Biomedical Research Support Research Articles

Analysis of Complex Disease Association and Linkage Studies Using the University of California Santa Cruz Genome Browser

The sequencing of the human genome, the identification of common single-nucleotide polymorphisms (SNPs) and haplotype blocks, and advances in microarray technology have enabled the study of complex diseases at a level of detail not previously imaginable. These have aided in the design and analyses of association and linkage studies of many complex diseases including cardiovascular disease. Recent technological advances have enabled the undertaking of large-scale genome-wide association studies (GWAS) that can assay hundreds of thousands of polymorphic sites on hundreds to thousands of individuals to find genomic regions associated with disease. Although results from these experiments enable the identification of smaller regions of association compared with previous studies, as with all linkage and association studies, there is the need for the further investigation of regions of interest for the causal genes or variants. The purpose of this review is to present a detailed demonstration as to how publicly available resources can be used to easily guide more detailed research into genomic regions of interest identified in linkage and association study data. Large-scale projects, such as the Human Genome Sequencing project,1,2 have generated large volumes and varieties of annotated genomic data necessitating the development of Internet-based tools to organize and make practically available these public data. One important tool in human disease research is the web-based graphical genome browsers that use the human genome sequence as the framework on which to organize genomic annotations, providing various ways for researchers to view and extract important information. Currently, there are 3 human genome browsers that have been developed for public use: (1) the National Center for Biotechnology Information (NCBI) Map Viewer3; (2) the University of California Santa Cruz (UCSC) Genome Browser4; and (3) the European Bioinformatics Institute’s Ensembl system.5 Although these genome browsers share common features and …

Global biosecurity in a complex, dynamic world.

Biosecurity is emerging as a major global health priority for which innovative and unprecedented solutions are needed. Biosecurity is a challenging biocomplexity problem involving multifaceted processes such as interactions between humans and nonhuman biota, anthropogenic environmental and ecological factors, and socioeconomic and political pressures. Key to an effective biosecurity strategy will be fundamental understanding of evolutionary, anthropogenic and environmental driving forces at play in transmission and perpetuation of infectious diseases. Biosecurity solutions will depend on increased support of basic biomedical research and public education, enhanced healthcare preparedness, alternative strategies for ensuringsafety, and improved interagency cooperation regarding global health policy. © 2008 Wiley Periodicals, Inc. Complexity, 2008.

Informationist programme in support of biomedical research: a programme description and preliminary findings of an evaluation

The informationist programme at the Library of the National Institutes of Health (NIH) in Bethesda, MD, USA has grown to 14 informationists working with 40 clinical and basic science research teams. This case report, intended to contribute to the literature on informationist programmes, describes the NIH informationist programme, including implementation experiences, the informationists' training programme, their job responsibilities and programme outcomes. The NIH informationist programme was designed to enhance the library's service capacity. Over time, the steps for introducing the service to new groups were formalized to ensure support by leadership, the team being served and the library. Job responsibilities also evolved from traditional library roles to a wide range of knowledge management activities. The commitment by the informationist, the team and the library to continuous learning is critical to the programme's success. RESULTS / OUTCOMES: NIH scientists reported that informationists saved them time and contributed to teamwork with expert searching and point-of-need instruction. Process evaluation helped refine the programme. High-level, preliminary outcomes were identified from a survey of scientists receiving informationist services, along with key informant interviews. Process evaluation examined service implementation, informationists' training and service components. Anecdotal evidence has also indicated a favourable response to the programme.

Canadian Association of Gastroenterology Research Committee Report

A primary goal of the Canadian Association of Gastroenterology (CAG) and its Foundation, the Canadian Digestive Health Foundation (CDHF), in collaboration with the Canadian Institutes of Health Research (CIHR) and the CAG-CDHF partners, is to promote excellence in research. This research will lead to new discoveries that will translate into improved health for Canadians. Moreover, this partnership will sustain and increase this capacity through high-quality education of talented trainees. The CAG strategic plan is to sustain its strong support of biomedical research while increasing support for research in CIHR pillars 3 and 4 including outcomes research, quality assurance and knowledge translation. The present report, on behalf of the Research Committee (Table 1), outlines another very successful year for this partnership program.

