The Behavior Analyst 2011, 34, 47–54 No. 1 (Spring)

Tuberculosis Detection by Giant African Pouched Alan Poling Western Michigan University and Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling Bart Weetjens, Christophe Cox, and Negussie Beyene Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling Amy Durgin and Amanda Mahoney Western Michigan University and Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling

In recent years, operant discrimination training procedures have been used to teach giant African pouched rats to detect (TB) in human sputum samples. This article summarizes how the rats are trained and used operationally, as well as their performance in studies published to date. Available data suggest that pouched rats, which can evaluate many samples quickly, are sufficiently accurate in detecting TB to merit further investigation as a diagnostic tool. Key words: behavior analysis, discrimination training, tuberculosis, pouched rats, transla- tional research

The article by Critchfield (2011) articles describing how these rats are and the accompanying commentaries trained and used have recently ap- in this issue of The Behavior Analyst peared in behavior-analytic journals highlight the potential importance of (Poling, Weetjens, Cox, Beyene, & translational research in behavior Sully, 2010, 2011; Poling, Weetjens, analysis. Also in this issue, Jones Cox, Mgode, et al., 2010;). Anti- (2011) provides an informative illus- Persoonsmijnen Ontmijnende Prod- tration of this type of research, uct Ontwikkeling (Anti-Personnel specifically the use of behavior-ana- Landmine Detection Product Devel- lytic strategies to teach dogs to detect opment, APOPO), a nonprofit hu- explosives and to evaluate their manitarian organization located in performance in doing so. Jones fo- Morogoro, , is responsible cused on scent detection of remote for the use of rats as mine-detection explosives, in which samples that animals. APOPO is also exploring may or may not contain explosives other humanitarian applications of are collected in one area and ana- scent-detecting rats. One that shows lyzed by animals located elsewhere. considerable promise is using the As he notes, dogs also are used animals to detect tuberculosis (TB) operationally for the direct detection in humans. The purpose of the of land mines and other explosive present article is to provide a sum- remnants of war and are sometimes mary of APOPO’s work in this area. used to detect cancers in humans (e.g., Moser & McCulloch, 2010). An Introduction to TB Like dogs, giant African pouched Tuberculosis is an infection, often rats (Cricetomys gambianus) are used but not always of the lungs, caused operationally to detect land mines; by Mycobacterium tuberculosis.As data reported by the World Health Address correspondence to Alan Poling, Department of Psychology, Western Michigan Organization (WHO, 2008, 2009a, University, Kalamazoo, Michigan 49008 (e- 2009b) make clear, it is a serious mail: [email protected]). and common disease. According to

47 48 ALAN POLING et al. the WHO, TB was responsible for the common problem in everyday appli- deaths of 1,770,000 people in 2007. cations in the developing world (Bur- About 2,000,000,000 people currently gess et al., 2001; Hargreaves et al., are infected with TB, and roughly 1 2001; Steingart et al., 2006). For in 10 of them will become seriously ill example, a recent study in Nigeria with the disease. Most people infect- revealed a sensitivity of only 23% ed with TB live in developing coun- (Ani et al., 2009). That is, fewer than tries. The disease is especially com- one in four people with active TB mon in sub-Saharan Africa, where it were detected. is the primary cause of death in people with HIV. Despite this, in Pouched Rats as TB Detectors 2008 only 1% of people with HIV were tested for TB. A major reason In the hope of developing a viable for the scarcity of TB testing in alternative to or adjunct for micros- people with HIV, and in the popula- copy, APOPO is exploring the use of tion at large, is the unavailability of a African giant pouched rats (Cricet- cheap, fast, and accurate test. omys gambianus) to detect the pres- The purpose of any TB detection ence of TB. These large and long- system is to classify people into two lived rats, which are native to much discrete categories: those who have of Africa and have an excellent sense the disease and those who do not. of smell, detect TB by sniffing The sensitivity of a given test refers to sputum samples. They are trained to its ability to do the former, whereas respond consistently in one way its specificity refers to its ability to do (pause) if the sample contains the the latter. At present, the technique TB bacillus (is positive) and respond most widely used to diagnose TB in in another way (not pause) if the the developing world is sputum sample does not contain the bacillus smear microscopy (hereafter micros- (i.e., is negative). Each can test copy) (Dye, Watt, Bleed, Hosseini, & hundreds of samples each day, allow- Raviglione, 2005; Steingart et al., ing inexpensive testing. 