ChromaX: a fast and scalable breeding program simulator.

SUMMARY: ChromaX is a Python library that enables the simulation of genetic recombination, genomic estimated breeding value calculations, and selection processes. By utilizing GPU processing, it can perform these simulations up to two orders of magnitude faster than existing tools with standard hardware. This offers breeders and scientists new opportunities to simulate genetic gain and optimize breeding schemes. AVAILABILITY AND IMPLEMENTATION: The documentation is available at https://chromax.readthedocs.io. The code is available at https://github.com/kora-labs/chromax.

Natural Age-Related Slow-Wave Sleep Alterations Onset Prematurely in the Tg2576 Mouse Model of Alzheimer's Disease.

INTRODUCTION: Sleep insufficiency or decreased quality have been associated with Alzheimer's disease (AD) already in its preclinical stages. Whether such traits are also present in rodent models of the disease has been poorly addressed, somewhat disabling the preclinical exploration of sleep-based therapeutic interventions for AD. METHODS: We investigated age-dependent sleep-wake phenotype of a widely used mouse model of AD, the Tg2576 line. We implanted electroencephalography/electromyography headpieces into 6-month-old (plaque-free, n = 10) and 11-month-old (moderate plaque-burdened, n = 10) Tg2576 mice and age-matched wild-type (WT, 6 months old n = 10, 11 months old n = 10) mice and recorded vigilance states for 24 h. RESULTS: Tg2576 mice exhibited significantly increased wakefulness and decreased non-rapid eye movement sleep over a 24-h period compared to WT mice at 6 but not at 11 months of age. Concomitantly, power in the delta frequency was decreased in 6-month old Tg2576 mice in comparison to age-matched WT controls, rendering a reduced slow-wave energy phenotype in the young mutants. Lack of genotype-related differences over 24 h in the overall sleep-wake phenotype at 11 months of age appears to be the result of changes in sleep-wake characteristics accompanying the healthy aging of WT mice. CONCLUSION: Therefore, our results indicate that at the plaque-free disease stage, diminished sleep quality is present in Tg2576 mice which resembles aged healthy controls, suggesting an early-onset of sleep-wake deterioration in murine AD. Whether such disturbances in the natural patterns of sleep could in turn worsen disease progression warrants further exploration.

SPINDLE: End-to-end learning from EEG/EMG to extrapolate animal sleep scoring across experimental settings, labs and species.

Understanding sleep and its perturbation by environment, mutation, or medication remains a central problem in biomedical research. Its examination in animal models rests on brain state analysis via classification of electroencephalographic (EEG) signatures. Traditionally, these states are classified by trained human experts by visual inspection of raw EEG recordings, which is a laborious task prone to inter-individual variability. Recently, machine learning approaches have been developed to automate this process, but their generalization capabilities are often insufficient, especially across animals from different experimental studies. To address this challenge, we crafted a convolutional neural network-based architecture to produce domain invariant predictions, and furthermore integrated a hidden Markov model to constrain state dynamics based upon known sleep physiology. Our method, which we named SPINDLE (Sleep Phase Identification with Neural networks for Domain-invariant LEearning) was validated using data of four animal cohorts from three independent sleep labs, and achieved average agreement rates of 99%, 98%, 93%, and 97% with scorings from five human experts from different labs, essentially duplicating human capability. It generalized across different genetic mutants, surgery procedures, recording setups and even different species, far exceeding state-of-the-art solutions that we tested in parallel on this task. Moreover, we show that these scored data can be processed for downstream analyzes identical to those from human-scored data, in particular by demonstrating the ability to detect mutation-induced sleep alteration. We provide to the scientific community free usage of SPINDLE and benchmarking datasets as an online server at https://sleeplearning.ethz.ch. Our aim is to catalyze high-throughput and well-standardized experimental studies in order to improve our understanding of sleep.

Pipeline validation for connectivity-based cortex parcellation.

