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Harald Binder

Publications and source records attributed to Harald Binder.

At least 19 recordsLinked to original sources
arXiv2026

Large language models as synthetic clinical experts to inform longitudinal rare-disease modeling

Due to the limited amount of information, modeling longitudinal rare-disease data can benefit from integrating clinical knowledge. Yet, elicitation of expert knowledge and formalization for model fitting is challenging, in particular due to limited time of clinical experts. To nevertheless make domain knowledge accessible during model fitting, we use large language models (LLMs) as synthetic clinical experts to supervise a variational-autoencoder-based approach that learns low-dimensional latent summaries of visit-level observations. Specifically, LLMs are queried offline on textual descriptions of patient observations to obtain judgments, e.g., the suspected clinical category. To improve the variational autoencoder fit, we train a differentiable surrogate model on these judgments and augment the loss function to encourage reconstructions that preserve the clinical-label distribution of their corresponding input profile. In an application to longitudinal motor-function assessments from children with spinal muscular atrophy, we map visit-level clinical profiles to low-dimensional representations that are linked by a multivariate mixed-effects model. The synthetic expert loss discourages reconstructions that remain numerically close in data space but alter the clinical interpretation of the reconstructed motor function profile, such as by crossing a disease-type boundary. We thus reduced disagreement between original and reconstructed SMA type labels from about 11 to 7 percent. Furthermore, informing the latent representation by the synthetic expert improved prediction of motor function milestones compared with unsupervised latent representations and a data-level baseline. These results suggest that incorporating LLMs into model fitting can make clinical knowledge available to representation learning and improve clinical faithfulness for longitudinal rare-disease data.

cs.AI↗
arXiv2026

Distinguishing case-mix from context heterogeneity in prognostic regression model synthesis settings

Prognostic regression models often synthesize data from multiple sites, whether within a multi-site study, across federated settings, or in individual participant data meta-analysis. Here, a site is any data source, such as a hospital, registry, trial, or study, and need not be a physical center. Analysts must then decide whether one regression model represents all sites or whether site-specific models are needed. Established measures such as coefficient-level tau^2 quantify heterogeneity but do not distinguish its source. We focus on diagnosing whether coefficient heterogeneity reflects case-mix or site-specific context effects. Case-mix heterogeneity can arise when linear regression terms approximate multivariable non-linear relationships in populations with different covariate distributions. Contextual heterogeneity arises when comparable patients require different regression relationships across sites. We do this by fitting site-specific local regressions in a dimension-reduced space and partitioning the smoothed coefficient surfaces into a cross-site reference and site-specific deviations. An autoencoder and custom loss structure the latent space around local prognostic relationships. We then project this partition onto the outcome scale to derive observation- and site-level summaries. We demonstrate the approach on a COPD trial with two sites. In the three leading latent slope coordinates, coefficient-surface variation was predominantly contextual. The derived observation-level outcome-scale variance partition was case-mix-leading, whereas its between-site aggregation was concentrated in contextual differences rather than case-mix shifts. A permuted-site negative control assesses whether the contextual summary can arise when site labels carry no signal. This diagnostic distinction can inform whether joint or site-specific regression models should be evaluated.

stat.ME↗
arXiv2026

Typical Healthcare Pathways as a Basis for Admixture Modeling of Patient Trajectories