2006), a technique in use for decades APOPO’s goal is to produce rats and still recommended for low- and that consistently emit an easily ob- middle-income countries (e.g., Cor- served indicator response when they bett et al., 2003; Dye et al., 2005). In smell a sputum sample that contains microscopy, trained technicians view M. tuberculosis and not to emit this slides (typically magnified 100 times) response at other times. In essence, that contain sputum samples stained this is a signal-detection task (Green by the Ziehl-Neelsen (or less often the & Swets, 1966), in which the odor Kinyoun) method (see Steingart et uniquely associated with M. tubercu- al., 2006), which makes Mycobacte- losis constitutes a signal and all other rium tuberculosis, an acid-fast bacil- odors constitute noise. The rats’ task lus, fairly easy to see and count. is to respond only to the signal. This Microscopy has very good specificity, is accomplished by training the rats characteristically above 90% in pub- in an operant stimulus discrimination lished studies (Steingart et al., 2006). task in which the designated indica- The sensitivity of the method, which tor response, pausing for at least 5 s is comprehensively reviewed by Stein- at a hole immediately above a spu- gart et al., varies widely in published tum sample, is reinforced when the studies, ranging from roughly 20% to sputum sample is known to contain 80%. Strategies for improving sensi- M. tuberculosis but not when the tivity have been developed, such as sample does not contain the bacillus. increasing the time that microscopists Such differential reinforcement estab- view slides (e.g., Ramsay et al., 2009), lishes the odor of TB as a discrimi- but low and variable sensitivity is a native stimulus (SD) that reliably RATS DETECT TB 49 evokes the operant response (paus- emphasize that an evidence-based ing), which rarely occurs in its approached to TB diagnosis is es- absence. sential (Pai, Ramsay, & O’Brien, In signal-detection terminology, 2008). That is, high-quality research, emitting the indicator (operant) typically reported in peer-refereed response when the signal (SD)is journal articles, must document the present on a given trial is termed a value of new diagnostic techniques hit and emitting that response when before they are widely adopted. the signal is not present is termed a APOPO recently has published three false alarm. Indicating that the signal studies describing the use of rats as is not present on a given trial, either TB detectors. by withholding the response indicat- In the first study, Weetjens, ing a signal (as in our procedure) or Mgode, Machang’u, et al. (2009) by emitting another response (as in described a procedure in which procedures used by others), is termed pouched rats were trained in a a correct rejection if the signal is not rectilinear cage to sniff each of 10 present and a miss if the signal is holes. A small pot containing a present. Hits and correct rejections sputum sample taken from a patient are correct responses, whereas false at a direct observation of treatment alarms and misses are incorrect. In short course (DOTS) TB center in operational TB systems it is highly Dar es Salaam, Tanzania, was placed desirable to have a high rate of hits immediately below each hole. DOTS and a relatively low rate of false centers are open to all citizens with alarms. respiratory difficulties and are in- By dividing total hits by total hits tended to detect and provide treat- plus total misses and multiplying the ment for TB. The rats were trained result by 100%, one can produce a by operant conditioning to pause for quantitative (i.e., percentage) mea- at least 5 s at holes where the sputum sure of the sensitivity of the rats, or of sample was positive for TB (as any other TB diagnostic. In essence, confirmed by other methods) but as noted previously, sensitivity sum- not to pause at holes where the marizes how good the test is at sputum sample was negative. In detecting patients with TB. Specific- essence, the training procedure in- ity, in contrast, refers to how good volved differential reinforcement, ar- the test is at detecting patients who ranged so that rats (which were do not have the disease. A percentage mildly food deprived) received food measure of sensitivity can be deter- (bananas mixed with food pellets, mined by dividing total correct rejec- both mashed) only when they paused tions by total correct rejections plus for the required time (5 s) at holes total false alarms and multiplying by with positive samples. The training is 100%. As noted previously, an ideal equivalent to that used to establish diagnostic has high sensitivity and the odor of 2,4,6-trinitrotoluene high specificity. In addition, if the (TNT), the primary explosive in most diagnostic is to be useful in develop- land mines, as an SD for mine- ing countries, where TB is most detection rats, except that the odor common and the gravest problem, it of sputum samples that contain the also has to be affordable and produce TB bacillus is established as the SD. results quickly with minimal reliance We detail how rats are trained to on equipment (WHO, 2009a). detect TNT (and land mines) else- Major organizations concerned where (Poling, Weetjens, Cox, Be- with TB as a worldwide health issue, yene, Bach, et al., 2010; Poling, including the Stop TB Partnership, Weetjens, Cox, Beyene, & Sully, the Foundation for Innovative Diag- 2010) and summarize how they are nostics, and the WHO, strongly trained to detect TB below. 50 ALAN POLING et al.

