# New Ebola Paper

OK, not exactly new new, but certainly newish. This post is part of my new attempt to update my blog more with stories about science, research, and education in an attempt to avoid the vicious cycle of anxiety and depression that comes from spending too much time reading the news and engaging in social media.

Our paper on the prevalence of asymptomatic Ebola cases in Sierra Leone was published in PLoS Neglected Tropical Diseases on 15 November. In it, we show that nearly 10% of a sample of people from an Ebola hotspot in Kono District, Sierra Leone, tested positive for Ebola virus antibodies despite having reported no symptoms of Ebola Virus Disease.

The West African Ebola epidemic of 2014-2015 was the biggest outbreak of the disease ever recorded, with over 28,000 reported cases.  Our results suggest that the total number of cases may have been quite a bit more than this. They also suggest that Ebola is, as we suspected, like other pathogens and causes a wide variety of clinical manifestations.

The paper received quite a bit of media attention from outlets such as NPR, The Wall Street Journal, The LA Times, and Gizmodo.

This work was led by my rock-star Ph.D. student, Gene Richardson and involved a great many collaborators.  It was a great honor to be able to publish with such luminaries as George Rutherford, Megan Murray, and Paul Farmer. With several papers in the works or already submitted and ongoing research, I'm really looking forward to more results in the near future!

# Ebola Event at UCI: Planning, Not Panic

I am just back from an event at the University of California, Irvine organized by medical demographer Andrew Noymer. The event drew a big crowd, with probably 500-600 people in attendance.

There were five invited plenary speakers: Michael Buchmeier (UCI) spoke about the virology of Ebola and the Filovriuses more generally. Hearing Mike's insights on the not one, but two vaccines for Ebola that have been shelved for a decade due to lack of interest was particularly illuminating. George Rutherford (UCSF) talked about the epidemiology of the current EVD epidemic and placed control efforts within the broader context of Global Health Initiatives. This is a guy with a ton of experience in global health and on the ground in Africa and his cool demeanor was calming for the crowd. Victoria Fan (Hawai'i) discussed the economic implications of the epidemic. Spoiler alert: they're not good. Shruti Gohil (UCI Medical Center) talked about infection control in a hospital setting. Finally, I talked about the disease ecology, broadly construed, of Ebola. Following our talks, we got together as a panel and took questions for the audience.

Given the crazy hysteria surrounding the EVD epidemic and the arrival of a handful of cases in the United States, it was reassuring to participate in a couple hours of such sober, scientifically-informed discussion. Shruti's insights as chief of infection control at the UCI medical center particularly struck me. She noted that Texas Health Presbyterian Hospital in Dallas, where the first American EVD case (Thomas Duncan) was treated, was clearly completely unprepared to handle an acute EVD case. Despite this, Shruti estimated that the attack rate of health care workers who attended to Duncan was about 4%. Not that horrible for an unprepared hospital. She also noted that no health care workers have become infected in the special units specifically designed to handle infectious diseases like EVD at Emory, Nebraska, and Bethesda. Planning, strict adherence to protocols, and personal protective gear work!

So, let's summarize a bit about EVD in the US (these are the numbers as best as I can remember them, with citations where I can find them):

Number of cases of evacuated aid workers infected in Africa: 4

Number of deaths of evacuated aid workers infected in Africa: 0

Number of travel-associated cases in US: 4

Number of deaths of travel-associated cases in US: 1

Number of cases of American health care workers: 2

Number of deaths of American health care workers: 0

Note that the one death (Thomas Duncan) might have been prevented if he hadn't been sent home from the emergency room and gotten so much sicker.

Another interesting point that Shruti made is that none of Duncan's close personal contacts have contracted EVD and the 21-day window has now passed. The clear implication of all these data is that Ebola is not that infectious. It is controllable if we are prepared and follow protocols.

This gives me hope that we can control the EVD epidemic in West Africa if we were to decide to get serious about its control. But the international community needs to fight this epidemic where it is currently raging. This is clearly in the national interest of the United States and the collective interest of the international community. If we want to remain secure from EVD, we need to stop it where the epidemic continues to grow. World Bank President, and medical anthropologist extraordinaire, Jim Kim pulled out a great analogy in an interview on NPR on 17 October:

It's like you're in your room and the house is on fire, and your approach is to put wet towels under the door. That might work for a while, but unless you put the fire out, you're still in trouble.

Let's get over our fear, stop politicizing this crisis, stop demonizing the heroes. Let's roll up our sleeves, get out our checkbooks, and bring a speedy end to this crisis.  Let's put out the fire.

# Quick and Dirty Analysis of Ebola

I've been traveling all summer while this largest Ebola Virus Disease (EVD) outbreak in recorded history has raged in the West African countries of Guinea, Sierra Leone, Liberia, and (worryingly) Nigeria. My peripatetic state has meant that I haven't been able to devote as much attention to this outbreak as I would like to. There is a great deal of concern -- some might say hysteria -- about EVD and the possibility that it may go pandemic. Tara Smith at least, on her Aetiology blog, has written something sensible, noting that EVD, while terrifying, is controllable with careful public health protective measures, as the historical record from Uganda shows. A recent post by Greg Laden got me to thinking about the numbers from the current EVD outbreak and what we might be able to learn.