Background: Understanding whether patients follow similar or distinct patterns of care is important for characterizing clinical practice, identifying patient subgroups, and supporting quality improvement. However, routine healthcare trajectories are difficult to compare directly because patients may differ in their diagnostic workup, treatment sequencing, timing of clinical events, and documentation practices. Despite this variation, trajectories often contain recurring patterns at the cohort level. Methods: To address this challenge, we present a framework that explicitly separates cohort-level typical pathway identification from patient-level inference. At the cohort level, we derive an interpretable representation of care processes using a rule-based algorithm to identify typical healthcare pathways, resulting in a compact pathway graph. These pathways are then modeled as Markov chains and used as structured components in an admixture model, allowing each patient to be represented as a probabilistic mixture of typical pathways rather than being assigned to a single pathway component. The resulting admixture weights provide a compact representation of patient trajectories for subgroup characterization. We further assess the stability of the identified pathways and inferred admixture representations across multiple train-test splits. Results: Across train-test splits, the framework demonstrated consistent pathway structures and patient-level mixture patterns. Applied to routine care data from prostate cancer patients undergoing radical prostatectomy, the framework identified interpretable care patterns and supported the identification of patient subgroups with similar clinical event patterns. Conclusion: Overall, the proposed framework provides an interpretable and stable approach for summarizing treatment pathways and characterizing patient subgroups in real-world practice.

stat.ME↗
arXiv2026

Learning study similarity to investigate heterogeneity in meta-analysis using LLMs and triplet loss

Meta-analyses of observational studies often show substantial between-study heterogeneity, limiting the interpretability of pooled estimates. Meta-regression can be used to explore heterogeneity, but it is often underpowered to handle multiple effect modifiers. We propose a novel framework that integrates large language models (LLMs) with deep metric learning to infer study-level similarity prior to meta-analysis. Study-level clinical and methodological characteristics were processed by an LLM to generate study triplets (anchor, similar, dissimilar). These triplets were constructed by treating each study as an anchor and comparing it with pairs of other studies to identify, in each instance, the study most similar to the anchor. Then, the triplets were used into an embedding model trained with triplet loss; a deep learning approach that learns an embedding space where clinically and methodologically similar studies are clustered together. We apply our framework to a meta-analysis dataset of 58 observational studies comparing cognitive outcomes between preterm- and term-born children. Subsequently, we fit meta-analysis models within the identified study clusters and compare the results with those of the overall analysis. Results suggested three clusters two of which retained considerable between-study heterogeneity. The remaining cluster comprised the most homogeneous group of studies and exhibited a more extreme pooled effect estimate together with a narrower prediction interval compared with the overall analysis. This work presents a novel approach for exploring heterogeneity in meta-analysis by incorporating study characteristics prior to model fitting. By transforming study information into a similarity space, the framework identifies coherent subgroups and supports more precise inference in heterogeneous real-world evidence.

stat.ME↗
arXiv2026

Eliciting associations between clinical variables from LLMs via comparison questions across populations

The training data of large language models (LLMs) comprises a wide range of biomedical literature, reflecting data from many different patient populations. We investigate how it might be possible to recover information on correlation and causal links between patient characteristics, as a key building block for medical decision making. To avoid the pitfalls of direct elicitation, we propose an approach based on structured comparison questions, specifically patient comparison triplet questions. This is combined with a statistical model for the LLM representation that provides estimates of correlations without access to activations or model internals. Intuitively, we consider how similarity decisions of LLMs based on a first variable are affected by providing information on a second variable for one of the patients being assessed. We then induce prompt-level environment shifts to obtain correlation estimates for different subpopulations, which enables an invariant causal prediction (ICP) approach to obtain conservative candidate parent links. We demonstrate the method in two clinical domains, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS). Across prompted environments, the elicited correlations are smooth, stable, and clinically interpretable, yet vary in a statistically significant way that supports downstream invariance testing, such that ICP provides a small set of candidate invariant parent links. These results show that indirect elicitation via triplet comparisons can recover meaningful association structure from LLMs and offer a cautious route from implicit correlations to causal statements that are congruent with LLM answering patterns.

