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

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?

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?

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

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

SAGE < 4 T0-T SAGE ≥4 291 with histology 370 without histology T0-T2 40

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) Natural history of potential celiac disease in children

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

3 cases diagnosed by SAGE score Case SAGE Total I22n.d. 4 II2n.d.114 III21104 Are you sure that all are celiac?

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

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

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

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

A patient wth a classic picture of CD

A first degree relative

In the general population

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

BiopsyNo. with TGAse level TGA se < 10 X N TGA se ≥ 10 X N Total M0-M M Total Histology according to TGAse level 10 x N (all centers) Sens. 58% Spec. 55% LR LR- 0.77

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: 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: 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: All these studies used a 100 AU cut-off

BiopsyNo. with TGAse level TGA se < 100 UA TGA se ≥ 100 UA Total M0-M2180 M Total Histology according to TGAse level 100 UA in 100 cases from Sicily

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 account revising the celiac disease diagnostic protocol

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?

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

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 Prospective study critical issues

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?

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

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?

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