1. © 2004 Aeras Global TB Vaccine Foundation Clinical Research Practice Epidemiology & Biostatistics 1

2. © 2004 Aeras Global TB Vaccine Foundation 2 Epidemiology & Biostatistics 1 This course will introduce you to basic concepts of: the study of disease (who gets sick, where disease occurs, why people get disease, what factors affect disease). the study of disease (who gets sick, where disease occurs, why people get disease, what factors affect disease). research methods for studying disease (how disease studies are designed). research methods for studying disease (how disease studies are designed). how research can be used to improve public health. how research can be used to improve public health.

3. © 2004 Aeras Global TB Vaccine Foundation 3 Objectives Define epidemiology. Define epidemiology. Identify the key roles of epidemiology in public health. Identify the key roles of epidemiology in public health. Given a study protocol, restate the question to be answered in your own words. Given a study protocol, restate the question to be answered in your own words. Differentiate between retrospective, cross- sectional and prospective studies. Differentiate between retrospective, cross- sectional and prospective studies.

4. © 2004 Aeras Global TB Vaccine Foundation 4 Objectives Identify the advantages of prospective studies for answering a research question. Identify the advantages of prospective studies for answering a research question. State the advantages of a randomized controlled study as compared to other types of study design. State the advantages of a randomized controlled study as compared to other types of study design. Define the term evidence-based medicine. Define the term evidence-based medicine. List the steps in the evidence-based medicine process. List the steps in the evidence-based medicine process.

5. © 2004 Aeras Global TB Vaccine Foundation 5 Epidemiology? Doesn’t that have something to do with epidemics?

6. © 2004 Aeras Global TB Vaccine Foundation 6 What is Epidemiology? Epidemiology is a branch of medical science that studies a group of people to see: who has disease (young/old, male/female) who has disease (young/old, male/female) where is the disease occurring (urban/rural, Africa/Europe, etc.) where is the disease occurring (urban/rural, Africa/Europe, etc.) why people get disease (environmental, genetic, etc) why people get disease (environmental, genetic, etc) what is associated with disease and health (diet, other disease, environment, etc) what is associated with disease and health (diet, other disease, environment, etc) With the goal of preventing disease and promoting good health.

7. © 2004 Aeras Global TB Vaccine Foundation 7 Surveillance of disease and general health – ongoing survey to see who gets sick. Surveillance of disease and general health – ongoing survey to see who gets sick. Investigation of disease – study outbreaks of disease. Investigation of disease – study outbreaks of disease. Analytic studies – how and why people get sick. Analytic studies – how and why people get sick. Evaluation of health programs – study effectiveness of public health programs. Evaluation of health programs – study effectiveness of public health programs. Epidemiological Studies Examine Public Health Issues Photo courtesy of the Stop TB Partnership.

8. © 2004 Aeras Global TB Vaccine Foundation 8 Epidemiology Research Process Define the hypothesis or question. State in detail what question you need answered. Define the hypothesis or question. State in detail what question you need answered. Choose the appropriate study design. Decide the best way to answer research question. Choose the appropriate study design. Decide the best way to answer research question. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Analyze the data. Analyze the data. Use biostatistics to examine data. Report your findings. Report your findings. Share what you learn so that findings are used to improve public health.

9. © 2004 Aeras Global TB Vaccine Foundation 9 Define the hypothesis or question. State in detail what question you need answered. Define the hypothesis or question. State in detail what question you need answered. Choose the appropriate Study Design. Decide the best way to answer research question. Choose the appropriate Study Design. Decide the best way to answer research question. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Analyze the data. Analyze the data. Use biostatistics to examine data. Report your findings. Report your findings. Share what you learn with research community so that findings are used to improve public health. Epidemiology Research Process

10. © 2004 Aeras Global TB Vaccine Foundation 10 The Research Question The hypothesis or question to be answered is outlined in the study protocol and usually stated as an assumption to be tested. Sample Hypothesis: The annual risk of infection with M. tuberculosis in adults over 21 in the greater Worcester community of South Africa will be 4% or more.