EVD was the model disease for the terrible (1995) Dustin Hoffman movie, Outbreak. As we learned in the much more scientifically-accurate (2011) movie Contagion (which is based on an equally terrifying aerosolized Nipah virus), one of the key pieces of information regarding an epidemic is the basic reproduction number, $R_0$. The basic reproduction number tells us how many secondary infections are expected (i.e., on average) to be produced by a single, typical case at the outset of an epidemic before the pool of susceptible people has been depleted.  $R_0$ provides lots of information about epidemics, including: (1) the epidemic threshold (i.e., whether or not an epidemic will occur, which happens in the deterministic case when $R_0 > 1$), (2) the initial rate of increase of an epidemic, (3) the critical vaccination threshold (i.e., what fraction of the population you need to vaccinate to prevent an outbreak), (4) the endemic equilibrium of an infection (i.e., the fraction of the population that is infected in between outbreaks), and (5) the final size of the epidemic (i.e., the fraction of the total population that is ever infected when the epidemic is over).

Thus, for a novel outbreak, it's good to have an idea of $R_0$. I've been a bit out of the loop this summer and haven't seen any estimates so I figured that I would see what I could do. I fully realize that someone may have already done this and that I am not yet aware of it. I also recognize that, if someone has done this, they've probably done it better. This is a blog, not a peer-reviewed paper, and I am away from my usual resources, so please take this in the back-of-the-envelope spirit in which it is intended. I reserve the right to retract, etc. I will also post the R code that I used to make the calculations. I hope that this may prove helpful to others interested in the dynamics of outbreaks.

In their terrific (2003) paper on the SARS outbreak, Marc Lipsitch and colleagues provided a method for estimating the reproduction number from outbreak data. Note that this is a more generalized reproduction number, which we call $R$, than is the basic reproduction number, $R_0$. The key difference is that a reproduction number can be calculated at any point in an outbreak, whereas $R_0$ is only technically correct at the outset (the zero index in $R_0$ indicates the "generation" of the outbreak where "0" refers to the index case, a.k.a., "patient zero"). I've simply used the count of total cases from this week. It is straightforward to extend the calculation to previous counts. I haven't yet had a chance to do this because there is no convenient collection of data that I can find with my current access constraints.

The method involves equating $R_0$ for a simplified SEIR system to the observed rate of increase of the outbreak at some point in time $t$, using the fact that the reproduction number is approximately equivalent to the growth rate of the epidemic. See the supplementary information from Lipsitch et al. (2003) for details of the method. In brief, we calculate the dominant eigenvalue of the linearized SEIR model, for which it is straightforward to write an analytical formula, and equate this to $log[Y(t)]/t$, the empirical growth rate of the epidemic (where $Y(t)$ is the cumulative number of cases at time $t$). Lipsitch et al. (2003) note that using the standard formula for the characteristic equation of the eigenvalues of the linearized SEIR model, we can solve for the reproduction number as:

where $V$ is the serial interval (i.e., the summed duration of the incubation period, $L$, and the duration of the infectious period, $D$), $\lambda$ is the positive root of the characteristic equation which we set equal to $\log[Y(t)]/t$, and $f$ is the ratio of the infectious period of the serial interval.

I got the case data from the weekly WHO outbreak report for 11 August 2014. For this week $Y(t)=1848$. For the start time of the epidemic in the currently afflicted countries, I used the date of 10 March 2014, taken from this week's NEJM paper by Blaize et al. (2014). For the serial interval data, I used the values provided by the Legrand et al. (2007). Because Legrand et al. (2007) provide mean values of the relevant parameters -- and this is a different epidemic -- I used a variety of values for $D$ and $L$ to calculate $R$. It turns out that it doesn't matter all that much; the estimates of $R$ are pretty stable.

I plot the values of $R$ against the duration of the latent period. The different lines are for the different values of the duration of infectiousness. $R$ increases with both. What we see is that at this point in the epidemic at least, $R$ ranges from around 1.3 to 2.6, depending on specifics of the course of the disease. This is not all that high -- about the same as various flavors of influenza and considerably less than, say, pertussis. This is good news for potential control, if we could just rally some more international support for control of this serious infection...

Here is the R code for doing the calculations and creating this figure:

