1. OUTCOME EVALUATION AND COST-EFFECTIVENESS IN HEALTHCARE INDUSTRY Jung-Der Wang, M.D., Sc. D. National Taiwan University College of Public Health National Taiwan University Hospital

2. OUTLINES Introducing the needs and concepts of survival, quality of life (QOL), and quality- adjusted survival as final outcome indicators with QALY (quality-adjusted life year) as a common unit for risk/outcome evaluation and cost-effectiveness Extended to psychometric measurement for QOL and clinical decision making Integration with medical cost to the NHI Increased value for the spending of NHI (Cost-effectiveness)

3. No. articles in PubMed database with two specific key words

4. Evidence based medicine: There is no room for spending money on ineffective diagnosis and treatment for any medical condition. Quality assurance, safety, and efficacy for all medical managements. Find the real causes and effects for all studies and practices Minimize the cost and share with all colleagues

5. Redefining health care (2006) : by Michael Porter and Elizabeth Teisberg Value is the health outcomes per dollar spent in providing services. Outcomes are multidimensional, and include not only survival but extent of recovery or disability, errors, complications, recovery time, recurrences, and other aspects of the patient’s health experience. (Cost-effectiveness)

6. Healthcare reformed: Outcome-based pricing system McCain: Reform of Medicare to make bundled payments for episodes of care and to pay on the basis of outcomes Obama: Payment of providers on the basis of performance and outcomes ( Oberlander J. The Partisan Divide — The McCain and Obama Plans for U.S. Health Care Reform. New Engl J Med 2008:359: 781-4 )

7. What are the outcomes in health care industry? Exposure Internal dose => target organ dose Early biological indicators, e.g., blood pressure, HbA1c, creatinine, ALT, AST, cholesterol, A/G, chromosome aberration, sister chromatid exchange, etc. Impairment of organ-systems (hemiplegia, acute myocardial infarction, etc.) Functional disability (ADL, iADL, etc.) Change of quality of life or patient reported outcomes Survival vs. mortality

8. Why do we need to assess QOL and survival ? All the intermediate indicators (exposure, dose, early biological indicators, diagnosis of illness or impairment, functional disability, etc.) must be demonstrated to have direct link with these final outcome indicators: Change of quality of life or patient reported outcomes Survival vs. mortality

9. Significance of final outcome indicators Intermediate outcome indicators are useful for early proactive and/or reactive prevention of poor final outcomes All kinds of intermediate outcome indicators must validate or establish their relationships with the final outcomes, or, survival and quality of life and the combination of them Final outcome indicators provide evidence of evaluation for every healthcare products along the same metric

10. Preventive Measures (NEJM2008;358:661-3) Haemophilus influenzae type b vaccination of toddlers Cost-saving One-time colonoscopy screening for colorectal cancer in men 60-64yr of age Cost-saving Newborn screening for medium-chain acyl- coenzyme A dehydrogenase deficiency $160/QALY High-intensity smoking-relapse prevention program, as compared with a low-intensity program $190/QALY Intensive tobacco use prevention program for 7th and 8th graders $23,000/QALY

11. Treatments for Existing Conditions Cognitive-behavioral family intervention for patients with Alzheimer’s disease Cost-saving Cochlear implants in profoundly deaf children Cost-saving Combination antiretroviral therapy for HIV-infected patients $29,000/QALY Liver transplantation in patients with primary sclerosing cholangitis $41,000/QALY Implantation of cardioverter defibrillators in appropriate populations, compared with medical management alone $52,000/QALY

12. Environmental and Occupational Health Risk Assessment For sustainable development, we always want to reduce health risk or replace toxic substances by a less toxic compound. But how do you compare nephrotoxicity with hepatotoxicity? Procedures of risk assessment involve: Hazard identification  Exposure assessment  Dose-response function  Risk characterization  Can we compare different types of risks?

13. Cost-effectiveness is necessary to make the National Health Insurance more sustainable under limited resources –Priority is given from a high to a low cost per unit of benefit or health –How can we measure health ? –Is there any common unit in measuring health ?

