Efficient Maximum Likelihood Estimation for Pedigree Data with the Sum-Product Algorithm

In this paper, we analyze data sets consisting of pedigrees where the response is the age at onset of colorectal cancer (CRC). The occurrence of familial clusters of CRC suggests the existence of a latent, inheritable risk factor. We aimed to compute the probability of a family possessing this risk factor, as well as the hazard rate increase for these risk factor carriers. Due to the inheritability of this risk factor, the estimation necessitates a costly marginalization of the likelihood. We therefore developed an EM algorithm by applying factor graphs and the sum-product algorithm in the E-step, reducing the computational complexity from exponential to linear in the number of family members. Our algorithm is as precise as a direct likelihood maximization in a simulation study and a real family study on CRC risk. For 250 simulated families of size 19 and 21, the runtime of our algorithm is faster by a factor of 4 and 29, respectively. On the largest family (23 members) in the real data, our algorithm is 6 times faster. We introduce a flexible and runtime-efficient tool for statistical inference in biomedical event data that opens the door for advanced analyses of pedigree data

Efficient Maximum Likelihood Estimation for Pedigree Data with the Sum-Product Algorithm

OBJECTIVE We analyze data sets consisting of pedigrees with age at onset of colorectal cancer (CRC) as phenotype. The occurrence of familial clusters of CRC suggests the existence of a latent, inheritable risk factor. We aimed to compute the probability of a family possessing this risk factor as well as the hazard rate increase for these risk factor carriers. Due to the inheritability of this risk factor, the estimation necessitates a costly marginalization of the likelihood. METHODS We propose an improved EM algorithm by applying factor graphs and the sum-product algorithm in the E-step. This reduces the computational complexity from exponential to linear in the number of family members. RESULTS Our algorithm is as precise as a direct likelihood maximization in a simulation study and a real family study on CRC risk. For 250 simulated families of size 19 and 21, the runtime of our algorithm is faster by a factor of 4 and 29, respectively. On the largest family (23 members) in the real data, our algorithm is 6 times faster. CONCLUSION We introduce a flexible and runtime-efficient tool for statistical inference in biomedical event data with latent variables that opens the door for advanced analyses of pedigree data

Ridepooling in der Modellierung des Gesamtverkehrs - Methodenbericht zur MOIA Begleitforschung

In der MOIA Begleitforschung wurden über zwei Jahre Effekte von Ridepooling auf das Hamburger Verkehrssystem untersucht. Die Studie liefert auf Basis umfassender empirischer Daten und einer Modellierung in hohem Detailgrad Erkenntnisse zu der noch neuen Verkehrsform und trägt dazu bei, die Potenziale von Ridepooling künftig noch zielgerichteter zu erschließen. Das im Rahmen der Begleitforschung entwickelte Verkehrsmodell besteht aus dem agentenbasierten Verkehrsnachfragemodell mobiTopp sowie dem Flottensimulationsmodell FleetPy und berücksichtigt die Angebots- und Nachfrageseite. mobiTopp bildet die Mobilität der gesamten Bevölkerung von Hamburg und Umland sowie der Privat- und Geschäftsreisenden im Wochenverlauf ab. Die Implementierung aktueller empirischer Erkenntnisse zur Nutzung neuer Mobilitätsangebote wie Ridepooling aber auch Car- , Bike- oder E-Scootersharing resultiert in besonders belastbaren Ergebnissen. Die Kopplung mit dem Flottenmodell sorgt für eine realitätsnahe Abbildung des Ridepooling-Dienstes, der Angebotsqualität und der verkehrlichen Wirkungen. Im Rahmen der Simulationsstudie wurden vier Szenarien entwickelt, die zeigen, wie sich die Mobilität in der Hansestadt zukünftig entwickeln kann

The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury

The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after strok

Analysis of Osteosarcoma Cell Lines and Patient Tissue Using a 3D In Vivo Tumor Model—Possible Effects of Punicalagin

