Veterans Affairs (VA) Office of Research and Development (ORD): Research Programs and Emerging Opportunities in Digestive Diseases Research

The medical and prosthetic research program of the Veterans Health Administration (VHA), though specifically dedicated to improving the health and well-being of those who have served the United States in the uniformed services (Army, Navy, Air Force, Marines, Coast Guard, and Commissioned Corps’ of the Public Health Service and the National Oceanographic and Atmospheric Administration), has nevertheless had a significant impact on the care of all Americans. In particular, VHA has contributed substantially to the understanding and treatment of digestive diseases, and in the training of researchers – particularly clinician-researchers, to conduct digestive disease research. Unlike the NIH, which provides broad support to investigators through grants and cooperative agreements, the VA research program is an intramural program that is, by law, carried out “in connection with the provision of medical care and treatment to veterans.”

VA research benefits greatly from its position in a health care system that is united by a common mission and common policies, a patient population of nearly seven million Veterans that is dedicated to service, including participation in research, electronic health records (EHR) stretching back nearly 20 years, and embedded research infrastructure that includes not only physical facilities, but core support such as VA Cooperative Studies Program (vide infra) and the VA Informatics and Computing Infrastructure (VINCI). VA research also benefits from academic affiliations with medical schools, which train almost 121,000 health professionals yearly. Almost all VA researchers have academic appointments; many laboratory researchers maintain laboratories both at the VA and at academic affiliates, and many have received national recognition (Table 1). This Commentary highlights the impact of VA research on the understanding and treatment of digestive disease, provides an overview of the structure of the VA research program and opportunities for research engagement, insight into a few of the ongoing research efforts in digestive diseases, and consideration of emerging research opportunities.

Table 1.

Notable VA Digestive Disease Researchers^*

Investigator	Research Focus	Comments
Crabbe, John C	Genetic basis of alcoholism	Middleton Award 2004
Gerding, Dale	Clostridium Difficile Infection	Middleton Award 2013
Goyal, Raj	Esophageal Physiology and Barrett’s Esophagus	Middleton Award 2013, Editor-in-Chief, Gastroenterology 1986–1991
Herbert, Victor	Nutrition research	Middleton Award 1978
Kaplowitz, Neil	Regulation of hepatic glutathione, alcoholic liver disease	Middleton Award 1993
Kim, Young S	Glycoprotein metabolism and glycolipids in colon cancer	Middleton Award 1991
Lieber, Charles	Alcohol toxicity, fatty liver	Middleton Award 1977
Sachs, George	H-K ATPase in gastric parietal cells	Middleton Award 1992
Schally, Andrew V	Somatostatin; growth hormone-releasing hormone	Lasker 1975, Nobel 1977
Schnazi, Ray	Antiviral therapeutic development	Middleton Award 2015, VA Senior Research Career Scientist
Schuckit, Marc A	Alcoholism and drug addiction	Middleton Award 1997
Starzl, Thomas	Liver Transplant	Lasker 2012; William Beaumont Prize in Gastroenterology 1991
Tache, Yvette	Functional Bowel Disorders	Middleton Award 2014
Yalow, Rosalyn	Radioimmunoassay (gastrin, CCK, insulin)	Lasker 1976; Nobel 1977

^*Listing was limited to awardees of Nobel Prize and Lasker Award in addition to VA William S. Middleton Award, given the space limitation despite many other noteworthy VA-based, VA-supported scientists. The Middleton Award is awarded the highest honor awarded annually by the BLR&D Service to senior VHA research scientist in recognition of their research relevant to healthcare of Veterans. It was established in 1960 to honor Dr. William S. Middleton M.D. (a distinguished educator, physician-scientist, and Department of Veterans Affairs Chief Medical Director from 1955 to 1963) who developed the VA medical research program including the VA cooperative studies (http://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=3021).

