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Education How to Make Epidemiological Training Infectious Steve E. Bellan1*, Juliet R. C. Pulliam2,3, James C. Scott4, Jonathan Dushoff5, the MMED Organizing Committee" 1Department of Environmental Science, Policy & Management, University of California, Berkeley, California, United States of America, 2Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America, 3Department of Biology and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, United States of America, 4Department of Mathematics and Statistics, Colby College, Waterville, Maine, United States of America, 5Department of Biology, McMaster University, Hamilton, Ontario, Canada Introduction The goal of epidemiology is to identify the biological, behavioral, and environ- mental causes of health outcomes or diseases and apply this knowledge to the development of effective disease interven- tions to improve public health [1–3]. Diseases are complex phenomena that arise from various interacting processes, chal- lenging epidemiologists to extract impor- tant causal relationships from observational and experimental data . Infectious diseases add a level of complexity because infection occurs through (direct or indirect) interaction between susceptible and infec- tious individuals. The rate of new infections depends on the number or proportion of individuals who are susceptible and infec- tious. These quantities themselves evolve through time as new individuals become infected. In other words, infectious disease dynamics are nonlinear. The biological, behavioral, evolutionary, and environmen- tal nuances of each disease–host system determine the dynamics of disease inci- dence and have important implications for designing and evaluating interventions. Patterns of disease do not only arise from individual-level characteristics (e.g., genet- ics, behavior, age, sex, health status), but also from the history of infection in the greater population. Thus, consideration of individual-level data independent of the population context may be misleading [4,5]. In fact, the number or proportion of susceptible, infected, and immune indi- viduals in the population often plays a greater role in determining the current individual-level risk of infection than an individual’s characteristics [6,7]. Thus, population-level epidemiological patterns emerge from the complex, inter- acting processes governing pathogen biolo- gy, host biology, host behavior, the envi- ronment, and their interactions [4,8]. The field of epidemiology has taken two broad methodological approaches to understand these interacting processes. While various terms have been used to describe these two subfields, we call them classical epidemiol- ogy and dynamical epidemiology (see Text S1 for more details). Classical epidemiology builds on assumptions of independence between individuals (or clusters thereof) to identify correlations between risk (or pro- tective) factors and disease, with the goal of establishing a causal relationship between them [1,3,9]. Dynamical (mechanistic) ep- idemiology has largely developed from ecology and its subfield, population dynam- ics, along with other applications of math- ematics to biological systems [10,11]. In contrast to the correlational approach of classical epidemiology, dynamical epidemi- ology aims to understand disease dynamics with nonlinear transmission models that explicitly account for the interactions be- tween individuals [5,8,12]. Citation: Bellan SE, Pulliam JRC, Scott JC, Dushoff J, the MMED Organizing Committee (2012) How to Make Epidemiological Training Infectious. PLoS Biol 10(4): e1001295. doi:10.1371/journal.pbio.1001295 Published April 3, 2012 Copyright: 2012 Bellan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The Meaningful Modeling of Epidemiological Data Clinics have been generously funded by the National Institute of Health Framework Programs for Global Health Innovations (R24TW008822 to Lee Riley), the Henry Wheeler Center for Emerging and Neglected Diseases, the African Biomathematics Initiative (National Science Foundation grant DMS-829652 awarded to Fred S. Roberts and Avner Friedman), the NSF-NIH Ecology of Infectious Diseases program (NSF award 1134964 to J.R.C.P.), the Center for Discrete Mathematics and Theoretical Computer Science, the African Institute for Mathematical Sciences, and the South African Centre for Excellence in Epidemiological Modelling and Analysis. This work was also partially supported by Chang-Lin Tien Environmental Fellowship, Andrew and Mary Thompson Rocca Fellowships, University of California, Berkeley Environmental Science, Policy & Management and Entomology Society Travel Grants to S.E.B., and National Institute of Health Ecology of Infectious Disease grant (GM83863) to Wayne M. Getz. J.R.C.P is supported by the Research and Policy in Infectious Disease Dynamics (RAPIDD) Program of the Science and Technology