11. © 2004 Aeras Global TB Vaccine Foundation 11 What Does It Mean? Break the hypothesis down into parts: The annual risk of infection with M. tuberculosis The probability of becoming infected, given TB exposure in a year. in adults over 21 in the greater Worcester community of South Africa in adults in the Worcester community will be 4% or more.

12. © 2004 Aeras Global TB Vaccine Foundation 12 What Do You Think This Means? The incidence of TB among neonates (newborn infants up to a month old) in multiple sites from South Africa and India in an actively monitored group will be estimated to be at least two-times greater than in the group that is not actively monitored. Photo courtesy of Aeras Global TB Vaccine Foundation.

13. © 2004 Aeras Global TB Vaccine Foundation 13 will be 2 times greater in the group that is tested regularly for TB than the group not tested regularly for TB. in an actively monitored group will be estimated to be at least two-times greater than in the group that is not actively monitored. During the 2 year study, the incidence of TB among neonates (newborn infants up to a month old) in multiple sites from South Africa and India The number of new cases of TB that occur in newborns participating in the 2-year study in South Africa and India What Do You Think It Means? Break the hypothesis down into parts:

14. © 2004 Aeras Global TB Vaccine Foundation 14 Your Turn In a clinical trial in the Boland Overberg region infants who are vaccinated at birth with BCG by either percutaneous or intradermal routes will have the same incidence of TB during the first two years of life, with the expected incidence being 2.5% in both groups. In the Boland Overberg region Babies vaccinated with BCG by two different methods will have the same rate of TB until 2 years of age, with 2.5% infected with TB in both groups.

15. © 2004 Aeras Global TB Vaccine Foundation 15 Define the hypothesis or question. State in detail what question you need answered. Define the hypothesis or question. State in detail what question you need answered. Choose the appropriate Study Design. Decide the best way to answer research question. Choose the appropriate Study Design. Decide the best way to answer research question. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Analyze the data. Analyze the data. Use biostatistics to examine data. Report your findings. Report your findings. Share what you learn with research community so that findings are used to improve public health. Epidemiology Research Process

16. © 2004 Aeras Global TB Vaccine Foundation 16 How Will The Question Be Answered? Retrospective Study: Collect data from the past. Retrospective Study: Collect data from the past. Cross-sectional Study: Collect data at the present point in time. Cross-sectional Study: Collect data at the present point in time. Prospective Study: Collect data from start of the study & follow into the future. Prospective Study: Collect data from start of the study & follow into the future.

17. © 2004 Aeras Global TB Vaccine Foundation 17 Retrospective Study or Case-Control Study Why do people have lung cancer? Was smoking a factor? Retrospective study design looks backwards in time, selecting patients who have lung cancer and asking how much they smoked. Retrospective study design looks backwards in time, selecting patients who have lung cancer and asking how much they smoked. Since lung cancer takes decades to develop, this study design offers a quicker way to get an answer. Since lung cancer takes decades to develop, this study design offers a quicker way to get an answer.

18. © 2004 Aeras Global TB Vaccine Foundation 18 Retrospective Study Design Advantages Relatively quick and easy to conduct study. Relatively quick and easy to conduct study. Allows a look at the relationship between disease and other factors. Allows a look at the relationship between disease and other factors.Disadvantages Difficult to measure exposure to disease accurately. Difficult to measure exposure to disease accurately. Unable to conclude what factors cause disease. Unable to conclude what factors cause disease. Information can be biased when participants recall past events inaccurately. Information can be biased when participants recall past events inaccurately. Asks… What were people exposed to in the past?

19. © 2004 Aeras Global TB Vaccine Foundation 19 What is the current prevalence of diabetes? What factors affect diabetes? Cross-sectional study design provides a current picture of how many people have diabetes. Cross-sectional study design provides a current picture of how many people have diabetes. In this type of study design you collect information about who has diabetes and other factors like health status, weight, economic status, environment, that could be linked to diabetes. In this type of study design you collect information about who has diabetes and other factors like health status, weight, economic status, environment, that could be linked to diabetes. Cross-Sectional Study Design

20. © 2004 Aeras Global TB Vaccine Foundation 20 Cross-Sectional Study Design Advantages Relatively quick and easy to conduct study. Relatively quick and easy to conduct study.Disadvantages Will not show trends of disease over time. Will not show trends of disease over time. Allows for association of disease factors, but does not allow one to determine cause-effect relationship. Allows for association of disease factors, but does not allow one to determine cause-effect relationship. Asks… How much disease is there now?