I. Structure of the VA Research and Development Program

Organizational Structure at the National Level

The VHA Office of Research and Development (ORD) is headed by a Chief Research and Development Officer (CRADO) with detailed information on ORD and its organizational structure shown in http://www.research.va.gov. The CRADO is charged with responsibility for the overall policy, planning, coordination, and direction of R&D activities within VHA, including development of VHA policy related to the research program, development and implementation of educational programs in support of ORD’s research mission, and allocation of appropriated Medical and Prosthetic Research funds to VA medical facilities for scientifically meritorious research conducted by VA investigators that is related to the high priority health care needs of Veterans and is to be conducted by VA employees. The budget estimate for Medical and Prosthetic Research in fiscal year 2016 is $622 million; this represents a significant increase from the fiscal year 2015 budget of $589 million, which had been relatively flat for several years. These review and funding responsibilities are exercised, in part, through four research services that evaluateresearch proposals that are, for the most part, investigator-initiated as described below:

1. Biomedical Laboratory R&D (BLR&D) Service: BLR&D supports preclinical research to understand life processes from the molecular, genomic, and physiological level in regard to decisions affecting Veterans. The work generally involves wet bench laboratory research with the use of pre-clinical models (e.g. animals, cell lines) and biologic specimens from humans (e.g. tissue, blood).

2. Clinical Science R&D (CSR&D) Service: CSR&D supports investigations, including human subject research (e.g. intact human subjects examined for clinical, epidemiological, biological and genetic measures), to determine the feasibility or effectiveness of new treatments such as drugs, therapy, or devices. In addition to observational studies, CSR&D supports small clinical trials or multisite studies conducted by the Cooperative Studies Program (CSP), aimed at learning more about the causes of disease and providing the evidence base for more effective clinical care.

3. Health Services R&D (HSR&D) Service: HSR&D supports studies to identify and promote effective and efficient strategies to improve the organization, cost-effectiveness, and delivery of quality health care for Veterans. Health services research is often based upon the analysis of existing medical records, but extends to predictive analytics and the conduct of randomized clinical trials designed to assess the effectiveness of delivery strategies. HSR&D supports 19 Centers of Innovation (COINs: http://www.hsrd.research.va.gov/centers/) and three Resources Centers including Health Economics Resource Center (HERC: http://www.herc.research.va.gov/include/page.asp?id=about-us), a VA Information Resource Center (ViREC: http://www.virec.research.va.gov) and a Center for Information Dissemination and Education Resources (CIDER: http://www.cider.research.va.gov) with additional support of various Quality Enhancement Research Initiative (QUERI) studies that adopt new evidence-based treatments, tests and models of care to routine clinical practice.

4. Rehabilitation R&D (RR&D) Service: RR&D develops novel approaches to restore Veterans with traumatic amputation, central nervous system injuries, loss of sight or hearing, or other physical and cognitive impairments to full and productive lives. This is the primary source of support for biomedical engineering investigations in VA.

Research Funding Mechanisms

Funding mechanisms in VA ORD (Table 2) are similar to those used at NIH, with a peer review system that is managed electronically through the NIH eRA Commons. VA does not set a “payline” for funding. Although the evaluation of scientific merit by peer review is by far the strongest factor in funding decisions, program balance and relevance to health care delivery to Veterans served by VHA are also important factors in making funding decisions.

Table 2.

Office of Research and Development Award Mechanisms

VA Award	New Code	NIH Equivalent Code	Mechanism (years of support)	Description
Merit Review	I01	R01	Non-HHS Research Project (3–5 years)	To support research projects of non-DHHS entities. For the VA, this is used for intramural research projects.
Pilot	I21	R21 R03	Non-HHS Exploratory/Developmental Award (1–2 years)	To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.)
Multi Site Planning	I34	R34	Non-HHS Clinical Trial Planning Award (typically 1 year)	To provide support for the initial development of a clinical trial, including the establishment of the research team; the development of tools for data management and oversight of the research; the development of a trial design and other essential elements of the study, such as the protocol, recruitment strategies, and procedure manuals; and to collect feasibility data.
REAPs and Centers	I50	P50	Non-HHS Specialized Center (3–7 years)	Research Enhancement Award Program to support any part of the full range of research and development from very basic to clinical in a multi-disciplinary manner. Centers may also serve as regional or national resources for special research purposes.
CDA1	IK1	K08	Non-HHS Career Development Award (2 years)	To provide support to individuals with health professional or science doctoral degrees who are not fully established investigators and who want to pursue research careers. The IK1 award includes support for specialized didactic study and mentored research in scientific areas relevant to the awarding agency
CDA2	IK2	K01 K08 K23	Non-HHS Mentored Research Scientist Development Award (3–5 years)	To provide research and salary support for a supervised/mentored career development experience leading to research independence. Awards are not renewable, nor are they transferable from one principal investigator to another.
NRI	IK3	IK3	Non-HHS Nursing Research Initiative (3–4 years)	To provide research and salary support for a supervised/mentored career development experience for nurses. Awards are not renewable, nor are they transferable from one principal investigator to another.
CDTA	IK4	K02	Non-HHS Independent Scientist Award (3–5 years of salary support)	To foster outstanding scientists and enable them to expand their potential to make significant contributions to their field of research. It provides a minimum of 75% “protected time” for newly independent scientists with peer reviewed research support for research and relevant career development activities.
CDEA	IK5	K18	Non-HHS Career Development Enhancement Award (CDEA) (1 year)	To provide support for experienced scientists who wish to broaden their scientific capabilities or to make changes in their research careers by acquiring new research skills or knowledge. Career enhancement experiences supported by this award should last no more than one year.
RCS	IK6	K06	Non-HHS Research Career Scientist (RCS) Award (3–5 years)	To enable institutions to finance positions favorable to the intellectual growth and research productivity of established investigators of exceptionally high competence. The award may be renewed every 3 or 5 years.
Program Project	IP1	P01	Non-HHS Research Program Project (3–5 years)	To support a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. Each research project is usually under the leadership of an established investigator. The award can provide support for a limited number of cores activities, the sharing of which facilitates the total research effort.
Shared Equipment	IS1	S10	Non-HHS Biomedical Research Support Shared Instrumentation Award (1 year)	To make available to institutions with a high concentration of agency research awards, research instruments and/or animal facility equipment which will be used on a shared (common use) basis.
Multisite Trials	IU1	U01	Non-HHS Research Project–Cooperative Agreement (3–15 years)	To support clinical evaluation of various methods of therapy and/or prevention in specific disease areas. These represent cooperative programs between multiple institutions and participating principal investigators, and are usually conducted under established protocols.

