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Measurements of systems taken along a continuous functional dimension, such as time or space, are ubiquitous in many fields, from the physical and biological sciences to economics and engineering. Such measurements can be viewed as realisations of an underlying smooth process sampled over the continuum. However, traditional methods for independence testing and causal learning are not directly applicable to such data, as they do not take into account the dependence along the functional dimension. By using specifically designed kernels, we introduce statistical tests for bivariate, joint, and conditional independence for functional variables. Our method not only extends the applicability to functional data of the Hilbert-Schmidt independence criterion (hsic) and its d-variate version ( d -hsic), but also allows us to introduce a test for conditional independence by defining a novel statistic for the conditional permutation test (cpt) based on the Hilbert-Schmidt conditional independence criterion (hscic), with optimised regularisation strength estimated through an evaluation rejection rate. Our empirical results of the size and power of these tests on synthetic functional data show good performance, and we then exemplify their application to several constraint- and regression-based causal structure learning problems, including both synthetic examples and real socioeconomic data.

Epigenetic modifications are dynamic mechanisms involved in the regulation of gene expression. Unlike the DNA sequence, epigenetic patterns vary not only between individuals, but also between different cell types within an individual. Environmental factors, somatic mutations and ageing contribute to epigenetic changes that may constitute early hallmarks or causal factors of disease. Epigenetic modifications are reversible and thus promising therapeutic targets for precision medicine. However, mapping efforts to determine an individual's cell-type-specific epigenome are constrained by experimental costs and tissue accessibility. To address these challenges, we developed eDICE, an attention-based deep learning model that is trained to impute missing epigenomic tracks by conditioning on observed tracks. Using a recently published set of epigenomes from four individual donors, we show that transfer learning across individuals allows eDICE to successfully predict individual-specific epigenetic variation even in tissues that are unmapped in a given donor. These results highlight the potential of machine learning-based imputation methods to advance personalized epigenomics., (© 2023. Springer Nature Limited.)

In oncology, intratumoural heterogeneity is closely linked with the efficacy of therapy, and can be partially characterized via tumour biopsies. Here we show that intratumoural heterogeneity can be characterized spatially via phenotype-specific, multi-view learning classifiers trained with data from dynamic positron emission tomography (PET) and multiparametric magnetic resonance imaging (MRI). Classifiers trained with PET-MRI data from mice with subcutaneous colon cancer quantified phenotypic changes resulting from an apoptosis-inducing targeted therapeutic and provided biologically relevant probability maps of tumour-tissue subtypes. When applied to retrospective PET-MRI data of patients with liver metastases from colorectal cancer, the trained classifiers characterized intratumoural tissue subregions in agreement with tumour histology. The spatial characterization of intratumoural heterogeneity in mice and patients via multimodal, multiparametric imaging aided by machine-learning may facilitate applications in precision oncology., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

We develop a model to retrospectively evaluate age-dependent counterfactual vaccine allocation strategies against the coronavirus disease 2019 (COVID-19) pandemic. To estimate the effect of allocation on the expected severe-case incidence, we employ a simulation-assisted causal modeling approach that combines a compartmental infection-dynamics simulation, a coarse-grained causal model, and literature estimates for immunity waning. We compare Israel's strategy, implemented in 2021, with counterfactual strategies such as no prioritization, prioritization of younger age groups, or a strict risk-ranked approach; we find that Israel's implemented strategy was indeed highly effective. We also study the impact of increasing vaccine uptake for given age groups. Because of its modular structure, our model can easily be adapted to study future pandemics. We demonstrate this by simulating a pandemic with characteristics of the Spanish flu. Our approach helps evaluate vaccination strategies under the complex interplay of core epidemic factors, including age-dependent risk profiles, immunity waning, vaccine availability, and spreading rates., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

The number of published metagenome assemblies is rapidly growing due to advances in sequencing technologies. However, sequencing errors, variable coverage, repetitive genomic regions, and other factors can produce misassemblies, which are challenging to detect for taxonomically novel genomic data. Assembly errors can affect all downstream analyses of the assemblies. Accuracy for the state of the art in reference-free misassembly prediction does not exceed an AUPRC of 0.57, and it is not clear how well these models generalize to real-world data. Here, we present the Residual neural network for Misassembled Contig identification (ResMiCo), a deep learning approach for reference-free identification of misassembled contigs. To develop ResMiCo, we first generated a training dataset of unprecedented size and complexity that can be used for further benchmarking and developments in the field. Through rigorous validation, we show that ResMiCo is substantially more accurate than the state of the art, and the model is robust to novel taxonomic diversity and varying assembly methods. ResMiCo estimated 7% misassembled contigs per metagenome across multiple real-world datasets. We demonstrate how ResMiCo can be used to optimize metagenome assembly hyperparameters to improve accuracy, instead of optimizing solely for contiguity. The accuracy, robustness, and ease-of-use of ResMiCo make the tool suitable for general quality control of metagenome assemblies and assembly methodology optimization., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mineeva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The UK Biobank (UKBB) and German National Cohort (NAKO) are among the largest cohort studies, capturing a wide range of health-related data from the general population, including comprehensive magnetic resonance imaging (MRI) examinations. The purpose of this study was to demonstrate how MRI data from these large-scale studies can be jointly analyzed and to derive comprehensive quantitative image-based phenotypes across the general adult population., Materials and Methods: Image-derived features of abdominal organs (volumes of liver, spleen, kidneys, and pancreas; volumes of kidney hilum adipose tissue; and fat fractions of liver and pancreas) were extracted from T1-weighted Dixon MRI data of 17,996 participants of UKBB and NAKO based on quality-controlled deep learning generated organ segmentations. To enable valid cross-study analysis, we first analyzed the data generating process using methods of causal discovery. We subsequently harmonized data from UKBB and NAKO using the ComBat approach for batch effect correction. We finally performed quantile regression on harmonized data across studies providing quantitative models for the variation of image-derived features stratified for sex and dependent on age, height, and weight., Results: Data from 8791 UKBB participants (49.9% female; age, 63 ± 7.5 years) and 9205 NAKO participants (49.1% female, age: 51.8 ± 11.4 years) were analyzed. Analysis of the data generating process revealed direct effects of age, sex, height, weight, and the data source (UKBB vs NAKO) on image-derived features. Correction of data source-related effects resulted in markedly improved alignment of image-derived features between UKBB and NAKO. Cross-study analysis on harmonized data revealed comprehensive quantitative models for the phenotypic variation of abdominal organs across the general adult population., Conclusions: Cross-study analysis of MRI data from UKBB and NAKO as proposed in this work can be helpful for future joint data analyses across cohorts linking genetic, environmental, and behavioral risk factors to MRI-derived phenotypes and provide reference values for clinical diagnostics., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

