Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction.

Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.

AACR Project GENIE: 100,000 Cases and Beyond.

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from the United States, Canada, the United Kingdom, France, the Netherlands, and Spain. Here, we demonstrate the use of these real-world data, harmonized through a centralized data resource, to accurately predict enrollment on genome-guided trials, discover driver alterations in rare tumors, and identify cancer types without actionable mutations that could benefit from comprehensive genomic analysis. The extensible data infrastructure and governance framework support additional deep patient phenotyping through biopharmaceutical collaborations and expansion to include new data types such as cell-free DNA sequencing. AACR Project GENIE continues to serve a global precision medicine knowledge base of increasing impact to inform clinical decision-making and bring together cancer researchers internationally. SIGNIFICANCE: AACR Project GENIE has now accrued data from >110,000 tumors, placing it among the largest repository of publicly available, clinically annotated genomic data in the world. GENIE has emerged as a powerful resource to evaluate genome-guided clinical trial design, uncover drivers of cancer subtypes, and inform real-world use of genomic data. This article is highlighted in the In This Issue feature, p. 2007.

A Crowdsourcing Approach to Develop Machine Learning Models to Quantify Radiographic Joint Damage in Rheumatoid Arthritis.

Importance: An automated, accurate method is needed for unbiased assessment quantifying accrual of joint space narrowing and erosions on radiographic images of the hands and wrists, and feet for clinical trials, monitoring of joint damage over time, assisting rheumatologists with treatment decisions. Such a method has the potential to be directly integrated into electronic health records. Objectives: To design and implement an international crowdsourcing competition to catalyze the development of machine learning methods to quantify radiographic damage in rheumatoid arthritis (RA). Design, Setting, and Participants: This diagnostic/prognostic study describes the Rheumatoid Arthritis 2-Dialogue for Reverse Engineering Assessment and Methods (RA2-DREAM Challenge), which used existing radiographic images and expert-curated Sharp-van der Heijde (SvH) scores from 2 clinical studies (674 radiographic sets from 562 patients) for training (367 sets), leaderboard (119 sets), and final evaluation (188 sets). Challenge participants were tasked with developing methods to automatically quantify overall damage (subchallenge 1), joint space narrowing (subchallenge 2), and erosions (subchallenge 3). The challenge was finished on June 30, 2020. Main Outcomes and Measures: Scores derived from submitted algorithms were compared with the expert-curated SvH scores, and a baseline model was created for benchmark comparison. Performances were ranked using weighted root mean square error (RMSE). The performance and reproductivity of each algorithm was assessed using Bayes factor from bootstrapped data, and further evaluated with a postchallenge independent validation data set. Results: The RA2-DREAM Challenge received a total of 173 submissions from 26 participants or teams in 7 countries for the leaderboard round, and 13 submissions were included in the final evaluation. The weighted RMSEs metric showed that the winning algorithms produced scores that were very close to the expert-curated SvH scores. Top teams included Team Shirin for subchallenge 1 (weighted RMSE, 0.44), HYL-YFG (Hongyang Li and Yuanfang Guan) subchallenge 2 (weighted RMSE, 0.38), and Gold Therapy for subchallenge 3 (weighted RMSE, 0.43). Bootstrapping/Bayes factor approach and the postchallenge independent validation confirmed the reproducibility and the estimation concordance indices between final evaluation and postchallenge independent validation data set were 0.71 for subchallenge 1, 0.78 for subchallenge 2, and 0.82 for subchallenge 3. Conclusions and Relevance: The RA2-DREAM Challenge resulted in the development of algorithms that provide feasible, quick, and accurate methods to quantify joint damage in RA. Ultimately, these methods could help research studies on RA joint damage and may be integrated into electronic health records to help clinicians serve patients better by providing timely, reliable, and quantitative information for making treatment decisions to prevent further damage.