Funding mechanisms explored by most researchers relevant for this Commentary include the VA Merit Review (similar to NIH R01), Career Development Awards (similar to NIH F and K awards) VA research and Cooperative Studies Program (similar to NIH U01) with additional mechanisms for VA Research and/or Clinical Centers (Table 2). There are distinct eligibility criteria for these funding mechanisms that require careful review and clarification. These include US citizenship (required for CDAs) or permanent residence status (VA Merit Review), Letter of Intent (needed in most cases except for BLR&D VA Merit Review), approval of off-site waivers (for work performed in non-VA environment) and the VA Medical Center Director’s letter of commitment for VA appointment for the duration of funding award (at least 5/8 for VA Merit Review). In addition, PhD investigators interested in applying for VA funding through the BLR&D and CSR&D (but not RR&D and HSR&D) need prior approval through the Non-Clinician Eligibility Program, based on research vitality (with active funding from national agencies), demonstrated independence, productivity and VA-relevant research (as described in: http://www.research.va.gov/services/shared_docs/merit_review_guidance_docs/RequestingAcceptanceIRP.pdf). Actively VA-funded PhD investigators are also eligible for Research Career Scientist Award and Senior Research Scientist Award which can provide support for 5 and 7 years, respectively; approximately 185 such investigators are supported across ORD in FY15. Furthermore, approximately 60% of funded researchers have clinical training and responsibility currently.

ORD attempts to maintain an inventory of about 2200 funded projects at any one time. Of 2027 new and competing renewal applications (all mechanisms), 465 were funded in 2014. Overall, the “success rate” (i.e. the number of proposals funded/number of applications received) was 18% for I01 (VA Merit Review) proposals in 2014 (Table 3), with similar success rates for each of the four research services. This number has been dropping steadily for several years as the number of applications has increased while funding has grown at a rate lower than that of biomedical inflation. Overall, about 150 of these projects fall within the realm of digestive diseases, with a total annual direct cost of approximately thirty-five million dollars. Of note, as intramural researchers, VA research awards do not pay overhead costs, such as building maintenance, and clinician salaries are assumed by the individual VA Medical Centers—providing greater value for the funding.

Table 3.

Success Rates for Merit Review (I01) Projects in 2014

	Proposals	Funded	Success Rate
Health Services	206	42	20%
Rehabilitation	304	56	18%
Biomedical Laboratory	854	148	17%
Clinical Sciences (excluding CSP)	227	38	17%

Research Funding Application and Review Process

Funding applications follow a distinct schedule–typically with BLR&D and CSR&D submissions in March/September, and HSR&D and RR&D submissions in December/June (http://www.research.va.gov/funding/process/submission-calendar.cfm). Letters of intent are generally required for career development award applications and applications that will propose a clinical trial funded by the Clinical Sciences Research Service, may be required for special solicitations, but are not always required for Merit Review (I01) awards. The application and review processes are managed electronically through the eRA Commons. The peer review process resembles that in NIH study sections, through scientific review panels or subcommittees comprised of a Scientific Review Officer, Chair and members with appropriate scientific expertise. Some potentially GI-relevant subcommittees include: Gastroenterology, Clinical Trials, Immunology, Oncology, Cellular and Molecular Medicine, Healthcare Informatics, Health Care System Organization and Delivery.

