This is a retrospective, longitudinal analysis of 9 years (FY2002-FY2010) of national VA medical data bases to assess morbidity, mortality, and utilization associated with Clostridium difficile infection (CDI) in veterans with spinal cord injury and disorder (SCI/D). The primary hypotheses are that 1) rates of CDI in veterans with SCI/D have increased over time, 2) recent fluoroquinolone exposure will be a significant risk factor for CDI in SCI/D veterans, 3) in-hospital mortality will be higher for SCI/D veterans with CDI diagnosis compared to those without such a diagnosis, 4) length of stay (LOS) will be higher for SCI/D veterans with CDI diagnosis compared to those without such a diagnosis, and 5) oral vancomycin treatment will be associated with lower failure rates and 30-day case fatality than Metronidazole treatments for CDI. Review Criteria 1. Importance of the Problem Addressed. CDI would appear to be an increasingly important community and health-care related cause of morbidity and mortality in the U.S. and the VA. The SCI/D population would appear to be a particularly vulnerable population because of substantial risk factors for CDI. Thus, this study would appear to be able to provide important and useful data that could be used to develop plans for treating and preventing CDI in SCI/D veterans. 2. Contribution to VHA. CDI in SCI/D veterans appears to be a major concern for VHA. While smaller studies in SCI/D populations have provided some information on this subject, the size of the study should provide valuable information that VHA could use to guide treatment decisions and to develop plans for future studies. 3. Adequacy of Response to Previous Feedback This is a resubmission. The P.I. has been fairly responsive to previous feedback. This has resulted in the inclusion of a validation plan to validate the definitions of CDI, failure, recurrence and treatments received (record review of 300 CDI cases and 300 non-CDI cases), dropping the cost analyses from the study, changing the definition of CDI to remove requirement of treatment with vancomycin or metronidazole, and changing some of the analysis plans. These changes have improved the study. 4. Methods. 1. Study Design: The retrospective, longitudinal design is an appropriate design for the first four of the hypotheses. While a RCT would be the preferred method for the 5th hypothesis, given the other purposes of the project, the proposed retrospective cohort design is an acceptable alternative and would provide justification for the need of potential RCT if the results warrant it. The secondary objective for the validation plan is also appropriate. 2. Approach: A quantitative approach is acceptable. 3. Theoretical Model and Conceptualization of Key Components: While the P.I. presents a conceptual model of the project, it basically just describes the work proposed as opposed to being a theoretical model. The background material justifies the work proposed and the conceptualization of the key components. 4. Population and Sample, Sampling Plan and/or Comparison Groups: The population consists of all SCI/D veterans meeting inclusion/exclusion criteria, who are in both the spinal cord dysfunction registry and the VA Allocation Resource Center cumulative lists (about 16,000 to 20,000 SCI/D veterans). This population is appropriate. One question is whether SCI/D veterans will be included more than once in the analyses or just once each year, or for each hospitalization. If all hospitalizations are used, how will this be adjusted for in the analyses? If a patient is only used once, which hospitalization will be used (especially for non CDI cases)? In addition, how will the randomized validation plan cases be randomized? Finally, it was also unclear if the list of patients in D.2 starting with traumatic lesions of the spinal cord are inclusions or exclusions. 5. Statistical Power: While using the entire population of available SCI/D veterans, which is in the thousands, should provide adequate statistical power for most of their hypotheses, the P.I. uses a significance level of 0.05 to calculate the sample sizes. This would lead to the assumption that all of the statistical tests will be done at the 0.05 level. Given the number of comparisons to be done, this could lead to many chance findings. Consideration should be given to reducing the p-value to guard against chance findings. 6. Key Variables and Their Measurement: The key variables for the study are the CDI related variables, which are based on published clinical practice guidelines. The pilot data and the added validation plan are reassuring support for these measures (CDI, failure, recurrence). The SCI/D definition also is reasonable given the change to include all treatments for CDI. Other variables are taken from existing data bases and are adequate. 7. Data Analysis Plan: The analysis plan is quite extensive and well-thought out. The P.I. has included unadjusted and adjusted analyses, using propensity analyses and an instrumental variable analysis plan as suggested in the previous review. As previously mentioned, how significance will be determined (chance findings) needs to be discussed. 8. Data Collection Issues, Including Respondent Burden: Since already existing VA data bases will be used, there are no patient burden issues. The investigators appear to have used these data bases in the past. 9. Definition and Feasibility of Any Intervention: NA 10. Recognition and Appreciation of Methodical Issues: The P.I. has a limitation section which addresses some possible concerns. 5. Adequacy of Data. The PI will be using a number of VA data bases that appear to be appropriate to do the work outlined. The study team seems to be familiar with these data bases. They have included a validation plan for the main outcome measures relating to CDI. 6. Project Organization and Management. The roles and responsibilities of the study team are spelled out and are adequate to conduct the study. A two-year timeline is also adequate. The FTE's proposed seem to be adequate with the reduction of the Biostatistician's time to 50%. The dissemination/implementation plan is adequate. 7. Investigator Qualifications. The P.I. and the study team are qualified to conduct this project. They seem to have worked together for some time on similar projects. There is appropriate medical expertise, a biostatistician and other methodologists, and a programmer in addition to support staff. They should successfully complete the study. 8. Human Subjects. Since existing data bases are being used, there are no physical, mental or emotional risks to the subjects. Only possible risk is loss of personal information. Adequate security measures appear to be in place. 9. Inclusion of Women and Minorities. Since already existing data bases are being used, women and minorities will be included to the extent that they are included in the data bases and meet SCI/D criteria. 10. Facilities and Resources. Facilities and resources are adequate. There are letters of support from the P.I.'s hospital director and from the co-P.I.s and consultants. 11. Budget. The budget is quite modest at $359,329 over two years. The timeline and the requested funds are quite appropriate. 12. Overall Strengths. This is an important topic being conducted by a qualified team. The overall objective and analyses are appropriate. 13. Overall Weaknesses. Since patients can be included many times over the course of 9 years, some guidelines need to be presented on how multiple cases for the same patient will be handled. How the validation cases will be selected (other than randomly) needs to be discussed. How the reporting of chance findings will be guarded against needs to be stated. Key Issues (Summary Points): 1. This is an important project with a strong study team. 2. Discussion of how multiple events from the same patient will be handled is needed. 3. How guarding against chance findings and selection of the validation cases is needed.
With the rise in prevalence of C. difficile, increased fluoroquinolone resistance, and recent data showing an increase in the community spread of this organism, it is clearly becoming part of an important group of organisms that are associated with significant morbidity and mortality in patients. This study will provide crucial information for VA Operations staff (Infectious Disease Program Office) and SCI/D Services in planning prevention strategies, improving ongoing initiatives to promote patient safety and prevention of C. difficile, and improve the ongoing rehabilitation management of Veterans with SCI/D. This study is part of a larger effort by this partnership to reduce the effects of HAIs in Veterans with SCI/D and the methodology employed could be used to assess other infections in this population. We propose examining 9 years (FY2002-FY2010) of national VA medical encounter, pharmacy, and microbiology laboratory data to assess burden of C. difficile and effectiveness of treatment strategies in veterans with SCI/D.