Biomedical research funding: when the game gets tough, winners start to play

Extramural funding provides major support for biomedical research in academia, and National Institutes of Health (NIH) grants often constitute direct evaluation criteria for promotions and tenure. Therefore, NIH budget trends influence long-term scientific strategies and career decisions, as well as the progress of science itself. Our analysis of the last 37 years of NIH awards, however, reveals that the success rate of grant applications submitted for funding is negatively related to the total yearly amount of (inflation-adjusted) NIH extramural expenditure. Instead, as might be expected, the ratio between available funding and the number of submission directly predicts the probability of winning support in any given year. We purport that the considerable success rate variability can be parsimoniously explained by a proportional but delayed reaction of the number of applications to budget fluctuations. As a counterintuitive consequence, grant proposals conceived during lean periods might stand the best chance of success.

Social Value and the Speed of Innovation

Murphy and Topel (2006, henceforth MT) develop methods for valuing health improvements based on individuals’ willingness to pay. Our results indicate that past health improvements have been enormously valuable. We estimate that gains in life expectancy over the twentieth century were worth more than $1.2 million per person to the current US population, and that rising longevity added about $3.2 trillion per year to national wealth between 1970 and 2000, as mortality rates among older adults fell sharply. Looking ahead, we estimate that even modest progress against major lifethreatening diseases would be extremely valuable. For example, the two most prominent causes of disease-related mortality in the United States are cardiovascular diseases (CVD) and cancer. We find that a permanent 10 percent reduction in mortality rates from CVD would be worth about $5.7 trillion to current and future Americans, while similar progress against cancer would be worth $4.7 trillion. A 10 percent reduction in overall mortality would be worth about $18 trillion. If past progress is an indication, there is little doubt that these or greater gains will eventually be realized. The questions are when and at what cost? In comparison to these prospective benefits of health progress, expenditures on basic and applied health research in the United States are modest. Public support for basic biomedical research—mainly through the National Institutes of Health (NIH) and associated grants to research universities—totals about $28 billion annually. Adding expenditures on health research and development (R&D) by private institutions and by pharmaceutical and medical products companies brings the total for basic and applied health research to about $60 billion Social Value and the Speed of Innovation

Relationship between Funding Source and Conclusion among Nutrition-Related Scientific Articles

BackgroundIndustrial support of biomedical research may bias scientific conclusions, as demonstrated by recent analyses of pharmaceutical studies. However, this issue has not been systematically examined in the area of nutrition research. The purpose of this study is to characterize financial sponsorship of scientific articles addressing the health effects of three commonly consumed beverages, and to determine how sponsorship affects published conclusions.Methods and FindingsMedline searches of worldwide literature were used to identify three article types (interventional studies, observational studies, and scientific reviews) about soft drinks, juice, and milk published between 1 January, 1999 and 31 December, 2003. Financial sponsorship and article conclusions were classified by independent groups of coinvestigators. The relationship between sponsorship and conclusions was explored by exact tests and regression analyses, controlling for covariates. 206 articles were included in the study, of which 111 declared financial sponsorship. Of these, 22% had all industry funding, 47% had no industry funding, and 32% had mixed funding. Funding source was significantly related to conclusions when considering all article types (p = 0.037). For interventional studies, the proportion with unfavorable conclusions was 0% for all industry funding versus 37% for no industry funding (p = 0.009). The odds ratio of a favorable versus unfavorable conclusion was 7.61 (95% confidence interval 1.27 to 45.73), comparing articles with all industry funding to no industry funding.ConclusionsIndustry funding of nutrition-related scientific articles may bias conclusions in favor of sponsors' products, with potentially significant implications for public health.

