Browsing by Subject "Immunopathology"
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Item An Economic Analysis of Texas' Measles Vaccination Program: 1990-1996(2000-08-01) MacDonald, Tammy O.; Claudia S. CogginIn order to get the most benefit out of limited resources, public health departments must examine the costs and benefits of their activities to determine the most cost-effective method to allocate these scarce resources. The use of economic analysis can inform and help clarify upon which decisions are to be made. (CDC, 1996). The resources used to produce most goods and services in society are efficiently allocated through markets. However, markets can fail to efficiently provide goods and services that largely benefit individuals other than the consumer. The types of goods and services that public health departments provide often fall into that category. Cost-benefit analysis is one type of economic decision-making tool used when market forces are not in control Cost-benefit analysis (CBA) places a dollar value on the costs and benefits of each outcome so they can be compared. This type of economic analysis can then be taken one step further. An incremental or marginal analysis can determine changes in the relative costs and benefits’ resulting from increase or decreases in the amount of resources used in a program. Such an analysis should be part of the decision making process, so that scarce resources can be used efficiently. This paper examines not only the costs and benefits of the measles immunization program in Texas but also, the expansion of the program in the 1990’s. The most significant changes in Texas’ immunization program took place in 1994 as a result of the measles outbreak of 1989-1990. The years 1992, 1993, 1994 and 1996 were chosen for this analysis because of the difference in immunization rates, incidence rates and the level of State funding. This time period represents the most dramatic changes to these three areas. Since the measles vaccination was put into use in 1963, the number of measles cases in the United States has decreased dramatically. An average of 450 measles-associated deaths was reported each year between 1953 and 1963. (TDH, unpublished). Widespread use of the vaccine has led to a 95% reduction in measles compared with the pre-vaccine era. (TDH, unpublished). However, during 1989-1990, the number of measles cases and deaths rose sharply. During 1989, more than 18,000 cases and 41 deaths were reported. The largest number of reported cases since 1978 and the largest number of deaths in two decades in the U.S. (National Vaccine Advisory Committee, 1991). The major cause of the epidemic of 1989 and 1990 was a low vaccination rate among preschool children. (TDH, unpublished). The Centers for Disease Control and Prevention (CDC) estimates national measles vaccine coverage for 2-year-olds in 1985 was 61%, compared with 82% in 1991 and 1992. (CDC, 1994). The CDC has set a goal of 90% of 2-year-olds to be immunized against measles, mumps and rubella. Texas reported 11% of all measles cases in the U.S. between 1989 and 1990, although it only accounted for 7% of the total U.S. population (Schulte et al. 1996). This is likely due to the fact that immunization rates were low throughout the state. In 1989, only 66% of the children in Dallas and 58% in Houston were estimated to be immunized against polio, diphtheria, pertussis, tetanus, measles, mumps, and rubella by the age of two. Nationally, immunization rates were estimated to be 70% at the same time (Schulte et al., 1996). This paper will proceed as follows. Two benefit/cost studies will be outlined in the background section. These studies compare the total benefits and costs of current vaccination programs to no vaccination program. Then a history of Texas’ measles vaccination program will be discussed. It will explain how the measles outbreak of 1989-1990 brought about organizational and financial changes to the immunization program within the Texas Department of Health (TDH). In the method section, the disease costs and costs associated with a vaccination program are used to calculate a benefit/cost ratio. The changes in immunization rates and the associated marginal costs and benefits are then compared. The results of the CBA and marginal analysis indicate that the benefit to cost (B/C) ratios range from 17 to 30:1. After reaching an immunization rate of about 81%, marginal benefits become smaller and smaller while the cost of increasing the immunization rate rises. Finally, the results will be discussed and conclusions made as to the efficiency of Texas’ measles vaccination program. There is some evidence that the CDC’s goal to immunize 90% of 2-year-old children for measles may not the most efficient goal for Texas.Item Characterization of MRSA Infection at Childrens