Objective The capability to share data, and harness its potential to generate knowledge rapidly and inform decisions, can have transformative effects that improve health. The infrastructure to achieve this goal at scale—marrying technology, process, and policy—is commonly referred to as the Learning Health System (LHS). Achieving an LHS raises numerous scientific challenges.Materials and methods The National Science Foundation convened an invitational workshop to identify the fundamental scientific and engineering research challenges to achieving a national-scale LHS. The workshop was planned by a 12-member committee and ultimately engaged 45 prominent researchers spanning multiple disciplines over 2 days in Washington, DC on 11–12 April 2013.Results The workshop participants collectively identified 106 research questions organized around four system-level requirements that a high-functioning LHS must satisfy. The workshop participants also identified a new cross-disciplinary integrative science of cyber-social ecosystems that will be required to address these challenges.Conclusions The intellectual merit and potential broad impacts of the innovations that will be driven by investments in an LHS are of great potential significance. The specific research questions that emerged from the workshop, alongside the potential for diverse communities to assemble to address them through a ‘new science of learning systems’, create an important agenda for informatics and related disciplines.

Our current health research enterprise is painstakingly slow and cumbersome, and its results seldom translate into practice. The slow pace of health research contributes to findings that are less relevant and potentially even obsolete. To produce more rapid, responsive, and relevant research, we propose approaches that increase relevance via greater stakeholder involvement, speed research via innovative designs, streamline review processes, and create and/or better leverage research infrastructure. Broad stakeholder input integrated throughout the research process can both increase relevance and facilitate study procedures. More flexible and rapid research designs should be considered before defaulting to the traditional two‐arm randomized controlled trial (RCT), but even traditional RCTs can be designed for more rapid findings. Review processes for grant applications, IRB protocols, and manuscript submissions can be better streamlined to minimize delays. Research infrastructures such as rapid learning systems and other health information technologies can be leveraged to rapidly evaluate new and existing treatments, and alleviate the extensive recruitment delays common in traditional research. These and other approaches are feasible but require a culture shift among the research community to value not only methodological rigor, but also the pace and relevance of research.

Compelling public interest is propelling national efforts to advance the evidence base for cancer treatment and control measures and to transform the way in which evidence is aggregated and applied. Substantial investments in health information technology, comparative effectiveness research, health care quality and value, and personalized medicine support these efforts and have resulted in considerable progress to date. An emerging initiative, and one that integrates these converging approaches to improving health care, is "rapid-learning health care." In this framework, routinely collected real-time clinical data drive the process of scientific discovery, which becomes a natural outgrowth of patient care. To better understand the state of the rapid-learning health care model and its potential implications for oncology, the National Cancer Policy Forum of the Institute of Medicine held a workshop entitled "A Foundation for Evidence-Driven Practice: A Rapid-Learning System for Cancer Care" in October 2009. Participants examined the elements of a rapid-learning system for cancer, including registries and databases, emerging information technology, patient-centered and -driven clinical decision support, patient engagement, culture change, clinical practice guidelines, point-of-care needs in clinical oncology, and federal policy issues and implications. This Special Article reviews the activities of the workshop and sets the stage to move from vision to action.

Private-and public-sector initiatives, using electronic health record (EHR) databases from millions of people, could rapidly advance the U.S. evidence base for clinical care. Rapid learning could fill major knowledge gaps about health care costs, the benefits and risks of drugs and procedures, geographic variations, environmental health influences, the health of special populations, and personalized medicine. Policymakers could use rapid learning to revitalize value-based competition, redesign Medicare's payments, advance Medicaid into national health care leadership, foster national collaborative research initiatives, and design a national technology assessment system. [Health Affairs 26,no. 2