Marshfield Clinic Research Foundation Research Articles

The Use of Pharmacogenetics in Targeting SGLT2 and its Variants

When the contents of the bloodstream are filtered by the kidney, glucose is reabsorbed. Familial glycosuria, a benign disorder often attributed to genetic variants in the gene SLC5A2 which encodes the protein Sodium Glucose Transporter 2 (SGLT2), prevents reabsorption of glucose leading to an excess amount in urine. SGLT2 is used for glucose reabsorption, and when functioning properly, about 90% of glucose from the urine is reabsorbed into the bloodstream. Upon glucose and sodium binding, SGLT2 undergoes a conformational change, where the structure shifts from an outward to an inward facing orientation, allowing glucose to be released. Recently, two novel variants in SLC5A2 have been identified in the Marshfield Clinic patient population; further research is being conducted to determine whether these variants impact glucose transportation and how they affect physiological output. To research this, homology models of WT SGLT2 were constructed and analyzed based on a previously solved structure of a bacterial SGLT protein (vSGLT). It can be concluded that SGLT2's structure is composed of 14 transmembrane helices which surround both galactose/glucose and sodium binding sites. Recently, SGLT2 has become a popular target for Type II diabetes therapeutics. These drugs inhibit SGLT2, as they prevent glucose to be reabsorbed; thus, glucose is excreted out of the body. Further understanding how genetic variants effect SGLT2 structure and function may allow practitioners to properly prescribe medications and prevent adverse drug reactions when treating patients with Type II diabetes.Support or Funding InformationMarshfield Clinic Research FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

“Peer Reviewer of the Year” 2017: Honorable Mention

Casper Bendixsen, PhD, National Farm Medicine Center. Dr. Bendixsen, a cultural anthropologist, is an Associate Research Scientist in the Marshfield Clinic Research Foundation. He was the driving f...

Differential Lipid Response to Statins Is Associated With Variants in the BUD13-APOA5 Gene Region.

Genetic variants within the BUD13-APOA5 gene region are known to be associated with high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. Recent studies suggest that single nucleotide polymorphisms (SNPs) within this region affect HDL-C response to statin-fibrate combination therapy and low-density lipoprotein cholesterol (LDL-C) response to statin therapy. We hypothesized that SNPs within the BUD13-APOA5 region are associated with TG, HDL-C, and LDL-C response to statin therapy. We examined 1520 observations for 1086 patients from the Personalized Medicine Research Project, a large biorepository at the Marshfield Clinic Research Foundation, who had received statin therapy and been previously genotyped for polymorphisms in the 11q23 chromosomal region. A significant differential response to statin therapy was observed for 3 SNPs. The minor allele at rs11605293 significantly attenuated TG-lowering response to pravastatin (P = 0.000159), whereas the minor allele at rs12806755 was associated with a similar response to lovastatin (P = 0.000192). Genotypes at rs947990 significantly attenuated LDL-C reduction to atorvastatin therapy (P = 0.000668) with some patients with the minor allele having LDL-C increase after therapy. No SNPs within the BUD13-APOA5 region were associated with a significant effect on HDL-C reduction in response to statin therapy. In conclusion, this study suggests that common SNPs within the BUD13-APOA5 can affect TG and LDL-C response to statin therapy in a North American population.

SU‐E‐T‐576: Obesity as a Factor in Prostate Cancer Treatment Modality and Outcomes

