1. BME 301
Lecture Twelve

2. Review of Lecture 11 Belmont Report Respect for persons Beneficence
Justice
Process of informed consent

3. Four Questions What are the major health problems worldwide?
Who pays to solve problems in health care?
How can technology solve health care problems?
How are health care technologies managed?

4. Three Case Studies Prevention of infectious disease
HIV/AIDS
Early detection of cancer
Cervical Cancer
Ovarian Cancer
Prostate Cancer
Treatment of heart disease
Atherosclerosis and heart attack
Heart failure

5. Where do innovations come from? Technology Assessment: The Big Picture
Start here
How can we use science and technology to solve problems in health care?
Advance to next unit
Where do innovations come from?
Technology Assessment: The Big Picture
Patient Outcomes
Biological plausibility
Science Drives Engineering
Clinical Trials
Scientific Method
Societal Outcomes
Technical Feasibility
Engineering design
How do we test and refine innovations? Case studies
Treatment of Heart Disease
Early Detection of Cancer
Prevention of Infectious Diseases
Pre-cancer  cancer transformation
The circulatory system
Detection of Morphologic Changes
Gene Chips – molecular changes
Microorganisms
Arteriosclerosis
CABG
PTCA
Heart Failure
LVAD
Transplant
Ovary
Cervix
Prostate
Immunity
Vaccines
Outcomes
Cost effectiveness
Cost effectiveness
HIV
Outcomes
Cost effectiveness

6. Outline The burden of cancer How does cancer develop?
Why is early detection so important?
Strategies for early detection
Example cancers/technologies
Cervical cancer
Ovarian cancer
Prostate cancer

7. The Burden of Cancer: U.S.
2nd leading cause of death in US
1 of every 4 deaths is from cancer
5-year survival rate for all cancers:
62%
Annual costs for cancer:
$172 billion
$61 billion - direct medical costs
$16 billion - lost productivity to illness
$95 billion - lost productivity to premature death

8. U.S. Cancer Incidence & Mortality 2004
New cases of cancer:
United States: 1,368,030
Texas: 84,530
Deaths due to cancer:
United States: 563,700
Cancer Facts & Figures

9. US Mortality, 2001 No. of deaths % of all deaths Rank Cause of Death
1. Heart Diseases 700,
2. Cancer ,
3. Cerebrovascular diseases 163,
4. Chronic lower respiratory diseases 123,
5. Accidents (Unintentional injuries) 101,
6. Diabetes mellitus 71,
7. Influenza and Pneumonia 62,
8. Alzheimer’s disease 53,
9. Nephritis 39,
10. Septicemia 32,
Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart disease. In 2001, there were 553,768 cancer deaths in the US.
Source: US Mortality Public Use Data Tape 2001, National Center for Health Statistics, Centers for Disease Control and Prevention, 2003.

10. 2004 Estimated US Cancer Cases*
Men 699,560
Women 668,470
32% Breast
12% Lung & bronchus
11% Colon & rectum
6% Uterine corpus
4% Ovary
4% Non-Hodgkin lymphoma
4% Melanoma of skin
3% Thyroid
2% Pancreas
2% Urinary bladder
20% All Other Sites
Prostate 33%
Lung & bronchus 13%
Colon & rectum 11%
Urinary bladder 6%
Melanoma of skin 4%
Non-Hodgkin lymphoma 4%
Kidney 3%
Oral Cavity 3%
Leukemia 3%
Pancreas 2%
All Other Sites 18%
Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that 1.37 million new cases of cancer will be diagnosed in Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers both in men and in women.
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2004.

11. 2004 Estimated US Cancer Deaths*
Men 290,890
Women 272,810
Lung & bronchus 32%
Prostate 10%
Colon & rectum 10%
Pancreas 5%
Leukemia 5%
Non-Hodgkin 4% lymphoma
Esophagus 4%
Liver & intrahepatic 3% bile duct
Urinary bladder 3%
Kidney 3%
All other sites 21%
25% Lung & bronchus
15% Breast
10% Colon & rectum
6% Ovary
6% Pancreas
4% Leukemia
3% Non-Hodgkin lymphoma
3% Uterine corpus
2% Multiple myeloma
2% Brain/ONS
24% All other sites
Lung cancer is, by far, the most common fatal cancer in men (32%), followed by prostate (10%), and colon & rectum (10%). In women, lung (25%), breast (15%), and colon & rectum (10%) are the leading sites of cancer death.
ONS=Other nervous system.
Source: American Cancer Society, 2004.

