Statistical modeling based on structured surveys of Australian native possum excreta harboring Mycobacterium ulcerans predicts Buruli ulcer occurrence in humans
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eLife assessment
This study is an important contribution to the understanding of Buruli ulcer transmission in Australia. The authors provide compelling evidence that the carriage of Mycobacterium ulcerans by possums, within their small home range, can predict cases of Buruli ulcer disease in individuals who visit those areas. While not directly relevant to the transmission of Buruli ulcer in West and Central Africa, the work will be of great interest to those studying the transmission of opportunistic environmental pathogens.
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Abstract
Buruli ulcer (BU) is a neglected tropical disease caused by infection of subcutaneous tissue with Mycobacterium ulcerans . BU is commonly reported across rural regions of Central and West Africa but has been increasing dramatically in temperate southeast Australia around the major metropolitan city of Melbourne, with most disease transmission occurring in the summer months. Previous research has shown that Australian native possums are reservoirs of M. ulcerans and that they shed the bacteria in their fecal material (excreta). Field surveys show that locales where possums harbor M. ulcerans overlap with human cases of BU, raising the possibility of using possum excreta surveys to predict the risk of disease occurrence in humans.
Methods:
We thus established a highly structured 12 month possum excreta surveillance program across an area of 350 km 2 in the Mornington Peninsula area 70 km south of Melbourne, Australia. The primary objective of our study was to assess using statistical modeling if M. ulcerans surveillance of possum excreta provided useful information for predicting future human BU case locations.
Results:
Over two sampling campaigns in summer and winter, we collected 2,282 possum excreta specimens of which 11% were PCR positive for M. ulcerans -specific DNA. Using the spatial scanning statistical tool SaTScan , we observed non-random, co-correlated clustering of both M. ulcerans positive possum excreta and human BU cases. We next trained a statistical model with the Mornington Peninsula excreta survey data to predict the future likelihood of human BU cases occurring in the region. By observing where human BU cases subsequently occurred, we show that the excreta model performance was superior to a null model trained using the previous year’s human BU case incidence data (AUC 0.66 vs 0.55). We then used data unseen by the excreta-informed model from a new survey of 661 possum excreta specimens in Geelong, a geographically separate BU endemic area to the southwest of Melbourne, to prospectively predict the location of human BU cases in that region. As for the Mornington Peninsula, the excreta-based BU prediction model outperformed the null model (AUC 0.75 vs 0.50) and pinpointed specific locations in Geelong where interventions could be deployed to interrupt disease spread.
Conclusions:
This study highlights the One Health nature of BU by confirming a quantitative relationship between possum excreta shedding of M. ulcerans and humans developing BU. The excreta survey-informed modeling we have described will be a powerful tool for the efficient targeting of public health responses to stop BU.
Funding:
This research was supported by the National Health and Medical Research Council of Australia and the Victorian Government Department of Health (GNT1152807 and GNT1196396).
Article activity feed
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eLife assessment
This study is an important contribution to the understanding of Buruli ulcer transmission in Australia. The authors provide compelling evidence that the carriage of Mycobacterium ulcerans by possums, within their small home range, can predict cases of Buruli ulcer disease in individuals who visit those areas. While not directly relevant to the transmission of Buruli ulcer in West and Central Africa, the work will be of great interest to those studying the transmission of opportunistic environmental pathogens.
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Reviewer #1 (Public Review):
This study presents a useful study, proposing the modelling of Buruli ulcer occurrence in humans based on detection of M. ulcerans in Australia. The data were collected and analyzed using solid and validated methodology and can be used as a starting point for the elucidation of M. ulcerans transmission in Australia.
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Reviewer #2 (Public Review):
In this work, the authors have carried out an extensive and highly granular survey of Mycobacterium ulcerans carriage by possums who are living on the outskirts of Melbourne Australia, in areas that are known hot spots for cases of Buruli ulcer (BU). The work is the culmination of many years of endeavour by this team, who first identified that the faeces of possums can be highly positive for M. ulcerans DNA, genetically linked to the strains found in BU patients who live in, or have visited, the area.
Surveys across two seasons were performed. Based on qPCR data to identify M. ulcerans carriage, spatial mapping of this, and BU case data, a statistical model was generated using data from the Mornington Peninsula that was better predicted than a null model. This statistical model was then validated using a …
Reviewer #2 (Public Review):
In this work, the authors have carried out an extensive and highly granular survey of Mycobacterium ulcerans carriage by possums who are living on the outskirts of Melbourne Australia, in areas that are known hot spots for cases of Buruli ulcer (BU). The work is the culmination of many years of endeavour by this team, who first identified that the faeces of possums can be highly positive for M. ulcerans DNA, genetically linked to the strains found in BU patients who live in, or have visited, the area.
Surveys across two seasons were performed. Based on qPCR data to identify M. ulcerans carriage, spatial mapping of this, and BU case data, a statistical model was generated using data from the Mornington Peninsula that was better predicted than a null model. This statistical model was then validated using a second independent site at Geelong. As a result of this data, there can now be little doubt that possums play a vital role in the transmission cycles of BU in the region, and will allow mitigation strategies to be designed and tested. As BU is a necrotising skin disease that can cause disability and permanent disfiguration even in a high-resource setting such as Australia, such approaches are urgently needed.
Strengths:
The scale (both in terms of geographic reach/granularity and time) of the surveillance effort to understand the distribution of M. ulcerans DNA in the local possum population is unprecedented.
Since BU is a notifiable disease in Australia, the researchers have access to comprehensive clinical information across the study period.
The statistical model developed had a strongly positive influence over the ability to predict where BU cases will arise, over areas with a small radius (several km) which is the first time this has been achieved. The process by which this model was developed and validated seems robust.
Weaknesses:
In their model, the authors have used an assumed "exposure window" for when patients were infected with M. ulcerans in the Mornington Peninsula. Correctly defining, and assigning, this is absolutely critical to the accuracy of the statistical model, as is "blinding" of researchers assigning mesh boxes to patients to the results of surveillance data (and vice versa). These aspects are not fully clear in the current version. Furthermore, the effects on the model of changing these assumptions are not discussed.
The presence of M. ulcerans DNA in possum excreta and in patient samples is defined by qPCR for IS2404, a multicopy insertion sequence. Greater justification for using this as the sole marker is required, as this insertion sequence is also present in other mycolactone-producing mycobacteria. Moreover, some samples were claimed to be 'positive' with Ct values of 40 without justification for using this value (such as standard curves).
Comparing the summer and winter surveys at the Mornington Peninsula, the distribution of M. ulcerans positive excreta appears to have changed quite substantially, especially given that the possums are reported to be highly territorial with a range of only 100m. This version of the manuscript does not formally compare these spatial distributions, only the averages. Such an analysis would help understand if it is the possums that are moving, whether the possums undergo 'waves' of carriage (or indeed any other explanation), or if these apparent differences are down to chance.
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Reviewer #3 (Public Review):
K. Vandelannoote and collaborators report on using spatially-localized possum feces investigated for Mycobacterium ulcerans, as a proxy for cases of Buruli ulcer, South Australia. The report is a contributive, enforcing survey of animal excreta and is based on strong pieces of evidence.
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