@article{MuellerLausserWilhelmetal.2020, author = {M{\"u}ller, Andr{\´e} and Lausser, Ludwig and Wilhelm, Adalbert and Ropinski, Timo and Platzer, Matthias and Neumann, Heiko and Kestler, Hans A.}, title = {A perceptually optimised bivariate visualisation scheme for high-dimensional fold-change data}, volume = {15}, journal = {Advances in Data Analysis and Classification}, number = {2}, publisher = {Springer}, address = {Berlin}, issn = {1862-5355}, doi = {https://doi.org/10.1007/s11634-020-00416-5}, pages = {463 -- 480}, year = {2020}, abstract = {Visualising data as diagrams using visual attributes such as colour, shape, size, and orientation is challenging. In particular, large data sets demand graphical display as an essential step in the analysis. In order to achieve comprehension often different attributes need to be displayed simultaneously. In this work a comprehensible bivariate, perceptually optimised visualisation scheme for high-dimensional data is proposed and evaluated. It can be used to show fold changes together with confidence values within a single diagram. The visualisation scheme consists of two parts: a uniform, symmetric, two-sided colour scale and a patch grid representation. Evaluation of uniformity and symmetry of the two-sided colour scale was performed in comparison to a standard RGB scale by twenty-five observers. Furthermore, the readability of the generated map was validated and compared to a bivariate heat map scheme.}, language = {en} } @article{BuchholzLausserSchenketal.2024, author = {Buchholz, Malte and Lausser, Ludwig and Schenk, Miriam and Earl, Julie and Lawlor, Rita T. and Scarpa, Aldo and Sanjuanbenito, Alfonso and Carrato, Alfredo and Malats, Nuria and Tjaden, Christine and Giese, Nathalia A. and B{\"u}chler, Markus and Hackert, Thilo and Kestler, Hans A. and Gress, Thomas M.}, title = {Combined analysis of a serum mRNA/miRNA marker signature and CA 19-9 for timely and accurate diagnosis of recurrence after resection of pancreatic ductal adenocarcinoma: A prospective multicenter cohort study}, volume = {13}, journal = {United European Gastroenterology Journal}, number = {3}, publisher = {Wiley}, address = {Hoboken}, issn = {2050-6414}, doi = {https://doi.org/10.1002/ueg2.12676}, pages = {353 -- 363}, year = {2024}, abstract = {Background and Aims Timely and accurate detection of tumor recurrence in pancreatic ductal adenocarcinoma (PDAC) patients is an urgent and unmet medical need. This study aimed to develop a noninvasive molecular diagnostic procedure for the detection of recurrence after PDAC resection based on quantification of circulating mRNA and miRNA biomarkers in serum samples. Methods In a multicentric study, serum samples from a total of 146 patients were prospectively collected after resection. Samples were classified into a "No Evidence of Disease" and a "Recurrence" group based on clinical follow-up data. A multianalyte biomarker panel was composed of mRNAs and miRNA markers and simultaneously analyzed in serum samples using custom microfluidic qPCR arrays (TaqMan array cards). A diagnostic algorithm was developed combining a 7-gene marker signature with CA19-9 data. Results The best-performing marker combination achieved 90\% diagnostic accuracy in predicting the presence of tumor recurrence (98\% sensitivity; 84\% specificity), clearly outperforming the singular CA 19-9 analysis. Moreover, time series data obtained by analyzing successively collected samples from 5 patients during extended follow-up suggested that molecular diagnosis has the potential to detect recurrence earlier than routine clinical procedures. Conclusions TaqMan array card measurements were found to be biologically valid and technically reproducible. The BioPac multianalyte marker panel is capable of sensitive and accurate detection of recurrence in patients resected for PDAC using a simple blood test. This could allow a closer follow-up using shorter time intervals than currently used for imaging, thus potentially prompting an earlier work-up with additional modalities to allow for earlier therapeutic intervention. This study provides a promising approach for improved postoperative monitoring of resected PDAC patients, which is an urgent and unmet clinical need.}, language = {en} } @article{LausserKubisRottbaueretal.2018, author = {Lausser, Ludwig and Kubis, Lea and Rottbauer, Wolfgang and Frank, Derk and Just, Steffen and Kestler, Hans A.}, title = {Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species}, volume = {8 (2018)}, pages = {158}, journal = {Biomolecules}, number = {4}, publisher = {MDPI}, address = {Basel}, issn = {2218-273X}, doi = {https://doi.org/10.3390/biom8040158}, year = {2018}, abstract = {Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract but precise high-level characterization of experimental findings. In this work, we provide a large-scale analysis of seven weak contractility/heart failure genotypes of the model organism zebrafish which all share a weak contractility phenotype. In supervised classification experiments, we screen for discriminative patterns that distinguish between observable phenotypes (homozygous mutant individuals) as well as wild-type (homozygous wild-types) and carriers (heterozygous individuals). As the method of choice we use semantic multi-classifier systems, a knowledge-based approach which constructs hypotheses from a predefined vocabulary of high-level terms (e.g., Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or Gene Ontology (GO) terms). Evaluating these models leads to a compact description of the underlying processes and guides the screening for new molecular markers of heart failure. Furthermore, we were able to independently corroborate the identified processes in Wistar rats.