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Cherry)] TJ ET 0.271 0.267 0.267 rg BT 248.950 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 254.371 663.247 Td /F1 9.8 Tf [(Cecile Viboud)] TJ ET 0.271 0.267 0.267 rg BT 314.519 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 319.940 663.247 Td /F1 9.8 Tf [(Eugene Koonin)] TJ ET 0.271 0.267 0.267 rg BT 386.610 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 392.031 663.247 Td /F1 9.8 Tf [(David J. Lipman)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Wolf Y, Nikolskaya A, Cherry JL, Viboud C, Koonin E, Lipman DJ. Projection of seasonal influenza severity from sequence and )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(serological data. PLOS Currents Influenza. 2010 Dec 6 . Edition 1. doi: 10.1371/currents.RRN1200.)] TJ ET q 15.000 26.911 577.500 610.146 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Severity of seasonal influenza A epidemics is related to the antigenic novelty of the predominant viral strains circulating each )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(year. Support for a strong correlation between epidemic severity and antigenic drift comes from infectious challenge )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(experiments on vaccinated animals and human volunteers, field studies of vaccine efficacy, prospective studies of subjects with )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(laboratory-confirmed prior infections, and analysis of the connection between drift and severity from surveillance data. We show )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(that, given data on the antigenic and sequence novelty of the hemagglutinin protein of clinical isolates of H3N2 virus from a )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(season along with the corresponding data from prior seasons, we can accurately predict the influenza severity for that season. )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(This model therefore provides a framework for making projections of the severity of the upcoming season using assumptions )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(based on viral isolates collected in the current season. Our results based on two independent data sets from the US and Hong )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(Kong suggest that seasonal severity is largely determined by the novelty of the hemagglutinin protein although other factors, )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(including mutations in other influenza genes, co-circulating pathogens and weather conditions, might also play a role. These )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(results should be helpful for the control of seasonal influenza and have implications for improvement of influenza surveillance.)] TJ ET BT 26.250 434.731 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 414.777 Td /F1 9.8 Tf [(This research was supported by the Intramural Research Program of the NCBI/NLM/NIH and FIC/NIH.)] TJ ET BT 26.250 385.674 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 365.720 Td /F1 9.8 Tf [(Kilbourne has described influenza as an unvarying disease \(three-day fever\) caused by a varying virus )] TJ ET 0.267 0.267 0.267 rg BT 494.981 367.227 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 499.800 365.720 Td /F1 9.8 Tf [(. In 1934, Torrens )] TJ ET BT 26.250 353.815 Td /F1 9.8 Tf [(noted an apparent paradox: although influenza survivors of the epidemic of 1890 largely seemed to escape the 1918 epidemic, )] TJ ET BT 26.250 341.910 Td /F1 9.8 Tf [(annual influenza attacks were common. He proposed that influenza was caused by a pleomorphic virus that may exhibit )] TJ ET BT 26.250 330.006 Td /F1 9.8 Tf [(mutation from one type to another to explain this puzzling pattern of post-influenzal immunity )] TJ ET 0.267 0.267 0.267 rg BT 440.264 331.513 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 445.083 330.006 Td /F1 9.8 Tf [(. The challenge this would )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(represent for vaccination became clear by 1947 when a vaccine that was effective in the 1943-1944 and 1945-1946 seasons )] TJ ET BT 26.250 306.196 Td /F1 9.8 Tf [(had no effect for the 1946-1947 influenza season )] TJ ET 0.267 0.267 0.267 rg BT 240.887 307.703 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 245.705 306.196 Td /F1 9.8 Tf [(. Salk and Suriano, in a study of the 1946-1947 strain, raised the possibility )] TJ ET BT 26.250 294.291 Td /F1 9.8 Tf [(that this strain is a mutation and that this might mean that we will always be immunizing against a disease that occurred the )] TJ ET BT 26.250 282.387 Td /F1 9.8 Tf [(year before although they remained hopeful that there would be a limited number of antigenic varieties )] TJ ET 0.267 0.267 0.267 rg BT 472.800 283.894 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 477.619 282.387 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 262.982 Td /F1 9.8 Tf [(The variation of influenza by mutation, i.e., antigenic drift, was soon recognized as the basis for the difficulty of predicting )] TJ ET BT 26.250 251.077 Td /F1 9.8 Tf [(epidemics )] TJ ET 0.267 0.267 0.267 rg BT 72.845 252.584 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 77.664 251.077 Td /F1 9.8 Tf [(, and better understanding the quantitative impact of drift on seasonal epidemics has become an important goal in )] TJ ET BT 26.250 239.172 Td /F1 9.8 Tf [(influenza research. Given that varying levels of cross-protection by earlier viruses are likely to be an important factor in epidemic )] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(severity, one experimental strategy has been to immunize subjects with known strains and determine susceptibility to a )] TJ ET BT 26.250 215.363 Td /F1 9.8 Tf [(challenge with another known strain. McLaren et al. )] TJ ET 0.267 0.267 0.267 rg BT 251.143 216.870 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 255.962 215.363 Td /F1 9.8 Tf [( vaccinated ferrets with A/Hong Kong/1/68 or A/England/42/72, later )] TJ ET BT 26.250 203.458 Td /F1 9.8 Tf [(challenged with a A/England/42/72-like virus, and indeed found greater protection by the matching strain. A similar, more )] TJ ET BT 26.250 191.553 Td /F1 9.8 Tf [(extensive study has been performed on horses using equine influenza virus in order to estimate the parameters of an )] TJ ET BT 26.250 179.649 Td /F1 9.8 Tf [(epidemiological model of outbreak risk as a function of immune escape )] TJ ET 0.267 0.267 0.267 rg BT 335.130 181.156 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 339.949 179.649 Td /F1 9.8 Tf [(. In a study with human volunteers immunized with one )] TJ ET BT 26.250 167.744 Td /F1 9.8 Tf [(of four influenza strains isolated in 1968, 1972, 1973, or 1974, and then challenged with a 1974 strain, Potter et al. )] TJ ET 0.267 0.267 0.267 rg BT 521.082 169.251 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 525.901 167.744 Td /F1 9.8 Tf [( found that )] TJ ET BT 26.250 155.839 Td /F1 9.8 Tf [(susceptibility increased linearly with the number of years separating the challenge and vaccine strains. Consistent results were )] TJ ET BT 26.250 143.934 Td /F1 9.8 Tf [(obtained in a similar study by Larson et al. )] TJ ET 0.267 0.267 0.267 rg BT 211.042 145.442 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 215.860 143.934 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 124.530 Td /F1 9.8 Tf [(Field studies of vaccine efficacy have confirmed the results of these experimental approaches \(c.f. )] TJ ET 0.267 0.267 0.267 rg BT 451.642 126.037 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 461.280 124.530 Td /F1 9.8 Tf [(\). As expected, efficacy is )] TJ ET BT 26.250 112.625 Td /F1 9.8 Tf [(substantially higher when the vaccine strain matches the dominant seasonal strain than when there is a measurable mismatch )] TJ ET BT 26.250 100.720 Td /F1 9.8 Tf [(between the vaccine strain and the dominant strain )] TJ ET 0.267 0.267 0.267 rg BT 248.989 102.227 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 258.626 100.720 Td /F1 9.8 Tf [(. Gupta et al. )] TJ ET 0.267 0.267 0.267 rg BT 317.165 102.227 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 326.802 100.720 Td /F1 9.8 Tf [( compiled an extensive set of vaccine efficacy data and )] TJ ET BT 26.250 88.815 Td /F1 9.8 Tf [(found a strong correlation \(R )] TJ ET BT 152.512 92.704 Td /F1 8.7 Tf [(2)] TJ ET BT 157.331 88.815 Td /F1 9.8 Tf [( = 0.81\) between vaccine efficacy in a given season and the fraction of amino acid replacements )] TJ ET BT 26.250 76.911 Td /F1 9.8 Tf [(in the antigenic regions of the hemagglutinin protein between the vaccine strain and the dominant circulating strain. Evidence of )] TJ ET BT 26.250 65.006 Td /F1 9.8 Tf [(a more direct quantitative connection between the antigenic novelty of the viruses from a given season and susceptibility to )] TJ ET BT 26.250 53.101 Td /F1 9.8 Tf [(influenza can be found in a prospective study of the 1976 seasonal epidemic by Gill and Murphy )] TJ ET 0.267 0.267 0.267 rg BT 443.004 54.608 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 452.641 53.101 Td /F1 9.8 Tf [(. The researchers )] TJ ET BT 26.250 41.196 Td /F1 9.8 Tf [(determined the most recent year of laboratory confirmed influenza for a set of volunteers and found a strong linear relationship )] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Projection of seasonal influenza severity from sequence and )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(serological data)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(December 6, 2010)] TJ ET BT 91.625 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 96.500 675.088 Td /F3 9.8 Tf [(Influenza)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Yuri Wolf)] TJ ET 0.271 0.267 0.267 rg BT 65.796 663.247 Td /F1 9.8 Tf [(, )] TJ ET BT 71.217 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 76.638 663.247 Td /F1 9.8 Tf [(Anastasia Nikolskaya)] TJ ET 0.271 0.267 0.267 rg BT 169.292 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 174.713 663.247 Td /F1 9.8 Tf [(Joshua L. Cherry)] TJ ET 0.271 0.267 0.267 rg BT 248.950 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 254.371 663.247 Td /F1 9.8 Tf [(Cecile Viboud)] TJ ET 0.271 0.267 0.267 rg BT 314.519 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 319.940 663.247 Td /F1 9.8 Tf [(Eugene Koonin)] TJ ET 0.271 0.267 0.267 rg BT 386.610 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 392.031 663.247 Td /F1 9.8 Tf [(David J. Lipman)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Wolf Y, Nikolskaya A, Cherry JL, Viboud C, Koonin E, Lipman DJ. Projection of seasonal influenza severity from sequence and )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(serological data. PLOS Currents Influenza. 2010 Dec 6 . Edition 1. doi: 10.1371/currents.RRN1200.)] TJ ET q 15.000 26.911 577.500 610.146 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Severity of seasonal influenza A epidemics is related to the antigenic novelty of the predominant viral strains circulating each )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(year. Support for a strong correlation between epidemic severity and antigenic drift comes from infectious challenge )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(experiments on vaccinated animals and human volunteers, field studies of vaccine efficacy, prospective studies of subjects with )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(laboratory-confirmed prior infections, and analysis of the connection between drift and severity from surveillance data. We show )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(that, given data on the antigenic and sequence novelty of the hemagglutinin protein of clinical isolates of H3N2 virus from a )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(season along with the corresponding data from prior seasons, we can accurately predict the influenza severity for that season. )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(This model therefore provides a framework for making projections of the severity of the upcoming season using assumptions )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(based on viral isolates collected in the current season. Our results based on two independent data sets from the US and Hong )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(Kong suggest that seasonal severity is largely determined by the novelty of the hemagglutinin protein although other factors, )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(including mutations in other influenza genes, co-circulating pathogens and weather conditions, might also play a role. These )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(results should be helpful for the control of seasonal influenza and have implications for improvement of influenza surveillance.)] TJ ET BT 26.250 434.731 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 414.777 Td /F1 9.8 Tf [(This research was supported by the Intramural Research Program of the NCBI/NLM/NIH and FIC/NIH.)] TJ ET BT 26.250 385.674 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 365.720 Td /F1 9.8 Tf [(Kilbourne has described influenza as an unvarying disease \(three-day fever\) caused by a varying virus )] TJ ET 0.267 0.267 0.267 rg BT 494.981 367.227 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 499.800 365.720 Td /F1 9.8 Tf [(. In 1934, Torrens )] TJ ET BT 26.250 353.815 Td /F1 9.8 Tf [(noted an apparent paradox: although influenza survivors of the epidemic of 1890 largely seemed to escape the 1918 epidemic, )] TJ ET BT 26.250 341.910 Td /F1 9.8 Tf [(annual influenza attacks were common. He proposed that influenza was caused by a pleomorphic virus that may exhibit )] TJ ET BT 26.250 330.006 Td /F1 9.8 Tf [(mutation from one type to another to explain this puzzling pattern of post-influenzal immunity )] TJ ET 0.267 0.267 0.267 rg BT 440.264 331.513 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 445.083 330.006 Td /F1 9.8 Tf [(. The challenge this would )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(represent for vaccination became clear by 1947 when a vaccine that was effective in the 1943-1944 and 1945-1946 seasons )] TJ ET BT 26.250 306.196 Td /F1 9.8 Tf [(had no effect for the 1946-1947 influenza season )] TJ ET 0.267 0.267 0.267 rg BT 240.887 307.703 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 245.705 306.196 Td /F1 9.8 Tf [(. Salk and Suriano, in a study of the 1946-1947 strain, raised the possibility )] TJ ET BT 26.250 294.291 Td /F1 9.8 Tf [(that this strain is a mutation and that this might mean that we will always be immunizing against a disease that occurred the )] TJ ET BT 26.250 282.387 Td /F1 9.8 Tf [(year before although they remained hopeful that there would be a limited number of antigenic varieties )] TJ ET 0.267 0.267 0.267 rg BT 472.800 283.894 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 477.619 282.387 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 262.982 Td /F1 9.8 Tf [(The variation of influenza by mutation, i.e., antigenic drift, was soon recognized as the basis for the difficulty of predicting )] TJ ET BT 26.250 251.077 Td /F1 9.8 Tf [(epidemics )] TJ ET 0.267 0.267 0.267 rg BT 72.845 252.584 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 77.664 251.077 Td /F1 9.8 Tf [(, and better understanding the quantitative impact of drift on seasonal epidemics has become an important goal in )] TJ ET BT 26.250 239.172 Td /F1 9.8 Tf [(influenza research. Given that varying levels of cross-protection by earlier viruses are likely to be an important factor in epidemic )] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(severity, one experimental strategy has been to immunize subjects with known strains and determine susceptibility to a )] TJ ET BT 26.250 215.363 Td /F1 9.8 Tf [(challenge with another known strain. McLaren et al. )] TJ ET 0.267 0.267 0.267 rg BT 251.143 216.870 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 255.962 215.363 Td /F1 9.8 Tf [( vaccinated ferrets with A/Hong Kong/1/68 or A/England/42/72, later )] TJ ET BT 26.250 203.458 Td /F1 9.8 Tf [(challenged with a A/England/42/72-like virus, and indeed found greater protection by the matching strain. A similar, more )] TJ ET BT 26.250 191.553 Td /F1 9.8 Tf [(extensive study has been performed on horses using equine influenza virus in order to estimate the parameters of an )] TJ ET BT 26.250 179.649 Td /F1 9.8 Tf [(epidemiological model of outbreak risk as a function of immune escape )] TJ ET 0.267 0.267 0.267 rg BT 335.130 181.156 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 339.949 179.649 Td /F1 9.8 Tf [(. In a study with human volunteers immunized with one )] TJ ET BT 26.250 167.744 Td /F1 9.8 Tf [(of four influenza strains isolated in 1968, 1972, 1973, or 1974, and then challenged with a 1974 strain, Potter et al. )] TJ ET 0.267 0.267 0.267 rg BT 521.082 169.251 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 525.901 167.744 Td /F1 9.8 Tf [( found that )] TJ ET BT 26.250 155.839 Td /F1 9.8 Tf [(susceptibility increased linearly with the number of years separating the challenge and vaccine strains. Consistent results were )] TJ ET BT 26.250 143.934 Td /F1 9.8 Tf [(obtained in a similar study by Larson et al. )] TJ ET 0.267 0.267 0.267 rg BT 211.042 145.442 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 215.860 143.934 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 124.530 Td /F1 9.8 Tf [(Field studies of vaccine efficacy have confirmed the results of these experimental approaches \(c.f. )] TJ ET 0.267 0.267 0.267 rg BT 451.642 126.037 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 461.280 124.530 Td /F1 9.8 Tf [(\). As expected, efficacy is )] TJ ET BT 26.250 112.625 Td /F1 9.8 Tf [(substantially higher when the vaccine strain matches the dominant seasonal strain than when there is a measurable mismatch )] TJ ET BT 26.250 100.720 Td /F1 9.8 Tf [(between the vaccine strain and the dominant strain )] TJ ET 0.267 0.267 0.267 rg BT 248.989 102.227 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 258.626 100.720 Td /F1 9.8 Tf [(. Gupta et al. )] TJ ET 0.267 0.267 0.267 rg BT 317.165 102.227 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 326.802 100.720 Td /F1 9.8 Tf [( compiled an extensive set of vaccine efficacy data and )] TJ ET BT 26.250 88.815 Td /F1 9.8 Tf [(found a strong correlation \(R )] TJ ET BT 152.512 92.704 Td /F1 8.7 Tf [(2)] TJ ET BT 157.331 88.815 Td /F1 9.8 Tf [( = 0.81\) between vaccine efficacy in a given season and the fraction of amino acid replacements )] TJ ET BT 26.250 76.911 Td /F1 9.8 Tf [(in the antigenic regions of the hemagglutinin protein between the vaccine strain and the dominant circulating strain. Evidence of )] TJ ET BT 26.250 65.006 Td /F1 9.8 Tf [(a more direct quantitative connection between the antigenic novelty of the viruses from a given season and susceptibility to )] TJ ET BT 26.250 53.101 Td /F1 9.8 Tf [(influenza can be found in a prospective study of the 1976 seasonal epidemic by Gill and Murphy )] TJ ET 0.267 0.267 0.267 rg BT 443.004 54.608 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 452.641 53.101 Td /F1 9.8 Tf [(. The researchers )] TJ ET BT 26.250 41.196 Td /F1 9.8 Tf [(determined the most recent year of laboratory confirmed influenza for a set of volunteers and found a strong linear relationship )] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Projection of seasonal influenza severity from sequence and )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(serological data)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(December 6, 2010)] TJ ET BT 91.625 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 96.500 675.088 Td /F3 9.8 Tf [(Influenza)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Yuri Wolf)] TJ ET 0.271 0.267 0.267 rg BT 65.796 663.247 Td /F1 9.8 Tf [(, )] TJ ET BT 71.217 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 76.638 663.247 Td /F1 9.8 Tf [(Anastasia Nikolskaya)] TJ ET 0.271 0.267 0.267 rg BT 169.292 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 174.713 663.247 Td /F1 9.8 Tf [(Joshua L. Cherry)] TJ ET 0.271 0.267 0.267 rg BT 248.950 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 254.371 663.247 Td /F1 9.8 Tf [(Cecile Viboud)] TJ ET 0.271 0.267 0.267 rg BT 314.519 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 319.940 663.247 Td /F1 9.8 Tf [(Eugene Koonin)] TJ ET 0.271 0.267 0.267 rg BT 386.610 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 392.031 663.247 Td /F1 9.8 Tf [(David J. Lipman)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Wolf Y, Nikolskaya A, Cherry JL, Viboud C, Koonin E, Lipman DJ. Projection of seasonal influenza severity from sequence and )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(serological data. PLOS Currents Influenza. 2010 Dec 6 . Edition 1. doi: 10.1371/currents.RRN1200.)] TJ ET q 15.000 26.911 577.500 610.146 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Severity of seasonal influenza A epidemics is related to the antigenic novelty of the predominant viral strains circulating each )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(year. Support for a strong correlation between epidemic severity and antigenic drift comes from infectious challenge )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(experiments on vaccinated animals and human volunteers, field studies of vaccine efficacy, prospective studies of subjects with )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(laboratory-confirmed prior infections, and analysis of the connection between drift and severity from surveillance data. We show )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(that, given data on the antigenic and sequence novelty of the hemagglutinin protein of clinical isolates of H3N2 virus from a )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(season along with the corresponding data from prior seasons, we can accurately predict the influenza severity for that season. )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(This model therefore provides a framework for making projections of the severity of the upcoming season using assumptions )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(based on viral isolates collected in the current season. Our results based on two independent data sets from the US and Hong )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(Kong suggest that seasonal severity is largely determined by the novelty of the hemagglutinin protein although other factors, )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(including mutations in other influenza genes, co-circulating pathogens and weather conditions, might also play a role. These )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(results should be helpful for the control of seasonal influenza and have implications for improvement of influenza surveillance.)] TJ ET BT 26.250 434.731 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 414.777 Td /F1 9.8 Tf [(This research was supported by the Intramural Research Program of the NCBI/NLM/NIH and FIC/NIH.)] TJ ET BT 26.250 385.674 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 365.720 Td /F1 9.8 Tf [(Kilbourne has described influenza as an unvarying disease \(three-day fever\) caused by a varying virus )] TJ ET 0.267 0.267 0.267 rg BT 494.981 367.227 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 499.800 365.720 Td /F1 9.8 Tf [(. In 1934, Torrens )] TJ ET BT 26.250 353.815 Td /F1 9.8 Tf [(noted an apparent paradox: although influenza survivors of the epidemic of 1890 largely seemed to escape the 1918 epidemic, )] TJ ET BT 26.250 341.910 Td /F1 9.8 Tf [(annual influenza attacks were common. He proposed that influenza was caused by a pleomorphic virus that may exhibit )] TJ ET BT 26.250 330.006 Td /F1 9.8 Tf [(mutation from one type to another to explain this puzzling pattern of post-influenzal immunity )] TJ ET 0.267 0.267 0.267 rg BT 440.264 331.513 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 445.083 330.006 Td /F1 9.8 Tf [(. The challenge this would )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(represent for vaccination became clear by 1947 when a vaccine that was effective in the 1943-1944 and 1945-1946 seasons )] TJ ET BT 26.250 306.196 Td /F1 9.8 Tf [(had no effect for the 1946-1947 influenza season )] TJ ET 0.267 0.267 0.267 rg BT 240.887 307.703 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 245.705 306.196 Td /F1 9.8 Tf [(. Salk and Suriano, in a study of the 1946-1947 strain, raised the possibility )] TJ ET BT 26.250 294.291 Td /F1 9.8 Tf [(that this strain is a mutation and that this might mean that we will always be immunizing against a disease that occurred the )] TJ ET BT 26.250 282.387 Td /F1 9.8 Tf [(year before although they remained hopeful that there would be a limited number of antigenic varieties )] TJ ET 0.267 0.267 0.267 rg BT 472.800 283.894 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 477.619 282.387 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 262.982 Td /F1 9.8 Tf [(The variation of influenza by mutation, i.e., antigenic drift, was soon recognized as the basis for the difficulty of predicting )] TJ ET BT 26.250 251.077 Td /F1 9.8 Tf [(epidemics )] TJ ET 0.267 0.267 0.267 rg BT 72.845 252.584 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 77.664 251.077 Td /F1 9.8 Tf [(, and better understanding the quantitative impact of drift on seasonal epidemics has become an important goal in )] TJ ET BT 26.250 239.172 Td /F1 9.8 Tf [(influenza research. Given that varying levels of cross-protection by earlier viruses are likely to be an important factor in epidemic )] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(severity, one experimental strategy has been to immunize subjects with known strains and determine susceptibility to a )] TJ ET BT 26.250 215.363 Td /F1 9.8 Tf [(challenge with another known strain. McLaren et al. )] TJ ET 0.267 0.267 0.267 rg BT 251.143 216.870 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 255.962 215.363 Td /F1 9.8 Tf [( vaccinated ferrets with A/Hong Kong/1/68 or A/England/42/72, later )] TJ ET BT 26.250 203.458 Td /F1 9.8 Tf [(challenged with a A/England/42/72-like virus, and indeed found greater protection by the matching strain. A similar, more )] TJ ET BT 26.250 191.553 Td /F1 9.8 Tf [(extensive study has been performed on horses using equine influenza virus in order to estimate the parameters of an )] TJ ET BT 26.250 179.649 Td /F1 9.8 Tf [(epidemiological model of outbreak risk as a function of immune escape )] TJ ET 0.267 0.267 0.267 rg BT 335.130 181.156 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 339.949 179.649 Td /F1 9.8 Tf [(. In a study with human volunteers immunized with one )] TJ ET BT 26.250 167.744 Td /F1 9.8 Tf [(of four influenza strains isolated in 1968, 1972, 1973, or 1974, and then challenged with a 1974 strain, Potter et al. )] TJ ET 0.267 0.267 0.267 rg BT 521.082 169.251 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 525.901 167.744 Td /F1 9.8 Tf [( found that )] TJ ET BT 26.250 155.839 Td /F1 9.8 Tf [(susceptibility increased linearly with the number of years separating the challenge and vaccine strains. Consistent results were )] TJ ET BT 26.250 143.934 Td /F1 9.8 Tf [(obtained in a similar study by Larson et al. )] TJ ET 0.267 0.267 0.267 rg BT 211.042 145.442 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 215.860 143.934 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 124.530 Td /F1 9.8 Tf [(Field studies of vaccine efficacy have confirmed the results of these experimental approaches \(c.f. )] TJ ET 0.267 0.267 0.267 rg BT 451.642 126.037 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 461.280 124.530 Td /F1 9.8 Tf [(\). As expected, efficacy is )] TJ ET BT 26.250 112.625 Td /F1 9.8 Tf [(substantially higher when the vaccine strain matches the dominant seasonal strain than when there is a measurable mismatch )] TJ ET BT 26.250 100.720 Td /F1 9.8 Tf [(between the vaccine strain and the dominant strain )] TJ ET 0.267 0.267 0.267 rg BT 248.989 102.227 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 258.626 100.720 Td /F1 9.8 Tf [(. Gupta et al. )] TJ ET 0.267 0.267 0.267 rg BT 317.165 102.227 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 326.802 100.720 Td /F1 9.8 Tf [( compiled an extensive set of vaccine efficacy data and )] TJ ET BT 26.250 88.815 Td /F1 9.8 Tf [(found a strong correlation \(R )] TJ ET BT 152.512 92.704 Td /F1 8.7 Tf [(2)] TJ ET BT 157.331 88.815 Td /F1 9.8 Tf [( = 0.81\) between vaccine efficacy in a given season and the fraction of amino acid replacements )] TJ ET BT 26.250 76.911 Td /F1 9.8 Tf [(in the antigenic regions of the hemagglutinin protein between the vaccine strain and the dominant circulating strain. Evidence of )] TJ ET BT 26.250 65.006 Td /F1 9.8 Tf [(a more direct quantitative connection between the antigenic novelty of the viruses from a given season and susceptibility to )] TJ ET BT 26.250 53.101 Td /F1 9.8 Tf [(influenza can be found in a prospective study of the 1976 seasonal epidemic by Gill and Murphy )] TJ ET 0.267 0.267 0.267 rg BT 443.004 54.608 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 452.641 53.101 Td /F1 9.8 Tf [(. 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0.267 0.267 rg q 15.000 22.646 577.500 754.354 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(between the probability of infection in the 1976 season and the number of years since the previous infection. The above studies )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(suggest that the number of susceptible individuals for a given season, and hence the number of influenza cases, will be strongly )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(correlated with measures of the antigenic distance between prevailing viruses for that season and viruses that circulated in )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(previous seasons.)] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(In light of the compelling evidence for a quantitative relationship between antigenic drift and seasonal severity, it is perhaps )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(surprising that until recently no study demonstrated a positive correlation between drift and severity using data derived directly )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(from influenza surveillance. A recent study by Wu et al. )] TJ ET 0.267 0.267 0.267 rg BT 266.305 690.055 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 275.942 688.548 Td /F1 9.8 Tf [( focuses on influenza H1N1 and considers major antigenic strains )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(based on hemagglutination inhibition \(HI\) assays a method traditionally used by the Centers for Disease Control \(CDC\) to )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(characterize seasonal viruses for vaccine selection and surveillance purposes. Wu et al. then estimate the excess mortality )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(attributable to each antigenic strain using the fraction of isolates positive for that strain among all those tested in seasons in )] TJ ET BT 26.250 640.929 Td /F1 9.8 Tf [(which the strain was detected. This analysis has shown a strong correlation between estimates of the multi-season excess )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(mortality due to an antigenic strain and its antigenic distance from previous strains for H1N1, and a weaker correlation for H3N2. )] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(Given that in recent years, most of the inter-pandemic influenza morbidity was caused by H3N2 viruses )] TJ ET 0.267 0.267 0.267 rg BT 473.297 618.626 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 482.935 617.119 Td /F1 9.8 Tf [(, we were interested )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(in investigating the relationships between sequence and antigenic variation in the H3N2 HA and the seasonal severity \(health )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(burden\) of influenza caused by this subtype. In this analysis, we aimed at reaching beyond correlations and developing a )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(practical model for projecting the health burden of influenza H3N2.)] TJ ET BT 26.250 562.000 Td /F1 9.8 Tf [(Extending previous work on the relationship of antigenic drift and seasonal severity, we here use sequences of hemagglutinin )] TJ ET BT 26.250 550.095 Td /F1 9.8 Tf [(proteins from H3N2 clinical isolates and the corresponding HI data from two countries to demonstrate that one can )] TJ ET BT 521.550 550.095 Td /F5 9.8 Tf [(reconstruct)] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(with surprising accuracy the severity of a given season. That is, given only data on the antigenic novelty of the viruses from a )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(season we can predict its epidemiological severity. Furthermore, our statistical model provides a framework for making )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(projections of the severity of the upcoming season using assumptions based on viral isolates collected in the current season. )] TJ ET BT 26.250 502.476 Td /F1 9.8 Tf [(These results are expected to be helpful in the planning process for the control of seasonal influenza and have implications for )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(influenza surveillance.)] TJ ET BT 26.250 453.969 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 434.015 Td /F4 9.8 Tf [(Epidemiological indices)] TJ ET BT 26.250 414.610 Td /F1 9.8 Tf [(The seasonal impact of influenza on a population is notably difficult to measure precisely due to the non-specificity of symptoms )] TJ ET BT 26.250 402.705 Td /F1 9.8 Tf [(and the lack of diagnostic tests conducted in routine, and morbidity data are especially scarce. To overcome this problem, we )] TJ ET BT 26.250 390.801 Td /F1 9.8 Tf [(used several epidemiological indicators and validated our predictive algorithm by considering two separate countries: the US )] TJ ET BT 26.250 378.896 Td /F1 9.8 Tf [(and Hong Kong. In the US analysis, we used seven independently-collected epidemiological indicators, each representing a )] TJ ET BT 26.250 366.991 Td /F1 9.8 Tf [(slightly different aspect of influenza A/H3 seasonal disease burden. These indicators were available for 16 consecutive seasons )] TJ ET BT 26.250 355.086 Td /F1 9.8 Tf [(from 1993-1994 to 2008-2009 and comprised:)] TJ ET BT 32.206 335.699 Td /F1 9.8 Tf [(1.)] TJ ET BT 45.750 335.682 Td /F1 9.8 Tf [(a seasonal indicator of the dominance of influenza A/H3 over the A/H1 subtype for each season \()] TJ ET BT 464.132 335.682 Td /F6 9.8 Tf [(F-H3)] TJ ET BT 485.797 335.682 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 320.045 Td /F1 9.8 Tf [(2.)] TJ ET BT 45.750 320.027 Td /F1 9.8 Tf [(the seasonal fraction of positive influenza specimens over all respiratory samples tested \()] TJ ET BT 430.485 320.027 Td /F6 9.8 Tf [(F-Pos)] TJ ET BT 457.571 320.027 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 304.390 Td /F1 9.8 Tf [(3.)] TJ ET BT 45.750 304.372 Td /F1 9.8 Tf [(a proxy for the seasonal number of H3 cases, H3 severity \()] TJ ET BT 299.894 304.372 Td /F6 9.8 Tf [(S-H3)] TJ ET BT 322.104 304.372 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 288.735 Td /F1 9.8 Tf [(4.)] TJ ET BT 45.750 288.717 Td /F1 9.8 Tf [(influenza-related seasonal excess mortality rate \()] TJ ET BT 257.618 288.717 Td /F6 9.8 Tf [(R-Mo)] TJ ET BT 281.983 288.717 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 273.080 Td /F1 9.8 Tf [(5.)] TJ ET BT 45.750 273.063 Td /F1 9.8 Tf [(influenza-related seasonal excess hospitalization rate \()] TJ ET BT 282.558 273.063 Td /F6 9.8 Tf [(R-Ho)] TJ ET BT 305.841 273.063 Td /F1 9.8 Tf [(\),)] TJ ET BT 32.206 257.426 Td /F1 9.8 Tf [(6.)] TJ ET BT 45.750 257.408 Td /F1 9.8 Tf [(seasonal percent of Influenza-Like Illnesses \()] TJ ET BT 240.838 257.408 Td /F6 9.8 Tf [(F-ILI)] TJ ET BT 261.420 257.408 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 241.771 Td /F1 9.8 Tf [(7.)] TJ ET BT 45.750 241.753 Td /F1 9.8 Tf [(index of speed of spread \()] TJ ET BT 158.480 241.753 Td /F6 9.8 Tf [(I-Sp)] TJ ET BT 176.897 241.753 Td /F1 9.8 Tf [(\))] TJ ET BT 26.250 218.598 Td /F1 9.8 Tf [(Percent of Influenza-Like Illnesses \()] TJ ET BT 180.690 218.598 Td /F5 9.8 Tf [(F-ILI)] TJ ET BT 200.736 218.598 Td /F1 9.8 Tf [(\) was calculated as percent of consultations for influenza-like illness out of the total )] TJ ET BT 26.250 206.694 Td /F1 9.8 Tf [(number of consultations reported to the surveillance system for a given season. Fraction of positive specimens \()] TJ ET BT 508.534 206.694 Td /F5 9.8 Tf [(F-Pos)] TJ ET BT 534.537 206.694 Td /F1 9.8 Tf [(\) was )] TJ ET BT 26.250 194.789 Td /F1 9.8 Tf [(calculated as percent of specimens positive for influenza virus of all specimens collected during the season. \(Data source: CDC )] TJ ET 0.267 0.267 0.267 rg BT 26.250 182.884 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 42.513 182.884 Td /F1 9.8 Tf [(\). An indicator of the dominance of influenza A/H3 over the A/H1 \( )] TJ ET BT 328.110 182.884 Td /F5 9.8 Tf [(F-H3)] TJ ET BT 349.774 182.884 Td /F1 9.8 Tf [(\) was calculated as the logarithm of the ratio of H1 to )] TJ ET BT 26.250 170.979 Td /F1 9.8 Tf [(H3 isolates \(Data source: CDC )] TJ ET 0.267 0.267 0.267 rg BT 162.243 172.487 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 171.880 170.979 Td /F1 9.8 Tf [(\).)] TJ ET BT 26.250 151.575 Td /F1 9.8 Tf [(H3 epidemic severity \()] TJ ET BT 122.687 151.575 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 144.898 151.575 Td /F1 9.8 Tf [(\) was calculated as the product of total influenza epidemic severity and the fraction of H3 isolates )] TJ ET BT 26.250 139.670 Td /F1 9.8 Tf [(among all influenza isolates )] TJ ET 0.267 0.267 0.267 rg BT 148.720 141.177 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 158.357 139.670 Td /F1 9.8 Tf [(. Total epidemic severity was calculated using two sources of data because no available data )] TJ ET BT 26.250 127.765 Td /F1 9.8 Tf [(source covers the entire period of 1993-2008. For the period of 1997/98 2008/09, total epidemic severity was calculated as )] TJ ET BT 26.250 115.860 Td /F5 9.8 Tf [(F-ILI x F-Pos)] TJ ET BT 82.595 115.860 Td /F1 9.8 Tf [( . For the period of 1993/94-1996/97, we first calculated seasonal excess mortality impact \()] TJ ET BT 473.307 115.860 Td /F5 9.8 Tf [(R-Mo)] TJ ET BT 497.136 115.860 Td /F1 9.8 Tf [( , excess death )] TJ ET BT 26.250 103.956 Td /F1 9.8 Tf [(rate from pneumonia and influenza per 100,000\) as in )] TJ ET 0.267 0.267 0.267 rg BT 260.913 105.463 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 270.550 103.956 Td /F1 9.8 Tf [(. Excess mortality is a traditional indicator of influenza disease burden )] TJ ET BT 26.250 92.051 Td /F1 9.8 Tf [(and is estimated from national vital statistics as mortality in excess of an expected seasonal baseline representing the level of )] TJ ET BT 26.250 80.146 Td /F1 9.8 Tf [(mortality in the absence of influenza )] TJ ET 0.267 0.267 0.267 rg BT 184.493 81.653 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 194.130 80.146 Td /F1 9.8 Tf [(. Then, the total severity was estimated as a normalized mortality impact, based on the )] TJ ET BT 26.250 68.241 Td /F1 9.8 Tf [(correlation between mortality impact and the ILI-based severity measure described above, over the years where both were )] TJ ET BT 26.250 56.337 Td /F1 9.8 Tf [(available \(1997/98-2005/06\) \(using the geometrical mean of the ratio ILI-based severity/mortality impact for 1997/98-2005/06\).)] TJ ET BT 26.250 36.932 Td /F1 9.8 Tf [(The index of speed of spread \()] TJ ET BT 158.489 36.932 Td /F5 9.8 Tf [(I-Sp)] TJ ET BT 176.371 36.932 Td /F1 9.8 Tf [(\) was calculated as the standard deviation of the dates of peak pneumonia and influenza )] TJ ET Q q 15.000 22.646 577.500 754.354 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(between the probability of infection in the 1976 season and the number of years since the previous infection. The above studies )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(suggest that the number of susceptible individuals for a given season, and hence the number of influenza cases, will be strongly )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(correlated with measures of the antigenic distance between prevailing viruses for that season and viruses that circulated in )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(previous seasons.)] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(In light of the compelling evidence for a quantitative relationship between antigenic drift and seasonal severity, it is perhaps )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(surprising that until recently no study demonstrated a positive correlation between drift and severity using data derived directly )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(from influenza surveillance. A recent study by Wu et al. )] TJ ET 0.267 0.267 0.267 rg BT 266.305 690.055 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 275.942 688.548 Td /F1 9.8 Tf [( focuses on influenza H1N1 and considers major antigenic strains )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(based on hemagglutination inhibition \(HI\) assays a method traditionally used by the Centers for Disease Control \(CDC\) to )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(characterize seasonal viruses for vaccine selection and surveillance purposes. Wu et al. then estimate the excess mortality )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(attributable to each antigenic strain using the fraction of isolates positive for that strain among all those tested in seasons in )] TJ ET BT 26.250 640.929 Td /F1 9.8 Tf [(which the strain was detected. This analysis has shown a strong correlation between estimates of the multi-season excess )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(mortality due to an antigenic strain and its antigenic distance from previous strains for H1N1, and a weaker correlation for H3N2. )] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(Given that in recent years, most of the inter-pandemic influenza morbidity was caused by H3N2 viruses )] TJ ET 0.267 0.267 0.267 rg BT 473.297 618.626 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 482.935 617.119 Td /F1 9.8 Tf [(, we were interested )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(in investigating the relationships between sequence and antigenic variation in the H3N2 HA and the seasonal severity \(health )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(burden\) of influenza caused by this subtype. In this analysis, we aimed at reaching beyond correlations and developing a )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(practical model for projecting the health burden of influenza H3N2.)] TJ ET BT 26.250 562.000 Td /F1 9.8 Tf [(Extending previous work on the relationship of antigenic drift and seasonal severity, we here use sequences of hemagglutinin )] TJ ET BT 26.250 550.095 Td /F1 9.8 Tf [(proteins from H3N2 clinical isolates and the corresponding HI data from two countries to demonstrate that one can )] TJ ET BT 521.550 550.095 Td /F5 9.8 Tf [(reconstruct)] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(with surprising accuracy the severity of a given season. That is, given only data on the antigenic novelty of the viruses from a )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(season we can predict its epidemiological severity. Furthermore, our statistical model provides a framework for making )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(projections of the severity of the upcoming season using assumptions based on viral isolates collected in the current season. )] TJ ET BT 26.250 502.476 Td /F1 9.8 Tf [(These results are expected to be helpful in the planning process for the control of seasonal influenza and have implications for )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(influenza surveillance.)] TJ ET BT 26.250 453.969 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 434.015 Td /F4 9.8 Tf [(Epidemiological indices)] TJ ET BT 26.250 414.610 Td /F1 9.8 Tf [(The seasonal impact of influenza on a population is notably difficult to measure precisely due to the non-specificity of symptoms )] TJ ET BT 26.250 402.705 Td /F1 9.8 Tf [(and the lack of diagnostic tests conducted in routine, and morbidity data are especially scarce. To overcome this problem, we )] TJ ET BT 26.250 390.801 Td /F1 9.8 Tf [(used several epidemiological indicators and validated our predictive algorithm by considering two separate countries: the US )] TJ ET BT 26.250 378.896 Td /F1 9.8 Tf [(and Hong Kong. In the US analysis, we used seven independently-collected epidemiological indicators, each representing a )] TJ ET BT 26.250 366.991 Td /F1 9.8 Tf [(slightly different aspect of influenza A/H3 seasonal disease burden. These indicators were available for 16 consecutive seasons )] TJ ET BT 26.250 355.086 Td /F1 9.8 Tf [(from 1993-1994 to 2008-2009 and comprised:)] TJ ET BT 32.206 335.699 Td /F1 9.8 Tf [(1.)] TJ ET BT 45.750 335.682 Td /F1 9.8 Tf [(a seasonal indicator of the dominance of influenza A/H3 over the A/H1 subtype for each season \()] TJ ET BT 464.132 335.682 Td /F6 9.8 Tf [(F-H3)] TJ ET BT 485.797 335.682 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 320.045 Td /F1 9.8 Tf [(2.)] TJ ET BT 45.750 320.027 Td /F1 9.8 Tf [(the seasonal fraction of positive influenza specimens over all respiratory samples tested \()] TJ ET BT 430.485 320.027 Td /F6 9.8 Tf [(F-Pos)] TJ ET BT 457.571 320.027 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 304.390 Td /F1 9.8 Tf [(3.)] TJ ET BT 45.750 304.372 Td /F1 9.8 Tf [(a proxy for the seasonal number of H3 cases, H3 severity \()] TJ ET BT 299.894 304.372 Td /F6 9.8 Tf [(S-H3)] TJ ET BT 322.104 304.372 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 288.735 Td /F1 9.8 Tf [(4.)] TJ ET BT 45.750 288.717 Td /F1 9.8 Tf [(influenza-related seasonal excess mortality rate \()] TJ ET BT 257.618 288.717 Td /F6 9.8 Tf [(R-Mo)] TJ ET BT 281.983 288.717 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 273.080 Td /F1 9.8 Tf [(5.)] TJ ET BT 45.750 273.063 Td /F1 9.8 Tf [(influenza-related seasonal excess hospitalization rate \()] TJ ET BT 282.558 273.063 Td /F6 9.8 Tf [(R-Ho)] TJ ET BT 305.841 273.063 Td /F1 9.8 Tf [(\),)] TJ ET BT 32.206 257.426 Td /F1 9.8 Tf [(6.)] TJ ET BT 45.750 257.408 Td /F1 9.8 Tf [(seasonal percent of Influenza-Like Illnesses \()] TJ ET BT 240.838 257.408 Td /F6 9.8 Tf [(F-ILI)] TJ ET BT 261.420 257.408 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 241.771 Td /F1 9.8 Tf [(7.)] TJ ET BT 45.750 241.753 Td /F1 9.8 Tf [(index of speed of spread \()] TJ ET BT 158.480 241.753 Td /F6 9.8 Tf [(I-Sp)] TJ ET BT 176.897 241.753 Td /F1 9.8 Tf [(\))] TJ ET BT 26.250 218.598 Td /F1 9.8 Tf [(Percent of Influenza-Like Illnesses \()] TJ ET BT 180.690 218.598 Td /F5 9.8 Tf [(F-ILI)] TJ ET BT 200.736 218.598 Td /F1 9.8 Tf [(\) was calculated as percent of consultations for influenza-like illness out of the total )] TJ ET BT 26.250 206.694 Td /F1 9.8 Tf [(number of consultations reported to the surveillance system for a given season. Fraction of positive specimens \()] TJ ET BT 508.534 206.694 Td /F5 9.8 Tf [(F-Pos)] TJ ET BT 534.537 206.694 Td /F1 9.8 Tf [(\) was )] TJ ET BT 26.250 194.789 Td /F1 9.8 Tf [(calculated as percent of specimens positive for influenza virus of all specimens collected during the season. \(Data source: CDC )] TJ ET 0.267 0.267 0.267 rg BT 26.250 182.884 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 42.513 182.884 Td /F1 9.8 Tf [(\). An indicator of the dominance of influenza A/H3 over the A/H1 \( )] TJ ET BT 328.110 182.884 Td /F5 9.8 Tf [(F-H3)] TJ ET BT 349.774 182.884 Td /F1 9.8 Tf [(\) was calculated as the logarithm of the ratio of H1 to )] TJ ET BT 26.250 170.979 Td /F1 9.8 Tf [(H3 isolates \(Data source: CDC )] TJ ET 0.267 0.267 0.267 rg BT 162.243 172.487 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 171.880 170.979 Td /F1 9.8 Tf [(\).)] TJ ET BT 26.250 151.575 Td /F1 9.8 Tf [(H3 epidemic severity \()] TJ ET BT 122.687 151.575 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 144.898 151.575 Td /F1 9.8 Tf [(\) was calculated as the product of total influenza epidemic severity and the fraction of H3 isolates )] TJ ET BT 26.250 139.670 Td /F1 9.8 Tf [(among all influenza isolates )] TJ ET 0.267 0.267 0.267 rg BT 148.720 141.177 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 158.357 139.670 Td /F1 9.8 Tf [(. Total epidemic severity was calculated using two sources of data because no available data )] TJ ET BT 26.250 127.765 Td /F1 9.8 Tf [(source covers the entire period of 1993-2008. For the period of 1997/98 2008/09, total epidemic severity was calculated as )] TJ ET BT 26.250 115.860 Td /F5 9.8 Tf [(F-ILI x F-Pos)] TJ ET BT 82.595 115.860 Td /F1 9.8 Tf [( . For the period of 1993/94-1996/97, we first calculated seasonal excess mortality impact \()] TJ ET BT 473.307 115.860 Td /F5 9.8 Tf [(R-Mo)] TJ ET BT 497.136 115.860 Td /F1 9.8 Tf [( , excess death )] TJ ET BT 26.250 103.956 Td /F1 9.8 Tf [(rate from pneumonia and influenza per 100,000\) as in )] TJ ET 0.267 0.267 0.267 rg BT 260.913 105.463 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 270.550 103.956 Td /F1 9.8 Tf [(. Excess mortality is a traditional indicator of influenza disease burden )] TJ ET BT 26.250 92.051 Td /F1 9.8 Tf [(and is estimated from national vital statistics as mortality in excess of an expected seasonal baseline representing the level of )] TJ ET BT 26.250 80.146 Td /F1 9.8 Tf [(mortality in the absence of influenza )] TJ ET 0.267 0.267 0.267 rg BT 184.493 81.653 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 194.130 80.146 Td /F1 9.8 Tf [(. Then, the total severity was estimated as a normalized mortality impact, based on the )] TJ ET BT 26.250 68.241 Td /F1 9.8 Tf [(correlation between mortality impact and the ILI-based severity measure described above, over the years where both were )] TJ ET BT 26.250 56.337 Td /F1 9.8 Tf [(available \(1997/98-2005/06\) \(using the geometrical mean of the ratio ILI-based severity/mortality impact for 1997/98-2005/06\).)] TJ ET BT 26.250 36.932 Td /F1 9.8 Tf [(The index of speed of spread \()] TJ ET BT 158.489 36.932 Td /F5 9.8 Tf [(I-Sp)] TJ ET BT 176.371 36.932 Td /F1 9.8 Tf [(\) was calculated as the standard deviation of the dates of peak pneumonia and influenza )] TJ ET Q q 15.000 22.646 577.500 754.354 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(between the probability of infection in the 1976 season and the number of years since the previous infection. The above studies )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(suggest that the number of susceptible individuals for a given season, and hence the number of influenza cases, will be strongly )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(correlated with measures of the antigenic distance between prevailing viruses for that season and viruses that circulated in )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(previous seasons.)] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(In light of the compelling evidence for a quantitative relationship between antigenic drift and seasonal severity, it is perhaps )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(surprising that until recently no study demonstrated a positive correlation between drift and severity using data derived directly )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(from influenza surveillance. A recent study by Wu et al. )] TJ ET 0.267 0.267 0.267 rg BT 266.305 690.055 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 275.942 688.548 Td /F1 9.8 Tf [( focuses on influenza H1N1 and considers major antigenic strains )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(based on hemagglutination inhibition \(HI\) assays a method traditionally used by the Centers for Disease Control \(CDC\) to )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(characterize seasonal viruses for vaccine selection and surveillance purposes. Wu et al. then estimate the excess mortality )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(attributable to each antigenic strain using the fraction of isolates positive for that strain among all those tested in seasons in )] TJ ET BT 26.250 640.929 Td /F1 9.8 Tf [(which the strain was detected. This analysis has shown a strong correlation between estimates of the multi-season excess )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(mortality due to an antigenic strain and its antigenic distance from previous strains for H1N1, and a weaker correlation for H3N2. )] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(Given that in recent years, most of the inter-pandemic influenza morbidity was caused by H3N2 viruses )] TJ ET 0.267 0.267 0.267 rg BT 473.297 618.626 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 482.935 617.119 Td /F1 9.8 Tf [(, we were interested )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(in investigating the relationships between sequence and antigenic variation in the H3N2 HA and the seasonal severity \(health )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(burden\) of influenza caused by this subtype. In this analysis, we aimed at reaching beyond correlations and developing a )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(practical model for projecting the health burden of influenza H3N2.)] TJ ET BT 26.250 562.000 Td /F1 9.8 Tf [(Extending previous work on the relationship of antigenic drift and seasonal severity, we here use sequences of hemagglutinin )] TJ ET BT 26.250 550.095 Td /F1 9.8 Tf [(proteins from H3N2 clinical isolates and the corresponding HI data from two countries to demonstrate that one can )] TJ ET BT 521.550 550.095 Td /F5 9.8 Tf [(reconstruct)] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(with surprising accuracy the severity of a given season. That is, given only data on the antigenic novelty of the viruses from a )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(season we can predict its epidemiological severity. Furthermore, our statistical model provides a framework for making )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(projections of the severity of the upcoming season using assumptions based on viral isolates collected in the current season. )] TJ ET BT 26.250 502.476 Td /F1 9.8 Tf [(These results are expected to be helpful in the planning process for the control of seasonal influenza and have implications for )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(influenza surveillance.)] TJ ET BT 26.250 453.969 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 434.015 Td /F4 9.8 Tf [(Epidemiological indices)] TJ ET BT 26.250 414.610 Td /F1 9.8 Tf [(The seasonal impact of influenza on a population is notably difficult to measure precisely due to the non-specificity of symptoms )] TJ ET BT 26.250 402.705 Td /F1 9.8 Tf [(and the lack of diagnostic tests conducted in routine, and morbidity data are especially scarce. To overcome this problem, we )] TJ ET BT 26.250 390.801 Td /F1 9.8 Tf [(used several epidemiological indicators and validated our predictive algorithm by considering two separate countries: the US )] TJ ET BT 26.250 378.896 Td /F1 9.8 Tf [(and Hong Kong. In the US analysis, we used seven independently-collected epidemiological indicators, each representing a )] TJ ET BT 26.250 366.991 Td /F1 9.8 Tf [(slightly different aspect of influenza A/H3 seasonal disease burden. These indicators were available for 16 consecutive seasons )] TJ ET BT 26.250 355.086 Td /F1 9.8 Tf [(from 1993-1994 to 2008-2009 and comprised:)] TJ ET BT 32.206 335.699 Td /F1 9.8 Tf [(1.)] TJ ET BT 45.750 335.682 Td /F1 9.8 Tf [(a seasonal indicator of the dominance of influenza A/H3 over the A/H1 subtype for each season \()] TJ ET BT 464.132 335.682 Td /F6 9.8 Tf [(F-H3)] TJ ET BT 485.797 335.682 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 320.045 Td /F1 9.8 Tf [(2.)] TJ ET BT 45.750 320.027 Td /F1 9.8 Tf [(the seasonal fraction of positive influenza specimens over all respiratory samples tested \()] TJ ET BT 430.485 320.027 Td /F6 9.8 Tf [(F-Pos)] TJ ET BT 457.571 320.027 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 304.390 Td /F1 9.8 Tf [(3.)] TJ ET BT 45.750 304.372 Td /F1 9.8 Tf [(a proxy for the seasonal number of H3 cases, H3 severity \()] TJ ET BT 299.894 304.372 Td /F6 9.8 Tf [(S-H3)] TJ ET BT 322.104 304.372 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 288.735 Td /F1 9.8 Tf [(4.)] TJ ET BT 45.750 288.717 Td /F1 9.8 Tf [(influenza-related seasonal excess mortality rate \()] TJ ET BT 257.618 288.717 Td /F6 9.8 Tf [(R-Mo)] TJ ET BT 281.983 288.717 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 273.080 Td /F1 9.8 Tf [(5.)] TJ ET BT 45.750 273.063 Td /F1 9.8 Tf [(influenza-related seasonal excess hospitalization rate \()] TJ ET BT 282.558 273.063 Td /F6 9.8 Tf [(R-Ho)] TJ ET BT 305.841 273.063 Td /F1 9.8 Tf [(\),)] TJ ET BT 32.206 257.426 Td /F1 9.8 Tf [(6.)] TJ ET BT 45.750 257.408 Td /F1 9.8 Tf [(seasonal percent of Influenza-Like Illnesses \()] TJ ET BT 240.838 257.408 Td /F6 9.8 Tf [(F-ILI)] TJ ET BT 261.420 257.408 Td /F1 9.8 Tf [(\);)] TJ ET BT 32.206 241.771 Td /F1 9.8 Tf [(7.)] TJ ET BT 45.750 241.753 Td /F1 9.8 Tf [(index of speed of spread \()] TJ ET BT 158.480 241.753 Td /F6 9.8 Tf [(I-Sp)] TJ ET BT 176.897 241.753 Td /F1 9.8 Tf [(\))] TJ ET BT 26.250 218.598 Td /F1 9.8 Tf [(Percent of Influenza-Like Illnesses \()] TJ ET BT 180.690 218.598 Td /F5 9.8 Tf [(F-ILI)] TJ ET BT 200.736 218.598 Td /F1 9.8 Tf [(\) was calculated as percent of consultations for influenza-like illness out of the total )] TJ ET BT 26.250 206.694 Td /F1 9.8 Tf [(number of consultations reported to the surveillance system for a given season. Fraction of positive specimens \()] TJ ET BT 508.534 206.694 Td /F5 9.8 Tf [(F-Pos)] TJ ET BT 534.537 206.694 Td /F1 9.8 Tf [(\) was )] TJ ET BT 26.250 194.789 Td /F1 9.8 Tf [(calculated as percent of specimens positive for influenza virus of all specimens collected during the season. \(Data source: CDC )] TJ ET 0.267 0.267 0.267 rg BT 26.250 182.884 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 42.513 182.884 Td /F1 9.8 Tf [(\). An indicator of the dominance of influenza A/H3 over the A/H1 \( )] TJ ET BT 328.110 182.884 Td /F5 9.8 Tf [(F-H3)] TJ ET BT 349.774 182.884 Td /F1 9.8 Tf [(\) was calculated as the logarithm of the ratio of H1 to )] TJ ET BT 26.250 170.979 Td /F1 9.8 Tf [(H3 isolates \(Data source: CDC )] TJ ET 0.267 0.267 0.267 rg BT 162.243 172.487 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 171.880 170.979 Td /F1 9.8 Tf [(\).)] TJ ET BT 26.250 151.575 Td /F1 9.8 Tf [(H3 epidemic severity \()] TJ ET BT 122.687 151.575 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 144.898 151.575 Td /F1 9.8 Tf [(\) was calculated as the product of total influenza epidemic severity and the fraction of H3 isolates )] TJ ET BT 26.250 139.670 Td /F1 9.8 Tf [(among all influenza isolates )] TJ ET 0.267 0.267 0.267 rg BT 148.720 141.177 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 158.357 139.670 Td /F1 9.8 Tf [(. Total epidemic severity was calculated using two sources of data because no available data )] TJ ET BT 26.250 127.765 Td /F1 9.8 Tf [(source covers the entire period of 1993-2008. For the period of 1997/98 2008/09, total epidemic severity was calculated as )] TJ ET BT 26.250 115.860 Td /F5 9.8 Tf [(F-ILI x F-Pos)] TJ ET BT 82.595 115.860 Td /F1 9.8 Tf [( . For the period of 1993/94-1996/97, we first calculated seasonal excess mortality impact \()] TJ ET BT 473.307 115.860 Td /F5 9.8 Tf [(R-Mo)] TJ ET BT 497.136 115.860 Td /F1 9.8 Tf [( , excess death )] TJ ET BT 26.250 103.956 Td /F1 9.8 Tf [(rate from pneumonia and influenza per 100,000\) as in )] TJ ET 0.267 0.267 0.267 rg BT 260.913 105.463 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 270.550 103.956 Td /F1 9.8 Tf [(. Excess mortality is a traditional indicator of influenza disease burden )] TJ ET BT 26.250 92.051 Td /F1 9.8 Tf [(and is estimated from national vital statistics as mortality in excess of an expected seasonal baseline representing the level of )] TJ ET BT 26.250 80.146 Td /F1 9.8 Tf [(mortality in the absence of influenza )] TJ ET 0.267 0.267 0.267 rg BT 184.493 81.653 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 194.130 80.146 Td /F1 9.8 Tf [(. Then, the total severity was estimated as a normalized mortality impact, based on the )] TJ ET BT 26.250 68.241 Td /F1 9.8 Tf [(correlation between mortality impact and the ILI-based severity measure described above, over the years where both were )] TJ ET BT 26.250 56.337 Td /F1 9.8 Tf [(available \(1997/98-2005/06\) \(using the geometrical mean of the ratio ILI-based severity/mortality impact for 1997/98-2005/06\).)] TJ ET BT 26.250 36.932 Td /F1 9.8 Tf [(The index of speed of spread \()] TJ ET BT 158.489 36.932 Td /F5 9.8 Tf [(I-Sp)] TJ ET BT 176.371 36.932 Td /F1 9.8 Tf [(\) was calculated as the standard deviation of the dates of peak pneumonia and influenza )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(2)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 148 0 obj << /Type /Font /Subtype /Type1 /Name /F5 /BaseFont /Helvetica-Oblique /Encoding /WinAnsiEncoding >> endobj 149 0 obj << /Type /Font /Subtype /Type1 /Name 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0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(mortality rates across 49 continental states \(48 states+ DC\) )] TJ ET 0.267 0.267 0.267 rg BT 284.995 768.983 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 294.633 767.476 Td /F1 9.8 Tf [(. This index has been shown to vary with the intensity of influenza )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(epidemics, with larger epidemics spreading faster across the continental US and resulting in a lower index of spread \(lower )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(standard deviation\).)] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(Hospitalization excess rate \()] TJ ET BT 148.164 724.262 Td /F5 9.8 Tf [(R-Ho)] TJ ET BT 170.911 724.262 Td /F1 9.8 Tf [(\) was derived from the State Inpatient databases maintained by the Agency for Healthcare )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Research and Quality. We chose 9 states which contributed data for 1989-2008 and represented 30% of the US population and )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(compiled weekly number of admissions with any mention of pneumonia and influenza in the list of diagnoses. We applied the )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(same method used to estimate excess mortality to hospitalization data and derived estimates of seasonal excess hospitalization )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(rates attributable to influenza in the US.)] TJ ET BT 26.250 657.238 Td /F4 9.8 Tf [(Analysis of epidemiological data)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(Epidemiological data were analyzed using the following protocol. First, visual inspection of scatterplots was performed to ensure )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(the absence of gross deviations from linear relationships between pairs of variables. All data vectors were standardized to an )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(average of 0 and a standard deviation of 1; missing data points were assigned the value of 0. Principal Component Analysis )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(\(PCA\) was performed without further scaling, so variables with more missing data contributed less to the principal components )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(due to reduced variance.)] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(Most of the seven indicators are highly correlated with each other \(e.g. Spearman rank correlation )] TJ ET BT 450.014 570.810 Td /F5 9.8 Tf [(r)] TJ ET BT 453.261 568.745 Td /F1 8.7 Tf [(s)] TJ ET BT 457.594 570.810 Td /F1 9.8 Tf [([ )] TJ ET BT 463.015 570.810 Td /F5 9.8 Tf [(S?H3)] TJ ET BT 487.400 570.810 Td /F1 9.8 Tf [( , )] TJ ET BT 495.532 570.810 Td /F5 9.8 Tf [(F?H3)] TJ ET BT 519.370 570.810 Td /F1 9.8 Tf [( ] = ?0.91 )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(and )] TJ ET BT 45.224 558.905 Td /F5 9.8 Tf [(r)] TJ ET BT 48.470 556.841 Td /F1 8.7 Tf [(s)] TJ ET BT 52.804 558.905 Td /F1 9.8 Tf [([)] TJ ET BT 55.514 558.905 Td /F5 9.8 Tf [(R?Mo)] TJ ET BT 81.517 558.905 Td /F1 9.8 Tf [(, )] TJ ET BT 86.938 558.905 Td /F5 9.8 Tf [(R?Ho)] TJ ET BT 111.859 558.905 Td /F1 9.8 Tf [(] = 0.71\). We used PCA to transform these correlated variables to a space of uncorrelated variables. The )] TJ ET BT 26.250 547.000 Td /F1 9.8 Tf [(first principal component \()] TJ ET BT 137.868 547.000 Td /F5 9.8 Tf [(PC1)] TJ ET BT 156.832 547.000 Td /F1 9.8 Tf [(\) accounted for 66% of the total variance; all original indicators are correlated with )] TJ ET BT 511.235 547.000 Td /F5 9.8 Tf [(PC1)] TJ ET BT 530.198 547.000 Td /F1 9.8 Tf [( with |)] TJ ET BT 555.490 547.000 Td /F5 9.8 Tf [(r)] TJ ET BT 558.737 544.936 Td /F1 8.7 Tf [(s)] TJ ET BT 563.070 547.000 Td /F1 9.8 Tf [(| = )] TJ ET BT 26.250 535.095 Td /F1 9.8 Tf [(0.57 .. 0.94. This variable was used as a single combined epidemiological index \(Figure 1\) for subsequent analyses with genetic )] TJ ET BT 26.250 523.191 Td /F1 9.8 Tf [(and antigenic information.)] TJ ET 0.965 0.965 0.965 rg 26.250 355.905 555.000 157.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 513.310 m 581.250 513.310 l 581.250 512.560 l 26.250 512.560 l f 26.250 355.905 m 581.250 355.905 l 581.250 356.655 l 26.250 356.655 l f q 112.500 0 0 112.500 35.250 391.060 cm /I4 Do Q q 35.250 367.155 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 375.536 Td /F4 9.8 Tf [(Fig. 1: First Principal Component \(epi.PC1\) of seven measures of epidemiological severity)] TJ ET Q BT 26.250 338.881 Td /F4 9.8 Tf [(Genetic distances)] TJ ET BT 26.250 319.476 Td /F1 9.8 Tf [(HA1 sequences of the H3N2 influenza A virus available from the NCBI Influenza Virus Resource )] TJ ET 0.267 0.267 0.267 rg BT 444.047 320.984 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 453.685 319.476 Td /F1 9.8 Tf [( as of June 2009 were used )] TJ ET BT 26.250 307.572 Td /F1 9.8 Tf [(for analysis \(see supplementary files )] TJ ET 0.267 0.267 0.267 rg BT 186.637 309.079 Td /F4 8.7 Tf [(20)] TJ ET BT 196.275 309.079 Td /F4 8.7 Tf [(21)] TJ ET BT 205.912 309.079 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 215.550 307.572 Td /F1 9.8 Tf [( \). All coding region \(CDS\) sequences of human H3N2 isolates \(excluding short )] TJ ET BT 26.250 295.667 Td /F1 9.8 Tf [(fragments\) were downloaded and aligned using the MUSCLE multiple alignment program )] TJ ET 0.267 0.267 0.267 rg BT 413.695 297.174 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 423.333 295.667 Td /F1 9.8 Tf [( with subsequent manual editing of )] TJ ET BT 26.250 283.762 Td /F1 9.8 Tf [(the alignment. Aligned HA1 sequences of H3N2 influenza isolates from the US were sorted by seasons \(from 1992-1993 to )] TJ ET BT 26.250 271.857 Td /F1 9.8 Tf [(2008-2009\). The Northern Hemisphere influenza season was considered to start in August and end in July of the next calendar )] TJ ET BT 26.250 259.953 Td /F1 9.8 Tf [(year. The distance between two seasons was taken to be the mean number of differences between sequences from one )] TJ ET BT 26.250 248.048 Td /F1 9.8 Tf [(season and those of the other season. Such distances were calculated for all pairs of seasons separated by three years or less. )] TJ ET BT 26.250 236.143 Td /F1 9.8 Tf [(This calculation included the comparison of every season to itself, which yields a measure of the within-season diversity. Overall )] TJ ET BT 26.250 224.238 Td /F1 9.8 Tf [(amino acid distances \( )] TJ ET BT 125.954 224.238 Td /F5 9.8 Tf [(sa)] TJ ET BT 136.250 224.238 Td /F1 9.8 Tf [( \), amino acid distances in \( )] TJ ET BT 257.627 224.238 Td /F5 9.8 Tf [(se)] TJ ET BT 267.923 224.238 Td /F1 9.8 Tf [( \) and outside \( )] TJ ET BT 335.666 224.238 Td /F5 9.8 Tf [(sn)] TJ ET BT 345.962 224.238 Td /F1 9.8 Tf [( \) of the commonly used set of presumed antigenic )] TJ ET BT 26.250 212.334 Td /F1 9.8 Tf [(epitope sites )] TJ ET 0.267 0.267 0.267 rg BT 83.697 213.841 Td /F4 8.7 Tf [(24)] TJ ET BT 93.334 213.841 Td /F4 8.7 Tf [(25)] TJ ET 0.271 0.267 0.267 rg BT 102.972 212.334 Td /F1 9.8 Tf [( and nucleotide synonymous \( )] TJ ET BT 235.201 212.334 Td /F5 9.8 Tf [(ss)] TJ ET BT 244.951 212.334 Td /F1 9.8 Tf [( \) distances were computed. For each given season \( )] TJ ET BT 476.884 212.334 Td /F5 9.8 Tf [(n)] TJ ET BT 482.305 212.334 Td /F1 9.8 Tf [( -th\), seven intra- and )] TJ ET BT 26.250 200.429 Td /F1 9.8 Tf [(inter-season distances were calculated \(Figure 2\).)] TJ ET 0.965 0.965 0.965 rg 26.250 72.893 555.000 117.655 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 190.548 m 581.250 190.548 l 581.250 189.798 l 26.250 189.798 l f 26.250 72.893 m 581.250 72.893 l 581.250 73.643 l 26.250 73.643 l f q 225.000 0 0 72.750 35.250 108.048 cm /I6 Do Q q 35.250 84.143 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 92.524 Td /F4 9.8 Tf [(Fig. 2: Computation of inter-season genetic and serological distances)] TJ ET Q BT 26.250 55.869 Td /F1 9.8 Tf [(In combination with the above four types of distances, 28 relative season distance variables were available for each season )] TJ ET BT 26.250 43.965 Td /F1 9.8 Tf [(\(e.g. for the 2005-2006 influenza season )] TJ ET BT 204.022 43.965 Td /F5 9.8 Tf [(se.n)] TJ ET BT 222.449 43.965 Td /F1 9.8 Tf [(1.)] TJ ET BT 230.581 43.965 Td /F5 9.8 Tf [(n)] TJ ET BT 236.002 43.965 Td /F1 9.8 Tf [(1 refers to the average epitope sequence differences in the season of 2004-)] TJ ET Q q 15.000 29.679 577.500 747.321 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(mortality rates across 49 continental states \(48 states+ DC\) )] TJ ET 0.267 0.267 0.267 rg BT 284.995 768.983 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 294.633 767.476 Td /F1 9.8 Tf [(. This index has been shown to vary with the intensity of influenza )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(epidemics, with larger epidemics spreading faster across the continental US and resulting in a lower index of spread \(lower )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(standard deviation\).)] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(Hospitalization excess rate \()] TJ ET BT 148.164 724.262 Td /F5 9.8 Tf [(R-Ho)] TJ ET BT 170.911 724.262 Td /F1 9.8 Tf [(\) was derived from the State Inpatient databases maintained by the Agency for Healthcare )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Research and Quality. We chose 9 states which contributed data for 1989-2008 and represented 30% of the US population and )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(compiled weekly number of admissions with any mention of pneumonia and influenza in the list of diagnoses. We applied the )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(same method used to estimate excess mortality to hospitalization data and derived estimates of seasonal excess hospitalization )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(rates attributable to influenza in the US.)] TJ ET BT 26.250 657.238 Td /F4 9.8 Tf [(Analysis of epidemiological data)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(Epidemiological data were analyzed using the following protocol. First, visual inspection of scatterplots was performed to ensure )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(the absence of gross deviations from linear relationships between pairs of variables. All data vectors were standardized to an )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(average of 0 and a standard deviation of 1; missing data points were assigned the value of 0. Principal Component Analysis )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(\(PCA\) was performed without further scaling, so variables with more missing data contributed less to the principal components )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(due to reduced variance.)] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(Most of the seven indicators are highly correlated with each other \(e.g. Spearman rank correlation )] TJ ET BT 450.014 570.810 Td /F5 9.8 Tf [(r)] TJ ET BT 453.261 568.745 Td /F1 8.7 Tf [(s)] TJ ET BT 457.594 570.810 Td /F1 9.8 Tf [([ )] TJ ET BT 463.015 570.810 Td /F5 9.8 Tf [(S?H3)] TJ ET BT 487.400 570.810 Td /F1 9.8 Tf [( , )] TJ ET BT 495.532 570.810 Td /F5 9.8 Tf [(F?H3)] TJ ET BT 519.370 570.810 Td /F1 9.8 Tf [( ] = ?0.91 )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(and )] TJ ET BT 45.224 558.905 Td /F5 9.8 Tf [(r)] TJ ET BT 48.470 556.841 Td /F1 8.7 Tf [(s)] TJ ET BT 52.804 558.905 Td /F1 9.8 Tf [([)] TJ ET BT 55.514 558.905 Td /F5 9.8 Tf [(R?Mo)] TJ ET BT 81.517 558.905 Td /F1 9.8 Tf [(, )] TJ ET BT 86.938 558.905 Td /F5 9.8 Tf [(R?Ho)] TJ ET BT 111.859 558.905 Td /F1 9.8 Tf [(] = 0.71\). We used PCA to transform these correlated variables to a space of uncorrelated variables. The )] TJ ET BT 26.250 547.000 Td /F1 9.8 Tf [(first principal component \()] TJ ET BT 137.868 547.000 Td /F5 9.8 Tf [(PC1)] TJ ET BT 156.832 547.000 Td /F1 9.8 Tf [(\) accounted for 66% of the total variance; all original indicators are correlated with )] TJ ET BT 511.235 547.000 Td /F5 9.8 Tf [(PC1)] TJ ET BT 530.198 547.000 Td /F1 9.8 Tf [( with |)] TJ ET BT 555.490 547.000 Td /F5 9.8 Tf [(r)] TJ ET BT 558.737 544.936 Td /F1 8.7 Tf [(s)] TJ ET BT 563.070 547.000 Td /F1 9.8 Tf [(| = )] TJ ET BT 26.250 535.095 Td /F1 9.8 Tf [(0.57 .. 0.94. This variable was used as a single combined epidemiological index \(Figure 1\) for subsequent analyses with genetic )] TJ ET BT 26.250 523.191 Td /F1 9.8 Tf [(and antigenic information.)] TJ ET 0.965 0.965 0.965 rg 26.250 355.905 555.000 157.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 513.310 m 581.250 513.310 l 581.250 512.560 l 26.250 512.560 l f 26.250 355.905 m 581.250 355.905 l 581.250 356.655 l 26.250 356.655 l f q 112.500 0 0 112.500 35.250 391.060 cm /I8 Do Q q 35.250 367.155 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 375.536 Td /F4 9.8 Tf [(Fig. 1: First Principal Component \(epi.PC1\) of seven measures of epidemiological severity)] TJ ET Q BT 26.250 338.881 Td /F4 9.8 Tf [(Genetic distances)] TJ ET BT 26.250 319.476 Td /F1 9.8 Tf [(HA1 sequences of the H3N2 influenza A virus available from the NCBI Influenza Virus Resource )] TJ ET 0.267 0.267 0.267 rg BT 444.047 320.984 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 453.685 319.476 Td /F1 9.8 Tf [( as of June 2009 were used )] TJ ET BT 26.250 307.572 Td /F1 9.8 Tf [(for analysis \(see supplementary files )] TJ ET 0.267 0.267 0.267 rg BT 186.637 309.079 Td /F4 8.7 Tf [(20)] TJ ET BT 196.275 309.079 Td /F4 8.7 Tf [(21)] TJ ET BT 205.912 309.079 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 215.550 307.572 Td /F1 9.8 Tf [( \). All coding region \(CDS\) sequences of human H3N2 isolates \(excluding short )] TJ ET BT 26.250 295.667 Td /F1 9.8 Tf [(fragments\) were downloaded and aligned using the MUSCLE multiple alignment program )] TJ ET 0.267 0.267 0.267 rg BT 413.695 297.174 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 423.333 295.667 Td /F1 9.8 Tf [( with subsequent manual editing of )] TJ ET BT 26.250 283.762 Td /F1 9.8 Tf [(the alignment. Aligned HA1 sequences of H3N2 influenza isolates from the US were sorted by seasons \(from 1992-1993 to )] TJ ET BT 26.250 271.857 Td /F1 9.8 Tf [(2008-2009\). The Northern Hemisphere influenza season was considered to start in August and end in July of the next calendar )] TJ ET BT 26.250 259.953 Td /F1 9.8 Tf [(year. The distance between two seasons was taken to be the mean number of differences between sequences from one )] TJ ET BT 26.250 248.048 Td /F1 9.8 Tf [(season and those of the other season. Such distances were calculated for all pairs of seasons separated by three years or less. )] TJ ET BT 26.250 236.143 Td /F1 9.8 Tf [(This calculation included the comparison of every season to itself, which yields a measure of the within-season diversity. Overall )] TJ ET BT 26.250 224.238 Td /F1 9.8 Tf [(amino acid distances \( )] TJ ET BT 125.954 224.238 Td /F5 9.8 Tf [(sa)] TJ ET BT 136.250 224.238 Td /F1 9.8 Tf [( \), amino acid distances in \( )] TJ ET BT 257.627 224.238 Td /F5 9.8 Tf [(se)] TJ ET BT 267.923 224.238 Td /F1 9.8 Tf [( \) and outside \( )] TJ ET BT 335.666 224.238 Td /F5 9.8 Tf [(sn)] TJ ET BT 345.962 224.238 Td /F1 9.8 Tf [( \) of the commonly used set of presumed antigenic )] TJ ET BT 26.250 212.334 Td /F1 9.8 Tf [(epitope sites )] TJ ET 0.267 0.267 0.267 rg BT 83.697 213.841 Td /F4 8.7 Tf [(24)] TJ ET BT 93.334 213.841 Td /F4 8.7 Tf [(25)] TJ ET 0.271 0.267 0.267 rg BT 102.972 212.334 Td /F1 9.8 Tf [( and nucleotide synonymous \( )] TJ ET BT 235.201 212.334 Td /F5 9.8 Tf [(ss)] TJ ET BT 244.951 212.334 Td /F1 9.8 Tf [( \) distances were computed. For each given season \( )] TJ ET BT 476.884 212.334 Td /F5 9.8 Tf [(n)] TJ ET BT 482.305 212.334 Td /F1 9.8 Tf [( -th\), seven intra- and )] TJ ET BT 26.250 200.429 Td /F1 9.8 Tf [(inter-season distances were calculated \(Figure 2\).)] TJ ET 0.965 0.965 0.965 rg 26.250 72.893 555.000 117.655 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 190.548 m 581.250 190.548 l 581.250 189.798 l 26.250 189.798 l f 26.250 72.893 m 581.250 72.893 l 581.250 73.643 l 26.250 73.643 l f q 225.000 0 0 72.750 35.250 108.048 cm /I10 Do Q q 35.250 84.143 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 92.524 Td /F4 9.8 Tf [(Fig. 2: Computation of inter-season genetic and serological distances)] TJ ET Q BT 26.250 55.869 Td /F1 9.8 Tf [(In combination with the above four types of distances, 28 relative season distance variables were available for each season )] TJ ET BT 26.250 43.965 Td /F1 9.8 Tf [(\(e.g. for the 2005-2006 influenza season )] TJ ET BT 204.022 43.965 Td /F5 9.8 Tf [(se.n)] TJ ET BT 222.449 43.965 Td /F1 9.8 Tf [(1.)] TJ ET BT 230.581 43.965 Td /F5 9.8 Tf [(n)] TJ ET BT 236.002 43.965 Td /F1 9.8 Tf [(1 refers to the average epitope sequence differences in the season of 2004-)] TJ ET Q q 15.000 29.679 577.500 747.321 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(mortality rates across 49 continental states \(48 states+ DC\) )] TJ ET 0.267 0.267 0.267 rg BT 284.995 768.983 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 294.633 767.476 Td /F1 9.8 Tf [(. This index has been shown to vary with the intensity of influenza )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(epidemics, with larger epidemics spreading faster across the continental US and resulting in a lower index of spread \(lower )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(standard deviation\).)] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(Hospitalization excess rate \()] TJ ET BT 148.164 724.262 Td /F5 9.8 Tf [(R-Ho)] TJ ET BT 170.911 724.262 Td /F1 9.8 Tf [(\) was derived from the State Inpatient databases maintained by the Agency for Healthcare )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Research and Quality. We chose 9 states which contributed data for 1989-2008 and represented 30% of the US population and )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(compiled weekly number of admissions with any mention of pneumonia and influenza in the list of diagnoses. We applied the )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(same method used to estimate excess mortality to hospitalization data and derived estimates of seasonal excess hospitalization )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(rates attributable to influenza in the US.)] TJ ET BT 26.250 657.238 Td /F4 9.8 Tf [(Analysis of epidemiological data)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(Epidemiological data were analyzed using the following protocol. First, visual inspection of scatterplots was performed to ensure )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(the absence of gross deviations from linear relationships between pairs of variables. All data vectors were standardized to an )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(average of 0 and a standard deviation of 1; missing data points were assigned the value of 0. Principal Component Analysis )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(\(PCA\) was performed without further scaling, so variables with more missing data contributed less to the principal components )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(due to reduced variance.)] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(Most of the seven indicators are highly correlated with each other \(e.g. Spearman rank correlation )] TJ ET BT 450.014 570.810 Td /F5 9.8 Tf [(r)] TJ ET BT 453.261 568.745 Td /F1 8.7 Tf [(s)] TJ ET BT 457.594 570.810 Td /F1 9.8 Tf [([ )] TJ ET BT 463.015 570.810 Td /F5 9.8 Tf [(S?H3)] TJ ET BT 487.400 570.810 Td /F1 9.8 Tf [( , )] TJ ET BT 495.532 570.810 Td /F5 9.8 Tf [(F?H3)] TJ ET BT 519.370 570.810 Td /F1 9.8 Tf [( ] = ?0.91 )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(and )] TJ ET BT 45.224 558.905 Td /F5 9.8 Tf [(r)] TJ ET BT 48.470 556.841 Td /F1 8.7 Tf [(s)] TJ ET BT 52.804 558.905 Td /F1 9.8 Tf [([)] TJ ET BT 55.514 558.905 Td /F5 9.8 Tf [(R?Mo)] TJ ET BT 81.517 558.905 Td /F1 9.8 Tf [(, )] TJ ET BT 86.938 558.905 Td /F5 9.8 Tf [(R?Ho)] TJ ET BT 111.859 558.905 Td /F1 9.8 Tf [(] = 0.71\). We used PCA to transform these correlated variables to a space of uncorrelated variables. The )] TJ ET BT 26.250 547.000 Td /F1 9.8 Tf [(first principal component \()] TJ ET BT 137.868 547.000 Td /F5 9.8 Tf [(PC1)] TJ ET BT 156.832 547.000 Td /F1 9.8 Tf [(\) accounted for 66% of the total variance; all original indicators are correlated with )] TJ ET BT 511.235 547.000 Td /F5 9.8 Tf [(PC1)] TJ ET BT 530.198 547.000 Td /F1 9.8 Tf [( with |)] TJ ET BT 555.490 547.000 Td /F5 9.8 Tf [(r)] TJ ET BT 558.737 544.936 Td /F1 8.7 Tf [(s)] TJ ET BT 563.070 547.000 Td /F1 9.8 Tf [(| = )] TJ ET BT 26.250 535.095 Td /F1 9.8 Tf [(0.57 .. 0.94. This variable was used as a single combined epidemiological index \(Figure 1\) for subsequent analyses with genetic )] TJ ET BT 26.250 523.191 Td /F1 9.8 Tf [(and antigenic information.)] TJ ET 0.965 0.965 0.965 rg 26.250 355.905 555.000 157.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 513.310 m 581.250 513.310 l 581.250 512.560 l 26.250 512.560 l f 26.250 355.905 m 581.250 355.905 l 581.250 356.655 l 26.250 356.655 l f q 112.500 0 0 112.500 35.250 391.060 cm /I12 Do Q q 35.250 367.155 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 375.536 Td /F4 9.8 Tf [(Fig. 1: First Principal Component \(epi.PC1\) of seven measures of epidemiological severity)] TJ ET Q BT 26.250 338.881 Td /F4 9.8 Tf [(Genetic distances)] TJ ET BT 26.250 319.476 Td /F1 9.8 Tf [(HA1 sequences of the H3N2 influenza A virus available from the NCBI Influenza Virus Resource )] TJ ET 0.267 0.267 0.267 rg BT 444.047 320.984 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 453.685 319.476 Td /F1 9.8 Tf [( as of June 2009 were used )] TJ ET BT 26.250 307.572 Td /F1 9.8 Tf [(for analysis \(see supplementary files )] TJ ET 0.267 0.267 0.267 rg BT 186.637 309.079 Td /F4 8.7 Tf [(20)] TJ ET BT 196.275 309.079 Td /F4 8.7 Tf [(21)] TJ ET BT 205.912 309.079 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 215.550 307.572 Td /F1 9.8 Tf [( \). All coding region \(CDS\) sequences of human H3N2 isolates \(excluding short )] TJ ET BT 26.250 295.667 Td /F1 9.8 Tf [(fragments\) were downloaded and aligned using the MUSCLE multiple alignment program )] TJ ET 0.267 0.267 0.267 rg BT 413.695 297.174 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 423.333 295.667 Td /F1 9.8 Tf [( with subsequent manual editing of )] TJ ET BT 26.250 283.762 Td /F1 9.8 Tf [(the alignment. Aligned HA1 sequences of H3N2 influenza isolates from the US were sorted by seasons \(from 1992-1993 to )] TJ ET BT 26.250 271.857 Td /F1 9.8 Tf [(2008-2009\). The Northern Hemisphere influenza season was considered to start in August and end in July of the next calendar )] TJ ET BT 26.250 259.953 Td /F1 9.8 Tf [(year. The distance between two seasons was taken to be the mean number of differences between sequences from one )] TJ ET BT 26.250 248.048 Td /F1 9.8 Tf [(season and those of the other season. Such distances were calculated for all pairs of seasons separated by three years or less. )] TJ ET BT 26.250 236.143 Td /F1 9.8 Tf [(This calculation included the comparison of every season to itself, which yields a measure of the within-season diversity. Overall )] TJ ET BT 26.250 224.238 Td /F1 9.8 Tf [(amino acid distances \( )] TJ ET BT 125.954 224.238 Td /F5 9.8 Tf [(sa)] TJ ET BT 136.250 224.238 Td /F1 9.8 Tf [( \), amino acid distances in \( )] TJ ET BT 257.627 224.238 Td /F5 9.8 Tf [(se)] TJ ET BT 267.923 224.238 Td /F1 9.8 Tf [( \) and outside \( )] TJ ET BT 335.666 224.238 Td /F5 9.8 Tf [(sn)] TJ ET BT 345.962 224.238 Td /F1 9.8 Tf [( \) of the commonly used set of presumed antigenic )] TJ ET BT 26.250 212.334 Td /F1 9.8 Tf [(epitope sites )] TJ ET 0.267 0.267 0.267 rg BT 83.697 213.841 Td /F4 8.7 Tf [(24)] TJ ET BT 93.334 213.841 Td /F4 8.7 Tf [(25)] TJ ET 0.271 0.267 0.267 rg BT 102.972 212.334 Td /F1 9.8 Tf [( and nucleotide synonymous \( )] TJ ET BT 235.201 212.334 Td /F5 9.8 Tf [(ss)] TJ ET BT 244.951 212.334 Td /F1 9.8 Tf [( \) distances were computed. For each given season \( )] TJ ET BT 476.884 212.334 Td /F5 9.8 Tf [(n)] TJ ET BT 482.305 212.334 Td /F1 9.8 Tf [( -th\), seven intra- and )] TJ ET BT 26.250 200.429 Td /F1 9.8 Tf [(inter-season distances were calculated \(Figure 2\).)] TJ ET 0.965 0.965 0.965 rg 26.250 72.893 555.000 117.655 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 190.548 m 581.250 190.548 l 581.250 189.798 l 26.250 189.798 l f 26.250 72.893 m 581.250 72.893 l 581.250 73.643 l 26.250 73.643 l f q 225.000 0 0 72.750 35.250 108.048 cm /I14 Do Q q 35.250 84.143 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 92.524 Td /F4 9.8 Tf [(Fig. 2: Computation of inter-season genetic and serological distances)] TJ ET Q BT 26.250 55.869 Td /F1 9.8 Tf [(In combination with the above four types of distances, 28 relative season distance variables were available for each season )] TJ ET BT 26.250 43.965 Td /F1 9.8 Tf [(\(e.g. for the 2005-2006 influenza season )] TJ ET BT 204.022 43.965 Td /F5 9.8 Tf [(se.n)] TJ ET BT 222.449 43.965 Td /F1 9.8 Tf [(1.)] TJ ET BT 230.581 43.965 Td /F5 9.8 Tf [(n)] TJ ET BT 236.002 43.965 Td /F1 9.8 Tf [(1 refers to the average epitope sequence differences in the season of 2004-)] TJ ET Q q 112.500 0 0 112.500 35.250 391.060 cm /I16 Do Q q 225.000 0 0 72.750 35.250 108.048 cm /I18 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(3)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 194 0 obj << /Type /Annot /Subtype /Link /A 195 0 R /Border [0 0 0] /H /I /Rect [ 284.9955 768.1817 294.6328 777.0000 ] >> endobj 195 0 obj << /Type /Action >> endobj 196 0 obj << /Type /Annot /Subtype /Link /A 197 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 391.0597 147.7500 503.5597 ] >> endobj 197 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2010/12/figurespage01.png) >> endobj 198 0 obj << /Type /XObject /Subtype /Image /Width 150 /Height 150 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 150 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 162>> stream x1 aK&> 2K:%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%jZ%j _9R endstream endobj 199 0 obj << /Type /XObject /Subtype /Image /Width 150 /Height 150 /SMask 198 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 150 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 12835>> stream xix[י..