Medical Center, Dallas, January 2005-June 2005(2006-05-01) Okoro, Ngozi M.; Raghbir Sandhu; Claudia S. Coggin; Sejong BaeOkoro, Ngozi M., Characterization of MRSA infection at Childrens Medical Center, Dallas, January 2005-June 2005. Master of Public Health (Epidemiology), May 2006, 33p., 14 tables, 10 illustrations, bibliography, 13 titles. MRSA infection is increasingly emerging in patients without the established risk factors hence the term CAMRSA. This study is a descriptive secondary data analysis from an ongoing study at UTSM/CMCD and describes the CMCD patients with MRSA infection. Data analysis showed a consistent increase in the incidence rate of the infection with slight female preponderance. Race distribution showed that blacks were the majority. Most children were less than 2years, used Medicaid, had superficial infections and community-acquired infections. All (100%) isolates were susceptible to Vancomycin and Linezolid while many (92.2%) were resistant to Erythromycin. The increasing incidence in CAMRSA infection remains a challenge for public health professionals and the resistant pattern a potential problem to the pharmaceuticals.Item Epidemiologic Assessment of a Targeted Tuberulosis Screening and Treatment Program Based on Geographic and Molecular Clustering(2005-08-01) Moonan, Patrick KevinMoonan, Patrick K., Epidemiologic Assessment of a Targeted Tuberculosis Screening and Treatment Program Based on Geographic and Molecular Clustering. Doctor of Public Health (Disease Prevention and Control), August 2005, 93 pp., 12 tables, 7 illustrations, bibliography, 148 tables. One of the primary goals of the tuberculosis elimination strategy is to interrupt the transmission of mycobacterium tuberculosis (TB). The most effective way to accomplish this goal is to identify and treat individuals who have active tuberculosis. However, even in highly effected tuberculosis control programs, M. tuberculosis continues to be transmitted to others, largely because most transmission occurs before diagnosis and initiation of therapy. Under the current recommendations, testing should be targeted at specific high-risk populations. While a strategy of targeted testing and treatment of persons most likely to develop tuberculosis is attractive, it is uncertain how best to accomplish this goal. This is the first study to assess the use of geographic and molecular surveillance in guiding a targeted tuberculosis screening and treatment of active tuberculosis and latent tuberculosis infection that monitors potential transmission in a defined high risk geographic area. The results of this geographically targeted program demonstrate significant yield for discovering active cases, latent tuberculosis infection, and recent transmission (TST converters). In this setting, geographically targeted screening identified as many as 19.8 tuberculosis cases per 1,000 persons screened and as many as 292.4 latent tuberculosis infections per 1,000 persons screened. Additionally, successful treatment of these individuals reduced the number of both cases and latent infection identified. Over a three-year period the case detection rate, latent infection detection rate, and TST conversion rate was reduced by 335%, 171% and 285% respectively.Item Immune and Inflammatory Responses Differ Between the Upper and Lower Respiratory Tract(2001-05-01) Hodge, Lisa M.; Simecka, Jerry; Goldfarb, Ronald H.; Mathew, Porunelloor A.The purpose of these studies was to evaluate the role of upper and lower respiratory immune responses during immunization against respiratory disease antigens, and to characterize which immune responses during immunization against respiratory disease antigens, and to characterize which immune responses contribute to protection in the respiratory tract during infection. After nasal immunization, antigen-specific IgA antibody forming cells dominated throughout the respiratory tract. However, IgG responses were significant in lungs, but not in nasal passages. Furthermore, parental immunization did not enhance humoral immunity in the upper respiratory tract even after a nasal challenge, whereas extrapulmonary lymphoid responses enhanced responses in the lung. After nasal immunization, inflammatory reactions developed within the lungs of mice, but not in nasal passages. Lowering dosages of CT reduced, but did not eliminate, these adverse reactions without compromising immunogenicity. Serum IgE responses were also enhanced in a dose dependent manner by inclusion of CT. During infection, mRNA expression for IL-4 was greater in the nasal passages, while both mRNAs for IL-4 and IFN-y were increased in the lungs. As well, we found increased mycoplasma organisms in the lungs of IFN-y-/- mice, suggesting a protective role for cell-mediated immunity in the lung. In contrast, IL-4-/- mice had greater