}, language = {en} } @article{KustermannMantaPaoneetal.2018, author = {Kustermann, Monika and Manta, Linda and Paone, Christoph and Kustermann, Jochen and Lausser, Ludwig and Wiesner, Cora and Eichinger, Ludwig and Clemen, Christoph S. and Schr{\"o}der, Rolf and Kestler, Hans A. and Sandri, Marco and Rottbauer, Wolfgang and Just, Steffen}, title = {Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo}, volume = {14 (2018)}, journal = {Autophagy}, number = {11}, publisher = {Taylor \& Francis}, address = {London}, issn = {1554-8627}, doi = {https://doi.org/10.1080/15548627.2018.1491491}, pages = {1911 -- 1927}, year = {2018}, abstract = {VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We found that targeted inactivation of either Vcp or Washc4, led to progressive impairment of cardiac and skeletal muscle function, structure and cytoarchitecture without interfering with the differentiation of both organ systems. Notably, loss of Vcp resulted in compromised protein degradation via the proteasome and the macroautophagy/autophagy machinery, whereas Washc4 deficiency did not affect the function of the ubiquitin-proteasome system (UPS) but caused ER stress and interfered with autophagy function in vivo. In summary, our findings provide novel insights into the in vivo functions of Vcp and its novel interactor Washc4 and their particular and distinct roles during proteostasis in striated muscle cells.}, language = {en} } @article{HuehneKesslerFuerstbergeretal.2018, author = {H{\"u}hne, Rolf and Kessler, Viktor and F{\"u}rstberger, Axel and Werle, Silke D. and Platzer, Matthias and S{\"u}hnel, J{\"u}rgen and Lausser, Ludwig and Kestler, Hans A.}, title = {3D Network exploration and visualisation for lifespan data}, volume = {19 (2018)}, pages = {390}, journal = {BMC Bioinformatics}, publisher = {BioMed Central}, address = {London}, issn = {1471-2105}, doi = {https://doi.org/10.1186/s12859-018-2393-x}, year = {2018}, abstract = {Background The Ageing Factor Database AgeFactDB contains a large number of lifespan observations for ageing-related factors like genes, chemical compounds, and other factors such as dietary restriction in different organisms. These data provide quantitative information on the effect of ageing factors from genetic interventions or manipulations of lifespan. Analysis strategies beyond common static database queries are highly desirable for the inspection of complex relationships between AgeFactDB data sets. 3D visualisation can be extremely valuable for advanced data exploration. Results Different types of networks and visualisation strategies are proposed, ranging from basic networks of individual ageing factors for a single species to complex multi-species networks. The augmentation of lifespan observation networks by annotation nodes, like gene ontology terms, is shown to facilitate and speed up data analysis. We developed a new Javascript 3D network viewer JANet that provides the proposed visualisation strategies and has a customised interface for AgeFactDB data. It enables the analysis of gene lists in combination with AgeFactDB data and the interactive visualisation of the results. Conclusion Interactive 3D network visualisation allows to supplement complex database queries by a visually guided exploration process. The JANet interface allows gaining deeper insights into lifespan data patterns not accessible by common database queries alone. These concepts can be utilised in many other research fields.}, language = {en} } @article{LausserSchaeferKestler2018, author = {Lausser, Ludwig and Sch{\"a}fer, Lisa M. and Kestler, Hans A.}, title = {Ordinal Classifiers Can Fail on Repetitive Class Structures}, volume = {4 (2018)}, journal = {Archives of Data Science, Series A}, number = {1}, publisher = {KIT Scientific Publishing}, address = {Karlsruhe}, issn = {2363-9881}, doi = {https://doi.org/10.5445/KSP/1000085951/25}, year = {2018}, abstract = {Ordinal classifiers are constrained classification algorithms that assume a predefined (total) order of the class labels to be reflected in the feature space of a dataset. This information is used to guide the training of ordinal classifiers and might lead to an improved classification performance. Incorrect assumptions on the order of a dataset can result in diminished detection rates. Ordinal classifiers can, therefore, be used to screen for ordinal class structures within a feature representation. While it was shown that algorithms could in principle reject incorrect class orderings, it is unclear if all remaining candidate orders reflect real ordinal structures in feature space. In this work we characterize the decision regions induced by ordinal classifiers. We show that they can fulfill different criteria that might be considered as ordinal reflections. These criteria are mainly determined by the connectedness and the neighborhood of the decision regions. We evaluate them for ordinal classifier cascades constructed from binary classifiers. We show that depending on the type of base classifier they bear the risk of not rejecting non ordinal, like partial repetitive, structures.}, language = {en} } @article{LausserSchaeferSchirraetal.2019, author = {Lausser, Ludwig and Sch{\"a}fer, Lisa M. and Schirra, Lyn-Rouven and Szekely, Robin and Schmid, Florian and Kestler, Hans A.