Training Rats to Detect TB evaluation of each sample is recorded. Samples are evaluated as negative (no All of APOPO’s rats come from its M. tuberculosis present) or positive breeding colony. At a young age the (M. tuberculosis present) and if the rat pups begin to interact with latter as a few bacteria (AFB), +1, +2, humans, and when the rats are 3 to or +3, depending on the number of 6 weeks of age trainers regularly bacteria present (see Fujika, 2005). At handle them; expose them to a wide APOPO’s laboratory, the frozen sam- range of sights, sounds, and smells; ples are thawed and autoclaved to kill and hand-feed them preferred foods M. tuberculosis and other microor- like bananas and peanuts. Training ganisms. Samples designated as TB then begins. The first step is clicker positive by microscopists are used as training, which occurs in a metal positive training samples, and samples cage. In this process, trainers repeat- designated as TB negative by micros- edly present food to rats through a copists are used as negative training plastic tube attached to a syringe, and samples. the rats soon learn to approach the The first step of discrimination trainers when the click sounds, be- training is accomplished in a small cause doing so produces food. As metal cage with a hole in the center of noted, the food presented is mashed the floor. A plastic pot containing a banana mixed with crushed commer- sputum sample deemed positive by a cial rat chow (to increase nutritional microcroscopist is presented immedi- value). To increase the reinforcing ately below the hole, and food is effectiveness of food, the rats receive immediately presented when the rat a major portion of their food during places its nose in or just above the the daily training sessions, which last hole. This typically occurs quickly, about half an hour. They are food but if not shaping is used to engender deprived for 17 hr when training the response. Over time, a progres- starts, which serves as an establishing sively longer period of pausing at the operation for food as a reinforcer hole is required for reinforcement. (Laraway, Snycerski, Michael, & The final criterion is 5 s. When this Poling, 2003). criterion is met reliably, discrimina- After being repeatedly paired with tion training begins. D food, the click is established as an S Discrimination training at APOPO for approaching the trainer as well as a historically has been done manually, conditioned reinforcer. When this is with data recorded and reinforcers accomplished, discrimination training delivered by the trainers. They begin begins. The first step in discrimination the second step of training in a metal training is teaching the rat to pause cage with three holes in the floor. when it smells a sputum sample that Pots that contain sputum samples contains the TB bacillus (i.e., a positive positive for TB are placed below half sample). Sputum samples are provided of the holes, on average, and pots by patients who visit DOTS centers to containing negative samples are seek diagnosis and treatment of respi- placed below the other half. Pausing ratory ailments. Each patient typically for 5 s above positive samples is provides two or three samples, taken at reinforced, and pausing at holes different times. A segment of each above negative samples has no pro- sample is analyzed by microscopy, and grammed consequences. Training theremainderisplacedinasmall continues in this manner, with 60 to plastic pot and frozen for subsequent 90 pots presented each day, until the evaluation by APOPO’s rats. A mi- hit rate for an individual rat is above croscopist at the organization at which 80% and the false alarm rate is below the sample is obtained prepares and 5%. When this criterion is met, it is analyzes the slide, and his or her trained in a 10-hole cage. RATS DETECT TB 51

