Priorities for neuropsychiatric genetics at the National Institutes of Health

Over the last decade, molecular genetics has become one of the most important technologies in medical research. However, the application of these approaches to neuropsychiatric disorders has been met with both unreasonable expectations, and at times, unreasonable criticism. Molecular genetics has opened a new window into these disorders that has great promise, but is likely to reveal a complex reality. Clearly, the potential exists to actually define some of the disorders that make up the syndromes that we are studying. In doing so, we will not only begin to address the fundamental pathophysiology of these disorders, but also begin to design treatments based on this new understanding. In this report, a series of four papers on the genetics programs of the National Institutes of Health will be introduced. © 1994 Wiley-Liss, Inc.     

Imaging Probe Development Center: a National Institutes of Health core synthesis resource for imaging probes

The Imaging Probe Development Center (IPDC) has been set up under the auspices of the National Institutes of Health (NIH) Roadmap as part of the molecular libraries and imaging initiatives. It comprises a core synthesis facility dedicated to the preparation of imaging probes, initially for intramural NIH scientists, and later, for the extramural scientific community. The facility opened fully in late 2006, in refurbished laboratories in Rockville, Maryland, and a staff of around a dozen was recruited into place by early 2007; the director was hired in late 2005. The IPDC provides a mechanism for the production of sensitive probes for use by imaging scientists who cannot obtain such probes commercially. The probes to be made will encompass all major imaging modalities including radionuclide, magnetic resonance, and optical. The operation of the IPDC is outlined, together with the results of interim achievements while the IPDC maintained a small temporary laboratory in Bethesda. As of December 2006, a total of eleven probe compositions had been made, and several of these are described with particular mention of those probes intended for use in optical applications.     

The life sciences computer resources program of the National Institutes of Health

This paper describes how NIH-supported computer resources relate, both organizationally and operationally, to life science research programs. Aggregate funding levels and trends involving the various types of computer centers over the past several years are reviewed. A number of specific resources are highlighted and examples of their scientific and technological accomplishments are given. Finally, the strengths and weaknesses of this NIH program, as derived through reflection on almost a decade of activity, are presented.     

The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases

PurposeThis report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program’s application of genomic technology to establish diagnoses, and details the Program’s success rate during its first 2 years.MethodsEach accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis.ResultsOf 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls.ConclusionThe National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.Genet Med 2012:14(1):51–59     

Distribution of research awards from the National Institutes of Health among medical schools

BACKGROUND: Previous studies have demonstrated that a small number of the 125 medical schools in the United States receive a disproportionately large share of the research awards granted by the National Institutes of Health (NIH). We assessed whether the distribution of NIH research awards to medical schools changed between 1986 and 1997. METHODS: We used NIH data to rank medical schools in each year from 1986 to 1997 according to the number of awards each school received (as a measure of each school's activity in research, also referred to as research intensity). The proportion of awards received by schools ranked 1 to 10, 11 to 30, 31 to 50, and 51 or lower in research activity was then calculated, and changes over time were examined. We also examined changes in the distribution of awards and changes in award amounts according to the type of department, the type of academic degree held by the principal investigator, and the awarding institute. RESULTS: Between 1986 and 1997, the proportion of research awards granted by the NIH to the 10 most research intensive medical schools increased slightly (from 24.6 percent of all awards to 27.1 percent), whereas the 75 least research intensive medical schools (those ranked 51 or lower) received proportionately fewer awards (declining from 24.3 percent to 21.8 percent). The increased proportion of awards to top-10 schools consisted primarily of increases in awards to clinical departments, awards to physicians, and awards from highly competitive NIH institutes. Basic-science departments received a smaller proportion of awards than clinical departments, both in 1986 and in 1997. CONCLUSIONS: Research funded by the NIH is becoming more concentrated in the medical schools that are most active in research.     

Analysis of the NIH workshop monoclonal antibodies to human melanoma antigens

Reagents exchanged at the 2nd workshop on monoclonal antibodies (MoAb) to human melanoma antigens were analyzed using both serological and immunochemical assays. The analysis by laboratories participating in the workshop of our MoAb 225.28S, 345.134S, 376.96S, 465.12S, and 763.24TS reaffirms our own analysis of these reagents in that (1) they all react with the majority of melanoma cell lines tested and (2) the reactivity of MoAb 225.28S and 763.24TS is much more restricted than that of MoAb 345.134S 376.96S, and 465.12S. Our serological analysis revealed that the majority of workshop reagents reacted with cultured melanoma cells. Immunochemical analysis of these monoclonal antibodies allowed for their division into three groups according to the molecular weights of the antigens recognized in immunoprecipitation experiments, greater than 100 kd, 80-100 kd, and DR antigens. Further analysis of the first two groups of monoclonal antibodies by immunodepletion and antibody binding inhibition assays revealed that MoAb 9.2.27, 225.28S, and 763.24TS recognize distinct determinants with a heterogeneous distribution on subpopulations of a high molecular weight melanoma associated antigen. MoAb 376.96S and 705.F6 recognize either the same or spatially close determinant(s).     

Translation of the National Institutes of Health Diabetes Prevention Program in African American churches

ObjectiveTo translate the Diabetes Prevention Program (DPP) for delivery in African American churches.MethodsTwo churches participated in a 6-week church-based DPP and 3 churches participated in a 16-week church-based DPP, with follow-up at 6 and 12 months. The primary outcomes were changes in fasting glucose and weight.ResultsThere were a total of 37 participants; 17 participated in the 6-session program and 20 participated in the 16-ses-sion program. Overall, the fasting glucose decreased from 108.1 to 101.7 mg/dL post intervention (p =.037), and this reduction persisted at the 12-month follow-up without any planned maintenance following the intervention. Weight decreased 1.7 kg post intervention with 0.9 kg regained at 12 months. Body mass index (BMI) decreased from 33.2 to 32.6 kg/m² post intervention with a final mean BMI of 32.9 kg/m² at the 12-month check (P <.05). Both the 6- and 16-session programs demonstrated similar reductions in glucose and weight; however, the material costs of implementing the modified 6-session DPP were $934.27 compared to $1075.09 for the modified 16-session DPP.ConclusionTranslation of DPP can be achieved in at-risk African Americans if research teams build successful community-based relationships with members of African American churches. The 6-session modified DPP was associated with decreased fasting glucose and weight similar to the 16-session program, with lowered material costs for implementation. Further trials are needed to test the costs and effectiveness of church-based DPPs across different at-risk populations.