Directorate, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: MMED, Meaningful Modeling of Epidemiological Data; MMF, Muizenberg Mathematical Fever * E-mail: firstname.lastname@example.org "Membership of the MMED Organizing Committee is provided in the Acknowledgments. Series Editor: Cheryl A. Kerfeld, University of California Berkeley/Joint Genome Institute, United States of America The Education Series features noteworthy, innova- tive open-education programs to enhance under- standing of biology. PLoS Biology | www.plosbiology.org 1 April 2012 | Volume 10 | Issue 4 | e1001295 Firmly rooted in empirical research, classical epidemiology takes a phenome- nalistic approach that focuses more on whether a causal relationship exists  than the mechanistic nature of the relationship . While extremely practi- cal, this reductionist approach frequently ignores the dependence between observa- tions of infectious outcomes and can lead to spurious conclusions [5,14,15]. Dy- namical epidemiology, in contrast, focuses on how mechanistic interactions between individuals lead to population-scale pat- terns and emphasizes understanding real- istic dynamics. Ironically, this realism often comes at the expense of being par- tially or completely divorced from real data, because detailed data on mechanis- tic processes are rare. Further, dynamic models frequently ignore sources of bias or random error in the data, which can dramatically alter model results [6,16]. For example, dynamic models often use parameters from the literature to describe mechanistic processes without careful attention to the original source of the parameter’s estimation and associated bias or error therein. Model results are also often used to claim strong conclu- sions without comparing model outputs to real epidemiological time series data. Dynamic epidemiologists nevertheless at- tempt to make robust conclusions using sensitivity analyses that explore model behavior over a large set of viable hypothetical scenarios. Both approaches have played successful roles in public health [8,17–19], though remaining rather distinct fields with studies using dynamical models often published in ecological, mathematical, or interdisciplinary journals but rarely in epidemiological jour- nals. Fifteen years ago Susser and Susser (1996) advocated the more coherent disci- pline of eco-epidemiology, with classical epidemiology subsumed by a greater ecolog- ical framework that considers mechanistic processes at various physical, temporal, and demographic scales [3,20,21]. And though, in our experience, scientists at advanced stages in either field are often largely unaware of the other field’s existence, projects integrating these approaches have increased in research practice, often yielding otherwise unattainable insight. For example, using a dynamic model Lietman et al. (1999) found that trachoma (the leading cause of infectious blindness worldwide) elimination may be feasible by biannual treatment of children with a single dose of azithromycin . They then formulated a cluster-ran- domized controlled trial that verified this finding empirically . Finally, after fitting a dynamic model to the empirical data collected during this trial they demonstrated that individual-level transmission efficiency decreaseswith decreasingdiseaseprevalence, making elimination of the disease easier than expected . As a second example, Eisen- berg et al. (2011) found that individual-level antibiotic use proved insufficient to explain geographic variation in the prevalence of Escherichia coli antibiotic resistance, but that this phenomenon could be explained by interactions between village-specific antibiot- ic use and transmission rates in a dynamic model . In both examples, a close alliance between methods in classical and dynamical epidemiology allowed systems mechanisms to inform study design and vice versa, yielding insight with a real potential to improve public health. Despite such successes, training options within the fields remain distinct. Further- more, the very few scientists with training in both disciplines seldom receive formal in- struction explaining how they complement each other. Reflecting the severity of this rift, a recent published symposium on the future of epidemiological education lacked any discussion of dynamical approaches [25– 28]. We do not believe that all dynamical epidemiologists must be able to design empirical studies nor that all classical epidemiologists must be able to construct dynamical models. However, understanding the utility of and fundamental concepts within each discipline will allow fruitful collaboration between the fields as demon- strated in the examples above. The ability to think from both perspectives allows research- ers to choose the most suitable set of methods for a given question [1,3,9,20,21]. The annual Clinic on the Meaningful Modeling of Epidemiological Data (MMED) at the African Institute for Mathematical Sciences