- Open Access
Interplay of generation time and spatial structure in epidemic dynamics and the reliability of reproduction ratio estimates
Phys. Rev. Research 8, 013136 – Published 9 February, 2026
DOI: https://doi.org/10.1103/32b8-x9z5
Abstract
The reproduction ratio is a central metric for monitoring infectious disease epidemics and guiding public health interventions. It is typically inferred from population-level surveillance data, but such estimates can be biased by the spatial structure of the underlying population and by complexities in disease natural history. Here, we develop a theoretical framework to study how the distribution of the generation time (the time from primary to secondary infection) interacts with spatial network structure of the host population, to shape epidemic dynamics and the accuracy of estimates. We show that the mean and dispersion of the generation time determine the contribution of subdominant epidemic modes, controlling the rate at which the system converges to its spatial equilibrium. Overdispersed generation times slow convergence near the epidemic threshold, whereas underdispersed distributions, common for respiratory pathogens, can markedly delay convergence at moderate and high transmissibility, producing long-lived biases in . We evaluate the performance of an existing correction to incidence data that removes bias from spatial structure under simpified dynamical conditions. We demonstrate that it remains valid for arbitrary generation time distributions only if both mean and dispersion are accurately specified. Otherwise, substantial residual errors persist, especially when is above the threshold. We extend the framework to short-lived perturbations, both exogenous (e.g., extreme weather, mass gatherings, and mobility restrictions) and endogenous (e.g., behavioral changes), and show that realistic dispersions can amplify their impact on spatial distributions and prolong bias on far beyond the perturbation. We illustrate these mechanisms through a case study of a respiratory pathogen in Spain, using colocation-based mobility data, and identify the conditions under which surveillance-derived is reliable and when precise measurements of the generation time distribution are critical.
Physics Subject Headings (PhySH)
Article Text
References (71)
- M. J. Keeling and P. Rohani, Modeling Infectious Diseases in Humans and Animals (Princeton University Press, Princeton, NJ, USA, 2008).
- H. Nishiura and G. Chowell, The effective reproduction number as a prelude to statistical estimation of time-dependent epidemic trends, in Mathematical and Statistical Estimation Approaches in Epidemiology, edited by G. Chowell, J. M. Hyman, L. M. A. Bettencourt, and C. Castillo-Chavez (Springer Netherlands, Dordrecht, 2009), pp. 103–121.
- J. Wallinga, M. van Boven, and M. Lipsitch, Optimizing infectious disease interventions during an emerging epidemic, Proc. Natl. Acad. Sci. USA 107, 923 (2010).
- R. N. Thompson, C. A. Gilligan, and N. J. Cunniffe, Control fast or control smart: When should invading pathogens be controlled? PLoS Comput. Biol. 14, e1006014 (2018).
- P. Nouvellet, et al., Reduction in mobility and COVID-19 transmission, Nat. Commun. 12, 1090 (2021).
- M. Biggerstaff, S. Cauchemez, C. Reed, M. Gambhir, and L. Finelli, Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: A systematic review of the literature, BMC Infect. Dis. 14, 480 (2014).
- F. M. Guerra, S. Bolotin, G. Lim, J. Heffernan, S. L. Deeks, Y. Li, and N. S. Crowcroft, The basic reproduction number () of measles: A systematic review, Lancet Infect. Dis. 17, e420 (2017).
- Y. Li, H. Campbell, D. Kulkarni, A. Harpur, M. Nundy, X. Wang, and H. Nair, The temporal association of introducing and lifting non-pharmaceutical interventions with the time-varying reproduction number () of SARS-CoV-2: A modelling study across 131 countries, Lancet Infect. Dis. 21, 193 (2021).
- C. T. Codeço, D. A. M. Villela, and F. C. Coelho, Estimating the effective reproduction number of dengue considering temperature-dependent generation intervals, Epidemics 25, 101 (2018).
- J. Wallinga and M. Lipsitch, How generation intervals shape the relationship between growth rates and reproductive numbers, Proc. R. Soc. B 274, 599 (2007).
- T. Obadia, R. Haneef, and P.-Y. Boëlle, The R0 package: A toolbox to estimate reproduction numbers for epidemic outbreaks, BMC Med. Inf. Decis. Making 12, 147 (2012).