12. Worldwide Causes of Death, 1996

13. Causes of Mortality, 1996

14. Worldwide Burden of Cancer
Today:
11 million new cases every year
6.2 million deaths every year (12% of deaths)
Can prevent 1/3 of these cases:
Reduce tobacco use
Implement existing screening techniques
Healthy lifestyle and diet
In 2020:
15 million new cases predicted in 2020
10 million deaths predicted in 2020
Increase due to ageing population
Increase in smoking

15. Worldwide Burden of Cancer
23% of cancers in developing countries caused by infectious agents
Hepatitis (liver)
HPV (cervix)
H. pylori (stomach)
Vaccination could be key to preventing these cancers

16. 1996 Estimated Worldwide Cancer Cases*
Men
Women
910 Breast
524 Cervix
Colon & rectum
Stomach
333 Lung & bronchus
192 Mouth
191 Ovary
Uterine corpus
Lung & bronchus 988
Stomach
Colon & rectum 445
Prostate 400
Mouth 384
Liver
Esophagus
Urinary bladder 236
Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that 1.37 million new cases of cancer will be diagnosed in Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers both in men and in women.

17. What is Cancer?
Characterized by uncontrolled growth & spread of abnormal cells
Can be caused by:
External factors:
Tobacco, chemicals, radiation, infectious organisms
Internal factors:
Mutations, hormones, immune conditions

18. Squamous Epithelial Tissue

19. Precancer  Cancer Sequence

20. Histologic Images
Normal
Cervical Pre-Cancer

22. Fig 7.33 – The Metastatic cascade Neoplasia

23. http://www. drugdevelopment-technology. com/projects/avastin/avastin2

25. Clinical Liver Metastases

26. What is Your Lifetime Cancer Risk?

27. Lifetime Probability of Developing Cancer, by Site, Men, US, 1998-2000
Risk
All sites in 2
Prostate in 6
Lung & bronchus 1 in 13
Colon & rectum 1 in 17
Urinary bladder 1 in 29
Non-Hodgkin lymphoma 1 in 48
Melanoma 1 in 55
Leukemia 1 in 70
Oral cavity 1 in 72
Kidney 1 in 69
Stomach 1 in 81
The next four slides look at the lifetime probability of developing cancer and relative survival rates of cancer.
Presently, the risk of an American man developing cancer over his lifetime is one in two. The leading cancer sites are prostate, lung, and colon & rectum.
Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 5.1 Statistical Research and Applications Branch, NCI,

28. Lifetime Probability of Developing Cancer, by Site, Women, US, 1998-2000
Risk
All sites in 3
Breast in 7
Lung & bronchus in 17
Colon & rectum in 18
Uterine corpus in 38
Non-Hodgkin lymphoma 1 in 57
Ovary in 59
Pancreas in 83
Melanoma in 82
Urinary bladder in 91
Uterine cervix 1 in 128
Approximately one in three women in the United States will develop cancer over her lifetime. The leading sites are breast, lung, and colon & rectum.
Source:DevCan: Probability of Developing or Dying of Cancer Software, Version 5.1 Statistical Research and Applications Branch, NCI,

29. How Can You Reduce Your Cancer Risk?

30. Tobacco Use in the US,
Per capita cigarette consumption
Male lung cancer death rate
The last set of slides describes at the prevalence of cancer risk factors, such as tobacco use and physical inactivity, and the prevalence of cancer screening, such as use of mammography.
Tobacco use is a major preventable cause of death, particularly from lung cancer. The year 2004 marks the anniversary of the release of the first Surgeon General’s report on Tobacco and Health, which initiated a decline of per capita cigarette smoking in the United States. As a result of the cigarette smoking epidemic, lung cancer death rates showed a steady increase through 1990, then began to decline. The lung cancer death rate among US women, who began regular cigarette smoking later than men, has continued to increase, but at a slower rate since the early 1990s.
Female lung cancer death rate
*Age-adjusted to 2000 US standard population Source: Death rates: US Mortality Public Use Tapes, , US Mortality Volumes, , National Center for Health Statistics, Centers for Disease Control and Prevention, Cigarette consumption: US Department of Agriculture,

31. Trends in Consumption of Five or More Recommended Vegetable and Fruit Servings for Cancer Prevention, Adults 18 and Older, US,
The American Cancer Society recommends that individuals eat five or more servings of vegetables and fruits a day for cancer prevention. Fruit and vegetable consumption may protect against cancers of the mouth and pharynx, esophagus, lung, stomach, and colon and rectum. However, there has been little improvement in consumption since the mid-1990s. Less than one in four adults was eating the recommended servings in 2002.
Note: Data from participating states and the District of Columbia were aggregated to represent the United States.
Source: Behavioral Risk Factor Surveillance System CD-ROM ( , 1996, 1998) and Public Use Data Tape (2000), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 1997, 1999, 2000, 2001.

