1. Raanan Shamir, MD Cost Effectiveness of Population Screening 15.9.2010

2. Screening-WHO Definition An investigation whereby:  a simple test is applied to  an asymptomatic population  without consulting a health care system in order to identify a disease.

3. Mass screening  Celiac disease fulfils all requirements for a mass screening program:  It is common  Specific screening tests are available  Definite treatment (gluten-free diet) is available  If unrecognized, morbidity and complications may ensue.

4. However…  Most available data about the epidemiology of CD is derived from studies in symptomatic patients  GFD is not easy to maintain and may constitute a cumbersome lifestyle  There is a paucity of data on the cost–effectiveness (CE) of CD screening

6.  On GFD IgA and IgG TTG decreased significantly over 12 months  About 25% admitted sub optimal compliance on social occasions explaining the continuing (although low) positivity in 8/28 subjects after 18 months

7.  Prevalence of CD is high in Italian schoolchildren.  2/3 of cases were asymptomatic.  Acceptance of the program was good, as was dietary compliance.  Given the high prevalence and possible complications of untreated CD, mass screening deserves careful consideration. Tommasini A, et al. Arch Dis Child 2004

8. Med Desc Making 2006;26:1-12

9. Methods  We developed a state-transition Markov model, from a societal perspective, to evaluate whether it is cost effective to screen the entire population at the age of 18 years (range 6-30 years), for CD.  Since the model uses values that can vary between studies and countries, the influence of establishing a certain value on the model was examined using the sensitivity analysis (examining the model within the range of preset values).

10. Markov Model for CD Screening Unknown CD No CD Known CD no GFD Known CD Strict diet Dead

11. Methods (Cont.)  Effectiveness was measured by life expectancy in each strategy (TTG, EMA, IgA and AGA IgA combinations).  We calculated the incremental average cost-effectiveness (CE) ratio for each strategy (additional expected cost divided by additional expected effectiveness) compared with the next least expensive strategy.

12. Costs  We considered only direct health care costs, representing the average payments for each coded procedure based on the 2004 Medicare Fee Schedule (http://www.hgsa.com/professionals/feedb- 2004.shtml)http://www.hgsa.com/professionals/feedb- 2004.shtml  The cost of biopsy includes additional average costs of endoscopy and its complications (bleeding, perforations, death)  The costs of evaluation of symptoms include the following: Physician’s visits, laboratory tests (two physicians visits, complete blood count, chemistry panel, CD serology), and endoscopy that is mandatory for the diagnosis of CD

13. Cost values in $

14. Results All screening strategies resulted in life year saving and reductions in mortality related to CD Base-case analysis at an annual discount rate of 3% revealed a US$ 49,491 per life-year gained for screening compared to no screening using the EMA strategy

15. ICER as a function of prevalence

16. ICER as a function of SMR in CD

17. Conclusions (1)  Mass screening would be CE in populations with a high prevalence of CD, over a wide range of ages at screening, assuming that the mortality rate is higher in undiagnosed CD, and that implementing and adhering to a GFD in cases diagnosed by screening reduces the mortality rate

18. Conclusions (2)  From a CE perspective, EMA is the best serological marker for mass screening for CD  Due to the uncertainties regarding the validity of our assumptions, screening for CD would be justified only if these assumptions are proved to be correct

19.  To determine the CE of mass screening within the young adult population for CD  To document the changes in quality of life produced by CD screening  To define the parameters constituting the highest impact on the CE T. Hershcovici 1 M. Leshno, E. Goldin, E. Israeli & R. Shamir. Aliment Pharmacol Ther 2010;31:901-10 Mass screening, the 2010 Update

20. METHODS  Design: State transition Markov model  Perspective: Third-party payer  Interventions: CD screening compared to a no-screening strategy  Outcome Measures:  Quality Adjusted Life Years (QALYs)  Incremental Cost-Effectiveness Rate (ICER)

21. Positive Serology IBS IDA Morbidity Mortality QALYs SMR LatentSilentOvert % over time Screening GFD QALYs

22. Strategy Cost (US$)QALYs ICER (US$/QALYs) No Screening24.9426.9031 Screening158.64 26.9057* 48.960 * The screening strategy resulted in a gain of 0.0027 QALYs. Results

23. Parameters with Significant Influence on ICER  Time delay to CD diagnosis  Utility of CD patients adhering to GFD  Prevalence of CD

24. Screening would be CE if the time delay to diagnosis is longer than 6 years, and utility of GFD adherence is greater than 0.978.