cs.LG↗
arXiv2026

Assessing Multimodal Chronic Wound Embeddings with Expert Triplet Agreement

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disorder for which clinicians greatly benefit from finding similar cases using images and clinical text. However, off-the-shelf foundation models do not reliably capture clinically meaningful features for this heterogeneous, long-tail disease, and structured measurement of agreement with experts is challenging. To address these gaps, we propose evaluating embedding spaces with expert ordinal comparisons (triplet judgments), which are fast to collect and encode implicit clinical similarity knowledge. We further introduce TriDerm, a multimodal framework that learns interpretable wound representations from small cohorts by integrating wound imagery, boundary masks, and expert reports. On the vision side, TriDerm adapts visual foundation models to RDEB using wound-level attention pooling and non-contrastive representation learning. For text, we prompt large language models with comparison queries and recover medically meaningful representations via soft ordinal embeddings (SOE). We show that visual and textual modalities capture complementary aspects of wound phenotype, and that fusing both modalities yields 73.5% agreement with experts, outperforming the best off-the-shelf single-modality foundation model by over 5.6 percentage points. We make the expert annotation tool, model code and representative dataset samples publicly available.

cs.CV↗
arXiv2026

Embedding interpretable $\ell_1$-regression into neural networks for uncovering temporal structure in cell imaging

While artificial neural networks excel in unsupervised learning of non-sparse structure, classical statistical regression techniques offer better interpretability, in particular when sparseness is enforced by $\ell_1$ regularization, enabling identification of which factors drive observed dynamics. We investigate how these two types of approaches can be optimally combined, exemplarily considering two-photon calcium imaging data where sparse autoregressive dynamics are to be extracted. We propose embedding a vector autoregressive (VAR) model as an interpretable regression technique into a convolutional autoencoder, which provides dimension reduction for tractable temporal modeling. A skip connection separately addresses non-sparse static spatial information, selectively channeling sparse structure into the $\ell_1$-regularized VAR. $\ell_1$-estimation of regression parameters is enabled by differentiating through the piecewise linear solution path. This is contrasted with approaches where the autoencoder does not adapt to the VAR model. Having an embedded statistical model also enables a testing approach for comparing temporal sequences from the same observational unit. Additionally, contribution maps visualize which spatial regions drive the learned dynamics.

cs.LG↗
arXiv2026

A statistical perspective on transformers for small longitudinal cohort data

Modeling of longitudinal cohort data typically involves complex temporal dependencies between multiple variables. There, the transformer architecture, which has been highly successful in language and vision applications, allows us to account for the fact that the most recently observed time points in an individual's history may not always be the most important for the immediate future. This is achieved by assigning attention weights to observations of an individual based on a transformation of their values. One reason why these ideas have not yet been fully leveraged for longitudinal cohort data is that typically, large datasets are required. Therefore, we present a simplified transformer architecture that retains the core attention mechanism while reducing the number of parameters to be estimated, to be more suitable for small datasets with few time points. Guided by a statistical perspective on transformers, we use an autoregressive model as a starting point and incorporate attention as a kernel-based operation with temporal decay, where aggregation of multiple transformer heads, i.e. different candidate weighting schemes, is expressed as accumulating evidence on different types of underlying characteristics of individuals. This also enables a permutation-based statistical testing procedure for identifying contextual patterns. In a simulation study, the approach is shown to recover contextual dependencies even with a small number of individuals and time points. In an application to data from a resilience study, we identify temporal patterns in the dynamics of stress and mental health. This indicates that properly adapted transformers can not only achieve competitive predictive performance, but also uncover complex context dependencies in small data settings.

stat.ME↗
arXiv2026

Contrasting Global and Patient-Specific Regression Models via a Neural Network Representation