We combine amortized neural posterior estimation with importance sampling for fast and accurate gravitational-wave inference. We first generate a rapid proposal for the Bayesian posterior using neural networks, and then attach importance weights based on the underlying likelihood and prior. This provides (1) a corrected posterior free from network inaccuracies, (2) a performance diagnostic (the sample efficiency) for assessing the proposal and identifying failure cases, and (3) an unbiased estimate of the Bayesian evidence. By establishing this independent verification and correction mechanism we address some of the most frequent criticisms against deep learning for scientific inference. We carry out a large study analyzing 42 binary black hole mergers observed by LIGO and Virgo with the SEOBNRv4PHM and IMRPhenomXPHM waveform models. This shows a median sample efficiency of ≈10% (2 orders of magnitude better than standard samplers) as well as a tenfold reduction in the statistical uncertainty in the log evidence. Given these advantages, we expect a significant impact on gravitational-wave inference, and for this approach to serve as a paradigm for harnessing deep learning methods in scientific applications.

A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analyzing 23 methods from the ENCODE Imputation Challenge. We find that imputation evaluations are challenging and confounded by distributional shifts from differences in data collection and processing over time, the amount of available data, and redundancy among performance measures. Our analyses suggest simple steps for overcoming these issues and promising directions for more robust research., (© 2023. The Author(s).)

The COVID-19 pandemic has spurred an unprecedented demand for interventions that can reduce disease spread without excessively restricting daily activity, given negative impacts on mental health and economic outcomes. Digital contact tracing (DCT) apps have emerged as a component of the epidemic management toolkit. Existing DCT apps typically recommend quarantine to all digitally-recorded contacts of test-confirmed cases. Over-reliance on testing may, however, impede the effectiveness of such apps, since by the time cases are confirmed through testing, onward transmissions are likely to have occurred. Furthermore, most cases are infectious over a short period; only a subset of their contacts are likely to become infected. These apps do not fully utilize data sources to base their predictions of transmission risk during an encounter, leading to recommendations of quarantine to many uninfected people and associated slowdowns in economic activity. This phenomenon, commonly termed as "pingdemic," may additionally contribute to reduced compliance to public health measures. In this work, we propose a novel DCT framework, Proactive Contact Tracing (PCT), which uses multiple sources of information (e.g. self-reported symptoms, received messages from contacts) to estimate app users' infectiousness histories and provide behavioral recommendations. PCT methods are by design proactive, predicting spread before it occurs. We present an interpretable instance of this framework, the Rule-based PCT algorithm, designed via a multi-disciplinary collaboration among epidemiologists, computer scientists, and behavior experts. Finally, we develop an agent-based model that allows us to compare different DCT methods and evaluate their performance in negotiating the trade-off between epidemic control and restricting population mobility. Performing extensive sensitivity analysis across user behavior, public health policy, and virological parameters, we compare Rule-based PCT to i) binary contact tracing (BCT), which exclusively relies on test results and recommends a fixed-duration quarantine, and ii) household quarantine (HQ). Our results suggest that both BCT and Rule-based PCT improve upon HQ, however, Rule-based PCT is more efficient at controlling spread of disease than BCT across a range of scenarios. In terms of cost-effectiveness, we show that Rule-based PCT pareto-dominates BCT, as demonstrated by a decrease in Disability Adjusted Life Years, as well as Temporary Productivity Loss. Overall, we find that Rule-based PCT outperforms existing approaches across a varying range of parameters. By leveraging anonymized infectiousness estimates received from digitally-recorded contacts, PCT is able to notify potentially infected users earlier than BCT methods and prevent onward transmissions. Our results suggest that PCT-based applications could be a useful tool in managing future epidemics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gupta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Acoustic waves exert forces when they interact with matter. Shaping ultrasound fields precisely in 3D thus allows control over the force landscape and should permit particulates to fall into place to potentially form whole 3D objects in "one shot." This is promising for rapid prototyping, most notably biofabrication, since conventional methods are typically slow and apply mechanical or chemical stress on biological cells. Here, we realize the generation of compact holographic ultrasound fields and demonstrate the one-step assembly of matter using acoustic forces. We combine multiple holographic fields that drive the contactless assembly of solid microparticles, hydrogel beads, and biological cells inside standard labware. The structures can be fixed via gelation of the surrounding medium. In contrast to previous work, this approach handles matter with positive acoustic contrast and does not require opposing waves, supporting surfaces or scaffolds. We envision promising applications of 3D holographic ultrasound fields in tissue engineering and additive manufacturing.

