Post-hoc standardisation of parametric T1 maps in cardiovascular magnetic resonance imaging: a proof-of-concept.

BACKGROUND: In cardiovascular magnetic resonance imaging parametric T1 mapping lacks universally valid reference values. This limits its extensive use in the clinical routine. The aim of this work was the introduction of our self-developed Magnetic Resonance Imaging Software for Standardization (MARISSA) as a post-hoc standardisation approach. METHODS: Our standardisation approach minimises the bias of confounding parameters (CPs) on the base of regression models. 214 healthy subjects with 814 parametric T1 maps were used for training those models on the CPs: age, gender, scanner and sequence. The training dataset included both sex, eleven different scanners and eight different sequences. The regression model type and four other adjustable standardisation parameters were optimised among 240 tested settings to achieve the lowest coefficient of variation, as measure for the inter-subject variability, in the mean T1 value across the healthy test datasets (HTE, N = 40, 156 T1 maps). The HTE were then compared to 135 patients with left ventricular hypertrophy including hypertrophic cardiomyopathy (HCM, N = 112, 121 T1 maps) and amyloidosis (AMY, N = 24, 24 T1 maps) after applying the best performing standardisation pipeline (BPSP) to evaluate the diagnostic accuracy. FINDINGS: The BPSP reduced the COV of the HTE from 12.47% to 5.81%. Sensitivity and specificity reached 95.83% / 91.67% between HTE and AMY, 71.90% / 72.44% between HTE and HCM, and 87.50% / 98.35% between HCM and AMY. INTERPRETATION: Regarding the BPSP, MARISSA enabled the comparability of T1 maps independently of CPs while keeping the discrimination of healthy and patient groups as found in literature. FUNDING: This study was supported by the BMBF / DZHK.

Efficient Radial-Shell Model for 3D Tumor Spheroid Dynamics with Radiotherapy.

Understanding the complex dynamics of tumor growth to develop more efficient therapeutic strategies is one of the most challenging problems in biomedicine. Three-dimensional (3D) tumor spheroids, reflecting avascular microregions within a tumor, are an advanced in vitro model system to assess the curative effect of combinatorial radio(chemo)therapy. Tumor spheroids exhibit particular crucial pathophysiological characteristics such as a radial oxygen gradient that critically affect the sensitivity of the malignant cell population to treatment. However, spheroid experiments remain laborious, and determining long-term radio(chemo)therapy outcomes is challenging. Mathematical models of spheroid dynamics have the potential to enhance the informative value of experimental data, and can support study design; however, they typically face one of two limitations: while non-spatial models are computationally cheap, they lack the spatial resolution to predict oxygen-dependent radioresponse, whereas models that describe spatial cell dynamics are computationally expensive and often heavily parameterized, impeding the required calibration to experimental data. Here, we present an effectively one-dimensional mathematical model based on the cell dynamics within and across radial spheres which fully incorporates the 3D dynamics of tumor spheroids by exploiting their approximate rotational symmetry. We demonstrate that this radial-shell (RS) model reproduces experimental spheroid growth curves of several cell lines with and without radiotherapy, showing equal or better performance than published models such as 3D agent-based models. Notably, the RS model is sufficiently efficient to enable multi-parametric optimization within previously reported and/or physiologically reasonable ranges based on experimental data. Analysis of the model reveals that the characteristic change of dynamics observed in experiments at small spheroid volume originates from the spatial scale of cell interactions. Based on the calibrated parameters, we predict the spheroid volumes at which this behavior should be observable. Finally, we demonstrate how the generic parameterization of the model allows direct parameter transfer to 3D agent-based models.

Digital sufficiency: conceptual considerations for ICTs on a finite planet.

ICT hold significant potential to increase resource and energy efficiencies and contribute to a circular economy. Yet unresolved is whether the aggregated net effect of ICT overall mitigates or aggravates environmental burdens. While the savings potentials have been explored, drivers that prevent these and possible counter measures have not been researched thoroughly. The concept digital sufficiency constitutes a basis to understand how ICT can become part of the essential environmental transformation. Digital sufficiency consists of four dimensions, each suggesting a set of strategies and policy proposals: (a) hardware sufficiency, which aims for fewer devices needing to be produced and their absolute energy demand being kept to the lowest level possible to perform the desired tasks; (b) software sufficiency, which covers ensuring that data traffic and hardware utilization during application are kept as low as possible; (c) user sufficiency, which strives for users applying digital devices frugally and using ICT in a way that promotes sustainable lifestyles; and (d) economic sufficiency, which aspires to digitalization supporting a transition to an economy characterized not by economic growth as the primary goal but by sufficient production and consumption within planetary boundaries. The policies for hardware and software sufficiency are relatively easily conceivable and executable. Policies for user and economic sufficiency are politically more difficult to implement and relate strongly to policies for environmental transformation in general. This article argues for comprehensive policies for digital sufficiency, which are indispensible if ICT are to play a beneficial role in overall environmental transformation.