When developing clinical prediction models, it can be challenging to balance between global models that are valid for all patients and personalized models tailored to individuals or potentially unknown subgroups. To aid such decisions, we propose a diagnostic tool for contrasting global regression models and patient-specific (local) regression models. The core utility of this tool is to identify where and for whom a global model may be inadequate. We focus on regression models and specifically suggest a localized regression approach that identifies regions in the predictor space where patients are not well represented by the global model. As localization becomes challenging when dealing with many predictors, we propose modeling in a dimension-reduced latent representation obtained from an autoencoder. Using such a neural network architecture for dimension reduction enables learning a latent representation simultaneously optimized for both good data reconstruction and for revealing local outcome-related associations suitable for robust localized regression. We illustrate the proposed approach with a clinical study involving patients with chronic obstructive pulmonary disease. Our findings indicate that the global model is adequate for most patients but that indeed specific subgroups benefit from personalized models. We also demonstrate how to map these subgroup models back to the original predictors, providing insight into why the global model falls short for these groups. Thus, the principal application and diagnostic yield of our tool is the identification and characterization of patients or subgroups whose outcome associations deviate from the global model.

stat.ME↗
arXiv2025

Using latent representations to link disjoint longitudinal data for mixed-effects regression

Many rare diseases offer limited established treatment options, leading patients to switch therapies when new medications emerge. To analyze the impact of such treatment switches within the low sample size limitations of rare disease trials, it is important to use all available data sources. This, however, is complicated when usage of measurement instruments change during the observation period, for example when instruments are adapted to specific age ranges. The resulting disjoint longitudinal data trajectories, complicate the application of traditional modeling approaches like mixed-effects regression. We tackle this by mapping observations of each instrument to a aligned low-dimensional temporal trajectory, enabling longitudinal modeling across instruments. Specifically, we employ a set of variational autoencoder architectures to embed item values into a shared latent space for each time point. Temporal disease dynamics and treatment switch effects are then captured through a mixed-effects regression model applied to latent representations. To enable statistical inference, we present a novel statistical testing approach that accounts for the joint parameter estimation of mixed-effects regression and variational autoencoders. The methodology is applied to quantify the impact of treatment switches for patients with spinal muscular atrophy. Here, our approach aligns motor performance items from different measurement instruments for mixed-effects regression and maps estimated effects back to the observed item level to quantify the treatment switch effect. Our approach allows for model selection as well as for assessing effects of treatment switching. The results highlight the potential of modeling in joint latent representations for addressing small data challenges.

stat.ML↗
arXiv2025

Small Data Explainer -- The impact of small data methods in everyday life

The emergence of breakthrough artificial intelligence (AI) techniques has led to a renewed focus on how small data settings, i.e., settings with limited information, can benefit from such developments. This includes societal issues such as how best to include under-represented groups in data-driven policy and decision making, or the health benefits of assistive technologies. We provide a conceptual overview, clarify the relationship between small data and big data, and identify common themes from exemplary case studies and application areas. Potential solutions are described in a more detailed technical overview of current data analysis and modelling techniques, highlighting contributions from different disciplines, such as knowledge-driven modelling from statistics and data-driven modelling from computer science. By linking application settings, conceptual contributions and specific techniques, we highlight what is already feasible and suggest what an agenda for fully leveraging small data might look like.

cs.CY↗
arXiv2025

Challenges and proposed solutions in modeling multimodal medical data: A systematic review

Multimodal data modeling has emerged as a powerful approach in clinical research, enabling the integration of diverse data types such as imaging, genomics, wearable sensors, and electronic health records. Despite its potential to improve diagnostic accuracy and support personalized care, modeling such heterogeneous data presents significant technical challenges. This systematic review synthesizes findings from 69 studies to identify common obstacles, including missing modalities, limited sample sizes, dimensionality imbalance, interpretability issues, and finding the optimal fusion techniques. We highlight recent methodological advances, such as transfer learning, generative models, attention mechanisms, and neural architecture search that offer promising solutions. By mapping current trends and innovations, this review provides a comprehensive overview of the field and offers practical insights to guide future research and development in multimodal modeling for medical applications.

cs.LG↗
arXiv2024

Improving prediction models by incorporating external data with weights based on similarity