Purpose:Prostate cancer is the most frequently diagnosed malignancy in American males. To date, no single study has examined the effect of obesity on the outcomes of all three treatment modalities in a single population. We examined the relationship between obesity and prostate cancer treatment decisions as well as outcomes.Methods:We conducted a retrospective observational cohort study of the patients treated for prostate cancer with curative intent between January 1998 and December 2010. Wilcoxon ranksum and Chi‐Square tests were used to analyze the association between treatment mode and body mass index (BMI). Cox proportional Hazards models adjusted for risk category, age, and androgen deprivation therapy (ADT) were performed to evaluate the effects of BMI on overall, disease‐free, biochemical recurrence‐free, incontinence‐free, and impotence‐free survival.Results:A total of 1681 patients were included in the analysis, including 338 that received BT, 439 that received EBRT, and 904 that received RP. When BMI was assessed as a continuous variable, median BMI was higher in patients treated with BT (29.4) than in those treated with EBRT (28.8) or RP (28.9) (P = 0.0677, Wilcoxon rank‐sum test). After stratifying BMI into two groups (BMI < 29.4 or ≥ 29.4), Chi‐Square test showed that the treatment mode was significantly related to BMI where the proportion of high BMI individuals undergoing was 50.9% for BT, 42.4% for EBRT, and 43.2% for RP (P = 0.0309). Cox proportional hazards modeling was used to assess the relationship between BMI and survival outcomes. For patients receiving EBRT, BMI was a significant risk factor for incontinence‐free survival where HR for incontinence in the lower BMI group was 0.515 (95% CI 0.307–0.865, P = 0.0121).Conclusion:BMI appears to be related to prostate cancer treatment decisions, High BMI (≥ 29.4) is associated with poorer incontinence‐free survival for EBRT.This study was supported by a grant from the Marshfield Clinic Research Foundation

Factors associated with maintenance of antibody responses to influenza vaccine in older, community-dwelling adults.

BackgroundLittle is known about factors associated with maintenance of hemagglutinin inhibition (HAI) antibodies after influenza vaccination in older adults.MethodsAdults ≥50 years of age were vaccinated prior to the 2009–10 influenza season. Serum was drawn pre-vaccination (S1), 21–28 days post-vaccination (S2), and after the influenza season (S3) for HAI assays. Seroconversion was defined as ≥ 4-fold increase S1 to S2 (or if S1 < 10, by an S2 ≥ 40) and seroprotection was defined as S2 ≥ 40. Maintenance of antibody response was measured in participants with an S2 ≥ 40, and defined as an S3 ≥ 40.ResultsWe enrolled 510 participants during Fall 2009 at Vanderbilt University Medical Center and Marshfield Clinic Research Foundation. Participants’ mean age was 64 years with 62% female and 96% white. Seroconversion and seroprotection rates were lowest for influenza A H1N1 (12% and 26%, respectively), highest for influenza A H3N2 (45% and 82%), and intermediate for influenza B (28% and 72%). Of the participants with an S2 ≥ 40, 36% (46/126), 71% (289/407), and 74% (263/354) maintained an S3 ≥ 40 for H1N1, H3N2, and B influenza vaccine strains, respectively. S1 HAI titer was strongly associated with both post-vaccination seroprotection and maintaining seroprotection at S3 for all three influenza antigens. Age, sex, body mass index, self-reported stress, and vaccination site were not consistently associated with vaccine response or maintenance of response.ConclusionsPre-vaccination antibody titer was the only study variable consistently and positively associated with both serologic response to vaccination and maintenance of response. Antibody responses were lowest for the H1N1 vaccine strain.ClinicalTrialsgov Identifier: NCT02401893Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-0926-8) contains supplementary material, which is available to authorized users.

D1-3: Marshfield Dictionary of Clinical and Translational Science (MD-CTS): An Online Reference for Clinical and Translational Science Terminology

Background/Aims New terms are rapidly appearing in the literature and practice of clinical medicine and translational research. To catalog real-world usage of medical terms, we report the first construction of an online dictionary of clinical and translational medicinal terms, which are computationally generated in near real-time using a big data approach. This project is NIH CTSA-funded and developed by the Marshfield Clinic Research Foundation in conjunction with University of Wisconsin - Madison. Currently titled Marshfield Dictionary of Clinical and Translational Science (MD-CTS), this application is a Google-like word search tool. By entering a term into the search bar, MD-CTS will display that term’s definition, usage examples, contextual terms, related images, and ontological information. A prototype is available for public viewing at http://spellchecker.mfldclin.edu/.