[r]

library(lubridate)
# number of cases as of 11 August 2014
# http://www.who.int/csr/don/2014_08_11_ebola/en/
cases <- 1848 # start of epidemic in Guinea: 10 March 2014 # Blaize et al. (2014), NEJM. DOI: 10.1056/NEJMoa1404505 s <- dmy("10-03-14") e <- dmy("11-08-14") t <- e-s # Time difference of 154 days ## incubation period 2-21 days ## http://www.who.int/mediacentre/factsheets/fs103/en/ ## duration of infectiousness: virus detected in of lab-infected man 61 days! ## Legrande et al. (2007) use L=7 and D=10 ## doi:10.1017/S0950268806007217 lambda <- log(cases)/t ## From Lipsitch et al. (2003) ## lambda is the dominant eigenvalue of the linearized SEIR model ## V is the serial interval V = D + L ## D is duration infectious period, L is duration of latent period ## f is the ratio of the the infectious period to the serial interval ## to solve for R set the eigenvalue equal to the observed exponential growth rate of the epidemic log(Y(t))/t Rapprox <- function(lambda,V,f) 1 + V*lambda + f*(1-f)*(V* lambda)^2 RR <- matrix(0, nr=10, nc=10) L <- seq(3,12) D <- seq(5,14) for(i in 1:length(L)){ for(j in 1:length(D)){ RR[i,j] <- Rapprox(lambda,L[i]+D[j],D[j]/(L[i]+D[j])) } } cols <- topo.colors(10) png(file="Ebola-R0-plot1.png") plot(L, RR[1,], type="n", xlab="Duration of Incubation", ylab="Reproduction Number",ylim=c(1,2.5)) for(i in 1:10) lines(L, RR[i,], lwd=2, col=cols[i]) dev.off() [/r]

# EEID 2014 Wrap-Up

It's been a long time since I've written in monkey's uncle. Life has gotten pretty busy and my seeming inability to write brief entries has led me to neglect the blog this year. However, I am freshly back from the Ecology and Evolution of Infectious Disease Conference in Fort Collins, Colorado and feel compelled to give my annual run-down. The conference was hosted by friend and colleague Mike Antolin, Sue Vandewoude, and my erstwhile post-doc, now CSU researcher, Dan Salkeld. Nice job, folks, on a very successful conference.

EEID is pretty much the best meeting. As I noted in last year's post, I love its future-orientation. EEID is a meeting that foregrounds the work of junior scientists and there was, as ever, a tremendous array of human capital on display at this meeting. This drives home to me the importance of investment in professional training and research programs that specifically develop human capital. This community exists in large measure because of the innovative program jointly offered by NSF and NIH. Thanks as ever to the vision and hard work of Josh Rosenthal, Sam Scheiner, and all the funders (e.g., support from The Gates Foundation can be found all around this conference) for this area. It's always great to catch up with smart, fun friends. Plenty of time was spent talking science and drinking craft beer (what a beer town Ft. Collins is!) with the likes of Peter Hudson, Jessica Metcalf, Ottar Bjornstad, Aaron King, Mike Antolin, Tony Goldberg, Issa Cattadori, Maciej Boni, Marm Kilpatrick and, of course, Dan Salkeld. It was nice to meet and chat, if only briefly, with my sometime remote collaborator Paul Sharp, who gave what I understand to be an extremely stimulating keynote on the complicated and surprising evolution of malaria (alas, I missed it as I was delayed getting to Ft. Collins). I also spent some quality time learning about acquired immunity in dogs with Colin Parrish. This may come in handy for some ideas that Jess Metcalf and I have been playing around with.

There is a great tradition of the EEID hike and closing banquet/dance. Ft. Collins provided a beautiful and challenging hike out in Lory State Park. The view from the top of Arthur's Peak was pretty amazing.

At Wednesday's banquet, I'm afraid to say that Princeton once again dominated the dance floor as we all rocked out to the amazing Denver funk/rock/jam band Kinetix (great choice, Mike). The Stanford showing was disappointing in part because of the early departure of some of our most enthusiastic dancers. Don't get cocky though, Princeton. We'll be gunning for you next year.

The entirety of Tuesday morning's session was given over to communicating science. Dan Salkeld warmed up the crowd with some hilarious examples of the reporting frenzy that ensued following the publication of our paper on plague dynamics in prairie dog towns or, more recently, Hillary Young's work showing that excluding large ruminants increases rodent density in Kenya. Wow. Dan also used my Stanford colleague Rebecca Bird's work as an example of how an unexpected story can engage readers and listeners. My collaborator Tony Goldberg gave a talk that was also not lacking in ridiculous headlines thanks to his "viral" nose-tick work. David Quammen, author of outstanding popular science books such as The Song of the Dodo and Spillover (which Bill Durham and I use for our class on environmental change and emerging infectious disease), gave a terrific presentation in which he consolidated a lot of nice, practical advice on the craft of writing engaging work into 18 points, amply illustrated by anecdotes of characters from our field. Sonia Altizer from the University of Georgia introduced the crowd to the opportunities (and pitfalls) of citizen science and suggested that it might just be possible to engage the public in disease ecology data collection. Some examples she identified included the granddaddy of citizen-science in the US run by the Laboratory of Ornithology at Cornell, the ZomBee Watch at SFSU, and her own Project MonarchHealth. If I had to summarize this session in one pithy phrase, I think it would have to be "Yay, ecologists!"

Quammen took to Twitter to call us out for being behind the curve with respect to social media.

While there were, in fact, a few of us tweeting the occasional tidbit from the conference, I think his general point is valid. This stuff is intrinsically interesting and we can do a much better job communicating to broad publics.

Some talks that really caught my attention.