Lazy Luna: Extendible software for multilevel reader comparison in cardiovascular magnetic resonance imaging.

BACKGROUND AND OBJECTIVES: Cardiovascular Magnetic Resonance (CMR) imaging is a growing field with increasing diagnostic utility in clinical routine. Quantitative diagnostic parameters are typically calculated based on contours or points provided by readers, e.g. natural intelligences (NI) such as clinicians or researchers, and artificial intelligences (AI). As clinical applications multiply, evaluating the precision and reproducibility of quantitative parameters becomes increasingly important. Although segmentation challenges for AIs and guidelines for clinicians provide quality assessments and regulation, the methods ought to be combined and streamlined for clinical applications. The goal of the developed software, Lazy Luna (LL), is to offer a flexible evaluation tool that is readily extendible to new sequences and scientific endeavours. METHODS: An interface was designed for LL, which allows for comparing annotated CMR images. Geometric objects ensure precise calculations of metric values and clinical results regardless of whether annotations originate from AIs or NIs. A graphical user interface (GUI) is provided to make the software available to non-programmers. The GUI allows for an interactive inspection of image datasets as well as implementing tracing procedures, which follow statistical reader differences in clinical results to their origins in individual image contours. The backend software builds on a set of meta-classes, which can be extended to new imaging sequences and clinical parameters. Following an agile development procedure with clinical feedback allows for a quick implementation of new classes, figures and tables for evaluation. RESULTS: Two application cases present LL's extendibility to clinical evaluation and AI development contexts. The first concerns T1 parametric mapping images segmented by two expert readers. Quantitative result differences are traced to reveal typical segmentation dissimilarities from which these differences originate. The meta-classes are extended to this new application scenario. The second applies to the open source Late Gadolinium Enhancement (LGE) quantification challenge for AI developers "Emidec", which illustrates LL's usability as open source software. CONCLUSION: The presented software Lazy Luna allows for an automated multilevel comparison of readers as well as identifying qualitative reasons for statistical reader differences. The open source software LL can be extended to new application cases in the future.

Translating principles of quality control to cardiovascular magnetic resonance: assessing quantitative parameters of the left ventricle in a large cohort.

Cardiac magnetic resonance (CMR) examinations require standardization to achieve reproducible results. Therefore, quality control as known as in other industries such as in-vitro diagnostics, could be of essential value. One such method is the statistical detection of long-time drifts of clinically relevant measurements. Starting in 2010, reports from all CMR examinations of a high-volume center were stored in a hospital information system. Quantitative parameters of the left ventricle were analyzed over time with moving averages of different window sizes. Influencing factors on the acquisition and on the downstream analysis were captured. 26,902 patient examinations were exported from the clinical information system. The moving median was compared to predefined tolerance ranges, which revealed an overall of 50 potential quality relevant changes ("alerts") in SV, EDV and LVM. Potential causes such as change of staff, scanner relocation and software changes were found not to be causal of the alerts. No other influencing factors were identified retrospectively. Statistical quality assurance systems based on moving average control charts may provide an important step towards reliability of quantitative CMR. A prospective evaluation is needed for the effective root cause analysis of quality relevant alerts.

Introduction of a cascaded segmentation pipeline for parametric T1 mapping in cardiovascular magnetic resonance to improve segmentation performance.

