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Development of a Performance Assessment Program for Research Animal Diagnostic Laboratories and Defining Microbiologic Testing Standards

Lela K. Riley

Department of Veterinary Pathology, University of Missouri, Columbia, MO

Efforts are being made in this country to develop an expanded performance assessment program (PAP) for research animal diagnostic laboratories to help ensure uniformity of diagnostic testing. All of us who are involved in health monitoring of laboratory animals recognize the importance of accurately assessing the health of animals to be used in biomedical research. Clearly, microbial infections can and do interfere with, alter, and even invalidate research studies by altering the physiology of animal models. Thus, it is critical that we as diagnosticians provide accurate health assessments of laboratory animals to the veterinarians who care for these animals and investigators who use these animals.

We also recognize that advances in genetic manipulation of rodents have led to an explosion in the numbers of transgenic and knock-out mutant mouse and rat models. Because these mutant mice and rats represent extremely valuable models to researchers worldwide, these rodents are frequently shared among researchers in institutions in United States, Japan, and other countries. With this increased trafficking of rodents, the importance of accurate health monitoring has never been greater.

As Dr. Shek has described, multiple assays are available for diagnostic evaluation of animals, each with their own advantages and disadvantages. In addition, individual diagnostic laboratories have developed their own reagents and methodologies for performance of diagnostic tests. Although different methods may be used by different laboratories, the important issue is not what test is used or what reagents are used but instead, the accuracy of results. To ensure that test results are accurate, several major diagnostic laboratories in the United States have recently initiated efforts to develop a comprehensive performance assess



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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE Development of a Performance Assessment Program for Research Animal Diagnostic Laboratories and Defining Microbiologic Testing Standards Lela K. Riley Department of Veterinary Pathology, University of Missouri, Columbia, MO Efforts are being made in this country to develop an expanded performance assessment program (PAP) for research animal diagnostic laboratories to help ensure uniformity of diagnostic testing. All of us who are involved in health monitoring of laboratory animals recognize the importance of accurately assessing the health of animals to be used in biomedical research. Clearly, microbial infections can and do interfere with, alter, and even invalidate research studies by altering the physiology of animal models. Thus, it is critical that we as diagnosticians provide accurate health assessments of laboratory animals to the veterinarians who care for these animals and investigators who use these animals. We also recognize that advances in genetic manipulation of rodents have led to an explosion in the numbers of transgenic and knock-out mutant mouse and rat models. Because these mutant mice and rats represent extremely valuable models to researchers worldwide, these rodents are frequently shared among researchers in institutions in United States, Japan, and other countries. With this increased trafficking of rodents, the importance of accurate health monitoring has never been greater. As Dr. Shek has described, multiple assays are available for diagnostic evaluation of animals, each with their own advantages and disadvantages. In addition, individual diagnostic laboratories have developed their own reagents and methodologies for performance of diagnostic tests. Although different methods may be used by different laboratories, the important issue is not what test is used or what reagents are used but instead, the accuracy of results. To ensure that test results are accurate, several major diagnostic laboratories in the United States have recently initiated efforts to develop a comprehensive performance assess

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE ment program for diagnostic testing of laboratory animals. A comprehensive program such as this currently does not exist in this country. The following institutions and companies are presently involved in initiating this effort: Anmed Biosafe, Inc.; Bioreliance; Charles River Laboratories; Harlan Sprague Dawley, Inc.; The National Cancer Institute; and our laboratory at the University of Missouri. This group is not intended to be exclusive. It simply represents institutions and companies that operate research animal diagnostic laboratories and are committed to high-quality testing of laboratory animals. This group has met on several occasions to set goals, establish priorities, and begin to organize the framework for a comprehensive performance assessment program. The goal of the program is to develop a comprehensive performance assessment program that will distribute unknown specimens to participating diagnostic laboratories for testing. Testing results will then be collected and analyzed by an unbiased external third party. Finally, the testing laboratories will be apprised of expected results for each specimen distributed. If testing laboratories correctly identify a microbial contaminant or infection, the laboratory is provided additional validation of its testing reagents and methods. If test results do not match expected results, the laboratory is alerted to the problem and can modify its testing procedures. Several fundamental principles will be emphasized in this program. The program will be comprehensive and will assess all types of diagnostic test methods including serology, bacteriology, molecular techniques such as polymerase chain reaction-based diagnostics, parasitology, histopathology, and new test modalities as they become available. Specimens distributed to participating laboratories will be well defined and will be made by experimental infection of rodents with well-characterized microorganisms. Alternatively, specimens may be collected from natural outbreak infections and documented extensively to identify the causative agent. Methods for documentation will include testing by a battery of sensitive and specific tests. For example, serum collected from an outbreak of natural infection will be tested by multiple serologic assays, including enzyme-linked immunosorbent assay, immunofluorescent assay, hemagglutination inhibition assay if appropriate, and Western blot analysis. Only if results of all tests are consistent for a specific etiologic agent or disease will the specimen be distributed to laboratories participating in the PAP. Distributed specimens will be relevant to infections found in laboratory animals, thus allowing diagnostic laboratories to focus attention on types of microbial infections that they are likely to encounter in laboratory animals. Infectious agents that are currently the most prevalent in laboratory animals will be emphasized. As new emerging agents are identified and diagnostic tests are developed, we anticipate including specimens that will test the ability of diagnostic laboratories to detect these newly recognized agents and infections.

