Background: Hyperbilirubinemia of the newborn infant is a common disease worldwide. However, recognized early and treated appropriately, it typically remains innocuous. We recently developed an early phototherapy prediction tool (EPPT) by means of machine learning (ML) utilizing just one bilirubin measurement and few clinical variables. The aim of this study is to test applicability and performance of the EPPT on a new patient cohort from a different population. Materials and methods: This work is a retrospective study of prospectively recorded neonatal data from infants born in 2018 in an academic hospital, Regensburg, Germany, meeting the following inclusion criteria: born with 34 completed weeks of gestation or more, at least two total serum bilirubin (TSB) measurement prior to phototherapy. First, the original EPPT—an ensemble of a logistic regression and a random forest—was used in its freely accessible version and evaluated in terms of the area under the receiver operating characteristic curve (AUROC). Second, a new version of the EPPT model was re-trained on the data from the new cohort. Third, the predictive performance, variable importance, sensitivity and specificity were analyzed and compared across the original and re-trained models. Results: In total, 1,109 neonates were included with a median (IQR) gestational age of 38.4 (36.6–39.9) and a total of 3,940 bilirubin measurements prior to any phototherapy treatment, which was required in 154 neonates (13.9%). For the phototherapy treatment prediction, the original EPPT achieved a predictive performance of 84.6% AUROC on the new cohort. After re-training the model on a subset of the new dataset, 88.8% AUROC was achieved as evaluated by cross validation. The same five variables as for the original model were found to be most important for the prediction on the new cohort, namely gestational age at birth, birth weight, bilirubin to weight ratio, hours since birth, bilirubin value. Discussion: The individual risk for treatment requirement in neonatal hyperbilirubinemia is robustly predictable in different patient cohorts with a previously developed ML tool (EPPT) demanding just one TSB value and only four clinical parameters. Further prospective validation studies are needed to develop an effective and safe clinical decision support system.

Imant Daunhawer, Kai Schumacher, Anna Badura, Julia E. Vogt, Holger Michel, Sven Wellmann

Frontiers in Pediatrics, 2023

09.10.2023

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Alice Bizeul, Imant Daunhawer, Emanuele Palumbo, Bernhard Schölkopf, Alexander Marx, Julia E. Vogt

Conference on Causal Learning and Reasoning (Datasets Track), CLeaR, 2023

08.04.2023

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Contrastive learning is a cornerstone underlying recent progress in multi-view and multimodal learning, e.g., in representation learning with image/caption pairs. While its effectiveness is not yet fully understood, a line of recent work reveals that contrastive learning can invert the data generating process and recover ground truth latent factors shared between views. In this work, we present new identifiability results for multimodal contrastive learning, showing that it is possible to recover shared factors in a more general setup than the multi-view setting studied previously. Specifically, we distinguish between the multi-view setting with one generative mechanism (e.g., multiple cameras of the same type) and the multimodal setting that is characterized by distinct mechanisms (e.g., cameras and microphones). Our work generalizes previous identifiability results by redefining the generative process in terms of distinct mechanisms with modality-specific latent variables. We prove that contrastive learning can block-identify latent factors shared between modalities, even when there are nontrivial dependencies between factors. We empirically verify our identifiability results with numerical simulations and corroborate our findings on a complex multimodal dataset of image/text pairs. Zooming out, our work provides a theoretical basis for multimodal representation learning and explains in which settings multimodal contrastive learning can be effective in practice.

Imant Daunhawer, Alice Bizeul, Emanuele Palumbo, Alexander Marx, Julia E. Vogt

The Eleventh International Conference on Learning Representations, ICLR 2023

23.03.2023

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Multimodal VAEs have recently gained attention as efficient models for weakly-supervised generative learning with multiple modalities. However, all existing variants of multimodal VAEs are affected by a non-trivial trade-off between generative quality and generative coherence. In particular mixture-based models achieve good coherence only at the expense of sample diversity and a resulting lack of generative quality. We present a novel variant of the mixture-of-experts multimodal variational autoencoder that improves its generative quality, while maintaining high semantic coherence. We model shared and modality-specific information in separate latent subspaces, proposing an objective that overcomes certain dependencies on hyperparameters that arise for existing approaches with the same latent space structure. Compared to these existing approaches, we show increased robustness with respect to changes in the design of the latent space, in terms of the capacity allocated to modality-specific subspaces. We show that our model achieves both good generative coherence and high generative quality in challenging experiments, including more complex multimodal datasets than those used in previous works.

