A Syndrome Definition Validation Approach for Zika Virus
Authors: Rumoro Dino , Shah Shital , Hallock Marilyn M. , Gibbs Gillian S. , Trenholme Gordon , Waddell Michael 
Published: May 2017

ObjectiveTo develop and validate a Zika virus disease syndrome definitionwithin the GUARDIAN (Geographic Utilization of ArtificialIntelligence in Real-Time for Disease Identification and AlertNotification) surveillance system.IntroductionIn 2016, the World Health Organization declared Zika virus aglobal public health emergency. Zika infection during pregnancycan cause microcephaly and other fetal brain defects. To facilitateclinicians’ ability to detect Zika, various syndrome definitions havebeen developed.MethodsTo create and validate a detailed syndrome definition for Zika,we utilized the literature based methodology developed anddocumented by GUARDIAN researchers.1,2The syndrome definitionutilized clinical signs and symptoms that were documented inhistorical Zika cases.A testing sample of 1000 randomly selected emergency departmentcases (i.e., true negative cases) and 200 synthetically generated cases(i.e., true positive cases) was created. These 1,200 sample cases wereevaluated by the GUARDIAN surveillance system to determine theprobability of matching the Zika syndrome definition. A probabilityof≥90% was utilized to designate positive Zika cases.We identified the main signs and symptoms contributing to theidentification of Zika cases and conducted statistical performancemetrics. Clinical review of the false positive and false negative casesalong with a sample of true positive and true negative cases wasconducted by a board certified emergency physician.ResultsThe Zika syndrome definition was developed with eleven articles(six used for developing the syndrome definition, and five used fortesting the definition). The sample size for these articles was between1 and 72 positive Zika cases, with a total of 139 cases across the11 articles. The article with the most number of Zika cases wasbased on pregnant women with rash. The publication timeframefor the articles was from 1962 to 2016. Some of the main signsand symptoms from the historical cases that contribute to the Zikasyndrome definition are presented in Table 1. The initial results forthe sample testing data showed accuracy, sensitivity, and specificitywere 94.7%, 93%, and 95% respectively. There were a total of14 false negative and 50 false positive cases.ConclusionsThe initial Zika syndrome definition utilized by the GUARDIANsurveillance system contains similar signs and symptoms to thecurrent CDC case definition, but also includes additional signs andsymptoms such as pruritus/itching, malaise/fatigue/generalizedweakness, headache, retro-orbital pain, myalgia/muscle pain, andlymphadenopathy In addition, the GUARDIAN system provides therelative importance of identified signs and symptoms and allows forproactive surveillance of emergency department patients in real-time.Though we did not include epidemiologic risk factors, such as travel toan infected region or contact with an infected person in the syndromedefinition, GUARDIAN has above 90% sensitivity and specificity.Thus, inclusion of epidemiologic risk factors would further enhancethe early detection of Zika, when used with the appropriate high riskpopulation.Table 1. Main signs and symptoms of Zika syndrome definition*Signs and symptoms included in the Centers for Disease Control andPrevention (CDC)’s Zika clinical case definition