in Muizenberg, South Africa, is working to address this gap. African capacity in epidemiology is in short supply despite the continent’s disproportionate burden of dis- ease and burgeoning new cohorts of African students trained in biomathematics, biology, and public health. MMED offers partici- pants (ranging from undergraduate students to professors) exposure to a broad range of concepts and techniques from both classical and dynamical epidemiology, while explicitly highlighting how the two approaches com- plement each other and fit into a larger context. Selected lecture material from MMED is provided in the Figures S1, S2, S3, S4, S5, S6, S7, S8. During MMED we designed the follow- ing pedagogical tool to address the rift between classical and dynamical epidemi- ology in which participants not only design studies and collect data prior to analysis, but also observe pathogen transmission in a way that reveals how epidemics are inherently nonlinear stochastic (i.e., random) process- es. The approach is hands-on, consisting of the real-time simulation of a stochastic Summary Modern infectious disease epidemiology builds on two independently developed fields: classical epidemiology and dynamical epidemiology. Over the past decade, integration of the two fields has increased in research practice, but training options within the fields remain distinct with few opportunities for integration in the classroom. The annual Clinic on the Meaningful Modeling of Epidemiological Data (MMED) at the African Institute for Mathematical Sciences has begun to address this gap. MMED offers participants exposure to a broad range of concepts and techniques from both epidemiological traditions. During MMED 2010 we developed a pedagogical approach that bridges the traditional distinction between classical and dynamical epidemiology and can be used at multiple educational levels, from high school to graduate level courses. The approach is hands-on, consisting of a real-time simulation of a stochastic outbreak in course participants, including realistic data reporting, followed by a variety of mathematical and statistical analyses, stemming from both epidemiological traditions. During the exercise, dynamical epidemiologists developed empirical skills such as study design and learned concepts of bias while classical epidemiologists were trained in systems thinking and began to understand epidemics as dynamic nonlinear processes. We believe this type of integrated educational tool will prove extremely valuable in the training of future infectious disease epidemiologists. We also believe that such interdisciplinary training will be critical for local capacity building in analytical epidemiology as Africa continues to produce new cohorts of well-trained mathematicians, statisticians, and scientists. And because the lessons draw on skills and concepts from many fields in biology—from pathogen biology, evolutionary dynamics of host– pathogen interactions, and the ecology of infectious disease to bioinformatics, computational biology, and statistics—this exercise can be incorporated into a broad array of life sciences courses. PLoS Biology | www.plosbiology.org 2 April 2012 | Volume 10 | Issue 4 | e1001295 outbreak among course participants, in- cluding realistic data reporting, followed by analyses from both epidemiological tradi- tions. We believe this type of integrated educational tool can stimulate the training of a cohort of infectious disease epidemiol- ogists who are well acquainted with boththe dynamical systems nature of epidemiologi- cal processes as well as the empirical design and analytical issues associated with inves- tigating causal relationships between risk factors and disease. The Emergence of an Infectious Disease: Muizenberg Mathematical Fever At the 2010 and 2011 MMED Clinics we instigated outbreaks of a novel infectious agent, Muizenberg Mathematical Fever (MMF), in our course participants. The infectious agent was a paper form (Text S2). Index cases were initiated through surrep- titious distribution of a small number of infection forms on the first day of the Clinic. The paper provided simple instruc- tions for newly infected individuals. Fol- lowing the instructions, individuals used random number generators in the free statistical programming language R  to determine a Poisson random number (see Box 1) of potentially infectious contacts they would generate. The infected individ- ual would then print out new infection forms from a webpage and discreetly hand these to other participants without knowl- edge of who had already been infected, recording the time of those infectious contacts. A Bernoulli random number generator was similarly used to determine whether or not an infection was symptom- atic. Only symptomatic individuals would report to our health care system (a specified faculty member) that they were sick. However, all new infections were reported to a second faculty member via