OpenPBTA: A New Collaborative Effort to Accelerate Discoveries Empowered by the Pediatric Brain Tumor Atlas

Originally published on September 29, 2019

According to the World Health Organization, over 300,000 children and adolescents under the age of 20 are diagnosed with cancer worldwide each year. In the United States, an average of 1 in every 285 children will develop cancer before the age of 20. While overall progress has been made, both nationally and internationally, brain tumors remain a leading cause of disease-related death for children and young adults. While the last several decades have seen transformative advances in biomedical research, there has been very little progress made in successfully treating and curing pediatric brain tumors. In fact there are currently no drug interventions specifically targeted for pediatric brain cancer patients.

Over the past year, the Children’s Brain Tumor Network (CBTN) and the Pacific Pediatric Neuro-Oncology Consortium (PNOC) have partnered with patients and their families to launch the Pediatric Brain Tumor Atlas (PBTA), a global effort to accelerate discoveries for therapeutic intervention for children diagnosed with brain tumors through the non-embargoed, pre-publication release of one of the largest genomic datasets for pediatric brain tumors to date. This foundational dataset was released on the NIH Common Fund-supported Gabriella Miller Kids First portal and CAVATICA workspace.

PBTA data include matched tumor/normal tissue, whole genomes (WGS), exomes (WES), transcriptomes (RNA-Seq), proteomics, miRNA, longitudinal clinical data, pathology reports, and imaging data, including MRIs, radiology reports, and histology slides. Additionally, processed data files for somatic mutations, somatic copy number and structural alterations, gene and transcript-level expression data, gene fusions, and harmonized clinical data are included.

Together, with our patient and foundation partners, CBTN and PNOC have amassed more than 381TB of clinical and multi-omic data - open to researchers anywhere on earth without embargo - to empower breakthroughs that will save childrens’ lives.

OpenPBTA Project

Recently, researchers from the Center for Data-Driven Discovery in Biomedicine (D3b) at Children’s Hospital of Philadelphia (CHOP) and the Childhood Cancer Data Lab (CCDL) at Alex’s Lemonade Stand Foundation, set out to launch the OpenPBTA Project, a first-in-kind collaborative, crowd-sourcing analytic global initiative. This new open science project seeks to harness the collective will and brain power of the biomedical research and data informatics community to comprehensively describe the PBTA and accelerate scientific discoveries that will lead to clinical impact for childhood cancer patients.

Alex’s Lemonade Stand Foundation, recognizing that big data represented a strategic opportunity that the pediatric cancer research field had not yet fully capitalized on, launched the Childhood Cancer Data Lab (CCDL) in August 2017 to empower pediatric cancer experts poised for the next big discovery with the knowledge, data, and tools to reach it. The team of data science, software engineering, and design experts is the first bioinformatics lab solely dedicated to childhood cancer research that is directly run by a pediatric cancer non-profit.

Dr. Jaclyn Taroni, who leads the CCDL’s data science team notes, “Performing analyses in the open with best practices (e.g., analytical code review, reproducibility) is well-aligned with the CCDL’s philosophy to produce rigorous, reusable workflows. OpenPBTA will build these skills and infrastructure within the research community enabling participants to take these best practices forward to subsequent projects.”

The OpenPBTA Project is organized on GitHub, which allows data scientists to work together. Bioinformaticians and data scientists anywhere on earth are invited to join the project at the OpenPBTA GitHub Analysis Repository.

This crowd-sourced, open analysis effort is leading to a manuscript that will provide a detailed, molecular picture of more than over 30 pediatric brain tumor types represented within the PBTA. The completed manuscript will help laboratory scientists and clinicians to more clearly identify, describe, and chart how cancerous brain cells mutate and propagate separate from normal tissue cells. The OpenPBTA Manuscript is currently a living document, with updates available in real time and on an on-going basis, allowing for continuous team science efforts and an expanding resource to empower scientific discovery. Similar to the open source approach utilized for data analysis, the development of this manuscript will marshall the talents of a broad community to contribute to its writing and accelerate discovery on behalf of clinical translation. The OpenPBTA Project organizers aim to produce a first draft manuscript within three months of this launch. Speeding the rate at which research is done to accelerate discoveries to clinical impact .

The OpenPBTA Project will rely on input from a broad cross-section of the pediatric brain cancer research community. Clinicians and researchers, including patients, can contribute immensely to the development of the manuscript, confirming the accuracy of tumor sub-typing and molecular alterations, and contributing to the overall scientific discussion.

Project Development

In the year since its launch, the PBTA dataset has empowered a number of research projects, and has already yielded significant scientific insights. One of the OpenPBTA organizers, Dr. Pichai Raman (Children’s Hospital of Philadelphia), recently developed a medulloblastoma classifier that allowed him to subtype medulloblastomas into four distinct sub-groups, which will allow the team to analyze each subtype independently to better understand the development of medulloblastoma brain tumors in patients.

In order to fully harness the resources within the PBTA, more work must be done. There remains a need for increased investigation of copy number and structural variation. There is also a need for researchers with expertise in cancer immunology, clinical analysis, and molecular subtyping of brain tumors to join the effort. Similar to Dr. Raman’s recent success in medulloblastoma subtyping, the OpenPBTA Project hopes to subtype all brain and central nervous system tumors within the PBTA, which will require a broad representation of standardized and integrated cancer subtype/grade diagnoses.