14. A common question raised: Is there a common unit to measure both the survival and utility or psychometry of quality of life? Live vs. Dead ---- counting the no. of lives saved More delicate measures: --Length of survival S(t) or S(t i |x i ) --Quality of life Qol(t i |x i ) Can we measure S(t i |x i ) or Qol(t i |x i )? Can we develop a method to combine both? (Can we quantify the cost paid by the NHI? )

15. Summary Measures of Population Health WHO 2002  Concepts, Ethics, Measurement and Applications  Edited by Christopher J.L. Murray, Joshua A. Salomon, Colin D. Mathers and Alan D. Lopez http://www.who.int/publications/smph/en/

16. Comparative Quantification of Health Risks- WHO2004  Global and Regional Burden of Disease Attributable to Selected Major Risk Factors  Edited by Majid Ezzati, Alan D. Lopez, Anthony Rodgers and Christopher J.L. Murray http://www.who.int/publications/cra/en/

19. Estimated survival function, mean QOL and quality adjusted survival curve; The area under the QAS curve is the expected quality adjusted survival time (Hwang JS, et al Statistics in Medicine 1996;15:93-102)

20. Notation of a typical life table with added columns of QOL (quality of life) and QAST (quality adjusted survival time)

21. A more general model: x i :determinant(s) of S(survival) and U(utility) functions e.g. head injury, stroke,….., etc. Quality adjusted survival Qol(t| x i ): quality of life function (Wang JD. Basic principles and practical applications in epidemiological research. 2002)

22. Cost of illness approach: Human capital left over for determinant x i W A (t| x i ): work ability function Direct medical cost of determinant x i Cost(t| x i ): medical cost function

23. ILLUSTRATIVE EXAMPLES: How much utility of health (in QALY) does it cost for a case of end stage renal disease or liver cancer? --- Survival curve --- Quality of life estimation --- General population of Taiwan in 1995 as the reference population assuming QOL=1

24. Observed survival rates for the patients with HCC stratified by treatment groups GroupNo.Age of diagnosis Mean (SD) Median survival in mo (95% CI) Survival rate 6 mo 1 yr 3 yr Entire cohort 259957.8 (13.9) 11 (10 – 13) 48 (42 – 54) 16 (15 – 19) 3 (3 – 4) 60.7 % 48.2 % ~28 % Tx Surgical84657.3 (13.3)90.1 % 78.4 % ~58 % Medical*63061.3 (11.9) 72.8 % 58.5 % ~24 % Support- ive 112356.2 (14.9) 32.5 % 20.4 % ~8%

25. Utility measured by standard gamble (SG)

26. Shaded area =233.6 QALM loss due to liver cancer

27. Pit dug for washing underground soil and water

28. Table Concentration ranges of the tested volatile organic compounds (VOCs) in groundwater samples collected from 52 civilian wells around a closed electronics-manufacturing factory. Lee LJH, et al. (J Toxicol Environ Health 2002;65:219-35)

29. *MCLG: Maximum Contaminant Level Goal † MCL: Maximum Contaminant Level

30. RISK: LIKELIHOOD OF EVENT (Incidence rate or probability) X CONSEQUENCE OF EVENT (loss of utility due to the event) (need to establish a cohort to estimate)

31. Cancer risks based on RME (reasonable maximal exposure) and cancer slopes Vinyl chloride QALM 8.4 x 10 -6 (X 233.6.002 Tetrachloroethylene QALM) = 1.9 x 10 -4.044 Trichloroethylene 1.4 x 10 -4.032 IF there are 1000 people at risk, then the above numbers must be multiplied with 1,000

32. Extrapolation of survival under high censored rate: Semi-parametric modeling (Hwang & Wang 1999, Fang et al. 2007) H (t | patient) = H (t | reference) + constant excess hazard C1 logit W(t) = ln [exp (C0 – C1 × t)/(1 – exp (C0 – C1 × t))] = C0 – C1 × t – ln [1 – exp (C0 – C1 × t)] Because C1 > 0, the residual item ln [1 – exp (C0 – C1 × t)] will converge to 0 when t . As a result, when t , logit W(t) will approximate to C0 – C1 × t, which is a straight line with a slope of – C1. Total HazardBackground Hazard age- and gender-matched

