafter, the pipeline is ready to be used for real-time applications of emotion classification.
transferGWAS
(2022)
Motivation:
Medical images can provide rich information about diseases and their biology. However, investigating their association with genetic variation requires non-standard methods. We propose transferGWAS, a novel approach to perform genome-wide association studies directly on full medical images. First, we learn semantically meaningful representations of the images based on a transfer learning task, during which a deep neural network is trained on independent but similar data. Then, we perform genetic association tests with these representations.
Results:
We validate the type I error rates and power of transferGWAS in simulation studies of synthetic images. Then we apply transferGWAS in a genome-wide association study of retinal fundus images from the UK Biobank. This first-of-a-kind GWAS of full imaging data yielded 60 genomic regions associated with retinal fundus images, of which 7 are novel candidate loci for eye-related traits and diseases.
The dynamic landscape of digital transformation entails an impact on industrial-age manufacturing companies that goes beyond product offerings, changing operational paradigms, and requiring an organization-wide metamorphosis. An initiative to address the given challenges is the creation of Digital Innovation Units (DIUs) – departments or distinct legal entities that use new structures and practices to develop digital products, services, and business models and support or drive incumbents’ digital transformation. With more than 300 units in German-speaking countries alone and an increasing number of scientific publications, DIUs have become a widespread phenomenon in both research and practice.
This dissertation examines the evolution process of DIUs in the manufacturing
industry during their first three years of operation, through an extensive longitudinal single-case study and several cross-case syntheses of seven DIUs. Building on the lenses of organizational change and development, time, and socio-technical systems, this research provides insights into the fundamentals, temporal dynamics, socio-technical interactions, and relational dynamics of a DIU’s evolution process. Thus, the dissertation promotes a dynamic understanding of DIUs and adds a two-dimensional perspective to the often one-dimensional view of these units and their interactions with the main organization throughout the startup and growth phases of a DIU.
Furthermore, the dissertation constructs a phase model that depicts the early stages of DIU evolution based on these findings and by incorporating literature from information systems research. As a result, it illustrates the progressive intensification of collaboration between the DIU and the main organization. After being implemented, the DIU sparks initial collaboration and instigates change within (parts of) the main organization. Over time, it adapts to the corporate environment to some extent, responding to changing circumstances in order to contribute to long-term transformation. Temporally, the DIU drives the early phases of cooperation and adaptation in particular, while the main organization triggers the first major evolutionary step and realignment of the DIU.
Overall, the thesis identifies DIUs as malleable organizational structures that are crucial for digital transformation. Moreover, it provides guidance for practitioners on the process of building a new DIU from scratch or optimizing an existing one.
An instance of the marriage problem is given by a graph G = (A boolean OR B, E), together with, for each vertex of G, a strict preference order over its neighbors. A matching M of G is popular in the marriage instance if M does not lose a head-to-head election against any matching where vertices are voters. Every stable matching is a min-size popular matching; another subclass of popular matchings that always exists and can be easily computed is the set of dominant matchings. A popular matching M is dominant if M wins the head-to-head election against any larger matching. Thus, every dominant matching is a max-size popular matching, and it is known that the set of dominant matchings is the linear image of the set of stable matchings in an auxiliary graph. Results from the literature seem to suggest that stable and dominant matchings behave, from a complexity theory point of view, in a very similar manner within the class of popular matchings. The goal of this paper is to show that there are instead differences in the tractability of stable and dominant matchings and to investigate further their importance for popular matchings. First, we show that it is easy to check if all popular matchings are also stable; however, it is co-NP hard to check if all popular matchings are also dominant. Second, we show how some new and recent hardness results on popular matching problems can be deduced from the NP-hardness of certain problems on stable matchings, also studied in this paper, thus showing that stable matchings can be employed to show not only positive results on popular matchings (as is known) but also most negative ones. Problems for which we show new hardness results include finding a min-size (resp., max-size) popular matching that is not stable (resp., dominant). A known result for which we give a new and simple proof is the NP-hardness of finding a popular matching when G is nonbipartite.
Knowledge about causal structures is crucial for decision support in various domains. For example, in discrete manufacturing, identifying the root causes of failures and quality deviations that interrupt the highly automated production process requires causal structural knowledge. However, in practice, root cause analysis is usually built upon individual expert knowledge about associative relationships. But, "correlation does not imply causation", and misinterpreting associations often leads to incorrect conclusions. Recent developments in methods for causal discovery from observational data have opened the opportunity for a data-driven examination. Despite its potential for data-driven decision support, omnipresent challenges impede causal discovery in real-world scenarios. In this thesis, we make a threefold contribution to improving causal discovery in practice.
(1) The growing interest in causal discovery has led to a broad spectrum of methods with specific assumptions on the data and various implementations. Hence, application in practice requires careful consideration of existing methods, which becomes laborious when dealing with various parameters, assumptions, and implementations in different programming languages. Additionally, evaluation is challenging due to the lack of ground truth in practice and limited benchmark data that reflect real-world data characteristics.
To address these issues, we present a platform-independent modular pipeline for causal discovery and a ground truth framework for synthetic data generation that provides comprehensive evaluation opportunities, e.g., to examine the accuracy of causal discovery methods in case of inappropriate assumptions.
(2) Applying constraint-based methods for causal discovery requires selecting a conditional independence (CI) test, which is particularly challenging in mixed discrete-continuous data omnipresent in many real-world scenarios. In this context, inappropriate assumptions on the data or the commonly applied discretization of continuous variables reduce the accuracy of CI decisions, leading to incorrect causal structures.
Therefore, we contribute a non-parametric CI test leveraging k-nearest neighbors methods and prove its statistical validity and power in mixed discrete-continuous data, as well as the asymptotic consistency when used in constraint-based causal discovery. An extensive evaluation of synthetic and real-world data shows that the proposed CI test outperforms state-of-the-art approaches in the accuracy of CI testing and causal discovery, particularly in settings with low sample sizes.
(3) To show the applicability and opportunities of causal discovery in practice, we examine our contributions in real-world discrete manufacturing use cases. For example, we showcase how causal structural knowledge helps to understand unforeseen production downtimes or adds decision support in case of failures and quality deviations in automotive body shop assembly lines.
The question if a given partial solution to a problem can be extended reasonably occurs in many algorithmic approaches for optimization problems.
For instance, when enumerating minimal vertex covers of a graph G = (V, E), one usually arrives at the problem to decide for a vertex set U subset of V (pre-solution), if there exists a minimal vertex cover S (i.e., a vertex cover S subset of V such that no proper subset of S is a vertex cover) with U subset of S (minimal extension of U).
We propose a general, partial-order based formulation of such extension problems which allows to model parameterization and approximation aspects of extension, and also highlights relationships between extension tasks for different specific problems.
As examples, we study a number of specific problems which can be expressed and related in this framework. In particular, we discuss extension variants of the problems dominating set and feedback vertex/edge set.
All these problems are shown to be NP-complete even when restricted to bipartite graphs of bounded degree, with the exception of our extension version of feedback edge set on undirected graphs which is shown to be solvable in polynomial time.
For the extension variants of dominating and feedback vertex set, we also show NP-completeness for the restriction to planar graphs of bounded degree.
As non-graph problem, we also study an extension version of the bin packing problem. We further consider the parameterized complexity of all these extension variants, where the parameter is a measure of the pre-solution as defined by our framework.