- A. Cori, N. M. Ferguson, C. Fraser, and S. Cauchemez, A new framework and software to estimate time-varying reproduction numbers during epidemics, Am. J. Epidemiol. 178, 1505 (2013).
- Ã. Svensson, A note on generation times in epidemic models, Math. Biosci. 208, 300 (2007).
- T. Britton and G. Scalia Tomba, Estimation in emerging epidemics: Biases and remedies, J. R. Soc. Interface 16, 20180670 (2019).
- W. Yang, M. Lipsitch, and J. Shaman, Inference of seasonal and pandemic influenza transmission dynamics, Proc. Natl. Acad. Sci. USA 112, 2723 (2015).
- D. Chen, Y.-C. Lau, X.-K. Xu, L. Wang, Z. Du, T. K. Tsang, P. Wu, E. H. Y. Lau, J. Wallinga, B. J. Cowling, and S. T. Ali, Inferring time-varying generation time, serial interval, and incubation period distributions for COVID-19, Nat. Commun. 13, 7727 (2022).
- O. Gressani and N. Hens, Nonparametric serial interval estimation with uniform mixtures, PLoS Comput. Biol. 21, e1013338 (2025).
- K. Ito, C. Piantham, H. Nishiura, K. Ito, C. Piantham, and H. Nishiura, Estimating relative generation times and reproduction numbers of Omicron BA.1 and BA.2 with respect to Delta variant in Denmark, Math. Biosci. Eng. 19, 9005 (2022).
- P. Birello, M. Re Fiorentin, B. Wang, V. Colizza, and E. Valdano, Estimates of the reproduction ratio from epidemic surveillance may be biased in spatially structured populations, Nat. Phys. 20, 1204 (2024).
- D. Balcan and A. Vespignani, Phase transitions in contagion processes mediated by recurrent mobility patterns, Nat. Phys. 7, 581 (2011).
- D. Soriano-Paños, L. Lotero, A. Arenas, and J. Gómez-Gardeñes, Spreading processes in multiplex metapopulations containing different mobility networks, Phys. Rev. X 8, 031039 (2018).
- S. Chang, E. Pierson, P. W. Koh, J. Gerardin, B. Redbird, D. Grusky, and J. Leskovec, Mobility network models of COVID-19 explain inequities and inform reopening, Nature (London) 589, 82 (2021).
- N. Gozzi, N. Perra, and A. Vespignani, Comparative evaluation of behavioral epidemic models using COVID-19 data, Proc. Natl. Acad. Sci. USA 122, e2421993122 (2025).
- L. Angeli, C. P. Caetano, N. Franco, P. Coletti, C. Faes, G. Molenberghs, P. Beutels, S. Abrams, L. Willem, and N. Hens, Assessing the role of children in the COVID-19 pandemic in Belgium using perturbation analysis, Nat. Commun. 16, 2230 (2025).
- G. Pullano, L. G. Alvarez-Zuzek, V. Colizza, and S. Bansal, Characterizing US spatial connectivity and implications for geographical disease dynamics and metapopulation modeling: Longitudinal observational study, JMIR Public Health Surveill. 11, e64914 (2025).
- E. Brooks-Pollock, J. M. Read, A. R. McLean, M. J. Keeling, and L. Danon, Mapping social distancing measures to the reproduction number for COVID-19, Philos. Trans. R. Soc. B 376, 20200276 (2021).
- J. D. Munday, C. I. Jarvis, A. Gimma, K. L. Wong, K. van Zandvoort, S. Funk, and W. J. Edmunds, Estimating the impact of reopening schools on the reproduction number of SARS-CoV-2 in England, using weekly contact survey data, BMC Med. 19, 233 (2021).
- B. Arregui-García, C. Ascione, A. Pera, B. Wang, D. Stocco, C. J. Carlson, S. Bansal, E. Valdano, and G. Pullano, Disruption of outdoor activities caused by wildfire smoke shapes circulation of respiratory pathogens, PLOS Climate 4, e0000542 (2025).
- C. Ascione and E. Valdano, How floods may affect the spatial spread of respiratory pathogens: The case of Emilia-Romagna, Italy in May 2023, EPJ Data Sci. 14, 43 (2025).
- S. Loreti, M. Keiler, and A. P. Zischg, A severe local flood and social events show a similar impact on human mobility, npj Complex. 2, 6 (2025).