33. AIDS group Non-AIDS group 3-year survival extrapolated to 6 years

35. Patients under hemodialysis adjusted for quality of life measured by standard gamble

36. Monthly cost (NT$) for hemodialysis

37. Lifetime cost (NT$) for hemodialysis Annual cost Discount rate Lifetime cost meanmedianmeanmedian Out patient clinic 476,553606,8000% 3,870,0844,927,820 2% 3,303,1394,205,923 4% 2,890,3983,680,375 Hospitalization 43,13324,6000% 350,279199,776 2% 298,965170,510 4% 261,608149,204 Total 422,863578,1000% 3,434,0734,694,748 2% 2,931,0014,006,994 4% 2,564,7603,506,303

38. Liver group Life expectancy : 3.45 years Loss of life expectancy : 15.61 years Health gap : 81.9%

39. Breast group Life expectancy : 20.01 years Loss of life expectancy : 9.35 years Health gap : 31.8%

40. 癌症種類人數估計損失壽命 估計健保資 源損失 * （千元 / 人） 口腔癌 6869 15.4 821.0 鼻咽癌 5547 17.2 665.6 食道癌 2936 12.4 582.2 胃癌 11938 7.9 977.5 大腸癌 16993 5.4 1,060.6 肝癌 16926 14.7 488.7 膽囊癌 1449 9.9 737.3 胰臟癌 2112 12.5 495.3 表 2 國人罹患一項癌症後將可能造成之預期壽命損失與 健保系統治療將給付之估計金額

41. 肺癌 16953 11.4 631.0 白血病 4197 17.5 3,707.1 皮膚癌 4130 0.9 519.2 乳房癌 10150 11.0 1,678.8 子宮頸癌 14964 5.8 1,232.9 卵巢癌 1910 11.5 1,846.3 前列腺癌 2948 1.6 644.7 膀胱癌 4490 2.8 687.5 腎臟癌 3172 6.2710.2 * 預估在 4 ％醫療服務膨脹率下，以 2 ％折現率之折現值。

42. WHOQOL (World Health Organization Quality of Life Questionnaire): Concepts: Individual perception of their position in life in the context of culture and value systems in which they live and in relation to their goals, expectations, standards and concerns

43. WHOQOL (continued): WHOQOL-BREF (24 facets, 4 domains, 26 questions) physical psychological cross-culturally socialconsistent environmental

44. Domains and facets of Taiwan version of WHOQOL questionnaire (Facet 25 and 26 are new ones developed from Taiwan version) Overall quality of life and health Physical Domain F 1. pain and discomfort F 2. energy and fatigue F 3. sleep and rest F 9. mobility F10. activity of daily living F11. dependance on medicine treatment F12. working capacity

45. Domains and facets of Taiwan version of WHOQOL questionnaire (continued) Psychological Domain F 4. positive feeling F 5. thinking, learning, memory and concentration F 6. self-esteem F 7. bodily image and appearance F 8. negative feelings F24. spirituality/religion/personal beliefs

46. Domains and facets of Taiwan version of WHOQOL questionnaire (continued): Social Relationships F13. personal relationships F14. social support F15. sexual activity F25. be respected/be accepted

47. Domains and facets of Taiwan version of WHOQOL questionnaire (continued): Environmental Domain F16. physical safety and security F17. home environment F18. financial resources F19. health and social care: availability and quality F20. opportunities for acquiring new information and skills

48. Domains and facets of Taiwan version of WHOQOL questionnaire (continued): Environmental Domain (continued) F21. participation in and opportunities for recreation /leisure F22. physical environment: (pollution/noise/traffic/climate) F23. transport F26. dietary