The National Institute of Biomedical Imaging and Bioengineering and NIH Grant Process: An Overview

The National Institutes of Health (NIH) comprise the largest single source of funding in the world for the support of biomedical research. Much of the work of the NIH focuses on the elucidation of fundamental biophysical, biochemical, and biologic aspects of the molecular, cellular, and tissue processes underlying both healthy and diseased states of biologic systems and on the development of cures for the latter. In 2000, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) was created with a somewhat different focus: Rather than concentration on a specific organ system or category of disease, the primary objective of the NIBIB is the advancement of technologies and tools that contribute to all aspects of biomedical research and health care delivery, especially in the imaging sciences and bioengineering. This article provides an overview of the ways in which NIH funds research, with an emphasis on NIBIB support of biomedical imaging. It is intended for radiologists, radiation oncologists, medical physicists, and other readers of this journal, especially those with limited experience in the complex process of obtaining NIH grant support.

Biomedical Research: Are we Getting Value for Money?

Abstract Billions of dollars are spent on biomedical research every year, but what tangible benefits for patients result from this massive investment? Iain Chalmers suggests that the research community has become seriously dysfunctional, that patients and the public should expect better dividends from their support of biomedical research, and that the entire research community must provide better, more effective research or risk losing the support of the public.

Medical Application of Computers at BBN

Early work at BBN involved hospital computer systems, computer aids for the physician's office, data management tools for clinical research, and database and computational support for biomedical research. The work included both development of prototype systems and later deployment of commercially viable software and services. This history also notes some of the challenges of working within an R & D defense-contractor environment and then concludes with lessons learned in developing medical computer applications.

Financial Anatomy of Biomedical Research

Public and private financial support of biomedical research have increased over the past decade. Few comprehensive analyses of the sources and uses of funds are available. This results in inadequate information on which to base investment decisions because not all sources allow equal latitude to explore hypotheses having scientific or clinical importance and creates a barrier to judging the value of research to society. To quantify funding trends from 1994 to 2004 of basic, translational, and clinical biomedical research by principal sponsors based in the United States. Publicly available data were compiled for the federal, state, and local governments; foundations; charities; universities; and industry. Proprietary (by subscription but openly available) databases were used to supplement public sources. Total actual research spending, growth rates, and type of research with inflation adjustment. Biomedical research funding increased from 37.1 billion dollars in 1994 to 94.3 billion dollars in 2003 and doubled when adjusted for inflation. Principal research sponsors in 2003 were industry (57%) and the National Institutes of Health (28%). Relative proportions from all public and private sources did not change. Industry sponsorship of clinical trials increased from 4.0 dollars to 14.2 billion dollars (in real terms) while federal proportions devoted to basic and applied research were unchanged. The United States spent an estimated 5.6% of its total health expenditures on biomedical research, more than any other country, but less than 0.1% for health services research. From an economic perspective, biotechnology and medical device companies were most productive, as measured by new diagnostic and therapeutic devices per dollar of research and development cost. Productivity declined for new pharmaceuticals. Enhancing research productivity and evaluation of benefit are pressing challenges, requiring (1) more effective translation of basic scientific knowledge to clinical application; (2) critical appraisal of rapidly moving scientific areas to guide investment where clinical need is greatest, not only where commercial opportunity is currently perceived; and (3) more specific information about sources and uses of research funds than is generally available to allow informed investment decisions. Responsibility falls on industry, government, and foundations to bring these changes about with a longer-term view of research value.

Public health premise for national research priorities: Mortality versus disability

When asked why the British government should support research, the caustically witty author and statesman–politician Benjamin Disraeli responded, “one day the Crown shall tax it.” Nearly 100 years later, advocates for various “killer diseases” use a similar justification to gain taxpayers’ support for biomedical research, holding out the promise that such an investment will “save lives.” The goals of finding the cause of a malady, thus reducing excess deaths attributable to a particular disease, are easy concepts for the general public to understand and accept. Since the 1930s, with the establishment of the National Cancer Institute at the National Institutes of Health (NIH), the generic argument of preserving life through biomedical research has been successfully deployed by an array of advocacy groups in gaining public support for research. The face validity of this logic, now accepted as a truism, has been extremely effective in shaping public policy on the allocation of research resources for cancer, heart disease, HIV, and other infectious diseases. Today, however, a new public health crisis looms over the heath care system. The extended lifespan, in a graying society, mandates a re-examination of past assumptions for determining national biomedical research priorities. Although it is easy to understand why traditional values place a premium on preserving life at any cost, it is not apparent to public policy formulators that an exclusive concern with mortality overshadows some of the newly emerging critical public health challenges posed by an ever-aging society: the impact of 20 to 40 years of protracted severe disability on the economic, social, and psychological well-being of families as well as the greater society. The Centers for Disease Control and Prevention (CDC) periodically issues a report on the national ranking for causes of death in the United States. The CDC report from