PS2-22: Accuracy of Diagnostic Codes to Identify Rheumatoid Arthritis in Archived Electronic Health System Data: Support for Future Cancer Research Network Studies of Lymphoma Risk Pathways

Background/AimsIn preliminary work toward Cancer Research Network-based studies of lymphoma risk pathways, we undertook an evaluation of the utility of ICD-9 CM diagnostic codes to accurately identify potential risk factor conditions, including rheumatoid arthritis (RA).MethodsUsing the enrolled Virtual Data Warehouse (VDW) cohort at Marshfield Clinic Research Foundation, we ascertained a set of potential RA cases diagnosed between 2000 and 2010 by the presence of one or more diagnostic codes for RA (ICD-9 CM 714–714.89). Medical records were abstracted by trained staff on a random sample of 206 cases. Cases were adjudicated into categories of confirmed, probable, documented physician diagnosis only, equivocal, and non-case using a literature-based gold standard definition scheme. Outcome measures included positive predictive value (PPV) and relative sensitivity, with the confirmed, probable and physician diagnosis categories considered valid cases for the main analysis.ResultsUpon review, 25 subjects did not have sufficient medical records available for evaluation, leaving 181 subjects for analysis, including 57 with only one RA code and 124 with 2 or more instances of an RA code. Overall PPV for patients with one or more RA codes was 56%. Subjects with only one diagnostic code had very low PPV (12%), while PPV was higher among those with 2 or more (76%). PPV improved to 91% when requiring a rheumatologist diagnosis, but only 40% of the true cases in the set were detectable in this way. The one algorithm that provided acceptably high PPV and relative sensitivity required 2 or more RA diagnostic codes and history of a rheumatoid factor test (PPV 83%, relative sensitivity 82%).ConclusionsA single ICD-9CM diagnostic code for RA was not highly predictive of a true diagnosis, but PPV was enhanced when requiring multiple codes and incorporating other VDW data elements. With one exception, algorithms with higher PPV had strong reductions in relative sensitivity. Limitations include non-systematic collection of RA medication data preventing the use of treatment in the algorithms, and the inability to evaluate absolute sensitivity. Next steps include a joint RA analysis with investigators at Kaiser Permanente Southern California, and possible inclusion of RA treatment data into the Marshfield algorithms.

Social and Physical Neighbourhood Environment and Risk of Depression in Adults With Diabetes

Social and Physical Neighbourhood Environment and Risk of Depression in Adults With Diabetes

Beta Interferon Protein Therapy for Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disorder in cause the demyelination of neurons, resulting in degenerative symptoms. MS activates inert autoreactive myelin T‐cells, lymphocytes specific to the destruction of central nervous system myelin, to cross the blood brain barrier and secrete inflammatory cytokines, recruiting other leukocytes and macrophages that demyelinate axons primarily through the release of myelinotoxic substances. The most effective treatment for MS is administration of β interferon, which reduces relapse rate of nervous tissue attacks. The Marshfield SMART Team (Students Modeling A Research Topic) designed a model of β interferon using 3D printing technology to understand its interaction with T‐cells to treat MS. β interferon is an endogenous polypeptide that regulates T‐cells and are hypothesized to convert autoreactive myelin T‐cells into suppressor cells that can deactivate other myelin targeting lymphocytes. β interferon may also lead to the inhibition of cytokines, preventing activation of the autoreactive T cells. Interferons may inhibit the leukocyte migration across the blood‐brain barrier to prevent access to myelin. Understanding the structure and function of β interferon could lead to more precise and effective drugs to treat MS. Supported by grants from the Marshfield Clinic Research Foundation and NIH‐SEPA.

PS2-37: Design Considerations and Population Identification for Implementing a Dental Virtual Data Warehouse: Feasibility, Table Structure and Data Elements

Jay Fuehrer1, Aaron Miller1, Jimmy Kayastha1, Paul Hitz1 and Amit Acharya 1Marshfield Clinic

The US Food and Drug Administration's Sentinel Initiative: Expanding the horizons of medical product safety

The US Food and Drug Administration's Sentinel Initiative: Expanding the horizons of medical product safety

PS1-10: Response to Metformin and Genetic Variants of Organic Cation and Multidrug and Toxin Extrusion Transporters