- Q. Wang and J. E. Taylor, Quantifying human mobility perturbation and resilience in hurricane sandy, PLoS ONE 9, e112608 (2014).
- C. M. Peak, A. Wesolowski, E. zu Erbach-Schoenberg, A. J. Tatem, E. Wetter, X. Lu, D. Power, E. Weidman-Grunewald, S. Ramos, S. Moritz, et al., Population mobility reductions associated with travel restrictions during the Ebola epidemic in Sierra Leone: Use of mobile phone data, Int. J. Epidemiol. 47, 1562 (2018).
- G. Pullano, E. Valdano, N. Scarpa, S. Rubrichi, and V. Colizza, Evaluating the effect of demographic factors, socioeconomic factors, and risk aversion on mobility during the COVID-19 epidemic in France under lockdown: A population-based study, Lancet Digit. Health 2, e638 (2020).
- M. Mazzoli, E. Pepe, D. Mateo, C. Cattuto, L. Gauvin, P. Bajardi, M. Tizzoni, A. Hernando, S. Meloni, and J. J. Ramasco, Interplay between mobility, multi-seeding and lockdowns shapes COVID-19 local impact, PLoS Comput. Biol. 17, e1009326 (2021).
- P. Shi, P. Keskinocak, J. L. Swann, and B. Y. Lee, The impact of mass gatherings and holiday traveling on the course of an influenza pandemic: A computational model, BMC Public Health 10, 778 (2010).
- M. Mazzoli, E. Valdano, and V. Colizza, Projecting the COVID-19 epidemic risk in France for the summer 2021, J. Travel Med. 28, taab129 (2021).
- O. Diekmann, J. A. P. Heesterbeek, and M. G. Roberts, The construction of next-generation matrices for compartmental epidemic models, J. R. Soc. Interface 7, 873 (2010).
- A. Vazquez, Multitype branching and graph product theory of infectious disease outbreaks, Phys. Rev. E 103, L030301 (2021).
- O. Diekmann, J. A. P. Heesterbeek, and J. A. J. Metz, On the definition and the computation of the basic reproduction ratio in models for infectious diseases in heterogeneous populations, J. Math. Biol. 28, 365 (1990).
- H. Nishiura, G. Chowell, M. Safan, and C. Castillo-Chavez, Pros and cons of estimating the reproduction number from early epidemic growth rate of influenza A (H1N1) 2009, Theor. Biol. Med. Modell. 7, 1 (2010).
- H. W. Hethcote and D. W. Tudor, Integral equation models for endemic infectious diseases, J. Math. Biol. 9, 37 (1980).
- H. J. Wearing, P. Rohani, and M. J. Keeling, Appropriate models for the management of infectious diseases, PLoS Med. 2, e174 (2005).
- A. Vazquez, Exact solution of infection dynamics with gamma distribution of generation intervals, Phys. Rev. E 103, 042306 (2021).
- G. de Meijere, E. Valdano, C. Castellano, M. Debin, C. Kengne-Kuetche, C. Turbelin, H. Noël, J. S. Weitz, D. Paolotti, L. Hermans, N. Hens, and V. Colizza, Attitudes towards booster, testing and isolation, and their impact on COVID-19 response in winter 2022/2023 in France, Belgium, and Italy: A cross-sectional survey and modelling study, Lancet Reg. Health Eur. 28, 100614 (2023).
- F. Deschâtres and D. Sornette, Dynamics of book sales: Endogenous versus exogenous shocks in complex networks, Phys. Rev. E 72, 016112 (2005).
- P. Linz, Analytical and Numerical Methods for Volterra Equations (SIAM, Philadelphia, PA, USA, 1985), pp. 213–227.
- T. W. Russell, J. T. Wu, S. Clifford, W. J. Edmunds, A. J. Kucharski, and M. Jit, Effect of internationally imported cases on internal spread of COVID-19: A mathematical modelling study, Lancet Public Health 6, e12 (2021).
- T. F. Menkir, T. Chin, J. A. Hay, E. D. Surface, P. M. De Salazar, C. O. Buckee, A. Watts, K. Khan, R. Sherbo, A. W. Yan, et al., Estimating internationally imported cases during the early COVID-19 pandemic, Nat. Commun. 12, 311 (2021).
