Founded in 2008, the Clinical and Translational Science Institute at Children's National (CTSI-CN) was designed to develop a uniquely pediatric perspective on the task of improving human health through research. This important initiative was based on several important insights regarding the pressing need to translate basic discovery into clinically effective preventive, diagnostic, and therapeutic pediatric interventions. First, we appreciated that the origins of adult morbidity and mortality arise from both genetic predisposition and environmental circumstances that occur much earlier in life, anytime from the pre-conception period through adolescence. This is obviously true for single gene disorders such as cystic fibrosis, Duchenne muscular dystrophy or the many inborn errors of metabolism. But it is also a useful perspective when considering much more common and complex conditions such as cardiovascular disease, asthma, obesity/metabolic syndrome, mild-to-moderate developmental disability, and even HPV-associated malignancies. Second, research to more definitively elucidate etiologic mechanisms may best be undertaken early in life. The complex impact of comorbid conditions, multiple treatments, and disease progression itself are much less pronounced in children and adolescents than in adults. This makes it possible to more readily identify the comparative contributions of genetic susceptibility, for example, and specific environmental insults. Third, we were especially concerned with the persistent and unacceptable burden of health disparities and recognized that these must be addressed in childhood to assure optimal health and development for all. Both health disparities in childhood itself and those arising later in adulthood can be investigated by carefully designed research and ameliorated through targeted intervention, both typically undertaken in collaboration with the communities we serve. Fourth, we understood that a variety of factors have historically disadvantaged research conducted to benefit children. These include, for example, the epidemiologic reality that childhood illness is much less common than adult illness (although predispositions and precursors of disease are universal) and is distributed across a highly diverse set of conditions. These facts limit the market for drug and device development, thus serving as a barrier to pediatric research. The simple fact that children range in size from premature infants of less than 1 kg in weight to morbidly obese adolescents of over 150 kg is a tremendous challenge for pediatric research. Of course, the evolving psychological and cognitive abilities of children impose additional demands with respect to their participation in research. For all these reasons, we appreciated the importance of pediatric research efforts in facilities specifically designed to meet the medical needs of children. Finally, pediatric research provides the unique opportunity to investigate rare diseases that typically manifest early in life, often with devastating consequences. Perhaps best represented by the inborn errors of metabolism, rigorous investigation of such diseases require not only multidisciplinary pediatric expertise, but also collaborative networks of investigators to accrue a sufficient number of representative patients for meaningful statistical analysis. Moreover, research on the pathophysiology and treatment of single gene disorders provides invaluable insights into normal physiology and the role of these genes in more complex and common disease and thus contributes to improving the general health of the public at large.
In spite of our focus on supporting pediatric research, the CTSI-CN was also committed to investigating adult conditions, with a special focus on those which have their origins in childhood, as discussed above. Increasingly, of course, this also includes previously fatal diagnoses such as cystic fibrosis, muscular dystrophy, and certain congenital heart defects for which new treatments have meant improving prognoses and survival into adulthood.
In July 2010, Children's National Medical Center and its partnering institution, The George Washington (GW) University, were funded by a Clinical and Translational Science Award to participate together in a newly established CTSI-CN. In addition to a well-established program of mechanistic T1 research, strengths at GW included its creative but rigorous educational programs, with nationally and internationally recognized expertise in distance education, and a preeminent group in health policy. The CTSI-CN at GW launched a master's degree in clinical and translational science in less than 1 year and is now developing an innovative doctoral degree in Clinical and Translational Practice for clinical practitioners committed to substantial involvement in such research. Additional CTSI-CN expertise in evaluation was provided by collaborators at RTI International, thereby, assuring a degree of separation between those who would be implementing the CTSI-CN and those who would be measuring and analyzing its progress. Below we briefly highlight what we see as the early notable accomplishments and strengths of the CTSI-CN.
Figure 1 illustrates the range of representative topics of research supported by the CTSI-CN and the position of the projects within the continuum from disease prevention to treatment and across T1 through T4 translation. Given our understanding of the importance of pediatric research for improving the health of the population at large, it is not surprising that many of our investigators are conducting research to prevent disease before it manifests with irreversible consequences. There is increasing National Institute of Health (NIH) and industry emphasis on the discovery, development, and approval of novel therapeutics based on the impressive accumulation of fundamental mechanistic knowledge, such as provided by the Human Genome Project. In addition, we maintain a committed focus on research with the potential to prevent illness or to detect it sufficiently early that the adverse trajectory of disease natural history can be modified and its consequences prevented or delayed. Rigorous research supported through the CTSI-CN targets prevention or early detection and treatment of diverse conditions including:
- 1Potentially life-threatening fetal conditions such as cardiac malformations and brain development disorders are researched in utero by noninvasive means, including monitoring of multiple physiological parameters and magnetic resonance imaging to be able to intervene early, either in utero or by early delivery and treatment.
- 2Inborn errors of metabolism, detected through newborn screening are investigated to understand the natural history of disease and how early interventions can improve outcome.
