Skip to main navigation menu Skip to main content Skip to site footer

Research Article

Vol. 18 No. 1 (2020)

Evaluating Uncertainty in Dengue Seroprevalence in the Absence of a Gold Standard Diagnostic Test

October 8, 2020


Background: Shortly after the introduction of the first licensed vaccine against dengue fever (Dengvaxia), a serious outcome was attributed to the vaccine: vaccinated individuals without a previous dengue infection were at increased risk of developing severe dengue if subsequently infected by a heterologous serotype. In response, the World Health Organization recommended vaccination in regions where the seroprevalence of dengue is at least 50% and, ideally, greater than 70%. Hence, accurate estimates of regional seroprevalence are crucial for both population vaccination strategies and test-then-vaccinate decisions at the individual level. Currently, estimates of seroprevalence are based on surveys, using screening tests for previous dengue exposure. These estimates must consider the sensitivity and specificity of the tests, which depend on identification of those who have been exposed, ostensibly through a test, regarded as the gold standard. There is, however, no easily accessible gold standard test for dengue.

Methods: We propose an approach to estimate the seroprevalence of dengue that does not require a gold standard test by modeling: (i) the uncertainty in the sensitivity and specificity, and (ii) the uncertainty in the “true” disease prevalence.

Results: Through simulations, we demonstrate the effect of these extra sources of uncertainty on post-test estimates of dengue seroprevalence. Our simulations show, for example, that in a population of 1 million it is possible to overestimate or underestimate the number who are truly seropositive by as much as 76,000.

Conclusions: Current estimates can substantially overestimate or underestimate the true probability of previous exposure when these extra sources of variability are not accounted for.