}, title = {Assessing phenotype order in molecular data}, volume = {9}, pages = {11746}, journal = {Scientific Reports}, publisher = {Springer Nature}, address = {London}, issn = {2045-2322}, doi = {https://doi.org/10.1038/s41598-019-48150-z}, year = {2019}, abstract = {Biological entities are key elements of biomedical research. Their definition and their relationships are important in areas such as phylogenetic reconstruction, developmental processes or tumor evolution. Hypotheses about relationships like phenotype order are often postulated based on prior knowledge or belief. Evidence on a molecular level is typically unknown and whether total orders are reflected in the molecular measurements is unclear or not assessed. In this work we propose a method that allows a fast and exhaustive screening for total orders in large datasets. We utilise ordinal classifier cascades to identify discriminable molecular representations of the phenotypes. These classifiers are constrained by an order hypothesis and are highly sensitive to incorrect assumptions. Two new error bounds, which are introduced and theoretically proven, lead to a substantial speed-up and allow the application to large collections of many phenotypes. In our experiments we show that by exhaustively evaluating all possible candidate orders, we are able to identify phenotype orders that best coincide with the high-dimensional molecular profiles.}, language = {en} } @article{LausserSzekelyKlimmeketal.2020, author = {Lausser, Ludwig and Szekely, Robin and Klimmek, Attila and Schmid, Florian and Kestler, Hans A.}, title = {Constraining classifiers in molecular analysis}, volume = {17 (2020)}, pages = {20190612}, journal = {Journal of the Royal Society Interface}, subtitle = {invariance and robustness}, number = {163}, publisher = {The Royal Society}, address = {London}, issn = {1742-5662}, doi = {https://doi.org/10.1098/rsif.2019.0612}, year = {2020}, abstract = {Analysing molecular profiles requires the selection of classification models that can cope with the high dimensionality and variability of these data. Also, improper reference point choice and scaling pose additional challenges. Often model selection is somewhat guided by ad hoc simulations rather than by sophisticated considerations on the properties of a categorization model. Here, we derive and report four linked linear concept classes/models with distinct invariance properties for high-dimensional molecular classification. We can further show that these concept classes also form a half-order of complexity classes in terms of Vapnik-Chervonenkis dimensions, which also implies increased generalization abilities. We implemented support vector machines with these properties. Surprisingly, we were able to attain comparable or even superior generalization abilities to the standard linear one on the 27 investigated RNA-Seq and microarray datasets. Our results indicate that a priori chosen invariant models can replace ad hoc robustness analysis by interpretable and theoretically guaranteed properties in molecular categorization.}, language = {en} } @article{BellmannLausserKestleretal.2022, author = {Bellmann, Peter and Lausser, Ludwig and Kestler, Hans A. and Schwenker, Friedhelm}, title = {A Theoretical Approach to Ordinal Classification}, volume = {12 (2022)}, pages = {1815}, journal = {Applied Sciences}, subtitle = {Feature Space-Based Definition and Classifier-Independent Detection of Ordinal Class Structures}, number = {4}, publisher = {MDPI}, address = {Basel}, issn = {2076-3417}, doi = {https://doi.org/10.3390/app12041815}, year = {2022}, abstract = {Ordinal classification (OC) is a sub-discipline of multi-class classification (i.e., including at least three classes), in which the classes constitute an ordinal structure. Applications of ordinal classification can be found, for instance, in the medical field, e.g., with the class labels order, early stage-intermediate stage-final stage, corresponding to the task of classifying different stages of a certain disease. While the field of OC was continuously enhanced, e.g., by designing and adapting appropriate classification models as well as performance metrics, there is still a lack of a common mathematical definition for OC tasks. More precisely, in general, a classification task is defined as an OC task, solely based on the corresponding class label names. However, an ordinal class structure that is identified based on the class labels is not necessarily reflected in the corresponding feature space. In contrast, naturally any kind of multi-class classification task can consist of a set of arbitrary class labels that form an ordinal structure which can be observed in the current feature space. Based on this simple observation, in this work, we present our generalised approach towards an intuitive working definition for OC tasks, which is based on the corresponding feature space and allows a classifier-independent detection of ordinal class structures. To this end, we introduce and discuss novel, OC-specific theoretical concepts. Moreover, we validate our proposed working definition in combination with a set of traditionally ordinal and traditionally non-ordinal data sets, and provide the results of the corresponding detection algorithm. Additionally, we motivate our theoretical concepts, based on an illustrative evaluation of one of the oldest and most popular machine learning data sets, i.e., on the traditionally non-ordinal Fisher's Iris data set.}, language = {en} } @article{WeidnerSchwabWerleetal.2021, author = {Weidner, Felix M. and Schwab, Julian D. and Werle, Silke D. and Ikonomi, Nensi and Lausser, Ludwig and Kestler, Hans A.