}'. 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Dw.))axÇ駟TvȐ!7nܐ ^Y pfbgg'w-_\fxTiv֬Y8Kͧ`T,h8jԨP@u~R*g"""""" tdOGttҥ8;;KH<G'NA STo=bfϛ7OAyhK;uTղzΔdr (u=01~|DEZTzˋY{AMl㶫fRY0[{޹a dnSrƍ;l0e(iYWMaCF455al`bbԤԧc(477K$كMee%z9pD"Arrrr'3JejOrwwЙ8q'O4Ub]\\P?;;; wwwIKH7tO &˗/?|t cJKKomm-OZ,T+Bӧ0tV\yi 2 Ɔ1cǎ "ӧO\C!,,:,`Yt ax̙)))::a=zhԩҧRꅴ3f`0<{TM(J ɓ'@RSSgϞݭ3k*ؑѣG2V\dd2߿g>x"{ kmmECt\>tpp@ϠPNNNwH*$r!!!SDy߾}!!!5w:99RlÇejkkkXX޽{UV"BR}}}ׯ__]]x*/^trr:y⩎?pU4Bٰa⻧t__ߵkVVVjնNttt\z~S`*bnK,A]A+W$''XѣG`цiӦm޼{ EQD"ǃ AWW#GL>]|o߾|򉚙p\vc;w޽{W^OAX,.0 ϙ3'==]0 8q 466F PVebbヂIua{{{y N633SƄXmӧOA)F͑ +++^ fȑL&C m^pAKfh$Bޮ v\,X15dW@Qn 6oܧOSSS ݻF9R!ft~~~JecdccW_ҔQ4>N&'N -qيۍںfգP$ HRʡ:l6;w_>,, l+.vPWxps$|W`[l T$õkמ;wNN||/ZPw: G???MI$8^:P$ݺukΝ.]bX+VȠ奤DEEܹsʕ+:?644433SfTaaajjjddd]]ijjJMMݼyÇI$ƍ׬Y#3- ӧO'HpYf{K (FBA@@@ZZFnqAY~אPf͚D 2g_K+ZÇׯ_?a L&UhiiquuP`JpuuEO򐎊JIIwrݨ(>l2n:9'&&Ya&Hl6[Nkkݻw6+@]#K]zB0?|y:\.wʔ)hٳgU@ ΪU9x?p6n 4@ | ?gt Է鵵R֭azz)Sб 2:b8<<ȑ#l=G=!,,,RSStT' ^wP@vڹs碞25 É>.n޼8ɌQDEEwסX,y󦃃C\\VPrss]222dH$/0J k׮9;;Zd{(**;w… ={&S&22=>>Jbg+}{gsܹ3fǃyV)..ꫯYŋ%I||<8ǎӶ% ##cݺuΛ6m" ۿ?ѶaͼW5kcǎ577CF%%%yxxر#//O$iӧO_9=$ؾ}; ֭G=s Y,Vrr'M>vUwww?uc,`~H<*x644\p!99qʕ3fPFЁ3.ǻ{nffǏ?3"hjj"bccmVYYYRRo߾`[:::Be˖ &h^~Ӭ,4dȐ 0G`\rҥKamU7+0ɓ3gΐdPOOO|̪3`h999yԩǏW#I0X:"Ž'C&o߾zjkk%K1Vq ߸q7$${joii)(((-----}՛7o򌭭%FBԔpܑ#GDkkka0)))iiig޼yK,QdU MH46>ȸ, SSSmllƏ"P2hkk[nݠALLL9h4ZEEEeeeMM Ba2Lsss [[;lA;пΔ C |:LfSSSSSSee7oMMMx[̺IhooYzzϟ` 7|gvvvӋ!H'O4hЛ7oFAmllSYYDR nj l[@YYY@5jzTuQ=V]]][[vP8zh<<---G9z0 Bijjh---3f* ˞3*-  lp$ fnnnnn>zhSSq 2DM]5 NH$,2LVP) :[YYr|P"H"P(Ĺ\n]]a"NӇf1 @)c 5550 WUUVr"6/ c`r~lll> endobj 271 0 obj << /Length 31604 >> stream 0.271 0.267 0.267 rg q 15.000 22.381 577.500 754.619 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(2005 and )] TJ ET BT 69.618 767.476 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 87.499 767.476 Td /F1 9.8 Tf [(.)] TJ ET BT 90.210 767.476 Td /F5 9.8 Tf [(n)] TJ ET BT 95.631 767.476 Td /F1 9.8 Tf [(2 is the average synonymous distance between all pairs of isolates from 2005-2006 and 2003-2004 seasons\).)] TJ ET BT 26.250 748.071 Td /F4 9.8 Tf [(Serological distances)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(We compiled hemagglutinin inhibition data from a variety of literature sources, including published articles, MMWR summaries, )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(and FDA reports \(see supplementary file for references )] TJ ET 0.267 0.267 0.267 rg BT 266.841 718.269 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 276.478 716.762 Td /F1 9.8 Tf [(\). A two-dimensional antigenic map was calculated from )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(hemagglutinin inhibition data according to )] TJ ET 0.267 0.267 0.267 rg BT 208.341 706.364 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 217.978 704.857 Td /F1 9.8 Tf [(. From this, antigenic distances were calculated for all pairs of isolates. Mean intra- )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(and inter-season pairwise distances were then calculated for North America \()] TJ ET BT 358.413 692.952 Td /F5 9.8 Tf [(aa)] TJ ET BT 369.255 692.952 Td /F1 9.8 Tf [(\) and Northern Hemisphere \()] TJ ET BT 493.334 692.952 Td /F5 9.8 Tf [(an)] TJ ET BT 504.175 692.952 Td /F1 9.8 Tf [(\) isolates, )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(corresponding to all of the types of distances calculated for sequence data \(Figure 2\) except that the )] TJ ET BT 460.895 681.048 Td /F5 9.8 Tf [(n)] TJ ET BT 466.316 681.048 Td /F1 9.8 Tf [(.)] TJ ET BT 469.027 681.048 Td /F5 9.8 Tf [(n)] TJ ET BT 474.448 681.048 Td /F1 9.8 Tf [( 3 distances were )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(omitted. In combination with the above two sources of the isolates, 12 relative season distance variables were available for each )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(season.)] TJ ET BT 26.250 637.833 Td /F4 9.8 Tf [(Model selection)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(Overall, we had 40 explanatory variables, comprising 7*4=28 genetic variables and 6*2=12 serological distance variables, and )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(only 16 epidemiological observations. Due to the potential for severe overfitting, the standard approach of stepwise reduction of )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(a model containing all variables was not feasible. Instead we adopted a two-stage approach to find the optimal balance between )] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(the goodness of fit and the number of degrees of freedom in the model. At the first stage we used a transformation of the )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(original distance variables to determine which of them contributed most to the prediction of the epidemiological variable; at the )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(second stage we applied this information to select the most statistically robust predictors using the original variables.)] TJ ET BT 26.250 539.500 Td /F4 9.8 Tf [(Transformation of distance variables)] TJ ET BT 26.250 520.095 Td /F1 9.8 Tf [(For each relative season, combination the data from different variables \()] TJ ET BT 336.758 520.095 Td /F5 9.8 Tf [(sa)] TJ ET BT 347.054 520.095 Td /F1 9.8 Tf [(, )] TJ ET BT 352.475 520.095 Td /F5 9.8 Tf [(se)] TJ ET BT 362.771 520.095 Td /F1 9.8 Tf [(, )] TJ ET BT 368.192 520.095 Td /F5 9.8 Tf [(sn)] TJ ET BT 378.488 520.095 Td /F1 9.8 Tf [( and )] TJ ET BT 400.172 520.095 Td /F5 9.8 Tf [(ss)] TJ ET BT 409.922 520.095 Td /F1 9.8 Tf [( for genetic and )] TJ ET BT 479.839 520.095 Td /F5 9.8 Tf [(aa)] TJ ET BT 490.681 520.095 Td /F1 9.8 Tf [( and )] TJ ET BT 512.365 520.095 Td /F5 9.8 Tf [(an)] TJ ET BT 523.207 520.095 Td /F1 9.8 Tf [( for )] TJ ET BT 26.250 508.191 Td /F1 9.8 Tf [(serological data\) are strongly correlated \(e.g. )] TJ ET BT 222.410 508.191 Td /F5 9.8 Tf [(r)] TJ ET BT 225.657 506.126 Td /F1 8.7 Tf [(s)] TJ ET BT 229.990 508.191 Td /F1 9.8 Tf [([)] TJ ET BT 232.701 508.191 Td /F5 9.8 Tf [(sa.n)] TJ ET BT 251.128 508.191 Td /F1 9.8 Tf [(.)] TJ ET BT 253.839 508.191 Td /F5 9.8 Tf [(n)] TJ ET BT 259.260 508.191 Td /F1 9.8 Tf [(1, )] TJ ET BT 270.102 508.191 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 287.983 508.191 Td /F1 9.8 Tf [(.)] TJ ET BT 290.694 508.191 Td /F5 9.8 Tf [(n)] TJ ET BT 296.115 508.191 Td /F1 9.8 Tf [(1] = 0.74\). Thus each of the 28 genetic variables and 12 )] TJ ET BT 26.250 496.286 Td /F1 9.8 Tf [(serological distance variables were subject to PCA \(Figure 3\). The first 2 principal components were retained for each data )] TJ ET BT 26.250 484.381 Td /F1 9.8 Tf [(series, reducing the number of potential explanatory variables from 40 to 26.)] TJ ET 0.965 0.965 0.965 rg 26.250 368.096 555.000 106.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 474.500 m 581.250 474.500 l 581.250 473.750 l 26.250 473.750 l f 26.250 368.096 m 581.250 368.096 l 581.250 368.846 l 26.250 368.846 l f q 225.000 0 0 61.500 35.250 403.250 cm /I20 Do Q q 35.250 379.346 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 387.726 Td /F4 9.8 Tf [(Fig. 3: Principal Component Analysis \(PCA\) of genetic and serological distance variables)] TJ ET Q BT 26.250 351.072 Td /F4 9.8 Tf [(Retrospective model: first stage)] TJ ET BT 26.250 331.667 Td /F1 9.8 Tf [(We tested linear models containing all combinations of 3 \(2600 models\), 4 \(14950 models\), 5 \(65780 models\) and 6 \(230230 )] TJ ET BT 26.250 319.762 Td /F1 9.8 Tf [(models\) variables. Model fitting was performed on the R platform using the )] TJ ET BT 350.291 319.762 Td /F5 9.8 Tf [(lm)] TJ ET BT 360.577 319.762 Td /F1 9.8 Tf [(\(\) function. Within each class the models were )] TJ ET BT 26.250 307.857 Td /F1 9.8 Tf [(ranked by decreasing residual sum of squares. Additionally, 19 variables most frequently present among the top 50 6-variable )] TJ ET BT 26.250 295.953 Td /F1 9.8 Tf [(models were used to generate all combinations of 7 \(50388 models\) and 8 \(75582 models\) variables; 7- and 8-variable models )] TJ ET BT 26.250 284.048 Td /F1 9.8 Tf [(were ranked in the same manner.)] TJ ET BT 26.250 264.643 Td /F1 9.8 Tf [(To test the models statistically, we used two variants of a jackknife resampling procedure )] TJ ET 0.267 0.267 0.267 rg BT 412.067 266.150 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 421.705 264.643 Td /F1 9.8 Tf [(. The first variant tests the statistical )] TJ ET BT 26.250 252.738 Td /F1 9.8 Tf [(robustness of the relationships between the explanatory variables and the target variable in general. The second tests the )] TJ ET BT 26.250 240.834 Td /F1 9.8 Tf [(statistical robustness of a model using a particular set of explanatory variables.)] TJ ET BT 26.250 221.429 Td /F1 9.8 Tf [(In the first variant we removed data for each single season from our dataset one-by-one and used the remaining 15 seasons to )] TJ ET BT 26.250 209.524 Td /F1 9.8 Tf [(find the best-fitting model \(both the set of the explanatory variables and coefficients\). Then we used this model to predict the )] TJ ET BT 26.250 197.619 Td /F1 9.8 Tf [(epidemiology for the remaining season \(leave-one-out jackknife scheme\). The sum of squares of the deviations of these )] TJ ET BT 26.250 185.715 Td /F1 9.8 Tf [(predictions from the observations was accumulated over all 16 seasons to serve as the robustness indicator.)] TJ ET BT 26.250 166.310 Td /F1 9.8 Tf [(In the second variant we generated all possible bipartitions of the 16 epidemiological observations into two classes of equal )] TJ ET BT 26.250 154.405 Td /F1 9.8 Tf [(size. With each bipartition, one half of the seasons data was used to train the model using the fixed set of the explanatory )] TJ ET BT 26.250 142.500 Td /F1 9.8 Tf [(variables; then these model coefficients were used to predict the epidemiology for the remaining 8 seasons \(leave-half-out )] TJ ET BT 26.250 130.596 Td /F1 9.8 Tf [(jackknife scheme\). The residual sums of squares for the control half of the data were accumulated over all bipartitions to serve )] TJ ET BT 26.250 118.691 Td /F1 9.8 Tf [(as the indicator of the model robustness. We tested the top 10 models from each class and ranked them by decreasing total )] TJ ET BT 26.250 106.786 Td /F1 9.8 Tf [(residual sum of squares.)] TJ ET BT 26.250 87.381 Td /F1 9.8 Tf [(In the leave-one-out jackknife test the 5-variable model family demonstrates a highly robust behavior, accounting for 0.96 of the )] TJ ET BT 26.250 75.477 Td /F1 9.8 Tf [(of the variance in )] TJ ET BT 103.207 75.477 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 132.466 75.477 Td /F1 9.8 Tf [( 1. The following 5-variable model demonstrated the best performance among all tested models:)] TJ ET BT 26.250 56.072 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 56.072 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 56.072 Td /F5 9.8 Tf [(n.n)] TJ ET BT 90.473 56.072 Td /F1 9.8 Tf [(2.)] TJ ET BT 98.605 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 112.147 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 131.394 56.072 Td /F5 9.8 Tf [(n.n)] TJ ET BT 144.946 56.072 Td /F1 9.8 Tf [(2.)] TJ ET BT 153.078 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 166.621 56.072 Td /F1 9.8 Tf [( 2 + )] TJ ET BT 185.867 56.072 Td /F5 9.8 Tf [(n)] TJ ET BT 191.288 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 196.709 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 204.841 56.072 Td /F1 9.8 Tf [(1. )] TJ ET BT 215.683 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 229.225 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 248.472 56.072 Td /F5 9.8 Tf [(a.n)] TJ ET BT 262.024 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 267.445 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 275.577 56.072 Td /F1 9.8 Tf [(1.)] TJ ET BT 283.708 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 297.251 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 316.498 56.072 Td /F5 9.8 Tf [(a.n)] TJ ET BT 330.050 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 335.471 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 343.603 56.072 Td /F1 9.8 Tf [(1.)] TJ ET BT 351.734 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 365.277 56.072 Td /F1 9.8 Tf [( 2 + 0)] TJ ET BT 26.250 36.667 Td /F1 9.8 Tf [(Hence this model includes genetic distance between the current season and 2 seasons before, and intra-season genetic and )] TJ ET Q q 15.000 22.381 577.500 754.619 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(2005 and )] TJ ET BT 69.618 767.476 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 87.499 767.476 Td /F1 9.8 Tf [(.)] TJ ET BT 90.210 767.476 Td /F5 9.8 Tf [(n)] TJ ET BT 95.631 767.476 Td /F1 9.8 Tf [(2 is the average synonymous distance between all pairs of isolates from 2005-2006 and 2003-2004 seasons\).)] TJ ET BT 26.250 748.071 Td /F4 9.8 Tf [(Serological distances)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(We compiled hemagglutinin inhibition data from a variety of literature sources, including published articles, MMWR summaries, )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(and FDA reports \(see supplementary file for references )] TJ ET 0.267 0.267 0.267 rg BT 266.841 718.269 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 276.478 716.762 Td /F1 9.8 Tf [(\). A two-dimensional antigenic map was calculated from )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(hemagglutinin inhibition data according to )] TJ ET 0.267 0.267 0.267 rg BT 208.341 706.364 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 217.978 704.857 Td /F1 9.8 Tf [(. From this, antigenic distances were calculated for all pairs of isolates. Mean intra- )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(and inter-season pairwise distances were then calculated for North America \()] TJ ET BT 358.413 692.952 Td /F5 9.8 Tf [(aa)] TJ ET BT 369.255 692.952 Td /F1 9.8 Tf [(\) and Northern Hemisphere \()] TJ ET BT 493.334 692.952 Td /F5 9.8 Tf [(an)] TJ ET BT 504.175 692.952 Td /F1 9.8 Tf [(\) isolates, )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(corresponding to all of the types of distances calculated for sequence data \(Figure 2\) except that the )] TJ ET BT 460.895 681.048 Td /F5 9.8 Tf [(n)] TJ ET BT 466.316 681.048 Td /F1 9.8 Tf [(.)] TJ ET BT 469.027 681.048 Td /F5 9.8 Tf [(n)] TJ ET BT 474.448 681.048 Td /F1 9.8 Tf [( 3 distances were )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(omitted. In combination with the above two sources of the isolates, 12 relative season distance variables were available for each )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(season.)] TJ ET BT 26.250 637.833 Td /F4 9.8 Tf [(Model selection)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(Overall, we had 40 explanatory variables, comprising 7*4=28 genetic variables and 6*2=12 serological distance variables, and )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(only 16 epidemiological observations. Due to the potential for severe overfitting, the standard approach of stepwise reduction of )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(a model containing all variables was not feasible. Instead we adopted a two-stage approach to find the optimal balance between )] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(the goodness of fit and the number of degrees of freedom in the model. At the first stage we used a transformation of the )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(original distance variables to determine which of them contributed most to the prediction of the epidemiological variable; at the )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(second stage we applied this information to select the most statistically robust predictors using the original variables.)] TJ ET BT 26.250 539.500 Td /F4 9.8 Tf [(Transformation of distance variables)] TJ ET BT 26.250 520.095 Td /F1 9.8 Tf [(For each relative season, combination the data from different variables \()] TJ ET BT 336.758 520.095 Td /F5 9.8 Tf [(sa)] TJ ET BT 347.054 520.095 Td /F1 9.8 Tf [(, )] TJ ET BT 352.475 520.095 Td /F5 9.8 Tf [(se)] TJ ET BT 362.771 520.095 Td /F1 9.8 Tf [(, )] TJ ET BT 368.192 520.095 Td /F5 9.8 Tf [(sn)] TJ ET BT 378.488 520.095 Td /F1 9.8 Tf [( and )] TJ ET BT 400.172 520.095 Td /F5 9.8 Tf [(ss)] TJ ET BT 409.922 520.095 Td /F1 9.8 Tf [( for genetic and )] TJ ET BT 479.839 520.095 Td /F5 9.8 Tf [(aa)] TJ ET BT 490.681 520.095 Td /F1 9.8 Tf [( and )] TJ ET BT 512.365 520.095 Td /F5 9.8 Tf [(an)] TJ ET BT 523.207 520.095 Td /F1 9.8 Tf [( for )] TJ ET BT 26.250 508.191 Td /F1 9.8 Tf [(serological data\) are strongly correlated \(e.g. )] TJ ET BT 222.410 508.191 Td /F5 9.8 Tf [(r)] TJ ET BT 225.657 506.126 Td /F1 8.7 Tf [(s)] TJ ET BT 229.990 508.191 Td /F1 9.8 Tf [([)] TJ ET BT 232.701 508.191 Td /F5 9.8 Tf [(sa.n)] TJ ET BT 251.128 508.191 Td /F1 9.8 Tf [(.)] TJ ET BT 253.839 508.191 Td /F5 9.8 Tf [(n)] TJ ET BT 259.260 508.191 Td /F1 9.8 Tf [(1, )] TJ ET BT 270.102 508.191 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 287.983 508.191 Td /F1 9.8 Tf [(.)] TJ ET BT 290.694 508.191 Td /F5 9.8 Tf [(n)] TJ ET BT 296.115 508.191 Td /F1 9.8 Tf [(1] = 0.74\). Thus each of the 28 genetic variables and 12 )] TJ ET BT 26.250 496.286 Td /F1 9.8 Tf [(serological distance variables were subject to PCA \(Figure 3\). The first 2 principal components were retained for each data )] TJ ET BT 26.250 484.381 Td /F1 9.8 Tf [(series, reducing the number of potential explanatory variables from 40 to 26.)] TJ ET 0.965 0.965 0.965 rg 26.250 368.096 555.000 106.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 474.500 m 581.250 474.500 l 581.250 473.750 l 26.250 473.750 l f 26.250 368.096 m 581.250 368.096 l 581.250 368.846 l 26.250 368.846 l f q 225.000 0 0 61.500 35.250 403.250 cm /I22 Do Q q 35.250 379.346 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 387.726 Td /F4 9.8 Tf [(Fig. 3: Principal Component Analysis \(PCA\) of genetic and serological distance variables)] TJ ET Q BT 26.250 351.072 Td /F4 9.8 Tf [(Retrospective model: first stage)] TJ ET BT 26.250 331.667 Td /F1 9.8 Tf [(We tested linear models containing all combinations of 3 \(2600 models\), 4 \(14950 models\), 5 \(65780 models\) and 6 \(230230 )] TJ ET BT 26.250 319.762 Td /F1 9.8 Tf [(models\) variables. Model fitting was performed on the R platform using the )] TJ ET BT 350.291 319.762 Td /F5 9.8 Tf [(lm)] TJ ET BT 360.577 319.762 Td /F1 9.8 Tf [(\(\) function. Within each class the models were )] TJ ET BT 26.250 307.857 Td /F1 9.8 Tf [(ranked by decreasing residual sum of squares. Additionally, 19 variables most frequently present among the top 50 6-variable )] TJ ET BT 26.250 295.953 Td /F1 9.8 Tf [(models were used to generate all combinations of 7 \(50388 models\) and 8 \(75582 models\) variables; 7- and 8-variable models )] TJ ET BT 26.250 284.048 Td /F1 9.8 Tf [(were ranked in the same manner.)] TJ ET BT 26.250 264.643 Td /F1 9.8 Tf [(To test the models statistically, we used two variants of a jackknife resampling procedure )] TJ ET 0.267 0.267 0.267 rg BT 412.067 266.150 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 421.705 264.643 Td /F1 9.8 Tf [(. The first variant tests the statistical )] TJ ET BT 26.250 252.738 Td /F1 9.8 Tf [(robustness of the relationships between the explanatory variables and the target variable in general. The second tests the )] TJ ET BT 26.250 240.834 Td /F1 9.8 Tf [(statistical robustness of a model using a particular set of explanatory variables.)] TJ ET BT 26.250 221.429 Td /F1 9.8 Tf [(In the first variant we removed data for each single season from our dataset one-by-one and used the remaining 15 seasons to )] TJ ET BT 26.250 209.524 Td /F1 9.8 Tf [(find the best-fitting model \(both the set of the explanatory variables and coefficients\). Then we used this model to predict the )] TJ ET BT 26.250 197.619 Td /F1 9.8 Tf [(epidemiology for the remaining season \(leave-one-out jackknife scheme\). The sum of squares of the deviations of these )] TJ ET BT 26.250 185.715 Td /F1 9.8 Tf [(predictions from the observations was accumulated over all 16 seasons to serve as the robustness indicator.)] TJ ET BT 26.250 166.310 Td /F1 9.8 Tf [(In the second variant we generated all possible bipartitions of the 16 epidemiological observations into two classes of equal )] TJ ET BT 26.250 154.405 Td /F1 9.8 Tf [(size. With each bipartition, one half of the seasons data was used to train the model using the fixed set of the explanatory )] TJ ET BT 26.250 142.500 Td /F1 9.8 Tf [(variables; then these model coefficients were used to predict the epidemiology for the remaining 8 seasons \(leave-half-out )] TJ ET BT 26.250 130.596 Td /F1 9.8 Tf [(jackknife scheme\). The residual sums of squares for the control half of the data were accumulated over all bipartitions to serve )] TJ ET BT 26.250 118.691 Td /F1 9.8 Tf [(as the indicator of the model robustness. We tested the top 10 models from each class and ranked them by decreasing total )] TJ ET BT 26.250 106.786 Td /F1 9.8 Tf [(residual sum of squares.)] TJ ET BT 26.250 87.381 Td /F1 9.8 Tf [(In the leave-one-out jackknife test the 5-variable model family demonstrates a highly robust behavior, accounting for 0.96 of the )] TJ ET BT 26.250 75.477 Td /F1 9.8 Tf [(of the variance in )] TJ ET BT 103.207 75.477 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 132.466 75.477 Td /F1 9.8 Tf [( 1. The following 5-variable model demonstrated the best performance among all tested models:)] TJ ET BT 26.250 56.072 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 56.072 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 56.072 Td /F5 9.8 Tf [(n.n)] TJ ET BT 90.473 56.072 Td /F1 9.8 Tf [(2.)] TJ ET BT 98.605 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 112.147 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 131.394 56.072 Td /F5 9.8 Tf [(n.n)] TJ ET BT 144.946 56.072 Td /F1 9.8 Tf [(2.)] TJ ET BT 153.078 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 166.621 56.072 Td /F1 9.8 Tf [( 2 + )] TJ ET BT 185.867 56.072 Td /F5 9.8 Tf [(n)] TJ ET BT 191.288 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 196.709 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 204.841 56.072 Td /F1 9.8 Tf [(1. )] TJ ET BT 215.683 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 229.225 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 248.472 56.072 Td /F5 9.8 Tf [(a.n)] TJ ET BT 262.024 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 267.445 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 275.577 56.072 Td /F1 9.8 Tf [(1.)] TJ ET BT 283.708 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 297.251 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 316.498 56.072 Td /F5 9.8 Tf [(a.n)] TJ ET BT 330.050 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 335.471 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 343.603 56.072 Td /F1 9.8 Tf [(1.)] TJ ET BT 351.734 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 365.277 56.072 Td /F1 9.8 Tf [( 2 + 0)] TJ ET BT 26.250 36.667 Td /F1 9.8 Tf [(Hence this model includes genetic distance between the current season and 2 seasons before, and intra-season genetic and )] TJ ET Q q 15.000 22.381 577.500 754.619 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(2005 and )] TJ ET BT 69.618 767.476 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 87.499 767.476 Td /F1 9.8 Tf [(.)] TJ ET BT 90.210 767.476 Td /F5 9.8 Tf [(n)] TJ ET BT 95.631 767.476 Td /F1 9.8 Tf [(2 is the average synonymous distance between all pairs of isolates from 2005-2006 and 2003-2004 seasons\).)] TJ ET BT 26.250 748.071 Td /F4 9.8 Tf [(Serological distances)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(We compiled hemagglutinin inhibition data from a variety of literature sources, including published articles, MMWR summaries, )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(and FDA reports \(see supplementary file for references )] TJ ET 0.267 0.267 0.267 rg BT 266.841 718.269 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 276.478 716.762 Td /F1 9.8 Tf [(\). A two-dimensional antigenic map was calculated from )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(hemagglutinin inhibition data according to )] TJ ET 0.267 0.267 0.267 rg BT 208.341 706.364 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 217.978 704.857 Td /F1 9.8 Tf [(. From this, antigenic distances were calculated for all pairs of isolates. Mean intra- )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(and inter-season pairwise distances were then calculated for North America \()] TJ ET BT 358.413 692.952 Td /F5 9.8 Tf [(aa)] TJ ET BT 369.255 692.952 Td /F1 9.8 Tf [(\) and Northern Hemisphere \()] TJ ET BT 493.334 692.952 Td /F5 9.8 Tf [(an)] TJ ET BT 504.175 692.952 Td /F1 9.8 Tf [(\) isolates, )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(corresponding to all of the types of distances calculated for sequence data \(Figure 2\) except that the )] TJ ET BT 460.895 681.048 Td /F5 9.8 Tf [(n)] TJ ET BT 466.316 681.048 Td /F1 9.8 Tf [(.)] TJ ET BT 469.027 681.048 Td /F5 9.8 Tf [(n)] TJ ET BT 474.448 681.048 Td /F1 9.8 Tf [( 3 distances were )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(omitted. In combination with the above two sources of the isolates, 12 relative season distance variables were available for each )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(season.)] TJ ET BT 26.250 637.833 Td /F4 9.8 Tf [(Model selection)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(Overall, we had 40 explanatory variables, comprising 7*4=28 genetic variables and 6*2=12 serological distance variables, and )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(only 16 epidemiological observations. Due to the potential for severe overfitting, the standard approach of stepwise reduction of )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(a model containing all variables was not feasible. Instead we adopted a two-stage approach to find the optimal balance between )] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(the goodness of fit and the number of degrees of freedom in the model. At the first stage we used a transformation of the )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(original distance variables to determine which of them contributed most to the prediction of the epidemiological variable; at the )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(second stage we applied this information to select the most statistically robust predictors using the original variables.)] TJ ET BT 26.250 539.500 Td /F4 9.8 Tf [(Transformation of distance variables)] TJ ET BT 26.250 520.095 Td /F1 9.8 Tf [(For each relative season, combination the data from different variables \()] TJ ET BT 336.758 520.095 Td /F5 9.8 Tf [(sa)] TJ ET BT 347.054 520.095 Td /F1 9.8 Tf [(, )] TJ ET BT 352.475 520.095 Td /F5 9.8 Tf [(se)] TJ ET BT 362.771 520.095 Td /F1 9.8 Tf [(, )] TJ ET BT 368.192 520.095 Td /F5 9.8 Tf [(sn)] TJ ET BT 378.488 520.095 Td /F1 9.8 Tf [( and )] TJ ET BT 400.172 520.095 Td /F5 9.8 Tf [(ss)] TJ ET BT 409.922 520.095 Td /F1 9.8 Tf [( for genetic and )] TJ ET BT 479.839 520.095 Td /F5 9.8 Tf [(aa)] TJ ET BT 490.681 520.095 Td /F1 9.8 Tf [( and )] TJ ET BT 512.365 520.095 Td /F5 9.8 Tf [(an)] TJ ET BT 523.207 520.095 Td /F1 9.8 Tf [( for )] TJ ET BT 26.250 508.191 Td /F1 9.8 Tf [(serological data\) are strongly correlated \(e.g. )] TJ ET BT 222.410 508.191 Td /F5 9.8 Tf [(r)] TJ ET BT 225.657 506.126 Td /F1 8.7 Tf [(s)] TJ ET BT 229.990 508.191 Td /F1 9.8 Tf [([)] TJ ET BT 232.701 508.191 Td /F5 9.8 Tf [(sa.n)] TJ ET BT 251.128 508.191 Td /F1 9.8 Tf [(.)] TJ ET BT 253.839 508.191 Td /F5 9.8 Tf [(n)] TJ ET BT 259.260 508.191 Td /F1 9.8 Tf [(1, )] TJ ET BT 270.102 508.191 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 287.983 508.191 Td /F1 9.8 Tf [(.)] TJ ET BT 290.694 508.191 Td /F5 9.8 Tf [(n)] TJ ET BT 296.115 508.191 Td /F1 9.8 Tf [(1] = 0.74\). Thus each of the 28 genetic variables and 12 )] TJ ET BT 26.250 496.286 Td /F1 9.8 Tf [(serological distance variables were subject to PCA \(Figure 3\). The first 2 principal components were retained for each data )] TJ ET BT 26.250 484.381 Td /F1 9.8 Tf [(series, reducing the number of potential explanatory variables from 40 to 26.)] TJ ET 0.965 0.965 0.965 rg 26.250 368.096 555.000 106.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 474.500 m 581.250 474.500 l 581.250 473.750 l 26.250 473.750 l f 26.250 368.096 m 581.250 368.096 l 581.250 368.846 l 26.250 368.846 l f q 225.000 0 0 61.500 35.250 403.250 cm /I24 Do Q q 35.250 379.346 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 387.726 Td /F4 9.8 Tf [(Fig. 3: Principal Component Analysis \(PCA\) of genetic and serological distance variables)] TJ ET Q BT 26.250 351.072 Td /F4 9.8 Tf [(Retrospective model: first stage)] TJ ET BT 26.250 331.667 Td /F1 9.8 Tf [(We tested linear models containing all combinations of 3 \(2600 models\), 4 \(14950 models\), 5 \(65780 models\) and 6 \(230230 )] TJ ET BT 26.250 319.762 Td /F1 9.8 Tf [(models\) variables. Model fitting was performed on the R platform using the )] TJ ET BT 350.291 319.762 Td /F5 9.8 Tf [(lm)] TJ ET BT 360.577 319.762 Td /F1 9.8 Tf [(\(\) function. Within each class the models were )] TJ ET BT 26.250 307.857 Td /F1 9.8 Tf [(ranked by decreasing residual sum of squares. Additionally, 19 variables most frequently present among the top 50 6-variable )] TJ ET BT 26.250 295.953 Td /F1 9.8 Tf [(models were used to generate all combinations of 7 \(50388 models\) and 8 \(75582 models\) variables; 7- and 8-variable models )] TJ ET BT 26.250 284.048 Td /F1 9.8 Tf [(were ranked in the same manner.)] TJ ET BT 26.250 264.643 Td /F1 9.8 Tf [(To test the models statistically, we used two variants of a jackknife resampling procedure )] TJ ET 0.267 0.267 0.267 rg BT 412.067 266.150 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 421.705 264.643 Td /F1 9.8 Tf [(. The first variant tests the statistical )] TJ ET BT 26.250 252.738 Td /F1 9.8 Tf [(robustness of the relationships between the explanatory variables and the target variable in general. The second tests the )] TJ ET BT 26.250 240.834 Td /F1 9.8 Tf [(statistical robustness of a model using a particular set of explanatory variables.)] TJ ET BT 26.250 221.429 Td /F1 9.8 Tf [(In the first variant we removed data for each single season from our dataset one-by-one and used the remaining 15 seasons to )] TJ ET BT 26.250 209.524 Td /F1 9.8 Tf [(find the best-fitting model \(both the set of the explanatory variables and coefficients\). Then we used this model to predict the )] TJ ET BT 26.250 197.619 Td /F1 9.8 Tf [(epidemiology for the remaining season \(leave-one-out jackknife scheme\). The sum of squares of the deviations of these )] TJ ET BT 26.250 185.715 Td /F1 9.8 Tf [(predictions from the observations was accumulated over all 16 seasons to serve as the robustness indicator.)] TJ ET BT 26.250 166.310 Td /F1 9.8 Tf [(In the second variant we generated all possible bipartitions of the 16 epidemiological observations into two classes of equal )] TJ ET BT 26.250 154.405 Td /F1 9.8 Tf [(size. With each bipartition, one half of the seasons data was used to train the model using the fixed set of the explanatory )] TJ ET BT 26.250 142.500 Td /F1 9.8 Tf [(variables; then these model coefficients were used to predict the epidemiology for the remaining 8 seasons \(leave-half-out )] TJ ET BT 26.250 130.596 Td /F1 9.8 Tf [(jackknife scheme\). The residual sums of squares for the control half of the data were accumulated over all bipartitions to serve )] TJ ET BT 26.250 118.691 Td /F1 9.8 Tf [(as the indicator of the model robustness. We tested the top 10 models from each class and ranked them by decreasing total )] TJ ET BT 26.250 106.786 Td /F1 9.8 Tf [(residual sum of squares.)] TJ ET BT 26.250 87.381 Td /F1 9.8 Tf [(In the leave-one-out jackknife test the 5-variable model family demonstrates a highly robust behavior, accounting for 0.96 of the )] TJ ET BT 26.250 75.477 Td /F1 9.8 Tf [(of the variance in )] TJ ET BT 103.207 75.477 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 132.466 75.477 Td /F1 9.8 Tf [( 1. The following 5-variable model demonstrated the best performance among all tested models:)] TJ ET BT 26.250 56.072 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 56.072 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 56.072 Td /F5 9.8 Tf [(n.n)] TJ ET BT 90.473 56.072 Td /F1 9.8 Tf [(2.)] TJ ET BT 98.605 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 112.147 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 131.394 56.072 Td /F5 9.8 Tf [(n.n)] TJ ET BT 144.946 56.072 Td /F1 9.8 Tf [(2.)] TJ ET BT 153.078 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 166.621 56.072 Td /F1 9.8 Tf [( 2 + )] TJ ET BT 185.867 56.072 Td /F5 9.8 Tf [(n)] TJ ET BT 191.288 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 196.709 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 204.841 56.072 Td /F1 9.8 Tf [(1. )] TJ ET BT 215.683 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 229.225 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 248.472 56.072 Td /F5 9.8 Tf [(a.n)] TJ ET BT 262.024 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 267.445 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 275.577 56.072 Td /F1 9.8 Tf [(1.)] TJ ET BT 283.708 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 297.251 56.072 Td /F1 9.8 Tf [( 1 + )] TJ ET BT 316.498 56.072 Td /F5 9.8 Tf [(a.n)] TJ ET BT 330.050 56.072 Td /F1 9.8 Tf [(1)] TJ ET BT 335.471 56.072 Td /F5 9.8 Tf [(.n)] TJ ET BT 343.603 56.072 Td /F1 9.8 Tf [(1.)] TJ ET BT 351.734 56.072 Td /F5 9.8 Tf [(PC)] TJ ET BT 365.277 56.072 Td /F1 9.8 Tf [( 2 + 0)] TJ ET BT 26.250 36.667 Td /F1 9.8 Tf [(Hence this model includes genetic distance between the current season and 2 seasons before, and intra-season genetic and )] TJ ET Q q 225.000 0 0 61.500 35.250 403.250 cm /I26 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(4)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 272 0 obj << /Type /Annot /Subtype /Link /A 273 0 R /Border [0 0 0] /H /I /Rect [ 266.8410 717.4674 276.4783 726.2858 ] >> endobj 273 0 obj << /Type /Action >> endobj 274 0 obj << /Type /Annot /Subtype /Link /A 275 0 R /Border [0 0 0] /H /I /Rect [ 208.3410 705.5627 217.9783 714.3810 ] >> endobj 275 0 obj << /Type /Action >> endobj 276 0 obj << /Type /Annot /Subtype /Link /A 277 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 403.2502 260.2500 464.7502 ] >> endobj 277 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2010/12/figurespage03.png) >> endobj 278 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 82 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 193>> stream xA 0 =fy9뀟\I]b endstream endobj 279 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 82 /SMask 278 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 10150>> stream x}ytGmI$ےIw;x $L N2a8o3VXN}>CC֭@ca@!arNfXI(j&p]zk9y'|x7o9Qp$p { h? 0$a6L&=py`83uzAg+AX,lέ@l {1d`0\a%5؈UWna͛] :X,4`0Y,3g01| ,!۷?í[֐Tz=///o#҅ -[V^^n:uE9stV/vmUϟ_jUqq? .۹sJ***8tЮ]l C~~+JKKׯ_닊,Xpʕ_]&=#|omh+V_^.%''n۶&11o^! ,hhhx;;;6o=<<߿m6rR7QB ?|ccT*h4 W^zަPT7nxmJ%u:K/DZ!3<<\"#e6߿aÆ:׷'2*/zVffsjjjmm-K,ABgg'ڸqrnܸa6V]]M 8www짟~ډw]<OT __K.رϯd2ǬʄBT*IIIĉ4 pA=!\remmm}}}ff^t=== ̙sΝ4 T*;;;{zzJs0kxxx]n\.obqSSV񉌌0,d&&&dJ둲P(UTT0 h ]]]rMP#""aUUUfyܹH5vvBQSSSWWvZ [ZZPNMMD|S8Ί+c=ގa۷SRRT*AoooRyժU566dhvR9<33nkkKHHq\ zyy pooooXr9JĔqGm]k9sfL(BBBΝk񀀀 GDDHRRY"DFF@@@][F,H ñk f LFUH$ HǮ tf!|}}-Z$HB$ٖd2Ba\\FQTHʶZ$Yd2E"X,R6""6;B&I$.Xq~d\" eXL`#:B0::ZR R~zrr2+B@ T$8^[[b?3޸E3 whhA,K0Y2  EE,`0!%%epp9::: !؊ 66smTMRkn&V^gy0pX,:va_O/_cux<8{̜go'`hh}a s3R[Y<Œnѳ#j>hx3:03 P6\Ά"gh4j40(m, RHw2AIƛi3w'T=j9uNvT+q˜ xp1&쌌,((xGKKKV\pb ?ng6u̦X0xĉ+WۻwohhhAAjcuuӧf]}ҝ]?ŋuHVBQQ*X #u0ʕ+hOta~ҥbN1 +))q): Aϟ///l6>}N BUwMMM4'NM0$%%͙3'???55… )))|>߮1AAiZQ {.r@  >\tm%p8T\dZV ǩ:c;+Ё`2FVHh4fSh sV5 ps@uݠ 8phs)PSOEEEDEEuttĀ=aXlW"WйPuVwD4@Ȼ 2V@K,W <# CO>$Y3e{:Ԗ@<ł( >8vu0q1L999LIc50Cq'!!`0`0 3Y` c[ +'AWх .V8ޮU+v\ aX|>F6a/ >>>>A6?!>6`#hmmtW*|RܿD"),,ttlj Y'qk]TUUUTT vZEE]Nh .)֝* *W eeeZ!S78S@QQQAuuutbH=Lz։"""T*UBBBLLJQ(& #{Bw! 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KJJг--8*~z|r\.aCCCawE `VRR" iaX!!!ւ~ *=sLTT >|>c[Sb$JZ655޻zjNNNaaaVVJG.6 m۶{BL ^z%o[G%;Apppppj1VM*2LcSMeZ-g\\z ɍAJ@Ƿmf0&ʇQ - ڵK.MXl=!A111h x'0 {'H{Od20B$բ&dKrEuK@:'Lz8pT d 0r]>L&3""%>'wq\.K#'|t̝;w|~wwP(d'O~NG`Gar|>^6Dct)1axօ8X,Dd2iq\&1 zuad2jlqeC<#B{ϝ;]__y G:va4=JoPPuwzG:(;jjjjkkݵBBEEE}}= pʕVzð'O(b}hbw-\.O?e24ݻkXՔn߾ݝz;v>|xƍmmm) LSH$E8:e2ق ȱV?F:ѹ/t]rOvtR@ $uyXX: w[u2 D4P.ٜP(]^:rL٥.]:00.ZtR ALsMMz5MBQ3UUd 8Xn.7L#'O`*xp,dfNx}g냄ltc }'hZN78 ,k: zi| uqRv%=I/@yֻ|?k:F޽] !מzzih)D],\8αcp) nUzd}Pph| 4~٧lA9j218ʂ\]@CK.+Z4ϧ]iBv,y 蕽^4I|Xp+Xs3s}[|>XA*%%Eii4XV8y1U?gy痓i+**: cFf00u|ЃQd<ȋ&[ 3Cgm,f,. 3:Sg6q  ݻw0U;ՠh} 63I;`6%0aMa:gCHL)M*%P1 &q2s^fSiksMm9xJJJJz'_x֮#h3䴙\!00 &i߾}l6{ڵ;zV}9w}vZy*R.--rĉॗ^/7ޘf>gϞmnnFo$koo?|BBڵkzꫯpAEJmjjz[oUYYaؿo GBP`2BannӧfeeW^555 F܍7;v===wܙj> ͹eeeGݹsZ>uԍ7j5 NF']=uK.^~V-..nkk+++s(((سgOjjFDǏX,ϟ}ߢ@ 8x---G`/\Gp>R Zرc?AX`0|Wdc}vYYtuu )\ڳg|,,% 44GݰaCZZZnn.{IM7/۹sgttU<磏>poowyg*y$xݻYJg}>>>^^^7oW/^,}||ŋ#8\nGGT3OH|- >CϧNg0<< Ү2P>o#|GS=!A&)..ϟ?<bN趐-S rXlpIS1u/Gd8=;UµC]_>-m<^j Z@RPػsY4M5z?w*Dȗ)h5;uϏflT\.'8JrDƔa3 Nhy03Xq<~]gBƯ${5EK&`>s+V<r_TFaXt:]TTUJ=N@?l۶ 6Pxܹ-[LCKo߾%_ytҥ_|Q|7</00PPD"RIh* N' F]]zRRݹsghhhӦM7nhkkaٲe===YYYxccڵkjN5L<̵kX,F1L cVA!KLT*dDCCC!88 %%%YYYAV{{{x<.r PT*FX,F[._yaFp|}} EDD@R R)XiiiFFP(<..n'OX,Z߿7xF^^ަM|||J7RRR?n6l6r@'e45Ll6[Pdgg]VәLG}bEGGk478W1 CLHH@nnn.**Zx/aofXHlڴl6|2]ljj"ƍWp8q\t8{9&Y^^e7@ʗ/_nkk{7- a7(,,0͛$33344ð )o߾͛]pAVW^zH /xA=zfǏ 5LJ^x1АkiZ\#Gv܉>w}',Xδy[jccPR֭["H$򰰰 zyyb .z"4V5x[U 455h4>T*}||z{{7m|֭ *(ġ)22)lT*駟mhhhll4͉XOI'(S83*JV_յhpsa ccce26L!!!W^x~~~f͚s疔 $&&d22 "$$5" a0k֬KKKE"Qtttn3l~KDFO0A |rdd$bk֬~:D-۷oGGG0L x<^^C=5kxyy]~̙3 ́~"+!8̿]C0<<p|||D"x,$66VEGG^l6_~\(vuu2 D?00޽{#QTv{넨؅Dڝ%g]plT^vk]6ן9ҙޜ[^oz| z9^#ީE< 65,~g7{0/_ߗs]MR:+[G2iTvING'ј_{,H,L'x0pR81-Yq:ƻͭҘ!ApÏ{6insV]b ZҘ~lhbctfSWKٶ*[̐cϐ g̊T\RR^^^r˗XLi I PYV='F_d0}n<^|ة)444444XAc0""":;;-Z.v=bc]V-:::u Sw@GG$ߜ=MsRJ!FRNn9fðzmwzRiXVl a4KJJ 0۷or_|EB'[}`|Ț455ݺu['GaةSi2cǎMncr9ϧa>2D9r$''ȑ#SOaq\T޿'Ip%IFF{BLӺ'H$芃e4[QB $ 8X,%K!w qG4ҿ)H:nݺu}}} ZnT*XlJϟ?>.%$$@vv6P+bJSRR'@yO di9kqKbŊ1\.b\'##>cMeGG͛7,XP\\&{Ӣ΁2 ^`61 <2Bv썇g18YzVA oɐ@L4K;MsrPF?s?8;;s,$GEMM͗_~h@%APi;wܹs9}t^^#(ISdŇQbٿ?zwe2>34.^wwwO0>|xՇ^rwl61aA"0LKX,][^^^3t@ Qs , ͦ7oiX#tFd&񱱱N'4#FNi5tt4KIHF'Ɔ hSBAct öoN|7Rd!\.wΝxoؚOziL.VUm+0I*ۚ(EĤ1"F{BCNSIo55iT>nuɩPR8yIQ~ǟCc:(ps##6:0f9 A [ޠ(_x6xX/NI=ףyࡼל->OAJ<2U<( ~~b6[v5 [Iچ?7+,f1Ť}b=&t邧9 Y43ì4 endstream endobj 304 0 obj << /Type /Page /Parent 3 0 R /Annots [ 306 0 R 310 0 R 314 0 R 318 0 R 322 0 R 326 0 R ] /Contents 305 0 R >> endobj 305 0 obj << /Length 31715 >> stream 0.271 0.267 0.267 rg q 15.000 -91.631 577.500 868.631 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(serological distances between isolates circulating in the previous season in the US \(genetic\) or North America and Northern )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Hemisphere \(serological\). When trained on the full complement of 16 seasons \(Figure 4\), this model explains 0.98 of the original )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(variance \(F-statistics p-value of 310 )] TJ ET BT 188.539 747.555 Td /F1 8.7 Tf [(-9)] TJ ET BT 196.243 743.667 Td /F1 9.8 Tf [(\), the coefficients being -1.36, -1.54, -0.32, -1.28 and -1.69 respectively \(PCA gives )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(arbitrary signs to the principal components, so the signs of coefficients do not indicate the kind of relationship by themselves\). In )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(the leave-half-out jackknife test it explains, on average, 0.89 of the variance in )] TJ ET BT 364.965 719.857 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 394.225 719.857 Td /F1 9.8 Tf [(1.)] TJ ET 0.965 0.965 0.965 rg 26.250 518.821 555.000 191.