Harald Binder

• Head of Department at University Medical Center Freiburg

Background The goal of evidence-based medicine is to make clinical decisions based on the best available, relevant evidence. For this to be possible, studies such as randomized controlled trials (RCTs), which are widely considered to provide the best evidence of all forms of primary research, must be visible and have an impact on clinical practice...

Dimensionality reduction greatly facilitates the exploration of cellular heterogeneity in single-cell RNA sequencing data. While most of such approaches are data-driven, it can be useful to incorporate biologically plausible assumptions about the underlying structure or the experimental design. We propose the boosting autoencoder (BAE) approach, wh...

There are various dimensionality reduction techniques for visually inspecting dynamical patterns in time-series single-cell RNA-sequencing (scRNA-seq) data. However, the lack of one-to-one correspondence between cells across time points makes it difficult to uniquely uncover temporal structure in a low-dimensional manifold. The use of different tec...

Background The integration of real-world evidence (RWE) from real-world data (RWD) in clinical research is crucial for bridging the gap between clinical trial results and real-world outcomes. Analyzing routinely collected data to generate clinical evidence faces methodological concerns like confounding and bias, similar to prospectively documented...

Background The integration of real-world evidence (RWE) from real-world data (RWD) in clinical research is crucial for bridging the gap between clinical trial results and real-world outcomes. Analyzing routinely collected data to generate clinical evidence faces methodological concerns like confounding and bias, similar to prospectively documented...

Background: The goal of evidence-based medicine is to make clinical decisions based on the best available, relevant evidence. For this to be possible, studies such as randomized controlled trials (RCTs), which are widely considered to provide the best evidence of all forms of primary research, must be visible and have an impact on clinical practice...

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 adaptatio...

Several approaches have been proposed to reconstruct interactions between groups of cells or individual cells from single-cell transcriptomics data, leveraging prior information about known ligand-receptor interactions. To enhance downstream analyses, we present an end-to-end dimensionality reduction workflow, specifically tailored for single-cell...

Background The advancement of Artificial Intelligence, particularly Large Language Models (LLMs), is rapidly progressing. LLMs, such as OpenAI’s GPT, are becoming vital in scientific and medical processes, including text production, knowledge synthesis, translation, patient communication and data analysis. However, the outcome quality needs to be e...

Several approaches have been proposed to reconstruct interactions between groups of cells or individual cells from single-cell transcriptomics data, leveraging prior information about known ligand-receptor interactions. To enhance downstream analyses, we present an end-to-end dimensionality reduction workflow, specifically tailored for single-cell...

Animal data can provide meaningful context for human gene expression at the single-cell level. This can improve cell-type detection and clarify how well animal models represent human biology. To achieve this, we propose a deep learning approach that identifies a unified latent space to map complex patterns between datasets. The proposed method is t...

Background: To provide more evidence in urolithiasis research, we have established the German Nationwide Register for RECurrent URolithiasis (RECUR) using local clinical data warehouses (CDWH). For RECUR and other registers relying on digitalized clinical data, it is crucial to ensure the data's reliability for answering scientific questions. In th...

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 o...

Background The integration of real-world evidence (RWE) from real-world data (RWD) in clinical research is crucial for bridging the gap between clinical trial results and real-world outcomes. Analyzing routinely collected data to generate clinical evidence faces methodological concerns like confounding and bias, similar to prospectively documented...

Animal data can provide meaningful context for human gene expression at the single-cell level. This context can improve cell-type or cell-state detection and clarify how well the animal models human biological processes. To achieve this, we propose a deep learning approach that identifies a unified latent space to map complex patterns between datas...

Dimension reduction greatly facilitates the exploration of cellular heterogeneity in single-cell RNA sequencing data. While most of such approaches are data-driven, it can be useful to incorporate biologically plausible assumptions about the underlying structure or the experimental design. We propose the boosting autoencoder (BAE) approach, which c...

