The near future, applications and activities G. Magazzù and L. Greco

1. The near future, applications and activitiesG. Magazzù and L. Greco

2. OUTLINE • Relevance and limits of the retrospective study • Importance of prospective studies which could also represent an opportunity “unique” for critically revising ESPGHAN criteria • Is useful to preliminarily perform the Point-of-care study in a setting with the same characteristics of the setting foreseen by the study but where it is easier to monitor all variables? • Is useful to perform studies of comparison between case finding vs screening for increasing CD diagnosis in order to detect the most cost/effective strategy for different countries and settings?

3. OUTLINE • Relevance and limits of the retrospective study • Importance of prospective studies which could also represent an opportunity “unique” for critically revising ESPGHAN criteria • Is useful to preliminarily perform the Point-of-care study in a setting with the same characteristics of the setting foreseen by the study but where it is easier to monitor all variables? • Is useful to perform studies of comparison between case finding vs screening for increasing CD diagnosis in order to detect the most cost/effective strategy for different countries and settings?

4. Retrospective study relevance • Diagnosis without biopsy in 370/661 (49.7%) • HLA can contribute to diagnosis if always and everywhere performed • SAGE allows the diagnosis even without serology and in absence of villus atrophy • most cases are symptomatic and the majority still show classical symptoms and therefore they have a high pre-test probability

5. Retrospective study limits • Diagnosis without biopsy in 370/661 (49.7%) • HLA can contribute to diagnosis if always and everywhere performed • SAGE allows the diagnosis even without serology and in absence of villus atrophy • most cases are symptomatic and the majority still show classical symptoms and therefore they have a high pre-test probability

7. Natural history of potential celiac disease in children Out of the patients who continued a gluten containing diet 15% developed villus atrophy and 15% normalized serology in a two-year follow-up (Clin Gastroenterol Hepatol 2011;9:320-5)

8. Retrospective study limits • Diagnosis without biopsy in 370/661 (49.7%) • HLA can contribute to diagnosis if always and everywhere performed • SAGE allows the diagnosis even without serology and in absence of villus atrophy • most cases are symptomatic and the majority still show classical symptoms and therefore they have a high pre-test probability

9. 3 cases diagnosed by SAGE score Are you sure that all are celiac?

10. Retrospective study limits • Diagnosis without biopsy in 370/661 (49.7%) • HLA can contribute to diagnosis if always and everywhere performed • SAGE allows the diagnosis even without serology and in absence of villus atrophy • most cases are symptomatic and the majority still show classical symptoms and therefore they have a high pre-test probability

11. How to calculate the post-test probability • Let’s calculate the Likelihood ratio (LR) positive (when the test is positive) and negative (when the test results negative) • Let’s apply LR to the pre-test probability of the subject

12. Let’s define the Likelihood ratio • The likelihood that a given test result would be expected in a patient with the target disorder compared with the likelihood that the same result would be expected in a patient without the target disorder. • LRpos = sensitivity / (1 - specificity) • LRneg = (1 - sensitivity) / specificity

13. Let’s apply LR to the pre-test probability of the subject

14. A patient wth a classic picture of CD

15. A first degree relative

16. In the general population

17. Let’s define the Likelihood ratio • The likelihood that a given test result would be expected in a patient with the target disorder compared with the likelihood that the same result would be expected in a patient without the target disorder. • LRpos = sensitivity / (1 - specificity) • LRneg = (1 - sensitivity) / specificity

18. Histology according to TGAse level 10 x N (all centers) Sens. 58% Spec. 55% LR+ 1.28 LR- 0.77

19. Why was “10xN” chosen as cut-off in SAGE? • Barker CC, Mitton C, Jevon G, et al . Can tissue transglutaminase antibody titers replace small-bowel biopsy to diagnose celiac disease in select pediatric populations? Pediatrics 2005;115:1341-6. • Donaldson MR, Firth SD, Wimpee H, et al. Correlation of duodenal histology with tissue transglutaminase and endomysial antibody levels in pediatric celiac disease. Clin Gastroenterol Hepatol 2007;5:567-73. • Donaldson MR, Book LS, Leiferman KM, et al. Strongly positive tissue transglutaminase antibodies are associated with Marsh 3 histopathology in adult and pediatric celiac disease. J Clin Gastroenterol 2008;42:256-60. • All these studies used a 100 AU cut-off

20. Histology according to TGAse level 100 UA in 100 cases from Sicily

21. Summing up • We need to validate SAGE score before applying it in different settings, assigning a different weight to the four items • Serology needs revision and standardization • The positive predictive value of serology and HLA-typing combination should be defined • Potential celiac disease is not negligible and should be taken into accountrevising the celiac disease diagnostic protocol

22. OUTLINE • Relevance and limits of the retrospective study • Importance of prospective studies which could also represent an opportunity “unique” for critically revising ESPGHAN criteria • Is useful to preliminarily perform the Point-of-care study in a setting with the same characteristics of the setting foreseen by the study but where it is easier to monitor all variables? • Is useful to perform studies of comparison between case finding vs screening for increasing CD diagnosis in order to detect the most cost/effective strategy for different countries and settings?

23. Prospective study critical issues • To define the diagnostic accuracy of non-invasive tests which can avoid in some cases intestinal biopsy • Standardization of serology • To overcome selection and self-fulfilling prophecy bias • Apply gold standard regardless of serological tests in all cases with high pre-test probability • Definition of cases by the web-database • To build a new diagnostic score and protocol through a prospective study

24. Prospective study critical issues • POCT could be very useful in peripheral villages or town far from hospital and/or laboratories where EMA and TGA are available • It should be validated likely (and together with) to conventional serology

25. OUTLINE • Relevance and limits of the retrospective study • Importance of prospective studies which could also represent an opportunity “unique” for critically revising ESPGHAN criteria • Is useful to preliminarily perform the Point-of-care study in a setting with the same characteristics of the setting foreseen by the study but where it is easier to monitor all variables? • Is useful to perform studies of comparison between case finding vs screening for increasing CD diagnosis in order to detect the most cost/effective strategy for different countries and settings?

26. Average prevalence of Celiac Disease got by different strategies • 0.6%-1.3% in blod donors • 0.3-1% in the general population • 0.12% in case finding studies Case finding is precious for increasing awareness of health operators for CD but it could not bridge the diagnostic gap

27. OUTLINE • Relevance and limits of the retrospective study • Importance of prospective studies which could also represent an opportunity “unique” for critically revising ESPGHAN criteria • Is useful to preliminarily perform the Point-of-care study in a setting with the same characteristics of the setting foreseen by the study but where it is easier to monitor all variables? • Is useful to perform studies of comparison between case finding vs screening for increasing CD diagnosis in order to detect the most cost/effective strategy for different countries and settings?

28. The role of Sicily in the MEDICEL project • Available an already established regional network • Involvement of Regional Government to facilitate project financing • Involvement of an already established organization for cooperation in the Mediterranean area • Involvement of patient Association (AIC – Sicilia onlus) for fund raising