Structural connectivity plays a dominant role in brain function and arguably lies at the core of understanding the structure-function relationship in the cerebral cortex. Connectivity-based cortex parcellation (CCP), a framework to process structural connectivity information gained from diffusion MRI and diffusion tractography, identifies cortical subunits that furnish functional inference. The underlying pipeline of algorithms interprets similarity in structural connectivity as a segregation criterion. Validation of the CCP-pipeline is critical to gain scientific reliability of the algorithmic processing steps from dMRI data to voxel grouping. In this paper we provide a proof of concept based upon a novel model validation principle that characterizes the trade-off between informativeness and robustness to assess the validity of the CCP pipeline, including diffusion tractography and clustering. We ultimately identify a pipeline of algorithms and parameter settings that tolerate more noise and extract more information from the data than their alternatives.

A generative model of whole-brain effective connectivity.

The development of whole-brain models that can infer effective (directed) connection strengths from fMRI data represents a central challenge for computational neuroimaging. A recently introduced generative model of fMRI data, regression dynamic causal modeling (rDCM), moves towards this goal as it scales gracefully to very large networks. However, large-scale networks with thousands of connections are difficult to interpret; additionally, one typically lacks information (data points per free parameter) for precise estimation of all model parameters. This paper introduces sparsity constraints to the variational Bayesian framework of rDCM as a solution to these problems in the domain of task-based fMRI. This sparse rDCM approach enables highly efficient effective connectivity analyses in whole-brain networks and does not require a priori assumptions about the network's connectivity structure but prunes fully (all-to-all) connected networks as part of model inversion. Following the derivation of the variational Bayesian update equations for sparse rDCM, we use both simulated and empirical data to assess the face validity of the model. In particular, we show that it is feasible to infer effective connection strengths from fMRI data using a network with more than 100 regions and 10,000 connections. This demonstrates the feasibility of whole-brain inference on effective connectivity from fMRI data - in single subjects and with a run-time below 1 min when using parallelized code. We anticipate that sparse rDCM may find useful application in connectomics and clinical neuromodeling - for example, for phenotyping individual patients in terms of whole-brain network structure.

Regression DCM for fMRI.

The development of large-scale network models that infer the effective (directed) connectivity among neuronal populations from neuroimaging data represents a key challenge for computational neuroscience. Dynamic causal models (DCMs) of neuroimaging and electrophysiological data are frequently used for inferring effective connectivity but are presently restricted to small graphs (typically up to 10 regions) in order to keep model inversion computationally feasible. Here, we present a novel variant of DCM for functional magnetic resonance imaging (fMRI) data that is suited to assess effective connectivity in large (whole-brain) networks. The approach rests on translating a linear DCM into the frequency domain and reformulating it as a special case of Bayesian linear regression. This paper derives regression DCM (rDCM) in detail and presents a variational Bayesian inversion method that enables extremely fast inference and accelerates model inversion by several orders of magnitude compared to classical DCM. Using both simulated and empirical data, we demonstrate the face validity of rDCM under different settings of signal-to-noise ratio (SNR) and repetition time (TR) of fMRI data. In particular, we assess the potential utility of rDCM as a tool for whole-brain connectomics by challenging it to infer effective connection strengths in a simulated whole-brain network comprising 66 regions and 300 free parameters. Our results indicate that rDCM represents a computationally highly efficient approach with promising potential for inferring whole-brain connectivity from individual fMRI data.

Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry.

Mass cytometry enables high-dimensional, single-cell analysis of cell type and state. In mass cytometry, rare earth metals are used as reporters on antibodies. Analysis of metal abundances using the mass cytometer allows determination of marker expression in individual cells. Mass cytometry has previously been applied only to cell suspensions. To gain spatial information, we have coupled immunohistochemical and immunocytochemical methods with high-resolution laser ablation to CyTOF mass cytometry. This approach enables the simultaneous imaging of 32 proteins and protein modifications at subcellular resolution; with the availability of additional isotopes, measurement of over 100 markers will be possible. We applied imaging mass cytometry to human breast cancer samples, allowing delineation of cell subpopulations and cell-cell interactions and highlighting tumor heterogeneity. Imaging mass cytometry complements existing imaging approaches. It will enable basic studies of tissue heterogeneity and function and support the transition of medicine toward individualized molecularly targeted diagnosis and therapies.