- M. G. Roberts and H. Nishiura, Early estimation of the reproduction number in the presence of imported cases: Pandemic influenza H1N1-2009 in New Zealand, PLoS One 6, e17835 (2011).
- Y. Yang, J. D. Sugimoto, M. E. Halloran, N. E. Basta, D. L. Chao, L. Matrajt, G. Potter, E. Kenah, and I. M. Longini, The transmissibility and control of pandemic influenza A (H1N1) virus, Science 326, 729 (2009).
- D. Cereda, M. Tirani, F. Rovida, V. Demicheli, M. Ajelli, P. Poletti, F. Trentini, G. Guzzetta, V. Marziano, A. Barone, et al., The early phase of the COVID-19 outbreak in Lombardy, Italy, Epidemics 37, 100528 (2021).
- S. W. Park, D. Champredon, J. S. Weitz, and J. Dushoff, A practical generation-interval-based approach to inferring the strength of epidemics from their speed, Epidemics 27, 12 (2019).
- S. Iyer, B. Karrer, D. T. Citron, F. Kooti, P. Maas, Z. Wang, E. Giraudy, A. Medhat, P. A. Dow, and A. Pompe, Large-scale measurement of aggregate human colocation patterns for epidemiological modeling, Epidemics 42, 100663 (2023).
- Z. Junmei and L. Liqin, Estimating parameters of the gamma distribution easily and efficiently, Commun. Stat. Theory Methods 53, 6197 (2024).
- R. Vani Lakshmi and V. Vaidyanathan, Three-parameter gamma distribution: Estimation using likelihood, spacings and least squares approach, J. Stat. Manage. Syst. 19, 37 (2016).
- S. Park, K. Sun, C. Viboud, B. T. Grenfell, J. R. Gog, and L. Simonsen, Forward‐looking serial interval helps estimate reproduction number more accurately, Proc. Natl. Acad. Sci. USA 118, e2011548118 (2021).
- S. Ali, B. Dong, S. Galea, L. Shrestha, J. Pan, and B. Cowling, Serial interval of SARS-CoV-2 was shortened over time by nonpharmaceutical interventions, Sci. Adv. 6, abc9004 (2020).
- M. A. Billah, M. M. Miah, and M. N. Khan, Reproductive number of coronavirus: A systematic review and meta-analysis based on global level evidence, PLoS One 15, e0242128 (2020).
- M. Manica, et al., Intrinsic generation time of the SARS-CoV-2 Omicron variant: An observational study of household transmission, Lancet Reg. Health Eur. 19 (2022).
- N. G. Davies, et al., Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England, Science 372, eabg3055 (2021).
- Y. Liu and J. Rocklöv, The reproductive number of the Delta variant of SARS-CoV-2 is far higher compared to the ancestral SARS-CoV-2 virus, J. Travel Med. 28, taab124 (2021).
- M. Manica, et al., Estimation of the incubation period and generation time of SARS-CoV-2 Alpha and Delta variants from contact tracing data, Epidemiol. Infect. 151, e5 (2023).
- S. Cauchemez, et al., Unraveling the drivers of MERS-CoV transmission, Proc. Natl. Acad. Sci. USA 113, 9081 (2016).
- L. Alessandretti, U. Aslak, and S. Lehmann, The scales of human mobility, Nature (London) 587, 402 (2020).
- F. Zhang, Z. Li, N. Li, and D. Fang, Assessment of urban human mobility perturbation under extreme weather events: A case study in Nanjing, China, Sustainable Cities Soc. 50, 101671 (2019).
- A. Guirao, The COVID-19 outbreak in Spain. A simple dynamics model, some lessons, and a theoretical framework for control response, Infect. Dis. Modell. 5, 652 (2020).
- J. Chu, A statistical analysis of the novel coronavirus (COVID-19) in Italy and Spain, PLoS One 16, e0249037 (2021).
- I. Locatelli, B. Trächsel, and V. Rousson, Estimating the basic reproduction number for COVID-19 in Western Europe, PLoS One 16, e0248731 (2021).
- https://dataforgood.facebook.com/dfg/tools/colocationmaps.
- https://www.ine.es/.
- Instituto Nacional de Estadística, Población por comunidad autónoma, provincia y sexo, 2025, https://www.ine.es/jaxiT3/Tabla.htm?t=67988.