External Review of the VA Medical Research Program

This is carried out through three committees chartered under the Federal Advisory Committee Act – the National Research Advisory Council, which provides overall guidance, a Research Advisory Committee on Gulf War Veterans’ Illnesses, and a Genomic Medicine Program Advisory Committee, each of which meets three to four times per year.

Research Organization and Infrastructure at the Local Level

The VA conducts research in approximately 100 of its 150 medical centers. Within each of these medical centers, a research service is headed by the Associate Chief of Staff for Research (ACOS/R), who reports to the Medical Center Director through the Chief of Staff. The ACOS/R is, on a day-to-day basis, responsible for the administration of the facility research program with the support of a Research and Development Committee, Institutional Review Board, Safety Committee and Institutional Animal Care and Use Committee (where required). A VA-based investigator may be supported by non-VA funding source (e.g. private foundations, industry, or from other federal agencies under interagency agreements or through grants administered by VA nonprofit corporations or university affiliates) in addition to funding from the VA Medical and Prosthetic Research appropriation. Indeed, non-VA sources provide more of the funding used to support VA research than does the Congressionally appropriated Medical and Prosthetic Research Appropriation. Research expenditures from projects approved by the local VA Research and Development Committee define the Veterans Equitable Resource Allocation–an overhead equivalent for the VA medical centers for providing infrastructure support for those studies.

Partnership with Academic Institutions

Formal partnerships with medical schools began in 1946 when President Truman signed the Public Law 293 and established the Department of Medicine and Surgery within the VA with great expansion of its physician workforce needed to care for millions of returning World War II Veterans. Since then, the partnership between VA and medical schools have been further strengthened by a number of milestones that provided the legal basis for the affiliation, authorized VA to enter into resource-sharing agreements with medical schools and provided statutory authority for VA’s research mission. Currently, VA affiliation exists in 135 of the 141 allopathic medical schools in the Unites States and 35 of 40 locations for osteopathic medical schools. These affiliations provide the VA with a pipeline of well-trained academic physicians and investigators with VA-relevant research expertise. They also enrich the affiliated medical schools by supporting clinical training and providing access to VA research funding for eligible VA investigators. Of note, over 60% of VA researchers are clinicians. In addition, 79% of the VA clinicians cited research as a factor for coming to the VA and over 90% cite research as a reason for staying at the VA, according to a 2012 Evaluation of the VA Medical Research Program conducted by Abt, Associates (http://www.research.va.gov/about/VAFinalReport.pdf). Thus, VA-based research has been a critical element in recruiting and retaining clinical faculty members and researchers.

II. Existing VA-funded research and resources in Digestive Diseases

There has been substantial support for digestive disease research, including those involving the luminal GI tract, the hepatobiliary system, the pancreas and nutrition. Some relevant highlights are shown in www.research.va.gov/pubs/docs/va_factsheets/GastrointestinalHealth.pdf. The following also provides some of the larger scale VA studies of interest in recent years.

Million Veteran Program (MVP)

The Million Veteran Program (MVP) is an important partnership between VA and Veterans to learn more about how genes, the environment, and their interactions affect Veteran health. Veterans who participate make available a blood specimen for genetic analysis, permit researcher access to their EHR, and provide health information by questionnaire, which can be made available for research analysis within a secure enclave. Enrollment started in 2011 and to date (9/10/15), 410,226 Veterans have enrolled in the program, which is part of the President’s Precision Medicine initiative, with about 100,000 per year signing up; seven proposals involving teams of VA and non-VA researchers have been funded to conduct studies. It is anticipated that MVP will enable: 1) identification and validation of novel genomic associations on an unprecedented scale; 2) studies validating the practical value of using genomic data in guiding therapy, facilitated by VA’s large clinical healthcare system and research program with extensive genetic and clinical trials experience under one roof; 3) studies of specific deployment conditions based on available data on risk factors and exposure history. Although designed and powered for genetic studies, this program also provides a framework for non-genetic epidemiologic, health services, and clinical trials, since participating Veterans have agreed to be contacted about other potential studies. Relevant for this commentary, MVP may be harnessed towards digestive and liver diseases.