Background and Aims: Metformin is the most widely-used anti-diabetic drug in the United States. However, medication management fails to achieve therapeutic goals in ~20% of patients. This study attempted to identify genetic polymorphisms associated with metformin treatment failure. We studied the associations between polymorphisms in two liver and kidney organic cation transporter genes (OCT1 & OCT2) and two kidney multidrug and toxin extrusion transporter genes, (MATE1 & MATE2K) and response to metformin monotherapy. Methods: At Kaiser Permanente Southeast and Marshfield Clinic Research Foundation we identified 304 type 2 diabetes (T2DM) patients on metformin monotherapy who: were enrolled for >=6 months prior to initiation; remained on metformin >= 90 days following initiation; and had a HgbA1c measured prior to first metformin prescription and then after initiation. From this group we selected 171 patients who had not received metformin or other anti-diabetics previously, and had baseline HbA1c levels >7.0% prior to metformin initiation. We genotyped 10 SNPs, and assessed response by measuring absolute and relative change in HbA1c after after metformin initiation. Results: Three SNPs were identified that were significantly associated with reduced response to metformin, after adjustment for baseline HbA1c, dose, and ethnicity. In a dominant model, heterozygosity or homozygosity for minor A allele in the MATE1 intronic SNP, rs2289669, resulted in a smaller absolute change in HbA1c (mean of 0.45% less reduction in absolute change in HbA1c; 95% CI 0.17 to 0.74%) compared to individuals homozygous for major G allele. In a recessive model, homozygosity for minor A allele in MATE2K 5′-UTR SNP, rs12943590, resulted in smaller absolute change in HbA1c (mean of 0.43% less reduction in absolute change in HbA1c, 95% CI 0.053 to 0.86%). The reduced function SNPs in OCT1 & OCT2 were not associated with metformin response, except for rs34059508 (G465R). This SNP showed a positive (but not statistically significant) association with smaller absolute change in HbA1c (mean of 0.49%; 95% CI −0.06354 to 1.045%). Conclusions: These three variants of metformin transporter genes may be important for personalizing treatment for patients with T2DM. A replication study in a larger population is currently being planned.

PS1-27: Use of Tumor Registry to Obtain Family History Information

Background: The Human Genome project has revolutionized the field of medicine to move toward personalized medicine. The family history is a screening tool to identify families at risk for common conditions allowing for personalized care. For breast cancer syndromes, genetic testing, counseling and prophylactic treatment are available. While there are data about the efficacy and clinical utility of the family history, there are areas that still need investigation. Does obtaining the family history lead to patient recommendations? Do patients FDA’s Mini-Sentinel Initiative: The HMORN’s Role. In May 2008, the FDA Commissioner announced FDA’s intention to create the Sentinel Initiative. The Sentinel Initiative is an effort by the FDA to create a coordinated national electronic medical product safety surveillance system. The Food and Drug Administration Amendments Act of 2007 (FDAAA) mandated FDA develop methods to obtain access to disparate data sources and to establish an active post-market risk identification and analysis system linking and analyzing data from multiple sources. The law sets a goal of 25 million patients under surveillance by July 1, 2010, and 100 million patients by July 1, 2012. With the funding and support provided by FDAAA, the FDA laid out the vision for Sentinel Initiative. In September 2009, the FDA awarded a single contract to a consortium of 28 institutions led by the Harvard Medical School Department of Population Medicine at the Harvard Pilgrim Health Care Institute, including 13 HMORN members (all Kaiser Permanente plans, Group Health Cooperative, Lovelace Clinic Foundation, Myers Primary Care Institute, Marshfield Clinic Research Foundation, HealthPartners Research Foundation and Henry Ford Health Services), CIGNA, Humana, WellPoint [HealthCore] and Tennessee’s Medicaid system, comprising ~60 million covered lives. Additional data resources include the HMORN’s ambulatory electronic medical records linked to enrollment and claims data for ~10 million patients; inpatient electronic medical records (EMRs), including blood product use from 88 adult and pediatric hospitals (approximately half are Kaiser plans); plus device and disease registries. Mini-Sentinel will create a ‘laboratory’ for developing and evaluating safety surveillance scientific methodologies and offers FDA the opportunity to evaluate safety issues in existing automated healthcare data system(s) while learning about the barriers and challenges inherent in these activities. The collaboration provides FDA with a public-private solution that leverages the strengths of the private sector and academia. Over the next five years, this collaboration will work with FDA to create the foundation for the Sentinel Initiative’s long-term goal of setting up a coordinated national post-market safety surveillance system.