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE Currently, this group is developing standard operating procedures for preparation and validation of specimens, storage of specimens, shipment of specimens to participating laboratories, and reporting of results. We are also currently in the process of identifying an external party who will distribute the specimens and collect and analyze reports from participating laboratories. We plan a two-phase implementation of this PAP. In phase I, we anticipate distribution of specimens to a small group of laboratories including those involved in the planning phases of this program. This phase is designed to allow identification of problems in any aspect of the program including preparation of specimens for testing, shipment of samples and reporting procedures. Procedures will be modified as needed to eliminate any identified problems. The goal is to initiate phase I of the PAP by July of 2000. Phase II will be initiated in 2001 and will expand the program to allow any laboratory to participate in the program, including diagnostic laboratories in the United States, Japan, and other countries. Fees will be assessed from participating laboratories to recover costs associated with production and shipment of test specimens and collection and analysis of test reports. As soon as this PAP is operational, results obtained from laboratories participating in the program should yield uniform testing results among diagnostic laboratories and provide users confidence in testing results. I believe this comprehensive PAP will benefit both diagnostic laboratories and the users and producers of laboratory animals. It will benefit diagnostic laboratories by providing an additional validation of their testing methods and reagents, and it will benefit users by ensuring that test results among participating laboratories are as consistent and uniform as possible. Nevertheless, it is important to remember that diagnostic testing does not always yield unequivocal results. Certain samples may contain interfering substances that confound testing. These interfering substances may be due to the health of the animal at the time the sample was collected, the strain of the animal, prior experimental manipulation of the animal, the procedure used for collection of the sample, or how the sample was stored between the time it was collected and the time it was tested. Therefore, it is unrealistic to think that every sample will yield unequivocal results. It is important to remember that accurate health monitoring requires the involvement of both the diagnostic laboratory and the laboratory animal veterinarian and his/her staff. Laboratory animal veterinarians and professionals must ensure that the appropriate number of animals are tested to provide a high confidence level of detecting the infection. For microorganisms that have a low incidence of infection, this may mean testing a large number of animals. Laboratory animal veterinarians must also ensure that specimens are collected from animals of the appropriate age and that samples are collected and stored appropriately before shipment to a diagnostic laboratory for testing. If sentinels are used to evaluate the infection status of an animal colony, it is

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE essential that the sentinel monitoring program is appropriately established and performed. Another issue that faces laboratory animal veterinarians and diagnostic laboratories is defining the microorganisms and infections for which we will test. Although it is absolutely critical that one ensures the health of animals within a facility and documents the health status of animals being imported into a facility to prevent outbreaks of disease, it is inappropriate to establish a list of organisms that are unacceptable. Microorganisms that are ubiquitously unacceptable in one facility may cause no problem in another facility. For example, Corynebacterium bovis, the agent of hyperkeratosis in nude mice, is carried on the skin of immunocompetent haired mice and causes no adverse effects in these mice. In a facility with only immunocompetent mice, this agent poses no threat. However, in a facility with nude mice, the presence of this organism poses a real and major threat. Thus, the organisms to test for must be determined on the basis of the individual situation. One possible approach to diagnostic testing of animals to be imported into a facility is for the receiving institution to request a recent health report from the donating facility. If the health report is not recent (within the last 1 to 2 months) or if any agent of concern for the recipient institution has not been evaluated, then the recipient institution should request that the donating institution perform additional health evaluations. Cost of additional health monitoring should be negotiated between the donating and recipient institution depending on the circumstances. Alternatively, the recipient may import and strictly quarantine the animals until it can be determined that their health status meets the standards of the facility. In summary, the importance of accurate health monitoring of laboratory animals is well recognized. I believe that diagnostic laboratories are committed to providing the best testing possible. To this end, several of the testing diagnostic laboratories in this country are involved in establishing a comprehensive PAP. We anticipate that this program will be available to diagnostic laboratories worldwide by 2001 and that this program will benefit the entire laboratory animal and biomedical research communities by ensuring uniform testing capabilities among participating diagnostic laboratories. We believe that joint efforts between diagnostic laboratories and laboratory animal veterinarians and professionals can achieve the common goal of healthy animals being used in biomedical research.