49. DomainFacets Epilepsy (yes/no) Frequency of seizure MarriageCo- morbid Environ -ment Health and social care 0.32** (0.06) Financial resources 0.22* (0.08)−0.017** (0.006) Participation in recreation −0.014* (0.006) −0.30* (0.12) Opportunities for new skills −0.017** (0.005) Physical safety and security −0.013* (0.006) −0.28* (0.11) Social Personal relationships −0.30** (0.07) −0.014* (0.005) 0.21** (0.06) −0.23* (0.10) Being respected−0.27** (0.06) −0.010* (0.005) 0.23** (0.06) Sexual activity−0.24** (0.07) 0.47** (0.08) * p < 0.05 ** p < 0.005 Quality of life of epilepsy patients (Liu HH, et al. Epilepsy Res 2005)

50. DomainFacetsBMI (25–32) BMI (32–35) BMI (35–40) BMI (>40) Employ -ment PhysicalPain and discomfort −0.33* (0.14) Energy and fatigue −0.37* (0.19) −0.57** (0.18) −0.56** (0.11) Sleep and rest−0.51* (0.22) −0.51** (0.20) −0.64** (0.12) Psychol- ogical Thinking & concentration −0.60** (0.21) −0.69** (0.20) −0.53** (0.12) 0.43** (0.11) Self-esteem−0.59** (0.20) −0.54** (0.18) −0.84** (0.11) 0.32** (0.10) Body image & appearance −1.13** (0.21) −1.32** (0.20) −1.35** (0.12) Sexual activity−0.47* (0.18) −0.43** (0.17) −0.54** (0.10) 0.24** (0.09) Being respected −0.52** (0.18) −0.41** (0.11) 0.36** (0.10) * p < 0.05 ** p < 0.005 Quality of life in obese patients ( Chang CY et al. Obesity Surg 2008)

51. EXTENSION TO HEALTH PROFILE (PSYCHOMETRIC SCORE) Consequence of the event can be replaced by QOL measured by psychometrics Hwang JS, Wang JD. Quality of Life Research 2004; 13:1-10

52. Psychometric mean score The sum of scores of those who are still alive plus those who die The following simple equation establishes the relationship between population mean QoL score function and survival function, where Q s (t) is the average QOL of surviving subjects at time t

53. Estimations The estimate of expected psychometric score-adjusted survival (PAS) for an index population, is obtained by firstly estimating and at chosen time points ’s

54. Survival-weighted Health Profile in Long-term Survivors of Acute Myelogenous Leukemia (AML) Chiun Hsu 1, Jung-Der Wang 1, Jing-Shiang Hwang 2, and Jih-Luh Tang 1 National Taiwan University Hospital 1 Academia Sinica 2 Taipei, Taiwan (Quality of Life Research 2003 ;12:503-517)

55. Comparison of life time psychometric Scores for BMT and chemotherapy (WHOQOL generic instrument)

56. Comparison of life time psychometric scores for BMT and chemotherapy (WHOQOL generic measurement)

57. Comparison of life time psychometric scores for BMT and chemotherapy (EORTC cancer specific instrument)

58. Comparison of life time psychometric scores for BMT and chemotherapy (EORTC cancer specific instrument)

59. Comparison of life time psychometric scores for BMT and chemotherapy (EORTC cancer specific instrument)

60. HOW MUCH DOES IT COST FOR A UNIT OF SCORE-TIME? Through questioning 157 patients with disability caused by occupational injury under contingent valuation method or stated preference, we found that people are willing to pay US$ 65.1-69.6 for a pain- killer pill that can remove pain for 24 hours. Ho JJ, et al. et al. (monetary value of score time) Accident Analysis & Prevention 2005;37:537-48 The WTP money for removing a longer duration of pain is even bigger

61. Conclusion: for outcome/risk assessment in health and medicine The QALY or life year gained or loss plus the psychometric score time can be estimated for comparative assessment of health risks/outcomes in national health resources allocation and clinical decision makings (and for cost-effectiveness analysis). Measurements of QOL had better be improved to an interval scale.

