Prediction Models for Cancer Risk and Prognosis using Clinical and DNA Methylation Biomarkers: Considerations in Study Design and Model Development

The ability to accurately predict the prognosis for any given disease is of immense value for clinicians and patients. It can dictate and optimize an individual treatment plan for a patient and ultimately improve their quality of life and reduce the financial burden associated with unnecessary treatment. To allow the accurate prediction of disease prognosis, ongoing development of prediction models is of crucial importance. We introduce a novel curated, ad-hoc, feature selection (CAFS) strategy in the context of the Prostate Cancer DREAM Challenge. We demonstrate enhanced prediction performance of overall survival differences in patients with metastatic castration-resistant prostate cancer by applying CAFS and identify clinically important risk-predictors. With ongoing advancements in the omics field promising molecular biomarkers are being identified in order to facilitate disease prognosis beyond the capability of clinical information. The identification of such biomarkers depends on the examination of omic marks in adequately powered studies. With the goal to assist researchers in study design and planning of epigenome wide association studies of DNA methylation, we present a user-friendly tool, pwrEWAS, for comprehensive power estimation for epigenome-wide association studies. The R package for pwrEWAS is publicly available at GitHub (https://github.com/stefangraw/pwrEWAS) and the web interface is available at https://biostats-shinyr.kumc.edu/pwrEWAS/. The enormous volume of omic marks requires stringent evaluation to discover combinations of complementary marks that assemble predictive biomarkers. We therefore present a heuristic feature selection approach that allows one to handle such high-dimensional data. Selection Probability Optimization for Feature Selection (SPOFS) is designed to identify an optimal subset of omic features from among a vast pool of such features, which collectively improves prediction accuracy and form a biomarker. The integration of such biomarkers can then be utilized in the development and improvement of prediction models

Is multidirectional UV exposure responsible for increasing melanoma prevalence with altitude? A hypothesis based on calculations with a 3D-human exposure model

In a recent study, melanoma incidence rates for Austrian inhabitants living at higher altitudes were found to increase by as much as 30% per 100 m altitude. This strong increase cannot simply be explained by the known increase of erythemally-weighted irradiance with altitude, which ranges between 0.5% and 4% per 100 m. We assume that the discrepancy is partially explainable by upwelling UV radiation; e.g., reflected by snow-covered surfaces. Therefore, we present an approach where the human UV exposure is derived by integrating incident radiation over the 3D geometry of a human body, which enables us to take upwelling radiation into account. Calculating upwelling and downwelling radiance with a radiative transfer model for a snow-free valley and for snow-covered mountain terrain (with albedo of 0.6) yields an increase in UV exposure by 10% per 100 m altitude. The results imply that upwelling radiation plays a significant role in the increase of melanoma incidence with altitude.Austrian Climate Research Program (ACRP

Biomechanical assessment of various punching techniques

Punches without the use of instruments/objects are a common type of body violence and as such a frequent subject of medicolegal analyses. The assessment of the injuries occurred as well as of the potential of the assault to produce severe body harm is based on objective traces (especially the documented injuries of both parties involved) as well as the-often divergent-descriptions of the event. Quantitative data regarding the punching characteristics that could be used for the assessment are rare and originate mostly in sports science. The aim of this study was to provide physical data enabling/facilitating the assessment of various punching techniques. A total of 50 volunteers took part in our study (29 males and 21 females) and performed severe punches with the fist, with the small finger edge of the hand (karate chop), and with the open hand with both the dominant and the non-dominant hands in randomized order. The strikes were performed on a boxing pad attached to a KISTLER force plate (sampling frequency 10,000 Hz) mounted on a vertical wall. The punching velocity was defined as the hand velocity over the last 10 cm prior to the contact to the pad and ascertained by using a high-speed camera (2000 Hz). Apart from the strike velocity, the maximum force, the impulse (the integral of the force-time curve), the impact duration, and the effective mass of the punch (the ratio between the impulse and the strike velocity) were measured/calculated. The results show a various degree of dependence of the physical parameters of the strikes on the punching technique, gender, hand used, body weight, and other factors. On the other hand, a high degree of variability was observed that is likely attributable to individual punching capabilities. In a follow-up study, we plan to compare the \textquotedblordinary\textquotedbl persons with highly trained (boxers etc.) individuals. Even though the results must be interpreted with great caution and a direct transfer of the quantitative parameters to real-world situations is in general terms not possible, the study offers valuable insights and a solid basis for a qualified forensic medical/biomechanical assessment