21. © 2004 Aeras Global TB Vaccine Foundation 21 What is the affect of lead paint exposure? Prospective study design provides a way to examine people from a known point (exposed or not exposed) and follow them forward in time to find out what happens. Prospective study design provides a way to examine people from a known point (exposed or not exposed) and follow them forward in time to find out what happens. It allows one to watch cause and effect as it develops over a period of time. It allows one to watch cause and effect as it develops over a period of time. Prospective Study Design

22. © 2004 Aeras Global TB Vaccine Foundation 22 Prospective Study Design Advantages Allows an association of cause and effect. Allows an association of cause and effect. Permits a precise measurement of exposure and disease diagnosis. Permits a precise measurement of exposure and disease diagnosis. Minimizes recall bias. Minimizes recall bias.Disadvantages Takes a lot of time. Takes a lot of time. Expensive to conduct. Expensive to conduct. Asks… What happens over time after an What happens over time after an intervention or exposure occurs? intervention or exposure occurs?

23. © 2004 Aeras Global TB Vaccine Foundation 23 Why Is A Prospective Study Better? Allows one to distinguish between cause and effect of factors affecting disease. Allows one to distinguish between cause and effect of factors affecting disease. Can control exposure/intervention (dose, route, frequency) Can control exposure/intervention (dose, route, frequency) Ensures that exposure/intervention comes before disease. Ensures that exposure/intervention comes before disease. Permits a precise measurement of exposure and disease diagnosis. Permits a precise measurement of exposure and disease diagnosis. Regulate handling of interventions. Regulate handling of interventions. Use same methods for diagnosing disease. Use same methods for diagnosing disease.

24. © 2004 Aeras Global TB Vaccine Foundation 24 The Best Way To Conduct a Prospective Study A Randomized Controlled Trial is the most reliable way to set up a study to ensure valid research results by: Assigning participants to study groups arbitrarily to avoid bias. Assigning participants to study groups arbitrarily to avoid bias. Comparing experimental groups to a control group receiving a standard intervention. Comparing experimental groups to a control group receiving a standard intervention.

25. © 2004 Aeras Global TB Vaccine Foundation 25 Define the hypothesis or question. State in detail what question you need answered. Define the hypothesis or question. State in detail what question you need answered. Choose the appropriate Study Design. Decide the best way to answer research question. Choose the appropriate Study Design. Decide the best way to answer research question. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Analyze the data. Analyze the data. Use biostatistics to examine data. Report your findings. Report your findings. Share what you learn with research community so that findings are used to improve public health. Epidemiology Research Process

26. © 2004 Aeras Global TB Vaccine Foundation 26 Doing the Research Research and data collection methods will vary according to the requirements of the study design. Research and data collection methods will vary according to the requirements of the study design. Research for an Epidemiology study can be very similar to clinical research. Research for an Epidemiology study can be very similar to clinical research. GCP and GLP guidelines should be followed to protect participants and ensure valid and reliable results. GCP and GLP guidelines should be followed to protect participants and ensure valid and reliable results.

27. © 2004 Aeras Global TB Vaccine Foundation 27 Define the hypothesis or question. State in detail what question you need answered. Define the hypothesis or question. State in detail what question you need answered. Choose the appropriate Study Design. Decide the best way to answer research question. Choose the appropriate Study Design. Decide the best way to answer research question. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Analyze the data. Analyze the data. Use biostatistics to examine data. Report your findings. Report your findings. Share what you learn with research community so that findings are used to improve public health. Epidemiology Research Process

28. © 2004 Aeras Global TB Vaccine Foundation 28 Analyze Data Using Biostatistics To analyze data we use statistics to interpret what is seen. To analyze data we use statistics to interpret what is seen. Put simply, biostatistics is statistics applied to biological or medical questions. Put simply, biostatistics is statistics applied to biological or medical questions. Biostatistics is the application of statistical techniques to scientific research in health- related fields and the development of new tools to study these areas. Biostatistics is the application of statistical techniques to scientific research in health- related fields and the development of new tools to study these areas.

