Preventive Veterinary Medicine 48 (2001) 303320

Methods to investigate spatial and temporal clustering in veterinary epidemiology

Tim E. Carpenter*
Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA Accepted 6 December 2000

Abstract Due to their contagious or point-source nature, ill-health and diseases often cluster in time and/or space. Overlooking this characteristic can lead to a delay in the control or eradication of the health problem. In addition to potentially expediting control efforts, cluster identification techniques enable the researcher or health-care official to identify and adjust for confounding factors and to generate new hypotheses regarding disease transmission. This paper examines a variety of temporal and spatial clustering techniques and focuses on those which have been reported recently in the veterinary literature. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: Diseases; Clustering; Epidemiology

1. Introduction Epidemiology is the study of the distribution and determinants of disease or other health-related issues. Typically, such study involves a spatial and/or temporal component. As with any good investigative reporter, an epidemiologist is interested in the ``who, what, where, when, why and how'' of the story. Although we do an adequate job investigating the ``who'' (host), ``what'' (disease), ``why'' (risk factors), and ``how'' (infection process or pathogenesis) questions, we come up short on the ``where'' (spatial location) and ``when'' (time) components. Whether it is an outbreak investigation or epidemiologic research, more emphasis should be placed on the spatial and temporal components of health events. It is in this way that we can identify unusual occurrences of events that happen close together in either time and/or space. As Rothman stated, ``With
Tel.: 1-530-752-1034; fax: 1-530-752-0414. E-mail address: tecarpenter@ucdavis.edu (T.E. Carpenter). 0167-5877/01/$ see front matter # 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 - 5 8 7 7 ( 0 0 ) 0 0 1 9 9 - 9
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this understanding of what we really mean by close together, the study of disease clusters becomes nearly synonymous with what we usually mean by epidemiologic research'' (Rothman, 1990, pp. S5S6). In animal populations, clusters of disease (ill-health) can occur at various levels and for different reasons. Obvious among these is clustering of disease within a litter, pen, group, house, or herd. It has become common practice in epidemiologic research to expect such clustering and to adjust for it when performing a statistical analysis. Additionally, it is logical to expect disease clustering to occur on a larger scale (e.g. among neighboring farms) with transmission via a wildlife reservoir, human or mechanical vector, or as a result of a common-source exposure. It is the identification of such clusters that might yield important information regarding the transmission and/or control of the problem but that often is overlooked by traditional epidemiologic investigation techniques. Similarly, these cluster detection techniques may be used to eliminate false clusters (based on their lack of statistical significance) thus enabling focus of more productive research elsewhere. The study of disease clusters has been relatively common in human epidemiologic research. Although, many of the techniques for cluster identification were developed in the 1960s and 1970s, their widespread application and acceptance really did not occur until later. In the 1990s and into the 21st century, we have seen the formation of several organizations, conferences and workshops focusing on the detection of disease clustering and their associated methodology development. In addition to the National Conference on Clustering of Health Events (also known as the ``Cluster Busters Conference,'' 1990, Atlanta, GA), there were several additional meetings and workshops dealing with spatial statistics and methods for detecting spatial and temporal clusters of health events. These included the Workshop on Statistics and Computing in Disease Clustering, Port Jefferson, NY, 1992; an International Conference on Statistics and Computing in Disease Clustering, Vancouver, BC, 1994; the Symposium on Statistical Methods, Atlanta, GA, 1995; the International Symposium on Computer Mapping in Epidemiology and Environmental Health, Tampa, FL, 1998; the First International Health Geographics Conferences, Baltimore, MD, 1998; Geographic Information Systems (GIS) in Public Health, Third National Conference, San Diego, CA, 1998; the 11th Colloquium of the Spatial Information Center, Dunedin, New Zealand, 1999; and the Second International Health Geographics Conferences, Washington, DC, 2000. While this virtual, cluster analysis renaissance was occurring in the human field, it has remained virtually the sleeping giant in veterinary medicine. Veterinary epidemiologists examining clustering of animal health problems have relied on venues provided by human health or geography to enhance their knowledge or present the findings in this field. In a review of the conferences of the International Society of Veterinary Epidemiology and Economics (ISVEE) in the 1990s, only a limited number of presentations have dealt with the topic of disease clustering in time and space. Specifically, at the Seventh Symposium of the ISVEE, Nairobi, Kenya, of the 42 oral presentations made in sections appropriate for spatial and temporal clustering (i.e., Animal Health Information Systems (10), Disease Monitoring and Decision Support Systems (26), Spatial Methods in Veterinary Epidemiology (6)), only two examined spatial clustering (Carpenter et al., 1994; De la Rua-Domenech et al., 1995). At the Eighth Symposium of the ISVEE, Paris, France, in

