1. STAT 6395 Special Topic in Statistics: Epidemiology Spring, 2008 Filardo and Ng, 2008

3. I. Epidemiology The study of the distribution and determinants of health- related states or events in specified populations and the translation of study results to control health problems

4. Distribution Persons affected Place Time Epidemiology: The study of the distribution and determinants of health-related states or events in specified populations and the translation of study results to control of health problems

5. Determinants All the physical, biological, social, cultural, and behavioral factors that influence health Epidemiology: The study of the distribution and determinants of health-related states or events in specified populations and the translation of study results to control of health problems

6. Health-related states or events Diseases Mortality (death) Specific causes of death Injuries Disability Health-related behaviors Physiological measurements Results of preventive regimens Clinical outcomes Provision and use of health services Epidemiology: The study of the distribution and determinants of health-related states or events in specified populations and the translation of study results to control of health problems

7. Specified populations Residents of a defined geographic area Students who attend a specified school Persons who belong to a specified organization Workers at a specified workplace Epidemiology: The study of the distribution and determinants of health-related states or events in specified populations and the translation of study results to control of health problems

8. Translation Study Results Epidemiology: The study of the distribution and determinants of health-related states or events in specified populations and the translation of study results to control of health problems Scientific articles and presentations at meetings Prevention programs Quality of care improvement programs Patient safety programs Clinical guidelines

9. Control Operations or programs aimed at reducing the adverse impact of the disease on the community 1)Prevention 2)Cure 3)Management Epidemiology: The study of the distribution and determinants of health-related states or events in specified populations and the translation of study results to control of health problems

10. Primary prevention An action taken to prevent the development of a disease in a person who is well and does not have the disease in question Operations or programs aimed at reducing the adverse impact of the disease on the community: 1) Prevention; 2) Cure; 3) Management

11. Secondary prevention (Cure and management) The identification and treatment of people who have already developed a disease or precursors of the disease, through screening, at an early enough stage in the disease’s natural history (early detection) such that intervention will be more effective than if the disease had been discovered later Operations or programs aimed at reducing the adverse impact of the disease on the community: 1) Prevention; 2) Cure; 3) Management

12. II. Objectives of Epidemiology To describe the extent of disease in the community To identify risk factors (factors that influence a person’s risk of acquiring a disease) for disease and the etiology or cause of disease To study the natural history (course from onset to resolution) and prognosis of disease To evaluate both existing and new preventive and therapeutic measures (including health care delivery) To provide the foundation for developing public policy and regulatory decisions relating to environmental problems

13. …bottom line, Epidemiology research requires a multidisciplinary effort and statisticians play a key role in: Hypothesis development Study execution

14. Hypothesis development Epidemiologists study the specific distribution and determinants of specific diseases Development of hypotheses to test in an epidemiologic study requires in-depth knowledge of the disease and determinants under study Medical and biological sciences Social and behavioral sciences Epidemiology Research  hypothesis development and study execution

15. Study execution Statistics ------------>Biostatistics Medical and biological sciences Social and behavioral sciences Epidemiology Research  hypothesis development and study execution

16. Biostatistics Separate chance observations from meaningful observations Sampling Sophisticated statistical analyses Epidemiology Research  Biostatistics, medical and biological sciences, social and behavioral sciences

17. Medical and biological sciences Microbiology, e.g., to identify infectious agents Clinical medicine and pathology, (e.g., to identify cases of disease) Molecular biology, (e.g., to identify genotype of individuals) Biochemistry, (e.g., to measure serum hormone levels) Epidemiology Research  Biostatistics, medical and biological sciences, social and behavioral sciences

18. Social and behavioral science Design questionnaires for obtaining valid information Design effective interventions for lifestyle changes Epidemiology Research  Biostatistics, medical and biological sciences, social and behavioral sciences

19. Epidemiology Sub-disciplines Disease-specific subject matter Exposure-specific subject matter Health services research

20. Infectious disease epidemiology HIV/AIDS epidemiology Malaria epidemiology Chronic disease epidemiology Cancer epidemiology Cardiovascular epidemiology Perinatal epidemiology Neuroepidemiology Psychiatric epidemiology Epidemiology disciplines  Disease-specific subject matter, Exposure-specific subject matter, Health services research Disease-specific subject matter