}, title = {Capturing dynamic relevance in Boolean networks using graph theoretical measures}, volume = {37}, journal = {Bioinformatics}, number = {20}, publisher = {Oxford University Press}, address = {Oxford}, issn = {1460-2059}, doi = {https://doi.org/10.1093/bioinformatics/btab277}, pages = {3530 -- 3537}, year = {2021}, abstract = {Motivation Interaction graphs are able to describe regulatory dependencies between compounds without capturing dynamics. In contrast, mathematical models that are based on interaction graphs allow to investigate the dynamics of biological systems. However, since dynamic complexity of these models grows exponentially with their size, exhaustive analyses of the dynamics and consequently screening all possible interventions eventually becomes infeasible. Thus, we designed an approach to identify dynamically relevant compounds based on the static network topology. Results Here, we present a method only based on static properties to identify dynamically influencing nodes. Coupling vertex betweenness and determinative power, we could capture relevant nodes for changing dynamics with an accuracy of 75\% in a set of 35 published logical models. Further analyses of the selected compounds' connectivity unravelled a new class of not highly connected nodes with high impact on the networks' dynamics, which we call gatekeepers. We validated our method's working concept on logical models, which can be readily scaled up to complex interaction networks, where dynamic analyses are not even feasible.}, language = {en} } @article{AnderlStraubLausserLombardietal.2021, author = {Anderl-Straub, Sarah and Lausser, Ludwig and Lombardi, Jolina and Uttner, Ingo and Fassbender, Klaus and Fliessbach, Klaus and Huppertz, Hans-J{\"u}rgen and Jahn, Holger and Kornhuber, Johannes and Obrig, Hellmuth and Schneider, Anja and Semler, Elisa and Synofzik, Matthis and Danek, Adrian and Prudlo, Johannes and Kassubek, Jan and Landwehrmeyer, Bernhard and Lauer, Martin and Volk, Alexander E. and Wiltfang, Jens and Diehl-Schmid, Janine and Ludolph, Albert C. and Schroeter, Matthias and Kestler, Hans A. and Otto, Markus}, title = {Predicting disease progression in behavioral variant frontotemporal dementia}, volume = {13}, pages = {e12262}, journal = {Alzheimer's \& Dementia: Diagnosis, Assessment \& Disease Monitoring}, number = {1}, publisher = {Alzheimer's Association}, address = {Chicago}, issn = {2352-8729}, doi = {https://doi.org/10.1002/dad2.12262}, year = {2021}, abstract = {Introduction The behavioral variant of frontotemporal dementia (bvFTD) is a rare neurodegenerative disease. Reliable predictors of disease progression have not been sufficiently identified. We investigated multivariate magnetic resonance imaging (MRI) biomarker profiles for their predictive value of individual decline. Methods One hundred five bvFTD patients were recruited from the German frontotemporal lobar degeneration (FTLD) consortium study. After defining two groups ("fast progressors" vs. "slow progressors"), we investigated the predictive value of MR brain volumes for disease progression rates performing exhaustive screenings with multivariate classification models. Results We identified areas that predict disease progression rate within 1 year. Prediction measures revealed an overall accuracy of 80\% across our 50 top classification models. Especially the pallidum, middle temporal gyrus, inferior frontal gyrus, cingulate gyrus, middle orbitofrontal gyrus, and insula occurred in these models. Discussion Based on the revealed marker combinations an individual prognosis seems to be feasible. This might be used in clinical studies on an individualized progression model.}, language = {en} } @article{NiederschweibererSchaeferSinghetal.2021, author = {Niederschweiberer, Moritz and Schaefer, Patrick M. and Singh, Larry N. and Lausser, Ludwig and Bhosale, Devyani and Hesse, Raphael and Calzia, Enrico and Kestler, Hans A. and Rueck, Angelika and Wallace, Douglas and Einem, Bjoern von and Arnim, Christine A. F. von}, title = {NADH Fluorescence Lifetime Imaging Microscopy Reveals Selective Mitochondrial Dysfunction in Neurons Overexpressing Alzheimer's Disease-Related Proteins}, volume = {8}, pages = {671274}, journal = {Frontiers in Molecular Biosciences}, publisher = {Frontiers}, address = {Lausanne}, issn = {2296-889X}, doi = {https://doi.org/10.3389/fmolb.2021.671274}, year = {2021}, abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, affects globally more than 30 million people suffering from cognitive deficits and neuropsychiatric symptoms. Substantial evidence for the involvement of mitochondrial dysfunction in the development and/or progression of AD has been shown in addition to the pathological hallmarks amyloid beta (Aβ) and tau. Still, the selective vulnerability and associated selective mitochondrial dysfunction cannot even be resolved to date. We aimed at optically quantifying mitochondrial function on a single-cell level in primary hippocampal neuron models of AD, unraveling differential involvement of cell and mitochondrial populations in amyloid precursor protein (APP)-associated mitochondrial dysfunction. NADH lifetime imaging is a highly sensitive marker-free method with high spatial resolution. However, deciphering cellular bioenergetics of complex cells like primary neurons has still not succeeded yet. To achieve this, we combined highly sensitive NADH lifetime imaging with respiratory inhibitor treatment, allowing characterization of mitochondrial function down to even the subcellular level in primary neurons. Measuring NADH lifetime of the same neuron before and after respiratory treatment reveals the metabolic delta, which can be taken as a surrogate for cellular redox capacity. Correlating NADH lifetime delta with overexpression strength of Aβ-related proteins on the single-cell level, we could verify the important role of intracellular Aβ-mediated mitochondrial toxicity. Subcellularly, we could demonstrate a higher respiration in neuronal somata in general than dendrites, but a similar impairment of somatic and dendritic mitochondria in our AD models. This illustrates the power of NADH lifetime imaging in revealing mitochondrial function on a single and even subcellular level and its potential to shed light into bioenergetic alterations in neuropsychiatric diseases and beyond.}, language = {en} } @article{KrausLausserKuhnetal.2018, author = {Kraus, Johann M. and Lausser, Ludwig and Kuhn, Peter and Jobst, Franz and Bock, Michaela and Halanke, Carolin and Hummel, Michael and Heuschmann, Peter and Kestler, Hans A.