Emanuele Palumbo, Imant Daunhawer, Julia E. Vogt

The Eleventh International Conference on Learning Representations, ICLR 2023

02.03.2023

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The robustness of machine learning algorithms to distributions shift is primarily discussed in the context of supervised learning (SL). As such, there is a lack of insight on the robustness of the representations learned from unsupervised methods, such as self-supervised learning (SSL) and auto-encoder based algorithms (AE), to distribution shift. We posit that the input-driven objectives of unsupervised algorithms lead to representations that are more robust to distribution shift than the target-driven objective of SL. We verify this by extensively evaluating the performance of SSL and AE on both synthetic and realistic distribution shift datasets. Following observations that the linear layer used for classification itself can be susceptible to spurious correlations, we evaluate the representations using a linear head trained on a small amount of out-of-distribution (OOD) data, to isolate the robustness of the learned representations from that of the linear head. We also develop "controllable" versions of existing realistic domain generalisation datasets with adjustable degrees of distribution shifts. This allows us to study the robustness of different learning algorithms under versatile yet realistic distribution shift conditions. Our experiments show that representations learned from unsupervised learning algorithms generalise better than SL under a wide variety of extreme as well as realistic distribution shifts.

Yuge Shi, Imant Daunhawer, Julia E. Vogt, Philip H.S. Torr, Amartya Sanyal

The Eleventh International Conference on Learning Representations, ICLR 2023

16.12.2022

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Multimodal variational autoencoders (VAEs) have shown promise as efficient generative models for weakly-supervised data. Yet, despite their advantage of weak supervision, they exhibit a gap in generative quality compared to unimodal VAEs, which are completely unsupervised. In an attempt to explain this gap, we uncover a fundamental limitation that applies to a large family of mixture-based multimodal VAEs. We prove that the sub-sampling of modalities enforces an undesirable upper bound on the multimodal ELBO and thereby limits the generative quality of the respective models. Empirically, we showcase the generative quality gap on both synthetic and real data and present the tradeoffs between different variants of multimodal VAEs. We find that none of the existing approaches fulfills all desired criteria of an effective multimodal generative model when applied on more complex datasets than those used in previous benchmarks. In summary, we identify, formalize, and validate fundamental limitations of VAE-based approaches for modeling weakly-supervised data and discuss implications for real-world applications.

Imant Daunhawer, Thomas M. Sutter, Kieran Chin-Cheong, Emanuele Palumbo, Julia E. Vogt

The Tenth International Conference on Learning Representations, ICLR 2022

07.04.2022

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Background: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. Study Design: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. Results: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (+/-8.8%) and an area-under-the-precision-recall-curve of 28.42% (+/-11.5%). The predictive performance of the model with RFs alone was comparable with random. Conclusions: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.

Martin Stocker, Imant Daunhawer, Wendy van Herk, Salhab el Helou, Sourabh Dutta, Frank A. B. A.Schuerman, Rita K. van den Tooren-de Groot, ; Jantien W. Wieringa, Jan Janota, Laura H. van der Meer-Kappelle, Rob Moonen, Sintha D. Sie, Esther de Vries, Albertine E. Donker, Urs Zimmerman, Luregn J. Schlapbach, Amerik C. de Mol, Angelique Hoffmann-Haringsma, Madan Roy, Maren Tomaske, René F. Kornelisse, Juliette van Gijsel, Frans B. Plötz, Sven Wellmann, Niek B Achten, Dirk Lehnick, Annemarie M. C. van Rossum, Julia E. Vogt

The Pediatric Infectious Disease Journal, 2022

09.09.2021

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Multiple data types naturally co-occur when describing real-world phenomena and learning from them is a long-standing goal in machine learning research. However, existing self-supervised generative models approximating an ELBO are not able to fulfill all desired requirements of multimodal models: their posterior approximation functions lead to a trade-off between the semantic coherence and the ability to learn the joint data distribution. We propose a new, generalized ELBO formulation for multimodal data that overcomes these limitations. The new objective encompasses two previous methods as special cases and combines their benefits without compromises. In extensive experiments, we demonstrate the advantage of the proposed method compared to state-of-the-art models in self-supervised, generative learning tasks.