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.976 m 581.250 709.976 l 581.250 709.226 l 26.250 709.226 l f 26.250 518.822 m 581.250 518.822 l 581.250 519.572 l 26.250 519.572 l f q 225.000 0 0 146.250 35.250 553.976 cm /I28 Do Q q 35.250 530.071 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 538.452 Td /F4 9.8 Tf [(Fig. 4: Comparison of first stage retrospective model \(retro.1\) with observed epidemiological severity \(epi.PC1\))] TJ ET Q BT 26.250 501.798 Td /F1 9.8 Tf [(To further ascertain the statistical validity of the relationship between the genetic and serological data and epidemiological )] TJ ET BT 26.250 489.893 Td /F1 9.8 Tf [(severity we implemented an additional test procedure. The epidemiological data vector \()] TJ ET BT 405.574 489.893 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 434.834 489.893 Td /F1 9.8 Tf [( 1\) was permuted and all )] TJ ET BT 26.250 477.988 Td /F1 9.8 Tf [(combinations of 5 out of 26 explanatory variables were tested as potential reconstruction models for the scrambled )] TJ ET BT 522.642 477.988 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 551.902 477.988 Td /F1 9.8 Tf [( 1 )] TJ ET BT 26.250 466.083 Td /F1 9.8 Tf [(data. Only 36 out of 100,000 permutations yielded a fit as good as that obtained with the unpermuted data.)] TJ ET BT 26.250 446.679 Td /F1 9.8 Tf [(The above shows that the sequence and antigenic data explain part of the variance in morbidity among seasons. We can reject )] TJ ET BT 26.250 434.774 Td /F1 9.8 Tf [(the hypothesis that the true )] TJ ET BT 146.575 434.774 Td /F5 9.8 Tf [(R)] TJ ET BT 153.614 438.662 Td /F1 8.7 Tf [(2)] TJ ET BT 158.433 434.774 Td /F1 9.8 Tf [( equals zero with high statistical confidence, and we estimate that the true )] TJ ET BT 479.257 434.774 Td /F5 9.8 Tf [(R)] TJ ET BT 486.296 438.662 Td /F1 8.7 Tf [(2)] TJ ET BT 491.115 434.774 Td /F1 9.8 Tf [( is 0.96. In order to )] TJ ET BT 26.250 422.869 Td /F1 9.8 Tf [(obtain a statistical lower bound on the true )] TJ ET BT 211.597 422.869 Td /F5 9.8 Tf [(R)] TJ ET BT 218.637 426.757 Td /F1 8.7 Tf [(2)] TJ ET BT 223.456 422.869 Td /F1 9.8 Tf [(, we generated epidemiological severity values that mimicked various levels of )] TJ ET BT 26.250 410.964 Td /F1 9.8 Tf [(unexplained variance, and determined the lowest )] TJ ET BT 240.857 410.964 Td /F5 9.8 Tf [(R)] TJ ET BT 247.897 414.853 Td /F1 8.7 Tf [(2)] TJ ET BT 252.715 410.964 Td /F1 9.8 Tf [( value that could not be rejected at the 5% level by the )] TJ ET BT 489.562 410.964 Td /F5 9.8 Tf [(R)] TJ ET BT 496.602 414.853 Td /F1 8.7 Tf [(2)] TJ ET BT 501.421 410.964 Td /F1 9.8 Tf [( observed for the )] TJ ET BT 26.250 399.060 Td /F1 9.8 Tf [(real data \(i.e., the lowest value for which the )] TJ ET BT 219.173 399.060 Td /F5 9.8 Tf [(R)] TJ ET BT 226.213 402.948 Td /F1 8.7 Tf [(2)] TJ ET BT 231.031 399.060 Td /F1 9.8 Tf [( of the fit was as good as the observed 98% in at least 2.5% of the replicates\). )] TJ ET BT 26.250 387.155 Td /F1 9.8 Tf [(To the epidemiological values predicted by the fitted model, which can be fit with )] TJ ET BT 375.241 387.155 Td /F5 9.8 Tf [(R)] TJ ET BT 382.281 391.043 Td /F1 8.7 Tf [(2)] TJ ET BT 387.100 387.155 Td /F1 9.8 Tf [( = 1, we added independent pseudo-)] TJ ET BT 26.250 375.250 Td /F1 9.8 Tf [(random numbers. Two distributions for these were used: a normal distribution and a Laplace \(double exponential\) distribution. )] TJ ET BT 26.250 363.345 Td /F1 9.8 Tf [(The Laplace distribution has an excess kurtosis of 3.0, and is used because the observed residuals have excess kurtosis )] TJ ET BT 26.250 351.441 Td /F1 9.8 Tf [(\(approximately 2.5\). For each trial quantity of added noise, many replicates were generated, and each was independently fit to )] TJ ET BT 26.250 339.536 Td /F1 9.8 Tf [(the sequence and antigenic data, with no constraint on the choice of combinations of explanatory variables.)] TJ ET BT 26.250 320.131 Td /F1 9.8 Tf [(The 95%-confidence lower bounds for )] TJ ET BT 193.160 320.131 Td /F5 9.8 Tf [(R)] TJ ET BT 200.200 324.019 Td /F1 8.7 Tf [(2)] TJ ET BT 205.018 320.131 Td /F1 9.8 Tf [( thus obtained were 0.88 with normally-distributed deviations and 0.84 with Laplace-)] TJ ET BT 26.250 308.226 Td /F1 9.8 Tf [(distributed deviations. Upper bounds, obtained similarly, were both close to 0.99. We conclude that the fitted model likely )] TJ ET BT 26.250 296.322 Td /F1 9.8 Tf [(accounts for the vast majority of the season-to-season variance in epidemic severity.)] TJ ET BT 26.250 276.917 Td /F4 9.8 Tf [(Retrospective model: second stage)] TJ ET BT 26.250 257.512 Td /F1 9.8 Tf [(In the first stage of the analysis, we found that genetic distances between the current season and a season two years ago \()] TJ ET BT 556.289 257.512 Td /F5 9.8 Tf [(n.n)] TJ ET BT 569.842 257.512 Td /F1 9.8 Tf [(2\) )] TJ ET BT 26.250 245.607 Td /F1 9.8 Tf [(and the genetic and antigenic diversity one season ago \()] TJ ET BT 270.137 245.607 Td /F5 9.8 Tf [(n)] TJ ET BT 275.558 245.607 Td /F1 9.8 Tf [(1)] TJ ET BT 280.978 245.607 Td /F5 9.8 Tf [(.n)] TJ ET BT 289.110 245.607 Td /F1 9.8 Tf [(1\) yield the most statistically robust retrospective reconstruction of )] TJ ET BT 26.250 233.703 Td /F1 9.8 Tf [(H3N2 influenza epidemiology. In the second stage, we apply a similar approach to prediction of influenza epidemiology in the )] TJ ET BT 26.250 221.798 Td /F1 9.8 Tf [(next season.)] TJ ET BT 26.250 202.393 Td /F1 9.8 Tf [(In the second stage, we apply the standard stepwise model reduction approach to find the optimal set of original variables. We )] TJ ET BT 26.250 190.488 Td /F1 9.8 Tf [(started with a model containing 8 variables based on the best-fit model identified in the 1st stage \()] TJ ET BT 447.333 190.488 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 473.892 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 484.734 190.488 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 511.293 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 522.135 190.488 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 548.148 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 558.990 190.488 Td /F5 9.8 Tf [(se.n)] TJ ET BT 26.250 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 31.671 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 39.803 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 50.645 178.584 Td /F5 9.8 Tf [(sn.n)] TJ ET BT 69.072 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 74.493 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 82.625 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 93.467 178.584 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 111.348 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 116.769 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 124.901 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 135.743 178.584 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 154.716 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 160.137 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 168.268 178.584 Td /F1 9.8 Tf [(1 and )] TJ ET BT 195.373 178.584 Td /F5 9.8 Tf [(an.n)] TJ ET BT 214.347 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 219.768 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 227.899 178.584 Td /F1 9.8 Tf [(1\) and removed one by one the variables that contribute the least to the model )] TJ ET BT 26.250 166.679 Td /F1 9.8 Tf [(\(i.e. with the lowest absolute )] TJ ET BT 151.430 166.679 Td /F5 9.8 Tf [(t)] TJ ET BT 154.141 166.679 Td /F1 9.8 Tf [( -value of the coefficient\). Each derived model was compared to its parent using the )] TJ ET BT 516.685 166.679 Td /F5 9.8 Tf [(anova)] TJ ET BT 543.244 166.679 Td /F1 9.8 Tf [(\(\) )] TJ ET BT 26.250 154.774 Td /F1 9.8 Tf [(function of R; if the reduced model was not rejected at significance threshold of 0.05, the process continued. The final model )] TJ ET BT 26.250 142.869 Td /F1 9.8 Tf [(that cannot be reduced any further without a significant drop of the goodness of fit contains the following 5 variables:)] TJ ET BT 26.250 123.465 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 123.465 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 123.465 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 103.480 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 120.016 123.465 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 146.575 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 163.111 123.465 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 189.124 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 205.660 123.465 Td /F5 9.8 Tf [(se.n)] TJ ET BT 224.087 123.465 Td /F1 9.8 Tf [(1)] TJ ET BT 229.508 123.465 Td /F5 9.8 Tf [(.n)] TJ ET BT 237.640 123.465 Td /F1 9.8 Tf [(1 + )] TJ ET BT 254.176 123.465 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 273.149 123.465 Td /F1 9.8 Tf [(1)] TJ ET BT 278.570 123.465 Td /F5 9.8 Tf [(.n)] TJ ET BT 286.702 123.465 Td /F1 9.8 Tf [(1 + 0)] TJ ET BT 26.250 104.060 Td /F1 9.8 Tf [(When trained on all 16 seasons \(Figure 5\), this model explains 0.98 of the original variance \(F-statistics p-value of 310 )] TJ ET BT 544.034 107.948 Td /F1 8.7 Tf [(-9)] TJ ET BT 551.738 104.060 Td /F1 9.8 Tf [(\), the )] TJ ET BT 26.250 92.155 Td /F1 9.8 Tf [(coefficients being 1.26, 1.78, 0.81, -0.41 and 2.08, respectively. In the leave-half-out jackknife test the model explains, on )] TJ ET BT 26.250 80.250 Td /F1 9.8 Tf [(average, 0.91 of the variance in the remaining 8 seasons.)] TJ ET 0.965 0.965 0.965 rg 26.250 -91.631 555.000 162.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 70.369 m 581.250 70.369 l 581.250 69.619 l 26.250 69.619 l f q 225.000 0 0 146.250 35.250 -85.631 cm /I30 Do Q q 35.250 -91.631 537.000 0.000 re W n Q Q q 15.000 -91.631 577.500 868.631 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(serological distances between isolates circulating in the previous season in the US \(genetic\) or North America and Northern )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Hemisphere \(serological\). When trained on the full complement of 16 seasons \(Figure 4\), this model explains 0.98 of the original )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(variance \(F-statistics p-value of 310 )] TJ ET BT 188.539 747.555 Td /F1 8.7 Tf [(-9)] TJ ET BT 196.243 743.667 Td /F1 9.8 Tf [(\), the coefficients being -1.36, -1.54, -0.32, -1.28 and -1.69 respectively \(PCA gives )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(arbitrary signs to the principal components, so the signs of coefficients do not indicate the kind of relationship by themselves\). In )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(the leave-half-out jackknife test it explains, on average, 0.89 of the variance in )] TJ ET BT 364.965 719.857 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 394.225 719.857 Td /F1 9.8 Tf [(1.)] TJ ET 0.965 0.965 0.965 rg 26.250 518.821 555.000 191.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.976 m 581.250 709.976 l 581.250 709.226 l 26.250 709.226 l f 26.250 518.822 m 581.250 518.822 l 581.250 519.572 l 26.250 519.572 l f q 225.000 0 0 146.250 35.250 553.976 cm /I32 Do Q q 35.250 530.071 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 538.452 Td /F4 9.8 Tf [(Fig. 4: Comparison of first stage retrospective model \(retro.1\) with observed epidemiological severity \(epi.PC1\))] TJ ET Q BT 26.250 501.798 Td /F1 9.8 Tf [(To further ascertain the statistical validity of the relationship between the genetic and serological data and epidemiological )] TJ ET BT 26.250 489.893 Td /F1 9.8 Tf [(severity we implemented an additional test procedure. The epidemiological data vector \()] TJ ET BT 405.574 489.893 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 434.834 489.893 Td /F1 9.8 Tf [( 1\) was permuted and all )] TJ ET BT 26.250 477.988 Td /F1 9.8 Tf [(combinations of 5 out of 26 explanatory variables were tested as potential reconstruction models for the scrambled )] TJ ET BT 522.642 477.988 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 551.902 477.988 Td /F1 9.8 Tf [( 1 )] TJ ET BT 26.250 466.083 Td /F1 9.8 Tf [(data. Only 36 out of 100,000 permutations yielded a fit as good as that obtained with the unpermuted data.)] TJ ET BT 26.250 446.679 Td /F1 9.8 Tf [(The above shows that the sequence and antigenic data explain part of the variance in morbidity among seasons. We can reject )] TJ ET BT 26.250 434.774 Td /F1 9.8 Tf [(the hypothesis that the true )] TJ ET BT 146.575 434.774 Td /F5 9.8 Tf [(R)] TJ ET BT 153.614 438.662 Td /F1 8.7 Tf [(2)] TJ ET BT 158.433 434.774 Td /F1 9.8 Tf [( equals zero with high statistical confidence, and we estimate that the true )] TJ ET BT 479.257 434.774 Td /F5 9.8 Tf [(R)] TJ ET BT 486.296 438.662 Td /F1 8.7 Tf [(2)] TJ ET BT 491.115 434.774 Td /F1 9.8 Tf [( is 0.96. In order to )] TJ ET BT 26.250 422.869 Td /F1 9.8 Tf [(obtain a statistical lower bound on the true )] TJ ET BT 211.597 422.869 Td /F5 9.8 Tf [(R)] TJ ET BT 218.637 426.757 Td /F1 8.7 Tf [(2)] TJ ET BT 223.456 422.869 Td /F1 9.8 Tf [(, we generated epidemiological severity values that mimicked various levels of )] TJ ET BT 26.250 410.964 Td /F1 9.8 Tf [(unexplained variance, and determined the lowest )] TJ ET BT 240.857 410.964 Td /F5 9.8 Tf [(R)] TJ ET BT 247.897 414.853 Td /F1 8.7 Tf [(2)] TJ ET BT 252.715 410.964 Td /F1 9.8 Tf [( value that could not be rejected at the 5% level by the )] TJ ET BT 489.562 410.964 Td /F5 9.8 Tf [(R)] TJ ET BT 496.602 414.853 Td /F1 8.7 Tf [(2)] TJ ET BT 501.421 410.964 Td /F1 9.8 Tf [( observed for the )] TJ ET BT 26.250 399.060 Td /F1 9.8 Tf [(real data \(i.e., the lowest value for which the )] TJ ET BT 219.173 399.060 Td /F5 9.8 Tf [(R)] TJ ET BT 226.213 402.948 Td /F1 8.7 Tf [(2)] TJ ET BT 231.031 399.060 Td /F1 9.8 Tf [( of the fit was as good as the observed 98% in at least 2.5% of the replicates\). )] TJ ET BT 26.250 387.155 Td /F1 9.8 Tf [(To the epidemiological values predicted by the fitted model, which can be fit with )] TJ ET BT 375.241 387.155 Td /F5 9.8 Tf [(R)] TJ ET BT 382.281 391.043 Td /F1 8.7 Tf [(2)] TJ ET BT 387.100 387.155 Td /F1 9.8 Tf [( = 1, we added independent pseudo-)] TJ ET BT 26.250 375.250 Td /F1 9.8 Tf [(random numbers. Two distributions for these were used: a normal distribution and a Laplace \(double exponential\) distribution. )] TJ ET BT 26.250 363.345 Td /F1 9.8 Tf [(The Laplace distribution has an excess kurtosis of 3.0, and is used because the observed residuals have excess kurtosis )] TJ ET BT 26.250 351.441 Td /F1 9.8 Tf [(\(approximately 2.5\). For each trial quantity of added noise, many replicates were generated, and each was independently fit to )] TJ ET BT 26.250 339.536 Td /F1 9.8 Tf [(the sequence and antigenic data, with no constraint on the choice of combinations of explanatory variables.)] TJ ET BT 26.250 320.131 Td /F1 9.8 Tf [(The 95%-confidence lower bounds for )] TJ ET BT 193.160 320.131 Td /F5 9.8 Tf [(R)] TJ ET BT 200.200 324.019 Td /F1 8.7 Tf [(2)] TJ ET BT 205.018 320.131 Td /F1 9.8 Tf [( thus obtained were 0.88 with normally-distributed deviations and 0.84 with Laplace-)] TJ ET BT 26.250 308.226 Td /F1 9.8 Tf [(distributed deviations. Upper bounds, obtained similarly, were both close to 0.99. We conclude that the fitted model likely )] TJ ET BT 26.250 296.322 Td /F1 9.8 Tf [(accounts for the vast majority of the season-to-season variance in epidemic severity.)] TJ ET BT 26.250 276.917 Td /F4 9.8 Tf [(Retrospective model: second stage)] TJ ET BT 26.250 257.512 Td /F1 9.8 Tf [(In the first stage of the analysis, we found that genetic distances between the current season and a season two years ago \()] TJ ET BT 556.289 257.512 Td /F5 9.8 Tf [(n.n)] TJ ET BT 569.842 257.512 Td /F1 9.8 Tf [(2\) )] TJ ET BT 26.250 245.607 Td /F1 9.8 Tf [(and the genetic and antigenic diversity one season ago \()] TJ ET BT 270.137 245.607 Td /F5 9.8 Tf [(n)] TJ ET BT 275.558 245.607 Td /F1 9.8 Tf [(1)] TJ ET BT 280.978 245.607 Td /F5 9.8 Tf [(.n)] TJ ET BT 289.110 245.607 Td /F1 9.8 Tf [(1\) yield the most statistically robust retrospective reconstruction of )] TJ ET BT 26.250 233.703 Td /F1 9.8 Tf [(H3N2 influenza epidemiology. In the second stage, we apply a similar approach to prediction of influenza epidemiology in the )] TJ ET BT 26.250 221.798 Td /F1 9.8 Tf [(next season.)] TJ ET BT 26.250 202.393 Td /F1 9.8 Tf [(In the second stage, we apply the standard stepwise model reduction approach to find the optimal set of original variables. We )] TJ ET BT 26.250 190.488 Td /F1 9.8 Tf [(started with a model containing 8 variables based on the best-fit model identified in the 1st stage \()] TJ ET BT 447.333 190.488 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 473.892 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 484.734 190.488 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 511.293 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 522.135 190.488 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 548.148 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 558.990 190.488 Td /F5 9.8 Tf [(se.n)] TJ ET BT 26.250 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 31.671 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 39.803 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 50.645 178.584 Td /F5 9.8 Tf [(sn.n)] TJ ET BT 69.072 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 74.493 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 82.625 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 93.467 178.584 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 111.348 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 116.769 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 124.901 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 135.743 178.584 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 154.716 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 160.137 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 168.268 178.584 Td /F1 9.8 Tf [(1 and )] TJ ET BT 195.373 178.584 Td /F5 9.8 Tf [(an.n)] TJ ET BT 214.347 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 219.768 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 227.899 178.584 Td /F1 9.8 Tf [(1\) and removed one by one the variables that contribute the least to the model )] TJ ET BT 26.250 166.679 Td /F1 9.8 Tf [(\(i.e. with the lowest absolute )] TJ ET BT 151.430 166.679 Td /F5 9.8 Tf [(t)] TJ ET BT 154.141 166.679 Td /F1 9.8 Tf [( -value of the coefficient\). Each derived model was compared to its parent using the )] TJ ET BT 516.685 166.679 Td /F5 9.8 Tf [(anova)] TJ ET BT 543.244 166.679 Td /F1 9.8 Tf [(\(\) )] TJ ET BT 26.250 154.774 Td /F1 9.8 Tf [(function of R; if the reduced model was not rejected at significance threshold of 0.05, the process continued. The final model )] TJ ET BT 26.250 142.869 Td /F1 9.8 Tf [(that cannot be reduced any further without a significant drop of the goodness of fit contains the following 5 variables:)] TJ ET BT 26.250 123.465 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 123.465 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 123.465 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 103.480 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 120.016 123.465 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 146.575 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 163.111 123.465 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 189.124 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 205.660 123.465 Td /F5 9.8 Tf [(se.n)] TJ ET BT 224.087 123.465 Td /F1 9.8 Tf [(1)] TJ ET BT 229.508 123.465 Td /F5 9.8 Tf [(.n)] TJ ET BT 237.640 123.465 Td /F1 9.8 Tf [(1 + )] TJ ET BT 254.176 123.465 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 273.149 123.465 Td /F1 9.8 Tf [(1)] TJ ET BT 278.570 123.465 Td /F5 9.8 Tf [(.n)] TJ ET BT 286.702 123.465 Td /F1 9.8 Tf [(1 + 0)] TJ ET BT 26.250 104.060 Td /F1 9.8 Tf [(When trained on all 16 seasons \(Figure 5\), this model explains 0.98 of the original variance \(F-statistics p-value of 310 )] TJ ET BT 544.034 107.948 Td /F1 8.7 Tf [(-9)] TJ ET BT 551.738 104.060 Td /F1 9.8 Tf [(\), the )] TJ ET BT 26.250 92.155 Td /F1 9.8 Tf [(coefficients being 1.26, 1.78, 0.81, -0.41 and 2.08, respectively. In the leave-half-out jackknife test the model explains, on )] TJ ET BT 26.250 80.250 Td /F1 9.8 Tf [(average, 0.91 of the variance in the remaining 8 seasons.)] TJ ET 0.965 0.965 0.965 rg 26.250 -91.631 555.000 162.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 70.369 m 581.250 70.369 l 581.250 69.619 l 26.250 69.619 l f q 225.000 0 0 146.250 35.250 -85.631 cm /I34 Do Q q 35.250 -91.631 537.000 0.000 re W n Q Q q 15.000 -91.631 577.500 868.631 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(serological distances between isolates circulating in the previous season in the US \(genetic\) or North America and Northern )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Hemisphere \(serological\). When trained on the full complement of 16 seasons \(Figure 4\), this model explains 0.98 of the original )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(variance \(F-statistics p-value of 310 )] TJ ET BT 188.539 747.555 Td /F1 8.7 Tf [(-9)] TJ ET BT 196.243 743.667 Td /F1 9.8 Tf [(\), the coefficients being -1.36, -1.54, -0.32, -1.28 and -1.69 respectively \(PCA gives )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(arbitrary signs to the principal components, so the signs of coefficients do not indicate the kind of relationship by themselves\). In )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(the leave-half-out jackknife test it explains, on average, 0.89 of the variance in )] TJ ET BT 364.965 719.857 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 394.225 719.857 Td /F1 9.8 Tf [(1.)] TJ ET 0.965 0.965 0.965 rg 26.250 518.821 555.000 191.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.976 m 581.250 709.976 l 581.250 709.226 l 26.250 709.226 l f 26.250 518.822 m 581.250 518.822 l 581.250 519.572 l 26.250 519.572 l f q 225.000 0 0 146.250 35.250 553.976 cm /I36 Do Q q 35.250 530.071 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 538.452 Td /F4 9.8 Tf [(Fig. 4: Comparison of first stage retrospective model \(retro.1\) with observed epidemiological severity \(epi.PC1\))] TJ ET Q BT 26.250 501.798 Td /F1 9.8 Tf [(To further ascertain the statistical validity of the relationship between the genetic and serological data and epidemiological )] TJ ET BT 26.250 489.893 Td /F1 9.8 Tf [(severity we implemented an additional test procedure. The epidemiological data vector \()] TJ ET BT 405.574 489.893 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 434.834 489.893 Td /F1 9.8 Tf [( 1\) was permuted and all )] TJ ET BT 26.250 477.988 Td /F1 9.8 Tf [(combinations of 5 out of 26 explanatory variables were tested as potential reconstruction models for the scrambled )] TJ ET BT 522.642 477.988 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 551.902 477.988 Td /F1 9.8 Tf [( 1 )] TJ ET BT 26.250 466.083 Td /F1 9.8 Tf [(data. Only 36 out of 100,000 permutations yielded a fit as good as that obtained with the unpermuted data.)] TJ ET BT 26.250 446.679 Td /F1 9.8 Tf [(The above shows that the sequence and antigenic data explain part of the variance in morbidity among seasons. We can reject )] TJ ET BT 26.250 434.774 Td /F1 9.8 Tf [(the hypothesis that the true )] TJ ET BT 146.575 434.774 Td /F5 9.8 Tf [(R)] TJ ET BT 153.614 438.662 Td /F1 8.7 Tf [(2)] TJ ET BT 158.433 434.774 Td /F1 9.8 Tf [( equals zero with high statistical confidence, and we estimate that the true )] TJ ET BT 479.257 434.774 Td /F5 9.8 Tf [(R)] TJ ET BT 486.296 438.662 Td /F1 8.7 Tf [(2)] TJ ET BT 491.115 434.774 Td /F1 9.8 Tf [( is 0.96. In order to )] TJ ET BT 26.250 422.869 Td /F1 9.8 Tf [(obtain a statistical lower bound on the true )] TJ ET BT 211.597 422.869 Td /F5 9.8 Tf [(R)] TJ ET BT 218.637 426.757 Td /F1 8.7 Tf [(2)] TJ ET BT 223.456 422.869 Td /F1 9.8 Tf [(, we generated epidemiological severity values that mimicked various levels of )] TJ ET BT 26.250 410.964 Td /F1 9.8 Tf [(unexplained variance, and determined the lowest )] TJ ET BT 240.857 410.964 Td /F5 9.8 Tf [(R)] TJ ET BT 247.897 414.853 Td /F1 8.7 Tf [(2)] TJ ET BT 252.715 410.964 Td /F1 9.8 Tf [( value that could not be rejected at the 5% level by the )] TJ ET BT 489.562 410.964 Td /F5 9.8 Tf [(R)] TJ ET BT 496.602 414.853 Td /F1 8.7 Tf [(2)] TJ ET BT 501.421 410.964 Td /F1 9.8 Tf [( observed for the )] TJ ET BT 26.250 399.060 Td /F1 9.8 Tf [(real data \(i.e., the lowest value for which the )] TJ ET BT 219.173 399.060 Td /F5 9.8 Tf [(R)] TJ ET BT 226.213 402.948 Td /F1 8.7 Tf [(2)] TJ ET BT 231.031 399.060 Td /F1 9.8 Tf [( of the fit was as good as the observed 98% in at least 2.5% of the replicates\). )] TJ ET BT 26.250 387.155 Td /F1 9.8 Tf [(To the epidemiological values predicted by the fitted model, which can be fit with )] TJ ET BT 375.241 387.155 Td /F5 9.8 Tf [(R)] TJ ET BT 382.281 391.043 Td /F1 8.7 Tf [(2)] TJ ET BT 387.100 387.155 Td /F1 9.8 Tf [( = 1, we added independent pseudo-)] TJ ET BT 26.250 375.250 Td /F1 9.8 Tf [(random numbers. Two distributions for these were used: a normal distribution and a Laplace \(double exponential\) distribution. )] TJ ET BT 26.250 363.345 Td /F1 9.8 Tf [(The Laplace distribution has an excess kurtosis of 3.0, and is used because the observed residuals have excess kurtosis )] TJ ET BT 26.250 351.441 Td /F1 9.8 Tf [(\(approximately 2.5\). For each trial quantity of added noise, many replicates were generated, and each was independently fit to )] TJ ET BT 26.250 339.536 Td /F1 9.8 Tf [(the sequence and antigenic data, with no constraint on the choice of combinations of explanatory variables.)] TJ ET BT 26.250 320.131 Td /F1 9.8 Tf [(The 95%-confidence lower bounds for )] TJ ET BT 193.160 320.131 Td /F5 9.8 Tf [(R)] TJ ET BT 200.200 324.019 Td /F1 8.7 Tf [(2)] TJ ET BT 205.018 320.131 Td /F1 9.8 Tf [( thus obtained were 0.88 with normally-distributed deviations and 0.84 with Laplace-)] TJ ET BT 26.250 308.226 Td /F1 9.8 Tf [(distributed deviations. Upper bounds, obtained similarly, were both close to 0.99. We conclude that the fitted model likely )] TJ ET BT 26.250 296.322 Td /F1 9.8 Tf [(accounts for the vast majority of the season-to-season variance in epidemic severity.)] TJ ET BT 26.250 276.917 Td /F4 9.8 Tf [(Retrospective model: second stage)] TJ ET BT 26.250 257.512 Td /F1 9.8 Tf [(In the first stage of the analysis, we found that genetic distances between the current season and a season two years ago \()] TJ ET BT 556.289 257.512 Td /F5 9.8 Tf [(n.n)] TJ ET BT 569.842 257.512 Td /F1 9.8 Tf [(2\) )] TJ ET BT 26.250 245.607 Td /F1 9.8 Tf [(and the genetic and antigenic diversity one season ago \()] TJ ET BT 270.137 245.607 Td /F5 9.8 Tf [(n)] TJ ET BT 275.558 245.607 Td /F1 9.8 Tf [(1)] TJ ET BT 280.978 245.607 Td /F5 9.8 Tf [(.n)] TJ ET BT 289.110 245.607 Td /F1 9.8 Tf [(1\) yield the most statistically robust retrospective reconstruction of )] TJ ET BT 26.250 233.703 Td /F1 9.8 Tf [(H3N2 influenza epidemiology. In the second stage, we apply a similar approach to prediction of influenza epidemiology in the )] TJ ET BT 26.250 221.798 Td /F1 9.8 Tf [(next season.)] TJ ET BT 26.250 202.393 Td /F1 9.8 Tf [(In the second stage, we apply the standard stepwise model reduction approach to find the optimal set of original variables. We )] TJ ET BT 26.250 190.488 Td /F1 9.8 Tf [(started with a model containing 8 variables based on the best-fit model identified in the 1st stage \()] TJ ET BT 447.333 190.488 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 473.892 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 484.734 190.488 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 511.293 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 522.135 190.488 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 548.148 190.488 Td /F1 9.8 Tf [(2, )] TJ ET BT 558.990 190.488 Td /F5 9.8 Tf [(se.n)] TJ ET BT 26.250 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 31.671 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 39.803 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 50.645 178.584 Td /F5 9.8 Tf [(sn.n)] TJ ET BT 69.072 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 74.493 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 82.625 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 93.467 178.584 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 111.348 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 116.769 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 124.901 178.584 Td /F1 9.8 Tf [(1, )] TJ ET BT 135.743 178.584 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 154.716 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 160.137 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 168.268 178.584 Td /F1 9.8 Tf [(1 and )] TJ ET BT 195.373 178.584 Td /F5 9.8 Tf [(an.n)] TJ ET BT 214.347 178.584 Td /F1 9.8 Tf [(1)] TJ ET BT 219.768 178.584 Td /F5 9.8 Tf [(.n)] TJ ET BT 227.899 178.584 Td /F1 9.8 Tf [(1\) and removed one by one the variables that contribute the least to the model )] TJ ET BT 26.250 166.679 Td /F1 9.8 Tf [(\(i.e. with the lowest absolute )] TJ ET BT 151.430 166.679 Td /F5 9.8 Tf [(t)] TJ ET BT 154.141 166.679 Td /F1 9.8 Tf [( -value of the coefficient\). Each derived model was compared to its parent using the )] TJ ET BT 516.685 166.679 Td /F5 9.8 Tf [(anova)] TJ ET BT 543.244 166.679 Td /F1 9.8 Tf [(\(\) )] TJ ET BT 26.250 154.774 Td /F1 9.8 Tf [(function of R; if the reduced model was not rejected at significance threshold of 0.05, the process continued. The final model )] TJ ET BT 26.250 142.869 Td /F1 9.8 Tf [(that cannot be reduced any further without a significant drop of the goodness of fit contains the following 5 variables:)] TJ ET BT 26.250 123.465 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 123.465 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 123.465 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 103.480 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 120.016 123.465 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 146.575 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 163.111 123.465 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 189.124 123.465 Td /F1 9.8 Tf [(2 + )] TJ ET BT 205.660 123.465 Td /F5 9.8 Tf [(se.n)] TJ ET BT 224.087 123.465 Td /F1 9.8 Tf [(1)] TJ ET BT 229.508 123.465 Td /F5 9.8 Tf [(.n)] TJ ET BT 237.640 123.465 Td /F1 9.8 Tf [(1 + )] TJ ET BT 254.176 123.465 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 273.149 123.465 Td /F1 9.8 Tf [(1)] TJ ET BT 278.570 123.465 Td /F5 9.8 Tf [(.n)] TJ ET BT 286.702 123.465 Td /F1 9.8 Tf [(1 + 0)] TJ ET BT 26.250 104.060 Td /F1 9.8 Tf [(When trained on all 16 seasons \(Figure 5\), this model explains 0.98 of the original variance \(F-statistics p-value of 310 )] TJ ET BT 544.034 107.948 Td /F1 8.7 Tf [(-9)] TJ ET BT 551.738 104.060 Td /F1 9.8 Tf [(\), the )] TJ ET BT 26.250 92.155 Td /F1 9.8 Tf [(coefficients being 1.26, 1.78, 0.81, -0.41 and 2.08, respectively. In the leave-half-out jackknife test the model explains, on )] TJ ET BT 26.250 80.250 Td /F1 9.8 Tf [(average, 0.91 of the variance in the remaining 8 seasons.)] TJ ET 0.965 0.965 0.965 rg 26.250 -91.631 555.000 162.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 70.369 m 581.250 70.369 l 581.250 69.619 l 26.250 69.619 l f q 225.000 0 0 146.250 35.250 -85.631 cm /I38 Do Q q 35.250 -91.631 537.000 0.000 re W n Q Q q 225.000 0 0 146.250 35.250 553.976 cm /I40 Do Q q 225.000 0 0 146.250 35.250 -85.631 cm /I42 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(5)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 306 0 obj << /Type /Annot /Subtype /Link /A 307 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 553.9762 260.2500 700.2262 ] >> endobj 307 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2010/12/figurespage04.png) >> endobj 308 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 195 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 419>> stream xA 0 =fy9뀟\7 endstream endobj 309 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 195 /SMask 308 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 14649>> stream x}yX28 "" .0)iM&9_<^M6MIb D YAeQeaa~|agcor{]}]QMM A²0,444""655m O"##)- \UEZCɒEE,\-@ C؂ $1P@qWI A "0 C|&`0B0??L)X"HbНÁs~w'Nh4PN YX8+[$4P Bt:]=& $LahLLLtt4,>*_O˶GF)GIrg"hlh;Os|mD~؂ $џ,G$H'RL*mɏKKH;!ۈ1k5mIpr kvEnIp"=@C R aMrԮ .C'buHb(a9:;;+˵]RNL&Ro^j'|aXVV֙3g<==Çi "G>pWZuV B 555--ڶ-"GSO=?O.**JYF&&&gA͛7BѼ@!q13 $6:: 6R;#84сH6 "HJ ݻ===6>ử|:BO*興ner/"[Y+>l\\BRT J_ PRmvGph]j%R>9l$ɬD6UjĒ neM ϋRΈQUs @dIgTnr) Z Gr r B_E9onnjQܟ6-GE"!GlDŽݻ BB`l G@pnsI-,,K?OsssuttDHP1gg,>~= PTTdm k j_}+;;;gff޽;==}۷;v_ ȹraQ(!FNNZW7>>nj 3>AWlٲpfS!( `YaEBTn":: ߇de'?i7uzGGw933|T`0fff\\\R)=zBI|[OKbMN۷0k2 WWW BR( t:`t:7!*7@@߇899ޝ ojQܟ6;JGlDŽ|?C9 23z5 Ih@__ ߽{#ӭj]9>F%f7 喖 //زX?9F؁v G.ee= A`YO2AQ01 +))p8ֳήU1#h 7rQ674+Wh||ܢ"!&GoݺJ333e'F'4(j d28kwo6@eegV9:33d2K4rIHHרYHEEE<57hEBA>FB4W/RHb^ "m)vyZONhQ.ԾAHs}OcJVSmm__$h4qE@PEA@vGknnMMBYd"/{\ __и6*!!%(ȫ(>>BL3\Bqh4ؾ= //BL$T@ `3T//9v&@cY Q{!5I}POF&iaB@?vBettSWkNr' Rxa|srΜy܌dӛ%"gd秧+**-G#@QC}}}{:@QQHǑ (G044 ^<^faELOӛ _SrґyJmii"'!"娝/)GoBB@Fs% B ww|ڵ/k7>AQ{,ET99OREr`zsM#t('H")++#',GkkkbI9jŎs8:''w󳳳iB]bmhhJ) 9CNhQ.Ծabs +V*+4ZHOBC(6ZhI㣬F1Ll^`R%$$Q,P!84˗/uuui<<?nXmׯbƓCp$bSj:㥝:UVV/:9XohJʹ}o^uVÇQIIlM'99]]=uʕojh)D暜#CB!/^1m?1͛`{`˗c؅ Ątbܹso{:6@ͽ{oKR Z[{G --ܹsb,2߿>O#QPBgLMMUUUa3Q._Ha}}}<<sfoe{%h׮M =Lv\oMR=<\57Bd$:90ֻqg*+|l6ے6ݾ+O@B׵kw܉&:apE\aʿ?q !*W %՗4899W  Ko dxxmZڧN @;i矇wuu^d`;|x @(_np>F[ĉ7n9c|>%G"U`B􌦍V_RZZk׮gϟx?FF21+io_A?p=ޔoxcǾD54:RMW4+33t $r;: cc}gg{{{-ZCP8d2M''M+GRSSmfJL uʕֶE PS+222:ZPZ:77He UZTc,L8Y2D4݇1I}vlii%F$/*D^,GRiyyn~x穒)TVow!4j1DFFFcғdee+-/45K./h %84ё B{{H$i4R7wh˫sFQaL`긐7"L3 }TTTLMMi5h,KJ9::*wMaP^^`0LJE\.ت7p %88xMzY)XtCk~P(WWW*{Ōbii9͛ULn?9-Z/_N 'g/@^^yFN:V&3KqQ84Q??Ç_M)  11Ѷ rR|ڀMA \}|i1ǔ`7ؑ#'rg}v}!?衵ђr c2**d,yhhF ,33ΝsyY4448=Ÿ75USScҍ `}UU)@RR[;:25{zDnn";,^V#?vwCt:sYtǰ2lf^/_߮ewؚa'[ҷoB(W^y ucvvvy޽a%%r\厷5Q:Oё$"+**F-Ck+~,E(\ "˗OmٲR6}7MNv˿ PHHh|ׯ_@"GYt+J_^T;k'333EØ#"/S")**2Pn.Nwy~[t  `AT*u**jҥ9= p6GdvVV@Ma!٪~OOFEŵfgghEyy.hO f>9ꖙ=3SSS-TT]]eZ'rf*ˆ >`aLz(ŋr"1,pG.zoܸ۬M^3W(8^[i'&'gRSS5jvw X7cVOzzzBØ#3<^˗nd޵{꥟Wf,4,rð6{Ș(//`06lhz#44T0jmC>=pIR\LxqLE__ݻw;:^8wΌ :X{6߁ruֹj4^~RlLP(50&=Ht|| =gw#$С#?5aܶmq #tӈkfwߵkhWgf&/jQZB6<<55enO0> ""p0 )}nGG9O>4 .t sQ Ö3ECEED7nPFrR wtAdem0&bѣx嗵EqIF&H'3XCUUku5WPTŔQuSm8LEtNB/E22s;vzpPd>yy=Xޱ2s " yhJzTB-DGG+V7rrF)Z=L&8wdٲe۶yՍGv#\Nseeef)(aXb| ({222^i 3#6A:<<*|}WKJˈU˱n} v< ĴѹT JoYJKKe2ʥD._.AiPsuuR;;TM7<<0KSI-edds/*8dm G^Ӽ ~nnnvv)RΝ;B \fϟ7Vg9X&D$PSsM tl3v'`B"7Jؿu۷ߺn]ɓW6t2I$??yB1jbbbAA}} ř7(kRbC^tdr#\~}͚5t:45`hhN+d*F8W:+ڶ,f"""^]σ@ 8p>fG<ɓ+WvءrI(JRTzt0@@a~֭/QTggg___<"=uԂ GUI,,v镭2}etTa;SR-Ȉ"[\CDaٸ M>0::-93N70-aN@DDzJxiۏ|ܸ F󽽽L&aٗONKK'9:(eoooSDѤRuW'~B:^3!ET*uxxؘ࣏dW_}e"ݫW9bmC0 Ng|YKJ*Lʨ{a8q4޼iRBq4{G1 [&d[R\\IPRRRUriuAЀ=ktj𴋋1hJݵkuww۝;&e;؁:by:@(7zrpp_& XkȀLt]V171zYN?4Ug1oo BS4ج1|imsj۟~i&<&a9-Srr@ii‚JA}*;k4\CWD"! 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Three epidemiological indicators \()] TJ ET BT 414.232 699.512 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 436.442 699.512 Td /F1 9.8 Tf [( , )] TJ ET BT 444.574 699.512 Td /F5 9.8 Tf [(F-H3)] TJ ET BT 466.238 699.512 Td /F1 9.8 Tf [( and )] TJ ET BT 487.922 699.512 Td /F5 9.8 Tf [(F-Pos)] TJ ET BT 513.926 699.512 Td /F1 9.8 Tf [(\) were )] TJ ET BT 26.250 687.607 Td /F1 9.8 Tf [(obtained for 13 seasons \(from 1997 to 2009\) using data from Hong Kong Centre for Health Protection )] TJ ET 0.267 0.267 0.267 rg BT 466.307 689.114 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 475.944 687.607 Td /F1 9.8 Tf [(. Influenza epidemics in )] TJ ET BT 26.250 675.702 Td /F1 9.8 Tf [(Hong Kong usually show two peaks \(February-March and May-June\). Both peaks were combined into the same season, and )] TJ ET BT 26.250 663.798 Td /F1 9.8 Tf [(therefore a season corresponds to a calendar year in this analysis.)] TJ ET BT 26.250 644.393 Td /F1 9.8 Tf [(Because Hong Kong Centre for Health Protection data lacks ILI raw numbers, only %ILI for each month is available. Therefore, )] TJ ET BT 26.250 632.488 Td /F1 9.8 Tf [(we calculated the total epidemic severity \(%ILI*%Positive Specimens\) for each month, and then totaled these numbers for a )] TJ ET BT 26.250 620.583 Td /F1 9.8 Tf [(year to obtain. \(As a test to show that this method gives results similar to the regular method \(using cumulative raw numbers for )] TJ ET BT 26.250 608.679 Td /F1 9.8 Tf [(each season to calculate %ILI and %Positive Specimens\), we checked the correlation between the epidemic severity numbers )] TJ ET BT 26.250 596.774 Td /F1 9.8 Tf [(calculated using the two methods for the USA data. The correlation between the two methods is very high \(r=0.97\). The H3 )] TJ ET BT 26.250 584.869 Td /F1 9.8 Tf [(epidemic severity \()] TJ ET BT 107.516 584.869 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 129.727 584.869 Td /F1 9.8 Tf [(\) was calculated as the total influenza epidemic severity prorated by the fraction of H3 isolates among )] TJ ET BT 26.250 572.964 Td /F1 9.8 Tf [(all isolates. These data were converted to a single epidemiological index using PCA \(Figure 6\). Interestingly, despite the fact )] TJ ET BT 26.250 561.060 Td /F1 9.8 Tf [(that Hong Kong, like USA, is a non-tropical Northern Hemisphere country, the epidemic severity measures between the two are )] TJ ET BT 26.250 549.155 Td /F1 9.8 Tf [(relatively weakly correlated \()] TJ ET BT 149.237 549.155 Td /F5 9.8 Tf [(r)] TJ ET BT 152.483 547.091 Td /F5 8.7 Tf [(s)] TJ ET BT 156.817 549.155 Td /F1 9.8 Tf [([)] TJ ET BT 159.527 549.155 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 188.787 549.155 Td /F1 9.8 Tf [( 1)] TJ ET BT 196.918 549.155 Td /F5 9.8 Tf [(.USA)] TJ ET BT 219.675 549.155 Td /F1 9.8 Tf [(,)] TJ ET BT 222.385 549.155 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 251.645 549.155 Td /F1 9.8 Tf [( 1)] TJ ET BT 259.777 549.155 Td /F5 9.8 Tf [(.HK)] TJ ET BT 276.030 549.155 Td /F1 9.8 Tf [( ] = 0.36 with the p-value of 0.21\). Thus the Hong Kong dataset )] TJ ET BT 26.250 537.250 Td /F1 9.8 Tf [(provides a largely independent test of the model applicability.)] TJ ET BT 26.250 517.845 Td /F1 9.8 Tf [(Sequence and antigenic distances were computed in a manner similar to that for the US data \(the list of Hong Kong isolates )] TJ ET BT 26.250 505.941 Td /F1 9.8 Tf [(used for genetic distance calculation is in the supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 304.252 507.448 Td /F4 8.7 Tf [(21)] TJ ET 0.271 0.267 0.267 rg BT 313.889 505.941 Td /F1 9.8 Tf [(\). Again, in this analysis, a season corresponds to a calendar )] TJ ET BT 26.250 494.036 Td /F1 9.8 Tf [(year. Due to a low number of serologically tested isolates from Hong Kong proper, antigenic data were computed for a )] TJ ET BT 26.250 482.131 Td /F1 9.8 Tf [(combined set of Hong Kong and mainland China isolates. The seasonal epidemiology seems to be the same in Hong Kong and )] TJ ET BT 26.250 470.226 Td /F1 9.8 Tf [(Southern mainland China, and only Northern mainland China follows the standard Northern Hemisphere pattern)] TJ ET 0.267 0.267 0.267 rg BT 507.998 471.734 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 517.635 470.226 Td /F1 9.8 Tf [(. Moreover, )] TJ ET BT 26.250 458.322 Td /F1 9.8 Tf [(the Northern China epidemics follow the Southern China epidemics and not vice versa )] TJ ET 0.267 0.267 0.267 rg BT 400.699 459.829 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 410.336 458.322 Td /F1 9.8 Tf [(. Based on this observation, two )] TJ ET BT 26.250 446.417 Td /F1 9.8 Tf [(possible ways of merging these data sets were implemented, producing two versions of the serological distances \()] TJ ET BT 518.284 446.417 Td /F5 9.8 Tf [(ac)] TJ ET BT 528.580 446.417 Td /F1 9.8 Tf [( and )] TJ ET BT 550.264 446.417 Td /F5 9.8 Tf [(as)] TJ ET BT 560.560 446.417 Td /F1 9.8 Tf [( in )] TJ ET BT 26.250 434.512 Td /F1 9.8 Tf [(contrast to )] TJ ET BT 74.483 434.512 Td /F5 9.8 Tf [(aa)] TJ ET BT 85.325 434.512 Td /F1 9.8 Tf [( and )] TJ ET BT 107.009 434.512 Td /F5 9.8 Tf [(an)] TJ ET BT 117.851 434.512 Td /F1 9.8 Tf [( serological distances for US\). The first one \()] TJ ET BT 310.209 434.512 Td /F5 9.8 Tf [(ac)] TJ ET BT 320.505 434.512 Td /F1 9.8 Tf [(\) corresponds to the scenario where for all isolates \(Hong )] TJ ET BT 26.250 422.607 Td /F1 9.8 Tf [(Kong and China\) the season was considered to correspond to a calendar year, following the Hong Kong pattern. The second )] TJ ET BT 26.250 410.703 Td /F1 9.8 Tf [(one \()] TJ ET BT 48.470 410.703 Td /F5 9.8 Tf [(as)] TJ ET BT 58.766 410.703 Td /F1 9.8 Tf [(\) considers Hong Kong isolates following the Hong Kong pattern and China isolates following the Northern Hemisphere )] TJ ET BT 26.250 398.798 Td /F1 9.8 Tf [(pattern with seasons starting in the fall.)] TJ ET 0.965 0.965 0.965 rg 26.250 203.762 555.000 185.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 388.917 m 581.250 388.917 l 581.250 388.167 l 26.250 388.167 l f 26.250 203.762 m 581.250 203.762 l 581.250 204.512 l 26.250 204.512 l f q 225.000 0 0 140.250 35.250 238.917 cm /I44 Do Q q 35.250 215.012 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 223.393 Td /F4 9.8 Tf [(Fig. 6: First Principal Component \(epi.PC1\) of three measures of epidemiological severity for Hong Kong)] TJ ET Q BT 26.250 186.738 Td /F1 9.8 Tf [(There are several possible ways to apply the model derived from the US data to the Hong Kong data. One would be to directly )] TJ ET BT 26.250 174.834 Td /F1 9.8 Tf [(compute the model prediction using the formula:)] TJ ET BT 26.250 155.429 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 155.429 Td /F1 9.8 Tf [( 1? = 1.26)] TJ ET BT 99.151 155.429 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 125.710 155.429 Td /F1 9.8 Tf [(2 + 1.78)] TJ ET BT 161.219 155.429 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 187.778 155.429 Td /F1 9.8 Tf [(2 + 0.81)] TJ ET BT 223.288 155.429 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 249.301 155.429 Td /F1 9.8 Tf [(2 0.41)] TJ ET BT 284.537 155.429 Td /F5 9.8 Tf [(se.n)] TJ ET BT 302.965 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 308.386 155.429 Td /F5 9.8 Tf [(.n)] TJ ET BT 316.517 155.429 Td /F1 9.8 Tf [(1 + 2.08)] TJ ET BT 352.027 155.429 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 371.000 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 376.421 155.429 Td /F5 9.8 Tf [(.n)] TJ ET BT 384.553 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 26.250 136.024 Td /F1 9.8 Tf [(and replacing )] TJ ET BT 87.490 136.024 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 106.463 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 111.884 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 120.016 136.024 Td /F1 9.8 Tf [(1 \(US data\) with either )] TJ ET BT 219.719 136.024 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 238.147 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 243.568 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 251.699 136.024 Td /F1 9.8 Tf [(1 or )] TJ ET BT 271.209 136.024 Td /F5 9.8 Tf [(as.n)] TJ ET BT 289.637 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 295.058 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 303.189 136.024 Td /F1 9.8 Tf [(1. Using )] TJ ET BT 341.663 136.024 Td /F5 9.8 Tf [(as.n)] TJ ET BT 360.090 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 365.511 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 373.643 136.024 Td /F1 9.8 Tf [(1 for the serological distance variable, this )] TJ ET BT 26.250 124.119 Td /F1 9.8 Tf [(formula produces a prediction that is reasonably well correlated with the real epidemiology data \()] TJ ET BT 442.419 124.119 Td /F5 9.8 Tf [(r)] TJ ET BT 445.666 122.055 Td /F1 8.7 Tf [(s)] TJ ET BT 449.999 124.119 Td /F1 9.8 Tf [([)] TJ ET BT 452.710 124.119 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 481.969 124.119 Td /F1 9.8 Tf [( 1,)] TJ ET BT 492.811 124.119 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 522.071 124.119 Td /F1 9.8 Tf [(1] = 0.60, )] TJ ET BT 26.250 112.215 Td /F1 9.8 Tf [(with the p-value of 0.012 in a permutation test; Figure 7, retro.direct plot\). This model allows rough prediction of the ups and )] TJ ET BT 26.250 100.310 Td /F1 9.8 Tf [(downs of the H3N2 influenza epidemics in 1997-2009, but gives a relatively poor quantitative estimate.)] TJ ET BT 26.250 80.905 Td /F1 9.8 Tf [(When the model is allowed to use the actual epidemiological data from Hong Kong to adjust its coefficients \(yielding 1.50, 1.46, -)] TJ ET BT 26.250 69.000 Td /F1 9.8 Tf [(0.82, 0.34 and 0.64 respectively\), the prediction is improved \(Figure 7, retro.adjust plot\). The adjusted model explains 0.75 of )] TJ ET BT 26.250 57.096 Td /F1 9.8 Tf [(the original variance with F-statistics p-value of 210 )] TJ ET BT 255.736 60.984 Td /F1 8.7 Tf [(-2)] TJ ET BT 263.440 57.096 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 37.691 Td /F1 9.8 Tf [(Finally, the stepwise reduction of the full model containing the genetic and serological distances from the corresponding )] TJ ET Q q 15.000 23.405 577.500 753.595 re W n 0.965 0.965 0.965 rg 26.250 747.845 555.000 29.