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Conducting a Case-Control Investigation of Buruli Ulcer Disease

Conducting a Case-Control Investigation of Buruli Ulcer Disease. Pratima Raghunathan, PhD, MPH Country Director, CDC-Cameroon US Centers for Disease Control and Prevention. Outline. BU Epidemiology Primer on Epidemiology Epidemiologic study designs

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Conducting a Case-Control Investigation of Buruli Ulcer Disease

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  1. Conducting a Case-Control Investigation of Buruli Ulcer Disease Pratima Raghunathan, PhD, MPH Country Director, CDC-Cameroon US Centers for Disease Control and Prevention

  2. Outline • BU Epidemiology • Primer on Epidemiology • Epidemiologic study designs • Answering BU research questions with epidemiology • Case-control study design for BU • Rationale for use • Theoretical considerations • Practical aspects • Desired outcomes of investigation

  3. BU Epidemiology

  4. Global Distribution of BU Source: van der Werf et al., Bulletin WHO 2005

  5. Lack of data highlights need for routine BU surveillance Global Burden of BU, 2005

  6. Global Leprosy Burden, 2005

  7. Epidemiology of Buruli Ulcer Disease • Disease common in areas adjacent to rivers and ponds • Route of transmission, environmental reservoir unknown • Children outnumber adults • No accurate estimates of burden of disease • Prevalence in endemic villages: 4 – 22% • True incidence unknown

  8. Environment and BU Transmission • Environmental characteristics of BU foci: • Swampy, riverine settings • Tropical climates • Flooding, damming, manmade changes to water bodies • Mycobacterium ulcerans = environmental mycobacterium • Recovered from plants, aquatic insects, molluscs, fish • Aquatic insects may concentrate M. ulcerans in salivary glands

  9. Epidemic vs. Endemic BU • Endemic disease in sub-Saharan Africa • Benin • Cote d’Ivoire • Ghana • Outbreaks • Uganda refugee camp, 1965-1968 • Nigeria, 1971-1975 • Australia, 1993-1995

  10. Hypothesized Modes of BU Transmission • Penetrating skin injuries • Bites of water insects (Naucoridae) • Aerosol deposition or inhalation • Person-to-person transmission • How to investigate? Creeping water insect of genus Naucoridae

  11. Primer on Epidemiology

  12. What is Epidemiology? • “The study of the distribution and determinants of disease frequency in populations.” Assumptions: • Disease does not occur at random • Disease determined by causal and preventive factors • Diseasedistribution = Descriptive Epi • Person, place, time • Disease determinants = Analytic Epi • Risk factors that predispose to disease • Preventive factors that protect against disease

  13. What can epidemiology reveal? • Descriptive epidemiology studies • Formulate hypotheses about relationship between exposure and disease • Where does BU occur geographically? • In which age group? Occupational group? • Analytic epidemiology studies • Test hypotheses: does exposure cause orprevent disease? • Does BCG vaccination prevent BU? • Does streptomycin/amikacin treatment reduce BU severity?

  14. Epidemiologic study designs • Descriptive: • Case series • Cross-sectional survey • Analytic • Observational: Case-control • Interventional: • Prospective cohort • Randomized clinical trial

  15. BU Research Priorities: WHO Global BU Initiative • Estimation of the burden of the disease • Vaccine development • Clinical trials of antimycobacterial agents • Environmental factors • Mode of transmission • Risk factors

  16. Epidemiological study designs appropriate for BU research • Burden of disease • Cross-sectional survey • Exposure and disease assessed at same time • Outcomes: prevalence by age, sex, region • Active data collection, e.g. household interview

  17. Geographic Distribution of BU, Ghana, 1998 • Data can be generated from: • Cross-sectional survey • Routine surveillance Source: Amofah et al, 2002

  18. Epi Study Design: Randomized Controlled Clinical Trial Does new treatment reduce rate of disease compared to control group?

  19. Appropriate BU research question: testing BCG or new anti-BU vaccines Best design: double-blinded, placebo-controlled Outcome measured after randomly assigned exposure Conclude treatment caused difference, because confounders balanced between groups Epi Study Design: Randomized Controlled Clinical Trial

  20. Appropriate BU research question E.g. surgery vs. streptomycin/amikacin Challenges: May not be placebo-controlled or blinded How to confirm BU cases in the absence of surgery? How to define clinical outcome rigorously? May require large numbers of cases to detect difference with statistical significance Clinical trial of antimycobacterial agents

  21. BU Research Priorities: WHO Global BU Initiative • Estimation of the burden of the disease • Vaccine development • Clinical trials of antimycobacterial agents • Environmental factors • Mode of transmission • Risk factors Case-control study

  22. Case-Control Study Design for BU

  23. What is a case-control study? • Observational analytic epi study • Compares exposures among ill people (cases) vs. non-ill people (controls) • Select participants on the basis of disease status • Retrospectively assess exposures

  24. Prospective Cohort vs. Case-Control START ? No Exposure Exposure Exposure or No Exposure? T I M E T I M E RETROSPECTIVE ANALYSIS Disease or No Disease? Disease No Disease ? START

  25. Analysis of Case-Control Studies Odds ratio (OR) compares odds of exposure among cases vs. controls: Odds of exposure among cases: a / c Odds of exposure among controls:b / d

  26. Strengths and weaknesses of case-control studies • Strengths • Useful for diseases with long latency periods, or rare diseases • Less costly and more efficient to conduct than prospective study • Can evaluate and explore multiple risk factors for hypothesis generation • Weaknesses • Susceptible to selection bias – choosing cases/controls on basis of exposure • Disease and exposure assessed simultaneously, so cannot conclude exposure caused disease