29. © 2004 Aeras Global TB Vaccine Foundation 29 Biostatistics and Epidemiology Biostatistics is an indispensable tool to help epidemiologists improve health and reduce illness. Biostatistics is an indispensable tool to help epidemiologists improve health and reduce illness. Biostatisticians design studies, analyze data and create methods to attack research problems as diverse as: Biostatisticians design studies, analyze data and create methods to attack research problems as diverse as: the determination of major risk factors for heart disease, lung disease and cancer. the determination of major risk factors for heart disease, lung disease and cancer. evaluation of potential environmental factors harmful to human health, such as tobacco smoke, asbestos or pollutants. evaluation of potential environmental factors harmful to human health, such as tobacco smoke, asbestos or pollutants.

30. © 2004 Aeras Global TB Vaccine Foundation 30 Define the hypothesis or question. State in detail what question you need answered. Define the hypothesis or question. State in detail what question you need answered. Choose the appropriate Study Design. Decide the best way to answer research question. Choose the appropriate Study Design. Decide the best way to answer research question. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Do research & collect data. Conduct investigations as appropriate for the study design and record all the information specified. Analyze the data. Analyze the data. Use biostatistics to examine data. Report your findings. Report your findings. Share what you learn with research community so that findings are used to improve public health. Epidemiology Research Process

31. © 2004 Aeras Global TB Vaccine Foundation 31 Using Results From Epidemiology Studies Evidence-based medicine uses results from epidemiology studies and other research to good use… improving public health and providing the best care to patients. Photo courtesy of Aeras Global TB Vaccine Foundation.

32. © 2004 Aeras Global TB Vaccine Foundation 32 Using Research Results to Improve Health and Health Care Evidence-Based Medicine (EBM) is the process of systematically reviewing clinical research findings and using the most significant results to aid the delivery of optimal healthcare to patients. Photo courtesy of the Stop TB Partnership.

33. © 2004 Aeras Global TB Vaccine Foundation 33 How Does Evidence-Based Medicine Work? When you are sick… How does a doctor or nurse find out what causes your sickness? How does a doctor or nurse find out what causes your sickness? How does the doctor or nurse decide on the best treatment for you? How does the doctor or nurse decide on the best treatment for you? Photo courtesy of the Stop TB Partnership.

34. © 2004 Aeras Global TB Vaccine Foundation 34 How Are Decisions Made About Diagnosis & Treatment? Most doctors and nurses make decisions based on: what was learned during training. what was learned during training. previous personal experience. previous personal experience. traditional practices and approaches. traditional practices and approaches. advice from experts or textbooks. advice from experts or textbooks. other factors, such as cost, time and personal prejudice. other factors, such as cost, time and personal prejudice.

35. © 2004 Aeras Global TB Vaccine Foundation 35 A Better Way to Treat Patients: Evidence-Based Medicine Process When treating patients, the doctor or nurse: Defines the hypothesis or question. Thinks in detail what needs to be answered related to a condition or intervention strategy. Defines the hypothesis or question. Thinks in detail what needs to be answered related to a condition or intervention strategy. Looks for research & other data. Search in current research findings for guidelines and information needed to answer the question. Looks for research & other data. Search in current research findings for guidelines and information needed to answer the question. Analyzes the data. Analyzes the data. Critically evaluate evidence in clinical research results looking for the most significant findings. Uses evidence to treat patients. Draw conclusions and use interventions based on research findings and best practices. Uses evidence to treat patients. Draw conclusions and use interventions based on research findings and best practices.

36. © 2004 Aeras Global TB Vaccine Foundation 36 Asking a specific question about the best treatment or intervention. Asking a specific question about the best treatment or intervention. Searching for best evidence in available journals, etc. Searching for best evidence in available journals, etc. Evaluating available evidence and making a judgment on best course of action. Evaluating available evidence and making a judgment on best course of action. Treating the patient based on the evidence. Treating the patient based on the evidence. Evaluating the success. Evaluating the success. Back In the Clinic… Doctor or nurse makes decisions based on evidence from clinical research by: Photo courtesy of the Stop TB Partnership.

