Biomedicine is undergoing a revolution driven by high throughput and connective computing that is transforming medical research and practice. Using oncology as an example, the speed and capacity of genomic sequencing technologies is advancing the utility of individual genetic profiles for anticipating risk and targeting therapeutics. The goal is to enable an era of “P4” medicine that will become increasingly more predictive, personalized, preemptive, and participative over time. This vision hinges on leveraging potentially innovative and disruptive technologies in medicine to accelerate discovery and to reorient clinical practice for patient-centered care. Based on a panel discussion at the Medicine 2.0 conference in Boston with representatives from the National Cancer Institute, Moffitt Cancer Center, and Stanford University School of Medicine, this paper explores how emerging sociotechnical frameworks, informatics platforms, and health-related policy can be used to encourage data liquidity and innovation. This builds on the Institute of Medicine’s vision for a “rapid learning health care system” to enable an open source, population-based approach to cancer prevention and control.
biomedical research; crowdsourcing; health information technology; innovation; precision medicine
State health departments in Michigan, Minnesota, Oregon, and Utah explored the use of genomic information, including family health history, in chronic disease prevention programs. To support these explorations, the Office of Public Health Genomics at the Centers for Disease Control and Prevention provided cooperative agreement funds from 2003 through 2008. The 4 states’ chronic disease programs identified advocates, formed partnerships, and assessed public data; they integrated genomics into existing state plans for genetics and chronic disease prevention; they developed projects focused on prevention of asthma, cancer, cardiovascular disease, diabetes, and other chronic conditions; and they created educational curricula and materials for health workers, policymakers, and the public. Each state’s program was different because of the need to adapt to existing culture, infrastructure, and resources, yet all were able to enhance their chronic disease prevention programs with the use of family health history, a low-tech “genomic tool.” Additional states are drawing on the experience of these 4 states to develop their own approaches.
The term P4 medicine is used to denote an evolving field of medicine that uses systems biology approaches and information technologies to enhance wellness rather than just treat disease. Its four components include predictive, preventive, personalized, and participatory medicine. In the current paper, it is argued that in order to fulfill the promise of P4 medicine, a “fifth P” must be integrated--the population perspective--into each of the other four components. A population perspective integrates predictive medicine into the ecologic model of health; applies principles of population screening to preventive medicine; uses evidence-based practice to personalize medicine; and grounds participatory medicine on the three core functions of public health: assessment, policy development, and assurance. Population sciences--including epidemiology; behavioral, social, and communication sciences; and health economics, implementation science, and outcomes research--are needed to show the value of P4 medicine. Balanced strategies that implement both population- and individual-level interventions can best maximize health benefits, minimize harms, and avoid unnecessary healthcare costs.
Advances in genomics and related fields promise a new era of personalized medicine in the cancer care continuum. Nevertheless, there are fundamental challenges in integrating genomic medicine into cancer practice. We explore how multilevel research can contribute to implementation of genomic medicine. We first review the rapidly developing scientific discoveries in this field and the paucity of current applications that are ready for implementation in clinical and public health programs. We then define a multidisciplinary translational research agenda for successful integration of genomic medicine into policy and practice and consider challenges for successful implementation. We illustrate the agenda using the example of Lynch syndrome testing in newly diagnosed cases of colorectal cancer and cascade testing in relatives. We synthesize existing information in a framework for future multilevel research for integrating genomic medicine into the cancer care continuum.
The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.
behavioral sciences; epidemiologic methods; evidence-based medicine; genetics; genetic testing; genomics; medicine; public health
Recent emphasis on translational research (TR) is highlighting the role of epidemiology in translating scientific discoveries into population health impact. The authors present applications of epidemiology in TR through 4 phases designated T1–T4, illustrated by examples from human genomics. In T1, epidemiology explores the role of a basic scientific discovery (e.g., a disease risk factor or biomarker) in developing a “candidate application” for use in practice (e.g., a test used to guide interventions). In T2, epidemiology can help to evaluate the efficacy of a candidate application by using observational studies and randomized controlled trials. In T3, epidemiology can help to assess facilitators and barriers for uptake and implementation of candidate applications in practice. In T4, epidemiology can help to assess the impact of using candidate applications on population health outcomes. Epidemiology also has a leading role in knowledge synthesis, especially using quantitative methods (e.g., meta-analysis). To explore the emergence of TR in epidemiology, the authors compared articles published in selected issues of the Journal in 1999 and 2009. The proportion of articles identified as translational doubled from 16% (11/69) in 1999 to 33% (22/66) in 2009 (P = 0.02). Epidemiology is increasingly recognized as an important component of TR. By quantifying and integrating knowledge across disciplines, epidemiology provides crucial methods and tools for TR.