New Home for Nation’s Research Hospital

BETHESDA, MD—The Mark O. Hatfield Clinical Research Center at the National Institutes of Health (NIH), which opened to patients in April, is a technological marvel with a human heart. The Hatfield Center adjoins the Warren Grant Magnuson Clinical Center, which opened in 1953. These two buildings, plus an ambulatory care research facility, constitute the NIH Clinical Center. Among federal buildings, the Clinical Center is second in size only to the Pentagon. The $596 million Hatfield Center is named for the Republican senator from Oregon, a longtime champion of government support for biomedical research. Before retiring in 1997, Hatfield helped break ground for the building’s construction. Four patient care wings house 242 inpatient beds and 90 day-hospital stations. Paired around two landscaped courtyards, the wings flank a 7-story glass-enclosed atrium, whose ground floor includes admitting and discharge areas and public services. Two of the patient wings stretch out into laboratory wings that command about one third of the center’s total space. Patient care units and laboratories occupy levels 1, 3, 5, and 7. Levels 2, 4, and 6 and a penthouse above level 7 house mechanical systems, offering workers walk-around room and full access to the floor below for maintenance and remodeling. Hatfield is the first NIH building to incorporate dedicated infrastructure levels. “It is designed to adapt to changes in medicine that have not yet been imagined,” says chief architect Robert Frasca. Two pedestrian bridges connect Hatfield to Magnuson. After the Hatfield building opens, about one third to half of Magnuson will be outfitted with new research laboratories and offices. Some services will remain in Magnuson; other areas will be mothballed pending future remodeling. A new entrance to the NIH campus will speed access to the hospital.

How to support the basic sciences

It has become axiomatic that basic science faculty and research programs at medical schools must support themselves. The days when excess clinical revenue was used to support basic research are long gone. With the pressure of managed care and faculty practice programs on medical school budgets, it appears that medical school leaders are looking everywhere but at clinical programs for critical support of biomedical research at their institutions, even as NIH support shrinks.

Democrats Focus On National Security, Science Support

Last week, the Democrats approved a platform focusing on national security, energy independence, and support for biomedical research. The Republicans will approve their platform at their convention beginning on Aug. 30. In the arena of national security, the Democrat platform includes efforts to fight the global war against terrorism and halt the spread of nuclear, chemical, and biological weapons. It calls for special military forces to find, secure, and destroy weapons of mass destruction and their production facilities. At the top of the to-do list is reform of the intelligence community, beginning with the creation of a director of national intelligence with control over personnel and budgets, a key recommendation of the 9/11 Commission. In the area of homeland security, the platform singles out the chemical industry as particularly vulnerable to attack and says Democrats will require guards, more fencing, and the use of less dangerous chemicals, when possible. Responsibility for responding to ...

ABOUT THE AUTHORS

ABOUT THE AUTHORS

John Gardner: a salute.

