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 Pointof-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 Pointof-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 pretest probability
744
83 SAGE < 4
T0-T2 61
661 SAGE ≥4
291 with histology
370 without
histology
T0-T2 40
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 twoyear follow-up (Clin Gastroenterol Hepatol 2011;9:320-5)
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 pretest probability
3 cases diagnosed by SAGE
score
Case
S
A
G
E
Total
I
2
2
n.d.
n.d.
4
II
2
n.d.
1
1
4
III
2
1
1
0
4
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 pretest 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
Histology according to TGAse level 10 x N
(all centers)
Biopsy
No. with TGAse level
TGAse < 10 TGAse ≥ 10 X
XN
N
Total
M0-M2
49
40
89
M3
255
346
601
304
386
690
Total
Sens. 58% Spec. 55% LR+ 1.28 LR- 0.77
Why was “10xN” chosen as cutoff in SAGE?
• Barker CC, Mitton C, Jevon G, et al . Can tissue
transglutaminase antibody titers replace smallbowel 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
Histology according to TGAse level 100 UA in
100 cases from Sicily
Biopsy
No. with TGAse level
TGAse <
100 UA
M0-M2
18
TGAse ≥
100 UA
0
Total
18
M3
56
26
82
Total
74
26
100
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 Pointof-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 noninvasive 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 pretest probability
• Definition of cases by the web-database
• To build a new diagnostic score and
protocol through a prospective study
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
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 Pointof-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 Pointof-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