Summary 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<0·0001; reference model: 2·56, 1·85–3·53, p<0·0001). The new model was validated further on the ENTHUSE M1 cohort with similarly high performance (iAUC 0·768). Meta-analysis across all methods confirmed previously identified...

Background Associations between childhood asthma phenotypes and genetic, immunological, and environmental factors have been previously established. Yet, strategies to integrate high‐dimensional risk factors from multiple distinct data sets, and thereby increase the statistical power of analyses, have been hampered by a preponderance of missing data and lack of methods to accommodate them. Methods We assembled questionnaire, diagnostic, genotype, microarray, RT‐qPCR, flow cytometry, and cytokine data (referred to as data modalities) to use as input factors for a classifier that could distinguish healthy children, mild‐to‐moderate allergic asthmatics, and nonallergic asthmatics. Based on data from 260 German children aged 4‐14 from our university outpatient clinic, we built a novel multilevel prediction approach for asthma outcome which could deal with a present complex missing data structure. Results The optimal learning method was boosting based on all data sets, achieving an area underneath the receiver operating characteristic curve (AUC) for three classes of phenotypes of 0.81 (95%‐confidence interval (CI): 0.65‐0.94) using leave‐one‐out cross‐validation. Besides improving the AUC, our integrative multilevel learning approach led to tighter CIs than using smaller complete predictor data sets (AUC = 0.82 [0.66‐0.94] for boosting). The most important variables for classifying childhood asthma phenotypes comprised novel identified genes, namely PKN2 (protein kinase N2), PTK2 (protein tyrosine kinase 2), and ALPP (alkaline phosphatase, placental). Conclusion Our combination of several data modalities using a novel strategy improved classification of childhood asthma phenotypes but requires validation in external populations. The generic approach is applicable to other multilevel data‐based risk prediction settings, which typically suffer from incomplete data.

Background The asthma syndrome is influenced by hereditary and environmental factors. With the example of farm exposure, we study whether genetic and environmental factors interact for asthma. Methods Statistical learning approaches based on penalized regression and decision trees were used to predict asthma in the GABRIELA study with 850 cases (9% farm children) and 857 controls (14% farm children). Single‐nucleotide polymorphisms (SNPs) were selected from a genome‐wide dataset based on a literature search or by statistical selection techniques. Prediction was assessed by receiver operating characteristics (ROC) curves and validated in the PASTURE cohort. Results Prediction by family history of asthma and atopy yielded an area under the ROC curve (AUC) of 0.62 [0.57‐0.66] in the random forest machine learning approach. By adding information on demographics (sex and age) and 26 environmental exposure variables, the quality of prediction significantly improved (AUC = 0.65 [0.61‐0.70]). In farm children, however, environmental variables did not improve prediction quality. Rather SNPs related to IL33 and RAD50 contributed significantly to the prediction of asthma (AUC = 0.70 [0.62‐0.78]). Conclusions Asthma in farm children is more likely predicted by other factors as compared to non‐farm children though in both forms, family history may integrate environmental exposure, genotype and degree of penetrance.