Four awards were made in July 2015 via BLR&D to beta-test single nucleotide polymorphisms (SNP) data generated from roughly 200,000 MVP samples via a customized MVP Affymetrix Axiom Biobank based chip with phenotype data relevant for cardiovascular risk factors, multi-substance use, kidney disease and metabolic conditions. These studies pave the way to better understanding of the associations between genetics, lifestyle factors, military exposure and health, towards the goal of the President’s Precision Medicine Initiative.

Millennium Cohort Study (MCS)

The Millennium Cohort Study is an epidemiologic research program conducted primarily by Department of Defense personnel with some support from the Department of Veterans Affairs. This study, which has now enrolled approximately 200,000 active duty and separated military personnel, began in 2001 to collect survey data on individuals who have served on active duty since 1997. Questionnaires are sent to participants every three years; biological specimens and health examinations are not performed. The baseline survey instrument included questions related to a GI symptoms and a past medical history of various GI conditions, such as gastroesophageal reflux disease (GERD), inflammatory bowel disease, pancreatitis, hepatitis and gallstones. An important facet of this study has been the analysis of the relationships between military service and the development of obesity and type 2 diabetes.^1–5

VA Cooperative Studies Program (CSP)

The VA CSP traces its roots to studies of the treatment of tuberculosis in the 1940’s and 1950’s. This program has produced landmark studies that have been the foundation of key aspects of medical care today, such as the role of antihypertensive therapy in preventing or delaying serious cardiovascular events. It also highlights a key strength of VA system in its large network of many medical centers, EHR that can be shared and available salary support for the clinician investigators participating in these studies, as well as the ability to implement the findings in a clinically relevant manner.

The Cooperative studies program supports five statistical coordinating centers (Boston MA, West Haven CT, Perry Point MD, Hines IL, and Palo Alto CA), four epidemiology centers (Boston MA, West Haven CT, Durham NC and Seattle WA), a pharmacy coordinating center which provides GMP-compliant pharmaceutical manufacturing and distribution (Albuquerque NM), a pharmacogenomics analysis laboratory (Little Rock, AK), a genomic analysis center (Palo Alto, CA) and a biobank (Boston, MA). These centers, plus a network of facility-based clinical trials centers, provides a robust framework to conduct large multisite clinical trials and epidemiologic studies in VA, including planning, management, monitoring, and analysis of both data and biospecimens. This backbone provides unique support for investigators who conduct large multisite studies in VA.

The application process for a VA Cooperative Study begins with submission of a letter of intent (LOI) by the proponent, which is reviewed administratively for relevance to Veteran health care, and scientifically to assess the importance of the problem to be addressed as well as the feasibility of conducting the study within VA. If the letter of intent is approved, funding is provided for a planning process which is supported by a designated CSP Coordinating Center. This process begins with the appointment of an executive committee for the study who assists in planning the study. The planning process typically takes about six months and involves several in-person planning meetings and numerous conference calls, with administrative, project management, and statistical support provided by the coordinating center, the pharmacy coordinating center, VA central office and, if appropriate, other CSP centers. The final proposal may, in some cases, differ substantially from than anticipated by the original letter of intent. This proposal undergoes an independent peer review by the Cooperative Study Scientific Evaluation Committee (CSSEC) and final funding decision by the Director of CSR&D Service based on CSSEC recommendation and score (www.research.va.gov/programs/csp/update/guide.pdf). Currently, there are 26 active and 5 recently approved CSP studies, with 8 in planning phase.

The CSP has begun to employ innovative methods, which we refer to as “Point of Care” trials, to engage the medical care system and EHR to facilitate the conduct of large comparative effectiveness trials.^6–8 Point of care trials begin with the premise that, in order to reflect “real world” medical treatment, the clinical trial should be embedded in routine health care operations. In such a design, recruitment and randomization is carried out by a patient’s usual healthcare provider using tools that are embedded in the EHR system. Following randomization, the regular healthcare provider continues to provide care, in accord with the clinical trial protocol. Clinical trial outcomes are assessed, to the extent possible, through analysis of the EHR, so that the trial intrudes only minimally on routine patient care. Such studies are not useful for assessing new medical interventions, but are well-suited for comparative effectiveness studies of interventions that have similar evidence bases supporting efficacy, but an insufficient evidence base to determine superiority, inferiority, or equivalence of the interventions. Since such studies are by definition unblinded, it is critical that strong objective outcome measures be employed in a trial design characterized by a thoughtful statistical framework.