epidemiology; genomics; medicine; public health; translational research
The recent success of genome-wide association studies in finding susceptibility genes for many common diseases presents tremendous opportunities for epidemiologic studies of environmental risk factors. Analysis of gene-environment interactions, included in only a small fraction of epidemiologic studies until now, will begin to accelerate as investigators integrate analyses of genome-wide variation and environmental factors. Nevertheless, considerable methodological challenges are involved in the design and analysis of gene-environment interaction studies. The authors review these issues in the context of evolving methods for assessing interactions and discuss how the current agnostic approach to interrogating the human genome for genetic risk factors could be extended into a similar approach to gene-environment-wide interaction studies of disease occurrence in human populations.
environment; epidemiologic methods; genetics; genomics
Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimer's disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues—especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P < 10−7). They also present a vision of collaboration that builds reliable cumulative evidence for genetic associations with common complex diseases and a transparent, distributed, authoritative knowledge base on genetic variation and human health. As a next step in the evolution of Human Genome Epidemiology reviews, the authors invite investigators to submit field synopses for possible publication in the American Journal of Epidemiology.
association; database; encyclopedias; epidemiologic methods; genome, human; genome-wide association study; genomics; meta-analysis
With the accelerated implementation of genomic medicine, health-care providers will depend heavily on professional guidelines and recommendations. Because genomics affects many diseases across the life span, no single professional group covers the entirety of this rapidly developing field.
To pursue a discussion of the minimal elements needed to develop evidence-based guidelines in genomics, the Centers for Disease Control and Prevention and the National Cancer Institute jointly held a workshop to engage representatives from 35 organizations with interest in genomics (13 of which make recommendations). The workshop explored methods used in evidence synthesis and guideline development and initiated a dialogue to compare these methods and to assess whether they are consistent with the Institute of Medicine report “Clinical Practice Guidelines We Can Trust.”
The participating organizations that develop guidelines or recommendations all had policies to manage guideline development and group membership, and processes to address conflicts of interests. However, there was wide variation in the reliance on external reviews, regular updating of recommendations, and use of systematic reviews to assess the strength of scientific evidence.
Ongoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine.
evidence synthesis; genomic medicine; guideline development
The authors describe the rationale and initial development of a new collaborative initiative, the Genomic Applications in Practice and Prevention Network. The network convened by the Centers for Disease Control and Prevention and the National Institutes of Health includes multiple stakeholders from academia, government, health care, public health, industry and consumers. The premise of Genomic Applications in Practice and Prevention Network is that there is an unaddressed chasm between gene discoveries and demonstration of their clinical validity and utility. This chasm is due to the lack of readily accessible information about the utility of most genomic applications and the lack of necessary knowledge by consumers and providers to implement what is known. The mission of Genomic Applications in Practice and Prevention Network is to accelerate and streamline the effective integration of validated genomic knowledge into the practice of medicine and public health, by empowering and sponsoring research, evaluating research findings, and disseminating high quality information on candidate genomic applications in practice and prevention. Genomic Applications in Practice and Prevention Network will develop a process that links ongoing collection of information on candidate genomic applications to four crucial domains: (1) knowledge synthesis and dissemination for new and existing technologies, and the identification of knowledge gaps, (2) a robust evidence-based recommendation development process, (3) translation research to evaluate validity, utility and impact in the real world and how to disseminate and implement recommended genomic applications, and (4) programs to enhance practice, education, and surveillance.