O n 17 February, John W. Gardner died in Stanford, California, at the age of 90. Science does not ordinarily run obituaries, having decided long ago that saluting some worthy lives and ignoring others offered more possibilities to offend than to reward. This page, however, is open to co-option for a more personal kind of editorial farewell. I'm taking advantage of that, but I promise that it won't happen often. John Gardner's is an American story, but I think it will have meaning for Science 's many friends abroad as well. Our long-term readers will remember that he served as secretary of the Department of Health, Education and Welfare during an especially bright period for science, education, and health in the United States. Appointed in 1965 by President Lyndon Johnson, Gardner described the still uncharted landscape of the future Great Society in this way: “What we have before us are some breathtaking opportunities disguised as insoluble problems.” In the 3 years that followed, he launched Medicare, enforced the 1964 Civil Rights Act, and presided over remarkable growth in the nation's support for biomedical research. He resigned in 1968 at the height of the Vietnam War protest. A decade later, when I had come to head an agency in his old department, I discovered that working folks all over the place still remembered his tenure with pride and affection—not a surprising memory to have about a boss who once said “the first and last task of a leader is to keep hope alive.” Even the generation of scientists too young to have known that period owe Gardner a debt for having built a big part of the infrastructure that now supports health research in the United States. But we all should be grateful to him for something else, too. Before his term in federal office, he had led both the Carnegie Corporation and the Carnegie Foundation for the Advancement of Teaching and laid the groundwork for the White House Fellows program. And after he left government, he played a founding or sustaining role in one vital civic organization after another: first the Urban League, then Common Cause, and then Independent Sector. In this later part of his life, he gradually emerged as the nation's civic conscience, arguing powerfully for citizen engagement with public need and then creating and leading new organizations that could implement that vision. In this work and in his earlier books [for example, Excellence (1961) and Self-Renewal (1964)], he undertook an uncommonly thoughtful exploration of the relationship between individual and society. He had a deep grasp of the chronic paradox in American life, one noted by de Tocqueville (among other wise European visitors): Our frontier devotion to personal freedom, even license, on the one hand; and our strongly felt commitment to social order on the other. It is a topic visited by many scholars, but Gardner had a unique ability to extract the essence of this age-old dilemma. He once compressed it into a nine-word summary of the social contract. “Freedom and responsibility, liberty and duty: that's the deal.” That is, indeed, the deal. In formulating it in this way, he reminds us, as he often did, that we need one another and that our society needs each of us. He also became a counselor and advisor to a host of younger people. Having started life as an academic (Ph.D. in psychology, University of California, Berkeley; assistant professor of Psychology, Connecticut College) he never stopped being a teacher; and one knew, without being told directly, that his mentorship carried a lifetime warranty. A frequent theme of his advice was that lives are built on the promises we make to others; he once told a group of Stanford students: “People run around searching for identity, but it isn't handed out free any more—not in this transient, rootless, pluralistic society. Your identity is what you've committed yourself to.” A colleague once asked him for advice on a choice, in which the preferred option contained a fairly rich mixture of risk and reward. He thought for a while, and then said this: “You don't want to die with the music still in you.” John Gardner left all his music here. It belongs to a legion of beneficiaries, to whom his gift was a special kind of personal inspiration. What a life; what a legacy; what an uncommon man.

Municipal support of biomedical research.

Difficulties in funding promising young researchers at the outset of their careers have led to efforts to find new kinds of sources of support. In the past four years the municipal administration in New York City has funded a program to help support new junior research faculty in the city's research-intensive institutions. Under the aegis of the New York Academy of Medicine a program has been designed that provides support for research proposals that are peer-reviewed and competitively awarded. As measured by the quality of the submitted proposals, progress toward realizing the scientific goals of each, and additional research funding received, the program has been a success, and should be considered for replication by other municipalities.

Differential expression of endothelial nitric oxide synthase (eNOS) in sperm of fertile and infertile males.