The CSP has been an outstanding funding avenue for GI and hepatology research, with several examples outlined below:

1. Gastroesophageal Reflux (GERD): In 1992, Spechler et al. published their landmark paper comparing antireflux surgery to medical therapy for the long-term treatment of complicated GERD.⁹ Currently, enrollment is ongoing for VA CSP#573 entitled “A Randomized Trial of Medical and Surgical Treatments for Patients with GERD Symptoms that are Refractory to Proton Pump Inhibitors,” a Phase 3 study comparing antireflux surgery (laparoscopic Nissen fundoplication) to two different medical therapies (baclofen, desipramine) or placebo in Veterans with PPI-refractory GERD. Fifteen VA Medical Centers are involved in this CSP to enroll 393 patients with refractory GERD.

2. Colorectal Cancer Screening: The recommended colorectal cancer screening by US Preventive Services Task Force in 1996 included annual fecal occult blood tests (FOBT), or sigmoidoscopy, or both¹⁰. However, this recommendation was changed, in part, by the findings from VA CSP#380 entitled “Prospective Evaluation of Risk Factors for Large (> 1 CM) Colonic Adenomas in Asymptomatic Subjects.” In CSP #380, screening colonoscopy in a cohort of 3196 Veterans showed that colonoscopy can detect advanced colonic neoplasia in asymptomatic individuals, and that over half of the advanced proximal neoplasia would have been missed by sigmoidoscopy alone.¹¹ Soon thereafter, screening colonoscopy was widely recommended, although randomized controlled-study evidence of its effectiveness in reducing cancer mortality was, and still is lacking. This is in contradistinction to available randomized, controlled trial evidence of the effectiveness of fecal occult blood testing and flexible sigmoidoscopy on reducing cancer mortality and incidence^12–14. In addition, fecal occult blood testing has improved with the introduction of the fecal immunochemical test.

   Therefore, the VA Cooperative Studies Program funded CSP#577, a 15 year study entitled “Colonoscopy versus Fecal Immunochemical Test in Reducing Mortality from Colorectal Cancer (CONFIRM)” with 45 participating VA Medical Centers. The CONFIRM study has enrolled approximately 31,000 of the planned 50,000 veterans at average risk for colorectal cancer and has randomized them to either screening colonoscopy or annual screening with a fecal immunochemical test. All participants will be followed for at least ten years to determine colorectal cancer mortality, incidence and complications of colonoscopy. CONFIRM is the largest VA intervention study ever undertaken, leveraging the VA’s EHR to help identify potentially eligible veterans and utilizing modifications of the clinical reminder system to aid with recruitment and minimize crossover. The CONFIRM study exemplifies the VA’s commitment to funding research that is designed to answer important clinical questions, even when the study results will not be available for over a decade.

3. c. Clostridium Difficile: Despite the first report of stool transplantation for the treatment of antibiotic associated diarrhea at the Denver VA medical center in 1958, recurrent C. difficile remains a vexing clinical problem today. CSP#596 entitled “Optimal Treatment for Recurrent Clostridium difficile Infection” is currently funded to compare two different vancomycin strategies to fidaxomycin for the treatment of recurrent C. difficile infection. Another study (CSP#2004) is in the planning stages to investigate the safety and efficacy of fecal microbiota transplantation for the treatment of recurrent C. difficile infection.

4. d. Hepatitis C: Veterans who use VHA facilities have been noted to have a high prevalence of hepatitis C virus (HCV) infection. In order to better understand the epidemiology of HCV infection in Veterans, VA CSP#488 was funded in 2001. This study demonstrated that an estimated 5.4% of VHA facility users had hepatitis C, more than twice the prevalence in the general population¹⁵. Given the high prevalence of HCV infection among Veterans, VHA has funded many studies related to better understanding and management of this disease.

VA Informatics and Computing Infrastructure (VINCI)

VINCI is an effort by the HSR&D Service and the VHA Office of Informatics and Analytics to improve access to VA data and to facilitate the analysis of those data while ensuring Veterans’ privacy and data security. The system hosts healthcare data on Veterans treated throughout VA in an anonymized and secure fashion, providing tools for analysis of both administrative data and clinical notes. A variety of statistical and programming tools, including SAS Grid, Stata MP, SPSS and R are provided for use in the computing environment. Each researcher is given a workspace within the environment, which can be accessed from anywhere within the VA network. VINCI staff collaborate with researchers across VA in such areas as natural language processing, and provide initial phenotypic characterization of subjects enrolled in MVP.