email for tracking purposes. Recovery consisted of delivering the infecting paper to a third faculty member. Thus, each outbreak generated two datasets: (1) a realistic provider-based surveillance system that recorded symptomatic cases and time of symptom onset; and (2) an unrealistically accurate knowledge of the underlying transmission dynamics. The outbreaks percolated through par- ticipants before burning out, much like Box 1. Teaching Tools Prior to adopting this exercise, we recommend reviewing Datasets S1–S7, Figures S1–S8, Texts S1–S5, and linked resources. These include: N MMED lecture slides (Figures S1–S8) N An example document that provides instructions that students are to carry out upon being exposed (this document doubles as the infectious agent; being handed this document constitutes exposure to MMF) N Data obtained (by the authors) from prior MMF outbreaks N An example survey used to identify risk factors associated with contracting MMF and corresponding data. N R code that organizers may experiment with to assist them in determining initial parameter values (for more information on the R computing language and to download the latest version of R, please see http://www.r-project.org) N Additional R code that provides illustrative exercises that can be performed using MMF data (e.g., identification of risk factors, calculating measures of effect, confidence intervals, etc.) N Additional online resources containing introductory materials on both epidemiological traditions N Information on infectious diseases and epidemics to share with students (e.g., ProMED, Center for Disease Control website, and other such resources) Preparation guide N Before implementation, organizers should set values for epidemiological parameters (initial number of infections, potential protective factors, R0, the proportion symptomatic) that take into account the number of participants and the types of analyses that students will perform; we suggest doing this by simulating outbreak dynamics and have provided example R code Texts S3–S4. N If a protective factor is induced (e.g., ‘‘vaccination’’ or other form of immunity), ensure that the number of immune individuals will be sufficient for an effect to be detected and that the epidemic is likely to take off when accounting for immunity; also, attempt to make the factor something that will be readily detectable via an appropriately designed questionnaire N Prepare a full roster of participating individuals (i.e., those that could be exposed) for tracking purposes N Provide some brief training for individuals so that they are able to generate the appropriate random numbers (note: while we have had success with R, any software package that can generate Poisson and Bernoulli random variables could be used) Tips for running the exercise as part of a course for credit N To ensure timely and full participation, we suggest using incentives (e.g., linking participation to student evaluation, course participation credit, etc.). N Do not initiate the outbreak until the course list has been finalized (i.e., after the end of the drop/add period) N If possible, provide a link to the infectious agent (i.e., the instruction document) that is only accessible to course participants (e.g., through a Blackboard or Sakai site) and cannot be found by searching; this will help ensure that the epidemic is confined to the closed population of course participants N Make sure participants know whom they may and may not infect (e.g., provide a course roster to each student or refer them to a course management website). N Once the outbreak is underway, discretely remind participants to follow through accordingly (i.e., ‘‘I was expecting to receive emails from some of you—don’t forget to follow up’’) PLoS Biology | www.plosbiology.org 3 April 2012 | Volume 10 | Issue 4 | e1001295 epidemics of biological pathogens. While we determined R0 (the number of suscep- tible individuals infected by an index case introduced into an entirely susceptible population; see glossary in Text S1) and the symptomatic proportion, participants’ behavior (e.g., who they infected and when they did it) also affected disease dynamics. The unpredictable nature of these events added to the realism of our outbreak. During the 2011 outbreak, we dictated that repeat attendees would be immune to MMF, thereby seeding a protective (risk) factor for participants to find during the analytical stage of the exercise. Figure 1. Muizenberg Mathematical Fever epidemic time series. Epidemic time series for the outbreaks at the 2010 (A) and 2011 (B) outbreaks. The former and latter outbreaks differ by their different basic reproductive numbers (defined as the average number of people an infectious individual infects if the rest of the population is susceptible; R0 =1.23 and 1.82, respectively), the initial number of infectious individuals in the population (2 and 4, respectively), and the number of individuals immune