Osteosarcomas are the most common primary malignant bone tumors and mostly affect children, adolescents, and young adults. Despite current treatment options such as surgery and polychemotherapy, the survival of patients with metastatic disease remains poor. In recent studies, punicalagin has reduced the cell viability, angiogenesis, and invasion in cell culture trials. The aim of this study was to examine the effects of punicalagin on osteosarcomas in a 3D in vivo tumor model. Human osteosarcoma biopsies and SaOs-2 and MG-63 cells, were grown in a 3D in vivo chorioallantoic membrane (CAM) model. After a cultivation period of up to 72 h, the tumors received daily treatment with punicalagin for 4 days. Weight measurements of the CAM tumors were performed, and laser speckle contrast imaging (LSCI) and a deep learning-based image analysis software (CAM Assay Application v.3.1.0) were used to measure angiogenesis. HE, Ki-67, and Caspase-3 staining was performed after explantation. The osteosarcoma cell lines SaOs-2 and MG-63 and osteosarcoma patient tissue displayed satisfactory growth patterns on the CAM. Treatment with punicalagin decreased tumor weight, proliferation, and tumor-induced angiogenesis, and the tumor tissue showed pro-apoptotic characteristics. These results provide a robust foundation for the implementation of further studies and show that punicalagin offers a promising supplementary treatment option for osteosarcoma patients. The 3D in vivo tumor model represents a beneficial model for the testing of anti-cancer therapies

Das vaskuläre Trauma: Analyse der Versorgungsrealität in einer deutschlandweiten Umfrage

Hintergrund und Ziel der Arbeit Die vaskuläre Beteiligung im Rahmen von Traumen ist selten. Für die Versorgung der Verletzungen gibt es nur wenige konkrete Handlungsempfehlungen, sodass von einer großen Varianz auszugehen ist. Ziel der vorliegenden Umfrage war die Statuserhebung der aktuellen Versorgungsrealität des Gefäßtraumas in Deutschland sowie die Eruierung des Bedarfs und der Form von entsprechenden Fortbildungsangeboten. Material und Methoden Es wurde eine Online-Umfrage über SurveyMonkey® mit den Mitgliedern der Gesellschaft für Gefäßchirurgie und Gefäßmedizin (DGG) durchgeführt. Ergebnisse An der Umfrage haben sich 10,6 % der angeschriebenen Mitglieder der DGG beteiligt. Hieraus ergab sich, dass die meisten Kliniken 5–10 traumatische Gefäßverletzungen pro Jahr versorgen, wobei die höchsten Behandlungszahlen erwartungsgemäß in den überregionalen Traumazentren erreicht werden. Die Versorgung des Gefäßtraumas ist nicht einheitlich, sondern findet abhängig von der anatomischen Lokalisation durch unterschiedliche Fachabteilungen statt. Kliniken für Gefäßchirurgie sind selten an der Versorgung beteiligt. Bei den meisten Befragten bestand der Wunsch nach Fortbildungen zum Erlernen von gefäßtraumatologischen Techniken. Diskussion Gefäßchirurgische Kliniken sind nach den vorliegenden Umfrageergebnissen selten an der Versorgung des vaskulären Traumas beteiligt. Mögliche Erklärungen hierfür liegen in lokalen und infrastrukturellen Gegebenheiten. Eine aktive Einbindung von gefäßchirurgisch ausgebildeten Ärztinnen und Ärzten in die Diagnostik und Therapie der vaskulären Traumata ist wünschenswert und sollte aktiv angeboten werden. Das Erlernen der hierfür notwendigen Techniken kann beispielsweise im Rahmen praktischer Kurse stattfinden

Polar Invasion and Translocation of Neisseria meningitidis and Streptococcus suis in a Novel Human Model of the Blood-Cerebrospinal Fluid Barrier

Acute bacterial meningitis is a life-threatening disease in humans. Discussed as entry sites for pathogens into the brain are the blood-brain and the blood-cerebrospinal fluid barrier (BCSFB). Although human brain microvascular endothelial cells (HBMEC) constitute a well established human in vitro model for the blood-brain barrier, until now no reliable human system presenting the BCSFB has been developed. Here, we describe for the first time a functional human BCSFB model based on human choroid plexus papilloma cells (HIBCPP), which display typical hallmarks of a BCSFB as the expression of junctional proteins and formation of tight junctions, a high electrical resistance and minimal levels of macromolecular flux when grown on transwell filters. Importantly, when challenged with the zoonotic pathogen Streptococcus suis or the human pathogenic bacterium Neisseria meningitidis the HIBCPP show polar bacterial invasion only from the physiologically relevant basolateral side. Meningococcal invasion is attenuated by the presence of a capsule and translocated N. meningitidis form microcolonies on the apical side of HIBCPP opposite of sites of entry. As a functionally relevant human model of the BCSFB the HIBCPP offer a wide range of options for analysis of disease-related mechanisms at the choroid plexus epithelium, especially involving human pathogens