32. The War on Cancer 1971 State of Union address: December 23, 1971
President Nixon requested $100 million for cancer research
December 23, 1971
Nixon signed National Cancer Act into law
"I hope in years ahead we will look back on this action today as the most significant action taken during my Administration."

33. Change in the US Death Rates* by Cause, 1950 & 2001
Rate Per 100,000
1950
2001
Compared to the rate in 1950, the cancer death rate was 0.2% higher in 2001, while rates for other major chronic diseases decreased during this period.
Heart Diseases
Cerebrovascular Diseases
Pneumonia/ Influenza
Cancer
* Age-adjusted to 2000 US standard population.
Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.
2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3.

34. Cancer Death Rates*, for Men, US, 1930-2000
Rate Per 100,000
Lung
Stomach
Prostate
Colon & rectum
Most of the increase in cancer death rates for men prior to 1990 was attributable to lung cancer. However, since 1990, the age-adjusted lung cancer death rate in men has been decreasing. Stomach cancer mortality has decreased considerably since Death rates from prostate and colorectal cancers have also been declining.
Pancreas
Leukemia
Liver
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Public Use Data Tapes , US Mortality Volumes ,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2003.

35. Cancer Death Rates*, for Women, US, 1930-2000
Rate Per 100,000
Lung
Uterus
Breast
Currently, the lung cancer death rate in women is about two-and-a-half times what it was 25 years ago, and lung cancer is the most common cause of cancer death. In comparison, breast cancer death rates were virtually unchanged between 1930 and 1990, and have since decreased. The death rates for stomach and uterine cancers have decreased steadily since 1930; colorectal cancer death rates have been decreasing for over 50 years.
Colon & rectum
Stomach
Ovary
Pancreas
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Public Use Data Tapes , US Mortality Volumes ,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2003.

36. Cancer Incidence Rates* for Men, US, 1975-2000
Rate Per 100,000
Prostate
Lung
Colon and rectum
Prostate cancer incidence rates increased sharply from 1988 to 1992, after increasing steadily from 1975 to The short-lived surge in prostate cancer incidence most likely reflects the widespread introduction of the prostate-specific antigen (PSA) screening test in the late 1980s. Lung cancer incidence rates in men have declined in recent years, while rates for cancers of the colon & rectum have stabilized.
Urinary bladder
Non-Hodgkin lymphoma
*Age-adjusted to the 2000 US standard population.
Source: Surveillance, Epidemiology, and End Results Program, , Division of Cancer Control and
Population Sciences, National Cancer Institute, 2003.

37. Cancer Incidence Rates* for Women, US, 1975-2000
Rate Per 100,000
Breast
In women, the breast cancer incidence rate increased rapidly (approximately 4% per year) from 1980 to 1986 and then increased at a slower rate from 1986 through The apparent decrease in female breast cancer incidence in 2000 is likely due to delay in reporting. Lung cancer incidence rates have continued to increase, although the rate of increase has slowed since the early 1990s. Colorectal cancer incidence rates have leveled off since the mid 1990s. Incidence rates for uterine corpus cancer stabilized from 1998 to 2000, after a slight increase from 1988 to Ovarian cancer rates have decreased 0.7% per year from 1989 through 2000.
Colon & rectum
Lung
Uterine corpus
Ovary
*Age-adjusted to the 1970 US standard population.
Source: Surveillance, Epidemiology, and End Results Program, , Division of Cancer Control and
Population Sciences, National Cancer Institute, 2001.
*Age-adjusted to the 2000 US standard population.
Source: Surveillance, Epidemiology, and End Results Program, , Division of Cancer Control and
Population Sciences, National Cancer Institute, 2003.

38. Relative Survival* (%) during Three Time Periods by Cancer Site
All sites
Breast (female)
Colon & rectum
Leukemia
Lung & bronchus
Melanoma
Non-Hodgkin lymphoma
Ovary
Pancreas 3 3 4
Prostate
Urinary bladder
The survival rate for all cancers combined and for certain site-specific cancers have improved significantly since the 1970s, due, in part, to both earlier detection and advances in treatment. Survival rates markedly increased for cancers of the prostate, ovary, breast, colon & rectum, and for leukemia. With new treatment techniques and increased utilization of screening, there is hope for even greater improvements in the not-too-distant future.
*5-year relative survival rates based on follow up of patients through 2000.
Source: Surveillance, Epidemiology, and End Results Program, , Division of Cancer Control and
Population Sciences, National Cancer Institute, 2003.