21. Environmental epidemiology Occupational epidemiology Pyschosocial epidemiology Genetic epidemiology Nutritional epidemiology Pharmacoepidemiology Epidemiology disciplines  Disease-specific subject matter, Exposure-specific subject matter, Health services research Determinant (exposure)-specific subject matter

22. Operations research: the study of the placement of health services in the community and the optimum utilization of such services Program evaluation Clinical epidemiology or outcomes research: the study of illness outcomes in persons seen by providers of health care; evaluation of medical treatments Epidemiology disciplines  Disease-specific subject matter, Exposure-specific subject matter, Health services research Health services research

23. Types of epidemiologic studies Experimental Observational (this course will focus on this second type of studies)

24. Experimental Studies Studies in which conditions are under the control of the investigator(s). The investigators assigns subjects to different study groups. The effect of the treatment is determined by comparing the outcome of interest in these groups. Type of studies  Experimental, Observational

25. Experimental studies (examples) Randomized clinical trial (unit of study is the individual) Community trial (unit of study is the community) Type of studies  Experimental, Observational

26. Observational studies Studies in which the investigators does not control conditions, but rather observe nature taking its course by gathering information, recording, classifying, counting, and analyzing the collected data. Exposure and disease outcomes would have occurred whether or not the studies have been performed because there were no ‘a priori’ intervention(s) on the part of the investigators. Type of studies  Experimental, Observational

27. Observational studies (examples) Descriptive Analytic Type of studies  Experimental, Observational

28. Descriptive studies Studies aimed at describing the distribution of disease or other health-related variables with respect to person (age, gender, race, socioeconomic status), place (census tract, county, state, country, urban/rural), and time (season, year) Type of studies  Experimental, Observational (descriptive)

29. Descriptive studies Often use routinely-collected data Can define high-risk groups Can be used for hypothesis generation, but generally not hypothesis testing Type of studies  Experimental, Observational (descriptive)

30. Analytic studies Test specific etiologic hypotheses To generate new etiologic hypotheses To suggest mechanisms of causation To generate preventive hypotheses To suggest or identify potential methods for disease prevention Type of studies  Experimental, Observational (analytic) In these studies, the epidemiologist observes the relationship between an exposure and a disease or other health outcome.

31. Definition: Exposure A potential causal agent or characteristic, such as infectious agent, behavior, dietary factor, medication, medical treatment, genetic makeup, environmental agent, or physiologic state (e.g., serum level of a hormone or nutrient; blood pressure). Type of studies  Observational  Analytic An exposure may be harmful or beneficial

32. Types of analytic studies Cohort studies Case-control studies Type of studies  Observational

33. Cohort studies A study in which a group of persons exposed to a factor of interest and a group of persons not exposed are followed Type of studies  Observational  Cohort studies and compared with respect to the incidence rate of the disease or other condition of interest Time

34. Cohort studies (study schema) Type of studies  Observational  Cohort studies

35. Case-Control studies Type of studies  Observational  Case-Control Studies in which a group of persons with a disease (cases) and a comparison group of persons without the disease (controls) are compared with respect to the history of past exposures to factors of interest PresentPast

36. Case-Control studies (study schema) Type of studies  Observational  Case-Control

37. Time

38. Either descriptive or analytic studies Type of studies  Observational Cross-sectional studies Ecologic studies

39. Cross-sectional studies Studies of the distribution of exposures and/or disease in a defined population at one given point in time Type of studies  Observational  Cross-sectional

41. Ecologic studies Studies of the association between exposures and disease in which the units of analysis are populations or groups of people, rather than individuals. This involves the assessment of the correlation of exposure rates and disease rates among different groups or populations. Causality, though??? Type of studies  Observational  Ecologic

42. Types of Epidemiologic studies

43. Example involving several types of study designs Ecologic study results Case-Control study results Cohort study results Randomized controlled trial results

44. Which type of study is the ‘Gold Standard’ and/or more common/feasible? Experimental Efficacy controlled setting (difficult to reproduce in real life) Observational Effectiveness real life setting

45. Focus of this course is on observational Epidemiologic research (research regarding the direct study of disease in human populations)