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 747.845 m 581.250 747.845 l 581.250 748.595 l 26.250 748.595 l f q 35.250 759.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 5: Comparison of second stage retrospective model \(retro.2\) with observed epidemiological severity \(epi.PC1\))] TJ ET Q BT 26.250 730.821 Td /F4 9.8 Tf [(Independent test: Hong Kong data)] TJ ET BT 26.250 711.417 Td /F1 9.8 Tf [(To test whether these results pertain only to US or are more generally applicable to H3N2 influenza epidemiology, we collected )] TJ ET BT 26.250 699.512 Td /F1 9.8 Tf [(a similar data set from Hong Kong and mainland China. Three epidemiological indicators \()] TJ ET BT 414.232 699.512 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 436.442 699.512 Td /F1 9.8 Tf [( , )] TJ ET BT 444.574 699.512 Td /F5 9.8 Tf [(F-H3)] TJ ET BT 466.238 699.512 Td /F1 9.8 Tf [( and )] TJ ET BT 487.922 699.512 Td /F5 9.8 Tf [(F-Pos)] TJ ET BT 513.926 699.512 Td /F1 9.8 Tf [(\) were )] TJ ET BT 26.250 687.607 Td /F1 9.8 Tf [(obtained for 13 seasons \(from 1997 to 2009\) using data from Hong Kong Centre for Health Protection )] TJ ET 0.267 0.267 0.267 rg BT 466.307 689.114 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 475.944 687.607 Td /F1 9.8 Tf [(. Influenza epidemics in )] TJ ET BT 26.250 675.702 Td /F1 9.8 Tf [(Hong Kong usually show two peaks \(February-March and May-June\). Both peaks were combined into the same season, and )] TJ ET BT 26.250 663.798 Td /F1 9.8 Tf [(therefore a season corresponds to a calendar year in this analysis.)] TJ ET BT 26.250 644.393 Td /F1 9.8 Tf [(Because Hong Kong Centre for Health Protection data lacks ILI raw numbers, only %ILI for each month is available. Therefore, )] TJ ET BT 26.250 632.488 Td /F1 9.8 Tf [(we calculated the total epidemic severity \(%ILI*%Positive Specimens\) for each month, and then totaled these numbers for a )] TJ ET BT 26.250 620.583 Td /F1 9.8 Tf [(year to obtain. \(As a test to show that this method gives results similar to the regular method \(using cumulative raw numbers for )] TJ ET BT 26.250 608.679 Td /F1 9.8 Tf [(each season to calculate %ILI and %Positive Specimens\), we checked the correlation between the epidemic severity numbers )] TJ ET BT 26.250 596.774 Td /F1 9.8 Tf [(calculated using the two methods for the USA data. The correlation between the two methods is very high \(r=0.97\). The H3 )] TJ ET BT 26.250 584.869 Td /F1 9.8 Tf [(epidemic severity \()] TJ ET BT 107.516 584.869 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 129.727 584.869 Td /F1 9.8 Tf [(\) was calculated as the total influenza epidemic severity prorated by the fraction of H3 isolates among )] TJ ET BT 26.250 572.964 Td /F1 9.8 Tf [(all isolates. These data were converted to a single epidemiological index using PCA \(Figure 6\). Interestingly, despite the fact )] TJ ET BT 26.250 561.060 Td /F1 9.8 Tf [(that Hong Kong, like USA, is a non-tropical Northern Hemisphere country, the epidemic severity measures between the two are )] TJ ET BT 26.250 549.155 Td /F1 9.8 Tf [(relatively weakly correlated \()] TJ ET BT 149.237 549.155 Td /F5 9.8 Tf [(r)] TJ ET BT 152.483 547.091 Td /F5 8.7 Tf [(s)] TJ ET BT 156.817 549.155 Td /F1 9.8 Tf [([)] TJ ET BT 159.527 549.155 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 188.787 549.155 Td /F1 9.8 Tf [( 1)] TJ ET BT 196.918 549.155 Td /F5 9.8 Tf [(.USA)] TJ ET BT 219.675 549.155 Td /F1 9.8 Tf [(,)] TJ ET BT 222.385 549.155 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 251.645 549.155 Td /F1 9.8 Tf [( 1)] TJ ET BT 259.777 549.155 Td /F5 9.8 Tf [(.HK)] TJ ET BT 276.030 549.155 Td /F1 9.8 Tf [( ] = 0.36 with the p-value of 0.21\). Thus the Hong Kong dataset )] TJ ET BT 26.250 537.250 Td /F1 9.8 Tf [(provides a largely independent test of the model applicability.)] TJ ET BT 26.250 517.845 Td /F1 9.8 Tf [(Sequence and antigenic distances were computed in a manner similar to that for the US data \(the list of Hong Kong isolates )] TJ ET BT 26.250 505.941 Td /F1 9.8 Tf [(used for genetic distance calculation is in the supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 304.252 507.448 Td /F4 8.7 Tf [(21)] TJ ET 0.271 0.267 0.267 rg BT 313.889 505.941 Td /F1 9.8 Tf [(\). Again, in this analysis, a season corresponds to a calendar )] TJ ET BT 26.250 494.036 Td /F1 9.8 Tf [(year. Due to a low number of serologically tested isolates from Hong Kong proper, antigenic data were computed for a )] TJ ET BT 26.250 482.131 Td /F1 9.8 Tf [(combined set of Hong Kong and mainland China isolates. The seasonal epidemiology seems to be the same in Hong Kong and )] TJ ET BT 26.250 470.226 Td /F1 9.8 Tf [(Southern mainland China, and only Northern mainland China follows the standard Northern Hemisphere pattern)] TJ ET 0.267 0.267 0.267 rg BT 507.998 471.734 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 517.635 470.226 Td /F1 9.8 Tf [(. Moreover, )] TJ ET BT 26.250 458.322 Td /F1 9.8 Tf [(the Northern China epidemics follow the Southern China epidemics and not vice versa )] TJ ET 0.267 0.267 0.267 rg BT 400.699 459.829 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 410.336 458.322 Td /F1 9.8 Tf [(. Based on this observation, two )] TJ ET BT 26.250 446.417 Td /F1 9.8 Tf [(possible ways of merging these data sets were implemented, producing two versions of the serological distances \()] TJ ET BT 518.284 446.417 Td /F5 9.8 Tf [(ac)] TJ ET BT 528.580 446.417 Td /F1 9.8 Tf [( and )] TJ ET BT 550.264 446.417 Td /F5 9.8 Tf [(as)] TJ ET BT 560.560 446.417 Td /F1 9.8 Tf [( in )] TJ ET BT 26.250 434.512 Td /F1 9.8 Tf [(contrast to )] TJ ET BT 74.483 434.512 Td /F5 9.8 Tf [(aa)] TJ ET BT 85.325 434.512 Td /F1 9.8 Tf [( and )] TJ ET BT 107.009 434.512 Td /F5 9.8 Tf [(an)] TJ ET BT 117.851 434.512 Td /F1 9.8 Tf [( serological distances for US\). The first one \()] TJ ET BT 310.209 434.512 Td /F5 9.8 Tf [(ac)] TJ ET BT 320.505 434.512 Td /F1 9.8 Tf [(\) corresponds to the scenario where for all isolates \(Hong )] TJ ET BT 26.250 422.607 Td /F1 9.8 Tf [(Kong and China\) the season was considered to correspond to a calendar year, following the Hong Kong pattern. The second )] TJ ET BT 26.250 410.703 Td /F1 9.8 Tf [(one \()] TJ ET BT 48.470 410.703 Td /F5 9.8 Tf [(as)] TJ ET BT 58.766 410.703 Td /F1 9.8 Tf [(\) considers Hong Kong isolates following the Hong Kong pattern and China isolates following the Northern Hemisphere )] TJ ET BT 26.250 398.798 Td /F1 9.8 Tf [(pattern with seasons starting in the fall.)] TJ ET 0.965 0.965 0.965 rg 26.250 203.762 555.000 185.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 388.917 m 581.250 388.917 l 581.250 388.167 l 26.250 388.167 l f 26.250 203.762 m 581.250 203.762 l 581.250 204.512 l 26.250 204.512 l f q 225.000 0 0 140.250 35.250 238.917 cm /I46 Do Q q 35.250 215.012 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 223.393 Td /F4 9.8 Tf [(Fig. 6: First Principal Component \(epi.PC1\) of three measures of epidemiological severity for Hong Kong)] TJ ET Q BT 26.250 186.738 Td /F1 9.8 Tf [(There are several possible ways to apply the model derived from the US data to the Hong Kong data. One would be to directly )] TJ ET BT 26.250 174.834 Td /F1 9.8 Tf [(compute the model prediction using the formula:)] TJ ET BT 26.250 155.429 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 155.429 Td /F1 9.8 Tf [( 1? = 1.26)] TJ ET BT 99.151 155.429 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 125.710 155.429 Td /F1 9.8 Tf [(2 + 1.78)] TJ ET BT 161.219 155.429 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 187.778 155.429 Td /F1 9.8 Tf [(2 + 0.81)] TJ ET BT 223.288 155.429 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 249.301 155.429 Td /F1 9.8 Tf [(2 0.41)] TJ ET BT 284.537 155.429 Td /F5 9.8 Tf [(se.n)] TJ ET BT 302.965 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 308.386 155.429 Td /F5 9.8 Tf [(.n)] TJ ET BT 316.517 155.429 Td /F1 9.8 Tf [(1 + 2.08)] TJ ET BT 352.027 155.429 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 371.000 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 376.421 155.429 Td /F5 9.8 Tf [(.n)] TJ ET BT 384.553 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 26.250 136.024 Td /F1 9.8 Tf [(and replacing )] TJ ET BT 87.490 136.024 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 106.463 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 111.884 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 120.016 136.024 Td /F1 9.8 Tf [(1 \(US data\) with either )] TJ ET BT 219.719 136.024 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 238.147 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 243.568 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 251.699 136.024 Td /F1 9.8 Tf [(1 or )] TJ ET BT 271.209 136.024 Td /F5 9.8 Tf [(as.n)] TJ ET BT 289.637 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 295.058 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 303.189 136.024 Td /F1 9.8 Tf [(1. Using )] TJ ET BT 341.663 136.024 Td /F5 9.8 Tf [(as.n)] TJ ET BT 360.090 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 365.511 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 373.643 136.024 Td /F1 9.8 Tf [(1 for the serological distance variable, this )] TJ ET BT 26.250 124.119 Td /F1 9.8 Tf [(formula produces a prediction that is reasonably well correlated with the real epidemiology data \()] TJ ET BT 442.419 124.119 Td /F5 9.8 Tf [(r)] TJ ET BT 445.666 122.055 Td /F1 8.7 Tf [(s)] TJ ET BT 449.999 124.119 Td /F1 9.8 Tf [([)] TJ ET BT 452.710 124.119 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 481.969 124.119 Td /F1 9.8 Tf [( 1,)] TJ ET BT 492.811 124.119 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 522.071 124.119 Td /F1 9.8 Tf [(1] = 0.60, )] TJ ET BT 26.250 112.215 Td /F1 9.8 Tf [(with the p-value of 0.012 in a permutation test; Figure 7, retro.direct plot\). This model allows rough prediction of the ups and )] TJ ET BT 26.250 100.310 Td /F1 9.8 Tf [(downs of the H3N2 influenza epidemics in 1997-2009, but gives a relatively poor quantitative estimate.)] TJ ET BT 26.250 80.905 Td /F1 9.8 Tf [(When the model is allowed to use the actual epidemiological data from Hong Kong to adjust its coefficients \(yielding 1.50, 1.46, -)] TJ ET BT 26.250 69.000 Td /F1 9.8 Tf [(0.82, 0.34 and 0.64 respectively\), the prediction is improved \(Figure 7, retro.adjust plot\). The adjusted model explains 0.75 of )] TJ ET BT 26.250 57.096 Td /F1 9.8 Tf [(the original variance with F-statistics p-value of 210 )] TJ ET BT 255.736 60.984 Td /F1 8.7 Tf [(-2)] TJ ET BT 263.440 57.096 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 37.691 Td /F1 9.8 Tf [(Finally, the stepwise reduction of the full model containing the genetic and serological distances from the corresponding )] TJ ET Q q 15.000 23.405 577.500 753.595 re W n 0.965 0.965 0.965 rg 26.250 747.845 555.000 29.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 747.845 m 581.250 747.845 l 581.250 748.595 l 26.250 748.595 l f q 35.250 759.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 5: Comparison of second stage retrospective model \(retro.2\) with observed epidemiological severity \(epi.PC1\))] TJ ET Q BT 26.250 730.821 Td /F4 9.8 Tf [(Independent test: Hong Kong data)] TJ ET BT 26.250 711.417 Td /F1 9.8 Tf [(To test whether these results pertain only to US or are more generally applicable to H3N2 influenza epidemiology, we collected )] TJ ET BT 26.250 699.512 Td /F1 9.8 Tf [(a similar data set from Hong Kong and mainland China. Three epidemiological indicators \()] TJ ET BT 414.232 699.512 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 436.442 699.512 Td /F1 9.8 Tf [( , )] TJ ET BT 444.574 699.512 Td /F5 9.8 Tf [(F-H3)] TJ ET BT 466.238 699.512 Td /F1 9.8 Tf [( and )] TJ ET BT 487.922 699.512 Td /F5 9.8 Tf [(F-Pos)] TJ ET BT 513.926 699.512 Td /F1 9.8 Tf [(\) were )] TJ ET BT 26.250 687.607 Td /F1 9.8 Tf [(obtained for 13 seasons \(from 1997 to 2009\) using data from Hong Kong Centre for Health Protection )] TJ ET 0.267 0.267 0.267 rg BT 466.307 689.114 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 475.944 687.607 Td /F1 9.8 Tf [(. Influenza epidemics in )] TJ ET BT 26.250 675.702 Td /F1 9.8 Tf [(Hong Kong usually show two peaks \(February-March and May-June\). Both peaks were combined into the same season, and )] TJ ET BT 26.250 663.798 Td /F1 9.8 Tf [(therefore a season corresponds to a calendar year in this analysis.)] TJ ET BT 26.250 644.393 Td /F1 9.8 Tf [(Because Hong Kong Centre for Health Protection data lacks ILI raw numbers, only %ILI for each month is available. Therefore, )] TJ ET BT 26.250 632.488 Td /F1 9.8 Tf [(we calculated the total epidemic severity \(%ILI*%Positive Specimens\) for each month, and then totaled these numbers for a )] TJ ET BT 26.250 620.583 Td /F1 9.8 Tf [(year to obtain. \(As a test to show that this method gives results similar to the regular method \(using cumulative raw numbers for )] TJ ET BT 26.250 608.679 Td /F1 9.8 Tf [(each season to calculate %ILI and %Positive Specimens\), we checked the correlation between the epidemic severity numbers )] TJ ET BT 26.250 596.774 Td /F1 9.8 Tf [(calculated using the two methods for the USA data. The correlation between the two methods is very high \(r=0.97\). The H3 )] TJ ET BT 26.250 584.869 Td /F1 9.8 Tf [(epidemic severity \()] TJ ET BT 107.516 584.869 Td /F5 9.8 Tf [(S-H3)] TJ ET BT 129.727 584.869 Td /F1 9.8 Tf [(\) was calculated as the total influenza epidemic severity prorated by the fraction of H3 isolates among )] TJ ET BT 26.250 572.964 Td /F1 9.8 Tf [(all isolates. These data were converted to a single epidemiological index using PCA \(Figure 6\). Interestingly, despite the fact )] TJ ET BT 26.250 561.060 Td /F1 9.8 Tf [(that Hong Kong, like USA, is a non-tropical Northern Hemisphere country, the epidemic severity measures between the two are )] TJ ET BT 26.250 549.155 Td /F1 9.8 Tf [(relatively weakly correlated \()] TJ ET BT 149.237 549.155 Td /F5 9.8 Tf [(r)] TJ ET BT 152.483 547.091 Td /F5 8.7 Tf [(s)] TJ ET BT 156.817 549.155 Td /F1 9.8 Tf [([)] TJ ET BT 159.527 549.155 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 188.787 549.155 Td /F1 9.8 Tf [( 1)] TJ ET BT 196.918 549.155 Td /F5 9.8 Tf [(.USA)] TJ ET BT 219.675 549.155 Td /F1 9.8 Tf [(,)] TJ ET BT 222.385 549.155 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 251.645 549.155 Td /F1 9.8 Tf [( 1)] TJ ET BT 259.777 549.155 Td /F5 9.8 Tf [(.HK)] TJ ET BT 276.030 549.155 Td /F1 9.8 Tf [( ] = 0.36 with the p-value of 0.21\). Thus the Hong Kong dataset )] TJ ET BT 26.250 537.250 Td /F1 9.8 Tf [(provides a largely independent test of the model applicability.)] TJ ET BT 26.250 517.845 Td /F1 9.8 Tf [(Sequence and antigenic distances were computed in a manner similar to that for the US data \(the list of Hong Kong isolates )] TJ ET BT 26.250 505.941 Td /F1 9.8 Tf [(used for genetic distance calculation is in the supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 304.252 507.448 Td /F4 8.7 Tf [(21)] TJ ET 0.271 0.267 0.267 rg BT 313.889 505.941 Td /F1 9.8 Tf [(\). Again, in this analysis, a season corresponds to a calendar )] TJ ET BT 26.250 494.036 Td /F1 9.8 Tf [(year. Due to a low number of serologically tested isolates from Hong Kong proper, antigenic data were computed for a )] TJ ET BT 26.250 482.131 Td /F1 9.8 Tf [(combined set of Hong Kong and mainland China isolates. The seasonal epidemiology seems to be the same in Hong Kong and )] TJ ET BT 26.250 470.226 Td /F1 9.8 Tf [(Southern mainland China, and only Northern mainland China follows the standard Northern Hemisphere pattern)] TJ ET 0.267 0.267 0.267 rg BT 507.998 471.734 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 517.635 470.226 Td /F1 9.8 Tf [(. Moreover, )] TJ ET BT 26.250 458.322 Td /F1 9.8 Tf [(the Northern China epidemics follow the Southern China epidemics and not vice versa )] TJ ET 0.267 0.267 0.267 rg BT 400.699 459.829 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 410.336 458.322 Td /F1 9.8 Tf [(. Based on this observation, two )] TJ ET BT 26.250 446.417 Td /F1 9.8 Tf [(possible ways of merging these data sets were implemented, producing two versions of the serological distances \()] TJ ET BT 518.284 446.417 Td /F5 9.8 Tf [(ac)] TJ ET BT 528.580 446.417 Td /F1 9.8 Tf [( and )] TJ ET BT 550.264 446.417 Td /F5 9.8 Tf [(as)] TJ ET BT 560.560 446.417 Td /F1 9.8 Tf [( in )] TJ ET BT 26.250 434.512 Td /F1 9.8 Tf [(contrast to )] TJ ET BT 74.483 434.512 Td /F5 9.8 Tf [(aa)] TJ ET BT 85.325 434.512 Td /F1 9.8 Tf [( and )] TJ ET BT 107.009 434.512 Td /F5 9.8 Tf [(an)] TJ ET BT 117.851 434.512 Td /F1 9.8 Tf [( serological distances for US\). The first one \()] TJ ET BT 310.209 434.512 Td /F5 9.8 Tf [(ac)] TJ ET BT 320.505 434.512 Td /F1 9.8 Tf [(\) corresponds to the scenario where for all isolates \(Hong )] TJ ET BT 26.250 422.607 Td /F1 9.8 Tf [(Kong and China\) the season was considered to correspond to a calendar year, following the Hong Kong pattern. The second )] TJ ET BT 26.250 410.703 Td /F1 9.8 Tf [(one \()] TJ ET BT 48.470 410.703 Td /F5 9.8 Tf [(as)] TJ ET BT 58.766 410.703 Td /F1 9.8 Tf [(\) considers Hong Kong isolates following the Hong Kong pattern and China isolates following the Northern Hemisphere )] TJ ET BT 26.250 398.798 Td /F1 9.8 Tf [(pattern with seasons starting in the fall.)] TJ ET 0.965 0.965 0.965 rg 26.250 203.762 555.000 185.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 388.917 m 581.250 388.917 l 581.250 388.167 l 26.250 388.167 l f 26.250 203.762 m 581.250 203.762 l 581.250 204.512 l 26.250 204.512 l f q 225.000 0 0 140.250 35.250 238.917 cm /I48 Do Q q 35.250 215.012 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 223.393 Td /F4 9.8 Tf [(Fig. 6: First Principal Component \(epi.PC1\) of three measures of epidemiological severity for Hong Kong)] TJ ET Q BT 26.250 186.738 Td /F1 9.8 Tf [(There are several possible ways to apply the model derived from the US data to the Hong Kong data. One would be to directly )] TJ ET BT 26.250 174.834 Td /F1 9.8 Tf [(compute the model prediction using the formula:)] TJ ET BT 26.250 155.429 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 155.429 Td /F1 9.8 Tf [( 1? = 1.26)] TJ ET BT 99.151 155.429 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 125.710 155.429 Td /F1 9.8 Tf [(2 + 1.78)] TJ ET BT 161.219 155.429 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 187.778 155.429 Td /F1 9.8 Tf [(2 + 0.81)] TJ ET BT 223.288 155.429 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 249.301 155.429 Td /F1 9.8 Tf [(2 0.41)] TJ ET BT 284.537 155.429 Td /F5 9.8 Tf [(se.n)] TJ ET BT 302.965 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 308.386 155.429 Td /F5 9.8 Tf [(.n)] TJ ET BT 316.517 155.429 Td /F1 9.8 Tf [(1 + 2.08)] TJ ET BT 352.027 155.429 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 371.000 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 376.421 155.429 Td /F5 9.8 Tf [(.n)] TJ ET BT 384.553 155.429 Td /F1 9.8 Tf [(1)] TJ ET BT 26.250 136.024 Td /F1 9.8 Tf [(and replacing )] TJ ET BT 87.490 136.024 Td /F5 9.8 Tf [(aa.n)] TJ ET BT 106.463 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 111.884 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 120.016 136.024 Td /F1 9.8 Tf [(1 \(US data\) with either )] TJ ET BT 219.719 136.024 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 238.147 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 243.568 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 251.699 136.024 Td /F1 9.8 Tf [(1 or )] TJ ET BT 271.209 136.024 Td /F5 9.8 Tf [(as.n)] TJ ET BT 289.637 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 295.058 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 303.189 136.024 Td /F1 9.8 Tf [(1. Using )] TJ ET BT 341.663 136.024 Td /F5 9.8 Tf [(as.n)] TJ ET BT 360.090 136.024 Td /F1 9.8 Tf [(1)] TJ ET BT 365.511 136.024 Td /F5 9.8 Tf [(.n)] TJ ET BT 373.643 136.024 Td /F1 9.8 Tf [(1 for the serological distance variable, this )] TJ ET BT 26.250 124.119 Td /F1 9.8 Tf [(formula produces a prediction that is reasonably well correlated with the real epidemiology data \()] TJ ET BT 442.419 124.119 Td /F5 9.8 Tf [(r)] TJ ET BT 445.666 122.055 Td /F1 8.7 Tf [(s)] TJ ET BT 449.999 124.119 Td /F1 9.8 Tf [([)] TJ ET BT 452.710 124.119 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 481.969 124.119 Td /F1 9.8 Tf [( 1,)] TJ ET BT 492.811 124.119 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 522.071 124.119 Td /F1 9.8 Tf [(1] = 0.60, )] TJ ET BT 26.250 112.215 Td /F1 9.8 Tf [(with the p-value of 0.012 in a permutation test; Figure 7, retro.direct plot\). This model allows rough prediction of the ups and )] TJ ET BT 26.250 100.310 Td /F1 9.8 Tf [(downs of the H3N2 influenza epidemics in 1997-2009, but gives a relatively poor quantitative estimate.)] TJ ET BT 26.250 80.905 Td /F1 9.8 Tf [(When the model is allowed to use the actual epidemiological data from Hong Kong to adjust its coefficients \(yielding 1.50, 1.46, -)] TJ ET BT 26.250 69.000 Td /F1 9.8 Tf [(0.82, 0.34 and 0.64 respectively\), the prediction is improved \(Figure 7, retro.adjust plot\). The adjusted model explains 0.75 of )] TJ ET BT 26.250 57.096 Td /F1 9.8 Tf [(the original variance with F-statistics p-value of 210 )] TJ ET BT 255.736 60.984 Td /F1 8.7 Tf [(-2)] TJ ET BT 263.440 57.096 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 37.691 Td /F1 9.8 Tf [(Finally, the stepwise reduction of the full model containing the genetic and serological distances from the corresponding )] TJ ET Q q 225.000 0 0 140.250 35.250 238.917 cm /I50 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(6)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 336 0 obj << /Type /Annot /Subtype /Link /A 337 0 R /Border [0 0 0] /H /I /Rect [ 466.3065 688.3127 475.9438 697.1310 ] >> endobj 337 0 obj << /Type /Action >> endobj 338 0 obj << /Type /Annot /Subtype /Link /A 339 0 R /Border [0 0 0] /H /I /Rect [ 304.2518 506.6462 313.8891 515.4645 ] >> endobj 339 0 obj << /Type /Action >> endobj 340 0 obj << /Type /Annot /Subtype /Link /A 341 0 R /Border [0 0 0] /H /I /Rect [ 507.9975 470.9319 517.6348 479.7502 ] >> endobj 341 0 obj << /Type /Action >> endobj 342 0 obj << /Type /Annot /Subtype /Link /A 343 0 R /Border [0 0 0] /H /I /Rect [ 400.6988 459.0272 410.3361 467.8455 ] >> endobj 343 0 obj << /Type /Action >> endobj 344 0 obj << /Type /Annot /Subtype /Link /A 345 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 238.9170 260.2500 379.1670 ] >> endobj 345 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2010/12/figurespage09.png) >> endobj 346 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 187 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 403>> stream xA 0 =fy9뀟\>zp endstream endobj 347 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 187 /SMask 346 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 21274>> stream x}w|SڒeI!oc03/@ i&Mi&Ioh%aYf`clޒe˲%ko l˒<0?ytsϼBR83VJcJ@ðuN8r^"afVN81IXN8 `JXUUW_9ǍN81MW !2 * Q(nݪ5 G[X$SBfNbW !Yф` !!""_әK`F9'SY_ܼySP$''#!h4Fx0fsYN0222&qb<Jh.84aXNb#A0쨳btFe 50T㔐Gŏ\xpobu{C‘[ق 58t9ĉƄU {`BN >8LQ|*|L`6h4ZѠh jQ(X,;S%ǎ(R p555CCC</**jǎ4mׯ_g!!!k p>w}d0._F&1LTT``0k׮0LRP ͛H[Rg ,ǎlڴ)**Jfff޸q+::H(zzz[n1?gΜaQQQ}}}bJOaƘA̒"wFߺ,W^ ֭[ ?1$W Fz۶mC1Ih4]]]Xg5aE'p„=wȑ#}NYǜp◂($ Ah4zxxiJeKK@ SщGG>r}}}555կ듓Tjmm7H$1xgpLӛzBddd?BQTaɒ%&I B%( HDc9L8pѣ ?۷o>22e0b= ÞS0RjHˍp`q {ĔN \>XrՊ3gŪ}}}R̙3+WȂx;jor !r_ Wȟ#-bY,@UU7Y|y[[`mllLNNv|l(Fr>z@XuR{NӅN&fhd܇%^,K}u'X,$ __IZF0׻V+D> w@ 'f3oᰉ LW&E4(sÃ64*nA؃Ia@6ڭ>IW2uw3 &2ޛФ>!+"!`Rb/]2|p cZ0 #~ι'fNjkk{ ơC֮]{С_oN؅fvI˃IU2:KVj]؍ p߅ 88yUٳ999<L| Qhlt~ƅe'A󌷒xbX\__`VXFR,YRWW@.?{:@lU"S=\L)z%LBH>o\DROfh0eL)$ :hb#q!+'!$$t/EDD"##ǫ;ves uuuNjmm5C-Bl'v >TS×6q E\}y8,'&MJJ*-- BĔJeCCϟPq TyZX,h}'70޽{I$𰯯/%--M.O8U <čNGuaIl'&ݸq]^arޖJ'b->Իevr`W8ݻ/(((K.e0 ̻Ƙ|D !V#̡UYpYK*mWӀ[=ǻ3''Ε+W^rB5k؛:N6crgd̻pPpE H>4[LLj8x[D@Ԥ9NlloMM ;q^7?vLMP8,otT@8uCю~>^+7DPh;}͟aaax<חB0|ԩ0:pC 0\PPPUU}v4 `ݽ>8xpOMMEիظ8`7|P[[KPn @!dzx0WNbz.i"Fjkk|ACC"Nwq‰ aČ.!+]݈r3@*oq;um9˒&4h=Id gGT1111Ŧ 4DĹsr2\ヒK߻1t(*'x:@PNSUTTdggH$_1bI-[i籀Pq!`OM&.0qJ2h4:4j;򎎮 I_k%? :l('E}\PPQQ 77w ff= }^V)z{L+,}1M9kc,Q.BfA&d*… nnnZt4E x-~q $73/gJZnFmMo'GDaSh&qX ðpP c4999. 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endstream endobj 374 0 obj << /Type /Page /Parent 3 0 R /Annots [ 376 0 R 380 0 R 384 0 R 386 0 R 388 0 R 392 0 R 396 0 R 398 0 R 400 0 R 404 0 R 408 0 R 410 0 R ] /Contents 375 0 R >> endobj 375 0 obj << /Length 21428 >> stream 0.271 0.267 0.267 rg q 15.000 45.512 577.500 731.488 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(seasons \()] TJ ET BT 68.516 767.476 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 95.075 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 105.917 767.476 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 132.476 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 143.318 767.476 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 169.331 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 180.173 767.476 Td /F5 9.8 Tf [(se.n)] TJ ET BT 198.601 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 204.022 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 212.153 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 222.995 767.476 Td /F5 9.8 Tf [(sn.n)] TJ ET BT 241.423 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 246.844 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 254.975 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 265.817 767.476 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 283.699 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 289.120 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 297.251 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 308.093 767.476 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 326.521 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 331.942 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 340.073 767.476 Td /F1 9.8 Tf [(1 and )] TJ ET BT 367.178 767.476 Td /F5 9.8 Tf [(as.n)] TJ ET BT 385.606 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 391.027 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 399.158 767.476 Td /F1 9.8 Tf [(1\) leads to the following 4-parameter )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(model \(Figure 7, retro.stepwise plot\):)] TJ ET BT 26.250 736.167 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 736.167 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 736.167 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 103.480 736.167 Td /F1 9.8 Tf [(2 + )] TJ ET BT 120.016 736.167 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 146.575 736.167 Td /F1 9.8 Tf [(2 + )] TJ ET BT 163.111 736.167 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 181.538 736.167 Td /F1 9.8 Tf [(1)] TJ ET BT 186.959 736.167 Td /F5 9.8 Tf [(.n)] TJ ET BT 195.091 736.167 Td /F1 9.8 Tf [(1 + )] TJ ET BT 211.627 736.167 Td /F5 9.8 Tf [(as.n)] TJ ET BT 230.054 736.167 Td /F1 9.8 Tf [(1)] TJ ET BT 235.475 736.167 Td /F5 9.8 Tf [(.n)] TJ ET BT 243.607 736.167 Td /F1 9.8 Tf [(1 + 0)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(The model coefficients are 1.25, 0.75, 0.76 and 1.10 respectively; it explains 0.78 of the original variance with F-statistics p-)] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(value of 510-3. When trained on 8 out of the 13 seasons \(leave-5-out jackknife test scheme\) , this model explains 0.42 of the )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(original variance on average.)] TJ ET 0.965 0.965 0.965 rg 26.250 497.917 555.000 185.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 683.072 m 581.250 683.072 l 581.250 682.322 l 26.250 682.322 l f 26.250 497.917 m 581.250 497.917 l 581.250 498.667 l 26.250 498.667 l f q 225.000 0 0 140.250 35.250 533.072 cm /I52 Do Q q 35.250 509.167 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 517.548 Td /F4 9.8 Tf [(Fig. 7: Comparison of different retrospective models with observed Hong Kong epidemiological severity \(epi.PC1\))] TJ ET Q BT 26.250 480.893 Td /F4 9.8 Tf [(Projection model: Southern Hemisphere isolates)] TJ ET BT 26.250 461.488 Td /F1 9.8 Tf [(The retrospective model allows us to accurately reconstruct the epidemiological severity of a season using sequence and )] TJ ET BT 26.250 449.583 Td /F1 9.8 Tf [(serological data from that seasons viral isolates. This provides a framework to project severity for the upcoming season based )] TJ ET BT 26.250 437.679 Td /F1 9.8 Tf [(on assumptions about the population of viruses that might circulate in that season. An obvious assumption to assess would be )] TJ ET BT 26.250 425.774 Td /F1 9.8 Tf [(that the population of viruses in an upcoming Northern Hemisphere season is identical to the population of viruses seen in the )] TJ ET BT 26.250 413.869 Td /F1 9.8 Tf [(preceding Southern Hemisphere influenza season. To this end we use the sequence and serological data for the isolates )] TJ ET BT 26.250 401.964 Td /F1 9.8 Tf [(observed in the Southern Hemisphere in the season preceding the flu season in the Northern Hemisphere. By September-)] TJ ET BT 26.250 390.060 Td /F1 9.8 Tf [(October the Southern Hemisphere isolates are, at least in principle, available for analysis before the start of the Northern )] TJ ET BT 26.250 378.155 Td /F1 9.8 Tf [(Hemisphere flu season. In any given season these Southern Hemisphere isolates are used as a substitute for the current )] TJ ET BT 26.250 366.250 Td /F1 9.8 Tf [(Northern Hemisphere isolates as shown in Figure 8.)] TJ ET 0.965 0.965 0.965 rg 26.250 187.060 555.000 169.310 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 356.369 m 581.250 356.369 l 581.250 355.619 l 26.250 355.619 l f 26.250 187.060 m 581.250 187.060 l 581.250 187.810 l 26.250 187.810 l f q 225.000 0 0 112.500 35.250 234.119 cm /I54 Do Q q 35.250 198.310 537.000 29.810 re W n 0.271 0.267 0.267 rg BT 35.250 218.595 Td /F4 9.8 Tf [(Fig. 8: Computation of inter-season genetic and serological distances using the isolates from the Southern )] TJ ET BT 35.250 206.691 Td /F4 9.8 Tf [(Hemisphere. Distances computed along the red arrows replace those, computed along the dashed arrows)] TJ ET Q BT 26.250 170.036 Td /F1 9.8 Tf [(For the purpose of this analysis, we considered Southern Hemisphere as comprising only non-tropical Southern countries )] TJ ET BT 26.250 158.131 Td /F1 9.8 Tf [(because of a different influenza epidemic pattern in the Tropics )] TJ ET 0.267 0.267 0.267 rg BT 300.469 159.638 Td /F4 8.7 Tf [(31)] TJ ET 0.271 0.267 0.267 rg BT 310.106 158.131 Td /F1 9.8 Tf [(. Southern Hemisphere seasons were considered to be )] TJ ET BT 26.250 146.226 Td /F1 9.8 Tf [(equivalent to calendar years, and correspond to the subsequent Northern Hemisphere seasons \(e.g., 2003 Southern )] TJ ET BT 26.250 134.322 Td /F1 9.8 Tf [(Hemisphere season corresponds to the 2003/04 Northern Hemisphere season\). There were no Southern Hemisphere )] TJ ET BT 26.250 122.417 Td /F1 9.8 Tf [(sequences from 2008, and we used the only January 2009 sequence as a substitute for 2008 because January is borderline )] TJ ET BT 26.250 110.512 Td /F1 9.8 Tf [(between the two Southern seasons \(2008 and 2009\). List of Southern Hemisphere isolates used for genetic distance calculation )] TJ ET BT 26.250 98.607 Td /F1 9.8 Tf [(is in the supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 144.381 100.115 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 154.018 98.607 Td /F1 9.8 Tf [(. Genetic and antigenic distances were computed as before.)] TJ ET BT 26.250 79.203 Td /F1 9.8 Tf [(We apply the second stage retrospective model \(list of explanatory variables together with the coefficients\) trained on the )] TJ ET BT 26.250 67.298 Td /F1 9.8 Tf [(original dataset to this modified dataset to obtain the model projections to the current season using the Southern Hemisphere )] TJ ET BT 26.250 55.393 Td /F1 9.8 Tf [(data from the preceding season \(Figure 9\).)] TJ ET Q q 15.000 45.512 577.500 731.488 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(seasons \()] TJ ET BT 68.516 767.476 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 95.075 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 105.917 767.476 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 132.476 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 143.318 767.476 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 169.331 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 180.173 767.476 Td /F5 9.8 Tf [(se.n)] TJ ET BT 198.601 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 204.022 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 212.153 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 222.995 767.476 Td /F5 9.8 Tf [(sn.n)] TJ ET BT 241.423 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 246.844 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 254.975 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 265.817 767.476 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 283.699 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 289.120 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 297.251 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 308.093 767.476 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 326.521 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 331.942 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 340.073 767.476 Td /F1 9.8 Tf [(1 and )] TJ ET BT 367.178 767.476 Td /F5 9.8 Tf [(as.n)] TJ ET BT 385.606 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 391.027 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 399.158 767.476 Td /F1 9.8 Tf [(1\) leads to the following 4-parameter )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(model \(Figure 7, retro.stepwise plot\):)] TJ ET BT 26.250 736.167 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 736.167 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 736.167 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 103.480 736.167 Td /F1 9.8 Tf [(2 + )] TJ ET BT 120.016 736.167 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 146.575 736.167 Td /F1 9.8 Tf [(2 + )] TJ ET BT 163.111 736.167 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 181.538 736.167 Td /F1 9.8 Tf [(1)] TJ ET BT 186.959 736.167 Td /F5 9.8 Tf [(.n)] TJ ET BT 195.091 736.167 Td /F1 9.8 Tf [(1 + )] TJ ET BT 211.627 736.167 Td /F5 9.8 Tf [(as.n)] TJ ET BT 230.054 736.167 Td /F1 9.8 Tf [(1)] TJ ET BT 235.475 736.167 Td /F5 9.8 Tf [(.n)] TJ ET BT 243.607 736.167 Td /F1 9.8 Tf [(1 + 0)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(The model coefficients are 1.25, 0.75, 0.76 and 1.10 respectively; it explains 0.78 of the original variance with F-statistics p-)] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(value of 510-3. When trained on 8 out of the 13 seasons \(leave-5-out jackknife test scheme\) , this model explains 0.42 of the )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(original variance on average.)] TJ ET 0.965 0.965 0.965 rg 26.250 497.917 555.000 185.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 683.072 m 581.250 683.072 l 581.250 682.322 l 26.250 682.322 l f 26.250 497.917 m 581.250 497.917 l 581.250 498.667 l 26.250 498.667 l f q 225.000 0 0 140.250 35.250 533.072 cm /I56 Do Q q 35.250 509.167 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 517.548 Td /F4 9.8 Tf [(Fig. 7: Comparison of different retrospective models with observed Hong Kong epidemiological severity \(epi.PC1\))] TJ ET Q BT 26.250 480.893 Td /F4 9.8 Tf [(Projection model: Southern Hemisphere isolates)] TJ ET BT 26.250 461.488 Td /F1 9.8 Tf [(The retrospective model allows us to accurately reconstruct the epidemiological severity of a season using sequence and )] TJ ET BT 26.250 449.583 Td /F1 9.8 Tf [(serological data from that seasons viral isolates. This provides a framework to project severity for the upcoming season based )] TJ ET BT 26.250 437.679 Td /F1 9.8 Tf [(on assumptions about the population of viruses that might circulate in that season. An obvious assumption to assess would be )] TJ ET BT 26.250 425.774 Td /F1 9.8 Tf [(that the population of viruses in an upcoming Northern Hemisphere season is identical to the population of viruses seen in the )] TJ ET BT 26.250 413.869 Td /F1 9.8 Tf [(preceding Southern Hemisphere influenza season. To this end we use the sequence and serological data for the isolates )] TJ ET BT 26.250 401.964 Td /F1 9.8 Tf [(observed in the Southern Hemisphere in the season preceding the flu season in the Northern Hemisphere. By September-)] TJ ET BT 26.250 390.060 Td /F1 9.8 Tf [(October the Southern Hemisphere isolates are, at least in principle, available for analysis before the start of the Northern )] TJ ET BT 26.250 378.155 Td /F1 9.8 Tf [(Hemisphere flu season. In any given season these Southern Hemisphere isolates are used as a substitute for the current )] TJ ET BT 26.250 366.250 Td /F1 9.8 Tf [(Northern Hemisphere isolates as shown in Figure 8.)] TJ ET 0.965 0.965 0.965 rg 26.250 187.060 555.000 169.310 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 356.369 m 581.250 356.369 l 581.250 355.619 l 26.250 355.619 l f 26.250 187.060 m 581.250 187.060 l 581.250 187.810 l 26.250 187.810 l f q 225.000 0 0 112.500 35.250 234.119 cm /I58 Do Q q 35.250 198.310 537.000 29.810 re W n 0.271 0.267 0.267 rg BT 35.250 218.595 Td /F4 9.8 Tf [(Fig. 8: Computation of inter-season genetic and serological distances using the isolates from the Southern )] TJ ET BT 35.250 206.691 Td /F4 9.8 Tf [(Hemisphere. Distances computed along the red arrows replace those, computed along the dashed arrows)] TJ ET Q BT 26.250 170.036 Td /F1 9.8 Tf [(For the purpose of this analysis, we considered Southern Hemisphere as comprising only non-tropical Southern countries )] TJ ET BT 26.250 158.131 Td /F1 9.8 Tf [(because of a different influenza epidemic pattern in the Tropics )] TJ ET 0.267 0.267 0.267 rg BT 300.469 159.638 Td /F4 8.7 Tf [(31)] TJ ET 0.271 0.267 0.267 rg BT 310.106 158.131 Td /F1 9.8 Tf [(. Southern Hemisphere seasons were considered to be )] TJ ET BT 26.250 146.226 Td /F1 9.8 Tf [(equivalent to calendar years, and correspond to the subsequent Northern Hemisphere seasons \(e.g., 2003 Southern )] TJ ET BT 26.250 134.322 Td /F1 9.8 Tf [(Hemisphere season corresponds to the 2003/04 Northern Hemisphere season\). There were no Southern Hemisphere )] TJ ET BT 26.250 122.417 Td /F1 9.8 Tf [(sequences from 2008, and we used the only January 2009 sequence as a substitute for 2008 because January is borderline )] TJ ET BT 26.250 110.512 Td /F1 9.8 Tf [(between the two Southern seasons \(2008 and 2009\). List of Southern Hemisphere isolates used for genetic distance calculation )] TJ ET BT 26.250 98.607 Td /F1 9.8 Tf [(is in the supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 144.381 100.115 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 154.018 98.607 Td /F1 9.8 Tf [(. Genetic and antigenic distances were computed as before.)] TJ ET BT 26.250 79.203 Td /F1 9.8 Tf [(We apply the second stage retrospective model \(list of explanatory variables together with the coefficients\) trained on the )] TJ ET BT 26.250 67.298 Td /F1 9.8 Tf [(original dataset to this modified dataset to obtain the model projections to the current season using the Southern Hemisphere )] TJ ET BT 26.250 55.393 Td /F1 9.8 Tf [(data from the preceding season \(Figure 9\).)] TJ ET Q q 15.000 45.512 577.500 731.488 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(seasons \()] TJ ET BT 68.516 767.476 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 95.075 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 105.917 767.476 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 132.476 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 143.318 767.476 Td /F5 9.8 Tf [(ss.n.n)] TJ ET BT 169.331 767.476 Td /F1 9.8 Tf [(2, )] TJ ET BT 180.173 767.476 Td /F5 9.8 Tf [(se.n)] TJ ET BT 198.601 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 204.022 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 212.153 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 222.995 767.476 Td /F5 9.8 Tf [(sn.n)] TJ ET BT 241.423 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 246.844 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 254.975 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 265.817 767.476 Td /F5 9.8 Tf [(ss.n)] TJ ET BT 283.699 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 289.120 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 297.251 767.476 Td /F1 9.8 Tf [(1, )] TJ ET BT 308.093 767.476 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 326.521 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 331.942 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 340.073 767.476 Td /F1 9.8 Tf [(1 and )] TJ ET BT 367.178 767.476 Td /F5 9.8 Tf [(as.n)] TJ ET BT 385.606 767.476 Td /F1 9.8 Tf [(1)] TJ ET BT 391.027 767.476 Td /F5 9.8 Tf [(.n)] TJ ET BT 399.158 767.476 Td /F1 9.8 Tf [(1\) leads to the following 4-parameter )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(model \(Figure 7, retro.stepwise plot\):)] TJ ET BT 26.250 736.167 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 55.510 736.167 Td /F1 9.8 Tf [( 1 ~ )] TJ ET BT 76.921 736.167 Td /F5 9.8 Tf [(se.n.n)] TJ ET BT 103.480 736.167 Td /F1 9.8 Tf [(2 + )] TJ ET BT 120.016 736.167 Td /F5 9.8 Tf [(sn.n.n)] TJ ET BT 146.575 736.167 Td /F1 9.8 Tf [(2 + )] TJ ET BT 163.111 736.167 Td /F5 9.8 Tf [(ac.n)] TJ ET BT 181.538 736.167 Td /F1 9.8 Tf [(1)] TJ ET BT 186.959 736.167 Td /F5 9.8 Tf [(.n)] TJ ET BT 195.091 736.167 Td /F1 9.8 Tf [(1 + )] TJ ET BT 211.627 736.167 Td /F5 9.8 Tf [(as.n)] TJ ET BT 230.054 736.167 Td /F1 9.8 Tf [(1)] TJ ET BT 235.475 736.167 Td /F5 9.8 Tf [(.n)] TJ ET BT 243.607 736.167 Td /F1 9.8 Tf [(1 + 0)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(The model coefficients are 1.25, 0.75, 0.76 and 1.10 respectively; it explains 0.78 of the original variance with F-statistics p-)] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(value of 510-3. When trained on 8 out of the 13 seasons \(leave-5-out jackknife test scheme\) , this model explains 0.42 of the )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(original variance on average.)] TJ ET 0.965 0.965 0.965 rg 26.250 497.917 555.000 185.