Background Chronic obstructive pulmonary disease (COPD) is an inflammatory multisystemic disease caused by environmental exposures and/or genetic factors. Inherited alpha-1-antitrypsin deficiency (AATD) is one of the best recognized genetic factors increasing the risk for an early onset COPD with emphysema. The aim of this study was to gain a bette...

Objectives: Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primar...

Cortical neurogenesis depends on the balance between self-renewal and differentiation of apical progenitors (APs). Here, we study the epigenetic control of AP's division mode by focusing on the enzymatic activity of the histone methyltransferase DOT1L. Combining lineage tracing with single-cell RNA sequencing of clonally related cells, we show at t...

Objective This study aimed to explore psychosocial consequences of (false) positive liver screening results and to identify influencing factors for perceived strain within a multistage screening programme for liver cirrhosis and fibrosis in Germany. Methods Between June 2018 and May 2019, all positively screened patients were asked to participate...

Background and purpose: Radiation therapy for glioblastoma (GBM) typically involves large target volumes. The aim of this study was to examine the recurrence pattern of GBM following modern radiochemotherapy according to EORTC guidelines and provide dose and distance information for the choice of optimal target volume margins. Materials and metho...

In order to investigate employees' needs of the Medical Faculty of the University of Freiburg regarding research data management, the BE-KONFORM study was performed in a two-step approach. First, guideline-based qualitative video interviews with four researchers were performed to identify key constructs of relevance. Second, a standardized online s...

Background The sodium-glucose co-transporter 2 inhibitor empagliflozin improves cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM) and heart failure. Experimental studies suggest a direct cardiac effect of empagliflozin associated with an improvement in left ventricular diastolic function. Methods In the randomized, double-bli...

Background and aims: Hepatorenal syndrome is a major complication in patients with cirrhosis and associated with high mortality. Predictive biomarkers for therapy response are largely missing. Cytokeratin18-based cell death markers are significantly elevated in patients with complications of chronic liver disease, but the role of these markers in...

Purpose One of the currently debated changes in scientific practice is the implementation of data sharing requirements for peer-reviewed publication to increase transparency and intersubjective verifiability of results. However, it seems that data sharing is a not fully adopted behavior among researchers. The theory of planned behavior was repeated...

Recent extensions of single-cell studies to multiple data modalities raise new questions regarding experimental design. For example, the challenge of sparsity in single-omics data might be partly resolved by compensating for missing information across modalities. In particular, deep learning approaches, such as deep generative models (DGMs), can po...

Zusammenfassung Erste Ergebnisse einer bundesweiten Studie deuten auf geschlechtsspezifische Muster mit weniger berichteten Fällen von Kindesvernachlässigung und Gewalt in den Neuen im Vergleich zu den Alten Bundesländern. Ziel der vorliegenden Studie war es diese Ergebnisse in zwei größeren regionalen Stichproben zu überprüfen. Methode: Prävalenze...

The BE-KONFORM project aimed to gather needs from employees of the Faculty of Medicine of the University of Freiburg. For this purpose, qualitative (phase 1) and quantitative (phase 2) methods were used to gain the broadest and deepest possible impressions. A total of 236 subjects completed the online questionnaire. Research data management was mos...

Background Urinary stone disease is a widespread disease with tremendous impact on those affected and on societies around the globe. Nevertheless, clinical and health care research in this area seem to lag far behind cardiovascular diseases or cancer. This may be due to the lack of an immediate deadly threat from the disease and therefore less publ...

To investigate the complexity arising from single-cell RNA-sequencing (scRNA-seq) data, researchers increasingly resort to deep generative models, specifically variational autoencoders (VAEs), which are trained by variational inference techniques. Similar to other dimension reduction approaches, this allows encoding the inherent biological signals...

Recent extensions of single-cell studies to multiple data modalities raise new questions regarding experimental design. For example, the challenge of sparsity in single-omics data might be partly resolved by compensating for missing information across modalities. In particular, deep learning approaches, such as deep generative models (DGMs), can po...