39. Mission: National Cancer Institute
Eliminate suffering and death due to cancer by 2015
Budget Request 2004: $5,986,000

40. Importance of Early Detection
Five Year Relative Survival Rates

41. Screening Use of simple tests in a healthy population Goal:
Identify individuals who have disease, but do not yet have symptoms
Should be undertaken only when:
Effectiveness has been demonstrated
Resources are sufficient to cover target group
Facilities exist for confirming diagnoses
Facilities exist for treatment and follow-up
When disease prevalence is high enough to justify effort and costs of screening

42. Cancer Screening We routinely screen for 4 cancers:
Female breast cancer
Mammography
Cervical cancer
Pap smear
Prostate cancer
Serum PSA
Digital rectal examination
Colon and rectal cancer
Fecal occult blood
Flexible sigmoidoscopy, Colonoscopy

43. Screening Guidelines for the Early Detection of Breast Cancer, American Cancer Society 2003
Yearly mammograms are recommended starting at age 40 and continuing for as long as a woman is in good health.
A clinical breast exam should be part of a periodic health exam, about every three years for women in their 20s and 30s, and every year for women 40 and older.
Women should know how their breast normally feel and report any breast changes promptly to their health care providers. Breast self-exam is an option for women starting in their 20s.
Women at increased risk (e.g., family history, genetic tendency, past breast cancer) should talk with their doctors about the benefits and limitations of starting mammography screening earlier, having additional tests (i.e., breast ultrasound and MRI), or having more frequent exams.
The American Cancer Society states that women aged 40 and older should have an annual mammogram and clinical breast exam (CBE) as part of a periodic health exam. Women should know how their breasts normally feel and report any changes to their health care provider. A breast self-examination (BSE) is an option for women starting in their 20s.

44. Mammogram Prevalence (%), by Educational Attainment and Health Insurance Status, Women 40 and Older, US,
All women 40 and older
Women with less than a high school education
Women with no health insurance
The prevalence of women reporting a recent mammogram increased almost 25% from 50% in 1991 to 62% in During this time, mammogram utilization varied considerably by educational attainment. The prevalence of women with less than a high school education reporting a recent mammogram was approximately 10 percentage points lower than the prevalence for all women. Even more striking is that the prevalence for women with no health insurance is approximately 20 percentage points lower than the prevalence for all women.
* A mammogram within the past year. Note: Data from participating states and the District of Columbia were aggregated to represent the United States.
Source: Behavior Risk Factor Surveillance System CD-ROM ( , , 1998, 1999) and Public Use Data Tape (2000, 2002), National Centers for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention 1997, 1999, 2000, 2000, 2001,2003.

45. Screening Guidelines for the Early Detection of Colorectal Cancer, American Cancer Society 2003
Beginning at age 50, men and women should follow one of the following examination schedules:
A fecal occult blood test (FOBT) every year
A flexible sigmoidoscopy (FSIG) every five years
Annual fecal occult blood test and flexible sigmoidoscopy every five years*
A double-contrast barium enema every five years
A colonoscopy every ten years
*Combined testing is preferred over either annual FOBT, or FSIG every 5 years alone.
People who are at moderate or high risk for colorectal cancer should talk with a doctor about a different testing schedule
The American Cancer Society recommends that beginning at age 50, men and women should receive a fecal occult blood test (FOBT) every year, or a flexible sigmoidoscopy (FSIG) every five years, or an annual FOBT and FSIG every five years (preferred to either method alone), or a double-contrast barium enema every five years, or a colonoscopy every ten years.

46. Trends in Recent* Fecal Occult Blood Test Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US,
Despite an increase in FOBT use among both men and women from 1999 to 2002, prevalence remains low. Adults with less than a high school education are less likely to report a recent FOBT. Even more striking is that the prevalence for adults with no health insurance is approximately 10 percentage points lower than the prevalence for all adults.
*A fecal occult blood test within the past year. Note: Data from participating states and the District of Columbia were aggregated to represent the United States.
Source: Behavioral Risk Factor Surveillance System CD-ROM ( , 1999) and Public Use Data Tape (2001, 2002), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention and Prevention, 1999, 2000, 2002, 2003.