Objective: We sought to compare endothelial nitric oxide synthase (eNOS) expression in sperm from normospermic and infertile males. Design: Prospective, observational study. Materials/Methods: Twenty-nine diagnostic semen specimens (15 normospermic, 6 multiple male-factor, 4 teratospermic, 4 asthenospermic), and 4 epididymal aspirations were used in this study. Motile sperm was selected by swim-up. For Western blot analysis, sperm proteins were separated by 1D-PAGE, 12% (20 μg protein/lane), and transferred to nitrocellulose sheets. The resulting Western blot was probed with polyclonal antibodies to eNOS and detection was accomplished using a biotinylated secondary antibody, a streptavidin-horseradish peroxidase complex, and enhanced chemiluminescence. Indirect immunofluorescence was accomplished using antibodies to eNOS and FITC-conjugated secondary antibody, and examined with an Olympus fluorescence microscope. Samples were characterized as normospermic, asthenospermic, teratospermic and epididymal. Endothelial NOS activity was examined by measuring nitrite, the stable end-product of NOS, using the Griess reaction. Our main outcome measures were localization of eNOS on human sperm and correlation with sperm characteristic (normospermic, teratospermic, asthenospermic, and epididymal), and comparison of eNOS activity in sperm from normospermic and infertile males. Results: Western blot analysis showed the presence of eNOS as a band of 135-140 kDa in both donor’s and infertile patient’s sperm. However, nitrite production in sperm cultures from asthenospermic males was nearly twenty-fold compared to sperm cultures from normospermic males (1.368 mM and 0.073 mM, respectively, P < 0.05). In addition, immunocytochemical analysis of eNOS showed distinct staining patterns on sperm. Staining patterns on asthenospermic specimens compared closely to normospermic, while teratospermic and epididymal were quite different. The most prevalent staining pattern for normospermic specimens was staining on both midpiece and equatorial regions, occurring in 70.5% of sperm scored. This compares to 54.0% for asthenospermic, 18.0% for teratospermic, and 8.9% for epididymal sperm. The majority of staining on teratospermic specimens was on midpiece only (43.3% of sperm scored), while 18.4% of sperm scored had no staining. On the other hand, the major patterns of staining for epididymal specimens was no staining on 28.8% of sperm scored, and equatorial only on 23.9% of sperm scored. Some epididymal sperm had a unique staining pattern not found on any of the other specimens. This was a speckled pattern occurring on the perimeter of the head only, and was observed in 12.5% of the sperm scored. Conclusions: The present study provides compelling evidence that eNOS is present in the sperm of both fertile and infertile males. Although the eNOS immunostaining patterns of normospermic and asthenospermic samples were similar, nitrite accumulation was significantly higher for asthenospermic samples suggesting a physiological role for nitric oxide in the regulation of sperm motility. Furthermore, the distinct eNOS immunostaining pattern in epididymal samples suggests that nitric oxide may also be involved in the regulation of sperm maturation. Supported By: Minority Biomedical Research Support Grant #GM08037-27 and SCORE Grant #2SO6GMO8037-28.

Retrospective comparison of rat recovery weights using inhalation and injectable anaesthetics, nutritional and fluid supplementation for right unilateral neurosurgical lesioning.

Current veterinary standards of biomedical research support include refinements in animal models that are targeted at enhancing humane care and decreasing inter-animal variability. This ultimately results in fewer numbers of animals being used and reduction in animal experimentation through mitigation of waste as well as faster research results. 6-hydroxydopamine-lesioning of the substantia nigra using a stereotactic frame device is a common procedure and is routinely performed under pentobarbital anaesthesia with monitoring by 8 h workforces. Our programme supports the humane care and use of several protocols involving the unilateral stereotactic-lesioning of rats for the purposes of creating research models of Parkinsonianism. Such procedures are commonly performed as unilateral in order to minimize aphagia and other untoward effects of the lesion. Generally, this procedure is considered minor because it involves a small incision, a cranial burrhole, and penetration of the dura. Inflammation and/or irritation of the ear canal can occur secondarily to the earbar placement procedure. Human patients undergoing similar procedures typically complain of headaches from loss of intracranial pressure; which is a transient outcome. Despite the perception of minor insult, we provided aggressive periprocedural care, and our veterinary staff documented weight loss that was often greater than 15% body weight during the first 3 days. The goal of this study was to evaluate refinements to improve this outcome. For humane concerns, and because of the need to begin experimental testing one week following surgery, a goal in the recent past has been to enhance outcome for researchers and animals by refining postoperative support modalities as well as by seeking the best anaesthetic regimen to shorten postoperative deviations from baseline. Analysis of three groups of rat patients lesioned by the same investigative group over the course of refinements made in our programme indicate that an early return of homeostasis was achieved by the use of inhalation anaesthetics as replacements for barbiturates in these models. Comparison with pentobarbital recipients also indicated that homeostasis is achieved earlier when barbiturates are utilized with fluid therapy and analgesics immediately after operative procedures rather than the next morning.