Background & aims: Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible. Methods: SEAL was a prospective cohort study with a control cohort...

Cortical neurogenesis depends on the tight balance between self-renewal and differentiation of apical progenitors (APs), the key progenitor type generating all other neural cells including neocortical neurons. We here report the activity of the histone methyltransferase DOT1L as a gatekeeper for AP cell identity. Combining lineage tracing with sing...

Background The dysregulation of glucose homeostasis via mental health stress is increasingly acknowledged, whereby depression independently increases the risk of the onset of type 2 diabetes by up to 60%. Contributing mental health factors starting in early life have further been considered, indicating that exposure to childhood emotional abuse is...

Background Suicidal ideation and behavior constitute important public mental health issues. In this study, we examined whether social integration prevents suicidal ideation over time and whether gender modifies this association. Methods Data from the Gutenberg Health Study (population-based representative community sample in midwest Germany) and t...

Aims To investigate the predictive ability of direct plasma renin and aldosterone concentrations as well as their ratio [aldosterone-to-renin (ARR)] for incident hypertension in the general population. Methods and results Concentration of renin and aldosterone were measured by a chemiluminescence immunoassay using the fully automated LIAISON® plat...

Deep generative models can learn the underlying structure, such as pathways or gene programs, from omics data. We provide an introduction as well as an overview of such techniques, specifically illustrating their use with single-cell gene expression data. For example, the low dimensional latent representations offered by various approaches, such as...

Background: Data of the EMPA-REG OUTCOME study have demonstrated a beneficial effect of the sodium-glucose cotransporter 2 inhibitor empagliflozin on cardiovascular outcome in patients with type 2 diabetes. The reduction in cardiovascular mortality and hospitalization due to heart failure might be in part explained by the direct effects of empagli...

Induction of neoangiogenesis is a hallmark feature during disease progression of hepatocellular carcinoma (HCC). Antiangiogenetic compounds represent a mainstay of therapeutic approaches; however, development of chemoresistance is observed in the majority of patients. Recent findings suggest that tumor-initiating cells (TICs) may play a key role in...

Coronavirus disease-2019, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was a disaster in 2020. Accurate and early diagnosis of coronavirus disease-2019 (COVID-19) is still essential for health policymaking. Reverse transcriptase-polymerase chain reaction (RT-PCR) has been performed as the operational gold standard for...

Covariates in regressions may be linked to each other on a network. Knowledge of the network structure can be incorporated into regularized regression settings via a network penalty term. However, when it is unknown whether the connection signs in the network are positive (connected covariates reinforce each other) or negative (connected covariates...

Aims : Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce. Methods and results : Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40-80 years...

Development of primary liver cancer is a multi-stage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA sequencing analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n=7), low- (n=4) and high-grade (n=9) dysplas...

BACKGROUND: Regular exercise training represents an important modifier of arterial stiffness (AS). Therefore, sex-specific relations between domains of physical activity (PA; commuting, domestic, and leisure-time PA, including active sport and occupational PA) with AS were investigated. METHODS AND RESULTS: Stiffness index by digital photoplethysmo...

Identifying the possible factors of psychiatric symptoms among children can reduce the risk of adverse psychosocial outcomes in adulthood. We designed a classification tool to examine the association between modifiable risk factors and psychiatric symptoms, defined based on the Persian version of the WHO-GSHS questionnaire in a developing country....

Despite conceptual research on hippocampus development and the application of single-cell-resolved technologies, the nature and maturation of its diverse progenitor populations are unexplored. The chromatin modifier DOT1L balances progenitor proliferation and differentiation, and conditional loss-of-function mice featured impaired hippocampus devel...

Childhood maltreatment has been shown to relate to adult obesity. In this epidemiological study, we investigate the association between childhood maltreatment and waist-to-height-ratio (WHtR) in a sample of the German adult population, comprising of N = 2936 participants. WHtR, an indicator for risk of obesity, was the primary outcome. Childhood ma...