  1. Guzman M, Halstead S, Artsob H, Buchy P, Farrar J, Gubler D et al. Dengue: a continuing global threat. Nature Reviews Microbiology. 2010;8(S12):S7-S16.
  2. Guzman M, Harris E. Dengue. The Lancet. 2015;385(9966):453-465.
  3. Snow, Grace E., Benjamin Haaland, Eng Eong Ooi, and Duane J. Gubler. "Research on dengue during World War II revisited." The American journal of tropical medicine and hygiene 91, no. 6 (2014): 1203-1217.
  4. Guzman M, Alvarez M, Halstead S. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Archives of Virology. 2013;158(7):1445-1459.
  5. Mondiale de la Santé O, World Health Organization. Dengue vaccine: WHO position paper–July 2016. Weekly Epidemiological Record= Relevé épidémiologique hebdomadaire. 2016 Jul 29;91(30):349-64.
  6. Hadinegoro S, Arredondo-García J, Capeding M, Deseda C, Chotpitayasunondh T, Dietze R et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. New England Journal of Medicine. 2015;373(13):1195-1206.
  7. Meltzer E, Bin H, Heyman Z, Schwartz E. Capillary Leakage in Travelers with Dengue Infection: Implications for Pathogenesis. The American Journal of Tropical Medicine and Hygiene. 2012;86(3):536-539.
  8. Flasche S, Jit M, Rodríguez-Barraquer I, Coudeville L, Recker M, Koelle K et al. The Long-Term Safety, Public Health Impact, and Cost-Effectiveness of Routine Vaccination with a Recombinant, Live-Attenuated Dengue Vaccine (Dengvaxia): A Model Comparison Study. PLOS Medicine. 2016;13(11):e1002181.
  9. Imai N, Dorigatti I, Cauchemez S, Ferguson NM. Estimating dengue transmission intensity from sero-prevalence surveys in multiple countries. PLoS Negl Trop Dis. 2015 Apr 16;9(4):e0003719.
  10. World Health Organization, Special Programme for Research, Training in Tropical Diseases, World Health Organization. Department of Control of Neglected Tropical Diseases, World Health Organization. Epidemic, Pandemic Alert. Dengue: guidelines for diagnosis, treatment, prevention and control. World Health Organization; 2009.
  11. World Health Organization. Informing vaccination programs: a guide to the design and conduct of dengue serosurveys. Geneva: World Health Organization; 2017.
  12. Thomas SJ, Yoon IK. A review of Dengvaxia®: Development to deployment. Human vaccines & immunotherapeutics. 2019 Oct 3;15(10):2295-314.
  13. Wilder-Smith A. Serostatus-dependent performance of the first licensed dengue vaccine: implications for travelers. Journal of Travel Medicine. 2018;25(1).
  14. Halstead SB, Russell PK. Protective and immunological behavior of chimeric yellow fever dengue vaccine. Vaccine. 2016 Mar 29;34(14):1643-7.
  15. Chatchen S, Sabchareon A, Sirivichayakul C. Serodiagnosis of asymptomatic dengue infection. Asian Pacific Journal of Tropical Medicine. 2017;10(1):11-14.
  16. Ochola L, Vounatsou P, Smith T, Mabaso M, Newton C. The reliability of diagnostic techniques in the diagnosis and management of malaria in the absence of a gold standard. The Lancet Infectious Diseases. 2006;6(9):582-588.
  17. Toft N, Jørgensen E, Højsgaard S. Diagnosing diagnostic tests: evaluating the assumptions underlying the estimation of sensitivity and specificity in the absence of a gold standard. Preventive Veterinary Medicine. 2005;68(1):19-33.
  18. Houghton-Triviño N, Montaña D, Castellanos J. Dengue-yellow fever sera cross-reactivity; challenges for diagnosis. Revista de Salud Pública. 2008;10(2):299-307.
  19. Felix A, Souza N, Figueiredo W, Costa A, Inenami M, da Silva R et al. Cross reactivity of commercial anti-dengue immunoassays in patients with acute Zika virus infection. Journal of Medical Virology. 2017;89(8):1477-1479.
  20. Mulherin SA, Miller WC. Spectrum bias or spectrum effect? Subgroup variation in diagnostic test evaluation. Annals of internal medicine. 2002 Oct 1;137(7):598-602.
  21. Shepard DS, Undurraga EA, Betancourt-Cravioto M, Guzman MG, Halstead SB, Harris E, Mudin RN, Murray KO, Tapia-Conyer R, Gubler DJ. Approaches to refining estimates of global burden and economics of dengue. PLoS Negl Trop Dis. 2014 Nov 20;8(11):e3306.
  22. Hernán MA, Hernández-Díaz S, Robins JM. A structural approach to selection bias. Epidemiology. 2004 Sep 1:615-25.
  23. Imai N, Ferguson N. Targeting vaccinations for the licensed dengue vaccine: Considerations for serosurvey design. PLOS ONE. 2018;13(6):e0199450.
  24. Pan-ngum W, Blacksell S, Lubell Y, Pukrittayakamee S, Bailey M, de Silva H et al. Estimating the True Accuracy of Diagnostic Tests for Dengue Infection Using Bayesian Latent Class Models. PLoS ONE. 2013;8(1):e50765.
  25. Speybroeck N, Praet N, Claes F, Van Hong N, Torres K, Mao S et al. True versus Apparent Malaria Infection Prevalence: The Contribution of a Bayesian Approach. PLoS ONE. 2011;6(2):e16705.
