Hypothesis generating and testing

1. Hypothesis generating and testing Epi 242 Cancer Epidemiology Fall, 2009

3. Descriptive Epidemiology • It is concerned with the distribution of disease, including consideration of: • what populations or subgroups do or do not develop a disease (person), • in what geographic locations it is most or least common (place). • how the frequency of occurrence varies over time (time)

4. Descriptive Epidemiology • It is associated with frequency and distribution of the disease. It describes the general characteristics of the distribution of a disease with regard to person (age, sex, race, marital status, occupation, etc.); place (variation among countries; within countries: urban/rural areas) and time (seasonal pattern in disease or time changes of the disease frequency).Information on each of these characteristics can provide clues leading to the formulation of an epidemiologic hypothesis that is consistent with existing knowledge of disease occurrence.

5. Descriptive Epidemiology • There are three types of study design for descriptive epidemiology: (1) case report and case-series study design are at the individual level; (2) correlation study or ecologic study designs are at the population level; and (3) cross-sectional study design is at the individual level.

6. Descriptive Epidemiology: Population Distribution Distribution of cancer in relation to person. • “Who is getting the disease?” • Demographic factors: age, sex, race, marital status, occupation. • Age, sex, and race are three most important factors in cancer descriptive epidemiology. • Age specific cancer rate (Figure).

8. Graph 1 indicates that an exogenous agent, acting continuously throughout life, is believed as the major etiologic factors as in lung and esophageal cancers.

9. Graph 2 suggests that the etiologic factors are strongest in early life. The decreased rate in very old age group could be explained by:Diminished exposure to an exogenous agent or a birth cohort effectElimination of a susceptible population subgroup (competing risk)Changes in host occurring in meddle age, as age at menopause;Serious under-reporting in old age.

10. Graph 3 (bimodal curve) as seen in breast cancer suggesting different etiologic factors act in early and late life.

11. Graph 4 Suggests a strong etiologic factor at the early age such as liver cancer

12. Graph 5, The curve peak in childhood and slow increase in later life as seen in leukemia or sarcomas, also indicates two different carcinogens

13. Graph 6 indicate the small number of cases and may not be reliable.

14. Figure 3 Age has no effect on susceptibility to some carcinogens. Left panel, cumulative mesothelioma risk in US insulation workers. Right panel, cumulative skin tumour risk in mice treated weekly with benzo(a)pyrene. Mesothelioma rates in humans65 and skin tumour rates in mice64 depend on time since first carcinogenic exposure but not on age, suggesting an initiating effect of these carcinogens. Lung cancer incidence in smokers depends on duration of smoking but not on age, and stops increasing when smoking stops67, indicating both early- and late-stage effects. Radiation-induced cancer incidence increases with age at exposure above age 20, suggesting predominantly late-stage effects3, although the large effect of childhood irradiation also indicates an early-stage effect.

15. Geographic Distributions Distribution of cancer in relation to place. “Where are the rates of disease highest and lowest?” • Variations among countries • Variations within countries, such as between urban and rural areas

23. Distribution of cancer according to time “Is the cancer rate at present different from the cancer rate in the past?” • Seasonal patterns of the disease • Time trends of the disease

28. Tobacco Use in the US, 1900-1999 Per capita cigarette consumption Male lung cancer death rate Female lung cancer death rate *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

29. Trends in Ethanol Consumption in the US, 1960-97 Source: NIAAA, NIH

30. Trends in oral cancer incidence rates* in 9 SEER areas in the US by gender and race from 1973-1975 through 1996-2000 *Age standardized to 2000 US population

31. Trends in Overweight* Prevalence (%), Adults 18 and Older, US, 1992-2001

33. Trends in esophageal cancer incidence rates* in 9 SEER areas in the US by gender, race, and cell type from 1973-1975 through 1996-2000 *Age standardized to 2000 US population

34. Change of the cancer rates may be caused by many factors: Changes in diagnostic techniques Changes in accuracy of tumor registry Changes in age distribution may cause the increase in crude rates Changes in survivals Improved treatment Early diagnosis or screening Changes in actual incidence of disease due to alterations in environmental or life-style factors

35. The Sequence of Investigation for Etiology of Disease • Formulating hypotheses • Testing hypotheses • Intervention

36. Formulate Hypotheses • The clinician makes an observation regarding cause, based on his/her experience (case report/case series study). The epidemiologist describes the distribution of the frequency of the disease with regard to person, place, and time (ecological studies, cross-sectional studies). In addition, the laboratory data will also supply certain information regarding to potential causes for the disease. These data from different sources can be employed to formulate the hypotheses.

37. Testing Hypotheses • These hypotheses may be tested in sequence by retrospective (case-control) studies, and if the results are positive, by the prospective (cohort) studies. Sometimes, there are only case-controls studies since prospective studies take a long time to accomplish.

38. Intervention • If risk factors are identified by both retrospective/prospective studies, an intervention trial may be designed to ascertain whether or not modification of such factors is followed by a reduction in amount of disease.

39. Hypothesis Generating • A new hypothesis can affect the direction of future research and the success or failure of the research depends on the soundness of the hypothesis. • By observing patterns and distribution of cancer incidence, three methods of hypothesis formulation about disease etiology.

40. Method of Difference • If the frequency is markedly different in two sets of circumstances, the disease may be caused by some particular factor that differs between them. • If the cancer rate is very rare in one country, but very common in another country, it may suggest potential life-style or environmental exposures.

43. Method of Agreement • The observation that a single factor is common to a number of circumstances in which a disease occurs with a high frequency. • Cervical cancer occurs higher in women with multiple sexual partners, in women whose husbands had multiple sexual partners, in women whose husbands had penial cancer. All those circumstances indicate that a sexually transmitted agent/agents may play an important role in the etiology of cervical cancer.

44. Method of Concomitant Variation • The frequency of a factor varies in proportion to the frequency of disease. Correlation studies are particularly useful sources of data for this type of hypothesis formulation.

46. Considerations in the Formation of Hypotheses • Biological basis and support of the hypothesis • New hypotheses are commonly formed by relating observations from several different fields (e.g., clinical, pathological, and laboratory observations) • The stronger a statistical association, the more likely it is to suggest a causal hypothesis (when you generate hypothesis from existing data).

47. Considerations in the Formation of Hypotheses • Observation of changes in frequency of a disease over time, especially changes that have occurred over the relatively short period of time (lung cancer, adenocarcinoma of esophageal cancer, etc.)  • Clustering unusual cases of cancer may indicate the potential environmental exposures

48. Starting A Hypothesis • Study subjects: the characteristics of the persons to whom the hypothesis applies. • The risk factor or potential cause: environmental or genetic factors • The disease: the expected effect • The exposure-response relationship • The time-response relationship • e.g., “By reducing dietary fat from 40% to 20% in white males with elevated PSA, the incidence of prostate cancer will reduce 30% within five years in this population”.

49. Hypothesis Testing • Study Design for Hypothesis Testing. There are several types of epidemiologic studies: Prospective or retrospective studies are classified according to time frame of the study; observational or experimental epidemiological studies are depended on whether or not the investigator has control of some factors (intervention factors, treatment) that may be associated with a different outcome; and descriptive or analytic studies are based on purposes of the study designs (formulating or testing hypotheses).

50. Hypothesis Testing • Analytic Epidemiology deals primarily with the determinants of the disease. In analytic study design, the investigator assembles groups of individuals to determine whether or not the risk of disease is different for individuals exposed then it is for individuals not exposed to a factor of interest.