III. VA Mentoring Awards: Pipeline for new VA-based GI physician scientists

VA’s Career Development Program (CDA) was established to ‘provide mentorship for junior researchers so they can learn from renowned, experienced VA researchers’ and to attract, foster and retain talented young researchers to become national and international leaders in research areas relevant to the VA and Veteran health care. The available funding mechanisms include Career Development Award 1 (CDA-1), Career Development 2 (CDA-2) and Career Development Enhancement Award (CDEA).

CDA-1 is an entry-level program open to both clinician and non-clinician researchers at an early stage of their academic career (similar to an NIH F32 or possibly K01/K08 award). It provides up to 2 years of support and is currently available only through RR&D Service with a funding rate of 18–27% in 2012–2014. CDA-2 is a mid-level program open to both clinicians and non-clinicians through all research services (BLR&D, CSR&D, HSR&D and RR&D) with 14–23% overall funding rate. CDA-2 is similar to the NIH K08 mechanism, providing 3–5 years of support for 75% protected research time towards independent research career development. CDEA is for more established VA investigators (both clinicians and non-clinicians) and provides up to 6 months of salary support to learn new research skills that can be combined with local support towards a year of ‘sabbatical.’

Relevant for this commentary, CDA-2 is a potentially attractive funding source for research-oriented GI fellows and junior faculty members, particularly those in VA-affiliated academic GI programs. Typically, a CDA-2 applicant should have demonstrated productivity and commitment to research (e.g. at least 1–2 publications). Since the award is intended to support VA-based investigators, the application should include: 1) a VA-based research program and career development; 2) a primary research mentor that is VA-based and preferably VA-funded; 2) written commitment from the VA Medical Center Director for at least partial FTE support after completion of CDA-2 funding and; 3) VA relevance of the research proposal. Applicants may apply for both CDA-2 and K08. However, only one award may be accepted if both are funded.

The mentoring committee should include scientific and career mentors from the VA and the academic affiliate—to help navigate the applicant in both areas. It is also important to plan in advance with the immediate clinical division (e.g. Gastroenterology), department (e.g. Internal Medicine) and VA Research Program (e.g. Associate Chief of Staff for Research or ACOS/R) in developing the career plan, securing research space, obtaining letters of commitment from the local VA leadership and mobilizing the VA research staff needed to submit the application in a timely manner (with submission of an LOI months ahead of the application deadline).

If and when the application is funded, ongoing monitoring is needed to ensure that the awardee remains on-track for proposed research aims, course work and publications. The awardee is expected to apply for a VA Merit award before completing the CDA-2. The ACOS/R plays a key role in guiding the applicant, his/her mentors and the relevant clinical programs (both VA and academic affiliate) while communicating with the VA program officers on behalf of the awardees. Since up to 75% salary support for a CDA-2 awardee generally comes through the VA Research Program, this could ‘free-up’ clinical efforts previously assigned to the CDA awardee and allow recruitment and partial support for another clinical faculty. Timely coordination of these processes is an important aspect of CDA2 process, anticipating up to 3 submissions over 1–2 years before successful funding (submission schedule found at http://www.research.va.gov/funding/process/submission-calendar.cfm) in addition to further Just-In-Time processes (up to 120 days) before funding release.

IV. Emerging Research Opportunities and Challenges

There are numerous clinical challenges and opportunities in GI within VA research as well as biomedical research in general.

Obesity and metabolic liver disease

There is an ongoing obesity epidemic with associated increase in non-alcoholic fatty liver disease in the US. This may be particularly relevant for Veterans, at risk for obesity and diabetes according to the Millenium Cohort Study.^1–5

Cirrhosis and Liver cancer

There is an increasing incidence of cirrhosis and liver cancer among US Veterans as a long-term consequence of chronic viral hepatitis, particularly HCV^16–19}. While HCV is now readily curable with available antiviral oral regimens, many HCV-infected patients already have advanced fibrosis and are at risk for liver cancer development. In addition, chronic hepatitis B with delta virus infection and non-alcoholic fatty liver disease in US Veterans have been associated with increased risk for liver cancer development.^{20, 21} Thus, there is a need to identify and treat patients with chronic liver disease and to find better surveillance and treatment for cirrhosis and liver cancer.²²

GI cancer surveillance and management (colon, stomach. esophagus, pancreas)

While there are ongoing CSP studies in GERD and colon cancer screening, there are further challenges and opportunities in this area, including cancer genetics as a guide to surveillance and treatment management, as well as immunotherapeutic approaches²³.