Simulating the spread of infectious diseases in human communities is critical for predicting the trajectory of an epidemic and verifying various policies to control the devastating impacts of the outbreak. Many existing simulators are based on compartment models that divide people into a few subsets and simulate the dynamics among those subsets using hypothesized differential equations. However, these models lack the requisite granularity to study the effect of intelligent policies that influence every individual in a particular way. In this work, we introduce a simulator software capable of modeling a population structure and controlling the disease's propagation at an individualistic level. In order to estimate the confidence of the conclusions drawn from the simulator, we employ a comprehensive probabilistic approach where the entire population is constructed as a hierarchical random variable. This approach makes the inferred conclusions more robust against sampling artifacts and gives confidence bounds for decisions based on the simulation results. To showcase potential applications, the simulator parameters are set based on the formal statistics of the COVID-19 pandemic, and the outcome of a wide range of control measures is investigated. Furthermore, the simulator is used as the environment of a reinforcement learning problem to find the optimal policies to control the pandemic. The obtained experimental results indicate the simulator's adaptability and capacity in making sound predictions and a successful policy derivation example based on real-world data. As an exemplary application, our results show that the proposed policy discovery method can lead to control measures that produce significantly fewer infected individuals in the population and protect the health system against saturation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mehrjou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The electronic band structure and crystal structure are the two complementary identifiers of solid-state materials. Although convenient instruments and reconstruction algorithms have made large, empirical, crystal structure databases possible, extracting the quasiparticle dispersion (closely related to band structure) from photoemission band mapping data is currently limited by the available computational methods. To cope with the growing size and scale of photoemission data, here we develop a pipeline including probabilistic machine learning and the associated data processing, optimization and evaluation methods for band-structure reconstruction, leveraging theoretical calculations. The pipeline reconstructs all 14 valence bands of a semiconductor and shows excellent performance on benchmarks and other materials datasets. The reconstruction uncovers previously inaccessible momentum-space structural information on both global and local scales, while realizing a path towards integration with materials science databases. Our approach illustrates the potential of combining machine learning and domain knowledge for scalable feature extraction in multidimensional data., (© 2022. The Author(s).)

Large epidemiological studies such as the UK Biobank (UKBB) or German National Cohort (NAKO) provide unprecedented health-related data of the general population aiming to better understand determinants of health and disease. As part of these studies, Magnetic Resonance Imaging (MRI) is performed in a subset of participants allowing for phenotypical and functional characterization of different organ systems. Due to the large amount of imaging data, automated image analysis is required, which can be performed using deep learning methods, e. g. for automated organ segmentation. In this paper we describe a computational pipeline for automated segmentation of abdominal organs on MRI data from 20,000 participants of UKBB and NAKO and provide results of the quality control process. We found that approx. 90% of data sets showed no relevant segmentation errors while relevant errors occurred in a varying proportion of data sets depending on the organ of interest. Image-derived features based on automated organ segmentations showed relevant deviations of varying degree in the presence of segmentation errors. These results show that large-scale, deep learning-based abdominal organ segmentation on MRI data is feasible with overall high accuracy, but visual quality control remains an important step ensuring the validity of down-stream analyses in large epidemiological imaging studies., (© 2022. The Author(s).)

We describe a publicly available dataset of annotated Positron Emission Tomography/Computed Tomography (PET/CT) studies. 1014 whole body Fluorodeoxyglucose (FDG)-PET/CT datasets (501 studies of patients with malignant lymphoma, melanoma and non small cell lung cancer (NSCLC) and 513 studies without PET-positive malignant lesions (negative controls)) acquired between 2014 and 2018 were included. All examinations were acquired on a single, state-of-the-art PET/CT scanner. The imaging protocol consisted of a whole-body FDG-PET acquisition and a corresponding diagnostic CT scan. All FDG-avid lesions identified as malignant based on the clinical PET/CT report were manually segmented on PET images in a slice-per-slice (3D) manner. We provide the anonymized original DICOM files of all studies as well as the corresponding DICOM segmentation masks. In addition, we provide scripts for image processing and conversion to different file formats (NIfTI, mha, hdf5). Primary diagnosis, age and sex are provided as non-imaging information. We demonstrate how this dataset can be used for deep learning-based automated analysis of PET/CT data and provide the trained deep learning model., (© 2022. The Author(s).)

The ongoing COVID-19 pandemic let to efforts to develop and deploy digital contact tracing systems to expedite contact tracing and risk notification. Unfortunately, the success of these systems has been limited, partly owing to poor interoperability with manual contact tracing, low adoption rates, and a societally sensitive trade-off between utility and privacy. In this work, we introduce a new privacy-preserving and inclusive system for epidemic risk assessment and notification that aims to address these limitations. Rather than capturing pairwise encounters between user devices as done by existing systems, our system captures encounters between user devices and beacons placed in strategic locations where infection clusters may originate. Epidemiological simulations using an agent-based model demonstrate that, by utilizing location and environmental information and interoperating with manual contact tracing, our system can increase the accuracy of contact tracing actions and may help reduce epidemic spread already at low adoption., (© 2022. The Author(s).)

We demonstrate unprecedented accuracy for rapid gravitational wave parameter estimation with deep learning. Using neural networks as surrogates for Bayesian posterior distributions, we analyze eight gravitational wave events from the first LIGO-Virgo Gravitational-Wave Transient Catalog and find very close quantitative agreement with standard inference codes, but with inference times reduced from O(day) to 20 s per event. Our networks are trained using simulated data, including an estimate of the detector noise characteristics near the event. This encodes the signal and noise models within millions of neural-network parameters and enables inference for any observed data consistent with the training distribution, accounting for noise nonstationarity from event to event. Our algorithm-called "DINGO"-sets a new standard in fast and accurate inference of physical parameters of detected gravitational wave events, which should enable real-time data analysis without sacrificing accuracy.

Obesity is one of the main drivers of type 2 diabetes, but it is not uniformly associated with the disease. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution, such as visceral fat, are closely related to insulin resistance. There might be further, hitherto unknown, features of body fat distribution that could additionally contribute to the disease. We used machine learning with dense convolutional neural networks to detect diabetes-related variables from 2371 T1-weighted whole-body MRI data sets. MRI was performed in participants undergoing metabolic screening with oral glucose tolerance tests. Models were trained for sex, age, BMI, insulin sensitivity, HbA1c, and prediabetes or incident diabetes. The results were compared with those of conventional models. The area under the receiver operating characteristic curve was 87% for the type 2 diabetes discrimination and 68% for prediabetes, both superior to conventional models. Mean absolute regression errors were comparable to those of conventional models. Heatmaps showed that lower visceral abdominal regions were critical in diabetes classification. Subphenotyping revealed a group with high future diabetes and microalbuminuria risk.Our results show that diabetes is detectable from whole-body MRI without additional data. Our technique of heatmap visualization identifies plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in diabetes pathogenesis.