25. Two-Way Sensitivity Analysis Screening is not CE for a time delay less than 3.5 years independent from CD prevalence* Screening is not CE for a time delay less than 5.2 years independent from the utility of adherence to GFD* *ICER=50,000US$/QALY

26.  Our model suggests that mass screening for CD of the young-adult general population is associated with improved QALYs and is a cost effectiveness strategy  However: Shortening of the time delay to diagnosis by heightened awareness of health-care professionals may be a valid alternative to screening Conclusions

28. Base-case values and ranges used in sensitivity analysis

29. Parameters that do not Influence ICER Significantly  Adherence to GFD  Probability to suffer of IDA or IBS-like symptoms  The utility of IDA or IBS-like symptoms  Cost of endoscopic biopsy and of serologic testing  Standardized Mortality Rate

31. Screening for Celiac Disease-Justified?  CD is the most common food-based disease  Clinically based early diagnosis is difficult and is frequently delayed**  There are diagnostic serologic tests that are both specific and sensitive and can be applied to a large population**  Undiagnosed patients remain at risk for complications  A gluten-free diet (GFD) relieves symptoms and decreases morbidity and mortality

32.  Perform CD screening in high-risk conditions associated with increased prevalence of disease  Mass-screening for CD remains controversial CD Screening-Recommendations Gastroenterology 2005;128:S104

33. Markov Model – No-Screening Arm

34. Markov Model–Screening Arm

35. Acceptability Curve  For a willingness to pay of US$50,000/QALYs, the probability that CD screening is CE is 60%

36. Mortality SMR No Screening IBS IDA Morbidity QALYs Celiac Disease GFD LatentSilentOvert Percentage over time

37. Base–Case Analysis: Estimation of Parameters  Prevalence of CD in the general population: 1%  Standardized Mortality Rate (SMR):  Untreated CD patients: 1.6  CD patients on GFD: 1.1  Average time delay to CD diagnosis from onset of symptoms: 6 years

38. Base–Case Analysis: Estimation of Parameters  Compliance to GFD:  Symptomatic CD patients: 82% at 10 years  Asymptomatic CD patients: 60% at 10 years  Utility of GFD: 0.98

39. Base–Case Analysis: Estimation of Parameters Sensitivity of IgA anti-tTG : 95% Specificity IgA anti-tTG :98% Sensitivity of IgG anti-tTG* :98.7% Specificity IgG anti-tTG* :98.6% *in IgA deficient patient

40. Base–Case Analysis: Estimation of Parameters  Annual probability to develop symptoms in asymptomatic CD patient:2.8%  Prevalence of symptoms in CD patients:  IBS-like symptoms: 30%  Iron-deficiency anemia: 50%  Utility of symptoms :  IBS-like symptoms: 0.73  Iron-deficiency anemia: 0.76

41. Sensitivity Analysis on Prevalence of CD  Screening remained cost-effective for a CD prevalence range between 0.875-2%.

42. Sensitivity Analysis on Time Delay to CD diagnosis  For a time delay of less than 5.9 years, screening for CD is not cost-effective.

43. Sensitivity Analysis on Utility of Adherence to GFD  For utility of adherence to GFD between 0.95-0.978, screening for CD is not cost-effective.  For an estimated utility less than 0.95, the no-screening strategy becomes dominant.

44. Sensitivity Analysis on SMR  A SMR between 1.2-2.7 for symptomatic CD patients had no major effect on ICER.

45. Developed a case-finding strategy based on testing for TTG IgA antibodies in subjects showing predefined signs and symptoms or belonging to at-risk groups. 69 primary care doctors and 60 primary care paediatricians agreed to participate. 1041 adults and 447 children were selected for TTG-Ab testing during the year of the study (2001).

46. Berti I, et al. Case-finding startegy, 2006

47. 31 subjects (2.08%, 19 adults and 12 children) were ultimately diagnosed as CD, while no cases of coeliac disease had been diagnosed by the participating doctors in the previous year, 29 subjects were diagnosed as coeliacs in the year after the completion of the study (2002). The prevalence of confirmed CD in the population under study increased from 1:1506 to 1:1073 in adults and from 1:827 to 1:687 in children from year 2000 to 2001. When cases diagnosed in 2002 are included, the prevalence is 1:832 and 1:602, respectively.

48. Berti I, et al. Case-finding startegy, 2006 Conclusions Case-finding is a feasible and successful strategy for detecting undiagnosed CD patients and has the important added value of increasing the awareness of the disease among primary care physicians It represents a cost-effective alternative to population screening for reducing the burden of undiagnosed CD