Advanced statistical methods for prognostic biomarkers and disease incidence models

Due to their prognostic value, biomarkers can support physicians in making the appropriate choice of therapy for a patient. In this thesis, several advanced statistical methods and machine learning algorithms were considered and applied to projects in collaboration with departments of the University Hospital Augsburg. A machine learning algorithm capturing hidden structures in binary immunohistologically stained images of colon cancer was developed to identify patients with a high risk of occurrence of distant metastases. Further, generalized linear models were used to estimate the probability of the need for a permanent shunt in patients after an aneurysmatic subarachnoid hemorrhage. Patients with oligometastatic colon cancer were stratified by a score developed using approaches from survival analysis to investigate which groups might benefit from surgical removal of metastases with prolonged overall survival. Another important point is the selection of suitable statistical models dependent on the structure of the data. We found that a linear regression may only be suited with a transformation of the response variable in the context of association of a COVID-19 infection with lymphocyte subsets. In addition, modeling the course of daily reported new COVID-19 cases is a relevant task and requires suitable statistical models. We compared non-seasonal and seasonal ARIMA models and examined the performance of different log-linear autoregressive Poisson models. To add more structure and enable theoretical prognosis for the further course depending on nonpharmaceutical interventions, we fitted a Bayesian SEIR model with several change points and set the determined change points in context with the distribution of variants of the virus.Biomarker können Ärzte durch ihren prognostischen Wert bei der Auswahl geeigneter Therapieoptionen unterstützen. In dieser Arbeit wurden mehrere fortgeschrittene statistische Methoden sowie Algorithmen des maschinellen Lernens eingeführt und in Zusammenarbeit mit verschiedenen Abteilungen des Universitätsklinikums Augsburg angewendet. Mit Hilfe eines Algorithmus des maschinellen Lernens, der versteckte Strukturen in binären, immunhistologisch gefärbten Bildern von Darmkrebstumoren feststellen kann, wurden Patienten mit einem hohen Risiko für auftretende Fernmetastasen identifiziert. Ebenso wurden Generalisierte Lineare Modelle verwendet, um eine Vorhersage der Wahrscheinlichkeit für eine dauerhafte Shunt-Anlegung nach einer aneurysmatischen Subarachnoidalblutung zu treffen. Patienten mit oligometastastischen Darmkrebs wurden mittels eines Scores, der anhand von Methoden der Survival Analysis entwickelt wurde, stratifiziert, um eine Gruppe zu identifizieren, die von einer operativen Entfernung der Metastasen durch ein langes Gesamtüberleben profitieren kann. Ein weiterer wichtiger Punkt bei der Datenanalyse ist die geeignete Auswahl der statistischen Methode abhängig von der Datenstruktur. Es konnten am Beispiel der Assoziation einer Coronainfektion mit der Anzahl von Lymphozytensubpopulationen gezeigt werden, dass eine Transformation der Zielvariable notwendig sein kann, um die Voraussetzungen der linearen Regression zu erfüllen. Die Modellierung der Anzahl an täglichen Neuinfektionen stellt eine relevante Aufgabe dar und benötigt passende statistische Modelle. Ein non-seasonal und ein seasonal ARIMA-Model wurden ebenso wie mehrere log-linearen autoregressiven Poisson-Modellen verglichen. Zusätzlich wurde ein weiterer Modellierungsansatz untersucht, der die biologischen Mechanismen stärker einbezieht und eine theoretische Prognose für den weiteren Verlauf unter verschiedenen Szenarien ermöglicht. Der Verlauf wurde mittels eines bayesschen SEIR Modell mit mehreren Wendepunkten an die Daten angepasst. Die gefundenen Wendepunkte wurden in Kontext der Verteilung der Virusvarianten analysiert

Consortial benchmarking: a method of academic-practitioner collaborative research and its application in a b2b environment

Purpose of the paper and literature addressed:\ud Development of a new method for academicpractitioner collaboration, addressing the literature on collaborative research\ud \ud Research method:\ud Model elaboration and test with an in-depth case study\ud \ud Research findings:\ud In consortial benchmarking, practitioners and academic researchers form a consortium and together benchmark best-practices firms. Consortial benchmarking includes practitioners as co-researchers, thus facilitating research relevant for both academics and practitioners. Rigorous research informs the entire process since consortial benchmarking collects evidence from multiple sources and uses different comparison techniques. We develop the method and illustrate it in a business-to-business environment with a case that identifies the nature of innovative suppliers\ud \ud Main contribution:\ud Consortial benchmarking combines rigor and relevance and can thus boost the stagnating field of academic-practitioner collaborative research