Brain ageing is a complex neurobiological process associated with morphological changes that can be assessed on MRI scans. Recently, Deep learning (DL)-based approaches have been proposed for the prediction of chronological brain age from MR images yielding high accuracy. These approaches, however, usually do not address quantification of uncertainty and, therefore, intrinsic physiological variability. Considering uncertainty is essential for the interpretation of the difference between predicted and chronological age. In addition, DL-based models lack in explainability compared to classical approaches like voxel-based morphometry. In this study, we aim to address both, modeling uncertainty and providing visual explanations to explore physiological patterns in brain ageing. T1-weighted brain MRI datasets of 10691 participants of the German National Cohort Study, drawn from the general population, were included in this study (chronological age from 20 to 72 years). A regression model based on a 3D Convolutional Neural Network taking into account aleatoric noise was implemented for global as well as regional brain age estimation. We observed high overall accuracy of global brain age estimation with a mean absolute error of 3.2 ± 2.5 years and mean uncertainty of 2.9 ± 0.6 years. Regional brain age estimation revealed higher estimation accuracy and lower uncertainty in central compared to peripheral brain regions. Visual explanations illustrating the importance of brain sub-regions were generated using Grad-CAM: the derived saliency maps showed a high relevance of the lateral and third ventricles, the insular lobe as well as parts of the basal ganglia and the internal capsule., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: A supervised learning framework is proposed to automatically generate MR sequences and corresponding reconstruction based on the target contrast of interest. Combined with a flexible, task-driven cost function this allows for an efficient exploration of novel MR sequence strategies., Methods: The scanning and reconstruction process is simulated end-to-end in terms of RF events, gradient moment events in x and y, and delay times, acting on the input model spin system given in terms of proton density, T 1 and T 2 , and Δ B 0 . As a proof of concept, we use both conventional MR images and T 1 maps as targets and optimize from scratch using the loss defined by data fidelity, SAR penalty, and scan time., Results: In a first attempt, MRzero learns gradient and RF events from zero, and is able to generate a target image produced by a conventional gradient echo sequence. Using a neural network within the reconstruction module allows arbitrary targets to be learned successfully. Experiments could be translated to image acquisition at the real system (3T Siemens, PRISMA) and could be verified in the measurements of phantoms and a human brain in vivo., Conclusions: Automated MR sequence generation is possible based on differentiable Bloch equation simulations and a supervised learning approach., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Coronavirus disease 2019 (COVID-19) is a respiratory disease with rapid human-to-human transmission caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the exponential growth of infections, identifying patients with the highest mortality risk early is critical to enable effective intervention and prioritisation of care. Here, we present the COVID-19 early warning system (CovEWS), a risk scoring system for assessing COVID-19 related mortality risk that we developed using data amounting to a total of over 2863 years of observation time from a cohort of 66 430 patients seen at over 69 healthcare institutions. On an external cohort of 5005 patients, CovEWS predicts mortality from 78.8% (95% confidence interval [CI]: 76.0, 84.7%) to 69.4% (95% CI: 57.6, 75.2%) specificity at sensitivities greater than 95% between, respectively, 1 and 192 h prior to mortality events. CovEWS could enable earlier intervention, and may therefore help in preventing or mitigating COVID-19 related mortality.

One of the most important tasks for humans is the attribution of causes and effects in all wakes of life. The first systematical study of visual perception of causality-often referred to as phenomenal causality -was done by Albert Michotte using his now well-known launching events paradigm. Launching events are the seeming collision and seeming transfer of movement between two objects-abstract, featureless stimuli ("objects") in Michotte's original experiments. Here, we study the relation between causal ratings for launching events in Michotte's setting and launching collisions in a photorealistically computer-rendered setting. We presented launching events with differing temporal gaps, the same launching processes with photorealistic billiard balls, as well as photorealistic billiard balls with realistic motion dynamics, that is, an initial rebound of the first ball after collision and a short sliding phase of the second ball due to momentum and friction. We found that providing the normal launching stimulus with realistic visuals led to lower causal ratings, but realistic visuals together with realistic motion dynamics evoked higher ratings. Two-dimensional versus three-dimensional presentation, on the other hand, did not affect phenomenal causality. We discuss our results in terms of intuitive physics as well as cue conflict., (© The Author(s) 2020.)

