Integrating genetic and epidemiological data to determine virus transmission pathways Eleanor COTTAM 2,3 , Gaël THÉBAUD 1,2 , Jemma WADSWORTH 3 , John GLOSTER 3 , Leonard MANSLEY 4 , David PATON 3 , Donald KING 3 , Dan HAYDON 2 1 UMR BGPI (INRA-Montpellier) 2 Division of Environmental and Evolutionary Biology (University of Glasgow) 3 Institute for Animal Health (Pirbright) 4 Animal Health Divisional Office (Perth) MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Introduction Molecular epidemiology and directionality • Genetic sequences: – phylogeny – clades / groups / types • Comparison between genetic similarity and – geographic proximity – ecological zone – host species – ... • Direction of transmission : – reference (more or less implicit) to additional information MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Introduction Why is directionality interesting? source “target” • Implications: ≈ ≈ - logical: cause consequences ≈ ≈ - legal: responsible victim Accessible information Use of the information epidemiology type of source and target individuals parameterise • • epidemiological models transmission distances • (e.g., network models) important or missing sources • limit virus propagation • likely transmission modes • evolution multiscale models evolution during 1 transmission cycle • • In theory, complete description of the epidemic In practice, data sets concerning few individuals MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Introduction Questions on FMDV • At which scale is there some viral genetic polymorphism? – animal, farm, disease focus? • Can we use the observed polymorphism to identify transmission chains? How? • What is the reliability of veterinary contact tracing? MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Biological system • Foot-and-mouth disease virus outbreak (2001) • 20 complete genomes (~10 kb each) – 5 initial infections with a known history – 15 farms from the same focus (Durham County) A A C C K K B B L L E E N N D D F F M M G G J J I I O O P P 10 km 10 km • Positive-strand RNA virus: – High mutation rate (~10 -4 errors/nucleotide/replication) – Limited recombination MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Genetic data TCS • Known root A A N N • 2 independent G G I I J J introductions F F • 4 groups K K nucleotide substitutions nucleotide substitutions L L SAR/19/2000 SAR/19/2000 1 1 24 24 E E B B M M A A C C D D K K B B 3 3 L L E E N N P P 2 2 D D F F M M C C G G J J I I O O 4 4 O O 5 5 P P 10 km 10 km 0 0 10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 90 90 100 100 110 110 Day of outbreak Day of outbreak MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Genetic data TCS • Known root A A N N • 2 independent G G I I J J introductions F F • 4 groups K K tions tions L L 0 0 200 200 itu itu nucleotide subst nucleotide subst SAR/19/ SAR/19/ 1 1 24 24 E E How to identify B B M M transmission D D history? 3 3 P P 2 2 C C 4 4 O O 5 5 0 0 10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 90 90 100 100 110 110 Day of outbreak Day of outbreak MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Genetic data Which is the most likely transmission tree? ? • Known root A A N N • 1 known chain of G G I I J J transmissions ? • 3 obvious F F K K ? transmissions nucleotide substitutions nucleotide substitutions L L SAR/19/2000 SAR/19/2000 ? • What about the ? 1 1 24 24 other ones?? E E ? B B Which is the most likely M M farm for each node ? ? D D ? 3 3 P P 2 2 C C 4 4 Use of contact O O 5 5 tracing data 0 0 10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 90 90 100 100 110 110 MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