Age and gender as determinants of the bone quality of the greater tuberosity: A HR-pQCT cadaver study

Background: Age-dependent trabecular changes of the humeral head might weaken the fixation of suture anchors used for rotator cuff (RC) repair. This might lead to suture anchor loosening and thus compromise the integrity of the repair. The aim of this study was to analyze whether the trabecular microstructure within the RC footprint is influenced by age, gender or handedness. Methods: Axial HR-pQCT scans (Scanco Medical) of 64 freshly frozen cadaveric human humeral head specimens (age 72.3 +/- 17.4 years) were analyzed to determine the bone volume-to-total volume ratio (BV/TV), trabecular thickness (Trab Th), trabecular number (Trab N) and connectivity density (Conn Dens). Within the RC footprint, 2 volumes of interest (VOI), posteromedial (PM) and anterolateral (AL) and one control VOI in the subarticular bone (SC) were set. Results: The highest BV/TV was found in SC: 0.22 +/- 0.06% vs. PM: 0.04 +/- 0.05% vs. AL: 0.02 +/- 0.04%; p < 0.05. Trab Th accounted for 0.26 +/- 0.05 mu m in SC, 0.23 +/- 0.09 mu m in AL and 0.21 +/- 0.05 mu m in PM. In parallel, Trab N and Conn Dens were found to be the highest in SC. Gender analysis yielded higher values for BV/TV, Trab Th, Trab N and Conn Dens for PM in males compared to females (p < 0.05). There were no significant findings when comparing both sides. We furthermore found a strong inverse correlation between age and BV/TV, which was more pronounced in the female specimens (r = -0.72, p < 0.00001). Conclusions: The presented microarchitectural data allow for future subtle biomechanical testing comprising knowledge on age-and sex-related changes of the tuberosities of the humeral head. Furthermore, the insights on the trabecular structure of the humeral head of the elderly may lead to the development of new fixation materials in bone with inferior bone quality

Differences in the Tumor Microenvironment between African-American and European-American Breast Cancer Patients

Background: African-American breast cancer patients experience higher mortality rates than European-American patients despite having a lower incidence of the disease. We tested the hypothesis that intrinsic differences in the tumor biology may contribute to this cancer health disparity. Methods and Results: Using laser capture microdissection, we examined genome-wide mRNA expression specific to tumor epithelium and tumor stroma in 18 African-American and 17 European-American patients. Numerous genes were differentially expressed between these two patient groups and a two-gene signature in the tumor epithelium distinguished between them. To identify the biological processes in tumors that are different by race/ethnicity, Gene Ontology and disease association analyses were performed. Several biological processes were identified which may contribute to enhanced disease aggressiveness in African-American patients, including angiogenesis and chemotaxis. African-American tumors also contained a prominent interferon signature. The role of angiogenesis in the tumor biology of African-American

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer : development of a prognostic model through a crowdsourced challenge with open clinical trial data

Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0.791; Bayes factor >5) and surpassed the reference model (iAUC 0.743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3.32, 95% CI 2.39-4.62, p Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer.Peer reviewe