Motivation: Methodological advances in metagenome assembly are rapidly increasing in the number of published metagenome assemblies. However, identifying misassemblies is challenging due to a lack of closely related reference genomes that can act as pseudo ground truth. Existing reference-free methods are no longer maintained, can make strong assumptions that may not hold across a diversity of research projects, and have not been validated on large-scale metagenome assemblies., Results: We present DeepMAsED, a deep learning approach for identifying misassembled contigs without the need for reference genomes. Moreover, we provide an in silico pipeline for generating large-scale, realistic metagenome assemblies for comprehensive model training and testing. DeepMAsED accuracy substantially exceeds the state-of-the-art when applied to large and complex metagenome assemblies. Our model estimates a 1% contig misassembly rate in two recent large-scale metagenome assembly publications., Conclusions: DeepMAsED accurately identifies misassemblies in metagenome-assembled contigs from a broad diversity of bacteria and archaea without the need for reference genomes or strong modeling assumptions. Running DeepMAsED is straight-forward, as well as is model re-training with our dataset generation pipeline. Therefore, DeepMAsED is a flexible misassembly classifier that can be applied to a wide range of metagenome assembly projects., Availability and Implementation: DeepMAsED is available from GitHub at https://github.com/leylabmpi/DeepMAsED., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: A multi-coil shim setup is designed and optimized for human brain shimming. Here, the size and position of a set of square coils are optimized to improve the shim performance without increasing the number of local coils. Utilizing such a setup is especially beneficial at ultrahigh fields where B 0 inhomogeneity in the human brain is more severe., Methods: The optimization started with a symmetric arrangement of 32 independent coils. Three parameters per coil were optimized in parallel, including angular and axial positions on a cylinder surface and size of the coil, which were constrained by cylinder size, construction consideration, and amplifiers specifications. B 0 maps were acquired at 9.4T in 8 healthy volunteers for use as training data. The global and dynamic shimming performance of the optimized multi-coil were compared in simulations and measurements to a symmetric design and to the scanner's second-order shim setup, respectively., Results: The optimized multi-coil performs better by 14.7% based on standard deviation (SD) improvement with constrained global shimming in comparison to the symmetric positioning of the coils. Global shimming performance was comparable with a symmetric 65-channel multi-coil and full fifth-order spherical harmonic shim coils. On average, an SD of 48.4 and 31.9 Hz was achieved for in vivo measurements after global and dynamic slice-wise shimming, respectively., Conclusions: An optimized multi-coil shim setup was designed and constructed for human whole-brain shimming. Similar performance of the multi-coils with many channels can be achieved with a fewer number of channels when the coils are optimally arranged around the target., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: A novel method for the acceleration of MRI acquisition is proposed that relies on the local modulation of magnetic fields. These local modulations provide additional spatial information for image reconstruction that is used to accelerate image acquisition., Methods: In experiments and simulations, eight local coils connected to current amplifiers were used for rapid local magnetic field variation. Acquired and simulated data were reconstructed to quantify reconstruction errors as a function of the acceleration factor and applied modulation frequency and strength., Results: Experimental results demonstrate a possible acceleration factor of 2 to 4. Simulations demonstrate the challenges and limits of this method in terms of required magnetic field modulation strengths and frequencies. A normalized mean squared error of below 10% can be achieved for acceleration factors of up to 8 using modulation field strengths comparable to the readout gradient strength at modulation frequencies in the range of 5 to 20 kHz., Conclusion: Spread-spectrum MRI represents a new approach to accelerate image acquisition, and it can be independently combined with traditional parallel imaging techniques based on local receive coil sensitivities., (© 2019 International Society for Magnetic Resonance in Medicine.)

The heart of the scientific enterprise is a rational effort to understand the causes behind the phenomena we observe. In large-scale complex dynamical systems such as the Earth system, real experiments are rarely feasible. However, a rapidly increasing amount of observational and simulated data opens up the use of novel data-driven causal methods beyond the commonly adopted correlation techniques. Here, we give an overview of causal inference frameworks and identify promising generic application cases common in Earth system sciences and beyond. We discuss challenges and initiate the benchmark platform causeme.net to close the gap between method users and developers.

Spaced repetition is a technique for efficient memorization which uses repeated review of content following a schedule determined by a spaced repetition algorithm to improve long-term retention. However, current spaced repetition algorithms are simple rule-based heuristics with a few hard-coded parameters. Here, we introduce a flexible representation of spaced repetition using the framework of marked temporal point processes and then address the design of spaced repetition algorithms with provable guarantees as an optimal control problem for stochastic differential equations with jumps. For two well-known human memory models, we show that, if the learner aims to maximize recall probability of the content to be learned subject to a cost on the reviewing frequency, the optimal reviewing schedule is given by the recall probability itself. As a result, we can then develop a simple, scalable online spaced repetition algorithm, MEMORIZE, to determine the optimal reviewing times. We perform a large-scale natural experiment using data from Duolingo, a popular language-learning online platform, and show that learners who follow a reviewing schedule determined by our algorithm memorize more effectively than learners who follow alternative schedules determined by several heuristics., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

We address the problem of inferring the causal direction between two variables by comparing the least-squares errors of the predictions in both possible directions. Under the assumption of an independence between the function relating cause and effect, the conditional noise distribution, and the distribution of the cause, we show that the errors are smaller in causal direction if both variables are equally scaled and the causal relation is close to deterministic. Based on this, we provide an easily applicable algorithm that only requires a regression in both possible causal directions and a comparison of the errors. The performance of the algorithm is compared with various related causal inference methods in different artificial and real-world data sets., Competing Interests: The authors declare there are no competing interests., (©2019 Blöbaum et al.)

Discovery of causal relationships from observational data is a fundamental problem. Roughly speaking, there are two types of methods for causal discovery, constraint-based ones and score-based ones. Score-based methods avoid the multiple testing problem and enjoy certain advantages compared to constraint-based ones. However, most of them need strong assumptions on the functional forms of causal mechanisms, as well as on data distributions, which limit their applicability. In practice the precise information of the underlying model class is usually unknown. If the above assumptions are violated, both spurious and missing edges may result. In this paper, we introduce generalized score functions for causal discovery based on the characterization of general (conditional) independence relationships between random variables, without assuming particular model classes. In particular, we exploit regression in RKHS to capture the dependence in a non-parametric way. The resulting causal discovery approach produces asymptotically correct results in rather general cases, which may have nonlinear causal mechanisms, a wide class of data distributions, mixed continuous and discrete data, and multidimensional variables. Experimental results on both synthetic and real-world data demonstrate the efficacy of our proposed approach.