Ary Hoffmann gave a great talk about the complexities of using bacteria of the genus Wolbachia to control the Aedes mosquitoes that transmit dengue in Australia (and elsewhere). Wolbachia infects mosquitoes and can have a variety of effects on their biology. The reason artificial infection of mosquitoes wit this bacterium seems so promising as a means of biological control is that the offspring of crosses between infected and uninfected mosquitoes are not viable. This is obviously a very substantial fitness cost to the mosquitoes and this creates serious challenges for getting the infected mosquitoes to persist and take over local populations. Hoffmann presented a cool result about the invasibility of infected mosquitoes wherein in the early phases of introduction there is an unstable point in the mosquito dynamics. At this point, if the infected mosquitoes are above a threshold, they will successfully invade, otherwise, they will die out because of the inherent fitness costs of the Wolbachia infection. One policy challenge that arises is that to get a local population of mosquitoes above the invasibility threshold, researchers and vector-control specialists have to sometimes introduce a lot of mosquitoes. This means that the number of mosquitoes locally can increase substantially and, as you can imagine, this isn't always popular with communities.

Fellow Anthropologist Aaron Blackwell from UCSB gave a fantastic talk on our "old friends", the helminths (cue the freaky electron micrograph of a helminth's mouth!). Aaron participates in the Tsimane Health and Life History Project which was started by colleagues Mike Gurven (also at UCSB) and Hilly Kaplan (New Mexico). Using sophisticated multi-state Markov hazard models (go Anthropology!), Aaron showed that co-infection with helminths and Giardia is less frequent than expected among this population that experiences ubiquitous exposure to both pathogens and that, in fact, infection with the one appears to be protective against infection with the other. One of the most provocative results he presented showed that helminth infection actually lowered systolic blood pressure in men by an amount equivalent to the increase that comes from aging ten years. Chronic helminthic infection may be a reason why Tsimane men's systolic blood pressure does not rise precipitously with age as it does in the US. This result, which may provide fresh insights into the mechanisms of hypertension, a major source of morbidity in the US, struck me as particularly poignant given the demeaning comments made about NSF funding for work among the Tsimane from none other than Lamar Smith (R–TX), the chair of the House Committee on Science, Space, and Technology.

Anna Savage, a post-doc with the National Zoo in Washington DC, gave an awesome talk on the comparative immunogenetics of of frogs with respect to infection with the devastating fungal infection, chytridiomycosis. Chytridiomycosis has been identified as a major cause of amphibian extinction worldwide and Anna showed surprising heterogeneity in immune response across frog species. This is a subject with which I have only passing familiarity, but her talk demonstrated an amazing sophistication in integrating different levels of biological organization and making sense of a dauntingly complex problem. I would wager that Dr. Savage is one to keep an eye on.

The organizers tried a scheduling format that was a bit different from last year, wherein each session started with two half-hour talks generally given by somewhat more senior people. The second half of each session was then given over to brief ten-minute talks, typically delivered by more junior people. This format is nicely in keeping with the great EEID tradition of promoting the research of junior scientists. A few short talks that I found especially interesting included one by Sarah Hamer, from Texas A&M, on Chagas disease in the United States. She presented sobering data from national blood-bank surveillance showing a surprising number of Chagas-infected samples coming from donors with no history of travel to Latin America. When pushed by a questioner, she suggested that she would consider Chagas to be endemic in the US, at least in dogs and possibly even in people. Carrie Cizauskas, formerly of Wayne Getz's shop at Berkeley and now with Andy Dobson and Andrea Graham at Princeton, give a nice talk on the role of both stress and sex hormones in mediating macroparasite infection in wild ungulates in Etosha National Park, Namibia. Romain Garnier from Princeton described a very nifty image-processing approach to scanning large volumes of histological slides for indications of infection.

I perhaps didn't see as many posters as I should have. The problem with the poster sessions is that one keeps running into various people one wants to talk to. I did manage to check out the poster of my former freshman advisee and current Princeton EEB student Cara Brook. She's got an awesome PhD project studying the multi-host ecology of infectious disease in Malagasy fruit bats.

I'm looking forward to next year's meeting at the University of Georgia already. I'm also looking forward to resuscitating the pedagogical workshop that used to be a signature feature of this EEID meeting. More on that later...

# More Guilt Over Agricultural Disease Names

In the spirit of my professed guilty amusement about the names of agricultural diseases, I just chuckled a bit at a promedmail update of what sounded like a biblical plague that had to be sent directly to the Apocrypha: Crayfish plague in Israel. Watch out, Pharaoh...

# Aedes aegypti in San Mateo County

The mosquito, Aedes aegypti, which is the vector for a number of world scourges (e.g., dengue, yellow fever), has been found in San Mateo County (just across San Francisquito Creek from Stanford) for the first time since 1979. That makes three counties in California where the mosquito has been found. While not a panic-inducing development, it would be most excellent if the good people of San Mateo and Santa Clara counties would make sure their yards are free of mosquito breeding habitat!