Hitzewellen und Hitzewarnungen in Städten

Stadtbewohner sind von Hitzewellen, die in Folge des Klimawandels häufiger, intensiver und länger auftreten, stärker betroffen als Bewohner auf dem Land. Die während des Tages aufgeheizten Gebäude in Städten kühlen nachts weniger stark aus als Gebäude im geringer verdichteten Umland. Dadurch wird das bereits beanspruchte Thermoregulationssystem des Körpers zusätzlich gefordert und nächtliche Ruhephasen werden verkürzt. Anhaltend hohe Temperaturen wirken auf diese Weise besonders belastend auf den menschlichen Körper. In Deutschland verstarben 2003 ca. 7.600 Menschen an den Folgen hitzebedingter Gesundheitsbelastung. Um auf bevorstehende Hitzewellen rechtzeitig reagieren zu können und Maßnahmen für den Gesundheitsschutz einzuleiten, hat sich das Hitzewarnsystem des Deutschen Wetterdienstes etabliert. Die besondere Belastung in Städten infolge des Effekts der Städtischen Wärmeinsel wird seit 2017 bei Hitzewarnungen besonders berücksichtigt. Untersuchungen in Berlin und Brandenburg haben ergeben, dass während der Hitzewelle 1994 die höchsten Abweichungen der Mortalität vom Erwartungswert in den am dichtesten bebauten Gebieten Berlins auftraten. Um zukünftig mit den intensiveren Hitzewellen umgehen zu können und Gesundheitsrisiken zu vermeiden, sollten daher insbesondere im städtischen Raum Anpassungsmaßnahmen entwickelt werden. Heat waves and heat warnings in cities: Urban dwellers are more affected by heat waves, which will occur more frequently, more intensively and will last longer as a result of climate change, than rural dwellers. The buildings in cities that are heated during the day cool down less at night than buildings in less densely populated areas. This places additional demands on the body‘s already stressed thermoregulation system and shortens rest periods at night. In this way, persistently high temperatures have a particularly stressful effect on the human body. In Germany, around 7600 people died in 2003 as a result of heat-related health problems. The heat warning system of the German Meteorological Service has established itself in order to be able to react in time to impending heat waves and to initiate measures for health protection. Since 2017, the specific heat stress in cities due to the Urban-Heat-Island effect has been given special consideration in heat warnings. Studies in Berlin and Brandenburg have revealed that during the heatwave in 1994 the highest deviation of mortality from the expected value occurred in the most densely built-up areas of Berlin. In order to be able to deal with the more intense heat waves in the future and to avoid health risks, adaptation measures should therefore be developed, especially in urban areas

Thermische Belastung von Bewohnern in Städten bei Hitzewellen am Beispiel von Freiburg (Breisgau)

Background!#!As a result of climate change, people are increasingly affected by heat and the negative health effects of heat. Air temperature is often used as a measurement. However, in order to characterize the effects of heat on humans, other factors must be considered in addition to air temperature.!##!Objectives!#!The aim of this paper is to characterize the thermal stress of urban dwellers by means of the perceived temperature during heat waves, compare it with rural dwellers, and highlight differences from air temperature.!##!Materials and methods!#!Data from the year 2019 are used from two different German Weather Service (DWD) stations located within the city of Freiburg im Breisgau, Germany, and its surroundings (Freiburg Airport). Air temperature as well as other meteorological elements were taken to calculate the perceived temperature by means of the Klima-Michel model. Additionally, days with heat warnings as well as nightly indoor temperatures from the heat health warning system are presented.!##!Results!#!The perceived temperature exceeds the air temperature during heat waves by up to 10 °C. The classic heat-island effect is particularly evident in the difference in the nightly air temperature while the difference in the daily air temperature is small. In the case of perceived temperature, the difference is significantly higher not only at night but also during the day.!##!Conclusions!#!In order to quantify negative impacts, not only the knowledge of air temperature is required, but also other factors that describe and control the thermal stress on humans. Urban-rural differences in air temperature and perceived temperature enable heat quantification. Adaptation measures taking into account the more intense conditions in cities are necessary