47. Some triumphs of observational Epidemiology Smoking causes lung cancer Identification of cardiovascular disease risk factors Characterization of how HIV spreads through a population Identification of occupational hazards (e.g., asbestos)

48. Three ‘Eras’ of Epidemiology Sanitary (1800-1875) Infectious disease (1875-1950) Chronic disease (1950-present)

49. Sanitary ‘Era’ (1800-1875) Miasma theory of disease – poisoning by foul emanations (miasma) from the soil, water, and air. Created national vital statistics systems: much valuable descriptive epidemiology Demonstrated clustering of disease in slums and among the poor Solutions – sewage systems, drainage, clean water supplies, garbage collection, decent housing Incorrect miasma theory, but solutions were a major contribution to public health Sanitary, Infectious disease, Chronic disease Lesson: prevention doesn’t necessarily require understanding of cause

50. Infectious disease ‘Era’ (1875-1950) Germ theory: single microscopic agents relate one-to- one to specific diseases Epidemiology took a back seat to laboratory science, although in the1920s-30s, the germ theory was broadened to accommodate the interactive roles of host (immune and nutritional status), environment, and agent in infectious disease Other epidemiologic contributions: – Occupational exposures as causes of cancer – Specific vitamin deficiencies as causes of disease Sanitary, Infectious disease, Chronic disease

51. Chronic Disease (Modern) ‘Era’ By end of World War II, infectious diseases were under control in the developed countries; coronary heart disease and lung cancer were epidemic Multifactor causation of chronic disease Focus on identification and control of risk factors at the individual level Black box approach: emphasis on risk factor identification with only a secondary concern about mechanism or pathogenesis Sanitary, Infectious disease, Chronic disease Most of the methodology we will cover in this course was developed during this ‘Modern Era’.

52. New ‘Era’(???) Emerging infectious diseases (e.g., HIV) Continued burden of infectious diseases in majority of world Traditional chronic disease epidemiology has hit a wall in its ability to discover important new risk factors Advances in molecular biology and genetics allow the study of pathogenesis and causality at the molecular and genetic levels using epidemiologic approaches The need to be concerned with causal pathways at multiple levels, including the societal level, as opposed to an exclusive focus on risk factors at the individual level, has become apparent to many Sanitary, Infectious disease, Chronic disease, ???

53. Levels of causality Societal or population Individual Biochemical Cellular Molecular

54. What causes lung cancer? Individual/societal: Cigarette smoking (nicotine addiction) Biochemical: Specific chemicals in cigarette smoke that cause the mutations Cellular: Specific phenotypic changes in the cells that result in loss of growth control Molecular: Mutations in DNA

55. What causes AIDS ? Societal: Poverty Prostitution Individual/societal: a. Multiple sexual partners; b. Intravenous drug use X Biochemical: Cellular: Infection -the HIV viruses progressively destroy lymphocytes (a types of white blood cells) Molecular: Mutations in DNA -the viral DNA is incorporated into the DNA of the infected lymphocyte

56. On the mode of communication of cholera John Snow, M.D. London, 1855

57. John Snow 1857

58. Why study Snow? Appreciate those who came before us and paved the way Brilliant piece of work: lucid and thorough Snow’s work on cholera illustrates a key epidemiologic principle: …the most important information to have about any communicable disease is its mode of communication

59. John Snow (1813-1858) Physician Pioneer in both epidemiology and anesthesiology Experiments in administration of anesthesia himself may have contributed to his early death

60. Snow administered chloroform to Queen Victoria for the birth of Prince Leopold and Princess Beatrice

61. Cholera: Acute Gastrointestinal Disease Incubation period: 12-72 hours Sudden onset of severe vomiting Followed shortly by voluminous, watery, non-bloody diarrhea, described as rice water stool (white and opalescent) Abdominal cramps Severe cases: severe dehydration, circulatory collapse, renal failure (death may occur within a few hours of first symptoms) Case fatality rate may range from 1-50%, depending on strain of Vibrio cholerae and treatment

62. In 1817, four years after John Snow’s birth, cholera emerged from the Indian subcontinent, where it had existed for centuries, to spread across the world.

