Real-time tracking, molecular epidemiology, and data sharing


Richard Neher
Biozentrum, University of Basel


slides at neherlab.org/201802_bellagio.html

Evolution of RNA viruses

HI virus, source wikipedia
  • Constant struggle to adapt to changing environments and host immunity
  • Mutation rates of about 0.00001/site and replication
  • Large viral populations explore every single mutation every day
  • Most mutations are detrimental, but some persist
  • Mutations can act like an approximate clock
Phylogenetic analysis
Phylogenetic analysis
Can we use sequences to track an ongoing outbreak?

Sequences record the spread of pathogens

The resolution is limited by the number of mutations!
images by Trevor Bedford

Influenza virus genome - 8 segments

Zika virus genome $\sim 10000$ bases

Ebola virus genome $\sim 20000$ bases

Many RNA viruses pick up one mutation every 2-4 weeks!
Need to sequence the entire genome!

Frequent mutations imply...

  • most viruses in an outbreak differ from each other
  • data suggest transmission chains
  • transmission can be ruled out!
  • geographic spread can be reconstructed


  • Influenza virus evolves to avoid human immunity
  • Vaccines need frequent updates

nextflu.org

joint work with Trevor Bedford & his lab

Real-time molecular epidemiology during outbreaks?

Ebola virus outbreak in West Africa -- Dudas et al, Nature 2017

How do we avoid the long delay?

nextstrain.org

joint work with Trevor Bedford & his lab

NextStrain architecture

Using treetime to rapidly compute timetrees

panX @ pangenome.de

S. pneumoniae data set by Croucher et al.

Barriers to data sharing: scientists

  • Fear of being scooped/ensure maximal return
  • Secondary analysis perceived as freeloading: "data parasites"
  • Don't want to be second guessed
  • Release and curation is laborious
  • Sloppy records
Also see Smith et al, F1000 2016

Barriers to data sharing: organizations and governments

  • Economic consequences of outbreaks (tourism, agriculture)
  • Conflicts between high and low/middle income countries
  • Concerns about IP and commercial exploitation
  • Legislative/regulatory barriers
See also: van Panhius et al, BMC Public health 2014

Overcoming Barriers

Open vs restricted sharing

  • Alternatives to GenBank: GenBank is "public domain", no requirement to credit data producers
  • GISAID/EpiFlu: sign-up and agree to terms and conditions
  • virological.org: Platform for sharing and discussing molecular epidemiology
  • Explicit data reuse terms
  • Outline planned projects in white-paper
  • Caveat: Very difficult to enforce...
See Bogner et al, 2006

Building Trust

  • Peter Bogner coordinated Influenza data sharing
  • Andrew Rambaut coordinated Ebola virus data sharing
  • During the EBV outbreak, WHO and journals explicitly encouraged data sharing
See also Smith et al, F1000 2016

Make sharing easy and provide incentives!

Grubaugh et al, samples from Florida
Metsky et al, sample from the Caribbean

Challenges and Opportunities

  • Software is not the bottleneck!
  • Lack of data sharing
  • timeliness of data sharing
  • inconsistent formats
  • Sharing is not a priority since nothing is done with data
  • Sites like nextstrain provide incentives for data sharing
  • Automated analysis and web dissemination are low maintenance
  • Lots of synergies...

nextstrain.org

  • Trevor Bedford
  • Colin Megill
  • Pavel Sagulenko
  • Emma Hodcroft
  • Sidney Bell
  • James Hadfield
  • Wei Ding

TreeTime & panX

TreeTime: Pavel Sagulenko

github.com/neherlab/treetime
webserver at treetime.ch
manuscript on bioRxiv
panX: Wei Ding
github.com/neherlab/pan-genome-analysis
live site at pangenome.de
manuscript on bioRxiv