Research Mentor: A Web-Based Resource Supporting Grantsmanship and Scientific Publication

As the largest physician-owned private multispecialty healthcare practice in central and northern Wisconsin and one of the largest in the nation, Marshfield Clinic has a long-standing track record in scientific research to support its healthcare mission. The Clinic’s staff of 790 physicians serves over 40 regional centers in a largely rural setting in 80 clinical specialties and undertakes research in a broad range of disciplines. In addition, the Clinic’s Research Foundation employs a staff of scientists who collaborate with clinician investigators. A rich research environment pervades the Marshfield system, supported by a state-of-the-art informatics environment, access to an epidemiologically-defined study population for which detailed medical and demographic data are available, with its status as the largest population-based genetics repository in the USA. Not surprisingly, this rich research environment attracts researchers with a broad range of expertise and experience. An additional layer of complexity is added with multidisciplinary or multi-institutional research. Preparing competitive scientific grant proposals responsive to emerging public health priorities is especially daunting for individuals collaborating on interdisciplinary and translational projects who lack experience and traditional training in grantsmanship. New page limits and a revision of the peer review process at the National Institutes of Health have created new challenges, even for seasoned investigators. To assist researchers in navigating the process of preparing successful grant proposals in an increasingly competitive research environment, a full-service research infrastructure was established over time at the Clinic’s Research Foundation, including a Clinical Research Center, Epidemiological Study Center, Bioinformatics Research Center, Offices of Scientific Writing and Publication, Research Integrity and Protection, Sponsored Programs, and a Core Laboratory. However, coordinating assistance to busy clinicians proved challenging, and supplemental, conveniently-accessible resources were required by researchers for navigating the rich, but complex research environment. To this end, Marshfield Clinic Research Foundation personnel teamed up to create a comprehensive informatics-based resource, Research Mentor, designed to support both new and established investigators in successful grant writing and manuscript preparation. The overarching purpose envisioned for Research Mentor was to serve as an educational resource on scientific writing related to research and as a bridge to internal resources, policies, and documents. The concept was to have scientific writing specialists centralize access to these resources to save investigators valuable time scouring the web in search of support tools. In addition, for internal personnel and investigators at institutions collaboratively working on research projects with Marshfield investigators, access to forms, policies, and support service personnel is also provided. Thus, Research Mentor was created as a web-based interactive resource that would provide direct links to other web-based educational resources which promote grantsmanship and scientific publication on the internet. Institutional resources that support investigators and sponsored programs offices are not unique. As example, Duke University,1 Stanford University,2 and Virginia Polytechnic Institute and State University (Virginia Tech),3 all have websites for their Sponsored Programs/Research office that provide some online tutorials regarding grant writing, and Purdue’s ‘The Owl’4 offers assistance with various aspects of manuscript development. However, we found none as comprehensive in their scope as Research Mentor, in providing support from research conceptualization, grant development, and submission to manuscript preparation within the context of the institutional research environment. To facilitate access across its network of regional centers, Research Mentor was originally launched on Marshfield Clinic’s intranet in 2008. Partially in response to requests for access from external collaborators who appreciated its value, and following exhibition of its contents and capabilities at several national conferences, Research Mentor was transferred to its current internet website at http://www.marshfieldclinic.org/mcrf/researchmentor in 2010, where it is a publically available resource. Access to research-related services and personnel, however, must remain limited to Marshfield Clinic investigators and their collaborators in the context of specific collaborative efforts, due to workload constraints on service personnel.

The Looming Rash of Herpes Zoster and the Challenge of Adult Immunization

Editorials4 May 2010The Looming Rash of Herpes Zoster and the Challenge of Adult ImmunizationJames G. Donahue, DVM, PhD and Edward A. Belongia, MDJames G. Donahue, DVM, PhDFrom Marshfield Clinic Research Foundation, Marshfield, WI 54449.Search for more papers by this author and Edward A. Belongia, MDFrom Marshfield Clinic Research Foundation, Marshfield, WI 54449.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-152-9-201005040-00011 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Herpes zoster is getting a lot of attention these days: A Google search on this topic will generate more than 1.3 million hits. There is good reason for this interest. At some point during their life, approximately 30% of people will develop herpes zoster, more commonly known as “shingles” (1). In raw numbers, approximately 1 million people in the United States are affected with herpes zoster every year (2). That number can be expected to increase because the risk for herpes zoster increases as cell-mediated immunity declines with advancing age, and an ever-increasing number of baby boomers are entering the ...