In clinical settings, we often face the challenge of building prediction models based on small observational data sets. For example, such a data set might be from a medical center in a multi-center study. Differences between centers might be large, thus requiring specific models based on the data set from the target center. Still, we want to borrow information from the external centers, to deal with small sample sizes. There are approaches that either assign weights to each external data set or each external observation. To incorporate information on differences between data sets and observations, we propose an approach that combines both into weights that can be incorporated into a likelihood for fitting regression models. Specifically, we suggest weights at the data set level that incorporate information on how well the models that provide the observation weights distinguish between data sets. Technically, this takes the form of inverse probability weighting. We explore different scenarios where covariates and outcomes differ among data sets, informing our simulation design for method evaluation. The concept of effective sample size is used for understanding the effectiveness of our subgroup modeling approach. We demonstrate our approach through a clinical application, predicting applied radiotherapy doses for cancer patients. Generally, the proposed approach provides improved prediction performance when external data sets are similar. We thus provide a method for quantifying similarity of external data sets to the target data set and use this similarity to include external observations for improving performance in a target data set prediction modeling task with small data.

stat.ME↗
arXiv2023

Combining propensity score methods with variational autoencoders for generating synthetic data in presence of latent sub-groups

In settings requiring synthetic data generation based on a clinical cohort, e.g., due to data protection regulations, heterogeneity across individuals might be a nuisance that we need to control or faithfully preserve. The sources of such heterogeneity might be known, e.g., as indicated by sub-groups labels, or might be unknown and thus reflected only in properties of distributions, such as bimodality or skewness. We investigate how such heterogeneity can be preserved and controlled when obtaining synthetic data from variational autoencoders (VAEs), i.e., a generative deep learning technique that utilizes a low-dimensional latent representation. To faithfully reproduce unknown heterogeneity reflected in marginal distributions, we propose to combine VAEs with pre-transformations. For dealing with known heterogeneity due to sub-groups, we complement VAEs with models for group membership, specifically from propensity score regression. The evaluation is performed with a realistic simulation design that features sub-groups and challenging marginal distributions. The proposed approach faithfully recovers the latter, compared to synthetic data approaches that focus purely on marginal distributions. Propensity scores add complementary information, e.g., when visualized in the latent space, and enable sampling of synthetic data with or without sub-group specific characteristics. We also illustrate the proposed approach with real data from an international stroke trial that exhibits considerable distribution differences between study sites, in addition to bimodality. These results indicate that describing heterogeneity by statistical approaches, such as propensity score regression, might be more generally useful for complementing generative deep learning for obtaining synthetic data that faithfully reflects structure from clinical cohorts.

cs.LG↗
arXiv2023

Investigating a domain adaptation approach for integrating different measurement instruments in a longitudinal clinical registry

In a longitudinal clinical registry, different measurement instruments might have been used for assessing individuals at different time points. To combine them, we investigate deep learning techniques for obtaining a joint latent representation, to which the items of different measurement instruments are mapped. This corresponds to domain adaptation, an established concept in computer science for image data. Using the proposed approach as an example, we evaluate the potential of domain adaptation in a longitudinal cohort setting with a rather small number of time points, motivated by an application with different motor function measurement instruments in a registry of spinal muscular atrophy (SMA) patients. There, we model trajectories in the latent representation by ordinary differential equations (ODEs), where person-specific ODE parameters are inferred from baseline characteristics. The goodness of fit and complexity of the ODE solutions then allows to judge the measurement instrument mappings. We subsequently explore how alignment can be improved by incorporating corresponding penalty terms into model fitting. To systematically investigate the effect of differences between measurement instruments, we consider several scenarios based on modified SMA data, including scenarios where a mapping should be feasible in principle and scenarios where no perfect mapping is available. While misalignment increases in more complex scenarios, some structure is still recovered, even if the availability of measurement instruments depends on patient state. A reasonable mapping is feasible also in the more complex real SMA dataset. These results indicate that domain adaptation might be more generally useful in statistical modeling for longitudinal registry data.