at the start of the outbreak (0 and 14, respectively). (C and D) demonstrate how the effective reproductive number (Reff; average number of individuals each infected person infects) changes during the course of the outbreak as the number of susceptibles decreases and that the epidemic begins to burn out when Reff decreases below 1 and infectious individuals no longer replace themselves with new infections. The script for production of and further detail on this figure are given in Text S3. doi:10.1371/journal.pbio.1001295.g001 Table 1. Examples of epidemiological methods that can be used during the exercise. Field Study Analysis Data Goal Pedagogical Value Risk factor Case-control or cohort Logistic or Poisson regression (generalized linear model) Disease outcomes, risk factors Understand what variables increase (or decrease) risk of disease/infection Exposure to survey design, data entry and cleaning, and statistical methods; understand effects of confounding and bias in data analysis Mathematical Estimation of R0 and infectious period Probability distribution fit to infectious contact data and infectious periods Contact tracing data and observed infectious periods Characterize individual heterogeneity in infectiousness and overall pathogen contagiousness Understand utility of contact tracing data in characterizing disease dynamics, understand R0 as an epidemic threshold, understand how individual variation can affect disease dynamics Outbreak simulation Stochastic SIR individual- based model with Gillespie algorithm Estimates of R0, incubation and infectious periods Understand how outbreak size is affected by immune proportion Awareness of effects of stochasticity in outbreaks of small sizes, gain intuition for how simulation can be used to answer applied questions Further explanation and R scripts are provided in Texts S1, S3, and S4. doi:10.1371/journal.pbio.1001295.t001 PLoS Biology | www.plosbiology.org 4 April 2012 | Volume 10 | Issue 4 | e1001295 Outbreak Investigation Initiation of the MMF outbreaks resulted in a complex epidemiological process (Figure 1) that produced several datasets. These data gave participants the opportu- nity to apply a variety of methods from both classical epidemiology and dynamical epidemiology to both characterize and understand the transmission process. Many participants were well trained in dynamical epidemiology, but lacked strong empirical skills. Thus, we placed an emphasis on understanding all the steps from data generation to analysis . Participants learned to clean raw datasets, putting them into analyzable form, formed small groups and chose one or more research goals, and then selected the appropriate methods to achieve those goals (Table 1), thereby learning concepts such as confounding, selection bias, information bias, and ran- dom error as they proceeded to identify risk factors for disease exposure (Box 2; Figure 2). In order to collect data for a retrospective cohort study participants crafted surveys (Text S5), learning aspects of survey design. Participants conducting mathematical analyses learned the relation- ship between susceptible depletion and epidemic fadeout (Box 2; Figure 1), simu- lated the effect of vaccination or immunity on outbreak dynamics (Figure 3), and explored how heterogeneity in disease network structure affects transmission dy- namics and, subsequently, disease inci- dence. Groups then presented their results, describing their goals, methods, results, an interpretation of these results, and any shortcomings. Importantly, these presenta- tions revealed methods’ assumptions and utilities, clarifying how the various risk factors and mathematical methods differ from and complement each other. After their presentations groups were asked various questions to assess their under- standings of the various concepts and methods presented (Box 3). A complete how to description of the exercise (including R scripts for reproducing the various projects, Figures 1–3, the necessary data- sets, and other analyses) and additional variations thereof are given in Texts S3, S4 and Datasets S1, S2, S3, S4, S5, S6, S7. Conclusion This educational approach provides a much-needed conceptual integration of risk factor and mathematical approaches in epidemiological training, illuminating their strengths, weaknesses, and how they complement each other. Further, this exercise is of interest and understandable to students in other fields. Much of the exercise is simple enough to be performed by adequately trained high school students and could therefore even serve as an early introduction to infectious disease epidemi- ology. The exercise is also perfectly suited to undergraduate or graduate courses in epidemiology, infectious diseases, public health, biomathematics, computational biology, statistics, and nonlinear dynamics. Such tools will stimulate training of epidemiologists able to think from both the classical and dynamical