decision support; genomics; information; medicine; network; public health
Despite the quickening momentum of genomic discovery, the communication, behavioral, and social sciences research needed for translating this discovery into public health applications has lagged behind. The National Human Genome Research Institute held a 2-day workshop in October 2008 convening an interdisciplinary group of scientists to recommend forward-looking priorities for translational research. This research agenda would be designed to redress the top three risk factors (tobacco use, poor diet, and physical inactivity) that contribute to the four major chronic diseases (heart disease, type 2 diabetes, lung disease, and many cancers) and account for half of all deaths worldwide. Three priority research areas were identified: (1) improving the public’s genetic literacy in order to enhance consumer skills; (2) gauging whether genomic information improves risk communication and adoption of healthier behaviors more than current approaches; and (3) exploring whether genomic discovery in concert with emerging technologies can elucidate new behavioral intervention targets. Important crosscutting themes also were identified, including the need to: (1) anticipate directions of genomic discovery; (2) take an agnostic scientific perspective in framing research questions asking whether genomic discovery adds value to other health promotion efforts; and (3) consider multiple levels of influence and systems that contribute to important public health problems. The priorities and themes offer a framework for a variety of stakeholders, including those who develop priorities for research funding, interdisciplinary teams engaged in genomics research, and policymakers grappling with how to use the products born of genomics research to address public health challenges.
In recent decades, extensive resources have been invested to develop cellular, molecular and genomic technologies with clinical applications that span the continuum of cancer care.
In December 2006, the National Cancer Institute sponsored the first workshop to uniquely examine the state of health services research on cancer-related cellular, molecular and genomic technologies and identify challenges and priorities for expanding the evidence base on their effectiveness in routine care.
This article summarizes the workshop outcomes, which included development of a comprehensive research agenda that incorporates health and safety endpoints, utilization patterns, patient and provider preferences, quality of care and access, disparities, economics and decision modeling, trends in cancer outcomes, and health-related quality of life among target populations.
Ultimately, the successful adoption of useful technologies will depend on understanding and influencing the patient, provider, health care system and societal factors that contribute to their uptake and effectiveness in ‘real-world’ settings.
Genomics; Health services research; Emerging technologies; Translational research
A major promise of genomic research is information that can transform health care and public health through earlier diagnosis, more effective prevention and treatment of disease, and avoidance of drug side effects. Although there is interest in the early adoption of emerging genomic applications in cancer prevention and treatment, there are substantial evidence gaps that are further compounded by the difficulties of designing adequately powered studies to generate this evidence, thus limiting the uptake of these tools into clinical practice. Comparative effectiveness research (CER) is intended to generate evidence on the “real-world” effectiveness compared with existing standards of care so informed decisions can be made to improve health care. Capitalizing on funding opportunities from the American Recovery and Reinvestment Act of 2009, the National Cancer Institute funded seven research teams to conduct CER in genomic and precision medicine and sponsored a workshop on CER on May 30, 2012, in Bethesda, Maryland. This report highlights research findings from those research teams, challenges to conducting CER, the barriers to implementation in clinical practice, and research priorities and opportunities in CER in genomic and precision medicine. Workshop participants strongly emphasized the need for conducting CER for promising molecularly targeted therapies, developing and supporting an integrated clinical network for open-access resources, supporting bioinformatics and computer science research, providing training and education programs in CER, and conducting research in economic and decision modeling.
The American College of Medical Genetics and Genomics recently issued recommendations for reporting incidental findings from clinical whole-genome sequencing and whole-exome sequencing. The recommendations call for evaluating a specific set of genes as part of all whole-genome sequencing/whole-exome sequencing and reporting all pathogenic variants irrespective of patient age. The genes are associated with highly penetrant disorders for which treatment or prevention is available. The effort to generate a list of genes with actionable findings is commendable, but the recommendations raise several concerns. They constitute a call for opportunistic screening, through intentional effort to identify pathogenic variants in specified genes unrelated to the clinical concern that prompted testing. Yet for most of the genes, we lack evidence about the predictive value of testing, genotype penetrance, spectrum of phenotypes, and efficacy of interventions in unselected populations. Furthermore, the recommendations do not allow patients to decline the additional findings, a position inconsistent with established norms. Finally, the recommendation to return adult-onset disease findings when children are tested is inconsistent with current professional consensus, including other policy statements of the American College of Medical Genetics and Genomics. Instead of premature practice recommendations, we call for robust dialogue among stakeholders to define a pathway to normatively sound, evidence-based guidelines.