Microbiome research

Despite the first fecal transplant performed in 1958 by a VA surgeon,²⁴ this is a relatively new field with numerous and growing implications, particularly of interest for Veterans that have been stationed abroad and who have endured adverse environmental exposures.

Endoscopic technologies

There are ongoing technical innovations in various aspects of GI (e.g. endoscopic therapies, such as bariatric devices, endoscopic submucosal dissection) that warrant careful consideration in training and care models needed to obtain optimal outcomes for Veterans.

Genetics

As mentioned above regarding the Million Veteran Program, the genetic basis for health and disease outcomes is an exciting new area for further investigation—including metabolic liver disease, nutrition, cancers and chronic inflammatory diseases. The MVP database is sufficiently large to address more detailed questions about the genetic basis of disease than have typically been asked, such as determining if there is a genetic predisposition to non-alcoholic steatohepatitis among diabetics, or whether there are genetic risk factors for pancreatitis in alcoholics. The range of potential problems to address seems endless.

Benefits of being a VA-based investigator

The VA offers many benefits to help attract and retain research investigators. For example, the diverse patient population with associated electronic databases presents an extremely rich resource for investigators interested in epidemiologic, health services, outcomes and other aspects of clinical research. VA also provides additional funding source that is available only to VA-based investigators, without precluding eligibility for NIH, private foundation and industry funding. Also, the VA has a long track record of investing in career development and offers competitive but reasonable paylines relative to current trends in NIH funding. Furthermore, as clinician-investigator salaries are supported directly by the medical center, funding can be focused on other research activities. Finally, the VA is a mission-driven organization that is focused on the care of the men and women who have served our nation. VA investigators take great pride in this mission as they seek new knowledge to improve the health status of our Veterans as well as those in our society at large.

V. Conclusion

Driven by its mission to provide the highest quality care to our nation’s Veterans, the VA has supported various GI research efforts for many years and remains committed to further enhancing its existing GI research portfolio, through a variety of funding mechanisms. The linkage between the research and the healthcare delivery system enables the VA to take a long-term perspective in its funding decisions and invest in research that will have high impact on clinical outcomes. Furthermore, the VA is motivated to invest in the career development of new investigators that can also bring their intellectual curiosity and dedication to the bedside.

VA considers the clinician-investigator to be a key element in maintaining high quality subspecialty care; the VA research program is designed to help attract and retain world-class clinician-scientists and research career scientists, and maintains a research program that is dominated by an investigator-initiated research agenda. The maintenance of a cadre of clinician-investigators and non-clinician scientists, working in close proximity and on related problems, helps to maintain strong cross-pollination among basic, preclinical, translational and clinical researchers, and helps to facilitate the progress of research through the translational pipeline. It does so in a manner that enables investigators to be successful without building for themselves the machinery required to execute a large clinical trial or a substantial epidemiologic or genomic study. It is advanced by a Veteran population that is altruistic and partners with investigators by participating in these studies in order to help other Veterans and the American people. As such, it provides an exceptional environment for those who wish to drive medical science forward while remaining actively engaged in the practice of medicine.

Abbreviations

VA

Veterans Affairs

VHA

Veterans Health Administration

VINCI

VA Informatics and Computing Infrastructure

ORD

Office of Research and Development

CRADO

Chief Research and Development Officer

BLR&D

Biomedical Laboratory R&D

CSR&D

Clinical Science R&D

HSR&D

Health Services R&D

RR&D

Rehabilitation R&D

CSP

Cooperative Studies Program

COINs

Centers of Innovation

QUERI

Quality Enhancement Research Initiative

HERC

Health Economics Resource Center

ViREC

VA Information Resource Center

CIDER

Center for Information Dissemination and Education Resources

MVP

Million Veteran Program

EHR

Electronic Health Record

MCS

Millenium cohort Study

GERD

Gastroesophageal reflux disease

CDA

Career Development Award

CDEA

Career Development Enhancement Award

CSSEC

Cooperative Studies Scientific Evaluation Committee