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1997, of the 103 oral presentations made in sections appropriate for spatial and temporal clustering (i.e. Epidemiological Surveillance (24), Disease Control Programs (10), Infectious Diseases Investigations (17), Tools in Epidemiology (25), Statistical Methods and Modeling (27)), only one examined spatial clustering (Giovannini et al., 1997) and one temporal clustering (De Vriew et al., 1997). At the Ninth Symposium of the ISVEE, Breckenridge, CO, with 14, 2 h sessions on Spatial Analysis (two sessions), Animal Health Monitoring Programs (4), Epidemiologic Methods and Theory (3), Statistical Methods for Epidemiology (2), and Surveillance Monitoring (3), the number of presentations on spatial and temporal clustering greatly exceeded the modest numbers seen at previous meetings. A number of books have been published on the topic of quantifying the spatial distribution and clustering of diseases in populations. Among these, the amount devoted to clustering range from a portion of a chapter in a statistical medical-research text (Armitage and Berry, 1994), a single chapter in an epidemiology text (Selvin, 1996), and seven textbooks (McGlashan, 1972; Cliff and Ord, 1981; Ebdon, 1985; Upton and Fingleton, 1985; Thomas, 1990; Elliot et al., 1992; Alexander and Boyle, 1996). However, none of these discusses the application of clustering techniques to veterinary problems (which by virtue of the livestock production process, limited life span and movement, or herd characteristics create both new problems and opportunities for the veterinary epidemiologist in spatial and temporal research). Seven manuscripts in the last 5 years and four in the last year alone, have reviewed and illustrated temporal, spatial, and spatialtemporal cluster analysis of disease (Elliott et al., 1995; Jacquez et al., 1996a,b; Moore and Carpenter, 1999; Ward and Armstrong, 1999; Ward and Carpenter, 2000a,b). Ward and Armstrong (1999) and Ward and Carpenter (2000a,b) presented a limited number of cluster detection techniques and the mathematics behind them and used blowfly data in Australia to illustrate them. The paper by Moore and Carpenter (1999) was a more extensive examination of spatial epidemiologic techniques (including diffusion modeling, GIS, and geostatistics) but focused on human epidemiologic examples, as Jacquez et al. (1996a,b) and Elliott et al. (1995) closely examined clustering from an environmental epidemiology perspective. The present paper presents a variety of statistical clustering techniques useful for temporal and/or spatial data, illustrating these techniques with examples, when available, in veterinary epidemiology. While epidemiologic research encompasses more than temporal and spatial relationships, such relationships involve more than cluster analysis. For example, important work in spatial epidemiology has been performed via mapping, modeling, and spatial geostatistics (including kriging) (Cressie, 1991). Similarly, temporal epidemiology is replete with applications of time-series analyses used to define patterns and unusual deviations of health events in an attempt to better understand disease distributions and ways to reduce disease. However, the same cannot be said of veterinary epidemiology and cluster analysis. There are three aims that cluster analysis of health events can address: (1) rapid identification of epidemic clusters, (2) identification of confounders, and (3) generation of research hypotheses. The purpose of this paper is to highlight some of the techniques used in cluster analysis to identify temporal, spatial, and temporalspatial clustering of

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disease, with the hope of enabling the practicing epidemiologist to add a valuable tool to his or her research arsenal. The paper will focus on those cluster detection techniques using veterinary examples which have been identified through an exhaustive electronic literature search, an exhausting manual examination of the literature (especially scientific proceedings) and personal experience of the author. 2. Spatial clustering In general, spatial clustering may be examined in three different dimensions and with four data forms. Spatial cluster analysis may be performed on line, point, and plane (area) data (Fig. 1). The data may be in general categorized as case-control data or case data only, and as such they may be dichotomous, categorical, rank, or continuous. 2.1. Linear clusters Examination for linear clustering may occur when the event location refers to, e.g. a roadway, river, coast line, degrees from the equator (latitude), transect, or row of pens or hutches. Two tests are used for linear clustering of case-control data (randomness of runs and sign test), and one test for case data (nearest neighbor distance). 2.1.1. Randomness of runs and sign tests These traditional statistical tests are appropriate for linearly distributed, case-control data. In these tests, runs are identified when adjacent points are dissimilar, i.e. a case next

Fig. 1. Diagram of statistical methods available for testing clusters in time, space, time and space, and timespace (interaction).

