J7ournal of Epidemiology and Community Health 1996;50:299-305

Estimating the incidence of coeliac disease withcapture-recapture methods within fourgeographic areas in Italy

G Corrao, P Usai, G Galatola, N Ansaldi, A Meini, M A Pelli, G Castellucci,G R Corazza and the Working Group of the Italian "Club del Tenue"

Institute of Statisticaland MathematicalSciences, University ofMilan, ItalyG Corrao

Department ofMedicine, Universityof Cagliari, ItalyP Usai

Division ofGastroenterology,Ospedale MaurizianoUmberto I, Turin,ItalyG Galatola

Department ofPaediatrics, Universityof Turin, ItalyN Ansaldi

Department ofPaediatrics, Universityof Brescia, ItalyA Meini

Department ofGastroenterology,University of Perugia,ItalyM A Pelli

Department ofPaediatrics, Universityof Perugia, ItalyG Castellucci

Department ofInternal Medicine,University of L'Aquila,ItalyG R Corazza

Correspondence to:Prof G Corrao,Chair of Medical Statisticsand Epidemiology,Institute of Statistical andMathematical Sciences"Marcello Boldrini",University of Milan,Via Conservatorio 7Milano, Italy

Accepted for publicationOctober 1995

AbstractStudy objective - To estimate the incidencerate of newly diagnosed cases of coeliacdisease in Italy.Design - This was a descriptive study ofcoeliac disease incidence in the period1990-91.Setting - During 1990-91 newly diagnosedcases of coeliac disease were signalled byseveral sources including diagnosticrecords of departments of paediatrics,general medicine and gastroenterology,national health service records for the sup-ply of gluten free diets and the archives ofthe Italian Coeliac Society.Patients - Altogether 1475 cases were

flagged throughout Italy, 478 ofwhom wereselected, corresponding to 270 individualpatients from a target population residentin four areas: Provices ofTurin and Cuneo(Piedmont Region, northern Italy); Prov-ince ofBrescia (Lombardia Region, north-ern Italy); Umbria Region (central Italy)and Sardinia Region (insular Italy). Onlyfor these areas were patients flagged fromseveral sources and the reference popu-lation was identifiable.Main results - The overall crude incidencerates for all ages per 100 000 residents peryear were 2-4, 2-7, 1-5, and 1*7 in the fourareas, respectively. The childhood cumul-ative incidence rates (aged < 15 years) per100000 live births were 143, 141, 72, and80 respectively. Themean ages at diagnosiswere similar for both childhood and adultcases throughout the areas - these werearound 4 and 34 years respectively. Foreach area, the incidence rate was con-

stantly higher in the main city thanelsewhere. Using the capture-recapturemethod, an estimated completeness ofcase archives of0-84 was obtained, whereasthis figure was only 0*47 for hospitalsources.

Conclusions - This population based studyon the incidence of coeliac disease showsthat several information sources should beused to avoid underestimation. The in-cidence rate of coeliac disease in Italy wasamong the highest in Europe, and was

widely variable showing highest figures in

Piedmont and Lombardia and the lowestin Umbria and Sardinia. This trend was

not due to different age at diagnosis, whichsuggests variable diagnostic awareness

of the disease rather than different en-vironmental patterns affecting the clinicalpresentation.

(J7 Epidemiol Community Health 1996;50:299-305)

Although coeliac disease (CD) is a health prob-lem that carries an increased risk ofmalignancy,epidemiological data concerning its incidenceare still incomplete. High frequencies of clin-ically manifest disease in children have beenreported from western Ireland' and Sweden,2whereas the lowest reported childhood in-cidence rates come from Finland3 and Den-mark.4 No information is available from theUnited States of America5 and few reports areavailable for Mediterranean countries." Thisepidemiological information is valuable as ithelps to improve understanding of aetiologicalfactors and the implementation of health pro-grammes aiming towards better recognitionand treatment of the disease.9

In the past two decades the timing of diag-nosis has gradually moved towards adulthood'0because of an increasing recognition of atypicaland subclinical cases." Nonetheless, the in-cidence of CD has been assessed, with a fewexceptions, '2-4 only in children.