The Cityscapes Dataset for Semantic Urban Scene Understanding

Visual understanding of complex urban street scenes is an enabling factor for a wide range of applications. Object detection has benefited enormously from large-scale datasets, especially in the context of deep learning. For semantic urban scene understanding, however, no current dataset adequately captures the complexity of real-world urban scenes. To address this, we introduce Cityscapes, a benchmark suite and large-scale dataset to train and test approaches for pixel-level and instance-level semantic labeling. Cityscapes is comprised of a large, diverse set of stereo video sequences recorded in streets from 50 different cities. 5000 of these images have high quality pixel-level annotations; 20000 additional images have coarse annotations to enable methods that leverage large volumes of weakly-labeled data. Crucially, our effort exceeds previous attempts in terms of dataset size, annotation richness, scene variability, and complexity. Our accompanying empirical study provides an in-depth analysis of the dataset characteristics, as well as a performance evaluation of several state-of-the-art approaches based on our benchmark.Comment: Includes supplemental materia

Crucial role of local peroxynitrite formation in neutrophil-induced endothelial cell activation

Introduction and methods: The reaction of superoxide anions and NO not only results in a decreased availability of NO, but also leads to the formation of peroxynitrite, the role of which in the cardiovascular system is still discussed controversially. In cultured human endothelial cells, we studied whether there is a significant interaction between endothelial NO and neutrophil-derived superoxide anions in terms of endothelial peroxynitrite formation. We particularly studied whether a significantly higher redox-stress can be found in those endothelial cells directly adjacent to an activated neutrophil. Results: A considerable part of the 2,7-dihydrodichlorofluoresceine signal in endothelial cells was due to oxidation by peroxynitrite. Providing superoxide radicals by enzymatic source or by the neutrophil respiratory burst increased the fluorescence, which was attenuated by blockade of endothelial NO-synthase, suggesting that peroxynitrite was formed from neutrophil- or extracellular enzyme-derived superoxide and endothelial NO. Considerably higher fluorescence intensity was observed in endothelial cells in direct neighborhood to a neutrophil. This was particularly pronounced in the presence of a NO-donor and was accompanied by a strong activation of NF-κB and increased expression of E-selectin in these cells. Conclusion: Endothelial cells adjacent to neutrophils may have elevated levels of peroxynitrite that result in an increased expression of adhesion molecules. Such cells might represent a preferential site for adhesion and migration of additional neutrophils when simultaneously high concentrations of NO and neutrophil-derived superoxide are present

Implementation of a dermatoscopy curriculum during residency at Augsburg University Hospital in Germany

Background and objectives To date, there is no structured program for dermatoscopy training during residency in Germany. Whether and how much dermatoscopy training is acquired is left to the initiative of each resident, although dermatoscopy is one of the core competencies of dermatological training and daily practice. The aim of the study was to establish a structured dermatoscopy curriculum during residency at the University Hospital Augsburg. Patients and methods An online platform with dermatoscopy modules was created, accessible regardless of time and place. Practical skills were acquired under the personal guidance of a dermatoscopy expert. Participants were tested on their level of knowledge before and after completing the modules. Test scores on management decisions and correct dermatoscopic diagnosis were analyzed. Results Results of 28 participants showed improvements in management decisions from pre- to posttest (74.0% vs. 89.4%) and in dermatoscopic accuracy (65.0% vs. 85.6%). Pre- vs. posttest differences in test score (7.05/10 vs. 8.94/10 points) and correct diagnosis were significant (p < 0.001). Conclusions The dermatoscopy curriculum increases the number of correct management decisions and dermatoscopy diagnoses. This will result in more skin cancers being detected, and fewer benign lesions being excised. The curriculum can be offered to other dermatology training centers and medical professionals

Prospective study on complications using different techniques for parotidectomy for benign tumors

