Canine ResearchAnimal olfactory detection of human diseases: Guidelines and systematic review
Introduction
It is common knowledge that many animals possess and rely heavily on a highly developed sense of smell when locating food, avoiding predators, finding mates, and navigating their environments. Humans, who have a relatively poor sense of smell, often use other animals in the detection of targeted substances by training them to make an identifiable response in the presence of volatile compounds that emanate from those substances. Dogs have been trained to locate explosives, landmines, illicit drugs and other contraband, missing persons, disaster victims, and a wide variety of other targets (Browne et al., 2006, Williams and Johnston, 2002). Bees, pigs, mice, rats, and a number of other animals have also been successfully trained to identify targeted substances (Bodyak and Slotnick, 1999, Poling et al., 2010a, Rains et al., 2008, Talou et al., 1990).
Several anecdotal reports of dogs spontaneously showing interest in skin cancer on their owners have been published. Williams and Pembroke (1989) wrote of a patient whose dog persistently sniffed a mole on her leg. The dog's excessive interest in the mole prompted the patient to visit a dermatologist, who identified the mole as a malignant melanoma. Church and Williams (2001) reported a man whose dog constantly sniffed at a patch of eczema on his leg. After excision of the lesion, it was found to be a basal cell carcinoma. Campbell et al. (2013) described a case in which a man's dog persistently licked a lesion behind his right ear, which was later confirmed to be malignant melanoma. In each of these cases, the dog was hypothesized to be able to detect and was attracted to volatile organic compounds (VOCs) emanating from the affected area on its owner's skin.
VOCs are organic chemicals with high vapor pressure at typical room temperature, resulting in evaporation or sublimation of the molecules into the air surrounding the source. VOC profiles reliably associated with asthma, several types of cancer, cholera, cystic fibrosis, diabetes mellitus, dental diseases, gut diseases, heart allograft rejection, heart diseases, liver diseases, pre-eclampsia, renal disease, and tuberculosis (TB) have been identified (Corradi et al., 2010, Dent et al., 2013, Shirasu and Touhara, 2011). Disease-related VOCs may be found in the blood, breath, feces, skin, sputum, sweat, urine, and vaginal secretions of affected individuals. Research investigating the VOCs associated with various human diseases is underway, primarily driven by the goal of developing instrumentation for use in clinical diagnostics that is capable of reliably identifying specific disease-associated VOC marker profiles. Currently, the development of this technology is limited by the prohibitively high cost of the necessary laboratory instrumentation and difficulties in standardizing sample collection and preparation procedures in clinical settings (Sethi et al., 2013).
An increasing number of experimental analyses examining animal detection of human diseases have appeared in the literature since Pickel et al. (2004) reported the high detection accuracy of 2 dogs trained to detect melanoma. The cumulative number of relevant studies published between 2004 and 2016 is displayed in Figure. The steepening gradient in the data path suggests that interest in this topic has increased over time. This body of literature on which Figure is based has been reviewed from various perspectives (Bijland et al., 2013, Boedeker et al., 2012, Dent et al., 2013, Desikan, 2013, Freeman and Vatz, 2015, Jezierski et al., 2015, Johnen et al., 2013, Lippi and Cervellin, 2012, Luque de Castro and Fernandez-Peralbo, 2012, Marcus, 2012, McCulloch et al., 2012, Moser and McCulloch, 2010, Oh et al., 2015, Wells, 2012). Many reviewers and researchers have remarked that critical components of the training and testing procedures in the relevant studies are often unreported or are deficient. Therefore, it is difficult to ascertain the potential of animals as detectors of various human diseases (e.g., Elliker et al., 2014, Jezierski et al., 2015). The purpose of the present article was, first, to suggest required and preferred conditions for training and testing animals for operational disease detection and, second, to evaluate the existing research with respect to these conditions. Our hope is that the guidelines we propose will be useful for researchers, animal trainers, and medical practitioners who are interested in olfactory detection of human diseases.
Section snippets
Training conditions
Operant discrimination training, in which indication responses (e.g., barks by a dog) to samples known to be positive for the disease in question are reinforced (rewarded, as by delivery of a preferred food) and responses to samples not known to be positive for the disease are not reinforced, is used to teach animals to detect the disease. Once an animal reliably emits the indication response only in the presence of known-positive samples, samples of unknown status are presented and the
Required conditions for testing
Testing is usually conducted to determine the sensitivity and specificity of the animal as a detector of the targeted disease after a period of training. Other variables may also be investigated when an animal detector is tested, such as evaluation speed, stamina, and resistance to extinction. For a test to provide a convincing demonstration of an animal's ability to detect human diseases, the following requirements must be met.
Required conditions for operations
The conditions that are required for successful operations with animal detectors depend heavily on the type of disease detection work and the setting in which the work will take place. Despite this, several overarching requirements can be identified and will be described briefly in the following.
Method
The PubMed and Web of Science databases were searched on 25 August 2016 using combinations of the terms: “animal,” “cancer,” “canine,” “chemota*”, “dog,” “detect*,” “disease,” “odour”, “odor,” “olfact*,” “scent,” and “smell.” Articles that described original research involving animal olfactory detection of human disease using samples collected from human participants were selected for inclusion. In evaluating the performance of the animal detectors, gold standard technology must have been used
Results
A brief summary of key information from each of the studies is provided in Table 1, including the disease targeted for detection, the type of sample, the animal detector, and the sensitivity and specificity obtained in the study. Cancer detection has clearly received the most attention, with 20 of the 27 studies targeting one or more cancers. Of the remaining 7 studies, 4 have targeted TB, 2 hypoglycemia, one bacteriuria, and 1 C. difficile. Urine samples have been used in 11 studies, breath
Discussion
In this review of 28 studies evaluating the use of animal olfaction for detection of human diseases, 9 studies used training and testing protocols that appear to be operationally viable (see shaded rows in Table 1). The primary reason for a lack of operational viability in the remaining studies was the presentation of a fixed number of positive samples in runs, which was the case in 19 of the reviewed studies, 14 of which used forced choice procedures. In these studies, the animal detectors
References (83)
- et al.
Odorant-selective genes and neurons mediate olfaction in C-elegans
Cell
(1993) - et al.
Another sniffer dog for the clinic?
Lancet
(2001) - et al.
Olfactory detection of prostate cancer by dogs sniffing urine: A step forward in early diagnosis
Eur. Urol.
(2011) Rapid diagnosis of infectious diseases: The role of giant African pouched rats, dogs and honeybees
Indian J. Med. Microbiol.
(2013)- et al.
Sample size calculation should be performed for design accuracy in diagnostic test studies
J. Clin. Epidemiol.
(2005) - et al.
Canine scent detection - Fact or fiction?
Appl. Anim. Behav. Sci.
(2013) - et al.
Explosives detection by military working dogs: Olfactory generalization from components to mixtures
Appl. Anim. Behav. Sci.
(2014) - et al.
Analytical methods based on exhaled breath for early detection of lung cancer
Trac Trends Anal. Chem.
(2012) - et al.
Pouched rats' (Cricetomys gambianus) detection of Salmonella in horse feces
J. Vet. Behav.: Clin. Appl. Res.
(2014) - et al.
Canine scent detection of human cancers: A review of methods and accuracy
J. Vet. Behav.: Clin. Appl. Res.
(2010)