47. Trends in Recent* Flexible Sigmoidoscopy Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US,
Similar to the fecal occult blood test, the prevalence of flexible sigmoidoscopy (FSIG) or colonoscopy within the past five years, while low, increased from 1999 to Adults with less than a high school education were less likely to report FSIG or colonoscopy than all adults. Even more striking is that the prevalence for adults with no health insurance is approximately 15 percentage points lower than the prevalence for all adults. In addition to continuing efforts to increase breast and cervical cancer screening, heightened awareness and enhanced cancer control measures are greatly needed to improve the use of early detection methods for colorectal cancer.
*A flexible sigmoidoscopy or colonoscopy within the past five years. Note: Data from participating states and the District of Columbia were aggregated to represent the United States.
Source: Behavioral Risk Factor Surveillance System CD-ROM ( , 1999) and Public Use Data Tape (2001, 2002), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention and Prevention, 1999, 2000, 2002, 2003.

48. How do we judge efficacy of a screening test?
Sensitivity/Specificity
Positive/Negative Predictive Value

49. Screening for Diabetes
Questionnaire
Se=72-78%
Sp=50-51%
Capillary Blood Glucose
>140 mg/dL
Se=56-65%
Sp=95-96%
>120 mg/dL
Se=75-84%
Sp=86-90%

50. Sensitivity & Specificity
Probability that given DISEASE, patient tests POSITIVE
Ability to correctly detect disease
100% - False Negative Rate
Specificity
Probability that given NO DISEASE, patient tests NEGATIVE
Ability to avoid calling normal things disease
100% - False Positive Rate

51. Possible Test Results Test Positive Test Negative Disease Present TPFN
# with Disease = TP+FN
Disease Absent FP TN
#without Disease = FP+TN
# Test Pos = TP+FP
# Test Neg = FN+TN
Total Tested = TP+FN+FP+TN
Se = TP/(# with disease) = TP/(TP+FN)
Sp = TN/(# without disease) = TN/(TN+FP)

52. Amniocentesis Example
Procedure to detect abnormal fetal chromosomes
Efficacy:
1, year-old women given the test
28 children born with chromosomal abnormalities
32 amniocentesis test were positive, and of those 25 were truly positive
Calculate:
Sensitivity & Specificity

53. What Information Do You Want?
As a patient:
What Information Do You Want?

54. Predictive Value Positive Predictive Value Negative Predictive Value
Probability that given a POSITIVE test result, you have DISEASE
Ranges from 0-100%
Negative Predictive Value
Probability that given a NEGATIVE test result, you do NOT HAVE DISEASE
Depends on the prevalence of the disease

55. Possible Test Results Test Positive Test Negative Disease Present TPFN
# with Disease = TP+FN
Disease Absent FP TN
#without Disease = FP+TN
# Test Pos = TP+FP
# Test Neg = FN+TN
Total Tested = TP+FN+FP+TN
PPV = TP/(# Test Pos) = TP/(TP+FP)
NPV = TN/(# Test Neg) = TN/(FN+TN)

56. Amniocentesis Example
Procedure to detect abnormal fetal chromosomes
Efficacy:
1, year-old women given the test
28 children born with chromosomal abnormalities
32 amniocentesis test were positive, and of those 25 were truly positive
Calculate:
Positive & Negative Predictive Value

57. Dependence on Prevalence
Prevalence – is a disease common or rare?
p = (# with disease)/total #
p = (TP+FN)/(TP+FP+TN+FN)
Does our test accuracy depend on p?
Se/Sp do not depend on prevalence
PPV/NPV are highly dependent on prevalence
PPV = pSe/[pSe + (1-p)(1-Sp)]
NPV = (1-p)Sp/[(1-p)Sp + p(1-Se)]

58. Is it Hard to Screen for Rare Disease?
Amniocentesis:
Procedure to detect abnormal fetal chromosomes
Efficacy:
1, year-old women given the test
28 children born with chromosomal abnormalities
32 amniocentesis test were positive, and of those 25 were truly positive
Calculate:
Prevalence of chromosomal abnormalities

59. Is it Hard to Screen for Rare Disease?
Amniocentesis:
Usually offered to women > 35 yo
Efficacy:
1, year-old women given the test
Prevalence of chromosomal abnormalities is expected to be 2.8/1000
Calculate:
Sensitivity & Specificity
Positive & Negative Predictive Value
Suppose a 20 yo woman has a positive test. What is the likelihood that the fetus has a chromosomal abnormality?

60. Summary of Lecture 12 The burden of cancer How does cancer develop?
Contrasts between developed/developing world
How does cancer develop?
Cell transformation  Angiogenesis  Motility  Microinvasion  Embolism  Extravasation
Why is early detection so important?
Treat before cancer develops  Prevention
Accuracy of screening/detection tests
Se, Sp, PPV, NPV

61. Assignments Due Next Time
HW5
WA7