Inferring causal metabolic signals that regulate the dynamic TORC1-dependent transcriptome.

Cells react to nutritional cues in changing environments via the integrated action of signaling, transcriptional, and metabolic networks. Mechanistic insight into signaling processes is often complicated because ubiquitous feedback loops obscure causal relationships. Consequently, the endogenous inputs of many nutrient signaling pathways remain unknown. Recent advances for system-wide experimental data generation have facilitated the quantification of signaling systems, but the integration of multi-level dynamic data remains challenging. Here, we co-designed dynamic experiments and a probabilistic, model-based method to infer causal relationships between metabolism, signaling, and gene regulation. We analyzed the dynamic regulation of nitrogen metabolism by the target of rapamycin complex 1 (TORC1) pathway in budding yeast. Dynamic transcriptomic, proteomic, and metabolomic measurements along shifts in nitrogen quality yielded a consistent dataset that demonstrated extensive re-wiring of cellular networks during adaptation. Our inference method identified putative downstream targets of TORC1 and putative metabolic inputs of TORC1, including the hypothesized glutamine signal. The work provides a basis for further mechanistic studies of nitrogen metabolism and a general computational framework to study cellular processes.

Inversion of hierarchical Bayesian models using Gaussian processes.

Over the past decade, computational approaches to neuroimaging have increasingly made use of hierarchical Bayesian models (HBMs), either for inferring on physiological mechanisms underlying fMRI data (e.g., dynamic causal modelling, DCM) or for deriving computational trajectories (from behavioural data) which serve as regressors in general linear models. However, an unresolved problem is that standard methods for inverting the hierarchical Bayesian model are either very slow, e.g. Markov Chain Monte Carlo Methods (MCMC), or are vulnerable to local minima in non-convex optimisation problems, such as variational Bayes (VB). This article considers Gaussian process optimisation (GPO) as an alternative approach for global optimisation of sufficiently smooth and efficiently evaluable objective functions. GPO avoids being trapped in local extrema and can be computationally much more efficient than MCMC. Here, we examine the benefits of GPO for inverting HBMs commonly used in neuroimaging, including DCM for fMRI and the Hierarchical Gaussian Filter (HGF). Importantly, to achieve computational efficiency despite high-dimensional optimisation problems, we introduce a novel combination of GPO and local gradient-based search methods. The utility of this GPO implementation for DCM and HGF is evaluated against MCMC and VB, using both synthetic data from simulations and empirical data. Our results demonstrate that GPO provides parameter estimates with equivalent or better accuracy than the other techniques, but at a fraction of the computational cost required for MCMC. We anticipate that GPO will prove useful for robust and efficient inversion of high-dimensional and nonlinear models of neuroimaging data.

Unsupervised modeling of cell morphology dynamics for time-lapse microscopy.

Analysis of cellular phenotypes in large imaging data sets conventionally involves supervised statistical methods, which require user-annotated training data. This paper introduces an unsupervised learning method, based on temporally constrained combinatorial clustering, for automatic prediction of cell morphology classes in time-resolved images. We applied the unsupervised method to diverse fluorescent markers and screening data and validated accurate classification of human cell phenotypes, demonstrating fully objective data labeling in image-based systems biology.

Automatic single cell segmentation on highly multiplexed tissue images.