perspectives. Particularly in developing countries where training is only slowly becoming more interdisciplinary, exercises such as MMF teach participants how subfields of public health complement each other and pro- duce professionals more able to collabo- rate across disciplines. The most recent updates to supplemen- tary material as well as an online webpage for running the epidemic without use of R are available at http:/lalashan.mcmaster. ca/theobio/mmed/index.php/MMF. Box 2. Concepts at a Glance Understanding Concepts in the Natural History of a Disease N Introduction to the concepts of incubation, latency, infectiousness, being a/symptomatic, virulence, pathogenicity, immunity, transmissibility, pathogen evolution Classical Epidemiology N Epidemiological study designs (e.g., case-control and cohort studies) N Outbreak investigation methodology (case definition, contact tracing, epidemic curves) N Measures of effect (e.g., odds ratios, relative risk) N Confounding, bias, and interaction Dynamical Epidemiology N Introduction to a simple Susceptible-Infected-Recovered (SIR) model N Introduction to concepts of the basic and effective reproduction numbers, attack rate, and herd immunity N Using dynamic models to answer public health questions (e.g., using models as a means to explore counterfactual instances of disease occurrence) Biostatistics and Probability N Probability distributions and generation of random variables N Regression, confidence intervals, and hypothesis testing N Parameter estimation (e.g., maximum likelihood estimation) Practical Experience with Broad Application N Questionnaire design N Data collection, cleaning, visualization, and analysis N Verbal communication skills (i.e., presentation of results) PLoS Biology | www.plosbiology.org 5 April 2012 | Volume 10 | Issue 4 | e1001295 Figure 2. Demonstration of information and confounding bias with simulated outbreak data. (A) Muizenberg Mathematical Fever 2011 outbreak data to illustrate how using a case definition with imperfect sensitivity (symptomatic disease) can cause nondifferential misclassification bias (the category of information bias where exposed and unexposed individuals are equally likely to be misclassified). Nondifferential misclassification biases the association between a risk factor and a disease outcome towards the null hypothesis of no association (odds ratio=1). While attendance at the prior year’s clinic was actually protective (black square and 95% CI), this bias was sufficient to cause the confidence interval for the odds ratio of this very protective variable to overlap (gray). (B) illustrates how a risk factor (arrival a day or more early to the clinic) that has no real association to a disease outcome can appear associated through confounding. Individuals who had attended the clinic in prior years were less likely to come to the clinic early and were also protected (i.e., A). Consequently, early attendance appeared associated with a higher risk of disease in a univariate analysis (gray) though the CI contains the null hypothesis of no association in a multivariate analysis that adjusts for prior attendance (black). The script for production of and further detail on this figure are given in Text S3. doi:10.1371/journal.pbio.1001295.g002 Figure 3. Utility of stochastic simulation to study the effect of vaccination on future outbreaks. (A) Five stochastic simulations of Muizenberg Mathematical Fever outbreaks using transmission parameters fit from the 2011 outbreak data but with only one infected individual initiating the outbreak (instead of four) but the same proportion initially immune (25%). In comparison to Figure 1A, the outbreak would appear less likely to take off (with four simulated outbreaks burning out by Wednesday) if only one infected individual initiated the outbreak. (B) shows the distribution of outbreak size (total number infected before burnout) among simulated outbreaks in populations with different immune proportions at the outbreak initiation. The black line shows the median outbreak size among 1,000 stochastic simulations for each immune proportion and the gray regions show 10% quantiles of outbreak size. Only small levels of immunity are necessary to make outbreaks rare (with a fifth of the population immune 50% of simulated outbreaks never exceed more than two secondary cases), but just by chance larger outbreaks still occur. The script for production of and further detail on this figure are given in Text S3. doi:10.1371/journal.pbio.1001295.g003 PLoS Biology | www.plosbiology.org 6 April 2012 | Volume 10 | Issue 4 | e1001295 Supporting Information Dataset S1 Line list of MMF infec- tions from MMED 2010. (CSV) Dataset S2 Contact tracing data from MMED 2010. (CSV) Dataset S3 Line list of MMF infec- tions from MMED 2011. (CSV) Dataset S4 Contact tracing data from MMED 2011. (CSV) Dataset S5 Risk factor data from MMED 2011, collected using the survey in Text S5. (CSV) Dataset