}, title = {Big data and precision medicine}, volume = {6 (2018)}, journal = {International Journal of Data Science and Analytics}, subtitle = {challenges and strategies with healthcare data}, number = {3}, publisher = {Springer Nature}, address = {Cham}, issn = {2364-4168}, doi = {https://doi.org/10.1007/s41060-018-0095-0}, pages = {241 -- 249}, year = {2018}, language = {en} } @article{HesseEinemWagneretal.2018, author = {Hesse, Raphael and Einem, Bjoern von and Wagner, Franziska and Bott, Patricia and Schwanzar, Daniel and Jackson, Rosemary and F{\"o}hr, Karl Josef and Lausser, Ludwig and Kroker, Katja S. and Proepper, Christian and Walther, Paul and Kestler, Hans A. and Spires-Jones, Tara and Boeckers, Tobias and Rosenbrock, Holger and Arnim, Christine A. F. von}, title = {sAPPβ and sAPPα increase structural complexity and E/I input ratio in primary hippocampal neurons and alter Ca2+ homeostasis and CREB1-signaling}, volume = {(2018)}, journal = {Experimental Neurology}, number = {304}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0014-4886}, doi = {https://doi.org/10.1016/j.expneurol.2018.02.010}, pages = {1 -- 13}, year = {2018}, language = {en} } @article{LausserSzekelyKestler2020, author = {Lausser, Ludwig and Szekely, Robin and Kestler, Hans A.}, title = {Chained correlations for feature selection}, volume = {14}, journal = {Advances in Data Analysis and Classification}, number = {4}, publisher = {Springer}, address = {Berlin}, issn = {1862-5355}, pages = {871 -- 884}, year = {2020}, abstract = {Data-driven algorithms stand and fall with the availability and quality of existing data sources. Both can be limited in high-dimensional settings (n≫m). For example, supervised learning algorithms designed for molecular pheno- or genotyping are restricted to samples of the corresponding diagnostic classes. Samples of other related entities, such as arise in differential diagnosis, are usually not utilized in this learning scheme. Nevertheless, they might provide domain knowledge on the background or context of the original diagnostic task. In this work, we discuss the possibility of incorporating samples of foreign classes in the training of diagnostic classification models that can be related to the task of differential diagnosis. Especially in heterogeneous data collections comprising multiple diagnostic categories, the foreign ones can change the magnitude of available samples. More precisely, we utilize this information for the internal feature selection process of diagnostic models. We propose the use of chained correlations of original and foreign diagnostic classes. This method allows the detection of intermediate foreign classes by evaluating the correlation between class labels and features for each pair of original and foreign categories. Interestingly, this criterion does not require direct comparisons of the initial diagnostic groups and therefore, might be suitable for settings with restricted data access.}, language = {en} } @article{LausserSchaeferWerleetal.2020, author = {Lausser, Ludwig and Sch{\"a}fer, Lisa M. and Werle, Silke D. and Kestler, Angelika M. R. and Kestler, Hans A.}, title = {Detecting Ordinal Subcascades}, volume = {52}, journal = {Neural Processing Letters}, number = {3}, publisher = {Springer Science+Business Media}, address = {Dordrecht}, issn = {1573-773X}, doi = {https://doi.org/10.1007/s11063-020-10362-0}, pages = {2583 -- 2605}, year = {2020}, abstract = {Ordinal classifier cascades are constrained by a hypothesised order of the semantic class labels of a dataset. This order determines the overall structure of the decision regions in feature space. Assuming the correct order on these class labels will allow a high generalisation performance, while an incorrect one will lead to diminished results. In this way ordinal classifier systems can facilitate explorative data analysis allowing to screen for potential candidate orders of the class labels. Previously, we have shown that screening is possible for total orders of all class labels. However, as datasets might comprise samples of ordinal as well as non-ordinal classes, the assumption of a total ordering might be not appropriate. An analysis of subsets of classes is required to detect such hidden ordinal substructures. In this work, we devise a novel screening procedure for exhaustive evaluations of all order permutations of all subsets of classes by bounding the number of enumerations we have to examine. Experiments with multi-class data from diverse applications revealed ordinal substructures that generate new and support known relations.}, language = {en} } @article{LausserSzekelySchmidetal.2022, author = {Lausser, Ludwig and Szekely, Robin and Schmid, Florian and Maucher, Markus and Kestler, Hans A.}, title = {Efficient cross-validation traversals in feature subset selection}, volume = {12}, pages = {21485}, journal = {Scientific Reports}, publisher = {Springer Nature}, address = {London}, issn = {2045-2322}, doi = {https://doi.org/10.1038/s41598-022-25942-4}, year = {2022}, abstract = {Sparse and robust classification models have the potential for revealing common predictive patterns that not only allow for categorizing objects into classes but also for generating mechanistic hypotheses. Identifying a small and informative subset of features is their main ingredient. However, the exponential search space of feature subsets and the heuristic nature of selection algorithms limit the coverage of these analyses, even for low-dimensional datasets. We present methods for reducing the computational complexity of feature selection criteria allowing for higher efficiency and coverage of screenings. We achieve this by reducing the preparation costs of high-dimensional subsets O(nm2) to those of one-dimensional ones O(m2). Our methods are based on a tight interaction between a parallelizable cross-validation traversal strategy and distance-based classification algorithms and can be used with any product distance or kernel. We evaluate the traversal strategy exemplarily in exhaustive feature subset selection experiments (perfect coverage). Its runtime, fitness landscape, and predictive performance are analyzed on publicly available datasets. Even in low-dimensional settings, we achieve approximately a 15-fold increase in exhaustively generating distance matrices for feature combinations bringing a new level of evaluations into reach.