The manual and often time-consuming segmentation of the myocardium in cardiovascular magnetic resonance is increasingly automated using convolutional neural networks (CNNs). This study proposes a cascaded segmentation (CASEG) approach to improve automatic image segmentation quality. First, an object detection algorithm predicts a bounding box (BB) for the left ventricular myocardium whose 1.5 times enlargement defines the region of interest (ROI). Then, the ROI image section is fed into a U-Net based segmentation. Two CASEG variants were evaluated: one using the ROI cropped image solely (cropU) and the other using a 2-channel-image additionally containing the original BB image section (crinU). Both were compared to a classical U-Net segmentation (refU). All networks share the same hyperparameters and were tested on basal and midventricular slices of native and contrast enhanced (CE) MOLLI T1 maps. Dice Similarity Coefficient improved significantly (p < 0.05) in cropU and crinU compared to refU (81.06%, 81.22%, 72.79% for native and 80.70%, 79.18%, 71.41% for CE data), while no significant improvement (p < 0.05) was achieved in the mean absolute error of the T1 time (11.94 ms, 12.45 ms, 14.22 ms for native and 5.32 ms, 6.07 ms, 5.89 ms for CE data). In conclusion, CASEG provides an improved geometric concordance but needs further improvement in the quantitative outcome.

Is cell segregation like oil and water: Asymptotic versus transitory regime.

Understanding the segregation of cells is crucial to answer questions about tissue formation in embryos or tumor progression. Steinberg proposed that separation of cells can be compared to the separation of two liquids. Such a separation is well described by the Cahn-Hilliard (CH) equations and the segregation indices exhibit an algebraic decay with exponent 1/3 with respect to time. Similar exponents are also observed in cell-based models. However, the scaling behavior in these numerical models is usually only examined in the asymptotic regime and these models have not been directly applied to actual cell segregation data. In contrast, experimental data also reveals other scaling exponents and even slow logarithmic scaling laws. These discrepancies are commonly attributed to the effects of collective motion or velocity-dependent interactions. By calibrating a 2D cellular automaton (CA) model which efficiently implements a dynamic variant of the differential adhesion hypothesis to 2D experimental data from Méhes et al., we reproduce the biological cell segregation experiments with just adhesive forces. The segregation in the cellular automaton model follows a logarithmic scaling initially, which is in contrast to the proposed algebraic scaling with exponent 1/3. However, within the less than two orders of magnitudes in time which are observable in the experiments, a logarithmic scaling may appear as a pseudo-algebraic scaling. In particular, we demonstrate that the cellular automaton model can exhibit a range of exponents ≤1/3 for such a pseudo-algebraic scaling. Moreover, the time span of the experiment falls into the transitory regime of the cellular automaton rather than the asymptotic one. We additionally develop a method for the calibration of the 2D Cahn-Hilliard model and find a match with experimental data within the transitory regime of the Cahn-Hilliard model with exponent 1/4. On the one hand this demonstrates that the transitory behavior is relevant for the experiment rather than the asymptotic one. On the other hand this corroborates the ambiguity of the scaling behavior, when segregation processes can be only observed on short time spans.

Modeling age-specific incidence of colon cancer via niche competition.

Cancer development is a multistep process often starting with a single cell in which a number of epigenetic and genetic alterations have accumulated thus transforming it into a tumor cell. The progeny of such a single benign tumor cell expands in the tissue and can at some point progress to malignant tumor cells until a detectable tumor is formed. The dynamics from the early phase of a single cell to a detectable tumor with billions of tumor cells are complex and still not fully resolved, not even for the well-known prototype of multistage carcinogenesis, the adenoma-adenocarcinoma sequence of colorectal cancer. Mathematical models of such carcinogenesis are frequently tested and calibrated based on reported age-specific incidence rates of cancer, but they usually require calibration of four or more parameters due to the wide range of processes these models aim to reflect. We present a cell-based model, which focuses on the competition between wild-type and tumor cells in colonic crypts, with which we are able reproduce epidemiological incidence rates of colon cancer. Additionally, the fraction of cancerous tumors with precancerous lesions predicted by the model agree with clinical estimates. The correspondence between model and reported data suggests that the fate of tumor development is majorly determined by the early phase of tumor growth and progression long before a tumor becomes detectable. Due to the focus on the early phase of tumor development, the model has only a single fit parameter, the time scale set by an effective replacement rate of stem cells in the crypt. We find this effective rate to be considerable smaller than the actual replacement rate, which implies that the time scale is limited by the processes succeeding clonal conversion of crypts.

Introduction of Lazy Luna an automatic software-driven multilevel comparison of ventricular function quantification in cardiovascular magnetic resonance imaging.