In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving towards more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating “big data” science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.
big data; clinical trials; cohort studies; epidemiology; genomics; medicine; public health; technologies; training; translational research
Cancer epidemiology is at the cusp of a paradigm shift--propelled by an urgent need to accelerate the pace of translating scientific discoveries into healthcare and population health benefits. As part of a strategic planning process for cancer epidemiologic research, the Epidemiology and Genomics Research Program (EGRP) at the National Cancer Institute (NCI) is leading a “longitudinal” meeting with members of the research community to engage in an on-going dialogue to help shape and invigorate the field. Here, we review a translational framework influenced by “drivers” that we believe have begun guiding cancer epidemiology towards translation in the past few years and are most likely to drive the field further in the next decade. The drivers include: (1) collaboration and team science; (2) technology; (3) multi-level analyses and interventions; and (4) knowledge integration from basic, clinical and population sciences. Using the global prevention of cervical cancer as an example of a public health endeavor to anchor the conversation, we discuss how these drivers can guide epidemiology from discovery to population health impact, along the translational research continuum.
cancer; epidemiology; medicine; public health; translational research
Remarkable progress has been made in the last decade in new methods for biological measurements using sophisticated technologies that go beyond the established genome, proteome, and gene expression platforms. These methods and technologies create opportunities to enhance cancer epidemiologic studies. In this article, we describe several emerging technologies and evaluate their potential in epidemiologic studies. We review the background, assays, methods, and challenges, and offer examples of the use of mitochondrial DNA and copy number assessments, epigenomic profiling (including methylation, histone modification, microRNAs (miRNAs), and chromatin condensation), metabolite profiling (metabolomics), and telomere measurements. We map the volume of literature referring to each one of these measurement tools and the extent to which efforts have been made at knowledge integration (e.g. systematic reviews and meta-analyses). We also clarify strengths and weaknesses of the existing platforms and the range of type of samples that can be tested with each of them. These measurement tools can be used in identifying at-risk populations and providing novel markers of survival and treatment response. Rigorous analytical and validation standards, transparent availability of massive data, and integration in large-scale evidence are essential in fulfilling the potential of these technologies.
Epigenetics; methylation; mitochondria; risk assessment; telomerase
To evaluate perceived risk, control, worry, and severity about diabetes, coronary heart disease (CHD) and stroke among individuals at increased familial risk of diabetes.
Data analyses were based on the Family Healthware™ Impact Trial. Baseline health beliefs were compared across three groups: (1) no family history of diabetes, CHD or stroke (n = 836), (2) family history of diabetes alone (n = 267), and (3) family history of diabetes and CHD and/or stroke (n = 978).
After adjusting for age, gender, race, education and BMI, scores for perceived risk for diabetes (p < 0.0001), CHD (p < 0.0001) and stroke (p < 0.0001) were lowest in Group 1 and highest in Group 3. Similar results were observed about worry for diabetes (p < 0.0001), CHD (p < 0.0001) and stroke (p < 0.0001). Perceptions of control or severity for diabetes, CHD or stroke did not vary across the three groups.
Among individuals at increased familial risk for diabetes, having family members affected with CHD and/or stroke significantly influenced perceived risk and worry. Tailored lifestyle interventions for this group that assess health beliefs and emphasize approaches for preventing diabetes, as well as its vascular complications, may be an effective strategy for reducing the global burden of these serious but related chronic disorders.
Family history; Health beliefs; Diabetes; Coronary heart disease; Stroke
We examined hospital use of the epidermal growth factor receptor (EGFR) assay for lung cancer patients. Our goal was to inform the development of a model to predict T3 translation of guideline-directed, molecular diagnostic tests.
This was a retrospective observational study. Using logistic regression, we analyzed the association between likelihood to order the EGFR assay and hospital’s institutional and regional characteristics.
Significant institutional predictors included: Affiliation with an academic medical center (odds ratio [OR], 1.48; 95% CI, 1.20–1.83), Participation in an NCI clinical research cooperative group (OR, 2.06, 1.66–2.55), PET scan (OR, 1.44, 1.07–1.94) and cardio thoracic surgery (OR, 1.90, 1.52–2.37) services. Significant regional predictors included: Metropolitan county (OR, 2.08, 1.48 to 2.91), Above average education (OR, 1.46, 1.09 to 1.96), Above average income (OR, 1.46, 1.04–2.05). Distance from an NCI cancer center was a negative predictor (OR, 0.996, 0.995–0.998), a 34% decrease in likelihood for every 100 miles.
In 2010, 12% of US acute care hospitals ordered the EGFR assay, suggesting most lung cancer patients did not have access to this test. This case study illustrated the need for: 1) Increased dissemination and implementation research. 2) Interventions to improve adoption of guideline-directed, molecular diagnostic tests by community hospitals.
equity; access; lung; cancer; genomics