The open source software movement has led to robust, widely-used software that serves as critical infrastructure. A previous effort to author a review manuscript by a similar approach, co-led by Dr. Casey Greene - an OpenPBTA organizer - resulted in an article that became the most downloaded preprint of 2017 on the bioRxiv preprint server. The OpenPBTA Project brings this approach to the area of pediatric cancer research. Dr. Jo Lynne Rokita, an OpenPBTA organizer, notes “With the rare incidence of any single pediatric tumor subtype, open science is crucial to accelerating discoveries that will ultimately benefit pediatric cancer patients. This is an opportunity to bring together diverse experts around a richly-annotated dataset to tackle pediatric cancer.”

Dr. Taroni developed a system to automatically test contributions from project participants against the PBTA dataset. She notes, “We designed the OpenPBTA infrastructure to regularly test contributions. As the underlying dataset continues to grow and improve, our analyses can be updated alongside it.”

The OpenPBTA Project underscores the importance of involving a broad base of collaborative partners with the data sharing efforts of the CBTN and PNOC. As investigators raise the call to the global community to aid in charting and defining the PBTA, the continued growth of this dataset will be essential. By contributing biosamples and patient data, by using the data for research and clinical applications, or by contributing toward the complete understanding of all that is contained within this atlas, anyone - including clinicians, researchers, and patients - can help to ensure that this data repository continues to grow even richer. Through the OpenPBTA’s open collaboration and contribution, the pediatric brain cancer community will continuously provide more pieces of the puzzle, building a comprehensive image of the genetic causes, development, and recurrence of these devastating diseases in children. This is a critical step towards identifying and developing cures.

Here’s what our patient partners, CBTN, PNOC, and CCDL leadership have to say about OpenPBTA:

“I’m excited about the possibilities of the entire world’s ideas coming together looking for a common solution. Only through shared ideas can we pursue accelerated discoveries,” says Jace Ward, who, at 20 years old, is currently battling a DIPG brain tumor. His mother, Lisa Ward, follows, “For too long children have perished while well-meaning researchers worked in isolation, waiting to publish promising results. It’s cures not credit we need most. Clinician awareness, open research, and incentives for sharing will bring cures. Time matters, because pediatric tumors won’t wait. Kudos to those who get it!”

Dr. Casey Greene, the CCDL’s Director, emphasized the opportunity to build a community of practice that continues beyond the project itself: “This open project complements the CCDL’s existing efforts by nucleating a community centered on big data analytics for pediatric brain tumors that includes data scientists, pediatric oncologists, genomics experts, and others with a drive to cure these cancers.”

“The CBTN has an unwavering focus on fostering a culture of team-science to accelerate clinical impact. I believe the OpenPBTA project is an example of this scientific culture; inviting data scientists, lab researchers, and clinicians worldwide to work together,” states Dr. Angela Waanders, CBTN Executive Chair. “I’m so grateful for our partnerships with PNOC, the Alex’s Lemonade Stand Foundation’s Childhood Cancer Data Lab, and with talented investigators around the globe who have contributed to the growth of the PBTA and continue to work hand-in-hand with us to uncover new insights for the benefit of children with brain tumors.”

“Pediatric brain tumors represent many rare tumor types, and few patients. As such, it is critical that we have the most complete data from as many children as possible, over the shortest time possible, to put together the information needed to truly inform treatment decisions. PNOC’s mission is to develop personalized, biologically informed, individualized treatment for every child. Real-time access to comprehensive data has yet to be achieved, but this is our goal. We believe OpenPBTA will help all of us achieve that goal, in an open-source environment freely shared by researchers, clinicians, and most importantly, our patients and their families,” claim Drs. Sabine Mueller and Michael Prados, PNOC Project Leaders.

“Increasing our understanding of the molecular characteristics, behavior, and causes of childhood brain tumors is critical in the development of effective therapies and cures for children. By involving laboratory scientists and clinicians along with data experts and bioinformaticians, OpenPBTA is a unique opportunity for the entire pediatric brain cancer community to work together in real-time toward swiftly making the discoveries that will lead to improved outcomes and lives saved,” says CBTN Principal Investigator Dr. Jay Storm.

According to Dr. Adam Resnick, CBTN & PNOC Scientific Co-Chair, “OpenPBTA reflects a sea-change in the academic research model; emphasizing continuously-growing opportunities for international collaboration that have been made possible by new technologies in genomic analysis paired with cloud-based compute tools and platforms. The project also represents an exciting next step in harnessing the full potential of the data held within the Pediatric Brain Tumor Atlas. Through the collective efforts of project participants, OpenPBTA will soon generate the insights needed to make significant scientific progress and clinical impact.”

“This is a critical step forward in thinking about how to approach cancer research. We are so fortunate that is happening for pediatric brain tumor patients,” concludes Amanda Haddock, Co-Founder of Dragon Master Foundation and parent to a son who lost his battle with brain cancer in 2012.

Once a doctor delivers a cancer diagnosis to a child or young adult, the clock on our time to intervene begins ticking. We are getting better each year at making those live-saving interventions in time (though often with long-lasting patient side effects). However, other patients have greatly limited time - sometimes only a few months - for us to find a cure before their diagnosis turns fatal. For these patients, we do not have years to discover life-saving cures. We must work to uncover better treatments right now to stop the clock and save today’s pediatric cancer patients.

None of this work would be possible without the staggering strength, commitment, and courage of our patients and their families, who are critical partners in our efforts. Whether pushing to have every possible biospecimen or clinical record donated for analysis, organizing or participating in a local 5k or a national campaign to raise research funds, or advocating that community leaders devote more resources to childhood cancer research, people from all walks of life repeatedly mobilize to defy the illness that has claimed the futures of so many of our young people.

The CBTN, PNOC, ALSF’s Childhood Cancer Data Lab, and each of our research partners are tremendously grateful for these patient and community partnerships, and this personally-felt determination to drive research toward new therapies and cures. We stand side-by-side with you, and pledge to work ceaselessly until there is a cure for every child, everywhere.