Cardiovascular magnetic resonance imaging is the gold standard for cardiac function assessment. Quantification of clinical results (CR) requires precise segmentation. Clinicians statistically compare CRs to ensure reproducibility. Convolutional Neural Network developers compare their results via metrics. Aim: Introducing software capable of automatic multilevel comparison. A multilevel analysis covering segmentations and CRs builds on a generic software backend. Metrics and CRs are calculated with geometric accuracy. Segmentations and CRs are connected to track errors and their effects. An interactive GUI makes the software accessible to different users. The software's multilevel comparison was tested on a use case based on cardiac function assessment. The software shows good reader agreement in CRs and segmentation metrics (Dice > 90%). Decomposing differences by cardiac position revealed excellent agreement in midventricular slices: > 90% but poorer segmentations in apical (> 71%) and basal slices (> 74%). Further decomposition by contour type locates the largest millilitre differences in the basal right cavity (> 3 ml). Visual inspection shows these differences being caused by different basal slice choices. The software illuminated reader differences on several levels. Producing spreadsheets and figures concerning metric values and CR differences was automated. A multilevel reader comparison is feasible and extendable to other cardiac structures in the future.

Plasticity within Aldehyde Dehydrogenase-Positive Cells Determines Prostate Cancer Radiosensitivity.

Tumor heterogeneity and cellular plasticity are key determinants of tumor progression, metastatic spread, and therapy response driven by the cancer stem cell (CSC) population. Within the current study, we analyzed irradiation-induced plasticity within the aldehyde dehydrogenase (ALDH)-positive (ALDH+) population in prostate cancer. The radiosensitivity of xenograft tumors derived from ALDH+ and ALDH-negative (ALDH-) cells was determined with local tumor control analyses and demonstrated different dose-response profiles, time to relapse, and focal adhesion signaling. The transcriptional heterogeneity was analyzed in pools of 10 DU145 and PC3 cells with multiplex gene expression analyses and illustrated a higher degree of heterogeneity within the ALDH+ population that even increases upon irradiation in comparison with ALDH- cells. Phenotypic conversion and clonal competition were analyzed with fluorescence protein-labeled cells to distinguish cellular origins in competitive three-dimensional cultures and xenograft tumors. We found that the ALDH+ population outcompetes ALDH- cells and drives tumor growth, in particular upon irradiation. The observed dynamics of the cellular state compositions between ALDH+ and ALDH- cells in vivo before and after tumor irradiation was reproduced by a probabilistic Markov compartment model that incorporates cellular plasticity, clonal competition, and phenotype-specific radiosensitivities. Transcriptional analyses indicate that the cellular conversion from ALDH- into ALDH+ cells within xenograft tumors under therapeutic pressure was partially mediated through induction of the transcriptional repressor SNAI2. In summary, irradiation-induced cellular conversion events are present in xenograft tumors derived from prostate cancer cells and may be responsible for radiotherapy failure. IMPLICATIONS: The increase of ALDH+ cells with stem-like features in prostate xenograft tumors after local irradiation represents a putative cellular escape mechanism inducing tumor radioresistance.

Model-Based Prediction of an Effective Adhesion Parameter Guiding Multi-Type Cell Segregation.

The process of cell-sorting is essential for development and maintenance of tissues. Mathematical modeling can provide the means to analyze the consequences of different hypotheses about the underlying mechanisms. With the Differential Adhesion Hypothesis, Steinberg proposed that cell-sorting is determined by quantitative differences in cell-type-specific intercellular adhesion strengths. An implementation of the Differential Adhesion Hypothesis is the Differential Migration Model by Voss-Böhme and Deutsch. There, an effective adhesion parameter was derived analytically for systems with two cell types, which predicts the asymptotic sorting pattern. However, the existence and form of such a parameter for more than two cell types is unclear. Here, we generalize analytically the concept of an effective adhesion parameter to three and more cell types and demonstrate its existence numerically for three cell types based on in silico time-series data that is produced by a cellular-automaton implementation of the Differential Migration Model. Additionally, we classify the segregation behavior using statistical learning methods and show that the estimated effective adhesion parameter for three cell types matches our analytical prediction. Finally, we demonstrate that the effective adhesion parameter can resolve a recent dispute about the impact of interfacial adhesion, cortical tension and heterotypic repulsion on cell segregation.

Sperm chemotaxis in marine species is optimal at physiological flow rates according theory of filament surfing.