1 1 B B K K O O O O C C 1 1 3 3 3 3 2 2 2 2 4 4 4 4 5 5 A A A A B B K K N N N N C C 5 5 L L L L E E E E G G G G M M M M J J J J F F F F P P P P D D D D Gaël Thébaud I I I I Animal movement ban 27 January 2001 27 January 2001 27J 27J 27 January 2001 27 January 2001 2001 2001 03 February 2001 03 February 2001 03 February 2001 03 February 2001 10 February 2001 10 February 2001 10 February 2001 10 February 2001 17 February 2001 17 February 2001 17 February 2001 17 February 2001 24 February 2001 24 February 2001 24 February 2001 24 February 2001 03 M 03 M 03 M 03 M arch 2001 arch 2001 arch 2001 arch 2001 10 M 10 M 10 M 10 M arch 2001 arch 2001 arch 2001 arch 2001 17 M 17 M 17 M 17 M arch 2001 arch 2001 arch 2001 arch 2001 24 M 24 M 24 M 24 M arch 2001 arch 2001 arch 2001 arch 2001 31 M 31 M 31 M 31 M arch 2001 arch 2001 arch 2001 arch 2001 07 April 2001 07 April 2001 07 April 2001 07 April 2001 Epidemiology 14 April 2001 14 April 2001 14 April 2001 14 April 2001 21 April 2001 21 April 2001 21 April 2001 21 April 2001 28 April 2001 28 April 2001 28 April 2001 28 April 2001 05 M 05 M 05 M 05 M ay 2001 ay 2001 ay 2001 ay 2001 12 M 12 M 12 M 12 M ay 2001 ay 2001 ay 2001 ay 2001 19 M 19 M 19 M 19 M ay 2001 ay 2001 ay 2001 ay 2001 26 M 26 M 26 M 26 M ay 2001 ay 2001 ay 2001 ay 2001 02 June 2001 02 June 2001 02 June 2001 02 June 2001 09 June 2001 09 June 2001 09 June 2001 09 June 2001 • F i ( t ) : Probability for • I i : Probability density • L : Probability density MIEP08 • Montpellier, France • 10-12/06/2008 at date t farm i to be infectious of farm i for the infection date for latency ( Γ )
Epidemiology Animal movement ban • L : Probability density J J I I for latency ( Γ ) M M G G • I i : Probability density D D for the infection date P P F F of farm i C C E E • F i ( t ) : Probability for O O farm i to be infectious N N L L at date t K K B B A A 5 5 ⎛ ⎞ ⎛ ⎞ min( C , C ) min( C , C ) n j i j k ∑ ∑ ∑ ⎜ ⎟ ⎜ ⎟ λ = ⋅ ⋅ 4 4 I ( t ) F ( t ) I ( t ) F ( t ) ⎜ ⎟ ⎜ ⎟ 2 2 ij i j i k ⎝ ⎠ ⎝ ⎠ = = = t 0 k 1 t 0 3 3 ≠ k i 1 1 λ ij : Likelihood of 03 February 2001 03 February 2001 10 February 2001 10 February 2001 17 February 2001 17 February 2001 24 February 2001 24 February 2001 • 27 January 2001 27 January 2001 arch 2001 arch 2001 arch 2001 arch 2001 arch 2001 arch 2001 arch 2001 arch 2001 arch 2001 arch 2001 07 April 2001 07 April 2001 14 April 2001 14 April 2001 21 April 2001 21 April 2001 28 April 2001 28 April 2001 ay 2001 ay 2001 ay 2001 ay 2001 ay 2001 ay 2001 ay 2001 ay 2001 02 June 2001 02 June 2001 09 June 2001 09 June 2001 i � { j rather than 05 M 05 M 12 M 12 M 19 M 19 M 26 M 26 M another observed farm } 03 M 03 M 10 M 10 M 17 M 17 M 24 M 24 M 31 M 31 M MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Genetics + epidemiology λ ij : likelihood of i � { j rather than another observed farm } • λ ij can be computed for each transmission • Thus, for a complete transmission tree ( k ), λ k = Π λ ij • • And λ k can be computed for any tree … if all the possible trees can be enumerated � Algorithm defining the possible trees by recurrence from the leaves back to the root G G I I 30 λ J J 2 {F,G} 25 {1,2,K} F F Frequency 20 K 1728 15 L L trees 1 {L,E} 10 E E 5 All differing from 0 contact tracing results -250 -200 -150 -100 Loglikelihood MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Genetics + epidemiology Which is the most likely group of trees? • Rescaled likelihood: λ ’ k = λ k / Σ λ k 4 trees • Which group of trees represent 95% of the most likely tree rescaled likelihood? MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Genetics + epidemiology Which is the most likely tree? ( # ) Number of distinct sources among the 4 most likely trees [ # ] Likelihood of the most probable transmission MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Genetics + epidemiology Which is the most likely tree? A A A N N G G I I J J F F F K K nucleotide substitutions nucleotide substitutions L L SAR/19/2000 SAR/19/2000 L 1 1 24 24 E E K B B M M D D O 3 3 P P 2 2 C C 4 4 O O 5 5 0 0 10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 90 90 100 100 110 110 MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
Genetics + epidemiology Spatial pattern P (1-sided) = 1.2 x 10 -3 20000 A A C C K B K B L L E E N N 15000 D D F F M M G G J J Frequency I I 10000 O O P 5000 P 10 km 10 km 0 4000 6000 8000 10000 7472 m Short distance MeanDistSim Mean distance transmission 4850 m MIEP08 • Montpellier, France • 10-12/06/2008 Gaël Thébaud
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