PS2-08: Development and Implementation of a Genetic Fingerprinting Assay for the Personalized Medicine Research Project

Deanna S Cross, PhD, Lynn C Ivacic, Elisha L Stefanski and Catherine McCarty, PhD MPH Deanna S Cross, PhD, Marshfield Clinic Research Foundation; Lynn C Ivacic, , Marshfield Clinic Research Foundation; Elisha L Stefanski, , Marshfield Clinic Research Foundation; Catherine McCarty, PhD MPH, Marshfield Clinic Research Foundation

PS1-25: Patient Outcomes in Systemic Lupus Erythematosus: A Collaborative Study Fostered by a New CTSA-based Partnership

Introduction: This project catalyzes a strategic partnership between Marshfield Clinic Research Foundation (MCRF) and the University of Wisconsin (UW), supported by an NIH Clinical and Translational Science Award (CTSA), to explore outcomes of systemic lupus erythematosus (SLE) in a community setting. The study pairs pilot funding and study staff from MCRF with a KL2 scholar/rheumatologist from the UW Institute for Clinical and Translational Research (ICTR). The project also uses ICTR-supported core resources at MCRF (Marshfield Epidemiologic Study Area [MESA]) and at UW (biostatistical support). Background: Survival among SLE patients has improved in recent decades, although studies continue to demonstrate excess mortality and cardiovascular disease. Whereas typical SLE studies represent urban tertiary referral populations, this study explores a community base, where the presence and extent of any mortality or cardiovascular excess is not clearly established. A past study described the spectrum of SLE in MESA from 19912001, finding cases were older, were less predominantly female, and had milder disease than in published reports from tertiary referral centers. Methods: Incident cases from 2002–2007 in this rural, population-based cohort are being ascertained and validated using the same American College of Rheumatology diagnostic criteria as the previous study. All incident cases 1991–2007 are being followed longitudinally to examine rates of all-cause and cardiovascular mortality, and of non-fatal cardiovascular events including MI, stroke, or heart failure hospitalization. Outcomes are to be compared with a matched set of MESA cohort members without SLE. Results/Conclusions: Automated data queries identified 167 new potential cases of SLE. After applying proportions of invalidation and non-incidence from the previous study, we estimate there will be an additional 31 incident cases from 2002–2007 to join the 44 cases previously identified. This represents one of only two rural US-based SLE cohorts with reported mortality outcomes. We anticipate that study results will support future funded research opportunities to ultimately inform evidence-based prevention strategies for SLE patients in real-world community practice.

PS1-10: Laboratory Content Area Development Within the Virtual Data Warehouse

Marsha A Raebel, PharmD, Gwyn Saylor, BA, Richard J Krajenta, BS, Jeremy McCauley, MBA, Paul Hitz, BS, Terese A DeFor, MS and Susan Andrade, ScD Marsha A Raebel, PharmD, Kaiser Permanente Colorado Institute for Health Research; Gwyn Saylor, BA, KPCO Institute for Health Research; Richard J Krajenta, BS, Henry Ford Health Systems; Jeremy McCauley, MBA, Marshfield Clinic Research Foundation; Paul Hitz, BS, Marshfield Clinic Research Foundation; Terese A DeFor, MS, HealthPartners Research Foundation; Susan Andrade, ScD, Meyers Primary Care Institute

PS1-30: Research Mentor: A Web-based Reference for Planning and Preparing a Research Proposal