The combination of mass cytometry and immunohistochemistry (IHC) enables new histopathological imaging methods in which dozens of proteins and protein modifications can be visualized simultaneously in a single tissue section. The power of multiplexing combined with spatial information and quantification was recently illustrated on breast cancer tissue and was described as next-generation IHC. Robust, accurate, and high-throughput cell segmentation is crucial for the analysis of this new generation of IHC data. To this end, we propose a watershed-based cell segmentation, which uses a nuclear marker and multiple membrane markers, the latter automatically selected based on their correlation. In comparison with the state-of-the-art segmentation pipelines, which are only using a single marker for object detection, we could show that the use of multiple markers can significantly increase the segmentation power, and thus, multiplexed information should be used and not ignored during the segmentation. Furthermore, we provide a novel, user-friendly open-source toolbox for the automatic segmentation of multiplexed histopathological images.

Near-optimal experimental design for model selection in systems biology.

MOTIVATION: Biological systems are understood through iterations of modeling and experimentation. Not all experiments, however, are equally valuable for predictive modeling. This study introduces an efficient method for experimental design aimed at selecting dynamical models from data. Motivated by biological applications, the method enables the design of crucial experiments: it determines a highly informative selection of measurement readouts and time points. RESULTS: We demonstrate formal guarantees of design efficiency on the basis of previous results. By reducing our task to the setting of graphical models, we prove that the method finds a near-optimal design selection with a polynomial number of evaluations. Moreover, the method exhibits the best polynomial-complexity constant approximation factor, unless P = NP. We measure the performance of the method in comparison with established alternatives, such as ensemble non-centrality, on example models of different complexity. Efficient design accelerates the loop between modeling and experimentation: it enables the inference of complex mechanisms, such as those controlling central metabolic operation. AVAILABILITY: Toolbox 'NearOED' available with source code under GPL on the Machine Learning Open Source Software Web site (mloss.org).

Generic comparison of protein inference engines.

Protein identifications, instead of peptide-spectrum matches, constitute the biologically relevant result of shotgun proteomics studies. How to appropriately infer and report protein identifications has triggered a still ongoing debate. This debate has so far suffered from the lack of appropriate performance measures that allow us to objectively assess protein inference approaches. This study describes an intuitive, generic and yet formal performance measure and demonstrates how it enables experimentalists to select an optimal protein inference strategy for a given collection of fragment ion spectra. We applied the performance measure to systematically explore the benefit of excluding possibly unreliable protein identifications, such as single-hit wonders. Therefore, we defined a family of protein inference engines by extending a simple inference engine by thousands of pruning variants, each excluding a different specified set of possibly unreliable identifications. We benchmarked these protein inference engines on several data sets representing different proteomes and mass spectrometry platforms. Optimally performing inference engines retained all high confidence spectral evidence, without posterior exclusion of any type of protein identifications. Despite the diversity of studied data sets consistently supporting this rule, other data sets might behave differently. In order to ensure maximal reliable proteome coverage for data sets arising in other studies we advocate abstaining from rigid protein inference rules, such as exclusion of single-hit wonders, and instead consider several protein inference approaches and assess these with respect to the presented performance measure in the specific application context.

Cancer genetics-guided discovery of serum biomarker signatures for diagnosis and prognosis of prostate cancer.

A key barrier to the realization of personalized medicine for cancer is the identification of biomarkers. Here we describe a two-stage strategy for the discovery of serum biomarker signatures corresponding to specific cancer-causing mutations and its application to prostate cancer (PCa) in the context of the commonly occurring phosphatase and tensin homolog (PTEN) tumor-suppressor gene inactivation. In the first stage of our approach, we identified 775 N-linked glycoproteins from sera and prostate tissue of wild-type and Pten-null mice. Using label-free quantitative proteomics, we showed that Pten inactivation leads to measurable perturbations in the murine prostate and serum glycoproteome. Following bioinformatic prioritization, in a second stage we applied targeted proteomics to detect and quantify 39 human ortholog candidate biomarkers in the sera of PCa patients and control individuals. The resulting proteomic profiles were analyzed by machine learning to build predictive regression models for tissue PTEN status and diagnosis and grading of PCa. Our approach suggests a general path to rational cancer biomarker discovery and initial validation guided by cancer genetics and based on the integration of experimental mouse models, proteomics-based technologies, and computational modeling.