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to a control. The fewer the number of dissimilar adjacent points, the fewer the runs and the greater the clustering. Singer et al. (1998) used the randomness-of-runs test to determine if antimicrobial-resistant isolates were clustered along latitudinal gradients in California. They reported significant linear clustering of dairy-specific Pasteurella multocida isolates being ampicillin- and tetracycline-resistant along a northsouth line. Their findings supported the hypothesis that antimicrobial-resistant organisms can cluster on the local level and emphasized the need to establish regional estimates of antimicrobial susceptibility. 2.1.2. Nearest neighbor The nearest-neighbor test may be used to describe the distribution of points on a line, or of points whose locations may be summarized linearly. It uses inter-event spatial distances to develop impressions of the strength of the clustering of linear data. Due to the typical non-random distribution of populations at risk, this test is more commonly used as an exploratory or descriptive statistics tool. The statistics for this test have been developed (Hammond and McCullagh, 1978) but not yet applied to a veterinary problem. 2.2. Areal clusters Clustering on an areal or regional basis may be detected by a variety of adjacency tests, depending on whether the data are dichotomous (blackwhite); categorical and rank (Ohno); or continuous (Moran's I and Geary's c) (Fig. 1). In each of these tests, areas are classified by category or value and compared with one another. If adjacent areas are more similar to one another than expected by chance, clustering is indicated. 2.2.1. Blackwhite test The blackwhite, or joincount, test examines the spatial distribution of dichotomous data. Adjacent areas are compared and situations where more than expected similar areas are adjacent, the greater the clustering. Examples include the presence or absence of disease or seroreactors, or values above or below mean or median. An application of this test to cluster detection in the veterinary literature is an investigation by Hungerford and Smith (1996), who found significant clustering of anaplasmosis in cattle on a county level in Illinois, on the basis of endemicity vs. non-endemicity and presence or absence of the disease in cattle. Giovannini et al. (1997) used the blackwhite test and Moran's I statistics (discussed below) to determine statistical clustering of bovine brucellosis within municipalities in Italy. Ekstrand and Carpenter used it to better understand the distribution of foot-pad dermatitis in broilers in Sweden (Ekstrand and Carpenter, 1998b). Results of such studies should enable the epidemiologic research focus to be expanded to the regional level due to the commonality observed at this level. 2.2.2. Ohno method The Ohno method is another adjacency test; however, it is applied to categorical or rank data. It was originally designed to evaluate clustering of cancer mortality in Japan (Ohno et al., 1979; Ohno and Aoki, 1981). The values in adjacent areas are compared

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with respect to concordance; adjacent areas are said to have concordant values if the values are the same, and discordant otherwise. Sakai et al. (1994) used the Ohno method to detect a clustering of antibodies of bovine Japanese encephalitis virus in dairy cows in Japan. These results led to the speculation that differences in insecticide resistance, presence of paddy fields, or areal differences in the degree of intensive management affect seroprevalence. The more concordant the adjacent areas, the greater the degree of clustering. One disadvantage of the Ohno technique is that it essentially treats the data as nominal and gives an equal score if adjacent areas have a slightly or greatly dissimilar score. Walter (1993) introduced an alternative rank test that overcomes this disadvantage by considering the absolute difference in ranks. 2.2.3. Moran's I Moran's I (Moran, 1950), similar to Geary's c (Geary, 1954), is one of the most commonly used tests for areal clustering. This is also true of its application in the veterinary literature. In epidemiologic research, it is typically used when evaluating areal clustering of proportion data (e.g. prevalence proportion). Although it is designed to evaluate event counts, the data typically are standardized because of differences in population at risk. The test statistic calculates the cross product of the adjacent areal values as compared with the overall mean. If adjacent areas are both either above or below the mean, the cross product will be positive. If one is greater than and the other less than the mean, the product will be negative. Hence, clustering is indicated by test statistic with a positive value. Moran's I was used by Hungerford (1991) to identify inter-county clustering of the seroprevalence of anaplasmosis in cattle in Illinois. The findings led them to focus on both cattle movements and ecologic or management characteristics of the disease as control program foci. Similar inter-area clustering was identified in an antibiotic-resistance study in California (Singer et al., 1998) and in the study of equine motor-neuron disease in the United States (De la Rua-Domenech et al., 1995). Additionally, non-significant results may aid the researcher as was the case in the study of fowl cholera in turkeys when no clustering of outbreaks was identified on the inter-county level (Carpenter et al., 1994) although smaller scale clustering later was found to be significant. When Moran's I uses proportion data, the population-size weighting information is lost. For example, the same calculation would be performed if the incidence proportion were 1/100 or 10,000/1,000,000. To take advantage of this information, an improved test was developed which uses the statistic Ipop (and includes population at risk in the calculation) (Oden, 1995). 2.3. Point clusters In human epidemiologic-cluster studies, the unit of interest is commonly the individual, household, or city all of which may be represented spatially by a point. In veterinary epidemiology, we commonly are concerned with the herd, flock, pen, cage, tribe; again, all may be represented spatially by a point. While some of these tests suffer from potential confounding due to varying population at risk, others have been developed specifically to deal with the problem. Four tests (nearest-neighbor, CuzickEdwards',