  27. Why conduct a case-control study for BU? • Identify exposures that are associated with disease • e.g. Modifiable risk factors for BU disease • Potential for public health intervention • Generate hypotheses to elucidate modes of transmission • Identify host genetic risk factors for disease

  28. Previous BU case-control studies

  29. Theoretical considerations in conducting BU case-control studies • To reduce or eliminate bias, must pay close attention to: • Choosing appropriate study base • Hospital-based vs. population-based • Definition and selection of cases • Selection of controls

  30. Choosing a case-control study base • Case-control study is efficient method of sampling cases at end of prospective study • “Study base”: the source population from which both cases & controls are drawn • Exposure rates in controls estimate exposure rates in source population STUDY BASE CONTROLS % exposed? CASES % exposed?

  31. Hospital-based case-control study for BU • Study base = patient medical records at hospital • Cases = patients hospitalized with BU • Controls • Must have equal chance of attending hospital and being diagnosed if they had BU • Select patients hospitalized for different diseases unrelated to exposures in question • Advantages: • Easy, inexpensive, convenient • No need to search outside hospital for control patients • Disadvantages: • Ill patients differ from healthy individuals • Exposures in question may be related to control patients’ reasons for hospitalization • Potential bias from including only severe BU cases

  32. Population-based BU case-control study • Study base = collection of subjects from precisely defined population at risk for BU • Cases = all BU patients from particular geographic area or community • Controls = Healthy persons from same geographic area or community at risk of becoming cases • Advantages: • Accurately represents disease in population, not hospitals • If population census exists, can randomly select controls • Disadvantage: • Must establish active surveillance for BU • If no population census, control selection subject to bias This is the better design.

  33. BU Case Definition • Establish strict diagnostic criteria for disease • Probable case: clinical diagnosis of active BU in resident of endemic area • Nodule: firm, painless, palpable subcutaneous lesion (1-2 cm) • Plaque: painless, elevated indurated lesion (>2cm) • Edema: diffuse, extensive, non-pitting, ill-defined margin, may be painful, with or without color change over affected skin • Active ulcer: painless skin lesion characterized by necrotic center, undermined edges, and edematous skin • Confirmed case: probable case with >1 positive lab test • AFB in smear from lesion • Culture of M. ulcerans • Positive PCR from lesion tissue • Characteristic histopathology

  34. Selection of BU cases • Include incident or prevalent cases? • Incident cases = newly diagnosed BU • Prevalent cases = pre-existing BU disease • Reflect determinants of BU duration (variable) as well as development of ulcerative disease PREULCER DISEASE SEVERE DISEASE EXPOSED INFECTED not exposed not infected no disease healed disease

  35. Selection of controls • Must be selected to represent population of individuals who would become cases in study • Must be comparable to cases • Exclusions, restrictions applied to cases must apply to controls • Sources of controls for BU studies • Neighborhood or community controls • But neighborhood may be related to exposure • Clinic-based controls • Family controls - genetic studies

  36. Matching • Matching of cases and controls by age or sex has often been done in case-control studies • Previous rationale: control for confounding factors that are associated with both exposure and disease, such as age and sex • Current thinking: matching can reduce study efficiency and introduce bias • No longer generally recommended for case-control studies (Rothman & Greenland, 1998)

  37. Practical aspects of conducting a BU case-control investigation

  38. How to select study sites? Essential elements: • BU treatment center in endemic area • Skilled clinicians and surgeon(s) • Commitment of hospital/clinic/lab staff • Accessibility • Patients • Researchers • Sufficient BU patients • First, calculate sample size • How many cases and controls needed? • Estimated BU incidence and prevalence • Can estimate duration of recruitment

  39. Recruitment of cases and controls • Hospital-based vs. community-based • Establish active surveillance in communities? • Prospective vs. retrospective • Provide incentives for participation? • Compensation for time and transport • Examples: soap, rice, cash (<2500 CFA)

  40. Ethical conduct • Obtain ethical approval from all participating institutions • Train study team in administering informed consent • Maintain patient confidentiality • Inclusion of HIV testing? • Minimize stigma for BU patients

  41. Basic requirements for lab confirmation of BU cases • At study site • Obtain skin biopsies from probable BU cases • Maintain constant surgical capacity at study site during recruitment • Track, store and transport biopsies to reference lab • At reference lab • Trained lab technicians who can detect AFB from lesion smear • Supply transport medium and perform M. ulcerans culture • Perform IS2404 PCR • Perform histopathology for BU Decide if lab confirmation is necessary – costly, complicated, but best practice

  42. Study team composition • Epidemiology • Epidemiologist • Study site coordinators • Interviewers/recruiters • Laboratory • Microbiologists • Clinical lab technicians • Pathologist • Clinical staff • Infectious disease physician • Surgeon • Anesthesiologist • Nurses • Data • Statistician • Data manager

  43. Study team logistics • Train study team prior to enrollment of first participant • Plan to follow up treatment of enrolled BU patients • Transportation and constant fuel supply are critical • For study participants from rural areas • For researchers coordinating study • Ongoing communication and coordination to resolve inevitable problems

  44. BU questionnaire content • What period of exposure for cases and controls? • Unknown latency between exposure to M. ulcerans, infection, and disease • Which exposures to query? • Contact with and proximity to water bodies • Use of protective clothing (which types? when? How often?) • Contact with insects, penetrating injuries • Unusual water-related activities

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