Background The Patient Health Questionnaire-9 (PHQ-9) has been proposed as a reliable and valid screening instrument for depressive symptoms with one latent factor. However, studies explicitly testing alternative model structures found support for a two-dimensional structure reflecting a somatic and a cognitive-affective dimension. We investigated...

Deep generative models, such as variational autoencoders (VAEs) or deep Boltzmann machines (DBMs), can generate an arbitrary number of synthetic observations after being trained on an initial set of samples. This has mainly been investigated for imaging data but could also be useful for single-cell transcriptomics (scRNA-seq). A small pilot study c...

Background: Already at the time of hospital admission, clinicians require simple tools to identify hospitalized COVID-19 patients at high risk of mortality. Such tools can significantly improve resource allocation and patient management within hospitals. From the statistical point of view, extended time-to-event models are required to account for c...

Aims Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of non-invasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality. Methods and results In a post-hoc analysis of the community-based Gutenberg Health...

The MICCAI Challenge 2020 “Anatomical Brain Barriers toCancer Spread: Segmentation from CT and MR Image” was about seg-menting brain structures automatically for further use in the definitionof the Clinical Target Volume (CTV) of glioblastoma patients and treat-ment planning optimization in radiation therapy. This paper describesthe methods of the...

In Germany, large, population-based cohort studies have been implemented in order to identify risk and protective factors for maintaining health across the life span. The purpose of this systematic review is to analyse findings from three large ongoing cohorts and to identify sex-specific prevalence rates, risk and protective factors for mental hea...

Background: Asymmetric dimethylarginine (ADMA) is considered an independent cardiovascular risk factor (cvRF) and thus represents a potential new biomarker for retinal vein occlusion (RVO). Methods: Overall, 92 patients with RVO and the same number of matched controls were included in the Gutenberg RVO study. All patients underwent a standardize...

Introduction Mental health is marked by gender differences. We formed a multi-cohort consortium to perform GEnder-Sensitive Analyses of mental health trajectories and study their implications for prevention (GESA). GESA aims at (1) identifying gender differences regarding symptoms and trajectories of mental health over the lifespan; (2) determining...

There are many settings where individual person data (IPD) are not available, due to privacy or technical reasons, and one must work with IPD proxies, such as summary statistics, to approximate original IPD inferences, that is, the results of statistical analyses that would ideally have been performed on individual‐level data. For instance, in a di...

Thrombin generation may be a potential tool to improve risk stratification for cardiovascular diseases. This study aims to explore the relation between thrombin generation and cardiovascular risk factors, cardiovascular diseases, and total mortality. For this study, N=5000 subjects from the population-based Gutenberg Health Study were analysed in a...

Purpose Fatigue has found increasing attention as a debilitating and lasting condition of cancer patients. However, it has remained unclear to what degree long-term survivors of malignant melanoma suffer from fatigue. Therefore, this study aimed to determine fatigue and its link with quality of life, aftercare behavior, and mental and physical symp...

Objective: Although several risk factors for retinal vein occlusion (RVO) are known, what triggers RVO is unclear in many cases. We aimed to evaluate the relevance of multiple risk factors in patients with RVO. Methods: The Gutenberg RVO Study is an observational case-control study that assessed thrombophilic, cardiovascular, ophthalmic, and dru...

Purpose: Since the role of short- and long-term intraocular pressure (IOP) fluctuation as a predictor of glaucoma progression is still controversial, the purpose of this study was to investigate the role of IOP fluctuation in a non-selected patient cohort. Materials and methods: Two-hundred and forty eyes of 120 glaucoma patients (51% female) wi...

Background: Diabetes mellitus (DM) has been associated with increased platelet reactivity as well as increased levels of platelet RNAs in plasma. Here, we sought to evaluate whether the platelet transcriptome is altered in the presence of uncontrolled DM. Methods: Next-generation sequencing (NGS) was performed on platelet RNA for 5 patients with...