}, language = {en} } @article{WerleIkonomiLausseretal.2023, author = {Werle, Silke D. and Ikonomi, Nensi and Lausser, Ludwig and Kestler, Annika M. T. U. and Weidner, Felix M. and Schwab, Julian D. and Maier, Julia and Buchholz, Malte and Gress, Thomas M. and Kestler, Angelika M. R. and Kestler, Hans A.}, title = {A systems biology approach to define mechanisms, phenotypes, and drivers in PanNETs with a personalized perspective}, volume = {9}, pages = {22}, journal = {npj Systems Biology and Applications}, number = {1}, publisher = {Springer}, address = {Heidelberg}, issn = {2056-7189}, doi = {https://doi.org/10.1038/s41540-023-00283-8}, year = {2023}, abstract = {AbstractPancreatic neuroendocrine tumors (PanNETs) are a rare tumor entity with largely unpredictable progression and increasing incidence in developed countries. Molecular pathways involved in PanNETs development are still not elucidated, and specific biomarkers are missing. Moreover, the heterogeneity of PanNETs makes their treatment challenging and most approved targeted therapeutic options for PanNETs lack objective responses. Here, we applied a systems biology approach integrating dynamic modeling strategies, foreign classifier tailored approaches, and patient expression profiles to predict PanNETs progression as well as resistance mechanisms to clinically approved treatments such as the mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We set up a model able to represent frequently reported PanNETs drivers in patient cohorts, such as Menin-1 (MEN1), Death domain associated protein (DAXX), Tuberous Sclerosis (TSC), as well as wild-type tumors. Model-based simulations suggested drivers of cancer progression as both first and second hits after MEN1 loss. In addition, we could predict the benefit of mTORC1 inhibitors on differentially mutated cohorts and hypothesize resistance mechanisms. Our approach sheds light on a more personalized prediction and treatment of PanNET mutant phenotypes.}, language = {en} } @inproceedings{KruegerLausser2023, author = {Kr{\"u}ger, Max and Lausser, Ludwig}, title = {Identifying Key Features in Aggregated Real-Life AIS-Messages for Classification of Maritime Vessels by Random Forests}, booktitle = {2023 26th International Conference on Information Fusion (FUSION)}, publisher = {IEEE}, address = {Piscataway}, doi = {https://doi.org/10.23919/FUSION52260.2023.10224109}, year = {2023}, language = {en} } @inproceedings{LausserSzekelyKessleretal.2018, author = {Lausser, Ludwig and Szekely, Robin and Kessler, Viktor and Schwenker, Friedhelm}, title = {Selecting Features from Foreign Classes}, booktitle = {Artificial Neural Networks in Pattern Recognition: 8th IAPR TC3 Workshop, ANNPR 2018, Siena, Italy, September 19-21, 2018: Proceedings}, editor = {Pancioni, Luca and Schwenker, Friedhelm and Trentin, Edmondo}, publisher = {Springer}, address = {Cham}, isbn = {978-3-319-99978-4}, doi = {https://doi.org/10.1007/978-3-319-99978-4_5}, pages = {66 -- 77}, year = {2018}, language = {en} } @inproceedings{BellmannLausserKestler2021, author = {Bellmann, Peter and Lausser, Ludwig and Kestler, Hans A.}, title = {Experimental Analysis of Bidirectional Pairwise Ordinal Classifier Cascades}, booktitle = {Structural, Syntactic, and Statistical Pattern Recognition: Joint IAPR International Workshops, S+SSPR 2020, Padua, Italy, January 21-22, 2021: Proceedings}, editor = {Torsello, Andrea and Rossi, Luca and Pelillo, Marcello and Biggio, Battista and Robles-Kelly, Antonio}, publisher = {Springer}, address = {Cham}, isbn = {978-3-030-73973-7}, doi = {https://doi.org/10.1007/978-3-030-73973-7_6}, pages = {55 -- 64}, year = {2021}, language = {en} } @inproceedings{BellmannLausserKestleretal.2021, author = {Bellmann, Peter and Lausser, Ludwig and Kestler, Hans A. and Schwenker, Friedhelm}, title = {Introducing Bidirectional Ordinal Classifier Cascades Based on a Pain Intensity Recognition Scenario}, booktitle = {Pattern Recognition: ICPR International Workshops and Challenges: Virtual Event, January 10-15, 2021: Proceedings, Part VI}, editor = {Del Bimbo, Alberto and Cucchiara, Rita and Sclaroff, Stan and Farinella, Giovanni Maria and Mei, Tao and Bertini, Marco and Escalante, Hugo Jair and Vezzani, Roberto}, publisher = {Springer}, address = {Cham}, isbn = {978-3-030-68780-9}, doi = {https://doi.org/10.1007/978-3-030-68780-9_58}, pages = {773 -- 787}, year = {2021}, language = {en} } @article{ThiamLausserKlothetal.2023, author = {Thiam, Patrick and Lausser, Ludwig and Kloth, Christopher and Blaich, Daniel and Liebold, Andreas and Beer, Meinrad and Kestler, Hans A.