Likelihood based observability analysis and confidence intervals for predictions of dynamic models

Mechanistic dynamic models of biochemical networks such as Ordinary Differential Equations (ODEs) contain unknown parameters like the reaction rate constants and the initial concentrations of the compounds. The large number of parameters as well as their nonlinear impact on the model responses hamper the determination of confidence regions for parameter estimates. At the same time, classical approaches translating the uncertainty of the parameters into confidence intervals for model predictions are hardly feasible. In this article it is shown that a so-called prediction profile likelihood yields reliable confidence intervals for model predictions, despite arbitrarily complex and high-dimensional shapes of the confidence regions for the estimated parameters. Prediction confidence intervals of the dynamic states allow a data-based observability analysis. The approach renders the issue of sampling a high-dimensional parameter space into evaluating one-dimensional prediction spaces. The method is also applicable if there are non-identifiable parameters yielding to some insufficiently specified model predictions that can be interpreted as non-observability. Moreover, a validation profile likelihood is introduced that should be applied when noisy validation experiments are to be interpreted. The properties and applicability of the prediction and validation profile likelihood approaches are demonstrated by two examples, a small and instructive ODE model describing two consecutive reactions, and a realistic ODE model for the MAP kinase signal transduction pathway. The presented general approach constitutes a concept for observability analysis and for generating reliable confidence intervals of model predictions, not only, but especially suitable for mathematical models of biological systems

Inguinal Lymph Node Metastasis of a Primary Serous Papillary Carcinoma of the Peritoneum One Year after CRS and HIPEC

Background: Primary peritoneal serous papillary carcinoma is a rare malignant epithelial tumor which was first described in 1959. Peritoneal serous papillary carcinoma arises from the peritoneal epithelium and originates from a single or multicentric focus of the peritoneum involving the peritoneum of the abdomen and pelvis. The involvement of retroperitoneal lymph nodes occurs in 64% of the patients diagnosed with this malignancy. So far, there is no report about inguinal lymph node metastasis in this disease. Case Report: We present a rare case of a 63-year-old female patient who developed singular inguinal lymph node metastasis 1 year after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy due to peritoneal serous papillary carcinoma. The lymph node metastasis was found by computed tomography (CT) scan and was resected and histologically confirmed. The postoperative course was uneventful, and the patient was discharged on postoperative day 1. The last CT scan 24 months after initial cytoreduction and 12 months after lymph node resection showed no further tumor recurrence. Conclusion: This case report should raise the awareness of potentially unexpected presentation of extraperitoneal metastasis and highlights the importance of patient follow-up including clinical examination and CT scans of thorax/abdomen/pelvis following a systematic schedule

In silico labeling reveals the time-dependent label half-life and transit-time in dynamical systems

Background: Mathematical models of dynamical systems facilitate the computation of characteristic properties that are not accessible experimentally. In cell biology, two main properties of interest are (1) the time-period a protein is accessible to other molecules in a certain state - its half-life - and (2) the time it spends when passing through a subsystem - its transit-time. We discuss two approaches to quantify the half-life, present the novel method of in silico labeling, and introduce the label half-life and label transit-time. The developed method has been motivated by laboratory tracer experiments. To investigate the kinetic properties and behavior of a substance of interest, we computationally label this species in order to track it throughout its life cycle. The corresponding mathematical model is extended by an additional set of reactions for the labeled species, avoiding any double-counting within closed circuits, correcting for the influences of upstream fluxes, and taking into account combinatorial multiplicity for complexes or reactions with several reactants or products. A profile likelihood approach is used to estimate confidence intervals on the label half-life and transit-time. Results: Application to the JAK-STAT signaling pathway in Epo-stimulated BaF3-EpoR cells enabled the calculation of the time-dependent label half-life and transit-time of STAT species. The results were robust against parameter uncertainties. Conclusions: Our approach renders possible the estimation of species and label half-lives and transit-times. It is applicable to large non-linear systems and an implementation is provided within the PottersWheel modeling framework (http://www.potterswheel.de)

Verordnungsentwurf der EU-Kommission zur künftigen Förderung der Entwicklung des ländlichen Raums: Vergleich zur derzeitigen Ausgestaltung der Förderpolitik und Kommentierung der Änderungen

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Analysis of Single-Cell RNA-Seq Identifies Cell-Cell Communication Associated with Tumor Characteristics