Thomas M. Sutter^*, Imant Daunhawer^*, Julia E. Vogt
^* denotes shared first authorship

Ninth International Conference on Learning Representations, ICLR 2021

04.05.2021

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In the quest for efficient and robust learning methods, combining unsupervised state representation learning and reinforcement learning (RL) could offer advantages for scaling RL algorithms by providing the models with a useful inductive bias. For achieving this, an encoder is trained in an unsupervised manner with two state representation methods, a variational autoencoder and a contrastive estimator. The learned features are then fed to the actor-critic RL algorithm Proximal Policy Optimization (PPO) to learn a policy for playing Open AI’s car racing environment. Hence, such procedure permits to decouple state representations from RL-controllers. For the integration of RL with unsupervised learning, we explore various designs for variational autoencoders and contrastive learning. The proposed method is compared to a deep network trained directly on pixel inputs with PPO. The results show that the proposed method performs slightly worse than directly learning from pixel inputs; however, it has a more stable learning curve, a substantial reduction of the buffer size, and requires optimizing 88% fewer parameters. These results indicate that the use of pre-trained state representations hasseveral benefits for solving RL tasks.

Juan M. Montoya, Imant Daunhawer, Julia E. Vogt, Marco Wiering

ICAART 2021

04.02.2021

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Learning from different data types is a long-standing goal in machine learning research, as multiple information sources co-occur when describing natural phenomena. However, existing generative models that approximate a multimodal ELBO rely on difficult or inefficient training schemes to learn a joint distribution and the dependencies between modalities. In this work, we propose a novel, efficient objective function that utilizes the Jensen-Shannon divergence for multiple distributions. It simultaneously approximates the unimodal and joint multimodal posteriors directly via a dynamic prior. In addition, we theoretically prove that the new multimodal JS-divergence (mmJSD) objective optimizes an ELBO. In extensive experiments, we demonstrate the advantage of the proposed mmJSD model compared to previous work in unsupervised, generative learning tasks.

Thomas M. Sutter, Imant Daunhawer, Julia E. Vogt

NeurIPS 2020

22.10.2020

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PET/CT imaging is the gold standard for the diagnosis and staging of lung cancer. However, especially in healthcare systems with limited resources, costly PET/CT images are often not readily available. Conventional machine learning models either process CT or PET/CT images but not both. Models designed for PET/CT images are hence restricted by the number of PET images, such that they are unable to additionally leverage CT-only data. In this work, we apply the concept of visual soft attention to efficiently learn a model for lung cancer segmentation from only a small fraction of PET/CT scans and a larger pool of CT-only scans. We show that our model is capable of jointly processing PET/CT as well as CT-only images, which performs on par with the respective baselines whether or not PET images are available at test time. We then demonstrate that the model learns efficiently from only a few PET/CT scans in a setting where mostly CT-only data is available, unlike conventional models.

Varaha Karthik Pattisapu, Imant Daunhawer, Thomas Weikert, Alexander Sauter, Bram Stieltjes, Julia E. Vogt

GCPR 2020

12.10.2020

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Multimodal generative models learn a joint distribution over multiple modalities and thus have the potential to learn richer representations than unimodal models. However, current approaches are either inefficient in dealing with more than two modalities or fail to capture both modality-specific and shared variations. We introduce a new multimodal generative model that integrates both modality-specific and shared factors and aggregates shared information across any subset of modalities efficiently. Our method partitions the latent space into disjoint subspaces for modality-specific and shared factors and learns to disentangle these in a purely self-supervised manner. In extensive experiments, we show improvements in representation learning and generative performance compared to previous methods and showcase the disentanglement capabilities.