mycoplasma organisms in the nasal passages, indicating IL-4 responses are crucial for upper respiratory tract protection. Consistent with antigen deposition, nasal inoculation with 10 μl volume of antigen plus CT resulted in significant IgA responses in the nasal passages compared to mice given 24 μl immunizations; however, lower respiratory tract immunizations generated antibody responses in both nasal passages and lungs. In addition, both immunizations resulted in equivalent serum antibody responses. Upper and total respiratory tract immunizations provided protection in the nasal passages when CT was added. However, in the lung, all immunizations resulted in protection against mycoplasma infection, regardless of the inclusion of CT, suggesting a different role for CT as an adjuvant in upper and lower respiratory tract immune protection. In conclusion, we found immune responses generated during immunization and infection are different between the upper and lower respiratory tracts, and the contribution of these responses to clearance of respiratory infection differs.Item Molecular Basis of Cancer Cell Recognition and Killing by Human Natural Killer Cells(2001-05-01) Boles, Kent S.; Bennett, Michale; Leudtke, Robert; Goldfarb, RonaldNatural Killer (NK) cells are a population of lymphocytes vital for the innate immune response. These cells protect the host during the early phase of infection before the adaptive immune response is effective. NK cells are direct effectors via cytoxicity towards neoplastic and infected cells. Additionally, they modulate the immune response by the production of cytokines, most notably interferon y and tumor necrosis factor a. Furthermore, NK cell receptors do not undergo rearrangement. Repetoires of activating and inhibitory receptors regulate the function of NK cells via a balance of signaling. NK cell receptors can broadly be divided by their ligand specificity as well. Most of the known receptors recognize MHC class I molecules and transduce inhibitory signals. This is the basis for the missing self hypothesis espoused by Karre and colleagues. The LY49 molecules server this function in the mouse and are related to the C-type lectins. In primates, a family of killer inhibitory receptors (KIR) appear to play the same role and are in the immunoglobulin (Ig) superfamily of receptors. Whether humans expressed the Ly49 receptors was a fundamental question in NK cell biology. In my attempt to address this issue, I isolated two receptors related to the C-type lectin receptors and localized to the human NK gene complex on chromosome 12 in a region syntenic to where the murine Ly49 genes reside. Functional characterization of these receptors will facilitate our understanding of NK cell biology. Additional activating receptors include the members of the CD2 subset of the immunoglobulin superfamily molecules expressed on NK cells and other leukocytes, including murine 2B4. 2B4 is the high affinity ligand for CD48. Engagement of 2B4 on NK cell surfaces with specific antibodies or CD 48 can trigger cell mediated cytotoxicity, IFN-y secretion, phosphoinositol turnover and NK cell invasiveness. This work describes the isolation and characterization of the human homologue of the 2B4 receptor. The putative peptide has a type I structure with one transmembrane domain. The extracellular region is comprised of two immunoglobulin like domains with six putative N-linked glycosylation sites. The cytoplasmic domain of 2B4 contains unique tyrosine motifs (TxYxxV/I) that associate with src homology 2 domain containing protein (SH2DIA) or signaling lymphocyte activation molecule (SLAM)-associate protein (SAP), whose mutation is the underlying genetic defect in the X-linked lymphoproliferative disease (XLPD). Impaired signaling via 2B4 and SLAM is implicated in the immunopathogenesis of XLPD. CS1 is a novel member of the CD2 subset that contains two of the unique tyrosine motifs present in 2B4 and SLAM. Signaling through 2B4, CS1 and other members of the CD2 subset may play a major role in the regulation of NK cells and other leukocyte functions.Item Next-Generation Sequencing of Culture Negative Bronchoalveolar Lavage Reveals the Presence of Potentially Pathogenic Microorganisms(2015-08-01) Smith, Ashley D.; Michael Allen; Rance E. Berg; Harlan P. JonesPatients undergoing mechanical ventilation are at increased risk for developing nosocomial pneumonia. Traditionally, the diagnosis of pneumonia has relied on the identification of an etiologic agent by the hospital pathology lab via quantitative culture. A problem arises when a patient experiences clinical signs and symptoms of pneumonia, but culturing of bronchoalveolar lavage (BAL) fluid reveals only normal “respiratory tract flora” or results in “no growth”. I hypothesize that culture-negative, presumptive