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 683.072 m 581.250 683.072 l 581.250 682.322 l 26.250 682.322 l f 26.250 497.917 m 581.250 497.917 l 581.250 498.667 l 26.250 498.667 l f q 225.000 0 0 140.250 35.250 533.072 cm /I60 Do Q q 35.250 509.167 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 517.548 Td /F4 9.8 Tf [(Fig. 7: Comparison of different retrospective models with observed Hong Kong epidemiological severity \(epi.PC1\))] TJ ET Q BT 26.250 480.893 Td /F4 9.8 Tf [(Projection model: Southern Hemisphere isolates)] TJ ET BT 26.250 461.488 Td /F1 9.8 Tf [(The retrospective model allows us to accurately reconstruct the epidemiological severity of a season using sequence and )] TJ ET BT 26.250 449.583 Td /F1 9.8 Tf [(serological data from that seasons viral isolates. This provides a framework to project severity for the upcoming season based )] TJ ET BT 26.250 437.679 Td /F1 9.8 Tf [(on assumptions about the population of viruses that might circulate in that season. An obvious assumption to assess would be )] TJ ET BT 26.250 425.774 Td /F1 9.8 Tf [(that the population of viruses in an upcoming Northern Hemisphere season is identical to the population of viruses seen in the )] TJ ET BT 26.250 413.869 Td /F1 9.8 Tf [(preceding Southern Hemisphere influenza season. To this end we use the sequence and serological data for the isolates )] TJ ET BT 26.250 401.964 Td /F1 9.8 Tf [(observed in the Southern Hemisphere in the season preceding the flu season in the Northern Hemisphere. By September-)] TJ ET BT 26.250 390.060 Td /F1 9.8 Tf [(October the Southern Hemisphere isolates are, at least in principle, available for analysis before the start of the Northern )] TJ ET BT 26.250 378.155 Td /F1 9.8 Tf [(Hemisphere flu season. In any given season these Southern Hemisphere isolates are used as a substitute for the current )] TJ ET BT 26.250 366.250 Td /F1 9.8 Tf [(Northern Hemisphere isolates as shown in Figure 8.)] TJ ET 0.965 0.965 0.965 rg 26.250 187.060 555.000 169.310 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 356.369 m 581.250 356.369 l 581.250 355.619 l 26.250 355.619 l f 26.250 187.060 m 581.250 187.060 l 581.250 187.810 l 26.250 187.810 l f q 225.000 0 0 112.500 35.250 234.119 cm /I62 Do Q q 35.250 198.310 537.000 29.810 re W n 0.271 0.267 0.267 rg BT 35.250 218.595 Td /F4 9.8 Tf [(Fig. 8: Computation of inter-season genetic and serological distances using the isolates from the Southern )] TJ ET BT 35.250 206.691 Td /F4 9.8 Tf [(Hemisphere. Distances computed along the red arrows replace those, computed along the dashed arrows)] TJ ET Q BT 26.250 170.036 Td /F1 9.8 Tf [(For the purpose of this analysis, we considered Southern Hemisphere as comprising only non-tropical Southern countries )] TJ ET BT 26.250 158.131 Td /F1 9.8 Tf [(because of a different influenza epidemic pattern in the Tropics )] TJ ET 0.267 0.267 0.267 rg BT 300.469 159.638 Td /F4 8.7 Tf [(31)] TJ ET 0.271 0.267 0.267 rg BT 310.106 158.131 Td /F1 9.8 Tf [(. Southern Hemisphere seasons were considered to be )] TJ ET BT 26.250 146.226 Td /F1 9.8 Tf [(equivalent to calendar years, and correspond to the subsequent Northern Hemisphere seasons \(e.g., 2003 Southern )] TJ ET BT 26.250 134.322 Td /F1 9.8 Tf [(Hemisphere season corresponds to the 2003/04 Northern Hemisphere season\). There were no Southern Hemisphere )] TJ ET BT 26.250 122.417 Td /F1 9.8 Tf [(sequences from 2008, and we used the only January 2009 sequence as a substitute for 2008 because January is borderline )] TJ ET BT 26.250 110.512 Td /F1 9.8 Tf [(between the two Southern seasons \(2008 and 2009\). List of Southern Hemisphere isolates used for genetic distance calculation )] TJ ET BT 26.250 98.607 Td /F1 9.8 Tf [(is in the supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 144.381 100.115 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 154.018 98.607 Td /F1 9.8 Tf [(. Genetic and antigenic distances were computed as before.)] TJ ET BT 26.250 79.203 Td /F1 9.8 Tf [(We apply the second stage retrospective model \(list of explanatory variables together with the coefficients\) trained on the )] TJ ET BT 26.250 67.298 Td /F1 9.8 Tf [(original dataset to this modified dataset to obtain the model projections to the current season using the Southern Hemisphere )] TJ ET BT 26.250 55.393 Td /F1 9.8 Tf [(data from the preceding season \(Figure 9\).)] TJ ET Q q 225.000 0 0 140.250 35.250 533.072 cm /I64 Do Q q 225.000 0 0 112.500 35.250 234.119 cm /I66 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(7)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 376 0 obj << /Type /Annot /Subtype /Link /A 377 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 533.0715 260.2500 673.3215 ] >> endobj 377 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2010/12/figurespage101.png) >> endobj 378 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 187 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 403>> stream xA 0 =fy9뀟\>zp endstream endobj 379 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 187 /SMask 378 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 22609>> stream x]w\SWnIFKdo܂`q/}U;S:jTȔ7a'+!H! !@?ssϹs9HRR͆ILbc lvhh\ APUL&1IIII|>@C\ILbJ8ILb 0h%<{lccX2IߕA1AS,IOO/,,$ELM$","J *++GGG_x![.AQTddL Ȍ(~r}}}Bp8%LB@QTMQ% {{G{2IƅJW 5'1. 7$Q tt(_&0bd*?)K<:00e+?)6)G,F X7?/ 6WYȠ8I2b2|$LQ(d;1]OPaX +77ݝb/~~~vvvqqqJC&GGU !7o>{,  Ǐb03g޾}L&eff82%%ET U$$1cU`bbrΝ)SX,OOϜ6999;wz@ D"QMNHRxܻ}1A!7o޼ybyx< x--B*aSS_~ƦS; ?)&P٠AƅLbL4 شi䍊u$%ME%_\JyL2|609::I3&$^XVɓ'$%bFſ -k?wED74F뭷6o|},r,׷sNwСz &6{\ZSSӼ3f C&6cP@,0߸nnn.\>}{cc[qqVss3@6mZNNN{{{wwҥK󵴴̙>2AI|*9I?,45,XAUV& ܴ|N{{FHH>BP(qqq4-((K,)--AE($%%-\ #*򐛅,-z{ASS&OtEuf̘!"vvv0vz饗$%#v`@wTL[[[\X[*([nrnr:mIE/jXaQmm%Kdff%8I+n߆ HMGѦϯ 1=&119Hl,rOO }}}eeeb DBQfS(.<==ElvKK @n"{xxHE'2z{!+ ޅ Ŭ6 :X,vɒ%ׯ_?ƍmdr222:;; @ٸqrbpQ8d=D@(+v|#l G4AAA )==]SS`466דd}}}]]]`0QQQ~mpp182 B%lxrر!WyshBCMصKHC4+V 6lGGǐMM͠ >ollfg̘aggp444drHHr-ȳv]T9(9I..hYhj*:m8:Ub*!!fO3E4/c? 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56kא ޿Zq砸x۶mDӧOϜ9rrrBNbߘL&:sH iVVVĜ;w-]mllbŊx]*(q8++k̙d2QII) =zq:VV7nŋ0|8,\]f|b޽qqq CMKK=zS6o_ZZ:j(||1c] bzŬ,===gg={TUU06xcwG"MMMј._|۶m8>|%r1#GGtN߽H$pG}B9 qƓ'O&N!]pɓ'ޚOZ-[߼ɭC9;ol!//xo߾ݺukaa;,X~}N4!//YCCc׽]Oa G8QrZ[Z_8rmMMSRRlggWVV6۷jiitӹXŵj%o|/))a2߿tR]]]PPPeez/= 1:zGfffnnѣ'L@ܛVWWݻ AY JJJ{hiiQ-* aΚK-Y_~... ._n]NN̛7o3_uu_7n^6YW{<)/OPWW`YG(JQQmHHBLJD"8`aaaaaAnظq#UO>9smxx8k֬:z(ŊCh4LNN&,Q(DB FwdpTlx௿`Dpt3@/~PS? d2?];'|}ahpu܈=pT(8x!!fҥ`d OXXv@lYx(gwmDK$XP<{`b{`EEb 13a033u\7p `<)iDuup*\ ,\_|%7Xp$tatv y8*n@XDFѰjXYAWT}`Jظko$< m[4lHHԞtX?sPuu9IJkװww߁fn.!О=?:/!Is37 |4"G!\_Â_}%_͛᫯ LÇs9$@As3DEŋt),Z$Ah(8[$*ZZAYCp *X',`X.hѥK-[]QQؐ!h*TT0yyrQ0A$ݻ°޽at|9a(1;qB~Lش 9;c&If?_"GEFb"Al,3PS7o«W`j L ǎ}0- ._{ VɓŰx{{L}…?)'۷(yjkS8tذye9@!"n@/^4t}MRS2mC}}tz-\!G"D))HQMREйshh>@0('6 4H3 Y/2ll 3&NPmT* 烉 1E把p$&b_~ 6ԩPY)W/n|Ԍ}Ԍ}Ԍ a:8tf󱜜%IInַ/㠨a`ȑW_a_}%Y|[÷)+J[AI%BcJJed`'Cn.aػwxM7ob]tVaXx88.;z4DGܹp,WEGQ3| Ӧ0nJA~||>`PQc` PR 8^*2O@zz0z4烦--0iXX@c#p|(*L ..w/<{Q+V͛oN5頮cU745AM &Lz02fPT޽a$MMASOS9䫣ݟ'ŋ(- fĜ6V;Kၙ=HUUxgݻZ3(D:NKVŋ;p49;w¢E˰9>fgr~^a*3mI l G 3: 0m;v쀎f8픈VPu}DULM1gg02G-[ 5zƾso+TWcff`^?`X͠y8* HL35 ?@D -,X/^@^BɕQoCXÂrUJ F{a ڸ&OeD+ꨬ àa׮A>h l|8X,t*w/l݊1ZV찤$ի;,0~D4޼˗!* ~,- #Ξ{kŨgB ))p2òe`dcO^^0kZ'VV<}-5ҁoDZ4Ì{ݻXB6p Lݽۉ{/BB$9I#++x+FtyʎV8Uԟ3cƔNdBy9Y2|pkk+W*y8*`07n۰aw}i)X, r…Ǐ[XXH`H_z Y``#[CCè(y8*pqq!H7o3gFDD|R!Ge/^􌏏:\ bccO:u ΐ!7,,GAAA~̘1BTVVJWFw&F}3$gnRmI/oBBQUU&;rHMtCQY#tQ<"L&S,S'9%"GeQEEEAAAs΍X`AFFQ oooxV{LxT<Yt: 1b\pիW#Gܺuy***8as6._fXQY#%,,LMMmɒ%DUUUMMM544ObllnF&7.%%ӹtvDO-MMMd2D"q6!?c\\vv{Yf1ccc<Yٚ"^~L+((  飮^SSӾOB5jzz2ᨬ>d20 [xq>}*---f``}GOFZhðB 222N\Kr??"|Ihjjڪ֭[NNN7 tww3SPPP~C GeB̬ƪUjXW7QY#*-n7"z'J%***AtݓQĨQ%sS{nʔ)W7QY#JHllet["Y/k+V;vL~<|p̘1ҕѝdbڵ:::6lکSFFF;V29ᨬ:tڵk'NېYfܹH0#-\amٲ%//oӦMh GTTT`` q_˗/R(&v>ޗ?ji#FԜ;w%KTUUE\!*gv>ʼnGرh|ͩ,ꨬ~baC|<\.?$T<`2!=<=!!8>)c-}1Xq~.*zhCe%pv! y8ڳ`p> ,d`aϟ-r y8*kD0(+c%{=<`.LUUs*SDV>xy HKK@S<f΄Eӓ&#p>DFB߾])N!Ge>},%/Ǩ[UT`%Hr*eQ9ի믰hAh(ܼ ?+VH\lB)r@_Fá(HK^`Rpteei jk!+ a (*aRƈ<C)CI9 ꨬyUNF߄rEM As3Lʂ)SL6!Gh[[XnhmPUsJ[Acaڇ*ؾ4 OC< |J0&8 ^ eQ9>Ey9,ZUU`fŐ C¬Y  F$U9?*f endstream endobj 416 0 obj << /Type /Page /Parent 3 0 R /Annots [ 418 0 R 422 0 R 424 0 R 426 0 R 428 0 R 430 0 R 434 0 R 438 0 R 440 0 R 442 0 R 444 0 R 446 0 R 450 0 R 454 0 R 456 0 R 458 0 R 460 0 R 462 0 R ] /Contents 417 0 R >> endobj 417 0 obj << /Length 17642 >> stream 0.271 0.267 0.267 rg q 15.000 30.835 577.500 746.165 re W n 0.965 0.965 0.965 rg 26.250 564.609 555.000 212.391 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 564.609 m 581.250 564.609 l 581.250 565.359 l 26.250 565.359 l f q 225.000 0 0 146.250 35.250 621.000 cm /I68 Do Q q 35.250 575.859 537.000 39.141 re W n 0.271 0.267 0.267 rg BT 35.250 605.476 Td /F4 9.8 Tf [(Fig. 9: Comparison of second stage projection model \(proj.2\) with observed epidemiological severity \(epi.PC1\).)] TJ ET BT 35.250 586.106 Td /F1 9.8 Tf [(Error bars show the root mean square deviation of the projections from the real observations)] TJ ET Q BT 26.250 547.585 Td /F1 9.8 Tf [(The projections explain 0.66 of the original )] TJ ET BT 212.134 547.585 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 241.393 547.585 Td /F1 9.8 Tf [(1 variance and shows an excellent correlation with the epidemiological )] TJ ET BT 26.250 535.680 Td /F1 9.8 Tf [(observations \()] TJ ET BT 87.480 535.680 Td /F5 9.8 Tf [(r)] TJ ET BT 90.727 533.616 Td /F1 8.7 Tf [(s)] TJ ET BT 95.060 535.680 Td /F1 9.8 Tf [([)] TJ ET BT 97.771 535.680 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 127.030 535.680 Td /F1 9.8 Tf [(1, )] TJ ET BT 137.872 535.680 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 167.132 535.680 Td /F1 9.8 Tf [(1] = 0.95, with the p-value <0.0001 in a permutation test\).)] TJ ET BT 26.250 516.276 Td /F4 9.8 Tf [(Projection using previous seasons)] TJ ET BT 26.250 496.871 Td /F1 9.8 Tf [(Although projections based on Southern Hemisphere data correlate quite well with the actual epidemiological observations in )] TJ ET BT 26.250 484.966 Td /F1 9.8 Tf [(the Northern Hemisphere, it would be useful to be able to make these projections earlier if possible, i.e. by the time when the )] TJ ET BT 26.250 473.061 Td /F1 9.8 Tf [(decisions concerning the next season vaccines are made. A straightforward application of our approach \(i.e. using only the data )] TJ ET BT 26.250 461.157 Td /F1 9.8 Tf [(from preceding years to predict the morbidity for the upcoming year\) proved to be insufficiently robust statistically \(not shown\). )] TJ ET BT 26.250 449.252 Td /F1 9.8 Tf [(Often, however, multiple lineages co-circulate in a given season, and the epidemiological picture may be different depending on )] TJ ET BT 26.250 437.347 Td /F1 9.8 Tf [(which lineage dominates the following season. Which of the co-circulating clades \(if any\) will become dominant in the next )] TJ ET BT 26.250 425.442 Td /F1 9.8 Tf [(season is not known in advance; however one can construct explicit hypotheses about the upcoming season by assuming each )] TJ ET BT 26.250 413.538 Td /F1 9.8 Tf [(of these clades taking over. Thus, it is possible to employ our model to explore the spectrum of possible predictions based on )] TJ ET BT 26.250 401.633 Td /F1 9.8 Tf [(such assumptions.)] TJ ET BT 26.250 382.228 Td /F1 9.8 Tf [(As a demonstration of this approach, we divided the USA isolates from the 2002-2003 season into two subgroups 9 Panama-)] TJ ET BT 26.250 370.323 Td /F1 9.8 Tf [(like \(members of the larger Sydney-like class\) \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 311.243 371.831 Td /F4 8.7 Tf [(32)] TJ ET 0.271 0.267 0.267 rg BT 320.880 370.323 Td /F1 9.8 Tf [(\) and 7 Fujian-like viruses \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 519.731 371.831 Td /F4 8.7 Tf [(33)] TJ ET 0.271 0.267 0.267 rg BT 529.368 370.323 Td /F1 9.8 Tf [(\), based on )] TJ ET BT 26.250 358.419 Td /F1 9.8 Tf [(the reconstructed phylogenetic tree for HA1 \(A/H3N2 influenza\) \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 387.146 359.926 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 396.784 358.419 Td /F1 9.8 Tf [(\) as described in )] TJ ET 0.267 0.267 0.267 rg BT 471.020 359.926 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 480.657 358.419 Td /F1 9.8 Tf [(. Each of the )] TJ ET BT 26.250 346.514 Td /F1 9.8 Tf [(subgroups was used to substitute for the real 2003-2004 season isolates in our data. The raw sequence distances computed for )] TJ ET BT 26.250 334.609 Td /F1 9.8 Tf [(these subgroups were normalized using means and standard deviations previously determined for the full dataset. Then we )] TJ ET BT 26.250 322.704 Td /F1 9.8 Tf [(used the list of variables and the coefficients determined for the second stage retrospective model to predict the severity of the )] TJ ET BT 26.250 310.800 Td /F1 9.8 Tf [(2003-2004 epidemics. The two subsets correspond to the two epidemiological hypotheses: one assumes that the 2003-2004 flu )] TJ ET BT 26.250 298.895 Td /F1 9.8 Tf [(season will be dominated by Panama-like H3N2 virus, whereas the other assumes the Fujian-like virus prevalence. The results )] TJ ET BT 26.250 286.990 Td /F1 9.8 Tf [(of these projections are shown on Figure 10.)] TJ ET 0.965 0.965 0.965 rg 26.250 74.050 555.000 203.060 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 277.109 m 581.250 277.109 l 581.250 276.359 l 26.250 276.359 l f 26.250 74.050 m 581.250 74.050 l 581.250 74.800 l 26.250 74.800 l f q 225.000 0 0 146.250 35.250 121.109 cm /I70 Do Q q 35.250 85.300 537.000 29.810 re W n 0.271 0.267 0.267 rg BT 35.250 105.585 Td /F4 9.8 Tf [(Fig. 10: Comparison of the previous-season projection models \(proj.Panama and proj.Fujian\) with observed )] TJ ET BT 35.250 93.681 Td /F4 9.8 Tf [(epidemiological severity \(epi.PC1\).)] TJ ET Q BT 26.250 57.026 Td /F1 9.8 Tf [(Using the Panama projection predicts a very mild flu season for 2003-2004; in contrast, the Fujian projection predicts a severe )] TJ ET BT 26.250 45.121 Td /F1 9.8 Tf [(epidemics. In reality the 2003-2004 flu season was dominated by the Fujian-like isolates worldwide and was the strongest on )] TJ ET Q q 15.000 30.835 577.500 746.165 re W n 0.965 0.965 0.965 rg 26.250 564.609 555.000 212.391 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 564.609 m 581.250 564.609 l 581.250 565.359 l 26.250 565.359 l f q 225.000 0 0 146.250 35.250 621.000 cm /I72 Do Q q 35.250 575.859 537.000 39.141 re W n 0.271 0.267 0.267 rg BT 35.250 605.476 Td /F4 9.8 Tf [(Fig. 9: Comparison of second stage projection model \(proj.2\) with observed epidemiological severity \(epi.PC1\).)] TJ ET BT 35.250 586.106 Td /F1 9.8 Tf [(Error bars show the root mean square deviation of the projections from the real observations)] TJ ET Q BT 26.250 547.585 Td /F1 9.8 Tf [(The projections explain 0.66 of the original )] TJ ET BT 212.134 547.585 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 241.393 547.585 Td /F1 9.8 Tf [(1 variance and shows an excellent correlation with the epidemiological )] TJ ET BT 26.250 535.680 Td /F1 9.8 Tf [(observations \()] TJ ET BT 87.480 535.680 Td /F5 9.8 Tf [(r)] TJ ET BT 90.727 533.616 Td /F1 8.7 Tf [(s)] TJ ET BT 95.060 535.680 Td /F1 9.8 Tf [([)] TJ ET BT 97.771 535.680 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 127.030 535.680 Td /F1 9.8 Tf [(1, )] TJ ET BT 137.872 535.680 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 167.132 535.680 Td /F1 9.8 Tf [(1] = 0.95, with the p-value <0.0001 in a permutation test\).)] TJ ET BT 26.250 516.276 Td /F4 9.8 Tf [(Projection using previous seasons)] TJ ET BT 26.250 496.871 Td /F1 9.8 Tf [(Although projections based on Southern Hemisphere data correlate quite well with the actual epidemiological observations in )] TJ ET BT 26.250 484.966 Td /F1 9.8 Tf [(the Northern Hemisphere, it would be useful to be able to make these projections earlier if possible, i.e. by the time when the )] TJ ET BT 26.250 473.061 Td /F1 9.8 Tf [(decisions concerning the next season vaccines are made. A straightforward application of our approach \(i.e. using only the data )] TJ ET BT 26.250 461.157 Td /F1 9.8 Tf [(from preceding years to predict the morbidity for the upcoming year\) proved to be insufficiently robust statistically \(not shown\). )] TJ ET BT 26.250 449.252 Td /F1 9.8 Tf [(Often, however, multiple lineages co-circulate in a given season, and the epidemiological picture may be different depending on )] TJ ET BT 26.250 437.347 Td /F1 9.8 Tf [(which lineage dominates the following season. Which of the co-circulating clades \(if any\) will become dominant in the next )] TJ ET BT 26.250 425.442 Td /F1 9.8 Tf [(season is not known in advance; however one can construct explicit hypotheses about the upcoming season by assuming each )] TJ ET BT 26.250 413.538 Td /F1 9.8 Tf [(of these clades taking over. Thus, it is possible to employ our model to explore the spectrum of possible predictions based on )] TJ ET BT 26.250 401.633 Td /F1 9.8 Tf [(such assumptions.)] TJ ET BT 26.250 382.228 Td /F1 9.8 Tf [(As a demonstration of this approach, we divided the USA isolates from the 2002-2003 season into two subgroups 9 Panama-)] TJ ET BT 26.250 370.323 Td /F1 9.8 Tf [(like \(members of the larger Sydney-like class\) \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 311.243 371.831 Td /F4 8.7 Tf [(32)] TJ ET 0.271 0.267 0.267 rg BT 320.880 370.323 Td /F1 9.8 Tf [(\) and 7 Fujian-like viruses \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 519.731 371.831 Td /F4 8.7 Tf [(33)] TJ ET 0.271 0.267 0.267 rg BT 529.368 370.323 Td /F1 9.8 Tf [(\), based on )] TJ ET BT 26.250 358.419 Td /F1 9.8 Tf [(the reconstructed phylogenetic tree for HA1 \(A/H3N2 influenza\) \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 387.146 359.926 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 396.784 358.419 Td /F1 9.8 Tf [(\) as described in )] TJ ET 0.267 0.267 0.267 rg BT 471.020 359.926 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 480.657 358.419 Td /F1 9.8 Tf [(. Each of the )] TJ ET BT 26.250 346.514 Td /F1 9.8 Tf [(subgroups was used to substitute for the real 2003-2004 season isolates in our data. The raw sequence distances computed for )] TJ ET BT 26.250 334.609 Td /F1 9.8 Tf [(these subgroups were normalized using means and standard deviations previously determined for the full dataset. Then we )] TJ ET BT 26.250 322.704 Td /F1 9.8 Tf [(used the list of variables and the coefficients determined for the second stage retrospective model to predict the severity of the )] TJ ET BT 26.250 310.800 Td /F1 9.8 Tf [(2003-2004 epidemics. The two subsets correspond to the two epidemiological hypotheses: one assumes that the 2003-2004 flu )] TJ ET BT 26.250 298.895 Td /F1 9.8 Tf [(season will be dominated by Panama-like H3N2 virus, whereas the other assumes the Fujian-like virus prevalence. The results )] TJ ET BT 26.250 286.990 Td /F1 9.8 Tf [(of these projections are shown on Figure 10.)] TJ ET 0.965 0.965 0.965 rg 26.250 74.050 555.000 203.060 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 277.109 m 581.250 277.109 l 581.250 276.359 l 26.250 276.359 l f 26.250 74.050 m 581.250 74.050 l 581.250 74.800 l 26.250 74.800 l f q 225.000 0 0 146.250 35.250 121.109 cm /I74 Do Q q 35.250 85.300 537.000 29.810 re W n 0.271 0.267 0.267 rg BT 35.250 105.585 Td /F4 9.8 Tf [(Fig. 10: Comparison of the previous-season projection models \(proj.Panama and proj.Fujian\) with observed )] TJ ET BT 35.250 93.681 Td /F4 9.8 Tf [(epidemiological severity \(epi.PC1\).)] TJ ET Q BT 26.250 57.026 Td /F1 9.8 Tf [(Using the Panama projection predicts a very mild flu season for 2003-2004; in contrast, the Fujian projection predicts a severe )] TJ ET BT 26.250 45.121 Td /F1 9.8 Tf [(epidemics. In reality the 2003-2004 flu season was dominated by the Fujian-like isolates worldwide and was the strongest on )] TJ ET Q q 15.000 30.835 577.500 746.165 re W n 0.965 0.965 0.965 rg 26.250 564.609 555.000 212.391 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 564.609 m 581.250 564.609 l 581.250 565.359 l 26.250 565.359 l f q 225.000 0 0 146.250 35.250 621.000 cm /I76 Do Q q 35.250 575.859 537.000 39.141 re W n 0.271 0.267 0.267 rg BT 35.250 605.476 Td /F4 9.8 Tf [(Fig. 9: Comparison of second stage projection model \(proj.2\) with observed epidemiological severity \(epi.PC1\).)] TJ ET BT 35.250 586.106 Td /F1 9.8 Tf [(Error bars show the root mean square deviation of the projections from the real observations)] TJ ET Q BT 26.250 547.585 Td /F1 9.8 Tf [(The projections explain 0.66 of the original )] TJ ET BT 212.134 547.585 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 241.393 547.585 Td /F1 9.8 Tf [(1 variance and shows an excellent correlation with the epidemiological )] TJ ET BT 26.250 535.680 Td /F1 9.8 Tf [(observations \()] TJ ET BT 87.480 535.680 Td /F5 9.8 Tf [(r)] TJ ET BT 90.727 533.616 Td /F1 8.7 Tf [(s)] TJ ET BT 95.060 535.680 Td /F1 9.8 Tf [([)] TJ ET BT 97.771 535.680 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 127.030 535.680 Td /F1 9.8 Tf [(1, )] TJ ET BT 137.872 535.680 Td /F5 9.8 Tf [(epi.PC)] TJ ET BT 167.132 535.680 Td /F1 9.8 Tf [(1] = 0.95, with the p-value <0.0001 in a permutation test\).)] TJ ET BT 26.250 516.276 Td /F4 9.8 Tf [(Projection using previous seasons)] TJ ET BT 26.250 496.871 Td /F1 9.8 Tf [(Although projections based on Southern Hemisphere data correlate quite well with the actual epidemiological observations in )] TJ ET BT 26.250 484.966 Td /F1 9.8 Tf [(the Northern Hemisphere, it would be useful to be able to make these projections earlier if possible, i.e. by the time when the )] TJ ET BT 26.250 473.061 Td /F1 9.8 Tf [(decisions concerning the next season vaccines are made. A straightforward application of our approach \(i.e. using only the data )] TJ ET BT 26.250 461.157 Td /F1 9.8 Tf [(from preceding years to predict the morbidity for the upcoming year\) proved to be insufficiently robust statistically \(not shown\). )] TJ ET BT 26.250 449.252 Td /F1 9.8 Tf [(Often, however, multiple lineages co-circulate in a given season, and the epidemiological picture may be different depending on )] TJ ET BT 26.250 437.347 Td /F1 9.8 Tf [(which lineage dominates the following season. Which of the co-circulating clades \(if any\) will become dominant in the next )] TJ ET BT 26.250 425.442 Td /F1 9.8 Tf [(season is not known in advance; however one can construct explicit hypotheses about the upcoming season by assuming each )] TJ ET BT 26.250 413.538 Td /F1 9.8 Tf [(of these clades taking over. Thus, it is possible to employ our model to explore the spectrum of possible predictions based on )] TJ ET BT 26.250 401.633 Td /F1 9.8 Tf [(such assumptions.)] TJ ET BT 26.250 382.228 Td /F1 9.8 Tf [(As a demonstration of this approach, we divided the USA isolates from the 2002-2003 season into two subgroups 9 Panama-)] TJ ET BT 26.250 370.323 Td /F1 9.8 Tf [(like \(members of the larger Sydney-like class\) \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 311.243 371.831 Td /F4 8.7 Tf [(32)] TJ ET 0.271 0.267 0.267 rg BT 320.880 370.323 Td /F1 9.8 Tf [(\) and 7 Fujian-like viruses \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 519.731 371.831 Td /F4 8.7 Tf [(33)] TJ ET 0.271 0.267 0.267 rg BT 529.368 370.323 Td /F1 9.8 Tf [(\), based on )] TJ ET BT 26.250 358.419 Td /F1 9.8 Tf [(the reconstructed phylogenetic tree for HA1 \(A/H3N2 influenza\) \(supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 387.146 359.926 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 396.784 358.419 Td /F1 9.8 Tf [(\) as described in )] TJ ET 0.267 0.267 0.267 rg BT 471.020 359.926 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 480.657 358.419 Td /F1 9.8 Tf [(. Each of the )] TJ ET BT 26.250 346.514 Td /F1 9.8 Tf [(subgroups was used to substitute for the real 2003-2004 season isolates in our data. The raw sequence distances computed for )] TJ ET BT 26.250 334.609 Td /F1 9.8 Tf [(these subgroups were normalized using means and standard deviations previously determined for the full dataset. Then we )] TJ ET BT 26.250 322.704 Td /F1 9.8 Tf [(used the list of variables and the coefficients determined for the second stage retrospective model to predict the severity of the )] TJ ET BT 26.250 310.800 Td /F1 9.8 Tf [(2003-2004 epidemics. The two subsets correspond to the two epidemiological hypotheses: one assumes that the 2003-2004 flu )] TJ ET BT 26.250 298.895 Td /F1 9.8 Tf [(season will be dominated by Panama-like H3N2 virus, whereas the other assumes the Fujian-like virus prevalence. The results )] TJ ET BT 26.250 286.990 Td /F1 9.8 Tf [(of these projections are shown on Figure 10.)] TJ ET 0.965 0.965 0.965 rg 26.250 74.050 555.000 203.060 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 277.109 m 581.250 277.109 l 581.250 276.359 l 26.250 276.359 l f 26.250 74.050 m 581.250 74.050 l 581.250 74.800 l 26.250 74.800 l f q 225.000 0 0 146.250 35.250 121.109 cm /I78 Do Q q 35.250 85.300 537.000 29.810 re W n 0.271 0.267 0.267 rg BT 35.250 105.585 Td /F4 9.8 Tf [(Fig. 10: Comparison of the previous-season projection models \(proj.Panama and proj.Fujian\) with observed )] TJ ET BT 35.250 93.681 Td /F4 9.8 Tf [(epidemiological severity \(epi.PC1\).)] TJ ET Q BT 26.250 57.026 Td /F1 9.8 Tf [(Using the Panama projection predicts a very mild flu season for 2003-2004; in contrast, the Fujian projection predicts a severe )] TJ ET BT 26.250 45.121 Td /F1 9.8 Tf [(epidemics. In reality the 2003-2004 flu season was dominated by the Fujian-like isolates worldwide and was the strongest on )] TJ ET Q q 225.000 0 0 146.250 35.250 621.000 cm /I80 Do Q q 225.000 0 0 146.250 35.250 121.109 cm /I82 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(8)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 418 0 obj << /Type /Annot /Subtype /Link /A 419 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 621.0000 260.2500 767.2500 ] >> endobj 419 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2010/12/figurespage08.png) >> endobj 420 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 195 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 419>> stream xA 0 =fy9뀟\7 endstream endobj 421 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 195 /SMask 420 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 13449>> stream x}y\3 !@8DVDD_hEZZW?Uֶ֫[֢x_WE|ADD[Dn;1$MEٙgyf7fvf%$$0 Abz9h I&)4޽{lgg IdYIIUȊ(:%U& tATHD:k… .] OBA!hS322)(--}EpHD)4D1vaRWWB&իW*7QpuJ$M ֶ`0d6mhhXTT^4hH Qg}>F3wnE>UD~r&W&BH:m";y)yU& 89*AC&h' QYFE< .Cxt}^~WWWO>222]GH*'##cr\(h̙xbGGG0778p 3f`bgg y:ey%֩9Qx4;99wD6U4N0TktjnArI0i9*rk"G\ĉOu ~諈7QhB`t G###}|| t^ _]4Crᤥ;'//OcAK hhĉ`;PQ0j ^Ar2c%' 80113;;͛7g0 &L4 -G*rٹUD~țlA}T45MߥHA!mlFX@|@oQ KRIюԛެ QZ+ujFS+`jLe?(ۧ֩( X ޾%6m3aj`퐺Fdo3G0q"Wf!OZR07*L!!11I@Qu#7kar|<UhzZ`Pt8v qJo ZhoCQv Cc#=F*CfԳ?R!zF[;44O녅 Ud֥z@2;*Xanr8i AWGA*4(1bDFFڵk19(DD@`R=St,G)S@<}ӧ'O>x`yРA};ah K@%}+M@y׭KLLS*4'GkkkSRRjjjZZZٴUffIII+Vnz5 _n߾}ɺ8dX, JAe ҝ޼y3mڴٳg^|} CWڝ 3f+N.(iiY$y1b۵֭[WWWךm.JGGi11nmm~͛7_EE`fd?8 hii!()dA e, `hhLD]]~aaakgψWڝHuu۷ 7!ԚYŋ...L&wU]]s8W-GiF}mm>ɾ8p`~&OV]L2 [B.(4)UZZ*'Bq;t;2`ٳ իWf#kYzKVh'}֮]#hhyN1 WсW^]2ۋ/E󳲲ڹsgAAcdY{! $.&Q_~_vhPA sSY{ 6A;wSj 9ׯ_޽ Dr(,o*n1 Cm/̙3njsԩDpqA\fbO n!GnZ6/!ֶGa2wf0+V -prRX F,̪w_6gvΟ?  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55fc ~W^y%""d+ʭ[B2 gpppxxx޼y^z7R-cdb۷lb ///RI8h~GY؞:X.Aoni¡!77ŋ[#]VƆ>zȚ|llq~G %qqqTr:p8 \s[~=xg-CPHӃlxHlllzz:ϟ(9gkh4Êl`P7\.,$$ړHӑ#GYdS¡nsrr O%Ν;֭pvY'Nݻ'?~qq\.2++{ j(=¨z! $,,,33F"[(d2VSU`\N' L&'JB(.YߟOYCCC}V~VYYyIؿ?Ʉ֫e˖>:fLA\1Y9Lr∥ݺu+NBVv9tuux b XtuV[I?|6̐ xӅVvڒ%K cZ={|x5y-jeV)..(!UUU6l׿uĉwyO&4G-JK2LOODzRRRrrryyB9(?$}]Q :1P8V\fƬDw`TD-&$ _׺&''VX;(++#ӗ۷<>,5LeJN ׽^VwvvrӉb3ByyyN%>>>O>䔑uH*ߢz7OWYYY/^|:'ӗhǏ;W QOOύ7 Yd2322|||P[]DwZ2'iMMe¡eCsԮ.H%KTWW:KQY'ǬҥK* |dґZzmX}}+rث:^RRZD"Lm1M S(Rk5Yop ΪnSb͟?Ţlkkk=zˮjΝ@kM;Nksډj@8z/p<{lxx8}`>.+JkjjǮɏիW B({ ;555x>@" OUYY CƁrHRyjXWsQ-[pi1$ϟGQzēhHBy3׆vttnذT'$$k43"P{xaQQԀp9(@JeC}8AٳgQ]~8\. fQ AAAk׮Qg#KKKU*i/_3rx{{GDDܼyg:CdBEYYj$Ι3v%%%NQŽ(0NxR-yŋ{{{xh4iiiPlٲYflv$22rƍΒ4s%rZ_2 T*ڦЀm5:v=SqX,=N4GcGOƹJvܹ^x?\|9~FEP!fX^"5U-BvaQ/z|Attڵk92o޼1Z.8Az)#celڬ,6MV@ )b 0~ .w^>bttСCW\AQ4((護ڱcGrr2`k`Μ9l6 5mhhݻ6lerʪ*Hba`` ==ݕq( -(**ҍȝ;w~yyy_x fD"aX|df2 =TVVV  WlG&X9"… ]]]~add$4;b. _h\" ,8vYzerbNvÚ"k5'ώ:-Ñdr9!ΦDo37@ 8 (b@8yg͛7^ l322BCC0rÇNq7J_w 1Z.8Az-WAAA?蕝`tttx;**ʑM@Cep8:~]WmmmWnٴ/fnx}",,̑M@2G&p 'Hɉl•VZZ Õz% (s\$%%e``ÇlV{vvvccH$BYKHHpdPĐ`F$"G`Q* .֣EMK\F)//3=e5`WssX,neYv%===$(s\A`Gc222jjjRP( upPĐ`F$"QQQhuu5͆EZڴz$//O.WTTDT2Gs Xuuu61\;s!\NM9J:211OC?K2|LUܹs\kTT"k5%>!'֬YCiFͅg{dOOtN0.FDD$&&ڪ7mwR(y`}aGGvŮ'@t,XN755uuuutt]FYXl<&!Zz//f???,*݌,%֤ %93gݻwQunZ?yppp@@"F n݊tzBBBgg'e8ԩSoʕ+m[_?QMI(ʀ AESSSSSSG@쭥Ě]X)HKRRRNz pa)yl6rkNe}j{f2G]A'.cF?_i2@2G)Pp&(st~(st~A(89j :P?9z :P?0iD"YOL O#Bh4w}W `ȈJ29]`XL$dЁ"8 섈?x ==]*pJ[Ɯ^- &}i?4Ɨ$s=ad}OOOEEL&LfFFeUZ?\gSh\\ܞ={Hz=%-an{E?ں0+)s=@Q#6L˟ atG z ~uI0^$L%-ГaN/ @GȠE@QW#dЁ" Q#dЁ" eRLP樫2@P2@2G)Pp&(st~(st~aH$===ϧNS`W4G/]jAQT`wS(i t~NJHHqƕ+W~D[N7I{2@wΞ={ H@@^L (Xhrrrrr2`:]@2G)KQsS$1?MȠE)P`[(P՝քB@葳@a&Ãf#ZٚP0`fG!l endstream endobj 470 0 obj << /Type /Page /Parent 3 0 R /Annots [ 472 0 R 474 0 R 476 0 R 478 0 R 480 0 R 482 0 R 484 0 R 486 0 R 488 0 R 490 0 R 492 0 R 494 0 R 496 0 R 498 0 R 500 0 R 502 0 R 504 0 R 506 0 R 508 0 R 510 0 R 512 0 R 514 0 R 516 0 R 518 0 R 520 0 R 522 0 R 524 0 R 526 0 R 528 0 R 530 0 R 532 0 R 534 0 R 536 0 R 538 0 R 540 0 R 542 0 R 544 0 R 546 0 R 548 0 R 550 0 R 552 0 R 554 0 R 556 0 R 558 0 R 560 0 R 562 0 R 564 0 R 566 0 R 568 0 R 570 0 R 572 0 R 574 0 R 576 0 R 578 0 R 580 0 R 582 0 R 584 0 R 586 0 R 588 0 R 590 0 R 592 0 R 594 0 R 596 0 R 598 0 R 600 0 R 602 0 R 604 0 R 606 0 R 608 0 R 610 0 R 612 0 R 614 0 R 616 0 R 618 0 R 620 0 R ] /Contents 471 0 R >> endobj 471 0 obj << /Length 33253 >> stream 0.271 0.267 0.267 rg q 15.000 25.087 577.500 751.913 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(record for our range of dates in the USA.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(All data series used in this work may be found in supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 319.413 749.579 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 329.050 748.071 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 711.469 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 691.515 Td /F1 9.8 Tf [(As reviewed above, an extensive body of research supports the notion that seasonal severity of Influenza A is strongly )] TJ ET BT 26.250 679.610 Td /F1 9.8 Tf [(correlated with the degree of antigenic drift. Nevertheless, it is surprising that even applying a highly conservative approach \(i.e. )] TJ ET BT 26.250 667.705 Td /F1 9.8 Tf [(leave-half-out jackknife test\), over 90% of the variance in epidemic severity can be explained by the antigenic and genetic )] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(novelty of the hemagglutinin protein. This implies that factors such as climate, school cycles, other co-circulating pathogens, )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(and changes in influenza genes other than the hemagglutinin gene all have at best minor effects on seasonal morbidity, )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(although they may affect epidemic timing. A number of studies have shown that temperature and humidity play important roles )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(in the spread of influenza \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 154.150 621.593 Td /F4 8.7 Tf [(37)] TJ ET BT 163.788 621.593 Td /F4 8.7 Tf [(38)] TJ ET BT 173.425 621.593 Td /F4 8.7 Tf [(39)] TJ ET BT 183.063 621.593 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 192.700 620.086 Td /F1 9.8 Tf [(\), however, for the scale of our analysis \(e.g. geographically across all of North America )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(and temporally for entire seasons\), it might be difficult to detect a significant impact. Other co-circulating pathogens might )] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(reduce the number of seasonal influenza cases, e.g. owing to a direct impact on the host immune system or because of indirect )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(effects on the host as the vector for spread. This interference effect has been reported for respiratory syncytial virus and )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(rhinoviruses )] TJ ET 0.267 0.267 0.267 rg BT 81.513 573.974 Td /F4 8.7 Tf [(41)] TJ ET BT 91.150 573.974 Td /F4 8.7 Tf [(42)] TJ ET BT 100.788 573.974 Td /F4 8.7 Tf [(43)] TJ ET BT 110.425 573.974 Td /F4 8.7 Tf [(44)] TJ ET 0.271 0.267 0.267 rg BT 120.062 572.467 Td /F1 9.8 Tf [( but, given our results, this interference does not appear to have been significant during the seasons )] TJ ET BT 26.250 560.562 Td /F1 9.8 Tf [(covered in this study.)] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(Competition between Influenza A virus subtypes has been noted in several focused studies )] TJ ET 0.267 0.267 0.267 rg BT 421.866 542.665 Td /F4 8.7 Tf [(45)] TJ ET BT 431.503 542.665 Td /F4 8.7 Tf [(46)] TJ ET BT 441.141 542.665 Td /F4 8.7 Tf [(47)] TJ ET 0.271 0.267 0.267 rg BT 450.778 541.158 Td /F1 9.8 Tf [( as well as in a broader )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(analysis of surveillance data )] TJ ET 0.267 0.267 0.267 rg BT 150.884 530.760 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 160.522 529.253 Td /F1 9.8 Tf [( . However, the impact of competition from H1N1 on variation of variation of H3N2 seasonal )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(severity is unlikely to have been significant during the time interval studied here because H3N2 was dominant most seasons, )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(and furthermore, there is little evidence of positive selection for H1N1 antigenic novelty )] TJ ET 0.267 0.267 0.267 rg BT 402.327 506.951 Td /F4 8.7 Tf [(35)] TJ ET BT 411.964 506.951 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 421.602 505.443 Td /F1 9.8 Tf [(. In addition, Wolf et al. )] TJ ET 0.267 0.267 0.267 rg BT 523.489 506.951 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 533.127 505.443 Td /F1 9.8 Tf [( have )] TJ ET BT 26.250 493.539 Td /F1 9.8 Tf [(shown that during this period, H1N1 tended to dominate only after mild H3N2 seasons, so the competition appeared to be one-)] TJ ET BT 26.250 481.634 Td /F1 9.8 Tf [(sided.)] TJ ET BT 26.250 462.229 Td /F1 9.8 Tf [(Although our results show that the degree of hemagglutinin novelty explains most of seasonal morbidity, other viral proteins )] TJ ET BT 26.250 450.324 Td /F1 9.8 Tf [(have been shown to play important roles. For example, consider the evolutionary history of the Fujian H3N2 strain: initially an )] TJ ET BT 26.250 438.420 Td /F1 9.8 Tf [(antigenically novel minor variant, succeeded by a reassortant containing the novel Fujian HA gene, which in turn is succeeded )] TJ ET BT 26.250 426.515 Td /F1 9.8 Tf [(by a later pure Fujian variant in which all genes are derived from the original Fujian strain. An analysis of these events led to a )] TJ ET BT 26.250 414.610 Td /F1 9.8 Tf [(proposal that deleterious mutations in genes other than HA prevented the earliest members of this clade from dominating )] TJ ET BT 26.250 402.705 Td /F1 9.8 Tf [(despite their antigenic novelty but subsequent compensatory mutations ultimately led to its dominance over the reassortant )] TJ ET BT 26.250 390.801 Td /F1 9.8 Tf [(strain )] TJ ET 0.267 0.267 0.267 rg BT 52.799 392.308 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 62.437 390.801 Td /F1 9.8 Tf [(. Recent experiments on the later Fujian variant support the idea that mutations in the polymerase PA gene were )] TJ ET BT 26.250 378.896 Td /F1 9.8 Tf [(responsible for the decreased fitness of the original Fujian strain )] TJ ET 0.267 0.267 0.267 rg BT 305.334 380.403 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 314.971 378.896 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(Antigenic diversity in the preceding season is an important component of our statistical model which is consistent with the above )] TJ ET BT 26.250 347.586 Td /F1 9.8 Tf [(observation that an antigenically novel strain may circulate for a season as a minor variant before compensating mutations allow )] TJ ET BT 26.250 335.682 Td /F1 9.8 Tf [(it to dominate the following season. Mutations in the hemagglutinin gene itself might have effects on fitness beyond that of )] TJ ET BT 26.250 323.777 Td /F1 9.8 Tf [(changing antigenicity. For example, mutations have been identified in the HA gene that might allow the virus to evade the hosts )] TJ ET BT 26.250 311.872 Td /F1 9.8 Tf [(immune response but also modify binding to the host receptor leading to decreased replication fitness \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 483.086 313.379 Td /F4 8.7 Tf [(51)] TJ ET BT 492.724 313.379 Td /F4 8.7 Tf [(52)] TJ ET BT 502.361 313.379 Td /F4 8.7 Tf [(53)] TJ ET 0.271 0.267 0.267 rg BT 511.998 311.872 Td /F1 9.8 Tf [(\). Our results )] TJ ET BT 26.250 299.967 Td /F1 9.8 Tf [(suggest that this could be a common feature of early drift variants.)] TJ ET BT 26.250 280.563 Td /F1 9.8 Tf [(Antigenic diversity in the preceding season is not the only warning of a rise in morbidity but it is difficult to extract other clear )] TJ ET BT 26.250 268.658 Td /F1 9.8 Tf [(signals or rules from our analysis. In addition to the underlying complexity of the system, the sequence and HI data we have for )] TJ ET BT 26.250 256.753 Td /F1 9.8 Tf [(clinical isolates are not sufficiently comprehensive or representative. For example, in the 2002-2003 season, according to the )] TJ ET BT 26.250 244.848 Td /F1 9.8 Tf [(CDCs antigenic characterization of the 2002 03 U.S. Influenza season )] TJ ET 0.267 0.267 0.267 rg BT 341.653 246.356 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 351.290 244.848 Td /F1 9.8 Tf [(, 85% of the H3N2 clinical isolates were similar to )] TJ ET BT 26.250 232.944 Td /F1 9.8 Tf [(A/Panama/2007/99 and 15% were similar to A/Fujian/411/2002. However, our sequence data were about half Panama and half )] TJ ET BT 26.250 221.039 Td /F1 9.8 Tf [(Fujian whereas virtually all of the HI data we were able to obtain were similar to Fujian.)] TJ ET BT 26.250 201.634 Td /F1 9.8 Tf [(While more representative input data could improve the performance of our statistical model, refinements in other aspects of the )] TJ ET BT 26.250 189.729 Td /F1 9.8 Tf [(method may also be useful. For example, other sequence-derived measures of novelty might work better than our simple amino )] TJ ET BT 26.250 177.825 Td /F1 9.8 Tf [(acid replacements-based approach. The method of Gupta et al. )] TJ ET 0.267 0.267 0.267 rg BT 302.643 179.332 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 312.280 177.825 Td /F1 9.8 Tf [( yielded equivalent results but there are additional sequence-)] TJ ET BT 26.250 165.920 Td /F1 9.8 Tf [(based methods that should be evaluated as well \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 253.327 167.427 Td /F4 8.7 Tf [(54)] TJ ET 0.271 0.267 0.267 rg BT 262.965 165.920 Td /F1 9.8 Tf [(\).)] TJ ET BT 26.250 146.515 Td /F1 9.8 Tf [(Because our method provides an accurate reconstruction of epidemiological severity given sequence and serological data, one )] TJ ET BT 26.250 134.610 Td /F1 9.8 Tf [(can evaluate the epidemiological consequences of various assumptions about the population of viruses for the upcoming )] TJ ET BT 26.250 122.706 Td /F1 9.8 Tf [(season. As seen in Figure 9, projections using data from Southern Hemisphere isolates provide realistic estimates of severity )] TJ ET BT 26.250 110.801 Td /F1 9.8 Tf [(for the Northern Hemisphere. When there is significant diversity among co-circulating clades in a given season, one can assess )] TJ ET BT 26.250 98.896 Td /F1 9.8 Tf [(different scenarios for the upcoming season, as was done using data from 2002-2003 seasonal isolates to project severity for )] TJ ET BT 26.250 86.991 Td /F1 9.8 Tf [(the 2003-2004 season. The panel advising the US Food and Drug Administration on vaccines had difficulties that season )] TJ ET BT 26.250 75.087 Td /F1 9.8 Tf [(because the Fujian strain a minor strain in 2002-2003 was antigenically novel but was difficult to grow in chicken eggs. )] TJ ET BT 26.250 63.182 Td /F1 9.8 Tf [(Scientists at the CDC influenza branch had been able to passage the Fujian strain through dog kidney cells and obtain egg-)] TJ ET BT 26.250 51.277 Td /F1 9.8 Tf [(adapted virus but concern about contamination steered the FDA advisory committee towards a decision to use the Panama )] TJ ET BT 26.250 39.372 Td /F1 9.8 Tf [(strain \( cf )] TJ ET 0.267 0.267 0.267 rg BT 69.053 40.880 Td /F4 8.7 Tf [(55)] TJ ET 0.271 0.267 0.267 rg BT 78.690 39.372 Td /F1 9.8 Tf [(\). The ability to make accurate projections of epidemiological severity might have been helpful to further inform this )] TJ ET Q q 15.000 25.087 577.500 751.913 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(record for our range of dates in the USA.