Fundamentals of Arthroscopic Surgery Training and beyond: a reinforcement learning exploration and benchmark.

PURPOSE: This work presents FASTRL, a benchmark set of instrument manipulation tasks adapted to the domain of reinforcement learning and used in simulated surgical training. This benchmark enables and supports the design and training of human-centric reinforcement learning agents which assist and evaluate human trainees in surgical practice. METHODS: Simulation tasks from the Fundamentals of Arthroscopic Surgery Training (FAST) program are adapted to the reinforcement learning setting for the purpose of training virtual agents that are capable of providing assistance and scoring to the surgical trainees. A skill performance assessment protocol is presented based on the trained virtual agents. RESULTS: The proposed benchmark suite presents an API for training reinforcement learning agents in the context of arthroscopic skill training. The evaluation scheme based on both heuristic and learned reward functions robustly recovers the ground truth ranking on a diverse test set of human trajectories. CONCLUSION: The presented benchmark enables the exploration of a novel reinforcement learning-based approach to skill performance assessment and in-procedure assistance for simulated surgical training scenarios. The evaluation protocol based on the learned reward model demonstrates potential for evaluating the performance of surgical trainees in simulation.

Uncertainty-aware MR-based CT synthesis for robust proton therapy planning of brain tumour.

BACKGROUND AND PURPOSE: Deep learning techniques excel in MR-based CT synthesis, but missing uncertainty prediction limits its clinical use in proton therapy. We developed an uncertainty-aware framework and evaluated its efficiency in robust proton planning. MATERIALS AND METHODS: A conditional generative-adversarial network was trained on 64 brain tumour patients with paired MR-CT images to generate synthetic CTs (sCT) from combined T1-T2 MRs of three orthogonal planes. A Bayesian neural network predicts Laplacian distributions for all voxels with parameters (µ, b). A robust proton plan was optimized using three sCTs of µ and µ±b. The dosimetric differences between the plan from sCT (sPlan) and the recalculated plan (rPlan) on planning CT (pCT) were quantified for each patient. The uncertainty-aware robust plan was compared to conventional robust (global ± 3 %) and non-robust plans. RESULTS: In 8-fold cross-validation, sCT-pCT image differences (Mean-Absolute-Error) were 80.84 ± 9.84HU (body), 35.78 ± 6.07HU (soft tissues) and 221.88 ± 31.69HU (bones), with Dice scores of 90.33 ± 2.43 %, 95.13 ± 0.80 %, and 85.53 ± 4.16 %, respectively. The uncertainty distribution positively correlated with absolute prediction error (Correlation Coefficient: 0.62 ± 0.01). The uncertainty-conditioned robust optimisation improved the rPlan-sPlan agreement, e.g., D95 absolute difference (CTV) was 1.10 ± 1.24 % compared to conventional (1.64 ± 2.71 %) and non-robust (2.08 ± 2.96 %) optimisation. This trend was consistent across all target and organs-at-risk indexes. CONCLUSION: The enhanced framework incorporates 3D uncertainty prediction and generates high-quality sCTs from MR images. The framework also facilitates conditioned robust optimisation, bolstering proton plan robustness against network prediction errors. The innovative feature of uncertainty visualisation and robust analyses contribute to evaluating sCT clinical utility for individual patients.

Variational Bayesian mixed-effects inference for classification studies.