Imant Daunhawer, Thomas M. Sutter, Ricards Marcinkevics, Julia E. Vogt

GCPR 2020

10.09.2020

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Clinical pharmacology is a multi-disciplinary data sciences field that utilizes mathematical and statistical methods to generate maximal knowledge from data. Pharmacometrics (PMX) is a well-recognized tool to characterize disease progression, pharmacokinetics and risk factors. Since the amount of data produced keeps growing with increasing pace, the computational effort necessary for PMX models is also increasing. Additionally, computationally efficient methods such as machine learning (ML) are becoming increasingly important in medicine. However, ML is currently not an integrated part of PMX, for various reasons. The goals of this article are to (i) provide an introduction to ML classification methods, (ii) provide examples for a ML classification analysis to identify covariates based on specific research questions, (iii) examine a clinically relevant example to investigate possible relationships of ML and PMX, and (iv) present a summary of ML and PMX tasks to develop clinical decision support tools.

Gilbert Koch, Marc Pfister, Imant Daunhawer, Melanie Wilbaux, Sven Wellmann, Julia E. Vogt

Clinical Pharmacology & Therapeutics, 2020

11.01.2020

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Learning from different data types is a long standing goal in machine learning research, as multiple information sources co-occur when describing natural phenomena. Existing generative models that try to approximate a multimodal ELBO rely on difficult training schemes to handle the intermodality dependencies, as well as the approximation of the joint representation in case of missing data. In this work, we propose an ELBO for multimodal data which learns the unimodal and joint multimodal posterior approximation functions directly via a dynamic prior. We show that this ELBO is directly derived from a variational inference setting for multiple data types, resulting in a divergence term which is the Jensen-Shannon divergence for multiple distributions. We compare the proposed multimodal JS-divergence (mmJSD) model to state-of-the-art methods and show promising results using our model in unsupervised, generative learning using a multimodal VAE on two different datasets.

Thomas Sutter, Imant Daunhawer, Julia E. Vogt

Visually Grounded Interaction and Language Workshop, NeurIPS 2019

12.12.2019

Multimodal generative models learn a joint distribution of data from different modalities---a task which arguably benefits from the disentanglement of modality-specific and modality-invariant information. We propose a factorized latent variable model that learns named disentanglement on multimodal data without additional supervision. We demonstrate the disentanglement capabilities on simulated data, and show that disentangled representations can improve the conditional generation of missing modalities without sacrificing unconditional generation.

Imant Daunhawer, Thomas Sutter, Julia E. Vogt

Bayesian Deep Learning Workshop, NeurIPS 2019

12.12.2019

Background Machine learning models may enhance the early detection of clinically relevant hyperbilirubinemia based on patient information available in every hospital. Methods We conducted a longitudinal study on preterm and term born neonates with serial measurements of total serum bilirubin in the first two weeks of life. An ensemble, that combines a logistic regression with a random forest classifier, was trained to discriminate between the two classes phototherapy treatment vs. no treatment. Results Of 362 neonates included in this study, 98 had a phototherapy treatment, which our model was able to predict up to 48 h in advance with an area under the ROC-curve of 95.20%. From a set of 44 variables, including potential laboratory and clinical confounders, a subset of just four (bilirubin, weight, gestational age, hours since birth) suffices for a strong predictive performance. The resulting early phototherapy prediction tool (EPPT) is provided as an open web application. Conclusion Early detection of clinically relevant hyperbilirubinemia can be enhanced by the application of machine learning. Existing guidelines can be further improved to optimize timing of bilirubin measurements to avoid toxic hyperbilirubinemia in high-risk patients while minimizing unneeded measurements in neonates who are at low risk.

Imant Daunhawer, Severin Kasser, Gilbert Koch, Lea Sieber, Hatice Cakal, Janina Tütsch, Marc Pfister, Sven Wellman, Julia E. Vogt

Pediatric Research, 2019

30.03.2019

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