S6 Risk factor data from MMED 2010. (CSV) Dataset S7 Infectious period data from the MMF outbreak at MMED 2011. (CSV) Figure S1 Lecture slide 1: introduc- tion to disease dynamics. (PDF) Figure S2 Lecture slide 2: introduc- tion to dynamics of vector-borne diseases. (PDF) Figure S3 Lecture slide 3: demo- graphic stochasticity. (PDF) Figure S4 Lecture slide 4: study design and analysis in epidemiology. (PDF) Figure S5 Lecture slide 5: introduc- tion to statistical philosophy. (PDF) Figure S6 Lecture slide 6: introduc- tion to likelihood. (PDF) Figure S7 Lecture slide 7: likeli- hood fitting and dynamic models I. (PDF) Figure S8 Lecture slide 8: likeli- hood fitting and dynamic models II. (PDF) Text S1 This file includes a glossa- ry and detailed information for Box 3. Evaluation Tools Questions to gauge knowledge and understanding of the exercise F o r s t u d e n t s w i t h l i t t l e o r n o p r i o r k n o w l e d g e o r t e c h n i c a l t r a i n i n g ( i . e . , h i g h s c h o o l l e v e l a n d e a r l y u n d e r g r a d u a t e s ) N What is the difference between an infectious disease and a communicable disease? N How might you collect information on a disease outbreak? N What might cause an outbreak to end? F o r s t u d e n t s w i t h s o m e p r i o r k n o w l e d g e a n d / o r t e c h n i c a l t r a i n i n g ( i . e . , a d v a n c e d u n d e r g r a d u a t e s a n d g r a d u a t e s t u d e n t s ) N What determines how many cases occur in an outbreak? N What determines how long an outbreak lasts and when the peak occurs? N Why aren’t data a perfect representation of reality? N Is it possible to predict whether an epidemic will occur when a pathogen is introduced into a population? N How and why might an individual’s risk of infection change over the course of an outbreak? When is average individual risk the highest? N What individuals are most likely to be infected in an outbreak of communicable disease? N Why do some pathogens cause epidemics while others do not? N Why don’t all individuals in a population have to be vaccinated to prevent an epidemic? Evaluative activities F o r s t u d e n t s w i t h l i t t l e o r n o p r i o r k n o w l e d g e o r t e c h n i c a l t r a i n i n g N Have students describe the life cycle of MMF by matching infectious disease terms (such as ‘‘latent period’’ and ‘‘transmission event’’) to aspects of the exercise and discussing in relation to a real pathogen N Have students plot and explain data (e.g., the epidemic curve, the cumulative incidence through time, the distribution of infectious contacts, latent periods, and infectious periods) F o r s t u d e n t s w i t h s o m e p r i o r k n o w l e d g e a n d t e c h n i c a l t r a i n i n g N Have students describe the epidemic curve, explain differences in data collection that might influence aspects of the observed curve (e.g., a case definition that relies on symptoms or reporting) N Have students estimate parameters (such as those describing the latent and infectious period distributions) on a dataset from another source N Have students pick a real immunizing infection with available estimates of the latent period, infectious period, and transmissibility (R0) are available and then reparameterize the stochastic simulations using the code available or their own code to compare the expected dynamics of MMF and their chosen pathogen N Have students discuss what aspects of the epidemic dynamics and data collection determine the ease with which a classical epidemiology study can detect which individual-level risk factors are associated with a higher probability of infection. N Have students conduct exercises/analyses as described and present on their projects, including data collection, cleaning, and analysis as well as any unexpected difficulties they encountered PLoS Biology | www.plosbiology.org 7 April 2012 | Volume 10 | Issue 4 | e1001295 instructors on implementation of the exercise, including ideas for development of group projects and description of possible variations. (DOC) Text S2 The infection notification form used as the infectious agent. Before use, the form should be tailored to the specific course or classroom setting by adjusting the parts of the form highlighted in yellow. Instructors may also want to change the name of the ‘‘disease’’ to fit the context of their course. (DOC) Text S3 Code for producing the figures in the article. (TXT) Text S4 Code for conducting anal- yses described in Text S1. (TXT) Text S5 Survey developed by MMED participants following the 2011 MMF outbreak to gather data on potential risk factors. (PDF) Acknowledgments The MMED Organizing Committee includes S.E.B., J.R.C.P., J.C.S., J.D., Travis C. Porco (The Francis I Proctor Foundation for Oph- thalmic Research and Department of Epidemi- ology and Biostatistics, University of California, San Francisco, California, US), Brian G. Williams (South African Centre for