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spatial-scan, and k-function), have been used to detect case clustering, while the latter 3 adjust for the underlying population at risk. 2.3.1. Nearest-neighbor test The nearest-neighbor test was developed by plant ecologists (Clark and Evans, 1954) for measuring arrangements in two and three dimensions. Basically, this technique examines all points and calculates the mean distance to their nearest neighbor. If this distance is less than expected, clustering is indicated. Because disease clusters are not limited to pair-wise occurrences, the nearest-neighbor test was expanded to account for multiple-case clusters of up to 10 (Thompson, 1965; Dacey and Tung, 1962). The nearestneighbor test often is used as an exploratory test but results are subject to confounding due to a non-random distribution of the population at risk. 2.3.2. CuzickEdwards' test One of the major concerns we deal with in epidemiology is confounding (especially, how to identify and control for it). This is also true in spatial- and temporal-cluster analyses. For instance, if the population in general tends to be clustered in a location (such as is true of food animals or wildlife), it is likely that health events associated with that population will be spatially clustered (e.g. by the nearest-neighbor test). Additional confounding may arise as the result of non-random distribution of animals by production type, breed, sex, age, management or feeding, and company. Although temporal-cluster tests such as the scan test are said to be inappropriate if seasonality (clustering) of the data occur naturally, others (such as the EdererMyersMantel; Ederer et al., 1984) adjust for it by stratifying growing populations into smaller time periods per spatial entity. In spatial-cluster testing, a number of tests (including the CuzickEdwards' (Cuzick and Edwards, 1990), Pike and Smith (Pike and Smith, 1974) and K-functions (Diggle et al., 1995) tests) adjust for the presence of heterogeneously distributed population at risk. This is accomplished by selecting appropriate controls for the cases. Under the null hypothesis, a similar cluster would be expected for the controls and cases, if no spatial disease-association were present. The test statistic is the number of cases whose nearest neighbors are also cases. As with the nearest neighbor test, the order (or number of nearest neighbors) may be expanded to evaluate the magnitude of clustering identified if it does in fact exist. The CuzickEdwards' test was applied to a database containing information on the spatial location of California turkey flocks infected with P. multocida (the causative agent for fowl cholera) (Carpenter et al., 1996). Although clustering had been identified from nearest-neighbor testing, it was evident from visual inspection and statistical testing that the population at risk was also clustered in the Central Valley of the state. Combining the results of the CuzickEdwards' test with earlier molecular investigations (Carpenter et al., 1991), cluster analyses (Carpenter, 1996) revealed valuable information regarding the transmission of the disease beyond what was learned from earlier, traditional risk-factor analyses (Carpenter et al., 1988; Campi et al., 1990; Hird et al., 1991). It was shown that significant clustering occurred in meat bird flocks but not in breeder flocks. This confirmed results from the molecular-level investigation about the transmission of the disease. This information was relayed to producers, who improved biosecurity measures