# Ecology and Evolution of Infectious Disease

I am recently back from the 2013 Ecology and Evolution of Infections Disease Conference at Penn State University. This was quite possibly the best meeting I have ever attended, not even for the science (which was nonetheless impeccable), but for the culture. I place the blame for this awesome culture firmly on the shoulders of the leaders of this field and, in particular, the primary motivating force behind the recent emergence of this field, Penn State's Peter Hudson. Since I had attended the other EEID conference at UGA earlier this Spring (another great conference), I had no intention on attending the Penn State conference this year. Then, one day in late March, Nita Bharti asked me if I was going and mentioned, "You know it's Pete's 60th birthday, right?" Well that sealed it; I really had no choice.  I simply had to go if for no other reason than to pay my due respect to this man I admire so greatly. Pete has the most relentless optimism about the future of science and a willingness to make things happen that I have ever encountered and, in this way, has provided me one of my primary role models as a university professor and mentor. He has played a role in developing so many of the brilliant people who make this field so exciting, it's amazing (just a sample that comes immediately to mind: Ottar Bjornstad, Matt Ferrari, Nita Bharti, Marcel Salathé, Isabella Cattadori, Jamie Lloyd-Smith, Shweta Bansal, Jess Metcalf...). Of course, even as I write this, I realize the joint influence of another major player in the field, Bryan Grenfell, formerly of Penn State but now at Princeton, becomes obvious. A great scientist in his own right, Pete is the master facilitator, providing the support (and institutional interference!) that allows young scholars to thrive. He is a talent-spotter extraordinaire.

The tone set by these great mentors carries through to the whole culture of the conference, where senior people attended the poster sessions, sat with students at lunches and dinners, and schmoozed at the plentiful open-bar mixers. For example, on the first full day of the conference, there was an afternoon poster session that started at 4:30 (we had been in back-to-back sessions since 8:30). This session was preceded by an hour-long poster-teaser session in which grad students and post-docs got up and presented 60-second (and, as Andrew Read noted, not one nanosecond more) teasers of their posters. Bear in mind, this session was entirely comprised of students and post-docs. It was striking that essentially every seat in the house was occupied and all the major players were present. The teasers were great – many were very funny, including a haiku apparently written by a triatomine bug and translated to us by Princeton EEB student Jennifer Peterson.

After the teasers, the conference went en masse to the fancy new Millenium Science Complex (it turns out that Pete Hudson has physical capital projects in addition to human capital ones!). There, participants milled about the 150 posters. After spending quite a bit of time doing this – and dutifully getting pictures of all my lab with their posters – I thought to check the time and realized it was nearly 6:30. The poster session had been going for two hours and nearly everyone was still there, including all the luminaries. It helped that there was free beer. I tweeted my amazement at this realization:

That is, in fact, Princeton's Bryan Grenfell moving fast in the middle of the picture, apparently making a bee-line for Michigan's Aaron King. Andrew Read is in the far background, talking to a poster-presenter (he has that posture).

Scientific highlights for me included Caroline Buckee's talk about measuring mobility in the context of malaria transmission in Kenya and Derek Cummings's talk on the Fluscape Project to measure spatial heterogeneity in influenza transmission in China. I am a long-time fan of this project and it's nice to see the great work that has come out of it. These talks were right in my wheelhouse of interest, but there were plenty other cool ones including Britt Koskella's talk on the dynamics of bacteria and phage on tree leaves.

Stanford was exceedingly well represented at this conference. My lab had no fewer than five posters. Ashley Hazel presented on her work with Carl Simon on modeling gonorrhea transmission dynamics in Kaokoland, Namibia. Whitney Bagge presented her work on remote-sensing of rodent-borne disease in Kenya. Alejandro Feged presented work on the transmission dynamics of malaria in the Colombian Amazon among the indigenous Nukak people. Laura Bloomfield presented her remote sensing and spatial analysis work from our project on the spillover of primate retroviruses in Western Uganda. I closed things out with a minimalist poster on simple graphical models for multiple attractors in vector-borne disease dynamics in multi-host ecologies. In addition to my lab group, Giulio De Leo (with whom I have been running a weekly disease ecology workshop at Woods since winter quarter) was there, helping to bridge all sorts of structural holes in our collective collaboration graphs.

The other thing that comes out of these meetings, especially more intimate ones like EEID, is some actual work on collaborative projects. I managed to find some time to sit down and discuss plans with collaborators as well as do some shameless recruitment for my planned re-submission of the Stanford Biodemography Workshops. I'm really excited about some of these collaborations, including one that brings together my two major areas of interest: biodemography and life history theory and infectious disease ecology.

Oh, and I'm convinced that there must be an interpretive dance component to the Ph.D. exam in the Grenfell lab. This is certainly the most parsimonious explanation for much of what I saw Wednesday night.

# Ecology and Evolution of Infectious Disease, 2013

I am recently back from the Ecology and Evolution of Infectious Disease (EEID) Principal Investigators' Meeting hosted by the Odum School of Ecology at the University of Georgia in lovely Athens. This is a remarable event, and a remarkable field, and I can't remember ever being so energized after returning from a professional conference (which often leave me dismayed or even depressed about my field). EEID  is an innovative, highly interdisciplinary funding program jointly managed by the National Science Foundation and the National Institutes of Health. I have been lucky enough to be involved with this program for the last six years. I've served on the scientific review panel a couple times and am now a Co-PI on two projects.