Introduction: Impaired glucose tolerance (IGT) is diagnosed by a standardized oral glucose tolerance test (OGTT). However, the OGTT is laborious, and when not performed, glucose tolerance cannot be determined from fasting samples retrospectively. We tested if glucose tolerance status is reasonably predictable from a combination of demographic, anthropometric, and laboratory data assessed at one time point in a fasting state., Methods: Given a set of 22 variables selected upon clinical feasibility such as sex, age, height, weight, waist circumference, blood pressure, fasting glucose, HbA1c, hemoglobin, mean corpuscular volume, serum potassium, fasting levels of insulin, C-peptide, triglyceride, non-esterified fatty acids (NEFA), proinsulin, prolactin, cholesterol, low-density lipoprotein, HDL, uric acid, liver transaminases, and ferritin, we used supervised machine learning to estimate glucose tolerance status in 2,337 participants of the TUEF study who were recruited before 2012. We tested the performance of 10 different machine learning classifiers on data from 929 participants in the test set who were recruited after 2012. In addition, reproducibility of IGT was analyzed in 78 participants who had 2 repeated OGTTs within 1 year., Results: The most accurate prediction of IGT was reached with the recursive partitioning method (accuracy = 0.78). For all classifiers, mean accuracy was 0.73 ± 0.04. The most important model variable was fasting glucose in all models. Using mean variable importance across all models, fasting glucose was followed by NEFA, triglycerides, HbA1c, and C-peptide. The accuracy of predicting IGT from a previous OGTT was 0.77., Conclusion: Machine learning methods yield moderate accuracy in predicting glucose tolerance from a wide set of clinical and laboratory variables. A substitution of OGTT does not currently seem to be feasible. An important constraint could be the limited reproducibility of glucose tolerance status during a subsequent OGTT.

We address two important issues in causal discovery from nonstationary or heterogeneous data, where parameters associated with a causal structure may change over time or across data sets. First, we investigate how to efficiently estimate the "driving force" of the nonstationarity of a causal mechanism. That is, given a causal mechanism that varies over time or across data sets and whose qualitative structure is known, we aim to extract from data a low-dimensional and interpretable representation of the main components of the changes. For this purpose we develop a novel kernel embedding of nonstationary conditional distributions that does not rely on sliding windows. Second, the embedding also leads to a measure of dependence between the changes of causal modules that can be used to determine the directions of many causal arrows. We demonstrate the power of our methods with experiments on both synthetic and real data.

Objective: Task-induced amplitude modulation of neural oscillations is routinely used in brain-computer interfaces (BCIs) for decoding subjects' intents, and underlies some of the most robust and common methods in the field, such as common spatial patterns and Riemannian geometry. While there has been some interest in phase-related features for classification, both techniques usually presuppose that the frequencies of neural oscillations remain stable across various tasks. We investigate here whether features based on task-induced modulation of the frequency of neural oscillations enable decoding of subjects' intents with an accuracy comparable to task-induced amplitude modulation., Approach: We compare cross-validated classification accuracies using the amplitude and frequency modulated features, as well as a joint feature space, across subjects in various paradigms and pre-processing conditions. We show results with a motor imagery task, a cognitive task, and also preliminary results in patients with amyotrophic lateral sclerosis (ALS), as well as using common spatial patterns and Laplacian filtering., Main Results: The frequency features alone do not significantly out-perform traditional amplitude modulation features, and in some cases perform significantly worse. However, across both tasks and pre-processing in healthy subjects the joint space significantly out-performs either the frequency or amplitude features alone. This result only does not hold for ALS patients, for whom the dataset is of insufficient size to draw any statistically significant conclusions., Significance: Task-induced frequency modulation is robust and straight forward to compute, and increases performance when added to standard amplitude modulation features across paradigms. This allows more information to be extracted from the EEG signal cheaply and can be used throughout the field of BCIs.

It is commonplace to encounter nonstationary or heterogeneous data, of which the underlying generating process changes over time or across data sets (the data sets may have different experimental conditions or data collection conditions). Such a distribution shift feature presents both challenges and opportunities for causal discovery. In this paper we develop a principled framework for causal discovery from such data, called Constraint-based causal Discovery from Nonstationary/heterogeneous Data (CD-NOD), which addresses two important questions. First, we propose an enhanced constraint-based procedure to detect variables whose local mechanisms change and recover the skeleton of the causal structure over observed variables. Second, we present a way to determine causal orientations by making use of independence changes in the data distribution implied by the underlying causal model, benefiting from information carried by changing distributions. Experimental results on various synthetic and real-world data sets are presented to demonstrate the efficacy of our methods.

Discovering causal structure of a dynamical system from observed time series is a traditional and important problem. In many practical applications, observed data are obtained by applying subsampling or temporally aggregation to the original causal processes, making it difficult to discover the underlying causal relations. Subsampling refers to the procedure that for every k consecutive observations, one is kept, the rest being skipped, and recently some advances have been made in causal discovery from such data. With temporal aggregation, the local averages or sums of k consecutive, non-overlapping observations in the causal process are computed as new observations, and causal discovery from such data is even harder. In this paper, we investigate how to recover causal relations at the original causal frequency from temporally aggregated data when k is known. Assuming the time series at the causal frequency follows a vector autoregressive (VAR) model, we show that the causal structure at the causal frequency is identifiable from aggregated time series if the noise terms are independent and non-Gaussian and some other technical conditions hold. We then present an estimation method based on non-Gaussian state-space modeling and evaluate its performance on both synthetic and real data.

Self-referential processing is a key cognitive process, associated with the serotonergic system and the default mode network (DMN). Decreased levels of serotonin and reduced activations of the DMN observed in amyotrophic lateral sclerosis (ALS) suggest that self-referential processing might be altered in patients with ALS. Here, we investigate the effects of ALS on the electroencephalography correlates of self-referential thinking. We find that electroencephalography (EEG) correlates of self-referential thinking are present in healthy individuals, but not in those with ALS. In particular, thinking about themselves or others significantly modulates the bandpower in the medial prefrontal cortex in healthy individuals, but not in ALS patients. This finding supports the view of ALS as a complex multisystem disorder which, as shown here, includes dysfunctional processing of the medial prefrontal cortex. It points towards possible alterations of self-consciousness in ALS patients, which might have important consequences for patients' self-conceptions, personal relations, and decision-making.