Tumor ecosystems are composed of multiple cell types that communicate by ligand-receptor interactions. Targeting ligand-receptor interactions (for instance, with immune checkpoint inhibitors) can provide significant benefits for patients. However, our knowledge of which interactions occur in a tumor and how these interactions affect outcome is still limited. We present an approach to characterize communication by ligand-receptor interactions across all cell types in a microenvironment using single-cell RNA sequencing. We apply this approach to identify and compare the ligand-receptor interactions present in six syngeneic mouse tumor models. To identify interactions potentially associated with outcome, we regress interactions against phenotypic measurements of tumor growth rate. In addition, we quantify ligand-receptor interactions between T cell subsets and their relation to immune infiltration using a publicly available human melanoma dataset. Overall, this approach provides a tool for studying cell-cell interactions, their variability across tumors, and their relationship to outcome. Tumors are composed of cancer cells and many non-malignant cell types, such as immune and stromal cells. To better understand how all cell types in a tumor cooperate to facilitate malignant growth, Kumar et al. studied communication between cells via ligand and receptor interactions using single-cell data and computational modeling. Keywords: computational analysis; single-cell RNA sequencing; cell-cell communication; ligand-receptor interaction; tumor microenvironment; syngeneic mouse models; cancer patient samplesNational Institute of General Medical Sciences (U.S.) (Grant T32-GM008334)National Cancer Institute (U.S.) (Grant U01-CA215798

A Study in Dataset Pruning for Image Super-Resolution

In image Super-Resolution (SR), relying on large datasets for training is a double-edged sword. While offering rich training material, they also demand substantial computational and storage resources. In this work, we analyze dataset pruning to solve these challenges. We introduce a novel approach that reduces a dataset to a core-set of training samples, selected based on their loss values as determined by a simple pre-trained SR model. By focusing the training on just 50\% of the original dataset, specifically on the samples characterized by the highest loss values, we achieve results comparable to or surpassing those obtained from training on the entire dataset. Interestingly, our analysis reveals that the top 5\% of samples with the highest loss values negatively affect the training process. Excluding these samples and adjusting the selection to favor easier samples further enhances training outcomes. Our work opens new perspectives to the untapped potential of dataset pruning in image SR. It suggests that careful selection of training data based on loss-value metrics can lead to better SR models, challenging the conventional wisdom that more data inevitably leads to better performance

Less is More: Proxy Datasets in NAS approaches

Neural Architecture Search (NAS) defines the design of Neural Networks as a search problem. Unfortunately, NAS is computationally intensive because of various possibilities depending on the number of elements in the design and the possible connections between them. In this work, we extensively analyze the role of the dataset size based on several sampling approaches for reducing the dataset size (unsupervised and supervised cases) as an agnostic approach to reduce search time. We compared these techniques with four common NAS approaches in NAS-Bench-201 in roughly 1,400 experiments on CIFAR-100. One of our surprising findings is that in most cases we can reduce the amount of training data to 25\%, consequently reducing search time to 25\%, while at the same time maintaining the same accuracy as if training on the full dataset. Additionally, some designs derived from subsets out-perform designs derived from the full dataset by up to 22 p.p. accuracy

AudioCLIP: Extending CLIP to Image, Text and Audio

In the past, the rapidly evolving field of sound classification greatly benefited from the application of methods from other domains. Today, we observe the trend to fuse domain-specific tasks and approaches together, which provides the community with new outstanding models. In this work, we present an extension of the CLIP model that handles audio in addition to text and images. Our proposed model incorporates the ESResNeXt audio-model into the CLIP framework using the AudioSet dataset. Such a combination enables the proposed model to perform bimodal and unimodal classification and querying, while keeping CLIP's ability to generalize to unseen datasets in a zero-shot inference fashion. AudioCLIP achieves new state-of-the-art results in the Environmental Sound Classification (ESC) task, out-performing other approaches by reaching accuracies of 90.07% on the UrbanSound8K and 97.15% on the ESC-50 datasets. Further it sets new baselines in the zero-shot ESC-task on the same datasets 68.78% and 69.40%, respectively). Finally, we also assess the cross-modal querying performance of the proposed model as well as the influence of full and partial training on the results. For the sake of reproducibility, our code is published.Comment: submitted to GCPR 202