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on the meat-bird premises to be more in line with the stricter measures in place on breeder premises. Additional veterinary applications of the Cuzick-Edwards' test have been made to identify clusters of bluetongue virus antibodies in cattle in Australia (Ward and Carpenter, 1995) and Corynebacterium pseudotuberculosis cases in horses in California (Doherr et al., 1999). 2.3.3. Spatial-scan The spatial-scan statistic is able both to locate the site and to test the significance of specific clusters (Turnbull et al., 1990). This test iteratively searches for case clusters (Kulldorff and Nagarwalla, 1995; Hjalmars et al., 1996). As with the scan test used to detect temporal clustering, it uses a variable (circular) window size to detect spatial clusters in large areas. If a cluster is identified, the test determines the significance (adjusting for the inherent problem of multiple testing). The scan test may identify secondary as well as primary clusters and orders them according to their likelihood ratios. The spatial-scan test has been applied to detect leukemia (Hjalmars et al., 1996) and cancer (Kulldorf et al., 1997) clusters in human populations; however, it apparently was not used for events in animal population investigations until the Ninth Symposium of the ISVEE. At that meeting, the spatial-scan test was used to examine the spatial clustering of BSE in Switzerland (Doherr et al., 2000), leptospirosis in Costa Rica (Maranda, 2000), and bovine leukosis virus in New Zealand (Teekayuwat et al., 2000). 2.3.4. K-function analysis Another approach that may eliminate population-at-risk confounding was taken by Gatrell and Bailey (1996), who estimated K-function analysis (Diggle et al., 1995; Bailey and Gatrell, 1995) for randomly selected cases and controls of childhood leukemia in Lancashire, UK. They examined the difference plots of these two functions against nearest-neighbor distances of controls and cases, respectively. Significant clustering was identified when peaks exceeded an analytic or simulated confidence interval. French et al. (1999, 2000) applied this technique to sheep scab, equine grass sickness and lymphosarcoma-outbreak data in the UK. They concluded that the spread of the disease was important on two scales: large (due to increased mixing of sheep throughout Great Britain), and small (due to neighboring-farm contact with sheep sharing common pasture). O'Brien et al. (1999) used this technique to examine the spatial and temporal clustering of incident cases of canine cancers in Michigan. They reported evidence of clustering, which may have been attributed to the clustering of the underlying, extraneous population at risk (which could not be controlled for in that study). Gerbier and Chadeouf (2000) used retrospective data from the 1967 to 1968 UK foot-and-mouth disease outbreak to determine clustering of cases within a period of 4 weeks and 13 km. 3. Temporal clustering Disease surveillance is an important tool for health-care workers; it enables them to detect either the appearance of a new disease or an unusual increase (epidemic) in an existing disease. Several techniques are available to analyze time-series data generated by

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a surveillance system. Several recent examples of traditional time-series analysis applied to veterinary problems have described or predicted the temporal distribution of diseases (Curk and Carpenter, 1994; Cherry et al., 1998; Doherr et al., 1999; Ekstrand and Carpenter, 1998a; Nrgaard et al., 1999; French et al., 1999; Courtin et al., 2000). However, traditional time-series analyses typically require at least 50 or 100 or more time periods and frequent observations per period. Because many cluster analysis studies use limited number of observations and address questions different from those typically examined in traditional time-series studies, additional methods have been developed to study temporal clustering of events. In addition, these methods have been designed specifically for surveillance or control programs and are often more efficient at early disease detection than time-series techniques. They also are designed to detect relatively large increases in disease rates which may involve a small number of cases and thus be missed by traditional time-series methods (Chen, 1987). Six statistical methods developed for (or otherwise used in) surveillance systems of birth defects and various diseases include the Poisson (Flynt, 1974), negative binomial (Hill et al., 1968; Weatherall and Haskey, 1976), two-stage (Hardy et al., 1990), sets (Chen, 1979, 1986, 1987; Chen et al., 1982) scan (Naus, 1982; Wallenstein, 1980; Wallenstein and Neff, 1987) and cusum (Bjerkdal and Bakketeig, 1975; Healy, 1968; Ewan and Kemp, 1960; Kennett and Pollack, 1983) techniques (Fig. 1). One feature these methods have in common is that they can be used to test the statistical significance of an unusual occurrence (cluster). Although some of these methods test the significance of the appearance of several cases or outbreaks in a single or limited series of time periods, others examine a time-series of data and test the significance of (typically infrequent) observations in time periods. In spite of their significance-testing capabilities, they do not attempt to quantify the costs associated with correctly or incorrectly identifying the early stage of an epidemic. Additionally, no attempt is made to quantify, e.g. the controversial value of human life or quality-of-life years (measures necessary to evaluate the economic impact of alternative surveillance levels). However, in veterinary medicine in general (and food-animal medicine in particular), the practice of quantifying disease losses and control is essential for rational decision making. 3.1. Poisson technique This technique is based on the Poisson distribution assumptions for rare events when the mean (i.e. expected number of events) is equal to the variance. This technique has been used in US surveillance programs monitoring congenital malformations (Flynt, 1974). It is based on calculating the probability of observing at least a given number of events, based on the mean number of events previously observed. I found no examples applying this technique in the veterinary literature. 3.2. Negative binomial technique This is similar to the Poisson technique; however, as the name implies, the assumption is that the distribution of events has a variance that exceeds the mean. It has been found to be more appropriate for several birth anomalies (Hill et al., 1968). Hill et al. (1968)