Purpose: We aimed to precisely estimate intra-tumoral heterogeneity using spatially regularized spectral clustering (SRSC) on multiparametric MRI data and compare the efficacy of SRSC with the previously reported segmentation techniques in MRI studies., Procedures: Six NMRI nu/nu mice bearing subcutaneous human glioblastoma U87 MG tumors were scanned using a dedicated small animal 7T magnetic resonance imaging (MRI) scanner. The data consisted of T2 weighted images, apparent diffusion coefficient maps, and pre- and post-contrast T2 and T2* maps. Following each scan, the tumors were excised into 2-3-mm thin slices parallel to the axial field of view and processed for histological staining. The MRI data were segmented using SRSC, K-means, fuzzy C-means, and Gaussian mixture modeling to estimate the fractional population of necrotic, peri-necrotic, and viable regions and validated with the fractional population obtained from histology., Results: While the aforementioned methods overestimated peri-necrotic and underestimated viable fractions, SRSC accurately predicted the fractional population of all three tumor tissue types and exhibited strong correlations (r necrotic  = 0.92, r peri-necrotic  = 0.82 and r viable  = 0.98) with the histology., Conclusions: The precise identification of necrotic, peri-necrotic and viable areas using SRSC may greatly assist in cancer treatment planning and add a new dimension to MRI-guided tumor biopsy procedures.

In this study, we described and validated an unsupervised segmentation algorithm for the assessment of tumor heterogeneity using dynamic 18 F-FDG PET. The aim of our study was to objectively evaluate the proposed method and make comparisons with compartmental modeling parametric maps and SUV segmentations using simulations of clinically relevant tumor tissue types. Methods: An irreversible 2-tissue-compartmental model was implemented to simulate clinical and preclinical 18 F-FDG PET time-activity curves using population-based arterial input functions (80 clinical and 12 preclinical) and the kinetic parameter values of 3 tumor tissue types. The simulated time-activity curves were corrupted with different levels of noise and used to calculate the tissue-type misclassification errors of spectral clustering (SC), parametric maps, and SUV segmentation. The utility of the inverse noise variance- and Laplacian score-derived frame weighting schemes before SC was also investigated. Finally, the SC scheme with the best results was tested on a dynamic 18 F-FDG measurement of a mouse bearing subcutaneous colon cancer and validated using histology. Results: In the preclinical setup, the inverse noise variance-weighted SC exhibited the lowest misclassification errors (8.09%-28.53%) at all noise levels in contrast to the Laplacian score-weighted SC (16.12%-31.23%), unweighted SC (25.73%-40.03%), parametric maps (28.02%-61.45%), and SUV (45.49%-45.63%) segmentation. The classification efficacy of both weighted SC schemes in the clinical case was comparable to the unweighted SC. When applied to the dynamic 18 F-FDG measurement of colon cancer, the proposed algorithm accurately identified densely vascularized regions from the rest of the tumor. In addition, the segmented regions and clusterwise average time-activity curves showed excellent correlation with the tumor histology. Conclusion: The promising results of SC mark its position as a robust tool for quantification of tumor heterogeneity using dynamic PET studies. Because SC tumor segmentation is based on the intrinsic structure of the underlying data, it can be easily applied to other cancer types as well., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

The ever-growing availability of high-quality genotypes for a multitude of species has enabled researchers to explore the underlying genetic architecture of complex phenotypes at an unprecedented level of detail using genome-wide association studies (GWAS). The systematic comparison of results obtained from GWAS of different traits opens up new possibilities, including the analysis of pleiotropic effects. Other advantages that result from the integration of multiple GWAS are the ability to replicate GWAS signals and to increase statistical power to detect such signals through meta-analyses. In order to facilitate the simple comparison of GWAS results, we present easyGWAS, a powerful, species-independent online resource for computing, storing, sharing, annotating, and comparing GWAS. The easyGWAS tool supports multiple species, the uploading of private genotype data and summary statistics of existing GWAS, as well as advanced methods for comparing GWAS results across different experiments and data sets in an interactive and user-friendly interface. easyGWAS is also a public data repository for GWAS data and summary statistics and already includes published data and results from several major GWAS. We demonstrate the potential of easyGWAS with a case study of the model organism Arabidopsis thaliana , using flowering and growth-related traits., (© 2016 American Society of Plant Biologists. All rights reserved.)

Objective: Electroencephalographic (EEG) brain-computer interfaces (BCIs) hold promise in restoring communication for patients with completely locked-in stage amyotrophic lateral sclerosis (ALS). However, these patients cannot use existing EEG-based BCIs, arguably because such systems rely on brain processes that are impaired in the late stages of ALS. In this work, we introduce a novel BCI designed for patients in late stages of ALS based on high-level cognitive processes that are less likely to be affected by ALS., Approach: We trained two ALS patients via EEG-based neurofeedback to use self-regulation of theta or gamma oscillations in the precuneus for basic communication. Because there is a tight connection between the precuneus and consciousness, precuneus oscillations are arguably generated by high-level cognitive processes, which are less likely to be affected by ALS than processes linked to the peripheral nervous system., Main Results: Both patients learned to self-regulate their precuneus oscillations and achieved stable online decoding accuracy over the course of disease progression. One patient achieved a mean online decoding accuracy in a binary decision task of 70.55% across 26 training sessions, and the other patient achieved 59.44% across 16 training sessions. We provide empirical evidence that these oscillations were cortical in nature and originated from the intersection of the precuneus, cuneus, and posterior cingulate., Significance: Our results establish that ALS patients can employ self-regulation of precuneus oscillations for communication. Such a BCI is likely to be available to ALS patients as long as their consciousness supports communication.

We describe a method for removing the effect of confounders to reconstruct a latent quantity of interest. The method, referred to as "half-sibling regression," is inspired by recent work in causal inference using additive noise models. We provide a theoretical justification, discussing both independent and identically distributed as well as time series data, respectively, and illustrate the potential of the method in a challenging astronomy application.