The final training step for TB at the DOTS center. Summary results detection rats is conducted in a 10- were presented for 16 rats that hole cage (205 cm long by 55 cm wide evaluated 2,597 sputum samples, of by 55 cm high). In this step, each rat which 345 were smear positive. The is exposed to 50 to 100 samples per mean sensitivity of these rats was day, of which 5% to 20% are known 87.9% and the mean specificity was positives and the rest are known 93.3%. More detailed analysis of the negatives. Animals are trained until performance of three animals yielded their hit rate is consistently above comparable results. Like compari- 80% and their false alarm rate is sons to the results of culturing, below 5%. When a rat meets this comparison to the results of micros- criterion, it becomes an operational copy suggest that Cricetomys are animal and can participate in TB accurate enough in detecting TB to detection studies. be of practical value. The results reported by Weetjens, Research Findings Mgode, Machang’u, et al. (2009a) were sufficiently promising that the In the study by Weetjens, Mgode, Tanzanian Ministery of Health al- Machang’u, et al. (2009), two rats lowed the rats to be used for second- trained as just described evaluat- line screening of sputum samples ed samples that were determined provided by DOTS center patients. through culturing, which is the gold An article by Weetjens, Mgode, standard for TB detection (Reid & Davis, et al. (2009) reports the initial Shah, 2009), as TB positive or TB results of this pilot project, in which negative. The status of these samples rats analyzed sputum samples col- was unknown to trainers. Over 7 days, lected from four DOTS centers in the rats were exposed to 817 test Dar es Salaam, Tanzania, from sputum samples, of which 67 were TB January 2008 to May 2009. In this positive. Both rats were exposed to study, sputum smears were first the same samples. Their performance analyzed by DOTS microscopists, is depicted in Table 1, which shows then by the rats. Positive indications their sensitivity (percentage correct by the rats on samples evaluated as identifications of samples known to negative by the microscopists were be positive) and their specificity (per- confirmed by a second microscopy. centage correct identifications of sam- Samples from 15,041 patients were ples known to be negative). Also evaluated by microscopy at the shown are their positive predictive DOTS centers and by the rats. The value (PPV) and their negative pre- DOTS centers found TB in 1,838 of dictive value (NPV). PPV is defined the patients (12.2%), whereas the as the number of true positives rats detected the disease in 2,415 divided by the number of true posi- patients (16.1%). The cases detected tives plus false positives. Similarly, by rats but missed by DOTS centers NPV is defined as the number of true (N 5 577) increased TB detection negatives divided by the number of by 31.4%, which is statistically, and true negatives plus false negatives. more important, clinically significant. Both rats had sensitivities of 73%, Poling, Weetjens, Cox, Mgode, et which is well above the usual sensi- al. (2010) reported data on evalua- tivity of microscopy (Steingart et al., tions of 23,101 sputum samples 2006), and acceptably high specifici- collected from 10,523 patients. The ties, PPVs, and NPVs. samples were evaluated first by Weetjens, Mgode, Machang’u, et DOTS center microscopists and then al. (2009) also compared rats’ evalu- by the rats. Microscopists identified ation of sputum samples to evalua- 2,487 sputum samples and 1,403 tions made by trained microscopists different patients (13.3% of the total 52 ALAN POLING et al.