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reported that this method could avoid some of the false alarms that may arise when the Poisson distribution is assumed. Again, it does not appear to have been applied in veterinary medicine. 3.3. Scan test The scan test is used to determine if the maximum number of cases observed in a series of sequential time periods (windows) is significantly greater than that expected by chance, given the number of cases observed. An example of the scan test in veterinary medicine was presented by Pare et al. (1996). They used it to determine whether or not temporal clustering of affected horses that shed Salmonella krefeld in their feces existed for horses hospitalized in the intensive care unit (ICU) of the veterinary medical teaching hospital during an S. krefeld epidemic (in which nosocomial salmonellosis was suspected). During the 8-month study period, 219 horses were hospitalized in the ICU. S. krefeld was cultured from feces of 20 horses. Five of these successful cultures occurred in November and three each in DecemberFebruary. A variable window of 214 days was used for the cluster detection. This was based on the mean duration of hospitalization in the ICU (5 days), a 2-day lag from infection to initial shedding of Salmonella spp., and the sensitivity of culture less than 100% (meaning that multiple cultures may be needed to detect infection). Results showed that significant temporal clustering of cases occurred when windows of 58 days were examined. Maximum temporal clustering was identified when five cases were detected within a 5-day period. Additional analysis was performed (see below) to determine if these temporally clustered cases also were clustered simultaneously in time and space. If so, this would be an indication that S. krefeld was transmitted from horses located in close proximity to one another (e.g. adjoining stalls). 3.4. Cusum technique This technique was originally developed to identify industrial production-process problems (Ewan and Kemp, 1960; Woodward and Goldsmith, 1964) but has been applied successfully in human epidemiology (Hill et al., 1968; Bjerkdal and Bakketeig, 1975; Weatherall and Haskey, 1976; Chen, 1979). The technique is based on the cumulative sum (cusum) in excess of the expected number of cases over time. It has the advantage of similar control-chart techniques (DeVor et al., 1992) in that by its cumulative nature, it is able to magnify small abrupt changes which individually are too small to be observed in the process (Healy, 1968). In addition to its potential for application in veterinary epidemiologic surveillance and research, the cusum technique is ideally suited for detecting production-performance problems found in food-production animals (De Vriew et al., 1997). 3.5. Sets technique The sets technique was developed by Chen for ongoing surveillance of birth defects or other rare diseases (Chen, 1979, 1986). It also has been applied in chronic-disease monitoring (Chen et al., 1982; Klingberg et al., 1971). It examines the time interval