63. Cholera Epidemics in Great Britain 1831-32 –56,000 deaths 1848-49 –125,000 deaths 1853-54 –Cholera returns to England

64. Cholera: Apparently contradictory facts in 1854 Local spread with evidence of direct communication from person to person Failure to spread to many in close contact with the sick Cases occur without traceable relation to prior cases Highest rates in low-lying areas and in filthy environments - Exceptions too numerous to be disregarded Unpredictability of its spread around the world and its geographic distribution

65. Cholera: Miasma Theory Report of the London General Board of Health on cholera epidemic of 1848-49: “…it appears as if some organic matter, which constitutes the essence of the epidemic, when brought in contact with other organic matter proceeding from living bodies, or from decomposition, has the power of so changing the condition of the latter as to impress it with poisonous qualities of a peculiar kind similar to its own.”

66. Cholera: Elaborations of Miasma theory Localizing influences Predisposition Spontaneous generation of “cholera poison” “Poison” spread by diffusion through the atmosphere vs. poison attached itself to solid bodies “Poison” communicated by an effluvium (contagion) given off by the sick

67. William Farr

68. Farr’s elaboration of Miasma theory Soil at low elevations, especially near the banks of the Thames River, contained much organic matter that produced deadly miasmata. Miasmata diffused through the atmosphere in a cloud or mist Concentration of miasmata would be greater at lower elevations than in higher elevations, accounting for the geographic distribution in the London epidemic of 1849. Farr’s theory did have some consistency with the facts.

69. John Snow’s Germ Theory Cholera caused by a germ cell, not yet identified 2 main modes of transmission of germ cell, which was found in the evacuations of cholera victims: 1. Drinking water contaminated with sewage 2. Contaminated food, bedding, or clothing Snow was firmly convinced of his theory by start of 1853-54 epidemic.

70. Snow’s ecologic observations prior to the 1853-54 epidemic Epidemics of cholera followed major routes of commerce and warfare. Cholera always appeared first at seaports, when extending to a new island or continent. Cholera “has never appeared except where there has been ample opportunity for it to be conveyed by human connections.”

71. Snow’s observations from ‘case’ histories Cholera can be communicated from the sick to the healthy. Persons attending those with cholera do not necessarily become afflicted. Close contact with a cholera patient is not necessary to become afflicted. Snow’s conclusion: “…cholera is communicated from person to person, but not through the air”

72. When cholera returned to London in August 1853, Snow had a definite hypothesis: cholera was spread by contaminated water.

73. Water supply of south districts of London Until 1852, drew water from the Thames River in London, contaminated with London’s sewage In 1852, moved intake 22 miles up river and far from the contaminated water Continued to draw water from the contaminated Thames Lambeth Water Company Southwark and Vauxhall Water Company

75. Cholera Deaths in South Districts of London Deaths/100,000 Water Company Epidemic 1849 1853 S&V, Lambeth 1290 61 S&V 1420 94 S&V, Kent 2050 107

76. Cholera deaths (per 100,000) in south districts of London District Water supply 1849 1853 BermondseyS&V 1610 150 St. SaviourS&V, Lam 1530 146 St. GeorgeS&V, Lam 1640 143 St. OlaveS&V 1810 134 RotherhitheS&V, Kent 2050 112 Newington S&V, Lam 1440 57 Wandsworth S&V, others 1000 51 Camberwell S&V, Lam 970 40 Lambeth Lam, S&V 120034 Notes: 1. Lambeth was supplied mostly by Lambeth Water Co. 2. Rotherhithe supplied partly by Kent in 1853

77. Cholera Deaths in south districts of London, 1853, sub-district analysis Water Cholera Deaths/ Supply Population Deaths 100,000 S&V 167,654 192 116 Lambeth 14,632 0 0 Both 301,149 182 60 How many cholera deaths would we expect in sub-districts supplied by Lambeth if they had the same death rate as those supplied by S&V?

78. Cholera Deaths in south districts of London, 1853, sub-district analysis Water Cholera Deaths/ Supply Population Deaths 100,000 S&V 167,654 192 116 Lambeth 14,632 0 0 Both 301,149 182 60 Expected deaths for Lambeth = (116/100,000)*14,632 = 16

79. Additional Observations on Sub-districts: Among the sub-districts supplied by both companies, those supplied mainly by Lambeth had a low death rate, while those supplied mainly by S&V had a high death rate. Two sub-districts supplied only by S&V also contained a number of pump-wells. These sub-districts had a low death rate.