Domain adaptation arises in supervised learning when the training (source domain) and test (target domain) data have different distributions. Let X and Y denote the features and target, respectively, previous work on domain adaptation mainly considers the covariate shift situation where the distribution of the features P ( X ) changes across domains while the conditional distribution P ( Y ∣ X ) stays the same. To reduce domain discrepancy, recent methods try to find invariant components [Formula: see text] that have similar [Formula: see text] on different domains by explicitly minimizing a distribution discrepancy measure. However, it is not clear if [Formula: see text] in different domains is also similar when P ( Y ∣ X ) changes. Furthermore, transferable components do not necessarily have to be invariant. If the change in some components is identifiable, we can make use of such components for prediction in the target domain. In this paper, we focus on the case where P ( X ∣ Y ) and P ( Y ) both change in a causal system in which Y is the cause for X . Under appropriate assumptions, we aim to extract conditional transferable components whose conditional distribution [Formula: see text] is invariant after proper location-scale (LS) transformations, and identify how P ( Y ) changes between domains simultaneously. We provide theoretical analysis and empirical evaluation on both synthetic and real-world data to show the effectiveness of our method.

We consider the task of inferring causal relations in brain imaging data with latent confounders. Using a priori knowledge that randomized experimental conditions cannot be effects of brain activity, we derive statistical conditions that are sufficient for establishing a causal relation between two neural processes, even in the presence of latent confounders. We provide an algorithm to test these conditions on empirical data, and illustrate its performance on simulated as well as on experimentally recorded EEG data., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Brain-computer interfaces (BCIs) are often based on the control of sensorimotor processes, yet sensorimotor processes are impaired in patients suffering from amyotrophic lateral sclerosis (ALS). We devised a new paradigm that targets higher-level cognitive processes to transmit information from the user to the BCI. We instructed five ALS patients and twelve healthy subjects to either activate self-referential memories or to focus on a process without mnemonic content while recording a high-density electroencephalogram (EEG). Both tasks are designed to modulate activity in the default mode network (DMN) without involving sensorimotor pathways. We find that the two tasks can be distinguished after only one experimental session from the average of the combined bandpower modulations in the theta- (4-7Hz) and alpha-range (8-13Hz), with an average accuracy of 62.5% and 60.8% for healthy subjects and ALS patients, respectively. The spatial weights of the decoding algorithm show a preference for the parietal area, consistent with modulation of neural activity in primary nodes of the DMN., (© 2016 Elsevier B.V. All rights reserved.)

Distributed neural processing likely entails the capability of networks to reconfigure dynamically the directionality and strength of their functional connections. Yet, the neural mechanisms that may allow such dynamic routing of the information flow are not yet fully understood. We investigated the role of gamma band (50-80 Hz) oscillations in transient modulations of communication among neural populations by using measures of direction-specific causal information transfer. We found that the local phase of gamma-band rhythmic activity exerted a stimulus-modulated and spatially-asymmetric directed effect on the firing rate of spatially separated populations within the primary visual cortex. The relationships between gamma phases at different sites (phase shifts) could be described as a stimulus-modulated gamma-band wave propagating along the spatial directions with the largest information transfer. We observed transient stimulus-related changes in the spatial configuration of phases (compatible with changes in direction of gamma wave propagation) accompanied by a relative increase of the amount of information flowing along the instantaneous direction of the gamma wave. These effects were specific to the gamma-band and suggest that the time-varying relationships between gamma phases at different locations mark, and possibly causally mediate, the dynamic reconfiguration of functional connections.

Causal terminology is often introduced in the interpretation of encoding and decoding models trained on neuroimaging data. In this article, we investigate which causal statements are warranted and which ones are not supported by empirical evidence. We argue that the distinction between encoding and decoding models is not sufficient for this purpose: relevant features in encoding and decoding models carry a different meaning in stimulus- and in response-based experimental paradigms.We show that only encoding models in the stimulus-based setting support unambiguous causal interpretations. By combining encoding and decoding models trained on the same data, however, we obtain insights into causal relations beyond those that are implied by each individual model type. We illustrate the empirical relevance of our theoretical findings on EEG data recorded during a visuo-motor learning task., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Physiological nonrigid motion is inevitable when imaging, e.g., abdominal viscera, and can lead to serious deterioration of the image quality. Prospective techniques for motion correction can handle only special types of nonrigid motion, as they only allow global correction. Retrospective methods developed so far need guidance from navigator sequences or external sensors. We propose a fully retrospective nonrigid motion correction scheme that only needs raw data as an input., Methods: Our method is based on a forward model that describes the effects of nonrigid motion by partitioning the image into patches with locally rigid motion. Using this forward model, we construct an objective function that we can optimize with respect to both unknown motion parameters per patch and the underlying sharp image., Results: We evaluate our method on both synthetic and real data in 2D and 3D. In vivo data was acquired using standard imaging sequences. The correction algorithm significantly improves the image quality. Our compute unified device architecture (CUDA)-enabled graphic processing unit implementation ensures feasible computation times., Conclusion: The presented technique is the first computationally feasible retrospective method that uses the raw data of standard imaging sequences, and allows to correct for nonrigid motion without guidance from external motion sensors., (© 2014 Wiley Periodicals, Inc.)

Despite decades of research on EEG-based brain-computer interfaces (BCIs) in patients with amyotrophic lateral sclerosis (ALS), there is still little known about how the disease affects the electromagnetic field of the brain. This may be one reason for the present failure of EEG-based BCI paradigms for completely locked-in ALS patients. In order to help understand this failure, we have recorded resting state data from six ALS patients and thirty-two healthy controls to investigate for group differences. While similar studies have been attempted in the past, none have used high-density EEG or tried to distinguish between physiological and non-physiological sources of the EEG. We find an ALS-specific global increase in gamma power (30-90 Hz) that is not specific to the motor cortex, suggesting that the mechanism behind ALS affects non-motor cortical regions even in the absence of comorbid cognitive deficits.