37. © 2004 Aeras Global TB Vaccine Foundation 37 A = Preferred B = Acceptable alternative C = Use when A & B can’t be given E = Should never be given Practical Evidence-Based Medicine Initial drug regimens for tuberculosis. DrugsInstructionsEvidence* 1 INH, RIF, PZA, EMB 7 days/week for 56 doses (8 wk) or 5 days/week for 40 doses (8 wk) A (I) 2 INH, RIF, EMB 7 days/week for 56 doses (8 wk) or 5 days/week for 40 doses (8 wk) C (II) I = randomized control trial II = trial data not randomized III = expert opinion * Typical Evidence Ratings on Guidelines: Approved guidelines from expert medical groups, simplify the process by providing evidence-based summaries of latest research data.

38. © 2004 Aeras Global TB Vaccine Foundation 38 How Does It Work? Example From a Current Study Define the hypothesis or question. The rate of TB in infants will be the same regardless of the method used to administer the BCG vaccine. Define the hypothesis or question. The rate of TB in infants will be the same regardless of the method used to administer the BCG vaccine. Do research & collect data. 5,500 infants received BCG vaccine by method 1, 5,500 by method 2. TB rates are being monitored to see if there is a difference in the rate of TB in the two groups. Do research & collect data. 5,500 infants received BCG vaccine by method 1, 5,500 by method 2. TB rates are being monitored to see if there is a difference in the rate of TB in the two groups. Analyze the data. TB rates monitored over 2-4 years. Results analyzed to determine effectiveness of methods. Analyze the data. TB rates monitored over 2-4 years. Results analyzed to determine effectiveness of methods. Use the information to treat patients. Results will be used to select vaccination method for new TB vaccines under development by Aeras. Use the information to treat patients. Results will be used to select vaccination method for new TB vaccines under development by Aeras.

39. © 2004 Aeras Global TB Vaccine Foundation 39 Review Epidemiology is a branch of medical science that studies a group of people to see who has disease, how much disease they have and why they have disease. Epidemiology is a branch of medical science that studies a group of people to see who has disease, how much disease they have and why they have disease. Typical studies for epidemiology include surveillance of disease, investigation of a disease outbreak, analytic studies of disease patterns, evaluation of public health programs. Typical studies for epidemiology include surveillance of disease, investigation of a disease outbreak, analytic studies of disease patterns, evaluation of public health programs.

40. © 2004 Aeras Global TB Vaccine Foundation 40 Review Interpreting a study hypothesis into plain English requires breaking it down into parts. Interpreting a study hypothesis into plain English requires breaking it down into parts. Study design is a critical step in the process. It ensures you get the right information to answer your research question. Study design is a critical step in the process. It ensures you get the right information to answer your research question. Three common study designs are: Three common study designs are: Retrospective - collect data from the past. Retrospective - collect data from the past. Cross-sectional – collect data from the present. Cross-sectional – collect data from the present. Prospective – collect data from the present into the future. Prospective – collect data from the present into the future.

41. © 2004 Aeras Global TB Vaccine Foundation 41 Review Prospective studies yield the best results because it allows for more precise and unbiased results. Prospective studies yield the best results because it allows for more precise and unbiased results. A randomized controlled study is the best method for conducting a prospective study with convincing results. A randomized controlled study is the best method for conducting a prospective study with convincing results. Evidence-based medicine (EBM) is the process of using clinical research results to deliver the best possible healthcare to patients. Evidence-based medicine (EBM) is the process of using clinical research results to deliver the best possible healthcare to patients.

42. © 2004 Aeras Global TB Vaccine Foundation 42 Epidemiology & Biostatistics 2 This presentation is produced by Aeras Global TB Vaccine Foundation SM in collaboration with the University of Cape Town and the South African Tuberculosis Vaccine Initiative. A special thanks to Professor Greg Hussey, Dr. Tony Hawkridge, MBChB, Dr. Hassan Mahomed, Marie Buchanan, Marijke Geldenhuys, MSHS CRA, Marwou De Kock, B.Tec., Dr. Sylvia Silver, D.A., Jen Page, M.Ed. Dr. Larry Geiter, PhD, and Peggy Goetz, MPH, for their contributions and support for this presentation.