80. By the return of cholera in July 1854, Snow recognized the full significance of the intermixing of the water supplies of the 2 companies “…in the sub-districts … supplied by both Companies, the mixing of the supply is of the most intimate kind… A few houses are supplied by one Company and a few by the other, according to the decision of the owner or occupier at that time when the Water Companies were in active competition …”

81. By the return of cholera in July 1854, Snow recognized the full significance of the intermixing of the water supplies of the 2 companies “…in many cases a single house has a supply different from that on either side. Each company supplies both rich and poor, both large houses and small; there is no difference either in the condition or occupation of the persons receiving the water of the different Companies.”

82. An Experiment on the Grandest Scale “…no fewer than three hundred thousand people of both sexes, of every age and occupation, and of every rank and station, from gentlefolks down to the very poor, were divided into two groups without their choice …”

83. An Experiment on the Grandest Scale “…one group being supplied with water containing the sewage of London, …the other group having water quite free from such impurity”

84. What type of study John Snow conducted?

86. Cohort Study A study in which a group of persons exposed to a factor of interest and a group of persons not exposed are followed and compared with respect to the incidence rate of the disease or other condition of interest. Exposed group: persons using S&V water supply Comparison group: persons using Lambeth water supply Compared cholera mortality rates in the two groups

87. Calculation of mortality rates required numerators and denominators Mortality rate in exposed group = (Cholera deaths among persons supplied with S&V water) / (Number of persons supplied with S&V water) Mortality rate in comparison group = (Cholera deaths among persons supplied with Lambeth water) / (Number of persons supplied with Lambeth water) To determine numerators and denominators, Snow needed a way to classify each death and every person in the population by water supply

88. The Numerators For each cholera death in the relevant districts, Snow obtained information on the water supply “The inquiry was necessarily attended with a good deal of trouble.” Chemical test problematic because S&V water had 40 times more NaCl than Lambeth

89. The Denominators Therefore Snow had to include all the south districts of London in his study, not just the districts where the water supply was intermingled. A daunting undertaking, so Snow obtained an assistant (Mr. Whiting) “ …a return had been made to Parliament of the entire number of houses supplied with water by each of the Water Companies, but... the number of houses which they supplied in particular districts was not stated…”

90. Cholera deaths in south London districts during first 4 weeks of 1854 Epidemic, by water supply Deaths/ Water Cholera 10,000 Supply Deaths Houses Houses S&V 286 40,046 71.4 Lambeth 14 26,107 5.4 Relative risk = 71.4/5.4 ≈ 13.2 Thames 22 Pump-wells 4 Ditches 4 Unknown 4 London 277 287,345 9.6 (-S&V) Note: Houses, not persons, used in denominator

91. More data … Cholera likely was imported from Baltic Fleet to Thames River, which was initially the primary source of the epidemic Later, cholera was also spread by other means, diluting the water company effect “ …as the epidemic advanced, the disproportion between the number of cases in houses supplied by the Southwark and Vauxhall Company and those supplied by the Lambeth Company, became not quite so great, although it continued very striking…”

92. Cholera deaths in south London districts during first 7 weeks of 1854 Epidemic, by water supply Deaths/ Water Cholera 10,000 Supply Deaths Houses Houses S&V 1263 40,046 315 Lambeth 98 26,107 37 Relative risk = 315/37 ≈ 8.5 London 1422 256,423 59 (-S&V, Lambeth)

93. Cholera deaths in south London districts during last 7 weeks of 1854 Epidemic, by water supply Deaths/ Water Cholera 10,000 Supply Deaths Houses Houses S&V 2353 40,046 573 Lambeth 302 26,107 115 Relative risk = 573/115 ≈ 5

94. Cholera deaths in south London districts during the 1854 epidemic, by water supply Water Cholera Deaths/ Supply Deaths Population 10,000 S&V 4,093 266,516 153 Lambeth 461 173,748 26 Relative risk = 153/26 ≈ 5.9 London 10,367 2,362,236 43 Note: populations supplied by water companies estimated by Registrar General.