We had a big turn-out for our Uganda team in Athens and team members presented no fewer than four posters. The Stanford social networks/human dimensions team (including Laura Bloomfield, Shannon Randolph and Lucie Clech) presented a poster ("Multiplex Social Relations and Retroviral Transmission Risk in Rural Western Uganda") on our preliminary analysis of the social network data. Simon Frost's student at Cambridge, James Lester, presented a poster ("Networks, Disease, and the Kibale Forest") analyzing our syndromic surveillance data. Sarah Paige from Wisconsin presented a poster on the socio-economic predictors of high-risk animal contact ("Beyond Bushmeat: Animal contact, injury, and zoonotic disease risk in western Uganda") and Maria Ruiz-López, who works with Nelson Ting at Oregon, presented a poster on their work on developing the resources to do some serious population genetics on the Kibale red colobus monkeys ("Use of RNA-seq and nextRAD for the development of red colobus monkey genomic resource").

Parviez Hosseini, from the EcoHealth Alliance, also presented a poster for our joint work on comparative spillover dynamics of avian influenza ("Comparative Spillover Dynamics of Avian Influenza in Endemic Countries"). I'm excited to get more work done on this project which is possible now that new post-doc Ashley Hazel has arrived from Michigan. Ashley will oversee the collection of relational data in Bangladesh and help us get this project into high gear.

The EEID conference has a unique take on poster presentations which make it much more enjoyable than the typical professional meeting. In general, I hate poster sessions. Now, don't get me wrong: I see lots of scientific value in them and they can be a great way for people to have extended conversations about their work. They can be an especially great forum for students to showcase their work and start the long process of forming professional networking. However, there is an awkwardness to poster sessions that can be painful for the hapless conference attender who might want, say, to walk through the room in which a poster session is being held. These rooms tend to be heavy with the smell of desperation and one has to negotiate a gauntlet of suit-clad, doe-eyed graduate students desperate to talk to anyone who will listen about their work. "Please talk to me; I'm so lonely" is what I imagine them all saying as I briskly walk through, trying to look busy and purposeful (while keeping half an eye out for something really interesting!).

The scene at EEID is much different. All posters go up at the same time and the site-fidelity of poster presenters is the lowest I have ever seen. It has to be since, if everyone stuck by their poster, there wouldn't be anyone to see any of them! What this did was allow far more mixing than I normally see at such sessions and avoid much of the inherent social awkwardness of a poster session. Posters also stayed up long past the official poster session. I continued to read posters for at least a day after the official session ended. Of course, it helps that there was all manner of great work being presented.

There were lots of great podium talks too. I was particularly impressed with the talks by Charlie King of Case Western on polyparasitism in Kenya, Maria Diuk-Wasser of Yale on the emergence of babesiosis in the Northeast, Jean Tsao (Michigan State) and Graham Hickling's (Tennessee) joint talk on Lyme disease in the Southeast, and Bethany Krebs's talk on the role of robin social behavior in West Nile Virus outbreaks. Laura Pomeroy, from Ohio State, represented one of the other few teams with a substantial anthropological component extremely well, talking about the transmission dynamics of foot-and-mouth disease in Cameroon. Probably my favorite talk of the weekend was the last talk by Penn State's Matt Thomas. They done awesome work elucidating the role of temperature variability on the transmission dynamics of malaria.

It turns out that this was the last EEID PI conference. Next year, the EEID PI conference will be combined with the other EEID conference which was originally organized at Penn State (and is there again this May). This combining of forces is, I'm sure, a good thing as it will reduce confusion and probably make it more likely that all the people I want to see have a better chance of showing up. I just hope that this new, larger conference retains the charms of the EEID PI conference.

EEID is a new, interdisciplinary field that has grown thanks to some disproportionately large contributions of a few, highly energetic people. One of the principals in this realm is definitely Sam Scheiner, the EEID program officer at NSF.  The EEID PI meeting has basically been Sam's baby for the past 10 years. Sam has done an amazing job creating a community of interdisciplinary scholars and I'm sure I speak for every researcher who has been heavily involved with EEID when I express my gratitude for all his efforts.

# On The Dilution Effect

A new paper written by Dan Salkeld (formerly of Stanford), Kerry Padgett (CA Department of Public Health), and myself just came out in the journal Ecology Letters this week.

One of the most important ideas in disease ecology is a hypothesis known as the "dilution effect". The basic idea behind the dilution effect hypothesis is that biodiversity -- typically measured by species richness, or the number of different species present in a particular spatially defined locality -- is protective against infection with zoonotic pathogens (i.e., pathogens transmitted to humans through animal reservoirs). The hypothesis emerged from analysis of Lyme disease ecology in the American Northeast by Richard Ostfeld and his colleagues and students from the Cary Institute for Ecosystem Studies in Millbrook, New York. Lyme disease ecology is incredibly complicated, and there are a couple different ways that the dilution effect can come into play even in this one disease system, but I will try to render it down to something easily digestible.