Background Preclinical data have indicated a link between use of vitamin K antagonists ( VKA ) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population. Methods and Results Clin...

Data S1. Supplemental methods. Table S1. Use of Medication According to VKA Intake Table S2. Vitamin K Dependent Proteins and Laboratory Tests According to VKA Intake Table S3. Profile of Humoral Biomarkers by VKA Use Table S4. SNPs Identified in GWAS Catalogue Known to Influence Warfarin Dose Requirements Table S5. Baseline Characteristic in...

Background Glaucoma is a neurodegenerative disease, leading to thinning of the retinal nerve fibre layer (RNFL). The exact influence of ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFL thickness (RNFLT) is unknown and was analysed in a subgroup of the Gutenberg Health Study (GHS). Methods Global peripapillary RNFLT was...

Background: Thrombin formation is one of the key enzymatic processes that direct the activity of the hemostatic system. Thrombin generation (TG), a method addressing the overall potential of a given plasma sample to form thrombin, may be a potential tool to improve risk stratification for cardiovascular diseases (CVD). This study aims to explore th...

The general relevance of the immune system for cancer development and therapy is increasingly recognized. However and although the immune contexture of most human cancer types has been determined, a global characterisation of the immune tumour microenvironment in hepatocellular carcinoma (HCC) is lacking. Equally, differences in the immune contextu...

Promoter proximal pausing of RNA polymerase II (Pol II) is a widespread transcriptional regulatory step across metazoans. Here we find that the nuclear exon junction complex (pre-EJC) plays a critical and conserved role in this process. Depletion of pre-EJC subunits leads to a global decrease in Pol II pausing and to premature entry into elongation...

The relation between inflammation, hemostasis and arterial stiffness is of pathophysiological relevance for the development of cardiovascular disease (CVD). Data investigating this interplay using stiffness index (SI) by digital photoplethysmography are not available yet. Therefore, sex-specific relation between SI and inflammatory and hemostatic b...

Introduction: Flow-mediated dilation (FMD) quantifies endothelium-dependent vasomotor responses to short-term increases in blood flow. Low-flow mediated vasoconstriction (L-FMC) has been more recently introduced as additional measure of endothelial function, and its relationship with changes in blood flow, cardiovascular risk factors and FMD ha∧s...

Mammography is the predominant screening method for early detection of breast cancer, but has limitations and could be rendered more accurate by combination with a blood-based biomarker profile. Circulating microRNAs (miRNAs) are increasingly recognized as strong biomarkers, and we previously developed a 9-miRNA profile using serum and LNA-based qP...

Background High-throughput technology allows for genome-wide measurements at different molecular levels for the same patient, e.g. single nucleotide polymorphisms (SNPs) and gene expression. Correspondingly, it might be beneficial to also integrate complementary information from different molecular levels when building multivariable risk prediction...

Clinical cohorts with time-to-event endpoints are increasingly characterized by measurements of a number of single nucleotide polymorphisms that is by a magnitude larger than the number of measurements typically considered at the gene level. At the same time, the size of clinical cohorts often is still limited, calling for novel analysis strategies...

Background: Recent reports suggest an elevated incidence of bioresorbable vascular scaffold (BVS) thrombosis (scaffold thrombosis [ScT]). Objectives: This study investigated occurrence rates, clinical and angiographic characteristics, and possible mechanisms of ScT in all-comer patients undergoing BVS implantation at 2 German and 2 Swiss hospita...

This study assessed whether different subsets of circulating endothelial and putative endothelial progenitor cells (CEC and EPC) correlate with stent strut coverage (SSC) using second generation optical coherence tomography (OCT). Due to the lack of imaging modalities with a resolution down to the magnitude of a few cells, the influence of EPC on e...

In network meta-analysis, several alternative treatments can be compared by pooling the evidence of all randomised comparisons made in different studies. Incorporated indirect conclusions require a consistent network of treatment effects. An assessment of this assumption and of the influence of deviations is fundamental for the validity evaluation....