Background: National emphasis on interdisciplinary and translational research as research priorities has created new challenges in grantsmanship. The Office of Scientific Writing and Publication at Marshfield Clinic Research Foundation utilized an informatics approach to create a comprehensive educational resource to assist new and established investigators engaged in research design. An interactive website accessible on the institutional intranet was designed to provide links to information, resources and support personnel to assist with navigating the central and peripheral processes required for successful procurement of institutional and external grants. Methods: Research Mentor was designed to provide comprehensive guidance to research fundamentals in a conveniently accessible interactive, user-friendly, online format. The website included resources and links to guidelines for grant development including feasibility analysis and study design planning, biostatistical considerations, peer review, grantsmanship, intellectual property protection, regulatory policies, computer-based training, institutional and national policies governing research, and access to funding agencies, forms, and appropriate support staff. The website was beta-tested by 25 physicians and scientists with varying degrees of research experience and refined based on user comments before the website was launched in spring of 2008. Results: Research Mentor proved to be an effective orientation tool for researchers by enhancing grantsmanship skills and providing access to research resources. Research Mentor has been effective in linking the researchers with appropriate support personnel who offer further assistance to researchers in producing competitive proposals. Tools custom-designed for Research Mentor to assist in project planning and design have been frequently accessed by investigators and reduce time spent by support staff on assisting with project planning. Conclusions: Informatics venues such as interactive user-friendly online educational websites can offer step-by-step guidance to research design and processes by providing a comprehensive cross-disciplinary research resource that offers value to new and established investigators alike. These tools promote networking with experienced support personnel to facilitate production of competitive grants.

Flu Vaccine Didn't Cut Pneumonia Risk

Fran Lowry is with the Orlando, Fla., bureau of Elsevier Global Medical News. Influenza vaccination was not associated with a significantly reduced risk of community-acquired pneumonia in a large population of people aged 65 and older. In the study of 1,173 cases and 2,346 controls, flu vaccine was associated with an 8% lower risk of community-acquired pneumonia among immunocompetent seniors during influenza season, investigators reported in The Lancet. The finding stands in contrast to a number of observational studies that suggest that vaccination substantially reduces the risk of hospital admission due to pneumonia in elderly adults. But these studies have not differentiated between healthy, mobile, immunocompetent seniors and frail seniors of advanced age or chronic health conditions, who are known to benefit from influenza vaccine. The investigators conducted a nested case-control study of individuals aged 65-94 years who were enrolled in Group Health, a health maintenance organization in Seattle, during 2000, 2001, and 2002. To ensure that they were removing any bias in their results, the researchers looked at both the preinfluenza and influenza periods of each year, reasoning that any benefit from the flu vaccine that was seen in the preinfluenza season could not be due to the protective effects of the vaccine. They found that in the preinfluenza season, there was an apparent strong benefit of the vaccine, with a 40% reduction in the risk of pneumonia. But after controlling for the presence of frail and sick seniors, they found essentially no effect of influenza vaccine during preinfluenza periods, reported the researchers, led by Michael L. Jackson, PhD, of the Group Health Center for Health Studies, Seattle (Lancet 2008;372:398-405). To look at the effect of the flu vaccine during influenza periods, they selected subjects who were immunocompetent and had no serious comorbidities. The age- and sex-adjusted odds ratio for the association between influenza vaccination and risk of community-acquired pneumonia was 1.04, but after adjustment for the confounding factors that were identified in the preinfluenza periods, the influenza season odds ratio was 0.92. In an interview, Dr. Jackson said that the findings are consistent with there being no link between flu vaccine and pneumonia risk in seniors. However, this does not mean that they should forego flu shots. “Randomized trials, which are the gold standard for public health-related evidence, have found that influenza vaccine reduces the risk of influenza infection in young—that is, 75 years and younger—healthy seniors. So they should still get their flu shots,” he said. He added that more work needs to be done to understand how well the vaccine prevents serious complications of the flu, such as pneumonia, in older seniors and those with chronic health problems. In an accompanying commentary, Edward A. Belongia, MD, of the Marshfield (Wis.) Clinic Research Foundation, and David K. Shay, MD, of the influenza division, Centers for Disease Control and Prevention, agreed with the need for additional studies about the causes of pneumonia in elderly adults, particularly in highly vaccinated populations (Lancet 2008;372:352-4). Calling the study by Dr. Jackson and his colleagues “well designed,” they added that standard methods of comparing the effectiveness of flu shots in different seasons and in different populations are also needed. The commentators also suggested that future studies of vaccine effectiveness should include other flu-related acute illnesses besides pneumonia and use sensitive and specific diagnostic tests, such as the polymerase chain reaction, for influenza. Dr. Belongia is director of the Epidemiology Research Center at the Marshfield Clinic Research Foundation. One of the authors of the study disclosed that she is a paid consultant to Sanofi Pasteur and to Novartis, manufacturers of the influenza vaccine. The other authors declared no conflict of interest.