Sperm of marine invertebrates have to find eggs cells in the ocean. Turbulent flows mix sperm and egg cells up to the millimeter scale; below this, active swimming and chemotaxis become important. Previous work addressed either turbulent mixing or chemotaxis in still water. Here, we present a general theory of sperm chemotaxis inside the smallest eddies of turbulent flow, where signaling molecules released by egg cells are spread into thin concentration filaments. Sperm cells 'surf' along these filaments towards the egg. External flows make filaments longer, but also thinner. These opposing effects set an optimal flow strength. The optimum predicted by our theory matches flow measurements in shallow coastal waters. Our theory quantitatively agrees with two previous fertilization experiments in Taylor-Couette chambers and provides a mechanistic understanding of these early experiments. 'Surfing along concentration filaments' could be a paradigm for navigation in complex environments in the presence of turbulent flow.

Three-dimensional billiards: Visualization of regular structures and trapping of chaotic trajectories.

The dynamics in three-dimensional (3D) billiards leads, using a Poincaré section, to a four-dimensional map, which is challenging to visualize. By means of the recently introduced 3D phase-space slices, an intuitive representation of the organization of the mixed phase space with regular and chaotic dynamics is obtained. Of particular interest for applications are constraints to classical transport between different regions of phase space which manifest in the statistics of Poincaré recurrence times. For a 3D paraboloid billiard we observe a slow power-law decay caused by long-trapped trajectories, which we analyze in phase space and in frequency space. Consistent with previous results for 4D maps, we find that (i) trapping takes place close to regular structures outside the Arnold web, (ii) trapping is not due to a generalized island-around-island hierarchy, and (iii) the dynamics of sticky orbits is governed by resonance channels which extend far into the chaotic sea. We find clear signatures of partial transport barriers. Moreover, we visualize the geometry of stochastic layers in resonance channels explored by sticky orbits.

Decision making improves sperm chemotaxis in the presence of noise.

To navigate their surroundings, cells rely on sensory input that is corrupted by noise. In cells performing chemotaxis, such noise arises from the stochastic binding of signalling molecules at low chemoattractant concentrations. We reveal a fundamental relationship between the speed of chemotactic steering and the strength of directional fluctuations that result from the amplification of noise in a chemical input signal. This relation implies a trade-off between steering that is slow and reliable, and steering that is fast but less reliable. We show that dynamic switching between these two modes of steering can substantially increase the probability to find a target, such as an egg to be found by sperm cells. This decision making confers no advantage in the absence of noise, but is beneficial when chemical signals are detectable, yet characterized by low signal-to-noise ratios. The latter applies at intermediate distances from a target, where signalling molecules are diluted, thus defining a 'noise zone' that cells have to cross. Our results explain decision making observed in recent experiments on sea urchin sperm chemotaxis. More generally, our theory demonstrates how decision making enables chemotactic agents to cope with high levels of noise in gradient sensing by dynamically adjusting the persistence length of a biased random walk.

Bifurcations of families of 1D-tori in 4D symplectic maps.

The regular structures of a generic 4d symplectic map with a mixed phase space are organized by one-parameter families of elliptic 1d-tori. Such families show prominent bends, gaps, and new branches. We explain these features in terms of bifurcations of the families when crossing a resonance. For these bifurcations, no external parameter has to be varied. Instead, the longitudinal frequency, which varies along the family, plays the role of the bifurcation parameter. As an example, we study two coupled standard maps by visualizing the elliptic and hyperbolic 1d-tori in a 3d phase-space slice, local 2d projections, and frequency space. The observed bifurcations are consistent with the analytical predictions previously obtained for quasi-periodically forced oscillators. Moreover, the new families emerging from such a bifurcation form the skeleton of the corresponding resonance channel.

Visualization and comparison of classical structures and quantum states of four-dimensional maps.

For generic 4D symplectic maps we propose the use of 3D phase-space slices, which allow for the global visualization of the geometrical organization and coexistence of regular and chaotic motion. As an example, we consider two coupled standard maps. The advantages of the 3D phase-space slices are presented in comparison to standard methods, such as 3D projections of orbits, the frequency analysis, and a chaos indicator. Quantum mechanically, the 3D phase-space slices allow for the comparison of Husimi functions of eigenstates of 4D maps with classical phase-space structures. This confirms the semiclassical eigenfunction hypothesis for 4D maps.