- 3Neglected diseases of poverty are researched for effective methods of prevention through the development of novel vaccines and immunizations such as HPV vaccine.
- 4Maltreatment/child abuse, which is disproportionally common in under-resourced communities and among children of adolescent mothers, is addressed in an HRSA-funded randomized trial being supported through the CTSI-CN to improve outcomes in vulnerable families.
- 5Sudden infant death syndrome (SIDS). Research into factors contributing to the disparity of SIDS and unexpected infant death rates in minority populations, particularly African Americans.
- 6Childhood obesity, metabolic syndrome, and type 2 diabetes research. The AIMMY study (Assessing Inherited Metabolic Markers in the Young) is an NIH/NCMHD P20 Health Disparities Center project involving five universities enrolling freshman into a gene and environment study to find predictors of metabolic syndrome and its complications.
- 7Injury and violence prevention research, including traumatic brain injury and studies of the association between vitamin D status and fractures in African Americans.
- 8Adolescent pregnancy research that informs and guides the development of effective interventions to strengthen adolescent-headed families.
- 9Learning and developmental disabilities and autism spectrum disorders with translational research into understanding cellular and genetic processes that govern normal development of the amygdala and underlying defects in these processes that occur in these disorders. An fMRI study delineates differences found in children with autism spectrum disorders in the functional organization of communicative information.
The CTSI-CN also contributes leadership to consortium-wide research to better understand and address rare disease with a particular focus on inborn errors of metabolism. The Urea Cycle Disorders Consortium, part of the NIH-funded Rare Diseases Clinical Research Network, is conducting a longitudinal study of these disorders as well as developing novel biomarkers, testing new drugs and using functional imaging to evaluate the outcome of new treatments. This consortium includes 12 CTSA-funded institutions throughout the United States.
One of the most promising therapeutic approaches for Duchenne muscular dystrophy is exon skipping. An antisense drug is delivered systemically, where it alters mRNA splicing patterns, restoring partial dystrophin expression to patient muscle. CTSI-CN investigators, collaborating with the National Institute of Neuroscience in Tokyo, showed a proof of principle for this approach, demonstrating efficacy in the canine large animal model. This approach requires the parallel development of a platform of drugs, with different drugs targeting different regions of the dystrophin gene—a form of “personalized drug development.”
Given our commitment to ameliorating health disparities, the CTSI-CN has also provided leadership for development of a new health policy dialogue across consortium members. This focus on “T4” research complements and extends our mechanistic translational studies by investigating optimal methods for assuring that proven preventive or therapeutic interventions are actually implemented in practice and widely available. As part of this effort, the CTSI-CN in partnership with University of California at San Francisco, CTSI-CN established the CTSA Consortium Health Policy Workgroup.
A particular strength of the CTSI-CN is provided by our large-scale, pediatric-specific medical informatics initiative, referred to as the “Children's Integrated Quality Network” or “Children's IQ Network®” (Figure 2). This capability is designed to link essential healthcare data from children in the mid-Atlantic region that encompasses the states of Maryland, Virginia, West Virginia, and the District of Columbia through a longitudinal electronic continuity of care document. Particularly important is the fact that stakeholders include not only Children's National with its inpatient and emergency department data, but also outpatient sites both at our clinics and at over 800 community providers, with additional linkages to the Washington, DC immunization registry and laboratory data from multiple providers. The covered patient population is diverse in its racial and ethnic composition, spans urban, suburban, and rural locations, and includes patients from birth through age 20. Complex issues related to technology, finances, governance, and security/privacy have been successfully addressed, and a Data Analytics and Reporting Group as well as a Quality and Data Steering Committee have both been established. This uniquely pediatric resource has already been accessed to examine the distribution of body mass index across this diverse group of 23,835 unique patients, and the relationship of weight to location of residence. Emerging applications will permit CTSI-CN and its investigators to quickly and efficiently identify the number of patients meeting specific criteria and potentially eligible for participation in clinical trials.
To assure future high quality clinical and translational research relevant to child health, we are pleased to have supported 30 pilot studies and distributed over $1,380,000 of institutional and CTSA funds in our first three rounds of funding competition. The successful investigations are conducting clinical and translational research relevant to a wide range of conditions that include asthma, autism, muscular dystrophy, type 2 diabetes, HIV/AIDS, pediatric brain tumors, and schizophrenia. After receipt of CTSI-CN funding, each pilot project is carefully supported with facilitated access to all the capabilities of the CTSI-CN and progress is tracked to identify barriers or challenges that need to be overcome.
Committed as the CTSI-CN is to the success of its many activities in the mid-Atlantic and nation's capital, we take particular pride in our collaborations with the CTSA Consortium, and especially its pediatric leadership. With the consortium's Child Health Oversight Committee, we join with others across the United States to strengthen pediatric research, training, and community engagement. Through our rigorous and innovative child health research, we can discover and successfully implement new methods to prevent, diagnose, and treat illness early in life. In this way, future health and well-being across the entire lifespan can be improved in the communities we serve.