positive BAL is infected with pathogenic bacteria that are not being cultivated on traditional culture media. To investigate this hypothesis, culture-independent techniques were chosen to examine culture-positive and culture-negative BAL. Sanger and Ion Torrent Sequencing were used to verify that molecular techniques are able to identify the same pathogens the hospital lab finds within culture-positive BAL. Ion Torrent sequencing was then used to characterize the microbial community within culture-negative BAL. Cytokine assays were used to determine if culture-positive and culture-negative patients mount a similar immune response. By sequencing colonies picked from the same culture plates used by the hospital lab, I confirmed the presence of the same pathogens identified by the hospital. Ion Torrent sequencing was able to identify hundreds of genera in both the culture-positive and culture-negative BAL samples. However, no difference in 16S copy number was found between the groups. A group of culture-negative BAL with high diversity and similar bacterial communities were observed. These samples clustered together upon principal coordinates analysis, I believe this grouping may represent a core microbiome. Production of pro-inflammatory cytokines were found to be increased in samples that were dominated by a particular pathogen/pathogens as opposed to those that were more diverse and had lower cytokine measurements. This work highlights the advantages associated with using culture-independent techniques for the diagnosis of pneumonia specifically when traditional culturing techniques fail to identify an etiologic agent.Item T-Helper Cell Responses in Lungs After Immunization and Chronic Respiratory Disease; And Their Association With Pulmonary Inflammation(2001-05-01) Jones, Harlan P.; Simecka, Jerry; Dimitrijevich, S. Dan; Goldfarb, Ronald H.The purpose of these studies was to characterize T helper cell responses in the lungs of mice after immunization and chronic respiratory infection. CD4+ T cells were the major population of T cells resident in the lung in comparison to CD8+ T cells. Polyclonal activation of resident CD4+T cells produced abundant levels of IL-4 in comparison to IFN-γ, indicating that Th2 cells were the major sub-population of CD4+ T cells. In contrast, resident CD8+ T cells were the sole producer of IFN-γ by naïve T lymphocytes. Furthermore, the distribution of T cells was similar between BALB/c, C3H/HeN, C57BL/6 and DBA/2N strains of mice. However differences in the distribution of CD8+T cells, as well as the levels of IL-4 and IFN-y production produced by resident T cells were found between C57 and the other strains of mice tested. These results demonstrate that host genetic factors may be involved in determining host susceptibility to respiratory disease. Differences in the intensity of antigenic stimulation provoke changes in the type of T cell response generated. Intranasal immunization with influenza (FLU) vaccine antigen alone initiated solely an antigen-specific Th2-like response. In contrast, the addition of the potent mucosal adjuvant cholera toxin (CT) in combination with FLU antigen induced not only resident Th2 responses, but also induced antigen-specific Th1-like responses. This change corresponded with a dramatic increase in the number of CD4+ T cells in the lung. Thus, intense immunization of respiratory T cells enhanced resident T helper cell responses, but also promoted the activation of Th1 responses. Chronic respiratory infection also elicited changes in the resident population of T cells consistent with pulmonary inflammatory immune responses. At early stages of infection, CD4+, but not CD8+ T cells increased in number within inductive respiratory lymphoid tissues (lower respiratory nodes [LRNs]). Between day 7 and 14 however, there was a dramatic increase in the number of CD4+ T cells in the lung. Interestingly, CD8+ T cells also increased in the lungs, suggesting their activation along mucosal sites during mycoplasma infection. Mycoplasma-specific IL-4 and IFN-γ production also increased in a tissue-specific/time-dependent manner. IL-4 production was initially observed in the LRNs, whereas significant levels of IL-4 and IFN-γ was produced in both tissues 14 days after infection. In comparison, IFN-γ was the predominate cytokine, produce at 14 days coinciding with pulmonary inflammation. Suggesting that intense activation promoted changes in the resident pulmonary Th2 environment, and possible is a major component of pulmonary inflammatory immune responses. Both CD4+ and CD8= T cells were shown to have a role in modulation of disease severity during mycoplasma disease. Observation of gross pulmonary lesions reveal that mycoplasma infected mice treated with anti-CD8 antibody showed increase clinical signs of disease and pronounced