Lyme disease is caused by a spirochete bacterium Borrelia burgdorferi. It is a vector-borne disease transmitted by hard-bodied ticks of the genus >Ixodes. These ticks are what is known as hemimetabolous, meaning that they experience incomplete metamorphosis involving larval and nymphal stages. Rather than a pupa, these larvae and nymphs resemble little bitty adults. An Ixodes tick takes three blood meals in its lifetime: one as a larva, once as a nymph, once as an adult. At different life-cycle stages, the ticks have different preferences for hosts. Larval ticks generally favor the white-footed mouse (Peromyscus leucopus) for their blood meal and this is where the catch is. It turns out that white-footed mice are extremely efficient reservoirs for Lyme disease. In fact, an infected mouse has as much as a 90% chance of transmitting infection to a larva feeding on it. The larvae then molt into nymphs and overwinter on the forest floor. Then, in spring or early summer a year after they first hatch from eggs, nymphs seek vertebrate hosts. If an individual tick acquired infection as a larva, it can now transmit to its next host. Nymphs are less particular about their choice of host and are happy to feed on humans (or just about any other available vertebrate host).

This is where the dilution effect comes in. The basic idea is that if there are more potential hosts such as chipmunks, shrews, squirrels, or skunks, there are more chances that an infected nymph will take a blood meal on a person. Furthermore, most of these hosts are much less efficient at transmitting the Lyme spirochete than are white-footed mice. This lowers the prevalence of infection and makes it more likely that it will go extinct locally. It's not difficult to imagine the dilution effect working at the larval stage blood-meal too: if there are more species present (and the larvae are not picky about their blood meal), the risk of initial infection is also diluted.

In the highly-fragmented landscape of northeastern temperate woodlands, when there is only one species in a forest fragment, it is quite likely that it will be a white-footed mouse. These mice are very adaptable generalists that occur in a wide range of habitats from pristine woodland to degraded forest. Therefore, species-poor habitats tend to have mice but no other species. The idea behind the dilution effect is that by adding different species to the baseline of a highly depauperate assemblage of simply white-footed mice, the prevalence of nymphal infection will decline and the risk for zoonotic infection of people will be reduced.

It is not an exaggeration to say that the dilution-effect hypothesis is one of the two or three most important ideas in disease ecology and much of the explosion of interest in disease ecology can be attributed in part to such ideas. The dilution effect is also a nice idea. Wouldn't it be great if every dollar we invested in the conservation of biodiversity potentially paid a dividend in reduced disease risk? However, its importance to the field or the beauty of the idea do not guarantee that it is actually scientifically correct.

One major issue with the dilution effect hypothesis is its problem with scale, arguably the central question in ecology. Numerous studies have shown that pathogen diversity is positively related to overall biodiversity at larger spatial scales. For example, in an analysis of global risk of emerging infectious diseases, Kate Jones and her colleagues form the London Zoological Society showed that globally, mammalian biodiversity is positively associated with the odds of an emerging disease. Work by Pete Hudson and colleagues at the Center for Infectious Disease Dynamics at Penn State showed that healthy ecosystems may actually be richer in parasite diversity than degraded ones. Given these quite robust findings, how is it that diversity at a smaller scale is protective?

We use a family of statistical tools known as "meta-analysis" to aggregate the results of a number of previous studies into a single synthetic test of the dilution-effect hypothesis. It is well known that inferences drawn from small samples generally have lower precision (i.e., the estimates carry more uncertainty) than inferences drawn from larger samples. A nice demonstration of this comes from the classical asymptotic statistics. The expected value of a sample mean is the "true mean" of a normal distribution and the standard deviation of this distribution is given by the standard error, which is defined as the standard deviation of the distribution divided by the square root of the sample size. Say that for two studies we estimate the standard deviation of our estimate of the mean to be 10. In the first study, this estimate is based on a single observation, whereas in the second, it is based on a sample of 100 observations. The estimated of the mean in the second study is 10 times more precise than the estimate based on the first because $10/\sqrt{1} = 10$ while $10/\sqrt{100} = 1$.

Meta-analysis allows us to pool estimates from a number of different studies to increase our sample size and, therefore, our precision. One of the primary goals of meta-analysis is to estimate the overall effect size and its corresponding uncertainty. The simplest way to think of effect size in our case is the difference in disease risk (e.g., as measured in the prevalence of infected hosts) between a species rich area and a species poor area. Unfortunately, a surprising number of studies don't publish this seemingly basic result. For such studies, we have to calculate a surrogate of effect size based on the reported test statistics of the hypothesis that the authors report. This is not completely ideal -- we would much rather calculate effect sizes directly, but to paraphrase a dubious source, you do a meta-analysis with the statistics that have been published, not with the statistics you wish had been published. On this note, one of our key recommendations is that disease ecologists do a better job reporting effect sizes to facilitate future meta-anlayses.