62. Life-time utility (Economist) 經濟學家：終生預期效用 survival function 人命 ( 存活函數 ) utility function --HRQL( 健康相關生活品質 ) --working ability, wages, medical costs 工作能力、薪資、醫療費用 Quality-adjusted life expectancy or healthy life expectancy ( 生活品質調整後預期壽命 )

64. Hwang JS, Tsauo JY, Wang JD. (theory of QAS) Stat Med 1996;15:93-102 Hwang JS, Wang JD. (QAS extrapolation to lifetime) Stat Med 1999;18:1627-40 Tsauo JY, et al. (Utility of enforcement of helmet law) Accident Anal Prev 1999;31:253-63 Yao KP, et al. (WHOQOL-BREF Taiwan version) J Formos Med Assoc 2002;101:342-51 Lee LJH, et al. (Risk assessment for water pollution) J Toxicol Environ Health 2002;65:219-35 Hwang JS, Wang JD (extended to psychometry) Quality Life Res 2004; 13:1-10 Hsu J, et al. (bone marrow transplantation for leukemia) Qual Life Res 2003 ;12:503-517 Chuang HY, et al. (occupational health policy for lead) J Toxicol Environ Health 2005; 68:1485- 96. Ho JJ, et al. (monetary value of score time) Accident Anal Prev 2005;37:537-48. Ho JJ, et al. (survival of occupational disability) Scand J Work Environ Health 2006; 32(2):91-98. Ho WL, et al. (survival and cost of thalassemia) Bone Marrow Transplant 2006; 37(6):569-574. Ho JJ, et al. Estimation of reduced life expectancy. Accident Anal Prev 2006; 38:961-968. Fang CT et al. (Life expectancy of patients with HIV/AIDS). Quarterly J Med 2007; 100:97-105. Fang CT et al. (Cost-effectiveness for HAART policy) J Formos Med Assoc 2007; 106(8):631 – 640 Chu PC et al. (Lifetime financial burden to the National Health Insurance for 17 different cancer in Taiwan) J Formos Med Assoc 2008; 107:54-63 Chu PC et al. (Life expectancy and loss of life expectancy for major cancer in Taiwan) Value in Health 2008; in press Chang CY et al (Quality of life in obese patients) Obesity Surg 2008; in press

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66. Lung group Life expectancy : 3.09 years Loss of life expectancy : 11.79 years Health gap : 79.2%

67. AIDS group Life expectancy : 10.61 years Loss of life expectancy : 23.12 years Health gap : 68.5%

68. HIV group Life expectancy : 21.53 years Loss of life expectancy : 17.31 years Health gap : 44.6%

69. Oral cavity group Life expectancy : 9.58 years Loss of life expectancy : 14.00 years Health gap : 59.4%

70. Nasopharynx group Life expectancy : 12.59 years Loss of life expectancy : 14.89 years Health gap : 54.2%

71. Esophagus group Life expectancy : 3.54 years Loss of life expectancy : 13.25 years Health gap : 78.9%

72. Stomach group Life expectancy : 7.51 years Loss of life expectancy : 8.80 years Health gap : 54.0%

73. Gallbladder & Extrahepatic bile duct group Life expectancy : 4.98 years Loss of life expectancy : 10.36 years Health gap : 67.5%

74. Pancreas group Life expectancy : 2.81 years Loss of life expectancy : 12.87 years Health gap : 82.1%

75. Leukemia group Life expectancy : 11.61 years Loss of life expectancy : 19.34 years Health gap : 62.5%

76. Cervix uteri group Life expectancy : 19.77 years Loss of life expectancy : 6.18 years Health gap : 23.8%

77. Ovary group Life expectancy : 17.71 years Loss of life expectancy : 11.91 years Health gap : 40.2%

78. Prostate group Life expectancy : 8.17 years Loss of life expectancy : 1.72 years Health gap : 17.4%

79. Urinary Bladder group Life expectancy : 10.99 years Loss of life expectancy : 3.83 years Health gap : 25.8%

80. Kidney group Life expectancy : 10.97 years Loss of life expectancy : 6.74 years Health gap : 38.1%

81. Skin group Life expectancy : 16.16 years Loss of life expectancy : 1.59 years Health gap : 9.0%

82. Colon & Rectum group Life expectancy : 10.86 years Loss of life expectancy : 6.36 years Health gap : 36.9%