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(All data series used in this work may be found in supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 319.413 749.579 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 329.050 748.071 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 711.469 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 691.515 Td /F1 9.8 Tf [(As reviewed above, an extensive body of research supports the notion that seasonal severity of Influenza A is strongly )] TJ ET BT 26.250 679.610 Td /F1 9.8 Tf [(correlated with the degree of antigenic drift. Nevertheless, it is surprising that even applying a highly conservative approach \(i.e. )] TJ ET BT 26.250 667.705 Td /F1 9.8 Tf [(leave-half-out jackknife test\), over 90% of the variance in epidemic severity can be explained by the antigenic and genetic )] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(novelty of the hemagglutinin protein. This implies that factors such as climate, school cycles, other co-circulating pathogens, )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(and changes in influenza genes other than the hemagglutinin gene all have at best minor effects on seasonal morbidity, )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(although they may affect epidemic timing. A number of studies have shown that temperature and humidity play important roles )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(in the spread of influenza \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 154.150 621.593 Td /F4 8.7 Tf [(37)] TJ ET BT 163.788 621.593 Td /F4 8.7 Tf [(38)] TJ ET BT 173.425 621.593 Td /F4 8.7 Tf [(39)] TJ ET BT 183.063 621.593 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 192.700 620.086 Td /F1 9.8 Tf [(\), however, for the scale of our analysis \(e.g. geographically across all of North America )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(and temporally for entire seasons\), it might be difficult to detect a significant impact. Other co-circulating pathogens might )] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(reduce the number of seasonal influenza cases, e.g. owing to a direct impact on the host immune system or because of indirect )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(effects on the host as the vector for spread. This interference effect has been reported for respiratory syncytial virus and )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(rhinoviruses )] TJ ET 0.267 0.267 0.267 rg BT 81.513 573.974 Td /F4 8.7 Tf [(41)] TJ ET BT 91.150 573.974 Td /F4 8.7 Tf [(42)] TJ ET BT 100.788 573.974 Td /F4 8.7 Tf [(43)] TJ ET BT 110.425 573.974 Td /F4 8.7 Tf [(44)] TJ ET 0.271 0.267 0.267 rg BT 120.062 572.467 Td /F1 9.8 Tf [( but, given our results, this interference does not appear to have been significant during the seasons )] TJ ET BT 26.250 560.562 Td /F1 9.8 Tf [(covered in this study.)] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(Competition between Influenza A virus subtypes has been noted in several focused studies )] TJ ET 0.267 0.267 0.267 rg BT 421.866 542.665 Td /F4 8.7 Tf [(45)] TJ ET BT 431.503 542.665 Td /F4 8.7 Tf [(46)] TJ ET BT 441.141 542.665 Td /F4 8.7 Tf [(47)] TJ ET 0.271 0.267 0.267 rg BT 450.778 541.158 Td /F1 9.8 Tf [( as well as in a broader )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(analysis of surveillance data )] TJ ET 0.267 0.267 0.267 rg BT 150.884 530.760 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 160.522 529.253 Td /F1 9.8 Tf [( . However, the impact of competition from H1N1 on variation of variation of H3N2 seasonal )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(severity is unlikely to have been significant during the time interval studied here because H3N2 was dominant most seasons, )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(and furthermore, there is little evidence of positive selection for H1N1 antigenic novelty )] TJ ET 0.267 0.267 0.267 rg BT 402.327 506.951 Td /F4 8.7 Tf [(35)] TJ ET BT 411.964 506.951 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 421.602 505.443 Td /F1 9.8 Tf [(. In addition, Wolf et al. )] TJ ET 0.267 0.267 0.267 rg BT 523.489 506.951 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 533.127 505.443 Td /F1 9.8 Tf [( have )] TJ ET BT 26.250 493.539 Td /F1 9.8 Tf [(shown that during this period, H1N1 tended to dominate only after mild H3N2 seasons, so the competition appeared to be one-)] TJ ET BT 26.250 481.634 Td /F1 9.8 Tf [(sided.)] TJ ET BT 26.250 462.229 Td /F1 9.8 Tf [(Although our results show that the degree of hemagglutinin novelty explains most of seasonal morbidity, other viral proteins )] TJ ET BT 26.250 450.324 Td /F1 9.8 Tf [(have been shown to play important roles. For example, consider the evolutionary history of the Fujian H3N2 strain: initially an )] TJ ET BT 26.250 438.420 Td /F1 9.8 Tf [(antigenically novel minor variant, succeeded by a reassortant containing the novel Fujian HA gene, which in turn is succeeded )] TJ ET BT 26.250 426.515 Td /F1 9.8 Tf [(by a later pure Fujian variant in which all genes are derived from the original Fujian strain. An analysis of these events led to a )] TJ ET BT 26.250 414.610 Td /F1 9.8 Tf [(proposal that deleterious mutations in genes other than HA prevented the earliest members of this clade from dominating )] TJ ET BT 26.250 402.705 Td /F1 9.8 Tf [(despite their antigenic novelty but subsequent compensatory mutations ultimately led to its dominance over the reassortant )] TJ ET BT 26.250 390.801 Td /F1 9.8 Tf [(strain )] TJ ET 0.267 0.267 0.267 rg BT 52.799 392.308 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 62.437 390.801 Td /F1 9.8 Tf [(. Recent experiments on the later Fujian variant support the idea that mutations in the polymerase PA gene were )] TJ ET BT 26.250 378.896 Td /F1 9.8 Tf [(responsible for the decreased fitness of the original Fujian strain )] TJ ET 0.267 0.267 0.267 rg BT 305.334 380.403 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 314.971 378.896 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(Antigenic diversity in the preceding season is an important component of our statistical model which is consistent with the above )] TJ ET BT 26.250 347.586 Td /F1 9.8 Tf [(observation that an antigenically novel strain may circulate for a season as a minor variant before compensating mutations allow )] TJ ET BT 26.250 335.682 Td /F1 9.8 Tf [(it to dominate the following season. Mutations in the hemagglutinin gene itself might have effects on fitness beyond that of )] TJ ET BT 26.250 323.777 Td /F1 9.8 Tf [(changing antigenicity. For example, mutations have been identified in the HA gene that might allow the virus to evade the hosts )] TJ ET BT 26.250 311.872 Td /F1 9.8 Tf [(immune response but also modify binding to the host receptor leading to decreased replication fitness \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 483.086 313.379 Td /F4 8.7 Tf [(51)] TJ ET BT 492.724 313.379 Td /F4 8.7 Tf [(52)] TJ ET BT 502.361 313.379 Td /F4 8.7 Tf [(53)] TJ ET 0.271 0.267 0.267 rg BT 511.998 311.872 Td /F1 9.8 Tf [(\). Our results )] TJ ET BT 26.250 299.967 Td /F1 9.8 Tf [(suggest that this could be a common feature of early drift variants.)] TJ ET BT 26.250 280.563 Td /F1 9.8 Tf [(Antigenic diversity in the preceding season is not the only warning of a rise in morbidity but it is difficult to extract other clear )] TJ ET BT 26.250 268.658 Td /F1 9.8 Tf [(signals or rules from our analysis. In addition to the underlying complexity of the system, the sequence and HI data we have for )] TJ ET BT 26.250 256.753 Td /F1 9.8 Tf [(clinical isolates are not sufficiently comprehensive or representative. For example, in the 2002-2003 season, according to the )] TJ ET BT 26.250 244.848 Td /F1 9.8 Tf [(CDCs antigenic characterization of the 2002 03 U.S. Influenza season )] TJ ET 0.267 0.267 0.267 rg BT 341.653 246.356 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 351.290 244.848 Td /F1 9.8 Tf [(, 85% of the H3N2 clinical isolates were similar to )] TJ ET BT 26.250 232.944 Td /F1 9.8 Tf [(A/Panama/2007/99 and 15% were similar to A/Fujian/411/2002. However, our sequence data were about half Panama and half )] TJ ET BT 26.250 221.039 Td /F1 9.8 Tf [(Fujian whereas virtually all of the HI data we were able to obtain were similar to Fujian.)] TJ ET BT 26.250 201.634 Td /F1 9.8 Tf [(While more representative input data could improve the performance of our statistical model, refinements in other aspects of the )] TJ ET BT 26.250 189.729 Td /F1 9.8 Tf [(method may also be useful. For example, other sequence-derived measures of novelty might work better than our simple amino )] TJ ET BT 26.250 177.825 Td /F1 9.8 Tf [(acid replacements-based approach. The method of Gupta et al. )] TJ ET 0.267 0.267 0.267 rg BT 302.643 179.332 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 312.280 177.825 Td /F1 9.8 Tf [( yielded equivalent results but there are additional sequence-)] TJ ET BT 26.250 165.920 Td /F1 9.8 Tf [(based methods that should be evaluated as well \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 253.327 167.427 Td /F4 8.7 Tf [(54)] TJ ET 0.271 0.267 0.267 rg BT 262.965 165.920 Td /F1 9.8 Tf [(\).)] TJ ET BT 26.250 146.515 Td /F1 9.8 Tf [(Because our method provides an accurate reconstruction of epidemiological severity given sequence and serological data, one )] TJ ET BT 26.250 134.610 Td /F1 9.8 Tf [(can evaluate the epidemiological consequences of various assumptions about the population of viruses for the upcoming )] TJ ET BT 26.250 122.706 Td /F1 9.8 Tf [(season. As seen in Figure 9, projections using data from Southern Hemisphere isolates provide realistic estimates of severity )] TJ ET BT 26.250 110.801 Td /F1 9.8 Tf [(for the Northern Hemisphere. When there is significant diversity among co-circulating clades in a given season, one can assess )] TJ ET BT 26.250 98.896 Td /F1 9.8 Tf [(different scenarios for the upcoming season, as was done using data from 2002-2003 seasonal isolates to project severity for )] TJ ET BT 26.250 86.991 Td /F1 9.8 Tf [(the 2003-2004 season. The panel advising the US Food and Drug Administration on vaccines had difficulties that season )] TJ ET BT 26.250 75.087 Td /F1 9.8 Tf [(because the Fujian strain a minor strain in 2002-2003 was antigenically novel but was difficult to grow in chicken eggs. )] TJ ET BT 26.250 63.182 Td /F1 9.8 Tf [(Scientists at the CDC influenza branch had been able to passage the Fujian strain through dog kidney cells and obtain egg-)] TJ ET BT 26.250 51.277 Td /F1 9.8 Tf [(adapted virus but concern about contamination steered the FDA advisory committee towards a decision to use the Panama )] TJ ET BT 26.250 39.372 Td /F1 9.8 Tf [(strain \( cf )] TJ ET 0.267 0.267 0.267 rg BT 69.053 40.880 Td /F4 8.7 Tf [(55)] TJ ET 0.271 0.267 0.267 rg BT 78.690 39.372 Td /F1 9.8 Tf [(\). The ability to make accurate projections of epidemiological severity might have been helpful to further inform this )] TJ ET Q q 15.000 25.087 577.500 751.913 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(record for our range of dates in the USA.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(All data series used in this work may be found in supplementary file )] TJ ET 0.267 0.267 0.267 rg BT 319.413 749.579 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 329.050 748.071 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 711.469 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 691.515 Td /F1 9.8 Tf [(As reviewed above, an extensive body of research supports the notion that seasonal severity of Influenza A is strongly )] TJ ET BT 26.250 679.610 Td /F1 9.8 Tf [(correlated with the degree of antigenic drift. Nevertheless, it is surprising that even applying a highly conservative approach \(i.e. )] TJ ET BT 26.250 667.705 Td /F1 9.8 Tf [(leave-half-out jackknife test\), over 90% of the variance in epidemic severity can be explained by the antigenic and genetic )] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(novelty of the hemagglutinin protein. This implies that factors such as climate, school cycles, other co-circulating pathogens, )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(and changes in influenza genes other than the hemagglutinin gene all have at best minor effects on seasonal morbidity, )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(although they may affect epidemic timing. A number of studies have shown that temperature and humidity play important roles )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(in the spread of influenza \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 154.150 621.593 Td /F4 8.7 Tf [(37)] TJ ET BT 163.788 621.593 Td /F4 8.7 Tf [(38)] TJ ET BT 173.425 621.593 Td /F4 8.7 Tf [(39)] TJ ET BT 183.063 621.593 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 192.700 620.086 Td /F1 9.8 Tf [(\), however, for the scale of our analysis \(e.g. geographically across all of North America )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(and temporally for entire seasons\), it might be difficult to detect a significant impact. Other co-circulating pathogens might )] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(reduce the number of seasonal influenza cases, e.g. owing to a direct impact on the host immune system or because of indirect )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(effects on the host as the vector for spread. This interference effect has been reported for respiratory syncytial virus and )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(rhinoviruses )] TJ ET 0.267 0.267 0.267 rg BT 81.513 573.974 Td /F4 8.7 Tf [(41)] TJ ET BT 91.150 573.974 Td /F4 8.7 Tf [(42)] TJ ET BT 100.788 573.974 Td /F4 8.7 Tf [(43)] TJ ET BT 110.425 573.974 Td /F4 8.7 Tf [(44)] TJ ET 0.271 0.267 0.267 rg BT 120.062 572.467 Td /F1 9.8 Tf [( but, given our results, this interference does not appear to have been significant during the seasons )] TJ ET BT 26.250 560.562 Td /F1 9.8 Tf [(covered in this study.)] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(Competition between Influenza A virus subtypes has been noted in several focused studies )] TJ ET 0.267 0.267 0.267 rg BT 421.866 542.665 Td /F4 8.7 Tf [(45)] TJ ET BT 431.503 542.665 Td /F4 8.7 Tf [(46)] TJ ET BT 441.141 542.665 Td /F4 8.7 Tf [(47)] TJ ET 0.271 0.267 0.267 rg BT 450.778 541.158 Td /F1 9.8 Tf [( as well as in a broader )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(analysis of surveillance data )] TJ ET 0.267 0.267 0.267 rg BT 150.884 530.760 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 160.522 529.253 Td /F1 9.8 Tf [( . However, the impact of competition from H1N1 on variation of variation of H3N2 seasonal )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(severity is unlikely to have been significant during the time interval studied here because H3N2 was dominant most seasons, )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(and furthermore, there is little evidence of positive selection for H1N1 antigenic novelty )] TJ ET 0.267 0.267 0.267 rg BT 402.327 506.951 Td /F4 8.7 Tf [(35)] TJ ET BT 411.964 506.951 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 421.602 505.443 Td /F1 9.8 Tf [(. In addition, Wolf et al. )] TJ ET 0.267 0.267 0.267 rg BT 523.489 506.951 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 533.127 505.443 Td /F1 9.8 Tf [( have )] TJ ET BT 26.250 493.539 Td /F1 9.8 Tf [(shown that during this period, H1N1 tended to dominate only after mild H3N2 seasons, so the competition appeared to be one-)] TJ ET BT 26.250 481.634 Td /F1 9.8 Tf [(sided.)] TJ ET BT 26.250 462.229 Td /F1 9.8 Tf [(Although our results show that the degree of hemagglutinin novelty explains most of seasonal morbidity, other viral proteins )] TJ ET BT 26.250 450.324 Td /F1 9.8 Tf [(have been shown to play important roles. For example, consider the evolutionary history of the Fujian H3N2 strain: initially an )] TJ ET BT 26.250 438.420 Td /F1 9.8 Tf [(antigenically novel minor variant, succeeded by a reassortant containing the novel Fujian HA gene, which in turn is succeeded )] TJ ET BT 26.250 426.515 Td /F1 9.8 Tf [(by a later pure Fujian variant in which all genes are derived from the original Fujian strain. An analysis of these events led to a )] TJ ET BT 26.250 414.610 Td /F1 9.8 Tf [(proposal that deleterious mutations in genes other than HA prevented the earliest members of this clade from dominating )] TJ ET BT 26.250 402.705 Td /F1 9.8 Tf [(despite their antigenic novelty but subsequent compensatory mutations ultimately led to its dominance over the reassortant )] TJ ET BT 26.250 390.801 Td /F1 9.8 Tf [(strain )] TJ ET 0.267 0.267 0.267 rg BT 52.799 392.308 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 62.437 390.801 Td /F1 9.8 Tf [(. Recent experiments on the later Fujian variant support the idea that mutations in the polymerase PA gene were )] TJ ET BT 26.250 378.896 Td /F1 9.8 Tf [(responsible for the decreased fitness of the original Fujian strain )] TJ ET 0.267 0.267 0.267 rg BT 305.334 380.403 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 314.971 378.896 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(Antigenic diversity in the preceding season is an important component of our statistical model which is consistent with the above )] TJ ET BT 26.250 347.586 Td /F1 9.8 Tf [(observation that an antigenically novel strain may circulate for a season as a minor variant before compensating mutations allow )] TJ ET BT 26.250 335.682 Td /F1 9.8 Tf [(it to dominate the following season. Mutations in the hemagglutinin gene itself might have effects on fitness beyond that of )] TJ ET BT 26.250 323.777 Td /F1 9.8 Tf [(changing antigenicity. For example, mutations have been identified in the HA gene that might allow the virus to evade the hosts )] TJ ET BT 26.250 311.872 Td /F1 9.8 Tf [(immune response but also modify binding to the host receptor leading to decreased replication fitness \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 483.086 313.379 Td /F4 8.7 Tf [(51)] TJ ET BT 492.724 313.379 Td /F4 8.7 Tf [(52)] TJ ET BT 502.361 313.379 Td /F4 8.7 Tf [(53)] TJ ET 0.271 0.267 0.267 rg BT 511.998 311.872 Td /F1 9.8 Tf [(\). Our results )] TJ ET BT 26.250 299.967 Td /F1 9.8 Tf [(suggest that this could be a common feature of early drift variants.)] TJ ET BT 26.250 280.563 Td /F1 9.8 Tf [(Antigenic diversity in the preceding season is not the only warning of a rise in morbidity but it is difficult to extract other clear )] TJ ET BT 26.250 268.658 Td /F1 9.8 Tf [(signals or rules from our analysis. In addition to the underlying complexity of the system, the sequence and HI data we have for )] TJ ET BT 26.250 256.753 Td /F1 9.8 Tf [(clinical isolates are not sufficiently comprehensive or representative. For example, in the 2002-2003 season, according to the )] TJ ET BT 26.250 244.848 Td /F1 9.8 Tf [(CDCs antigenic characterization of the 2002 03 U.S. Influenza season )] TJ ET 0.267 0.267 0.267 rg BT 341.653 246.356 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 351.290 244.848 Td /F1 9.8 Tf [(, 85% of the H3N2 clinical isolates were similar to )] TJ ET BT 26.250 232.944 Td /F1 9.8 Tf [(A/Panama/2007/99 and 15% were similar to A/Fujian/411/2002. However, our sequence data were about half Panama and half )] TJ ET BT 26.250 221.039 Td /F1 9.8 Tf [(Fujian whereas virtually all of the HI data we were able to obtain were similar to Fujian.)] TJ ET BT 26.250 201.634 Td /F1 9.8 Tf [(While more representative input data could improve the performance of our statistical model, refinements in other aspects of the )] TJ ET BT 26.250 189.729 Td /F1 9.8 Tf [(method may also be useful. For example, other sequence-derived measures of novelty might work better than our simple amino )] TJ ET BT 26.250 177.825 Td /F1 9.8 Tf [(acid replacements-based approach. The method of Gupta et al. )] TJ ET 0.267 0.267 0.267 rg BT 302.643 179.332 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 312.280 177.825 Td /F1 9.8 Tf [( yielded equivalent results but there are additional sequence-)] TJ ET BT 26.250 165.920 Td /F1 9.8 Tf [(based methods that should be evaluated as well \(cf. )] TJ ET 0.267 0.267 0.267 rg BT 253.327 167.427 Td /F4 8.7 Tf [(54)] TJ ET 0.271 0.267 0.267 rg BT 262.965 165.920 Td /F1 9.8 Tf [(\).)] TJ ET BT 26.250 146.515 Td /F1 9.8 Tf [(Because our method provides an accurate reconstruction of epidemiological severity given sequence and serological data, one )] TJ ET BT 26.250 134.610 Td /F1 9.8 Tf [(can evaluate the epidemiological consequences of various assumptions about the population of viruses for the upcoming )] TJ ET BT 26.250 122.706 Td /F1 9.8 Tf [(season. As seen in Figure 9, projections using data from Southern Hemisphere isolates provide realistic estimates of severity )] TJ ET BT 26.250 110.801 Td /F1 9.8 Tf [(for the Northern Hemisphere. When there is significant diversity among co-circulating clades in a given season, one can assess )] TJ ET BT 26.250 98.896 Td /F1 9.8 Tf [(different scenarios for the upcoming season, as was done using data from 2002-2003 seasonal isolates to project severity for )] TJ ET BT 26.250 86.991 Td /F1 9.8 Tf [(the 2003-2004 season. The panel advising the US Food and Drug Administration on vaccines had difficulties that season )] TJ ET BT 26.250 75.087 Td /F1 9.8 Tf [(because the Fujian strain a minor strain in 2002-2003 was antigenically novel but was difficult to grow in chicken eggs. )] TJ ET BT 26.250 63.182 Td /F1 9.8 Tf [(Scientists at the CDC influenza branch had been able to passage the Fujian strain through dog kidney cells and obtain egg-)] TJ ET BT 26.250 51.277 Td /F1 9.8 Tf [(adapted virus but concern about contamination steered the FDA advisory committee towards a decision to use the Panama )] TJ ET BT 26.250 39.372 Td /F1 9.8 Tf [(strain \( cf )] TJ ET 0.267 0.267 0.267 rg BT 69.053 40.880 Td /F4 8.7 Tf [(55)] TJ ET 0.271 0.267 0.267 rg BT 78.690 39.372 Td /F1 9.8 Tf [(\). 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rg BT 26.250 767.476 Td /F1 9.8 Tf [(decision.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Although, in some cases, projections based on co-circulating clades could be helpful prior to the availability of Southern )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(Hemisphere isolates, thus assisting in vaccine strain decisions, in other situations, such as the 1997-1998 Sydney season, the )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(rapid emergence of a new dominant strain makes earlier projections effectively useless. Deeper sampling of representative viral )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(isolates might provide an earlier warning of such novel clades, and more sophisticated models using additional data might also )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(eventually prove helpful.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(Finally, we note that our predictions of influenza morbidity based on sequence and serological data are limited to the inter-)] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(pandemic period, and that our model cannot be used to project the severity of an emerging pandemic influenza virus, such as )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(2009 H1N1pdm. In addition, it remains unclear whether this model rooted in empirical data collected before the 2009 pandemic )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(will be suitable to predict the severity of influenza A/H3N2 season in the post-pandemic period. Both H3N2 and H1N1 have )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(begun to co-circulate in 2010 )] TJ ET 0.267 0.267 0.267 rg BT 154.150 634.936 Td /F4 8.7 Tf [(56)] TJ ET 0.271 0.267 0.267 rg BT 163.788 633.429 Td /F1 9.8 Tf [(, and further studies will need to determine whether the dynamics of these two subtypes has )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(changed and whether the algorithms proposed here need to be revised to accommodate these changes.)] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(The results presented here should be useful in the planning process for seasonal influenza. This work, along with the extensive )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(earlier research that revealed the correlation between antigenic drift and seasonal severity, provides an objective function for )] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(refining measures to characterize antigenicity and seasonal morbidity. Given that we can now use surveillance data to make )] TJ ET BT 26.250 566.405 Td /F1 9.8 Tf [(useful projections of influenza morbidity, we should begin to consider those changes to surveillance that maximize the )] TJ ET BT 26.250 554.500 Td /F1 9.8 Tf [(effectiveness of this approach.)] TJ ET BT 26.250 517.898 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 497.943 Td /F1 9.8 Tf [(David Lipman, corresponding author, is one of the Editors of )] TJ ET BT 288.545 497.943 Td /F5 9.8 Tf [(PLoS Currents: Influenza)] TJ ET BT 397.472 497.943 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 461.341 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 441.387 Td /F1 9.8 Tf [(We thank Dr. A.I. Klimov \(Influenza Division, Centers for Disease Control and Prevention\) for kindly providing the )] TJ ET BT 26.250 429.482 Td /F1 9.8 Tf [(haemagglutination-inhibition assay data of Influenza A\(H3N2\) isolates performed in 1998 and 1999 at CDC. We thank Dr. )] TJ ET BT 26.250 417.577 Td /F1 9.8 Tf [(Cheong-Chi Lau and Dr. Flemy Yip \(Hong Kong Centre for Health Protection\) for assistance with Hong Kong influenza )] TJ ET BT 26.250 405.672 Td /F1 9.8 Tf [(surveillance data. We thank Dr. Derek Smith \(University of Cambridge, UK\) for advice on the antigenic distance calculation and )] TJ ET BT 26.250 393.768 Td /F1 9.8 Tf [(for kindly providing haemagglutination-inhibition assay data used in [27]. We thank Dr. John Spouge \(National Center for )] TJ ET BT 26.250 381.863 Td /F1 9.8 Tf [(Biotechnology Information, NLM, NIH\) for helpful discussions of statistical analysis procedures.)] TJ ET BT 26.250 352.760 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 325.306 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 325.306 Td /F1 9.8 Tf [( Kilbourne ED. The molecular epidemiology of influenza. J Infect Dis. 1973 Apr;127\(4\):478-87. PubMed PMID: 4121053.)] TJ ET BT 26.250 305.901 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 305.901 Td /F1 9.8 Tf [(Torrens J. Influenza: its sequelae and treatment. Br Med J. 1934 Feb 17;1\(3815\):274-276. PubMed PMID: 20778073; )] TJ ET BT 26.250 293.997 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2444160.)] TJ ET BT 26.250 274.592 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 274.592 Td /F1 9.8 Tf [(Francis T Jr, Salk JJ, Quilligan JJ Jr. Experience with vaccination against influenza in the spring of 1947; a preliminary report. )] TJ ET BT 26.250 262.687 Td /F1 9.8 Tf [(Am J Public Health. 1947 Aug;37\(8\):1013-6. PubMed PMID: 20256594.)] TJ ET BT 26.250 243.282 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 243.282 Td /F1 9.8 Tf [(Salk JE, Suriano PC. Importance of antigenic composition of influenza virus vaccine in protecting against the natural disease; )] TJ ET BT 26.250 231.378 Td /F1 9.8 Tf [(observations during the winter of 1947-1948. Am J Public Health Nations Health. 1949 Mar;39\(3\):345-55. PubMed PMID: )] TJ ET BT 26.250 219.473 Td /F1 9.8 Tf [(18124075; PubMed Central PMCID: PMC1527846.)] TJ ET BT 26.250 200.068 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 200.068 Td /F1 9.8 Tf [(Langmuir AD, Henderson DA, Serfling RE. The epidemiological basis for the control of influenza. Am J Public Health Nations )] TJ ET BT 26.250 188.163 Td /F1 9.8 Tf [(Health. 1964 Apr;54:563-71. PubMed PMID: 14136320; PubMed Central PMCID: PMC1254817.)] TJ ET BT 26.250 168.759 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 168.759 Td /F1 9.8 Tf [(McLaren C, Potter CW, Jennings R. Immunity to influenza in ferrets. XI. Cross-immunity between A/Hong Kong/68 and )] TJ ET BT 26.250 156.854 Td /F1 9.8 Tf [(A/England/72 viruses: serum antibodies produced by infection or immunization. J Hyg \(Lond\). 1974 Dec;73\(3\):389-99. PubMed )] TJ ET BT 26.250 144.949 Td /F1 9.8 Tf [(PMID: 4531448; PubMed Central PMCID: PMC2130465.)] TJ ET BT 26.250 125.544 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 125.544 Td /F1 9.8 Tf [(Park AW, Daly JM, Lewis NS, Smith DJ, Wood JL, Grenfell BT. Quantifying the impact of immune escape on transmission )] TJ ET BT 26.250 113.640 Td /F1 9.8 Tf [(dynamics of influenza. Science. 2009 Oct 30;326\(5953\):726-8. PubMed PMID: 19900931.)] TJ ET BT 26.250 94.235 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 94.235 Td /F1 9.8 Tf [(Potter CW, Jennings R, Nicholson K, Tyrrell DA, Dickinson KG. Immunity to attenuated influenza virus WRL 105 infection )] TJ ET BT 26.250 82.330 Td /F1 9.8 Tf [(induced by heterologous, inactivated influenza A virus vaccines. J Hyg \(Lond\). 1977 Dec;79\(3\):321-32. PubMed PMID: 270523; )] TJ ET BT 26.250 70.425 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2129958.)] TJ ET BT 26.250 51.021 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 51.021 Td /F1 9.8 Tf [(Larson HE, Tyrrell DA, Bowker CH, Potter CW, Schild GC. Immunity to challenge in volunteers vaccinated with an inactivated )] TJ ET Q q 15.000 36.735 577.500 740.265 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(decision.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Although, in some cases, projections based on co-circulating clades could be helpful prior to the availability of Southern )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(Hemisphere isolates, thus assisting in vaccine strain decisions, in other situations, such as the 1997-1998 Sydney season, the )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(rapid emergence of a new dominant strain makes earlier projections effectively useless. Deeper sampling of representative viral )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(isolates might provide an earlier warning of such novel clades, and more sophisticated models using additional data might also )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(eventually prove helpful.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(Finally, we note that our predictions of influenza morbidity based on sequence and serological data are limited to the inter-)] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(pandemic period, and that our model cannot be used to project the severity of an emerging pandemic influenza virus, such as )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(2009 H1N1pdm. In addition, it remains unclear whether this model rooted in empirical data collected before the 2009 pandemic )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(will be suitable to predict the severity of influenza A/H3N2 season in the post-pandemic period. Both H3N2 and H1N1 have )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(begun to co-circulate in 2010 )] TJ ET 0.267 0.267 0.267 rg BT 154.150 634.936 Td /F4 8.7 Tf [(56)] TJ ET 0.271 0.267 0.267 rg BT 163.788 633.429 Td /F1 9.8 Tf [(, and further studies will need to determine whether the dynamics of these two subtypes has )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(changed and whether the algorithms proposed here need to be revised to accommodate these changes.)] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(The results presented here should be useful in the planning process for seasonal influenza. This work, along with the extensive )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(earlier research that revealed the correlation between antigenic drift and seasonal severity, provides an objective function for )] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(refining measures to characterize antigenicity and seasonal morbidity. Given that we can now use surveillance data to make )] TJ ET BT 26.250 566.405 Td /F1 9.8 Tf [(useful projections of influenza morbidity, we should begin to consider those changes to surveillance that maximize the )] TJ ET BT 26.250 554.500 Td /F1 9.8 Tf [(effectiveness of this approach.)] TJ ET BT 26.250 517.898 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 497.943 Td /F1 9.8 Tf [(David Lipman, corresponding author, is one of the Editors of )] TJ ET BT 288.545 497.943 Td /F5 9.8 Tf [(PLoS Currents: Influenza)] TJ ET BT 397.472 497.943 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 461.341 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 441.387 Td /F1 9.8 Tf [(We thank Dr. A.I. Klimov \(Influenza Division, Centers for Disease Control and Prevention\) for kindly providing the )] TJ ET BT 26.250 429.482 Td /F1 9.8 Tf [(haemagglutination-inhibition assay data of Influenza A\(H3N2\) isolates performed in 1998 and 1999 at CDC. We thank Dr. )] TJ ET BT 26.250 417.577 Td /F1 9.8 Tf [(Cheong-Chi Lau and Dr. Flemy Yip \(Hong Kong Centre for Health Protection\) for assistance with Hong Kong influenza )] TJ ET BT 26.250 405.672 Td /F1 9.8 Tf [(surveillance data. We thank Dr. Derek Smith \(University of Cambridge, UK\) for advice on the antigenic distance calculation and )] TJ ET BT 26.250 393.768 Td /F1 9.8 Tf [(for kindly providing haemagglutination-inhibition assay data used in [27]. We thank Dr. John Spouge \(National Center for )] TJ ET BT 26.250 381.863 Td /F1 9.8 Tf [(Biotechnology Information, NLM, NIH\) for helpful discussions of statistical analysis procedures.)] TJ ET BT 26.250 352.760 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 325.306 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 325.306 Td /F1 9.8 Tf [( Kilbourne ED. The molecular epidemiology of influenza. J Infect Dis. 1973 Apr;127\(4\):478-87. PubMed PMID: 4121053.)] TJ ET BT 26.250 305.901 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 305.901 Td /F1 9.8 Tf [(Torrens J. Influenza: its sequelae and treatment. Br Med J. 1934 Feb 17;1\(3815\):274-276. PubMed PMID: 20778073; )] TJ ET BT 26.250 293.997 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2444160.)] TJ ET BT 26.250 274.592 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 274.592 Td /F1 9.8 Tf [(Francis T Jr, Salk JJ, Quilligan JJ Jr. Experience with vaccination against influenza in the spring of 1947; a preliminary report. )] TJ ET BT 26.250 262.687 Td /F1 9.8 Tf [(Am J Public Health. 1947 Aug;37\(8\):1013-6. PubMed PMID: 20256594.)] TJ ET BT 26.250 243.282 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 243.282 Td /F1 9.8 Tf [(Salk JE, Suriano PC. Importance of antigenic composition of influenza virus vaccine in protecting against the natural disease; )] TJ ET BT 26.250 231.378 Td /F1 9.8 Tf [(observations during the winter of 1947-1948. Am J Public Health Nations Health. 1949 Mar;39\(3\):345-55. PubMed PMID: )] TJ ET BT 26.250 219.473 Td /F1 9.8 Tf [(18124075; PubMed Central PMCID: PMC1527846.)] TJ ET BT 26.250 200.068 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 200.068 Td /F1 9.8 Tf [(Langmuir AD, Henderson DA, Serfling RE. The epidemiological basis for the control of influenza. Am J Public Health Nations )] TJ ET BT 26.250 188.163 Td /F1 9.8 Tf [(Health. 1964 Apr;54:563-71. PubMed PMID: 14136320; PubMed Central PMCID: PMC1254817.)] TJ ET BT 26.250 168.759 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 168.759 Td /F1 9.8 Tf [(McLaren C, Potter CW, Jennings R. Immunity to influenza in ferrets. XI. Cross-immunity between A/Hong Kong/68 and )] TJ ET BT 26.250 156.854 Td /F1 9.8 Tf [(A/England/72 viruses: serum antibodies produced by infection or immunization. J Hyg \(Lond\). 1974 Dec;73\(3\):389-99. PubMed )] TJ ET BT 26.250 144.949 Td /F1 9.8 Tf [(PMID: 4531448; PubMed Central PMCID: PMC2130465.)] TJ ET BT 26.250 125.544 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 125.544 Td /F1 9.8 Tf [(Park AW, Daly JM, Lewis NS, Smith DJ, Wood JL, Grenfell BT. Quantifying the impact of immune escape on transmission )] TJ ET BT 26.250 113.640 Td /F1 9.8 Tf [(dynamics of influenza. Science. 2009 Oct 30;326\(5953\):726-8. PubMed PMID: 19900931.)] TJ ET BT 26.250 94.235 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 94.235 Td /F1 9.8 Tf [(Potter CW, Jennings R, Nicholson K, Tyrrell DA, Dickinson KG. Immunity to attenuated influenza virus WRL 105 infection )] TJ ET BT 26.250 82.330 Td /F1 9.8 Tf [(induced by heterologous, inactivated influenza A virus vaccines. J Hyg \(Lond\). 1977 Dec;79\(3\):321-32. PubMed PMID: 270523; )] TJ ET BT 26.250 70.425 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2129958.)] TJ ET BT 26.250 51.021 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 51.021 Td /F1 9.8 Tf [(Larson HE, Tyrrell DA, Bowker CH, Potter CW, Schild GC. Immunity to challenge in volunteers vaccinated with an inactivated )] TJ ET Q q 15.000 36.735 577.500 740.265 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(decision.)] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Although, in some cases, projections based on co-circulating clades could be helpful prior to the availability of Southern )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(Hemisphere isolates, thus assisting in vaccine strain decisions, in other situations, such as the 1997-1998 Sydney season, the )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(rapid emergence of a new dominant strain makes earlier projections effectively useless. Deeper sampling of representative viral )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(isolates might provide an earlier warning of such novel clades, and more sophisticated models using additional data might also )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(eventually prove helpful.)] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(Finally, we note that our predictions of influenza morbidity based on sequence and serological data are limited to the inter-)] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(pandemic period, and that our model cannot be used to project the severity of an emerging pandemic influenza virus, such as )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(2009 H1N1pdm. In addition, it remains unclear whether this model rooted in empirical data collected before the 2009 pandemic )] TJ ET BT 26.250 645.333 Td /F1 9.8 Tf [(will be suitable to predict the severity of influenza A/H3N2 season in the post-pandemic period. Both H3N2 and H1N1 have )] TJ ET BT 26.250 633.429 Td /F1 9.8 Tf [(begun to co-circulate in 2010 )] TJ ET 0.267 0.267 0.267 rg BT 154.150 634.936 Td /F4 8.7 Tf [(56)] TJ ET 0.271 0.267 0.267 rg BT 163.788 633.429 Td /F1 9.8 Tf [(, and further studies will need to determine whether the dynamics of these two subtypes has )] TJ ET BT 26.250 621.524 Td /F1 9.8 Tf [(changed and whether the algorithms proposed here need to be revised to accommodate these changes.)] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(The results presented here should be useful in the planning process for seasonal influenza. This work, along with the extensive )] TJ ET BT 26.250 590.214 Td /F1 9.8 Tf [(earlier research that revealed the correlation between antigenic drift and seasonal severity, provides an objective function for )] TJ ET BT 26.250 578.310 Td /F1 9.8 Tf [(refining measures to characterize antigenicity and seasonal morbidity. Given that we can now use surveillance data to make )] TJ ET BT 26.250 566.405 Td /F1 9.8 Tf [(useful projections of influenza morbidity, we should begin to consider those changes to surveillance that maximize the )] TJ ET BT 26.250 554.500 Td /F1 9.8 Tf [(effectiveness of this approach.)] TJ ET BT 26.250 517.898 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 497.943 Td /F1 9.8 Tf [(David Lipman, corresponding author, is one of the Editors of )] TJ ET BT 288.545 497.943 Td /F5 9.8 Tf [(PLoS Currents: Influenza)] TJ ET BT 397.472 497.943 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 461.341 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 441.387 Td /F1 9.8 Tf [(We thank Dr. A.I. Klimov \(Influenza Division, Centers for Disease Control and Prevention\) for kindly providing the )] TJ ET BT 26.250 429.482 Td /F1 9.8 Tf [(haemagglutination-inhibition assay data of Influenza A\(H3N2\) isolates performed in 1998 and 1999 at CDC. We thank Dr. )] TJ ET BT 26.250 417.577 Td /F1 9.8 Tf [(Cheong-Chi Lau and Dr. Flemy Yip \(Hong Kong Centre for Health Protection\) for assistance with Hong Kong influenza )] TJ ET BT 26.250 405.672 Td /F1 9.8 Tf [(surveillance data. We thank Dr. Derek Smith \(University of Cambridge, UK\) for advice on the antigenic distance calculation and )] TJ ET BT 26.250 393.768 Td /F1 9.8 Tf [(for kindly providing haemagglutination-inhibition assay data used in [27]. We thank Dr. John Spouge \(National Center for )] TJ ET BT 26.250 381.863 Td /F1 9.8 Tf [(Biotechnology Information, NLM, NIH\) for helpful discussions of statistical analysis procedures.)] TJ ET BT 26.250 352.760 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 325.306 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 325.306 Td /F1 9.8 Tf [( Kilbourne ED. The molecular epidemiology of influenza. J Infect Dis. 1973 Apr;127\(4\):478-87. PubMed PMID: 4121053.)] TJ ET BT 26.250 305.901 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 305.901 Td /F1 9.8 Tf [(Torrens J. Influenza: its sequelae and treatment. Br Med J. 1934 Feb 17;1\(3815\):274-276. PubMed PMID: 20778073; )] TJ ET BT 26.250 293.997 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2444160.)] TJ ET BT 26.250 274.592 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 274.592 Td /F1 9.8 Tf [(Francis T Jr, Salk JJ, Quilligan JJ Jr. Experience with vaccination against influenza in the spring of 1947; a preliminary report. )] TJ ET BT 26.250 262.687 Td /F1 9.8 Tf [(Am J Public Health. 1947 Aug;37\(8\):1013-6. PubMed PMID: 20256594.)] TJ ET BT 26.250 243.282 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 243.282 Td /F1 9.8 Tf [(Salk JE, Suriano PC. Importance of antigenic composition of influenza virus vaccine in protecting against the natural disease; )] TJ ET BT 26.250 231.378 Td /F1 9.8 Tf [(observations during the winter of 1947-1948. Am J Public Health Nations Health. 1949 Mar;39\(3\):345-55. PubMed PMID: )] TJ ET BT 26.250 219.473 Td /F1 9.8 Tf [(18124075; PubMed Central PMCID: PMC1527846.)] TJ ET BT 26.250 200.068 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 200.068 Td /F1 9.8 Tf [(Langmuir AD, Henderson DA, Serfling RE. The epidemiological basis for the control of influenza. Am J Public Health Nations )] TJ ET BT 26.250 188.163 Td /F1 9.8 Tf [(Health. 1964 Apr;54:563-71. PubMed PMID: 14136320; PubMed Central PMCID: PMC1254817.)] TJ ET BT 26.250 168.759 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 168.759 Td /F1 9.8 Tf [(McLaren C, Potter CW, Jennings R. Immunity to influenza in ferrets. XI. Cross-immunity between A/Hong Kong/68 and )] TJ ET BT 26.250 156.854 Td /F1 9.8 Tf [(A/England/72 viruses: serum antibodies produced by infection or immunization. J Hyg \(Lond\). 1974 Dec;73\(3\):389-99. PubMed )] TJ ET BT 26.250 144.949 Td /F1 9.8 Tf [(PMID: 4531448; PubMed Central PMCID: PMC2130465.)] TJ ET BT 26.250 125.544 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 125.544 Td /F1 9.8 Tf [(Park AW, Daly JM, Lewis NS, Smith DJ, Wood JL, Grenfell BT. Quantifying the impact of immune escape on transmission )] TJ ET BT 26.250 113.640 Td /F1 9.8 Tf [(dynamics of influenza. Science. 2009 Oct 30;326\(5953\):726-8. PubMed PMID: 19900931.)] TJ ET BT 26.250 94.235 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 94.235 Td /F1 9.8 Tf [(Potter CW, Jennings R, Nicholson K, Tyrrell DA, Dickinson KG. Immunity to attenuated influenza virus WRL 105 infection )] TJ ET BT 26.250 82.330 Td /F1 9.8 Tf [(induced by heterologous, inactivated influenza A virus vaccines. J Hyg \(Lond\). 