In addition to allowing us to estimate the mean effect size across studies and its associated uncertainty, another goal of meta-analysis is to test for the existence of publication bias. Stanford's own John Ioannidis has written on the ubiquity of publication bias in medical research. The term "bias" has a general meaning that is not quite the same as the technical meaning. By "publication bias", there is generally no implication of nefarious motives on the part of the authors. Rather, it typically arises through a process of selection at both the individual authors' level and the institutional level of the journals to which authors submit their papers. An author, who is under pressure to be productive by her home institution and funding agencies, is not going to waste her time submitting a paper that she thinks has a low chance of being accepted. This means that there is a filter at the level of the author against publishing negative results. This is known as the "file-drawer effect", referring to the hypothetical 19 studies with negative results that never make it out of the authors' desk for every one paper publishing positive results. Of course, journals, editors, and reviewers prefer papers with results to those without as well. These very sensible responses to incentives in scientific publication unfortunately aggregate into systematic biases at the level of the broader literature in a field.

We use a couple methods for detecting publication bias. The first is a graphical device known as a funnel plot. We expect studies done on large samples to have estimates of the effect size that are close to the overall mean effect because estimates based on large samples have higher precision. On the other hand, smaller studies will have effect-size estimates that are more distributed because random error can have a bigger influence in small samples. If we plot the precision (e.g., measured by the standard error) against the effect size, we would expect to see an inverted triangle shape -- or a funnel -- to the scatter plot. Note -- and this is important -- that we expect the scatter around the mean effect size to be symmetrical. Random variation that causes effect-size estimates to deviate from the mean are just as likely to push the estimates above and below the mean. However, if there is a tendency to not publish studies that fail to support the hypothesis, we should see an asymmetry to our funnel. In particular, there should be a deficit of studies that have low power and effect-size estimates that are opposite of the hypothesis. This is exactly what we found. Only studies supporting the dilution-effect hypothesis are published when they have very small samples. Here is what our funnel plot looked like.

Note that there are no points in the lower right quadrant of the plot (where species richness and disease risk would be positively related).

While the graphical approach is great and provides an intuitive feel for what is happening, it is nice to have a more formal way of evaluating the effect of publication bias on our estimates of effect size. Note that if there is publication bias, we will over-estimate our precision because the studies that are missing are far away from the mean (and on the wrong side of it). The method we use to measure the impact of publication bias on our estimate of uncertainty formalizes this idea. Known as "trim-and-fill", it uses an algorithm to find the most divergent asymmetric observations. These are removed and the precision of the mean effect size is calculated. This sub-sample is known as the "truncated" sample. Then a sample of missing values is imputed (i.e., simulated from the implied distribution) and added to the base sample. This is known as the "augmented" sample. The precision is then re-calculated. If there is no publication bias, these estimates should not be too different. In our sample, we find that estimates of precision differ quite a bit between the truncated and augmented samples. We estimate that between 4-7 studies are missing from the sample.

Most importantly, we find that the 95% confidence interval for our estimated mean effect size crosses zero. That is, while the mean effect size is slightly negative (suggesting that biodiversity is protective against disease risk), we can't confidently say that it is actually different than zero. Essentially, our large sample suggests that there is no simple relationship between disease risk and biodiversity.

On Ecological Mechanisms One of the main conclusions of our paper is that we need to move beyond simple correlations between species richness and disease risk and focus instead on ecological mechanisms. I have no doubt that there are specific cases where the negative correlation between species richness and disease risk is real (note our title says that we think this link is idiosyncratic). However, I suspect where we see a significant negative correlation, what is really happening is that some specific ecological mechanism is being aliased by species richness. For example, a forest fragment with a more intact fauna is probably more likely to contain predators and these predators may be keeping the population of efficient reservoir species in check.

I don't think that this is an especially controversial idea. In fact, some of the biggest advocates for the dilution effect hypothesis have done some seminal work advancing our understanding of the ecological mechanisms underlying biodiversity-disease risk relationships. Ostfeld and Holt (2004) note the importance of predators of rodents for regulating disease. They also make the very important point that not all predators are created equally when it comes to the suppression of disease. A hallmark of simple models of predation is the cycling of abundances of predators and prey. A specialist predator which induces boom-bust cycles in a disease reservoir probably is not optimal for infection control. Indeed, it may exacerbate disease risk if, for example, rodents become more aggressive and are more frequently infected in agonistic encounters with conspecifics during steep growth phases of their population cycle. This phenomenon has been cited in the risk of zoonotic transmission of Sin Nombre Virus in the American Southwest.

I have a lot more to write on this, so, in the interest of time, I will end this post now but with the expectation that I will write more in the near future!

# This is Just What Greece Needs

Greece was officially deemed malaria-free in 1974. Recent reports, however, suggest that there is ongoing autochthonous transmission of of Plasmodium vivax malaria. According to a brief report from the Mediterranean Bureau of the Italian News Agency (ANSAmed), 40 cases of P. vivax malaria have been reported in the first seven months of 2012. Of these 40, six had no history of travel to areas known to be endemic for malaria transmission. The natural inference is thus that they acquired it locally (i.e., "autochthonously") and that malaria may be back in Greece.

More detail on the malaria cases in Greece can be found on this European Centre for Disease Prevention and Control website. The actual ECDC report on autochthonous malaria transmission in Greece can be found here. A point in that report that is not mentioned in the ANSAmed newswire is that 2012 marks the third consecutive year in which autochthonous transmission has been inferred in Greece. So much for Greece being malaria-free.