Epidemio- logical Modelling and Analysis, University of Stellenbosch, Stellenbosch, Republic of South Africa), and John W. Hargrove (South African Centre for Epidemiological Modelling and Analysis, University of Stellenbosch, Stellen- bosch, Republic of South Africa). We would like to thank Travis C. Porco, Brian G. Williams, John W. Hargrove, Alex Welte, Wim Delva, and Gavin Hitchcock for their continuing contribution to organization, teaching, and mentoring at the Meaningful Modeling of Epidemiological Data (MMED) clinic. We would also like to thank all the MMED clinic participants and, in particular, the project groups who enthusiastically analyzed Muizenberg Mathematical Fever outbreak data: Bibi Adams, Linsay Blows, Dario Fanucchi, Jacob Ismail Irunde, Jessica Nezar Gennrich, Piet Jones, Eric Maluta, Geoffrey Marutla, Cynthia Mazinu, Edinah Mudimu, Juliet Na- kakawa, Nthatheni Norman Nelufule, Olina Ngwenya, Dany Pascal, Tarylee Reddy, Wilcan Sekgobela, Valrie Mabu Serumula, Milaine Seuneu, Patrick Shabangu, Marinel Janse Van Rensburg, and Ben Wilson. We would especial- ly like to express our gratitude to Igsaan Kamalie, Jan Groenwald, Barry Green, and the rest of the staff at the African Institute of Mathematical Sciences for their superb logisti- cal support and housing of the Meaningful Modeling of Epidemiological Data clinics. References 1. Galea S, Riddle M, Kaplan GA (2009) Causal thinking and complex system approaches in epidemiology. Int J Epidemiol 39: 97–106. 2. 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Nature 446: 533–536. 8. Grassly NC, Fraser C (2008) Mathematical models of infectious disease transmission. Nat Rev Micro 6: 477–487. 9. Koopman JS, Lynch JW (1999) Individual causal models and population system models in epide- miology. Am J Public Health 89: 1170–1174. 10. Anderson RM, May RM (1992) Infectious diseases of humans: dynamics and control. Oxford; New York: Oxford University Press. 11. Heesterbeek H (2005) The law of mass-action: a historical perspective. Cuddington K, Beisner BE, eds. Ecological paradigms lost: routes of theory change. Amsterdam; Boston: Elsevier Academic Press. pp 81–105. 12. Hethcote HW (2000) The mathematics of infectious diseases. Siam Review 42: 599–653. 13. Rothman KJ, Greenland S (2005) Causation and causal inference in epidemiology. Am J Public Health 95 Suppl 1: S144–150. 14. Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, et al. (2004) Isolation measures in the hospital management of methicillin resistant Staphylococcus aureus (MRSA): systematic review of the literature. BMJ 329: 533. 15. Eisenberg JN, Goldstick J, Cevallos W, Trueba G, Levy K, et al. (2011) In-roads to the spread of antibiotic resistance: regional patterns of micro- bial transmission in northern coastal Ecuador. J R Soc Interface. 16. White LF, Wallinga J, Finelli L, Reed C, Riley S, et al. (2009) Estimation of the reproductive number and the serial interval in early phase of the 2009 influenza A/H1N1 pandemic in the USA. Influenza Other Respi Viruses 3: 267–276. 17. Rohani P, King AA (2010) Never mind the length, feel the quality: the impact of long-term epidemiological data sets on theory, application and policy. Trends Ecol Evol 25: 611–618. 18. Schwartz S, Susser E (2006) Commentary: What can epidemiology accomplish? Int J Epidemiol 35: 587–590. 19. (2009) Male circumcision for HIV prevention in high HIV prevalence settings: what can mathe- matical modelling contribute to informed decision making? PLoS Med 6: e1000109. doi:10.1371/ journal.pmed.1000109. 20. March D, Susser E (2006) The eco- in eco- epidemiology. Int J Epidemiol 35: 1379–1383. 21. Susser E (2004) Eco-epidemiology: thinking outside the black box. Epidemiology 15: 519–520. 22. Lietman T, Porco T, Dawson C, Blower S (1999) Global elimination of trachoma: how frequently should we administer mass chemotherapy? Nat Med 5: 572–576. 23. House JI, Ayele B, Porco TC, Zhou Z, Hong KC, et al. (2009) Assessment of herd protection against trachoma due to repeated mass antibiotic distri- butions: a cluster-randomised trial. The Lancet 373: 1111–1118. 24. Lietman TM, Gebre T, Ayele B, Ray KJ, Maher MC, et al. (2011) The epidemiological dynamics of infectious trachoma may facilitate elimination. Epidemics 3: 119–124. 25. Buring JE (2008) Primary data collection: what should well-trained epidemiology doctoral stu- dents be able to do? Epidemiology 19: 347–349. 26. Gange SJ (2008) Teaching epidemiologic meth- ods. Epidemiology 19: 353–356. 27. Perera FP, Herbstman JB (2008) Emerging technology in molecular epidemiology: what epidemiologists need to know. Epidemiology 19: 350–352. 28. Samet JM, Savitz DA (2008) Education in epidemiology: ‘‘The Times They Are a-Chan- gin’.’’ Epidemiology 19: 345–346. 310.1097/ EDE.1090b1013e31816453f31816458. 29. R Development Core Team (2011) R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria: R Development Core Team. PLoS Biology | www.plosbiology.org 8 Apri