  26. de Souza V, Tateno A, Oliveira R, Domingues R, Araújo E, Kuster G et al. Sensitivity and specificity of three ELISA-based assays for discriminating primary from secondary acute dengue virus infection. Journal of Clinical Virology. 2007;39(3):230-233.
  27. Shu PY, Chen LK, Chang SF, Yueh YY, Chow L, Chien LJ. Comparison of a capture immunoglobulin M (IgM) and IgG ELISA and non-structural protein NS1 serotype-specific IgG ELISA for differentiation of primary and secondary dengue virus infections. Clinical and Diagnostic Laboratory Immunology. 2003;10:622-30.
  28. Peeling RW, Artsob H, Pelegrino JL, Buchy P, Cardosa MJ, Devi S, Enria DA, Farrar J, Gubler DJ, Guzman MG, Halstead SB. Evaluation of diagnostic tests: dengue. Nature Reviews Microbiology. 2010 Dec;8(12):S30-7.
  29. Lee, P., 1997. Bayesian Statistics. p 81-83. London: E. Arnold.
  30. Garg S, Chakravarti A, Singh R, Masthi N, Goyal R, Jammy G et al. Dengue serotype-specific seroprevalence among 5- to 10-year-old children in India: a community-based cross-sectional study. International Journal of Infectious Diseases. 2017;54:25-30.
  31. Braga C, Luna C, Martelli C, Souza W, Cordeiro M, Alexander N et al. Seroprevalence and risk factors for dengue infection in socio-economically distinct areas of Recife, Brazil. Acta Tropica. 2010;113(3):234-240.
  32. Low S, Lam S, Wong W, Teo D, Ng L, Tan L. Dengue Seroprevalence of Healthy Adults in Singapore: Serosurvey Among Blood Donors, 2009. The American Journal of Tropical Medicine and Hygiene. 2015;93(1):40-45.
  33. Velasco-Salas Z, Zambrano J, Vivas D, Sierra G, Guzmán D, Wilschut J et al. Dengue Seroprevalence and Risk Factors for Past and Recent Viral Transmission in Venezuela: A Comprehensive Community-Based Study. The American Journal of Tropical Medicine and Hygiene. 2014;91(5):1039-1048.
  34. Prayitno A, Taurel A, Nealon J, Satari H, Karyanti M, Sekartini R et al. Dengue seroprevalence and force of primary infection in a representative population of urban dwelling Indonesian children. PLOS Neglected Tropical Diseases. 2017;11(6):e0005621.
  35. Kakkar M. Dengue fever is massively under-reported in India, hampering our response. BMJ. 2012;345(dec19 17):e8574-e8574.
  36. Vong S, Goyet S, Ly S, Ngan C, Huy R, Duong V et al. Under-recognition and reporting of dengue in Cambodia: a capture–recapture analysis of the National Dengue Surveillance System. Epidemiology and Infection. 2011;140(3):491-499.
  37. Beatty M, Stone A, Fitzsimons D, Hanna J, Lam S, Vong S et al. Best Practices in Dengue Surveillance: A Report from the Asia-Pacific and Americas Dengue Prevention Boards. PLoS Neglected Tropical Diseases. 2010;4(11):e890.
  38. dos Santos Franco L, Gushi L, Luiz W, Amorim J. Seeking Flavivirus Cross-Protective Immunity. Frontiers in Immunology. 2019;10.
  39. Atchareeya A, Panthuyosri N, Anantapreecha S, Chanama S, Sa-Ngasang A, Sawanpanyalert P, Kurane I. Cross-reactive IgM responses in patients with dengue or Japanese encephalitis. Journal of Clinical Virology. 2008 May 1;42(1):75-7.
  40. Vanlerberghe V, Gómez-Dantés H, Vazquez-Prokopec G, Alexander N, Manrique-Saide P, Coelho G, Toledo ME, Ocampo CB, Stuyft PV. Changing paradigms in Aedes control: considering the spatial heterogeneity of dengue transmission. Revista Panamericana de Salud Pública. 2018 Jun 26;41:e16.
  41. Wilder‐Smith A, Foo W, Earnest A, Sremulanathan S, Paton NI. Seroepidemiology of dengue in the adult population of Singapore. Tropical Medicine & International Health. 2004 Feb;9(2):305-8.
  42. Ukey PM, Bondade SA, Paunipagar PV, Powar RM, Akulwar SL. Study of seroprevalence of dengue fever in central India. Indian journal of community medicine: official publication of Indian Association of Preventive & Social Medicine. 2010 Oct;35(4):517.
  43. Balmaseda A, Hammond SN, Tellez Y, Imhoff L, Rodriguez Y, Saborío SI, Mercado JC, Perez L, Videa E, Almanza E, Kuan G. High seroprevalence of antibodies against dengue virus in a prospective study of schoolchildren in Managua, Nicaragua. Tropical medicine & international health. 2006 Jun;11(6):935-42.
  44. Vincenti-Gonzalez MF, Grillet ME, Velasco-Salas ZI, Lizarazo EF, Amarista MA, Sierra GM, Comach G, Tami A. Spatial analysis of dengue seroprevalence and modeling of transmission risk factors in a dengue hyperendemic city of Venezuela. PLoS neglected tropical diseases. 2017 Jan 23;11(1):e0005317.
  45. Pepe MS, Janes H. Insights into latent class analysis of diagnostic test performance. Biostatistics. 2007 Apr 1;8(2):474-84.
  46. Naaktgeboren CA, Bertens LC, van Smeden M, de Groot JA, Moons KG, Reitsma JB. Value of composite reference standards in diagnostic research. Bmj. 2013 Oct 25;347:f5605.
  47. Rodriguez-Barraquer I, Cordeiro M, Braga C, de Souza W, Marques E, Cummings D. From Re-Emergence to Hyperendemicity: The Natural History of the Dengue Epidemic in Brazil. PLoS Neglected Tropical Diseases. 2011;5(1):e935.


Metrics Loading ...