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

Sadeq Hedayat: His work and his wondrous world

Featuring contributions from leading scholars of Iranian studies and / or comparative literature, this edited comprehensive and critical edited collection provides detailed scholarly analysis of Hedayat's life and work using a variety of methodological and conceptual approaches. Hedayat is the author of The Blind Owl, the most famous Persian novel both in Iran and in Europe and America. Many of his short stories are in a critical realist style and are regarded as among some of the best written in twentieth century Iran. But his most original contribution was the use of modernist, more often surrealist, techniques in Persian fiction. Thus, he was not only a great writer, but also the founder of modernism in Persian fiction. Yet both Hedayat's life and his death came to symbolize much more than leading writers would normally claim. He still towers over modern Persian fiction and will remain a highly controversial figure so long as the clash of the modern and the traditional, the Persian and the European, and the religious and the secular, has not led to a synthesis and a consensus

The Persians: Ancient, mediaeval and modern Iran

In recent years, Iran has gained attention mostly for negative reasons-its authoritarian religious government, disputed nuclear program, and controversial role in the Middle East-but there is much more to the story of this ancient land than can be gleaned from the news. This authoritative and comprehensive history of Iran, written by Homa Katouzian, an acclaimed expert, covers the entire history of the area from the ancient Persian Empire to today's Iranian state. Writing from an Iranian rather than a European perspective, Katouzian integrates the significant cultural and literary history of Iran with its political and social history. Some of the greatest poets of human history wrote in Persian-among them Rumi, Omar Khayyam, and Saadi-and Katouzian discusses and occasionally quotes their work. In his thoughtful analysis of Iranian society, Katouzian argues that the absolute and arbitrary power traditionally enjoyed by Persian/Iranian rulers has resulted in an unstable society where fear and short-term thinking dominate. A magisterial history, this book also serves as an excellent background to the role of Iran in the contemporary world. © 2009 Homa Katouzian. All rights reserved

The short-term society: a study in the problems of long-term political and economic development in Iran

Iran was a short-term society in contrast to Europe’s long-term society. It was a society in which change - even important and fundamental change - tended to be a short-term phenomenon. And this was precisely due to the absence of an established and inviolable legal framework which would guarantee long term continuity. Over any short period of time, there could be notable military, administrative and property-owning classes, but their composition would not remain the same beyond one or two generations, unlike traditional European aristocracies, even merchant classes. In Iran, property and social positions were short term, precisely because they were regarded as personal privileges rather than inherited and inviolable social rights. The situation of those who possessed rank and property - except in very rare examples - was not the result of long-term inheritance (say, beyond two generations before) and they did not expect their heirs to continue in the same positions as a matter of course. The heirs could do so only if they managed to establish themselves on their own merits - merits being the personal traits necessary for success within the given social context. There thus was a high degree of social mobility, unthinkable in medieval and much of the modern European history. This did not exclude the position of the shah himself, since legitimacy and the right of succession were nearly always subject to serious challenge, even rebellion

Iran: Politics, history and literature

This book offers a view of Iran through politics, history and literature, showing how the three angles combine

The Persians: Ancient, mediaeval and modern Iran

In recent years, Iran has gained attention mostly for negative reasons-its authoritarian religious government, disputed nuclear program, and controversial role in the Middle East-but there is much more to the story of this ancient land than can be gleaned from the news. This authoritative and comprehensive history of Iran, written by Homa Katouzian, an acclaimed expert, covers the entire history of the area from the ancient Persian Empire to today's Iranian state. Writing from an Iranian rather than a European perspective, Katouzian integrates the significant cultural and literary history of Iran with its political and social history. Some of the greatest poets of human history wrote in Persian-among them Rumi, Omar Khayyam, and Saadi-and Katouzian discusses and occasionally quotes their work. In his thoughtful analysis of Iranian society, Katouzian argues that the absolute and arbitrary power traditionally enjoyed by Persian/Iranian rulers has resulted in an unstable society where fear and short-term thinking dominate. A magisterial history, this book also serves as an excellent background to the role of Iran in the contemporary world. © 2009 Homa Katouzian. All rights reserved