95. Was the Use of Houses in the Denominators Valid? Water Persons/ Supply Population Houses Household S&V 266,516 40,046 6.7 Lambeth 173,748 26,107 6.7 London 2,362,236 322,576 7.3

96. Cholera Deaths in South Districts of London, Sub-district Analysis, 1849 vs. 1854 Water Cholera Deaths Supply 1849 1854 S&V 2261 2458 Both 3905 2547 Lambeth 1644 89 Here we are back to ecologic analysis

97. Cholera Outbreak in the Golden Square Area of London, 8/31 - 9/9, 1854. Within 250 yards of the intersection of Cambridge and Broad Streets, there were more than 500 fatal cases

98. Snow immediately suspected contamination of the water of the much-used street pump on Broad Street near Cambridge Street.

99. Snow mapped the places of residence of cholera decedents from August 31 - September 2 in the broader neighborhood… …and found that 73 of 83 deaths had taken place within a short distance of the pump.

101. Snow investigated the water source of the 73 decedents who lived near Broad Street pump 61 -- drank water from the pump 6 -- did not 6 -- could get no information

102. 10 Deaths in houses located nearer to another street pump 5 always used the Broad Street pump, as they preferred its water 3 (children) went to school near the Broad Street pump

103. Handle of the pump was removed on September 8 Legend has it that the removal of the pump handle caused the end of the epidemic Snow himself wondered whether removing the pump handle had a beneficial effect –Epidemic was already subsiding –Much of the population in the neighborhood had fled “…it is impossible to decide whether the water from the pump still contained the cholera poison in an active state.”

104. Snow’s investigation of Golden Square Outbreak: workhouse near Broad St. Surrounded by houses in which deaths from cholera occurred Only 5 deaths among 535 inmates Workhouse had a pump-well on the premises Also received water from the Grand Junction Water Works Did not use Broad Street pump Would have expected more than 100 deaths based on mortality in surrounding streets

105. Snow’s investigation of Golden Square Outbreak: Brewery on Broad St. Located near the pump More than 70 workers None died of cholera Workers drank malt liquor, not water Deep well located in brewery Workers never obtained water from Broad Street Pump

106. Snow’s recommendations for prevention of cholera during an epidemic Observe strictest cleanliness around the sick. Wash linens of patients as soon as they are removed. Boil water for drinking and preparing food (unless known to come from clean source). Wash or heat to 212°F all food. Healthy should not live in same room as sick. Pit-men should work 4 hour shifts, and not eat in mines. Educate the people about communicability of cholera.

107. Snow’s recommendations for long-term prevention of cholera Effect good and perfect drainage. Provide water supply free from contamination with contents of sewers, cesspools, house-drains, and refuse of people who navigate the rivers. Provide model lodging-houses for the vagrant class and sufficient house room for the poor in general. Teach habits of personal and domestic cleanliness among the people. Screen persons arriving from infected places.

108. Medical establishment slow to catch on 1855 report of Scientific Committee for Scientific Enquiries in Relation to the Cholera Epidemic of 1854: “…on the whole of evidence, it seems impossible to doubt that the influences, which determine in mass the geographical distribution of cholera in London, belong less to the water than to the air.” 1856 Report on the last two cholera epidemics of London as affected by the consumption of impure water: “…under the specific influence which determines an epidemic period, fecalized drinking-water and fecalized air equally may breed and convey the poison.”

109. Sanitary ‘movement’ eventually succeeded in spite of its incorrect miasma theory Extensive improvements in several of London’s water supplies, including Southwark and Vauxhall, had already been ordered before the 1853-54 epidemic. In next London epidemic (1866), William Farr himself used epidemiology to show that the source of the epidemic was impure water from the East London Water Company.

110. What We Know Now? Cholera caused by a bacterium (Vibrio cholerae; discovered in 1883 by Robert Koch) Small intestine is primary site of infection Diarrhea caused by cholera toxin produced by Vibrio cholerae Treatment: intravenous or oral fluid and electrolytes, depending on severity of illness Environmental reservoir for Vibrio cholerae in the sea, where it lives on zooplankton and shellfish

111. Vibrio Cholerae

112. 2005