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About: Introduction: In the era of genetic engineering of pathogens, distinguishing unnatural epidemics from natural ones is a challenge. Successful identification of unnatural infectious disease events can assist in rapid response, which relies on a sensitive risk assessment tool used for the early detection of deliberate attacks (i.e., bioterrorism). Methods: A systematic review was conducted according to the outline of Preferred Reporting Items for Systematic Reviews. Published papers related to the detection of unnatural diseases were searched in MEDLINE (January 1927–April 2016), EMBASE (January 1937–March 2016), and Web of Science (January 1978–March 2016). Full texts were reviewed for the selection of studies on scoring systems specially designed to discern between unnatural and natural outbreaks. Results: A total of 1,753 papers were reviewed, of which we identified the following five scoring systems specifically designed for detecting unnatural outbreaks: (1) the Grunow–Finke epidemiological assessment tool, (2) potential epidemiological clues to a deliberate epidemic, (3) bioterrorism risk assessment scoring, (4) and (5) two modified scoring systems based on (3). Various criteria ranging from the information on perpetrators, type of agents, spatial distribution, and intelligence of deliberate release were involved. Of these systems, the Grunow–Finke assessment tool remains the most widely used, but has low sensitivity for correctly identifying unnatural epidemics when tested against actual historical outbreaks. Others were applied into a few scenarios but provided different perspectives for bioterrorism detection and bio-preparedness. Conclusion: There are few risk assessment tools for differentiating unnatural from natural epidemics. These tools are increasingly necessary and valuable, but improved scoring systems with higher sensitivity, specificity, timeliness, and wider application to biological attacks must be developed.

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