}, title = {Unsupervised domain adaptation for the detection of cardiomegaly in cross-domain chest X-ray images}, volume = {6}, pages = {1056422}, journal = {Frontiers in Artificial Intelligence}, publisher = {Frontiers Media}, address = {Lausanne}, issn = {2624-8212}, doi = {https://doi.org/10.3389/frai.2023.1056422}, year = {2023}, abstract = {In recent years, several deep learning approaches have been successfully applied in the field of medical image analysis. More specifically, different deep neural network architectures have been proposed and assessed for the detection of various pathologies based on chest X-ray images. While the performed assessments have shown very promising results, most of them consist in training and evaluating the performance of the proposed approaches on a single data set. However, the generalization of such models is quite limited in a cross-domain setting, since a significant performance degradation can be observed when these models are evaluated on data sets stemming from different medical centers or recorded under different protocols. The performance degradation is mostly caused by the domain shift between the training set and the evaluation set. To alleviate this problem, different unsupervised domain adaptation approaches are proposed and evaluated in the current work, for the detection of cardiomegaly based on chest X-ray images, in a cross-domain setting. The proposed approaches generate domain invariant feature representations by adapting the parameters of a model optimized on a large set of labeled samples, to a set of unlabeled images stemming from a different data set. The performed evaluation points to the effectiveness of the proposed approaches, since the adapted models outperform optimized models which are directly applied to the evaluation sets without any form of domain adaptation.}, language = {en} } @article{WeidnerSchwabWerleetal.2022, author = {Weidner, Felix M. and Schwab, Julian D. and Werle, Silke D. and Ikonomi, Nensi and Lausser, Ludwig and Kestler, Hans A.}, title = {Response to the letter to the editor: On the feasibility of dynamical analysis of network models of biochemical regulation}, volume = {38}, journal = {Bioinformatics}, number = {14}, publisher = {Oxford University Press}, address = {Oxford}, issn = {1367-4811}, doi = {https://doi.org/10.1093/bioinformatics/btac318}, pages = {3676}, year = {2022}, language = {en} } @article{SeufferleinLausserSteinetal.2024, author = {Seufferlein, Thomas and Lausser, Ludwig and Stein, Alexander and Arnold, Dirk and Prager, Gerald and Kasper-Virchow, Stefan and Niedermeier, Michael and M{\"u}ller, Lothar and Kubicka, Stefan and K{\"o}nig, Alexander and B{\"u}chner-Steudel, Petra and Wille, Kai and Berger, Andreas W. and Kestler, Angelika M. R. and Kraus, Johann M. and Werle, Silke D. and Perkhofer, Lukas and Ettrich, Thomas J. and Kestler, Hans A.}, title = {Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer—Results of the prospective multicenter PERMAD trial}, volume = {19}, pages = {e0304324}, journal = {PLOS ONE}, number = {6}, publisher = {PLOS}, address = {San Francisco}, issn = {1932-6203}, doi = {https://doi.org/10.1371/journal.pone.0304324}, year = {2024}, abstract = {Background Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. Patients and methods 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). Results Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2\% accuracy, 71.8\% sensitivity, and 82.5\% specificity. Conclusions We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.}, language = {en} } @article{LausserSzekelyKestler2024, author = {Lausser, Ludwig and Szekely, Robin and Kestler, Hans A.}, title = {Permutation-invariant linear classifiers}, volume = {113}, journal = {Machine Learning}, number = {10}, publisher = {Springer}, address = {Dordrecht}, issn = {1573-0565}, doi = {https://doi.org/10.1007/s10994-024-06561-8}, pages = {7195 -- 7221}, year = {2024}, abstract = {Invariant concept classes form the backbone of classification algorithms immune to specific data transformations, ensuring consistent predictions regardless of these alterations. However, this robustness can come at the cost of limited access to the original sample information, potentially impacting generalization performance. This study introduces an addition to these classes—the permutation-invariant linear classifiers. Distinguished by their structural characteristics, permutation-invariant linear classifiers are unaffected by permutations on feature vectors, a property not guaranteed by other non-constant linear classifiers. The study characterizes this new concept class, highlighting its constant capacity, independent of input dimensionality. In practical assessments using linear support vector machines, the permutation-invariant classifiers exhibit superior performance in permutation experiments on artificial datasets and real mutation profiles. Interestingly, they outperform general linear classifiers not only in permutation experiments but also in permutation-free settings, surpassing unconstrained counterparts. Additionally, findings from real mutation profiles support the significance of tumor mutational burden as a biomarker.}, language = {en} } @unpublished{GanzAmmelingRosbachetal.2024, author = {Ganz, Jonathan and Ammeling, Jonas and Rosbach, Emely and Lausser, Ludwig and Bertram, Christof and Breininger, Katharina and Aubreville, Marc}, title = {Is Self-Supervision Enough? Benchmarking Foundation Models Against End-to-End Training for Mitotic Figure Classification}, publisher = {arXiv}, address = {Ithaca}, doi = {https://doi.org/10.48550/arXiv.2412.06365}, year = {2024}, abstract = {Foundation models (FMs), i.e., models trained on a vast amount of typically unlabeled data, have become popular and available recently for the domain of histopathology. The key idea is to extract semantically rich vectors from any input patch, allowing for the use of simple subsequent classification networks potentially reducing the required amounts of labeled data, and increasing domain robustness. In this work, we investigate to which degree this also holds for mitotic figure classification. Utilizing two popular public mitotic figure datasets, we compared linear probing of five publicly available FMs against models trained on ImageNet and a simple ResNet50 end-to-end-trained baseline. We found that the end-to-end-trained baseline outperformed all FM-based classifiers, regardless of the amount of data provided. Additionally, we did not observe the FM-based classifiers to be more robust against domain shifts, rendering both of the above assumptions incorrect.