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(``or gap'') between consecutive diagnoses. The analysis is conducted for each new case and is thus well suited for an ongoing surveillance program. When all intervals of a preselected number are less than the appropriate critical duration, an alarm is ``sounded.'' One problem with this technique is that the number of intervals to be examined and the magnitude of increase are established arbitrarily. However, by assigning monetary values to the cost of investigating a true or false alarm (in addition to the cost of an epidemic), it is possible to design an economically optimal surveillance system for animal disease (Carpenter, 2001). 3.6. Two-stage method This method was developed by Hardy et al. (1990) to identify departures from expected temporal patterns of neonatal deaths for a Texas community. ``Two stage'' refers to the number of activity levels or phases that may be selected: alert phase (results from a moderate case-rate increase) and action phase (results from a severe or prolonged (two consecutive alert periods) case-rate increase). The method calculates the significance of either a standardized deviation of excess cases or standardized morbidity or mortality ratios. Once again, this is another appropriate method without evidence of application in either veterinary research or surveillance. 4. Interactive time and space clustering Typically, once clustering is determined to exist either temporally or spatially, the next step is to test for its presence in time and space simultaneously. This also may be done if clustering is not identified in either time or space. Time and space clustering may be differentiated from timespace clustering in that the latter detects a true timespace interaction of events, while the former detects a temporal clustering of events in specific locations, without regard to the proximity of locations to one another. There is one commonly used time and space clustering technique: the EdererMyersMantel (EMM) test (Ederer et al., 1984) (Fig. 1). 4.1. EMM test The EMM test is one of the most commonly used procedures for detecting clusters of disease in different locations. It works by using the total number of cases in a location and estimates the maximum number of cases in any one or two consecutive time periods, if they were randomly distributed. Significant clustering is identified if the observed number exceeds the expected (by comparing results to those found in a table) (Mantel et al., 1976). Fosgate et al. (2000) evaluated the time and space clustering of human cases of brucellosis in California. The analysis involved a variety of procedures to test for the presence of spatial clustering (Moran's I test) and clustering in time and space (EMM). Although, Moran's I test might indicate that clustering exists, if used alone the test cannot determine which locations (counties) were clustered. Once spatial clustering was established, temporal clustering within each county was further elucidated via the EMM

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test. This information can be used to focus on the high-attack rate ethnic group with nonautochthonous cases and may guide further investigations of zoonoses and food-borne disease outbreaks involving imported foods. 5. Simultaneous timespace clustering Events may be found to cluster in time and/or in space, but not be the result of a contagious process involving local transmission. For instance, there could be a global epidemic that has a definite temporal clustering; however, the spatial pattern may be random. On the other hand, clustering might be identified in a specific geographic location, although these cases had an inter-event interval exceeding the incubation period. (This may be the result of a point-source problem, or it may be the result of nonautochthonous cases having a common residence.) Timespace clustering techniques have been developed to address this question of whether or not there is a timespace interaction implying that transmission occurred in a given area and time interval. Techniques used to detect interactive timespace clustering in veterinary health include Barton's method (Barton et al., 1965; Barton and David, 1966), the Knox method (Knox, 1964a,b), the Mantel method (Mantel, 1967), and the spacetime scan method (Kulldorf et al., 1998) (Fig. 1). 5.1. Barton's method Barton's method examines the time and space distribution of point data (or area data, using the centroid or other measure of centrality as the spatial location) in a manner similar to an analysis-of-variance test where the temporal information is treated as a covariate. In doing so, the Barton method compares the spatial separation of cases located within the same time interval with the spatial separation of cases in other time intervals, i.e. a within- and between-cell variation comparison. Clustering is implied if the variation within these cells is less than between. Three examples of applications of this technique to problems in veterinary medicine exist. Ekstrand and Carpenter (1998b) reported significant clustering of footpad dermatitis in broilers in Sweden during the autumn and winter months in the southwestern region of Sweden, using this technique. Singer et al. (1998) were unable to detect spatialtemporal clustering of antimicrobial-resistant isolates in California. Ward and Carpenter (2000a) were unable to detect spatialtemporal clustering of blowfly catches in a recent study in Tasmania, Australia. 5.2. Knox method The Knox method (Knox, 1964a,b) examines the spatial and temporal separation of all case pairs. First, critical distances are determined, representing the time or space distance where disease transmission is believed to be feasible. The critical time distance may represent the incubation period and space distance may represent host or vector movement within that critical time period. Once these critical periods are defined, the proportion of case pairs ``close in time'' is multiplied by the proportion of case pairs