TABLE 1 Performance of Two Rats Relative to Culturing

Rat Sensitivity (%) Specificity (%) PPV NPV Mandela 73.1 93 48 97.5 Kingston 73.1 93.8 51 97.5 Note. Data are from Weetjens, Mgode, Machang’u, et al. (2009). patients) as TB positive. The rats ties for behavior analysts and other verified these findings, identifying scientists. 2,274 of these samples and 1,335 of the patients as TB positive. The rats Behavior Analysis and Future also identified as positive an addi- Research with TB Detecting Rats tional 927 TB samples deemed nega- As noted, any useful TB detection tive at the DOTS centers that were technology must have sufficiently found in a second microscopy to high sensitivity and specificity to be contain the bacillus. These samples of clinical value. Put differently, and came from 620 patients not previous- in terms perhaps more familiar to ly diagnosed with TB; therefore, the behavior analysts, such technology rats’ evaluations increased the case must have adequate accuracy. As detection rate by 44%. Further, the Johnston and Pennypacker (2009) rats evaluated many samples quickly point out, accuracy refers to ‘‘the and economically. The authors con- extent to which observed values cluded that the use of pouched rats approximate to the events that actu- for TB detection in developing coun- ally occurred’’ (p. 355) and is quan- tries certainly warrants further re- tified by comparing the values yielded search. by the detection system of interest These articles provide evidence of (e.g., APOPO’s rats) to the best proof of principle with respect to system comparison system available. using rats to detect human TB. They It is widely recognized that culturing also illustrate the possibility of con- is the best system for detecting TB in ducting significant medical research humans (Reid & Shah, 2009) and the in a developing country while de- results reported by Weetjens, Mgode, pending heavily on local labor (over Machang’u, et al. (2009) suggest that 90% of APOPO’s employees are the sensitivity and specificity of rats’ Tanzanians) and focusing on sustain- evaluations of sputum samples are able, humanitarian development. reasonably high when compared to Moreover, and important in the the results of culturing. These results present context, they provide an reflect evaluations of only 67 culture- example of what might be construed positive samples evaluated by two as translational research, in which rats, however. Further comparison of strategies commonly used to establish rats’ evaluations of sputum samples stimulus control in basic research relative to evaluation by culturing are with animals were used to train badly needed and are planned for pouched rats to perform a valuable early 2011. Culturing is, however, service for humans. At present, how- slow (it typically takes about 6 weeks ever, the use of Cricetomys to detect for M. tuberculosis to reproduce human TB is a promising but not sufficiently in culture medium to be proven technology, and additional very easy to detect) and relatively research is needed to ascertain its expensive. Moreover, it is not easy to true value. That research affords culture TB under the conditions significant challenges and opportuni- characteristic of laboratories in the RATS DETECT TB 53 developing world, and doing so gart et al., 2006); hence, some train- requires some expertise in microbiol- ing samples deemed negative are ogy. It is for these reasons that actually TB positive. This probably APOPO has not yet published a increases the level of what appear to large-scale evaluation of rats’ perfor- be false positives, because rats may mance relative to culturing. be identifying bacteria that micros- To conduct such a study requires copists missed in some training sam- substantial funding, even though ples, which they deemed negative and costs are low in Tanzania. APOPO were so considered by APOPO. has succeeded in securing sufficient Moreover, the vast majority of posi- funds to evaluate rats as a TB tive training samples contain relative- detection tool in large part because ly high bacterial counts; that is, they a good, cheap detection technique is are rated as +2or+3. The intensity of clearly needed and deemed by the training stimulus often influences wealthy institutions and individuals the shape of the generalization gradi- to be worthy of financial support. ent in discrimination training (e.g., Poling (2010) suggested that behavior Poling, Simmons, & Appel, 1978), analysts should ‘‘focus on a disease,’’ and it is probable that use of far fewer that is, work in an area of concern to AFB training samples than +2or+3 many people, and APOPO’s TB training samples affects the likelihood detection work has certainly done that rats will detect operational AFB so. It is important to emphasize, samples. An understanding of oper- however, that the idea of using rats ant stimulus control calls attention for detecting TB (and land mines) to the variables just described and came from Bart Weetjens, a product knowledge of research strategies with developer and Buddhist monk (and small numbers of subjects suggests not a behavior analyst) and that strategies for evaluating whether many people worked on the project. these variables actually affect TB Critchfield (2011) rightly notes that detection and, if the effect is harmful, ‘‘outside the behavioral sciences, the how to control them. Such work is problem of limited individual exper- planned for the coming year, and at tise often is solved through collabo- least three behavior analysts (Durgin, ration of individuals with different Mahoney, and Poling) will be in- types of skills (e.g., Mace & Critch- volved in it. field, 2010)’’ (p. 10). 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