1977 Dec;79\(3\):321-32. PubMed PMID: 270523; )] TJ ET BT 26.250 70.425 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2129958.)] TJ ET BT 26.250 51.021 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 51.021 Td /F1 9.8 Tf [(Larson HE, Tyrrell DA, Bowker CH, Potter CW, Schild GC. Immunity to challenge in volunteers vaccinated with an inactivated )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(10)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 624 0 obj << /Type /Annot /Subtype /Link /A 625 0 R /Border [0 0 0] /H /I /Rect [ 154.1505 634.1342 163.7878 642.9525 ] >> endobj 625 0 obj << /Type /Action >> endobj 626 0 obj << /Type /Annot /Subtype /Link /A 627 0 R /Border [0 0 0] /H /I /Rect [ 154.1505 634.1342 163.7878 642.9525 ] >> endobj 627 0 obj << /Type /Action >> endobj 628 0 obj << /Type /Annot /Subtype /Link /A 629 0 R /Border [0 0 0] /H /I /Rect [ 154.1505 634.1342 163.7878 642.9525 ] >> endobj 629 0 obj << /Type /Action >> endobj 630 0 obj << /Type /Page /Parent 3 0 R /Annots [ 632 0 R 634 0 R 636 0 R 638 0 R 640 0 R 642 0 R 644 0 R 646 0 R 648 0 R 650 0 R 652 0 R 654 0 R 656 0 R 658 0 R 660 0 R 662 0 R 664 0 R 666 0 R ] /Contents 631 0 R >> endobj 631 0 obj << /Length 21929 >> stream 0.271 0.267 0.267 rg q 15.000 46.808 577.500 730.192 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(current or earlier strain of influenza A\(H3N2\). J Hyg \(Lond\). 1978 Apr;80\(2\):243-8. PubMed PMID: 632564; PubMed Central )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(PMCID: PMC2129992.)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 736.167 Td /F1 9.8 Tf [(Jefferson T, Smith S, Demicheli V, Harnden A, Rivetti A, Di Pietrantonj C. Assessment of the efficacy and effectiveness of )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(influenza vaccines in healthy children: systematic review. Lancet. 2005 Feb 26-Mar 4;365\(9461\):773-80. Review. PubMed )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(PMID: 15733718.)] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 692.952 Td /F1 9.8 Tf [(Basta NE, Halloran ME, Matrajt L, Longini IM Jr. Estimating influenza vaccine efficacy from challenge and community-based )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(study data. Am J Epidemiol. 2008 Dec 15;168\(12\):1343-52. Epub 2008 Oct 29. Review. PubMed PMID: 18974084; PubMed )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(Central PMCID: PMC2638553.)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 649.738 Td /F1 9.8 Tf [(Gupta V, Earl DJ, Deem MW. Quantifying influenza vaccine efficacy and antigenic distance. Vaccine. 2006 May )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(1;24\(18\):3881-8. Epub 2006 Jan 19. PubMed PMID: 16460844.)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 618.429 Td /F1 9.8 Tf [(Gill PW, Murphy AM. Naturally acquired immunity to influenza type A: a further prospective study. Med J Aust. 1977 Dec )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(3;2\(23\):761-5. PubMed PMID: 611373.)] TJ ET BT 26.250 587.119 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 587.119 Td /F1 9.8 Tf [(Wu A, Peng Y, Du X, Shu Y, Jiang T. Correlation of influenza virus excess mortality with antigenic variation: application to )] TJ ET BT 26.250 575.214 Td /F1 9.8 Tf [(rapid estimation of influenza mortality burden. PLoS Comput Biol. 2010 Aug 12;6\(8\). pii: e1000882. PubMed PMID: 20711361; )] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2920844.)] TJ ET BT 26.250 543.905 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 543.905 Td /F1 9.8 Tf [(Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, Schonberger LB. The impact of influenza epidemics on )] TJ ET BT 26.250 532.000 Td /F1 9.8 Tf [(mortality: introducing a severity index. Am J Public Health. 1997 Dec;87\(12\):1944-50. Epidemiology. 1997 Jul;8\(4\):390-5.)] TJ ET BT 26.250 512.595 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 512.595 Td /F1 9.8 Tf [(United States Centers for Disease Control )] TJ ET 0.267 0.267 0.267 rg BT 26.250 504.109 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 485.559 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 485.559 Td /F1 9.8 Tf [(Simonsen L, Reichert TA, Viboud C, Blackwelder WC, Taylor RJ, Miller MA. Impact of influenza vaccination on seasonal )] TJ ET BT 26.250 473.655 Td /F1 9.8 Tf [(mortality in the US elderly population. Arch Intern Med. 2005 Feb 14;165\(3\):265-72. PubMed PMID: 15710788.)] TJ ET BT 26.250 454.250 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 454.250 Td /F1 9.8 Tf [(Viboud C, Bjrnstad ON, Smith DL, Simonsen L, Miller MA, Grenfell BT. Synchrony, waves, and spatial hierarchies in the )] TJ ET BT 26.250 442.345 Td /F1 9.8 Tf [(spread of influenza. Science. 2006 Apr 21;312\(5772\):447-51. Epub 2006 Mar 30. PubMed PMID: 16574822.)] TJ ET BT 26.250 422.940 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 422.940 Td /F1 9.8 Tf [(Bao Y, Bolotov P, Dernovoy D, Kiryutin B, Zaslavsky L, Tatusova T, Ostell J, Lipman D. The influenza virus resource at the )] TJ ET BT 26.250 411.036 Td /F1 9.8 Tf [(National Center for Biotechnology Information. J Virol. 2008 Jan;82\(2\):596-601. Epub 2007 Oct 17. PubMed PMID: 17942553; )] TJ ET BT 26.250 399.131 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2224563.)] TJ ET BT 26.250 379.726 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 379.726 Td /F1 9.8 Tf [(Supp1_USA.H3N2.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 371.240 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 352.690 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 352.690 Td /F1 9.8 Tf [(Supp2_HK.H3N2.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 344.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 325.654 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 325.654 Td /F1 9.8 Tf [(SH.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 317.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 298.618 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 298.618 Td /F1 9.8 Tf [(Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics. )] TJ ET BT 26.250 286.713 Td /F1 9.8 Tf [(2004 Aug 19;5:113. PubMed PMID: 15318951; PubMed Central PMCID: PMC517706.)] TJ ET BT 26.250 267.309 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 267.309 Td /F1 9.8 Tf [(Wiley DC, Wilson IA, Skehel JJ. Structural identification of the antibody-binding sites of Hong Kong influenza )] TJ ET BT 26.250 255.404 Td /F1 9.8 Tf [(haemagglutinin and their involvement in antigenic variation. Nature. 1981 Jan 29;289\(5796\):373-8. PubMed PMID: 6162101.)] TJ ET BT 26.250 235.999 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 235.999 Td /F1 9.8 Tf [(Muoz ET, Deem MW. Epitope analysis for influenza vaccine design. Vaccine. 2005 Jan 19;23\(9\):1144-8. PubMed PMID: )] TJ ET BT 26.250 224.094 Td /F1 9.8 Tf [(15629357.)] TJ ET BT 26.250 204.690 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 204.690 Td /F1 9.8 Tf [(Supp3__for_HI_Assay_Data)] TJ ET 0.267 0.267 0.267 rg BT 26.250 196.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 177.654 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 177.654 Td /F1 9.8 Tf [(Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD, Fouchier RA. Mapping the antigenic )] TJ ET BT 26.250 165.749 Td /F1 9.8 Tf [(and genetic evolution of influenza virus. Science. 2004 Jul 16;305\(5682\):371-6. Epub 2004 Jun 24. PubMed PMID: 15218094.)] TJ ET BT 26.250 146.344 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 146.344 Td /F1 9.8 Tf [(Efron B. The Jackknife, the Bootstrap, and Other Resampling Plans. CBMS-NSF Regional Conference Series in Applied )] TJ ET BT 26.250 134.439 Td /F1 9.8 Tf [(Mathematics 38, Society for Industrial Mathematics, ISBN: 978-0898711790, 1987)] TJ ET BT 26.250 115.035 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 115.035 Td /F1 9.8 Tf [(Hong Kong Centre for Health Protection)] TJ ET 0.267 0.267 0.267 rg BT 26.250 106.549 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 87.999 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 87.999 Td /F1 9.8 Tf [(Shu YL, Fang LQ, de Vlas SJ, Gao Y, Richardus JH, Cao WC. Dual seasonal patterns for influenza, China. Emerg Infect )] TJ ET BT 26.250 76.094 Td /F1 9.8 Tf [(Dis. 2010 Apr;16\(4\):725-6. PubMed PMID: 20350403.)] TJ ET BT 26.250 56.689 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 56.689 Td /F1 9.8 Tf [(Leo YS, Lye DC, Chow A. Influenza in the tropics. Lancet Infect Dis. 2009 Aug;9\(8\):457-8. PubMed PMID: 19628167.)] TJ ET Q q 15.000 46.808 577.500 730.192 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(current or earlier strain of influenza A\(H3N2\). J Hyg \(Lond\). 1978 Apr;80\(2\):243-8. PubMed PMID: 632564; PubMed Central )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(PMCID: PMC2129992.)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 736.167 Td /F1 9.8 Tf [(Jefferson T, Smith S, Demicheli V, Harnden A, Rivetti A, Di Pietrantonj C. Assessment of the efficacy and effectiveness of )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(influenza vaccines in healthy children: systematic review. Lancet. 2005 Feb 26-Mar 4;365\(9461\):773-80. Review. PubMed )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(PMID: 15733718.)] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 692.952 Td /F1 9.8 Tf [(Basta NE, Halloran ME, Matrajt L, Longini IM Jr. Estimating influenza vaccine efficacy from challenge and community-based )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(study data. Am J Epidemiol. 2008 Dec 15;168\(12\):1343-52. Epub 2008 Oct 29. Review. PubMed PMID: 18974084; PubMed )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(Central PMCID: PMC2638553.)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 649.738 Td /F1 9.8 Tf [(Gupta V, Earl DJ, Deem MW. Quantifying influenza vaccine efficacy and antigenic distance. Vaccine. 2006 May )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(1;24\(18\):3881-8. Epub 2006 Jan 19. PubMed PMID: 16460844.)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 618.429 Td /F1 9.8 Tf [(Gill PW, Murphy AM. Naturally acquired immunity to influenza type A: a further prospective study. Med J Aust. 1977 Dec )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(3;2\(23\):761-5. PubMed PMID: 611373.)] TJ ET BT 26.250 587.119 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 587.119 Td /F1 9.8 Tf [(Wu A, Peng Y, Du X, Shu Y, Jiang T. Correlation of influenza virus excess mortality with antigenic variation: application to )] TJ ET BT 26.250 575.214 Td /F1 9.8 Tf [(rapid estimation of influenza mortality burden. PLoS Comput Biol. 2010 Aug 12;6\(8\). pii: e1000882. PubMed PMID: 20711361; )] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2920844.)] TJ ET BT 26.250 543.905 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 543.905 Td /F1 9.8 Tf [(Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, Schonberger LB. The impact of influenza epidemics on )] TJ ET BT 26.250 532.000 Td /F1 9.8 Tf [(mortality: introducing a severity index. Am J Public Health. 1997 Dec;87\(12\):1944-50. Epidemiology. 1997 Jul;8\(4\):390-5.)] TJ ET BT 26.250 512.595 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 512.595 Td /F1 9.8 Tf [(United States Centers for Disease Control )] TJ ET 0.267 0.267 0.267 rg BT 26.250 504.109 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 485.559 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 485.559 Td /F1 9.8 Tf [(Simonsen L, Reichert TA, Viboud C, Blackwelder WC, Taylor RJ, Miller MA. Impact of influenza vaccination on seasonal )] TJ ET BT 26.250 473.655 Td /F1 9.8 Tf [(mortality in the US elderly population. Arch Intern Med. 2005 Feb 14;165\(3\):265-72. PubMed PMID: 15710788.)] TJ ET BT 26.250 454.250 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 454.250 Td /F1 9.8 Tf [(Viboud C, Bjrnstad ON, Smith DL, Simonsen L, Miller MA, Grenfell BT. Synchrony, waves, and spatial hierarchies in the )] TJ ET BT 26.250 442.345 Td /F1 9.8 Tf [(spread of influenza. Science. 2006 Apr 21;312\(5772\):447-51. Epub 2006 Mar 30. PubMed PMID: 16574822.)] TJ ET BT 26.250 422.940 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 422.940 Td /F1 9.8 Tf [(Bao Y, Bolotov P, Dernovoy D, Kiryutin B, Zaslavsky L, Tatusova T, Ostell J, Lipman D. The influenza virus resource at the )] TJ ET BT 26.250 411.036 Td /F1 9.8 Tf [(National Center for Biotechnology Information. J Virol. 2008 Jan;82\(2\):596-601. Epub 2007 Oct 17. PubMed PMID: 17942553; )] TJ ET BT 26.250 399.131 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2224563.)] TJ ET BT 26.250 379.726 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 379.726 Td /F1 9.8 Tf [(Supp1_USA.H3N2.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 371.240 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 352.690 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 352.690 Td /F1 9.8 Tf [(Supp2_HK.H3N2.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 344.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 325.654 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 325.654 Td /F1 9.8 Tf [(SH.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 317.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 298.618 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 298.618 Td /F1 9.8 Tf [(Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics. )] TJ ET BT 26.250 286.713 Td /F1 9.8 Tf [(2004 Aug 19;5:113. PubMed PMID: 15318951; PubMed Central PMCID: PMC517706.)] TJ ET BT 26.250 267.309 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 267.309 Td /F1 9.8 Tf [(Wiley DC, Wilson IA, Skehel JJ. Structural identification of the antibody-binding sites of Hong Kong influenza )] TJ ET BT 26.250 255.404 Td /F1 9.8 Tf [(haemagglutinin and their involvement in antigenic variation. Nature. 1981 Jan 29;289\(5796\):373-8. PubMed PMID: 6162101.)] TJ ET BT 26.250 235.999 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 235.999 Td /F1 9.8 Tf [(Muoz ET, Deem MW. Epitope analysis for influenza vaccine design. Vaccine. 2005 Jan 19;23\(9\):1144-8. PubMed PMID: )] TJ ET BT 26.250 224.094 Td /F1 9.8 Tf [(15629357.)] TJ ET BT 26.250 204.690 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 204.690 Td /F1 9.8 Tf [(Supp3__for_HI_Assay_Data)] TJ ET 0.267 0.267 0.267 rg BT 26.250 196.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 177.654 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 177.654 Td /F1 9.8 Tf [(Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD, Fouchier RA. Mapping the antigenic )] TJ ET BT 26.250 165.749 Td /F1 9.8 Tf [(and genetic evolution of influenza virus. Science. 2004 Jul 16;305\(5682\):371-6. Epub 2004 Jun 24. PubMed PMID: 15218094.)] TJ ET BT 26.250 146.344 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 146.344 Td /F1 9.8 Tf [(Efron B. The Jackknife, the Bootstrap, and Other Resampling Plans. CBMS-NSF Regional Conference Series in Applied )] TJ ET BT 26.250 134.439 Td /F1 9.8 Tf [(Mathematics 38, Society for Industrial Mathematics, ISBN: 978-0898711790, 1987)] TJ ET BT 26.250 115.035 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 115.035 Td /F1 9.8 Tf [(Hong Kong Centre for Health Protection)] TJ ET 0.267 0.267 0.267 rg BT 26.250 106.549 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 87.999 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 87.999 Td /F1 9.8 Tf [(Shu YL, Fang LQ, de Vlas SJ, Gao Y, Richardus JH, Cao WC. Dual seasonal patterns for influenza, China. Emerg Infect )] TJ ET BT 26.250 76.094 Td /F1 9.8 Tf [(Dis. 2010 Apr;16\(4\):725-6. PubMed PMID: 20350403.)] TJ ET BT 26.250 56.689 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 56.689 Td /F1 9.8 Tf [(Leo YS, Lye DC, Chow A. Influenza in the tropics. Lancet Infect Dis. 2009 Aug;9\(8\):457-8. PubMed PMID: 19628167.)] TJ ET Q q 15.000 46.808 577.500 730.192 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(current or earlier strain of influenza A\(H3N2\). J Hyg \(Lond\). 1978 Apr;80\(2\):243-8. PubMed PMID: 632564; PubMed Central )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(PMCID: PMC2129992.)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 736.167 Td /F1 9.8 Tf [(Jefferson T, Smith S, Demicheli V, Harnden A, Rivetti A, Di Pietrantonj C. Assessment of the efficacy and effectiveness of )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(influenza vaccines in healthy children: systematic review. Lancet. 2005 Feb 26-Mar 4;365\(9461\):773-80. Review. PubMed )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(PMID: 15733718.)] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 692.952 Td /F1 9.8 Tf [(Basta NE, Halloran ME, Matrajt L, Longini IM Jr. Estimating influenza vaccine efficacy from challenge and community-based )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(study data. Am J Epidemiol. 2008 Dec 15;168\(12\):1343-52. Epub 2008 Oct 29. Review. PubMed PMID: 18974084; PubMed )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(Central PMCID: PMC2638553.)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 649.738 Td /F1 9.8 Tf [(Gupta V, Earl DJ, Deem MW. Quantifying influenza vaccine efficacy and antigenic distance. Vaccine. 2006 May )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(1;24\(18\):3881-8. Epub 2006 Jan 19. PubMed PMID: 16460844.)] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 618.429 Td /F1 9.8 Tf [(Gill PW, Murphy AM. Naturally acquired immunity to influenza type A: a further prospective study. Med J Aust. 1977 Dec )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(3;2\(23\):761-5. PubMed PMID: 611373.)] TJ ET BT 26.250 587.119 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 587.119 Td /F1 9.8 Tf [(Wu A, Peng Y, Du X, Shu Y, Jiang T. Correlation of influenza virus excess mortality with antigenic variation: application to )] TJ ET BT 26.250 575.214 Td /F1 9.8 Tf [(rapid estimation of influenza mortality burden. PLoS Comput Biol. 2010 Aug 12;6\(8\). pii: e1000882. PubMed PMID: 20711361; )] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2920844.)] TJ ET BT 26.250 543.905 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 543.905 Td /F1 9.8 Tf [(Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, Schonberger LB. The impact of influenza epidemics on )] TJ ET BT 26.250 532.000 Td /F1 9.8 Tf [(mortality: introducing a severity index. Am J Public Health. 1997 Dec;87\(12\):1944-50. Epidemiology. 1997 Jul;8\(4\):390-5.)] TJ ET BT 26.250 512.595 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 512.595 Td /F1 9.8 Tf [(United States Centers for Disease Control )] TJ ET 0.267 0.267 0.267 rg BT 26.250 504.109 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 485.559 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 485.559 Td /F1 9.8 Tf [(Simonsen L, Reichert TA, Viboud C, Blackwelder WC, Taylor RJ, Miller MA. Impact of influenza vaccination on seasonal )] TJ ET BT 26.250 473.655 Td /F1 9.8 Tf [(mortality in the US elderly population. Arch Intern Med. 2005 Feb 14;165\(3\):265-72. PubMed PMID: 15710788.)] TJ ET BT 26.250 454.250 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 454.250 Td /F1 9.8 Tf [(Viboud C, Bjrnstad ON, Smith DL, Simonsen L, Miller MA, Grenfell BT. Synchrony, waves, and spatial hierarchies in the )] TJ ET BT 26.250 442.345 Td /F1 9.8 Tf [(spread of influenza. Science. 2006 Apr 21;312\(5772\):447-51. Epub 2006 Mar 30. PubMed PMID: 16574822.)] TJ ET BT 26.250 422.940 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 422.940 Td /F1 9.8 Tf [(Bao Y, Bolotov P, Dernovoy D, Kiryutin B, Zaslavsky L, Tatusova T, Ostell J, Lipman D. The influenza virus resource at the )] TJ ET BT 26.250 411.036 Td /F1 9.8 Tf [(National Center for Biotechnology Information. J Virol. 2008 Jan;82\(2\):596-601. Epub 2007 Oct 17. PubMed PMID: 17942553; )] TJ ET BT 26.250 399.131 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2224563.)] TJ ET BT 26.250 379.726 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 379.726 Td /F1 9.8 Tf [(Supp1_USA.H3N2.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 371.240 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 352.690 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 352.690 Td /F1 9.8 Tf [(Supp2_HK.H3N2.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 344.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 325.654 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 325.654 Td /F1 9.8 Tf [(SH.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 317.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 298.618 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 298.618 Td /F1 9.8 Tf [(Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics. )] TJ ET BT 26.250 286.713 Td /F1 9.8 Tf [(2004 Aug 19;5:113. PubMed PMID: 15318951; PubMed Central PMCID: PMC517706.)] TJ ET BT 26.250 267.309 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 267.309 Td /F1 9.8 Tf [(Wiley DC, Wilson IA, Skehel JJ. Structural identification of the antibody-binding sites of Hong Kong influenza )] TJ ET BT 26.250 255.404 Td /F1 9.8 Tf [(haemagglutinin and their involvement in antigenic variation. Nature. 1981 Jan 29;289\(5796\):373-8. PubMed PMID: 6162101.)] TJ ET BT 26.250 235.999 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 235.999 Td /F1 9.8 Tf [(Muoz ET, Deem MW. Epitope analysis for influenza vaccine design. Vaccine. 2005 Jan 19;23\(9\):1144-8. PubMed PMID: )] TJ ET BT 26.250 224.094 Td /F1 9.8 Tf [(15629357.)] TJ ET BT 26.250 204.690 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 204.690 Td /F1 9.8 Tf [(Supp3__for_HI_Assay_Data)] TJ ET 0.267 0.267 0.267 rg BT 26.250 196.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 177.654 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 177.654 Td /F1 9.8 Tf [(Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD, Fouchier RA. Mapping the antigenic )] TJ ET BT 26.250 165.749 Td /F1 9.8 Tf [(and genetic evolution of influenza virus. Science. 2004 Jul 16;305\(5682\):371-6. Epub 2004 Jun 24. PubMed PMID: 15218094.)] TJ ET BT 26.250 146.344 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 146.344 Td /F1 9.8 Tf [(Efron B. The Jackknife, the Bootstrap, and Other Resampling Plans. CBMS-NSF Regional Conference Series in Applied )] TJ ET BT 26.250 134.439 Td /F1 9.8 Tf [(Mathematics 38, Society for Industrial Mathematics, ISBN: 978-0898711790, 1987)] TJ ET BT 26.250 115.035 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 115.035 Td /F1 9.8 Tf [(Hong Kong Centre for Health Protection)] TJ ET 0.267 0.267 0.267 rg BT 26.250 106.549 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 87.999 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 87.999 Td /F1 9.8 Tf [(Shu YL, Fang LQ, de Vlas SJ, Gao Y, Richardus JH, Cao WC. Dual seasonal patterns for influenza, China. Emerg Infect )] TJ ET BT 26.250 76.094 Td /F1 9.8 Tf [(Dis. 2010 Apr;16\(4\):725-6. PubMed PMID: 20350403.)] TJ ET BT 26.250 56.689 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 56.689 Td /F1 9.8 Tf [(Leo YS, Lye DC, Chow A. Influenza in the tropics. Lancet Infect Dis. 2009 Aug;9\(8\):457-8. 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[(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 678.868 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 678.868 Td /F1 9.8 Tf [(Wolf YI, Viboud C, Holmes EC, Koonin EV, Lipman DJ. Long intervals of stasis punctuated by bursts of positive selection in )] TJ ET BT 26.250 666.963 Td /F1 9.8 Tf [(the seasonal evolution of influenza A virus. Biol Direct. 2006 Oct 26;1:34. PubMed PMID: 17067369; PubMed Central PMCID: )] TJ ET BT 26.250 655.059 Td /F1 9.8 Tf [(PMC1647279.)] TJ ET BT 26.250 635.654 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 635.654 Td /F1 9.8 Tf [(Season.Series.Data.xls)] TJ ET 0.267 0.267 0.267 rg BT 26.250 627.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 608.618 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 608.618 Td /F1 9.8 Tf [(Shaman J, Pitzer V, Viboud C, Lipsitch M, Grenfell B. Absolute humidity and the seasonal onset of influenza in the )] TJ ET BT 26.250 596.713 Td /F1 9.8 Tf [(continental US. PLoS Curr. 2009 Dec 18:RRN1138. Update in: PLoS Biol. 2010 Feb;8\(2\):e1000316. PubMed PMID: 20066155; )] TJ ET BT 26.250 584.808 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2803311.)] TJ ET BT 26.250 565.404 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 565.404 Td /F1 9.8 Tf [(Tellier R. Aerosol transmission of influenza A virus: a review of new studies. J R Soc Interface. 2009 Dec 6;6 Suppl 6:S783-)] TJ ET BT 26.250 553.499 Td /F1 9.8 Tf [(90. Epub 2009 Sep 22. Review. PubMed PMID: 19773292; PubMed Central PMCID: PMC2843947.)] TJ ET BT 26.250 534.094 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 534.094 Td /F1 9.8 Tf [(Shaman J, Kohn M. Absolute humidity modulates influenza survival, transmission, and seasonality. Proc Natl Acad Sci U S )] TJ ET BT 26.250 522.189 Td /F1 9.8 Tf [(A. 2009 Mar 3;106\(9\):3243-8. Epub 2009 Feb 9. PubMed PMID: 19204283; PubMed Central PMCID: PMC2651255.)] TJ ET BT 26.250 502.785 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 502.785 Td /F1 9.8 Tf [(du Prel JB, Puppe W, Grndahl B, Knuf M, Weigl JA, Schaaff F, Schmitt HJ. Are meteorological parameters associated with )] TJ ET BT 26.250 490.880 Td /F1 9.8 Tf [(acute respiratory tract infections? Clin Infect Dis. 2009 Sep 15;49\(6\):861-8. PubMed PMID: 19663691.)] TJ ET BT 26.250 471.475 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 471.475 Td /F1 9.8 Tf [(Anestad G, Nordbo SA. Interference between outbreaks of respiratory viruses. Euro Surveill. 2009 Oct 15;14\(41\):19359. )] TJ ET BT 26.250 459.570 Td /F1 9.8 Tf [(Erratum in: Euro Surveill. 2009;14\(42\). pii: 19367. PubMed PMID: 19883536.)] TJ ET BT 26.250 440.166 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 440.166 Td /F1 9.8 Tf [(Greer RM, McErlean P, Arden KE, Faux CE, Nitsche A, Lambert SB, Nissen MD, Sloots TP, Mackay IM. Do rhinoviruses )] TJ ET BT 26.250 428.261 Td /F1 9.8 Tf [(reduce the probability of viral co-detection during acute respiratory tract infections? J Clin Virol. 2009 May;45\(1\):10-5. Epub )] TJ ET BT 26.250 416.356 Td /F1 9.8 Tf [(2009 Apr 18. PubMed PMID: 19376742.)] TJ ET BT 26.250 396.951 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 396.951 Td /F1 9.8 Tf [(Glezen WP, Paredes A, Taber LH. Influenza in children. Relationship to other respiratory agents. JAMA. 1980 Apr )] TJ ET BT 26.250 385.047 Td /F1 9.8 Tf [(4;243\(13\):1345-9. PubMed PMID: 6244421.)] TJ ET BT 26.250 365.642 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 365.642 Td /F1 9.8 Tf [(Anestad G. Interference between outbreaks of respiratory syncytial virus and influenza virus infection. Lancet. 1982 Feb )] TJ ET BT 26.250 353.737 Td /F1 9.8 Tf [(27;1\(8270\):502. PubMed PMID: 6121154.)] TJ ET BT 26.250 334.332 Td /F1 9.8 Tf [(45.)] TJ ET BT 43.553 334.332 Td /F1 9.8 Tf [(Sonoguchi T, Sakoh M, Kunita N, Satsuta K, Noriki H, Fukumi H. Reinfection with influenza A \(H2N2, H3N2, and H1N1\) )] TJ ET BT 26.250 322.428 Td /F1 9.8 Tf [(viruses in soldiers and students in Japan. J Infect Dis. 1986 Jan;153\(1\):33-40. PubMed PMID: 3941288.)] TJ ET BT 26.250 303.023 Td /F1 9.8 Tf [(46.)] TJ ET BT 43.553 303.023 Td /F1 9.8 Tf [(Sonoguchi T, Naito H, Hara M, Takeuchi Y, Fukumi H. Cross-subtype protection in humans during sequential, overlapping, )] TJ ET BT 26.250 291.118 Td /F1 9.8 Tf [(and/or concurrent epidemics caused by H3N2 and H1N1 influenza viruses. J Infect Dis. 1985 Jan;151\(1\):81-8. PubMed PMID: )] TJ ET BT 26.250 279.213 Td /F1 9.8 Tf [(3965596.)] TJ ET BT 26.250 259.809 Td /F1 9.8 Tf [(47.)] TJ ET BT 43.553 259.809 Td /F1 9.8 Tf [(Epstein SL. Prior H1N1 influenza infection and susceptibility of Cleveland Family Study participants during the H2N2 )] TJ ET BT 26.250 247.904 Td /F1 9.8 Tf [(pandemic of 1957: an experiment of nature. J Infect Dis. 2006 Jan 1;193\(1\):49-53. Epub 2005 Nov 21. PubMed PMID: )] TJ ET BT 26.250 235.999 Td /F1 9.8 Tf [(16323131.)] TJ ET BT 26.250 216.594 Td /F1 9.8 Tf [(48.)] TJ ET BT 43.553 216.594 Td /F1 9.8 Tf [(Finkelman BS, Viboud C, Koelle K, Ferrari MJ, Bharti N, Grenfell BT. Global patterns in seasonal activity of influenza )] TJ ET BT 26.250 204.690 Td /F1 9.8 Tf [(A/H3N2, A/H1N1, and B from 1997 to 2005: viral coexistence and latitudinal gradients. PLoS One. 2007 Dec 12;2\(12\):e1296. )] TJ ET BT 26.250 192.785 Td /F1 9.8 Tf [(PubMed PMID: 18074020; PubMed Central PMCID: PMC2117904.)] TJ ET BT 26.250 173.380 Td /F1 9.8 Tf [(49.)] TJ ET BT 43.553 173.380 Td /F1 9.8 Tf [(Shen J, Ma J, Wang Q. Evolutionary trends of A\(H1N1\) influenza virus hemagglutinin since 1918. PLoS One. 2009 Nov )] TJ ET BT 26.250 161.475 Td /F1 9.8 Tf [(17;4\(11\):e7789. PubMed PMID: 19924230; PubMed Central PMCID: PMC2773012.)] TJ ET BT 26.250 142.071 Td /F1 9.8 Tf [(50.)] TJ ET BT 43.553 142.071 Td /F1 9.8 Tf [(Memoli MJ, Jagger BW, Dugan VG, Qi L, Jackson JP, Taubenberger JK. Recent human influenza A/H3N2 virus evolution )] TJ ET BT 26.250 130.166 Td /F1 9.8 Tf [(driven by novel selection factors in addition to antigenic drift. J Infect Dis. 2009 Oct 15;200\(8\):1232-41. PubMed PMID: )] TJ ET BT 26.250 118.261 Td /F1 9.8 Tf [(19743921; PubMed Central PMCID: PMC2778484.)] TJ ET BT 26.250 98.856 Td /F1 9.8 Tf [(51.)] TJ ET BT 43.553 98.856 Td /F1 9.8 Tf [(Hensley SE, Das SR, Bailey AL, Schmidt LM, Hickman HD, Jayaraman A, Viswanathan K, Raman R, Sasisekharan R, )] TJ ET BT 26.250 86.952 Td /F1 9.8 Tf [(Bennink JR, Yewdell JW. Hemagglutinin receptor binding avidity drives influenza A virus antigenic drift. Science. 2009 Oct )] TJ ET BT 26.250 75.047 Td /F1 9.8 Tf [(30;326\(5953\):734-6. PubMed PMID: 19900932; PubMed Central PMCID: PMC2784927.)] TJ ET BT 26.250 55.642 Td /F1 9.8 Tf [(52.)] TJ ET BT 43.553 55.642 Td /F1 9.8 Tf [(Chen Z, Zhou H, Jin H. The impact of key amino acid substitutions in the hemagglutinin of influenza A \(H3N2\) viruses on )] TJ ET BT 26.250 43.737 Td /F1 9.8 Tf [(vaccine production and antibody response. Vaccine. 2010 May 28;28\(24\):4079-85. PubMed PMID: 20399830.)] TJ ET Q q 15.000 33.856 577.500 743.144 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Projection.Panama.for2003.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 751.490 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 732.940 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 732.940 Td /F1 9.8 Tf [(Projection.Fujian.for2003.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 724.454 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 705.904 Td /F1 9.8 Tf [(34.)] TJ ET BT 43.553 705.904 Td /F1 9.8 Tf [(HA1.H3N2.2009.Tree.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 697.418 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 678.868 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 678.868 Td /F1 9.8 Tf [(Wolf YI, Viboud C, Holmes EC, Koonin EV, Lipman DJ. Long intervals of stasis punctuated by bursts of positive selection in )] TJ ET BT 26.250 666.963 Td /F1 9.8 Tf [(the seasonal evolution of influenza A virus. Biol Direct. 2006 Oct 26;1:34. PubMed PMID: 17067369; PubMed Central PMCID: )] TJ ET BT 26.250 655.059 Td /F1 9.8 Tf [(PMC1647279.)] TJ ET BT 26.250 635.654 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 635.654 Td /F1 9.8 Tf [(Season.Series.Data.xls)] TJ ET 0.267 0.267 0.267 rg BT 26.250 627.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 608.618 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 608.618 Td /F1 9.8 Tf [(Shaman J, Pitzer V, Viboud C, Lipsitch M, Grenfell B. Absolute humidity and the seasonal onset of influenza in the )] TJ ET BT 26.250 596.713 Td /F1 9.8 Tf [(continental US. PLoS Curr. 2009 Dec 18:RRN1138. Update in: PLoS Biol. 2010 Feb;8\(2\):e1000316. PubMed PMID: 20066155; )] TJ ET BT 26.250 584.808 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2803311.)] TJ ET BT 26.250 565.404 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 565.404 Td /F1 9.8 Tf [(Tellier R. Aerosol transmission of influenza A virus: a review of new studies. J R Soc Interface. 2009 Dec 6;6 Suppl 6:S783-)] TJ ET BT 26.250 553.499 Td /F1 9.8 Tf [(90. Epub 2009 Sep 22. Review. PubMed PMID: 19773292; PubMed Central PMCID: PMC2843947.)] TJ ET BT 26.250 534.094 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 534.094 Td /F1 9.8 Tf [(Shaman J, Kohn M. Absolute humidity modulates influenza survival, transmission, and seasonality. Proc Natl Acad Sci U S )] TJ ET BT 26.250 522.189 Td /F1 9.8 Tf [(A. 2009 Mar 3;106\(9\):3243-8. Epub 2009 Feb 9. PubMed PMID: 19204283; PubMed Central PMCID: PMC2651255.)] TJ ET BT 26.250 502.785 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 502.785 Td /F1 9.8 Tf [(du Prel JB, Puppe W, Grndahl B, Knuf M, Weigl JA, Schaaff F, Schmitt HJ. Are meteorological parameters associated with )] TJ ET BT 26.250 490.880 Td /F1 9.8 Tf [(acute respiratory tract infections? Clin Infect Dis. 2009 Sep 15;49\(6\):861-8. PubMed PMID: 19663691.)] TJ ET BT 26.250 471.475 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 471.475 Td /F1 9.8 Tf [(Anestad G, Nordbo SA. Interference between outbreaks of respiratory viruses. Euro Surveill. 2009 Oct 15;14\(41\):19359. )] TJ ET BT 26.250 459.570 Td /F1 9.8 Tf [(Erratum in: Euro Surveill. 2009;14\(42\). pii: 19367. PubMed PMID: 19883536.)] TJ ET BT 26.250 440.166 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 440.166 Td /F1 9.8 Tf [(Greer RM, McErlean P, Arden KE, Faux CE, Nitsche A, Lambert SB, Nissen MD, Sloots TP, Mackay IM. Do rhinoviruses )] TJ ET BT 26.250 428.261 Td /F1 9.8 Tf [(reduce the probability of viral co-detection during acute respiratory tract infections? J Clin Virol. 2009 May;45\(1\):10-5. Epub )] TJ ET BT 26.250 416.356 Td /F1 9.8 Tf [(2009 Apr 18. PubMed PMID: 19376742.)] TJ ET BT 26.250 396.951 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 396.951 Td /F1 9.8 Tf [(Glezen WP, Paredes A, Taber LH. Influenza in children. Relationship to other respiratory agents. JAMA. 1980 Apr )] TJ ET BT 26.250 385.047 Td /F1 9.8 Tf [(4;243\(13\):1345-9. PubMed PMID: 6244421.)] TJ ET BT 26.250 365.642 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 365.642 Td /F1 9.8 Tf [(Anestad G. Interference between outbreaks of respiratory syncytial virus and influenza virus infection. Lancet. 1982 Feb )] TJ ET BT 26.250 353.737 Td /F1 9.8 Tf [(27;1\(8270\):502. PubMed PMID: 6121154.)] TJ ET BT 26.250 334.332 Td /F1 9.8 Tf [(45.)] TJ ET BT 43.553 334.332 Td /F1 9.8 Tf [(Sonoguchi T, Sakoh M, Kunita N, Satsuta K, Noriki H, Fukumi H. Reinfection with influenza A \(H2N2, H3N2, and H1N1\) )] TJ ET BT 26.250 322.428 Td /F1 9.8 Tf [(viruses in soldiers and students in Japan. J Infect Dis. 1986 Jan;153\(1\):33-40. PubMed PMID: 3941288.)] TJ ET BT 26.250 303.023 Td /F1 9.8 Tf [(46.)] TJ ET BT 43.553 303.023 Td /F1 9.8 Tf [(Sonoguchi T, Naito H, Hara M, Takeuchi Y, Fukumi H. Cross-subtype protection in humans during sequential, overlapping, )] TJ ET BT 26.250 291.118 Td /F1 9.8 Tf [(and/or concurrent epidemics caused by H3N2 and H1N1 influenza viruses. J Infect Dis. 1985 Jan;151\(1\):81-8. PubMed PMID: )] TJ ET BT 26.250 279.213 Td /F1 9.8 Tf [(3965596.)] TJ ET BT 26.250 259.809 Td /F1 9.8 Tf [(47.)] TJ ET BT 43.553 259.809 Td /F1 9.8 Tf [(Epstein SL. Prior H1N1 influenza infection and susceptibility of Cleveland Family Study participants during the H2N2 )] TJ ET BT 26.250 247.904 Td /F1 9.8 Tf [(pandemic of 1957: an experiment of nature. J Infect Dis. 2006 Jan 1;193\(1\):49-53. Epub 2005 Nov 21. PubMed PMID: )] TJ ET BT 26.250 235.999 Td /F1 9.8 Tf [(16323131.)] TJ ET BT 26.250 216.594 Td /F1 9.8 Tf [(48.)] TJ ET BT 43.553 216.594 Td /F1 9.8 Tf [(Finkelman BS, Viboud C, Koelle K, Ferrari MJ, Bharti N, Grenfell BT. Global patterns in seasonal activity of influenza )] TJ ET BT 26.250 204.690 Td /F1 9.8 Tf [(A/H3N2, A/H1N1, and B from 1997 to 2005: viral coexistence and latitudinal gradients. PLoS One. 2007 Dec 12;2\(12\):e1296. )] TJ ET BT 26.250 192.785 Td /F1 9.8 Tf [(PubMed PMID: 18074020; PubMed Central PMCID: PMC2117904.)] TJ ET BT 26.250 173.380 Td /F1 9.8 Tf [(49.)] TJ ET BT 43.553 173.380 Td /F1 9.8 Tf [(Shen J, Ma J, Wang Q. Evolutionary trends of A\(H1N1\) influenza virus hemagglutinin since 1918. PLoS One. 2009 Nov )] TJ ET BT 26.250 161.475 Td /F1 9.8 Tf [(17;4\(11\):e7789. PubMed PMID: 19924230; PubMed Central PMCID: PMC2773012.)] TJ ET BT 26.250 142.071 Td /F1 9.8 Tf [(50.)] TJ ET BT 43.553 142.071 Td /F1 9.8 Tf [(Memoli MJ, Jagger BW, Dugan VG, Qi L, Jackson JP, Taubenberger JK. Recent human influenza A/H3N2 virus evolution )] TJ ET BT 26.250 130.166 Td /F1 9.8 Tf [(driven by novel selection factors in addition to antigenic drift. J Infect Dis. 2009 Oct 15;200\(8\):1232-41. PubMed PMID: )] TJ ET BT 26.250 118.261 Td /F1 9.8 Tf [(19743921; PubMed Central PMCID: PMC2778484.)] TJ ET BT 26.250 98.856 Td /F1 9.8 Tf [(51.)] TJ ET BT 43.553 98.856 Td /F1 9.8 Tf [(Hensley SE, Das SR, Bailey AL, Schmidt LM, Hickman HD, Jayaraman A, Viswanathan K, Raman R, Sasisekharan R, )] TJ ET BT 26.250 86.952 Td /F1 9.8 Tf [(Bennink JR, Yewdell JW. Hemagglutinin receptor binding avidity drives influenza A virus antigenic drift. Science. 2009 Oct )] TJ ET BT 26.250 75.047 Td /F1 9.8 Tf [(30;326\(5953\):734-6. PubMed PMID: 19900932; PubMed Central PMCID: PMC2784927.)] TJ ET BT 26.250 55.642 Td /F1 9.8 Tf [(52.)] TJ ET BT 43.553 55.642 Td /F1 9.8 Tf [(Chen Z, Zhou H, Jin H. The impact of key amino acid substitutions in the hemagglutinin of influenza A \(H3N2\) viruses on )] TJ ET BT 26.250 43.737 Td /F1 9.8 Tf [(vaccine production and antibody response. Vaccine. 2010 May 28;28\(24\):4079-85. PubMed PMID: 20399830.)] TJ ET Q q 15.000 33.856 577.500 743.144 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Projection.Panama.for2003.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 751.490 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 732.940 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 732.940 Td /F1 9.8 Tf [(Projection.Fujian.for2003.Isolates.Used.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 724.454 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 705.904 Td /F1 9.8 Tf [(34.)] TJ ET BT 43.553 705.904 Td /F1 9.8 Tf [(HA1.H3N2.2009.Tree.txt)] TJ ET 0.267 0.267 0.267 rg BT 26.250 697.418 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 678.868 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 678.868 Td /F1 9.8 Tf [(Wolf YI, Viboud C, Holmes EC, Koonin EV, Lipman DJ. Long intervals of stasis punctuated by bursts of positive selection in )] TJ ET BT 26.250 666.963 Td /F1 9.8 Tf [(the seasonal evolution of influenza A virus. Biol Direct. 2006 Oct 26;1:34. PubMed PMID: 17067369; PubMed Central PMCID: )] TJ ET BT 26.250 655.059 Td /F1 9.8 Tf [(PMC1647279.)] TJ ET BT 26.250 635.654 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 635.654 Td /F1 9.8 Tf [(Season.Series.Data.xls)] TJ ET 0.267 0.267 0.267 rg BT 26.250 627.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 608.618 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 608.618 Td /F1 9.8 Tf [(Shaman J, Pitzer V, Viboud C, Lipsitch M, Grenfell B. Absolute humidity and the seasonal onset of influenza in the )] TJ ET BT 26.250 596.713 Td /F1 9.8 Tf [(continental US. PLoS Curr. 2009 Dec 18:RRN1138. Update in: PLoS Biol. 2010 Feb;8\(2\):e1000316. PubMed PMID: 20066155; )] TJ ET BT 26.250 584.808 Td /F1 9.8 Tf [(PubMed Central PMCID: PMC2803311.)] TJ ET BT 26.250 565.404 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 565.404 Td /F1 9.8 Tf [(Tellier R. Aerosol transmission of influenza A virus: a review of new studies. J R Soc Interface. 2009 Dec 6;6 Suppl 6:S783-)] TJ ET BT 26.250 553.499 Td /F1 9.8 Tf [(90. Epub 2009 Sep 22. Review. PubMed PMID: 19773292; PubMed Central PMCID: PMC2843947.)] TJ ET BT 26.250 534.094 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 534.094 Td /F1 9.8 Tf [(Shaman J, Kohn M. Absolute humidity modulates influenza survival, transmission, and seasonality. Proc Natl Acad Sci U S )] TJ ET BT 26.250 522.189 Td /F1 9.8 Tf [(A. 2009 Mar 3;106\(9\):3243-8. Epub 2009 Feb 9. PubMed PMID: 19204283; PubMed Central PMCID: PMC2651255.)] TJ ET BT 26.250 502.785 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 502.785 Td /F1 9.8 Tf [(du Prel JB, Puppe W, Grndahl B, Knuf M, Weigl JA, Schaaff F, Schmitt HJ. Are meteorological parameters associated with )] TJ ET BT 26.250 490.880 Td /F1 9.8 Tf [(acute respiratory tract infections? Clin Infect Dis. 2009 Sep 15;49\(6\):861-8. PubMed PMID: 19663691.)] TJ ET BT 26.250 471.475 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 471.475 Td /F1 9.8 Tf [(Anestad G, Nordbo SA. Interference between outbreaks of respiratory viruses. Euro Surveill. 2009 Oct 15;14\(41\):19359. )] TJ ET BT 26.250 459.570 Td /F1 9.8 Tf [(Erratum in: Euro Surveill. 2009;14\(42\). pii: 19367. PubMed PMID: 19883536.)] TJ ET BT 26.250 440.166 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 440.166 Td /F1 9.8 Tf [(Greer RM, McErlean P, Arden KE, Faux CE, Nitsche A, Lambert SB, Nissen MD, Sloots TP, Mackay IM. Do rhinoviruses )] TJ ET BT 26.250 428.261 Td /F1 9.8 Tf [(reduce the probability of viral co-detection during acute respiratory tract infections? J Clin Virol. 2009 May;45\(1\):10-5. Epub )] TJ ET BT 26.250 416.356 Td /F1 9.8 Tf [(2009 Apr 18. PubMed PMID: 19376742.)] TJ ET BT 26.250 396.951 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 396.951 Td /F1 9.8 Tf [(Glezen WP, Paredes A, Taber LH. Influenza in children. Relationship to other respiratory agents. JAMA. 1980 Apr )] TJ ET BT 26.250 385.047 Td /F1 9.8 Tf [(4;243\(13\):1345-9. PubMed PMID: 6244421.)] TJ ET BT 26.250 365.642 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 365.642 Td /F1 9.8 Tf [(Anestad G. Interference between outbreaks of respiratory syncytial virus and influenza virus infection. Lancet. 1982 Feb )] TJ ET BT 26.250 353.737 Td /F1 9.8 Tf [(27;1\(8270\):502. PubMed PMID: 6121154.)] TJ ET BT 26.250 334.332 Td /F1 9.8 Tf [(45.)] TJ ET BT 43.553 334.332 Td /F1 9.8 Tf [(Sonoguchi T, Sakoh M, Kunita N, Satsuta K, Noriki H, Fukumi H. Reinfection with influenza A \(H2N2, H3N2, and H1N1\) )] TJ ET BT 26.250 322.428 Td /F1 9.8 Tf [(viruses in soldiers and students in Japan. J Infect Dis. 1986 Jan;153\(1\):33-40. PubMed PMID: 3941288.)] TJ ET BT 26.250 303.023 Td /F1 9.8 Tf [(46.)] TJ ET BT 43.553 303.023 Td /F1 9.8 Tf [(Sonoguchi T, Naito H, Hara M, Takeuchi Y, Fukumi H. Cross-subtype protection in humans during sequential, overlapping, )] TJ ET BT 26.250 291.118 Td /F1 9.8 Tf [(and/or concurrent epidemics caused by H3N2 and H1N1 influenza viruses. J Infect Dis. 1985 Jan;151\(1\):81-8. PubMed PMID: )] TJ ET BT 26.250 279.213 Td /F1 9.8 Tf [(3965596.)] TJ ET BT 26.250 259.809 Td /F1 9.8 Tf [(47.)] TJ ET BT 43.553 259.809 Td /F1 9.8 Tf [(Epstein SL. Prior H1N1 influenza infection and susceptibility of Cleveland Family Study participants during the H2N2 )] TJ ET BT 26.250 247.904 Td /F1 9.8 Tf [(pandemic of 1957: an experiment of nature. J Infect Dis. 2006 Jan 1;193\(1\):49-53. Epub 2005 Nov 21. 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