cs.LG↗
arXiv2023

A statistical approach to latent dynamic modeling with differential equations

Ordinary differential equations (ODEs) can provide mechanistic models of temporally local changes of processes, where parameters are often informed by external knowledge. While ODEs are popular in systems modeling, they are less established for statistical modeling of longitudinal cohort data, e.g., in a clinical setting. Yet, modeling of local changes could also be attractive for assessing the trajectory of an individual in a cohort in the immediate future given its current status, where ODE parameters could be informed by further characteristics of the individual. However, several hurdles so far limit such use of ODEs, as compared to regression-based function fitting approaches. The potentially higher level of noise in cohort data might be detrimental to ODEs, as the shape of the ODE solution heavily depends on the initial value. In addition, larger numbers of variables multiply such problems and might be difficult to handle for ODEs. To address this, we propose to use each observation in the course of time as the initial value to obtain multiple local ODE solutions and build a combined estimator of the underlying dynamics. Neural networks are used for obtaining a low-dimensional latent space for dynamic modeling from a potentially large number of variables, and for obtaining patient-specific ODE parameters from baseline variables. Simultaneous identification of dynamic models and of a latent space is enabled by recently developed differentiable programming techniques. We illustrate the proposed approach in an application with spinal muscular atrophy patients and a corresponding simulation study. In particular, modeling of local changes in health status at any point in time is contrasted to the interpretation of functions obtained from a global regression. This more generally highlights how different application settings might demand different modeling strategies.

stat.ME↗
arXiv2022

Deep learning and differential equations for modeling changes in individual-level latent dynamics between observation periods

When modeling longitudinal biomedical data, often dimensionality reduction as well as dynamic modeling in the resulting latent representation is needed. This can be achieved by artificial neural networks for dimension reduction, and differential equations for dynamic modeling of individual-level trajectories. However, such approaches so far assume that parameters of individual-level dynamics are constant throughout the observation period. Motivated by an application from psychological resilience research, we propose an extension where different sets of differential equation parameters are allowed for observation sub-periods. Still, estimation for intra-individual sub-periods is coupled for being able to fit the model also with a relatively small dataset. We subsequently derive prediction targets from individual dynamic models of resilience in the application. These serve as interpretable resilience-related outcomes, to be predicted from characteristics of individuals, measured at baseline and a follow-up time point, and selecting a small set of important predictors. Our approach is seen to successfully identify individual-level parameters of dynamic models that allows us to stably select predictors, i.e., resilience factors. Furthermore, we can identify those characteristics of individuals that are the most promising for updates at follow-up, which might inform future study design. This underlines the usefulness of our proposed deep dynamic modeling approach with changes in parameters between observation sub-periods.

stat.ML↗
arXiv2021

Deep dynamic modeling with just two time points: Can we still allow for individual trajectories?

Longitudinal biomedical data are often characterized by a sparse time grid and individual-specific development patterns. Specifically, in epidemiological cohort studies and clinical registries we are facing the question of what can be learned from the data in an early phase of the study, when only a baseline characterization and one follow-up measurement are available. Inspired by recent advances that allow to combine deep learning with dynamic modeling, we investigate whether such approaches can be useful for uncovering complex structure, in particular for an extreme small data setting with only two observations time points for each individual. Irregular spacing in time could then be used to gain more information on individual dynamics by leveraging similarity of individuals. We provide a brief overview of how variational autoencoders (VAEs), as a deep learning approach, can be linked to ordinary differential equations (ODEs) for dynamic modeling, and then specifically investigate the feasibility of such an approach that infers individual-specific latent trajectories by including regularity assumptions and individuals' similarity. We also provide a description of this deep learning approach as a filtering task to give a statistical perspective. Using simulated data, we show to what extent the approach can recover individual trajectories from ODE systems with two and four unknown parameters and infer groups of individuals with similar trajectories, and where it breaks down. The results show that such dynamic deep learning approaches can be useful even in extreme small data settings, but need to be carefully adapted.

stat.ML↗