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``close in space'' to give the expected proportion of case pairs ``close in time and space.'' The expected proportion is then multiplied by the total number of case pairs, to give the number of case pairs expected to be both close in time and space. This number is compared with the observed number of case pairs that were close in time and space. If the observed number exceeds the expected, this indicates clustering. Significance is determined by calculating the probability of observing at least the number of observed close in time and space case pairs (assuming a Poisson distribution). The Knox test first was used in veterinary research by White et al. (1989) to identify clustering of winter dysentery in New York dairy cattle. The test also was used for the S. krefeld example presented earlier (Pare et al., 1996). A total of 190 case pairs was examined with respect to their spatial and temporal separation. Because we were uncertain of the critical time and space distances, we examined multiple distances. The most significant timespace cluster was found when four case pairs were observed compared with an expected number of 3.24. Although this was an indication of clustering, a significance test showed that the probability of observing four or more case pairs close in time and space was 41% (i.e. far from statistical significance). Thus, Pare et al. (1996) concluded that the lack of temporalspatial clustering suggested that shedding was the result of infection acquired before horses were admitted to the ICU. On the other hand, if transmission were occurring within the ICU, it was unrelated to the proximity of susceptible horses to horses with salmonellosis. While this process of multiple testing may appear statistically unconventional (especially when a multiple comparison adjustments is not made), this is often seen in cluster detection. However, if such a process is used, it should be remembered that the power of temporalspatial cluster tests is traditionally low (Wartenberg and Greenberg, 1990; Pike and Smith, 1974) and often tests are applied to identify scenarios that are amenable to further investigation. 5.3. Mantel method Analogous to the Knox test, the Mantel method (Mantel, 1967) examines time and space differences of all case pairs being studied. In contrast, the Mantel method does not require pre-specified critical time and space distance separations between cases. Instead, the Mantel method determines the sum of the cross products of all timespace distance pairs. To place larger weights on closer pairs, the inverse of the time and space distances may be used. The result then is standardized and reported as a traditional correlation coefficient. One example of the application of this technique was found in which White et al. (1989) used it to reinforce the presence of clustering of winter dysentery (also identified by the Knox test). 5.4. Spacetime scan method This test operates similarly to the spatial-scan method except that it includes a temporal component by including a cylindrical window above the geographic location of the space point. The height of the cylindrical window reflects the time period of the potential cluster. Also, as with the spatial-scan test, the cylindrical window moves about

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with the spatial circle about each potential cluster. Recently, three examples have been presented where this technique has been applied to detect spatialtemporal disease clustering in animal populations. McKenzie et al. (2000) used it to detect clustering of tuberculosis in beef-breeding cattle in New Zealand. Stevenson et al. (2000) used the spacetime scan test to identify clustering of BSE in cattle in the UK. Ward (2000) applied the test to identify primary and secondary clustering of breach strike in southeastern Queensland sheep flocks. 6. Statistical software Perhaps one of the biggest stumbling blocks to using cluster analysis in epidemiologic research is the lack of availability of user-friendly software. Moore and Carpenter (1999) present an extensive review of the software available for spatial and temporalspatial cluster analysis. Briefly, while a few packages exist, they require unusual data formatting, are not user friendly, and/or are very limited in the number of cases they can examine. Therefore, the need still exists specially for the occasional user who has data with spatial and temporal attributes that may play an important link in the epidemiologic research of a disease to have a simple, convenient program to enable them to investigate such putative risk factors or confounders. 7. Conclusions What is the future direction we should be taking regarding investigation of spatial and temporal components in disease research? Alexander and Boyle (1996) specifically dealing with issues of clustering of non-infectious diseases facing health departments recently answered this question. Basically, they concluded that health departments could take one of two approaches: either proactive or reactive. As their names imply, a proactive approach is where the group or individual actively searches for clusters to investigate, whereas the reactive approach involves the evaluation of clusters as they arise but does not involve an attempt to find clusters. There are problems with both approaches. The reactive approach often is initiated by, e.g. a producer concern and suffers from the multiple-comparison problem. That is because only extreme situations come to the attention of the researcher or health official, the significance level is likely to be inflated (because those groups without concerns will typically not be included in the analysis). The reactive approach would mean that the researcher would miss clusters that are ``F F Fcaused by a new, unknown, or unanticipated aetiologic factor that produces cases of a common or unremarkable disease, and yields an increased incidence that is too small or diffuse to be noticed by a clinician or community'' (Alexander and Boyle, 1996, p. 1760). The proactive approach, on the other hand, would increase the likelihood that the researcher or surveillance system would respond to ``false alarms.'' With the level of significance of P 0X05, this would on average amount to 5% of the investigations. Although the proactive approach would diminish the impact of epidemics, it also has the associated costs of unnecessary

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investigations. Therefore, the advantages as well as disadvantages of cluster investigations must be considered simultaneously. In practice, some combination of these reactive and proactive approaches is probably optimal. In this way, initial alarms may be investigated on a limited scale. Those that warrant it then can be followed up with a more complete epidemiologic investigation. At the same time, a proactive surveillance program may be in operation that has a focus on emerging or catastrophic diseases. In either scenario, a major component of the surveillance/research plan would be cluster investigation. References
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