OBJECTIVES: Long‐term prospective studies on procedure‐related complications after parotid surgery for benign neoplasms (BNs) are scarce. This is the first prospective study on the use of extracapsular dissection (ECD) for BNs, and it aimed to examine the incidence of postoperative complications after parotid surgery for BN. METHODS: We collected data obtained in a prospective study of parotidectomy for BN at a university hospital and analyzed the transient and long‐term complications. RESULTS: The incidence rates of transient facial palsy immediately and 18 months after surgery were 15.0% and 3.7%, respectively. The rates of immediate postoperative facial palsy in patients who underwent ECD, partial superficial, superficial, and total parotidectomy were 5.8%, 29.3%, 20.0%, and 44.1%, respectively. Significant risk factors for facial palsy included multiple and larger lesions as well as surgery duration and extension. CONCLUSIONS: Postoperative facial palsy remains a common complication after parotidectomy for BN and is associated with the extent of parotidectomy, presence of multiple neoplasms, and operative duration. The results of this study showed that ECD could be a safe technique for avoiding facial palsy. Level of Evidence: 2

Endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma: long-term follow-up in a Western center

Background/Aims Endoscopic submucosal dissection (ESD) has been established as a treatment modality for superficial esophageal squamous cell carcinoma (ESCC). Long-term follow-up data are lacking in Western countries. The aim of this study was to analyze long-term survival in a Western center. Methods Patients undergoing ESD for ESCC were included. The analysis was performed retrospectively using a prospectively collected database. Results R0 resection rate was 96.7% (59/61 lesions in 58 patients). Twenty-seven patients (46.6%) fulfilled the curative resection criteria (M1/M2) (group A), 11 patients (19.0%) had M3 lesions without lymphovascular invasion (LVI) (group B), and 20 patients (34.5%) had lesions with submucosal invasion or LVI (group C). Additional treatment was recommended after non-curative resection. It was not performed in 20/31 patients (64.5%), mainly because of comorbidities (75%). Twenty-nine out of 58 (50.0%) patients died during a mean follow-up of 3.7 years. Death was related to ESCC in 17.2% (5/29) of patients. The disease-specific survival rate after curative resection was 100%. Overall survival rates after 5 years were 61.5%, 63.6% and 28.1% for groups A, B, and C, respectively. The overall survival was significantly worse after non-curative resection (p=0.038). Conclusions Non-curative resection is frequent after ESD for ESCC in Western patients. The long-term prognosis is limited and mainly determined by comorbidity. Early diagnosis and pre-interventional assessments need to be improved

Long-term and pathological outcomes of low- and intermediate-risk prostate cancer after radical prostatectomy: implications for active surveillance

Purpose!#!The safety of active surveillance (AS) in favorable intermediate-risk (FIR) prostate cancer (PCa) remains uncertain. To provide guidance on clinical decision-making, we examined long-term and pathological outcomes of low-risk and intermediate-risk PCa patients after radical prostatectomy (RP).!##!Methods!#!The study involved 5693 patients diagnosed between 1994 and 2019 with low-risk, FIR, and unfavorable intermediate-risk (UIR) PCa (stratification according to the AUA guidelines) who underwent RP. Pathological outcomes were compared, and Kaplan-Meier analysis determined biochemical recurrence-free survival (BRFS) and cancer-specific survival (CSS) at 5, 10, 15, and 20 years. Multiple Cox regression was used to simultaneously control for relevant confounders.!##!Results!#!Those at FIR had higher rates of upgrading and upstaging (12.8% vs. 7.2%, p &amp;lt; 0.001; 19.8% vs. 12.0%, p &amp;lt; 0.001) as well as pathological tumor and node stage (≥ pT3a: 18.8% vs. 11.6%, p &amp;lt; 0.001; pN1: 2.7% vs. 0.8%, p &amp;gt; 0.001) compared to patients at low risk. The 20-year BRFS was 69%, 65%, and 44% and the 20-year CSS was 98%, 95%, and 89% in low-risk, FIR, and UIR patients. On multiple Cox regression, FIR was not associated with a worse BRFS (HR 1.07, CI 0.87-1.32), UIR was associated with a worse BRFS (HR 1.49, CI 1.20-1.85).!##!Conclusion!#!Patients at FIR had only slightly worse pathological and long-term outcomes compared to patients at low risk, whereas the difference compared to patients at UIR was large. This emphasizes AS in these patients as a possible treatment strategy in well-counseled patients