gross pulmonary lesions. Additionally the number of total mononuclear cells increased dramatically in the absence of CD8+ T cells. Thus, CD8+ T cells may have a regulatory role in controlling resident CD4+ T cells that increased 14 days after infection. Chemokine production is known to mediate the recruitment of lymphocytes to enhance the initiation of immunity as well as be responsible for modulating inflammatory responses. We find that mycoplasma increase the number of dendritic cells in the lung 14 days after infection, and stimulated the production of dendritic cell-derived ABCD-1 chemokine. Also, β-chemokine MIP-1α and MIB-1β production was observed during intense immunization as well as during mycoplasma infection. These results provide evidence for a potential mechanism through which changes in resident pulmonary T cell responses occur given the intensity of the immune response generated.Item The Effects of Two Staphylococcal Global Regulators (agr and sar) on Acid Phosphatase production in Staphylococcus aureus(2003-05-01) Agouna-Deciat, Bahrka Olivier; Jerry Simecka; Michael SmithAgouna-Deciat, B. Olivier, The Effect of Two Staphylococcal Global Regulators (agr and sar) on Acid Phosphatase Production in Staphylococcus aureus. Master of Science (Molecular Biology and Immunology), May 2003, 75 pp., 3 tables, 14 illustrations, 16 titles. Staphylococcus aureus produces an extensive number of cell-surface associated proteins, extracellular proteins and enzymes that contribute to its virulence. The key to better preventative or curative approaches resides in identifying and targeting the very genes and their products that play major roles in the survival of the bacteria within the host and the establishment of diseases. Two well known regulatory loci, the accessory gene regulatory (agr) and the staphylococcal accessory regulator (sar), control the expression of most S. aureus genes that encode for its virulence factors. Other virulence gene regulators have recently been isolated. Over 40 proteins and enzymes produced by S. aureus have been identified and several of them have been linked to staphylococcal pathogenesis. In this study, we attempt to determine the role of agr and sar in the regulation of the production of a secreted staphylococcal acid phosphatase (Sap) suspected to contribute to virulence.Item The Functional Role of Human 2B4 (CD244) Isoforms in Natural Killer Cells(2007-05-01) Rao, Krithi K.; Porunelloor Mathew; Rance Berg; Harlan JonesRao, Krithi K., Functional role of human 2B4 (CD244) isoforms in natural killer cells. Master of Science (Immunology), July, 2007, 66 pp., 15 illustrations, bibliography. Natural killer (NK) cells are a subpopulation of lymphoctyes that play an important role against tumor metastasis and various viral and bacterial infections. NK cell functions are controlled by a balance between positive and negative signals through various receptors. We have identified, cloned, and characterized the 2B4 (CD244) receptor in mice and human. 2B4 is involved in killing cancer cells and virus-infected cells by NK cells. 2B4 is involved in killing cancer cells and virus-infected cells by NK cells. 2B4 is a counter-receptor for CD48 and recent findings show that 2B4-CD48 interactions plan an important role in NK, T and B cell functions. In humans, two isoforms of 2B4, h2B4-A and h2B4-B, are expressed that differ in the extracellular domain. In the present investigation, we have studied the functions of h2B4-A and h2B4-B. Our data demonstrate that these two isoforms differ in their binding affinity for CD48, resulting in differential cytolytic function as well as cytokine production by NK cells. Thus, differential expression of 2B4 isoforms by NK cells may regulate immune responses mediated through 2B4-CD48 interactions.Item Thymic involution perturbs negative selection and leads to chronic inflammation(2015-08-01) Coder, Brandon D.; Dong-Ming Su; Rance E. Berg; Hriday K. DasThe ubiquitous presence of chronic low-level pro-inflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality. The etiology of inflammaging is largely unknown. Recent evidence has identified the persistent activation of immune cells, thought to arise from latent viral infections, as key contributors towards the development of a chronic inflammatory environment. However, the contribution of autoreactive T cells towards the development of inflammaging has yet to be investigated. Another pervasive feature of the aging process is the age-related involution of the thymus gland, which has been linked with a predisposition toward developing autoimmunity. In the present study, we determined how age-related thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging. We utilized a FoxN1 conditional knock-out (FoxN1-cKO) mouse model that mimics thymic involution while maintaining a young periphery and naturally aged C57Bl/6 mice. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by cellular infiltration into non-lymphoid tissues, elevated serum IL-6, and enhanced production of TNFα. Additionally, activated autoreactive T cell clones were detected in the periphery of FoxN1-cKO mice. We determined that a failure of negative selection, facilitated by decreased AIRE expression rather than impaired regulatory T cell (Treg) generation, and led to autoreactive T cell activation in the periphery. Furthermore, we have demonstrated that the young environment can reverse the age-related accumulation of Tregs but not inflammatory infiltration. Together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a source of chronic age-related inflammation (inflammaging).Item Toll-like Receptor 2 Mediates the Host's Responses in Murine Respiratory Mycoplasmosis(2008-04-01) Love, Wees JaMar; Jerry W. Simecka; Duncan C. Krause; Stephen R. GrantLove, Wees J., The role of Toll-like receptor 2 in mediating the host’s defenses toward mycoplasma infection in the upper and lower respiratory tracts. Doctor of Philosophy (Microbiology and Immunology), April, 2008, 88 pp., 7 illustrations, bibliography, 144 titles. The purpose of these studies was to investigate the toll-like receptors (TLR) responsible for the recognition of invading mycoplasmas. They were also meant to evaluate the role of Toll-like receptors in the generation of immune responses and disease progression in mycoplasma respiratory disease. To determine the role of TLRs in recognizing viable Mycoplasma pulmonis, we utilized human embryonic kidney (HEK) cell lines that are known to have low basal expression of TLRs. The HEK cell lines used were stably transfected to express various combinations of TLRs. The HEK cell lines used were stably transfected to express various combinations of TLRs including TLR1, 2 and 6. The current paradigm of TLR recognition of mycoplasma is that TLR2 dimerizes with either TLR1 or TLR6 to recognize different subclasses of mycoplasma lipoproteins. However, the recognition of viable M. pulmonis organisms remains unclear. When stimulated with viable M. pulmonis, it was discovered that TLR2 was pivotal in mediating the host’s pro-inflammatory cytokine production and that the co-expression of TLR1 or TLR6 enhanced the response. To study their role in mycoplasma recognition and disease progression, we utilized TLR2 knockout (KO) mice. Bone-marrow derived dendritic cells (BMDC) from TLR2 KO mice showed an impaired ability to produce pro-inflammatory cytokines such as IL-12p40 in response to viable M. pulmonis. In addition, the host’s ability to clear the infection was also impaired in TLR2 KO animals. There were higher numbers of cfu in the lower respiratory tract where alveolar macrophages are known to mediate the host’s intrapulmonary clearance of organism. In the upper respiratory tract, where alveolar macrophages (AM) are absent, the production of anti-microbial peptides (e.g. β defensing) in response to TLR2 agonists has been demonstrated. Thus, TLR2 does mediate the host’s immune response to mycoplasma infection, by interfering with the host’s ability to clear the infection and be interfering with the host’s ability to mount an effective inflammatory response. These results also suggest that the TLR2 mediated anti-mycoplasma effects vary and are compartmentalized along the respiratory tract. These studies demonstrated diverse and novel roles of TLRs in respiratory infections and will serve as a platform for future studies investigating mycoplasma respiratory infections.Item Transmissions of Mycobacterium tuberculosis in Dallas and Tarrant Counties: The Use of RFLP to Evaluate MTB Control Programs(2001-05-01) Kosterman, Edward Donald; Stephen E. Weiss; Terrance GrattonKOSTERMAN, EDWARD DONALD; MASTERS OF PUBLIC HEALTH; MAY 19, 2001 TRANSMISSION OF Mycobacterium tuberculosis IN DALLAS AND TARRANT COUNTIES: THE USE OF RFLP ANALYSIS TO EVALUATE MTB CONTROL PROGRAMS; 108 PAGES; 3 TABLES; 39 REFERENCES Dallas and Tarrant Counties are adjacent, similar counties in North Central Texas. Each county manages MTB patients under similar contracts with the Texas Department of Health. In Dallas county culture positive patients MTB are treated with Selective Directly Observed Therapy. Patients with culture positive MTB in Tarrant county are treated with Universal Directly Observed Therapy. RFLP IS6110-based RFLP analysis revealed that more strains were clustered in Dallas county than Tarrant county. Significantly more drug resistant isolates and drug resistant isolates in clusters were observed in Dallas county. These results suggest that DNA typing methods may be used to assess the efficacy of MTB control programs in areas where traditional epidemiological analysis may be ineffective.