}, language = {en} } @inproceedings{LausserBertramKlopfleischetal.2023, author = {Lausser, Ludwig and Bertram, Christof and Klopfleisch, Robert and Aubreville, Marc}, title = {Limits of Human Expert Ensembles in Mitosis Multi-expert Ground Truth Generation}, booktitle = {Bildverarbeitung f{\"u}r die Medizin 2023: Proceedings, German Workshop on Medical Image Computing, Braunschweig, July 2-4, 2023}, editor = {Deserno, Thomas Martin and Handels, Heinz and Maier, Andreas and Maier-Hein, Klaus H. and Palm, Christoph and Tolxdorff, Thomas}, publisher = {Springer Vieweg}, address = {Wiesbaden}, isbn = {978-3-658-41657-7}, doi = {https://doi.org/10.1007/978-3-658-41657-7_27}, pages = {116 -- 121}, year = {2023}, language = {en} } @article{KubisSchwabWerleetal.2018, author = {Kubis, Lea and Schwab, Julian D. and Werle, Silke D. and Lausser, Ludwig and T{\"u}mpel, Stefan and Pfister, Astrid S. and K{\"u}hl, Michael and Kestler, Hans A.}, title = {A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells}, volume = {13}, pages = {e0195126}, journal = {PLOS ONE}, number = {3}, publisher = {PLOS}, address = {San Francisco}, issn = {1932-6203}, doi = {https://doi.org/10.1371/journal.pone.0195126}, year = {2018}, abstract = {Aging is a complex biological process, which determines the life span of an organism. Insulin-like growth factor (IGF) and Wnt signaling pathways govern the process of aging. Both pathways share common downstream targets that allow competitive crosstalk between these branches. Of note, a shift from IGF to Wnt signaling has been observed during aging of satellite cells. Biological regulatory networks necessary to recreate aging have not yet been discovered. Here, we established a mathematical in silico model that robustly recapitulates the crosstalk between IGF and Wnt signaling. Strikingly, it predicts critical nodes following a shift from IGF to Wnt signaling. These findings indicate that this shift might cause age-related diseases.}, language = {en} } @article{AmmelingGanzRosbachetal.2026, author = {Ammeling, Jonas and Ganz, Jonathan and Rosbach, Emely and Lausser, Ludwig and Bertram, Christof and Breininger, Katharina and Aubreville, Marc}, title = {Benchmarking Foundation Models for Mitotic Figure Classification}, volume = {3}, pages = {2026:003}, journal = {Machine Learning for Biomedical Imaging}, number = {MELBA-BVM 2025 Special Issue}, publisher = {Melba editors}, address = {[s. l.]}, issn = {2766-905X}, doi = {https://doi.org/10.59275/j.melba.2026-a3eb}, pages = {38 -- 55}, year = {2026}, abstract = {The performance of deep learning models is known to scale with data quantity and diversity. In pathology, as in many other medical imaging domains, the availability of labeled images for a specific task is often limited. Self-supervised learning techniques have enabled the use of vast amounts of unlabeled data to train large-scale neural networks, i.e., foundation models, that can address the limited data problem by providing semantically rich feature vectors that can generalize well to new tasks with minimal training effort increasing model performance and robustness. In this work, we investigate the use of foundation models for mitotic figure classification. The mitotic count, which can be derived from this classification task, is an independent prognostic marker for specific tumors and part of certain tumor grading systems. In particular, we investigate the data scaling laws on multiple current foundation models and evaluate their robustness to unseen tumor domains. Next to the commonly used linear probing paradigm, we also adapt the models using low-rank adaptation (LoRA) of their attention mechanisms. We compare all models against end-to-end-trained baselines, both CNNs and Vision Transformers. Our results demonstrate that LoRA-adapted foundation models provide superior performance to those adapted with standard linear probing, reaching performance levels close to 100 \% data availability with only 10 \% of training data. Furthermore, LoRA-adaptation of the most recent foundation models almost closes the out-of-domain performance gap when evaluated on unseen tumor domains. However, full fine-tuning of traditional architectures still yields competitive performance.}, language = {en} } @inproceedings{GanzAmmelingRosbachetal.2025, author = {Ganz, Jonathan and Ammeling, Jonas and Rosbach, Emely and Lausser, Ludwig and Bertram, Christof and Breininger, Katharina and Aubreville, Marc}, title = {Is Self-supervision Enough?}, booktitle = {Bildverarbeitung f{\"u}r die Medizin 2025: Proceedings, German Conference on Medical Image Computing, Regensburg March 09-11, 2025}, subtitle = {Benchmarking Foundation Models Against End-to-end Training for Mitotic Figure Classification}, editor = {Palm, Christoph and Breininger, Katharina and Deserno, Thomas Martin and Handels, Heinz and Maier, Andreas and Maier-Hein, Klaus H. and Tolxdorff, Thomas}, publisher = {Springer Vieweg}, address = {Wiesbaden}, isbn = {978-3-658-47422-5}, doi = {https://doi.org/10.1007/978-3-658-47422-5_15}, pages = {63 -- 68}, year = {2025}, language = {en} } @unpublished{AmmelingGanzRosbachetal.2025, author = {Ammeling, Jonas and Ganz, Jonathan and Rosbach, Emely and Lausser, Ludwig and Bertram, Christof and Breininger, Katharina and Aubreville, Marc}, title = {Benchmarking Foundation Models for Mitotic Figure Classification}, publisher = {arXiv}, address = {Ithaca}, doi = {https://doi.org/10.48550/arXiv.2508.04441}, year = {2025}, language = {en} }