Multivariate classification algorithms are powerful tools for predicting cognitive or pathophysiological states from neuroimaging data. Assessing the utility of a classifier in application domains such as cognitive neuroscience, brain-computer interfaces, or clinical diagnostics necessitates inference on classification performance at more than one level, i.e., both in individual subjects and in the population from which these subjects were sampled. Such inference requires models that explicitly account for both fixed-effects (within-subjects) and random-effects (between-subjects) variance components. While models of this sort are standard in mass-univariate analyses of fMRI data, they have not yet received much attention in multivariate classification studies of neuroimaging data, presumably because of the high computational costs they entail. This paper extends a recently developed hierarchical model for mixed-effects inference in multivariate classification studies and introduces an efficient variational Bayes approach to inference. Using both synthetic and empirical fMRI data, we show that this approach is equally simple to use as, yet more powerful than, a conventional t-test on subject-specific sample accuracies, and computationally much more efficient than previous sampling algorithms and permutation tests. Our approach is independent of the type of underlying classifier and thus widely applicable. The present framework may help establish mixed-effects inference as a future standard for classification group analyses.

A supervised learning approach for Crohn's disease detection using higher-order image statistics and a novel shape asymmetry measure.

Increasing incidence of Crohn's disease (CD) in the Western world has made its accurate diagnosis an important medical challenge. The current reference standard for diagnosis, colonoscopy, is time-consuming and invasive while magnetic resonance imaging (MRI) has emerged as the preferred noninvasive procedure over colonoscopy. Current MRI approaches assess rate of contrast enhancement and bowel wall thickness, and rely on extensive manual segmentation for accurate analysis. We propose a supervised learning method for the identification and localization of regions in abdominal magnetic resonance images that have been affected by CD. Low-level features like intensity and texture are used with shape asymmetry information to distinguish between diseased and normal regions. Particular emphasis is laid on a novel entropy-based shape asymmetry method and higher-order statistics like skewness and kurtosis. Multi-scale feature extraction renders the method robust. Experiments on real patient data show that our features achieve a high level of accuracy and perform better than two competing methods.

Weakly supervised inference of personalized heart meshes based on echocardiography videos.

Echocardiography provides recordings of the heart chamber size and function and is a central tool for non-invasive diagnosis of heart diseases. It produces high-dimensional video data with substantial stochasticity in the measurements, which frequently prove difficult to interpret. To address this challenge, we propose an automated framework to enable the inference of a high resolution personalized 4D (3D plus time) surface mesh of the cardiac structures from 2D echocardiography video data. Inferring such shape models arises as a key step towards accurate personalized simulation that enables an automated assessment of the cardiac chamber morphology and function. The proposed method is trained using only unpaired echocardiography and heart mesh videos to find a mapping between these distinct visual domains in a self-supervised manner. The resulting model produces personalized 4D heart meshes, which exhibit a high correspondence with the input echocardiography videos. Furthermore, the 4D heart meshes enable the automatic extraction of echocardiographic variables, such as ejection fraction, myocardial muscle mass, and volumetric changes of chamber volumes over time with high temporal resolution.

Decoding the perception of pain from fMRI using multivariate pattern analysis.

Pain is known to comprise sensory, cognitive, and affective aspects. Despite numerous previous fMRI studies, however, it remains open which spatial distribution of activity is sufficient to encode whether a stimulus is perceived as painful or not. In this study, we analyzed fMRI data from a perceptual decision-making task in which participants were exposed to near-threshold laser pulses. Using multivariate analyses on different spatial scales, we investigated the predictive capacity of fMRI data for decoding whether a stimulus had been perceived as painful. Our analysis yielded a rank order of brain regions: during pain anticipation, activity in the periaqueductal gray (PAG) and orbitofrontal cortex (OFC) afforded the most accurate trial-by-trial discrimination between painful and non-painful experiences; whereas during the actual stimulation, primary and secondary somatosensory cortex, anterior insula, dorsolateral and ventrolateral prefrontal cortex, and OFC were most discriminative. The most accurate prediction of pain perception from the stimulation period, however, was enabled by the combined activity in pain regions commonly referred to as the 'pain matrix'. Our results demonstrate that the neural representation of (near-threshold) pain is spatially distributed and can be best described at an intermediate spatial scale. In addition to its utility in establishing structure-function mappings, our approach affords trial-by-trial predictions and thus represents a step towards the goal of establishing an objective neuronal marker of pain perception.