Epidemiological evidence of different geo-graphical and/or temporal variability in the in-cidence of CD is difficult to interpret. This isbecause of wide variability in clinical aware-ness,'5 endoscopic duodenal biopsy,'6 and im-plementation of serological screening.'7 More-over, in the absence of a national register ofthe disease, several information sources shouldbe used to measure incidence, since the use ofsingle sources such as death certificates, CDsocieties, or hospital records have been shownto yield a quarter of the actual cases.'8These considerations prompted us to con-

stitute a working group within the Italian As-sociation for the Study ofSmall Bowel Diseases("Club del Tenue"), with the aim of assessingthe incidence of newly diagnosed cases of coel-iac disease in Italy. This paper reports theresults of the study for four well defined geo-graphic areas.

MethodsCATCHMENT AREASThe overall number of CD cases flagged by allparticipating centres was 1475. We selectedonly those areas where flagging satisfied thecriteria indicated below in "data collection".

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Corrao, Usai, Galatola, Ansaldi, Meini, Pelli, Castellucci, Corazza

Thus, the study includes cases of CD newlydiagnosed between 1 January 1990 and 31December 1991 in the resident population offour Italian areas: the provinces of Turin andCuneo (Piedmont Region), the Province ofBrescia (Lombardia Region), the Umbria Re-gion, and the Sardinia Region. In these areas,according to the 1991 Italian population censusthe resident population was 6 339 194 (11 0%of the whole Italian population) and 1 07 048live births were recorded during the studyperiod (9 4% of all live births in Italy).

DATA COLLECTIONCD patients were identified from four differentinformation sources:* Diagnostic lists of paediatric, general medi-cine and gastroenterology departments of hos-pitals in the study areas;* Diagnostic lists of leading Italian hospitalslikely to attract CD patients throughout thecountry;* National health service records of patientsfor whom gluten free food was provided on thebasis of histological evidence of CD;* Archives of the local branches of the ItalianCoeliac Society.Data of patients entered for the first time

during the study period were independentlycollected from each of the four sources con-sidered. Details included surname, name, dateof birth, date of first diagnosis, birthplace, andresidence area. Flagging archives were thusobtained where individual patients were ex-pected to be reported more than once, in-dicating flagging from multiple sources. Recordlinkage by surname, name, gender, and date ofbirth allowed us to build archives of newlydiagnosed cases of CD during the study. Weexcluded from the study patients whose namereappeared in the records after interruption oftheir gluten free diet and patients who werealready present in the national health serviceor Italian Coeliac Society records in the yearspreceding the study period (prevalent cases),in whom the diagnosis had therefore alreadybeen made. In order to calculate the incidenceof new cases within the selected geographicalareas, patients diagnosed within these areas butresident elsewhere were also excluded.

EVALUATING DIAGNOSTIC APPROACHThe diagnosis of CD for all patients includedin the study was performed by retrospectiveexamination of data collected routinely in thehospitals where the diagnoses were made.Patients were classified into three categoriesaccording to the diagnostic approach as follows:diagnosis unsupported by duodenal or jejunalbiopsy; based on a single abnormal duodeno-jejunal histology finding; on diagnosis for-mulated after the European Society of Pae-diatric Gastroenterology and Nutrition(ESPGAN) criteria. The latter entails ab-normal duodenal or jejunal histology followedby clinical or histological return to normal ongluten free diet.'9

ESTIMATING COMPLETENESS OF CASE ARCHIVESAND ITS SOURCES OF VARIABILITYTo estimate completeness of case ascertain-ment for the whole archives and each in-formation source we used the Lincoln-Petersoncapture-recapture method,202" which comparesresults for multiple independent sources as-certaining the same event. Completeness of thecase archives was expressed as the proportionbetween the observed and expected numbersof new diagnosis in the target population (N).To estimate N, we considered hospital flagging(sources 1 and 2 of data collection section) asprimary sources, while national health serviceand Italian Coeliac Society were considered assecondary sources. N was calculated accordingto the Chapman estimator"2:

(1)N=(M+)(n+l)-1(m+ 1)

whereM is the number of new diagnoses iden-tified by the primary sources; n is the numberof new diagnoses identified by at least one ofthe secondary sources; and m is the number ofnew diagnoses identified by both the primaryand at least one of the secondary sources. Anapproximate unbiased estimate of the varianceofN was derived by Seber23 and given as:

Var(N) =(M+ 1)(n+ 1)(M-m)(n-m)(m+ 1)2(m+ 2) (2)

The 95% confidence interval (CI) ofN wascalculated using the formula:

95%CI= + 196Var(N) (3)

Equation (1) produces a valid estimate of theexpected number of cases under the as-sumption of independence of data sources, -that is, each subject must have an equal chanceof being reported as case in the secondarysources, regardless of whether or not he/shewas identified as case by the primary sources.We then constructed a matrix that considers

the number of new diagnoses reported in thearchives and the estimated number of un-reported new diagnoses for each possible com-bination of gender, age (< 15 v >15 years),area of residence, and residence within or out-side the area's main city. The estimated numberof unreported diagnoses was calculated by thedifference between expected cases (equation1) and those reported in the archives. Thisstructure corresponds to a case-control study,where cases and controls are the patients un-reported and reported in the archives re-spectively. The risk of unreporting associatedwith the considered variables was estimated bya logistic regression model and expressed asthe maximum likelihood estimate of relativerisks and their 95% confidence intervals.24These calculations were performed using thelogistic procedure of the SAS package.25

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Incidence of coeliac disease in Italy

Table 1 Completeness of reporting newly diagnosed patients in the four Italian areas

Completeness indexes Piedmont Lombardia Umbria Sardinia Total

M* 78 34 12 27 151mt 54 23 8 19 104nt 110 46 20 47 223NS 158 68 29 66 322(95%CI)¶ (142,175) (57,78) (21,37) (54,78) (298,348)Cases archive completeness** 0-85 0-84 0-82 0-83 0-84Hospital source completenesstt 0 49 0 50 0-41 0-41 0-47

Piedmont=Turin and Cuneo Provinces; Lombardia=Brescia Province; Umbria & Sardinia=entire region; *number of newdiagnoses identified in the diagnostic lists of hospital departments (primary source); t number of new diagnoses identified in boththe primary and at least one of secondary sources; t number of new diagnoses identified in at least one of the secondary sources;§ number of new diagnoses estimated according to equation 1 ("Methods" section); ¶ 95% confidence interval of N (equation 3in "Methods" section); ** proportion of observed number of new diagnoses over those expected (N); f- proportion of newdiagnoses identified in the diagnostic list of hospital departments; (M) over the expected number of new diagnoses (N).

ESTIMATING OVERALL INCIDENCE RATE AND ITSSOURCES OF VARIABILITYThe overall crude incidence rate was calculatedas the number ofnew diagnoses referred to thetwo years of observation divided by twice the1991 census population, and expressed as theaverage number of cases per 0-' residents peryear. Incidence rates were calculated using boththe observed and expected number of new

diagnoses and the number of new diagnosesflagged only by hospital sources.

The relationship between the observed over-

all incidence rate and gender, age, and area ofresidence was assessed by a Poisson's multiplelinear regression model.26 This considers theincidence rate as the dependent variable, andgender, age, area of residence, and residencewithin or outside the area's main city as theindependent variables. We then calculated themaximum likelihood estimate of the relativerisk and the corresponding 95% confidenceinterval for each level of independent variables.These calculations were performed using theEGRET package.27

ESTIMATING CHILDHOOD CUMULATIVEINCIDENCEThe childhood cumulative incidence was notdirectly computable since our observationperiod covered only two years. We thereforeused the density method28 based on the func-tional relationship existing between incidencerate and childhood cumulative incidence:

CCI, = 1 - exp( -EIRj j) (4)

where CCI,j is the cumulative incidence oc-

curring between birth and age j, and EjIR&jsums the age specific annual incidence ratesoccurring between the first and the jth year ofage. Incidence rates used in equation (4) were

obtained from the observed number of cases.The childhood cumulative incidence was com-

puted for each of the four areas, and in-dividually for each main city, between the 1stand the 15th year of age and expressed as thenumber of cases occurring from birth to thejth year of age in a hypothetical cohort of100000 live births. Equation (4) produces a

valid estimate of the childhood cumulative in-cidence under the assumption that the in-cidence rate remains constant during thecalendar period from the age of birth of thehypothetical cohort and the year of observationof cases.

EVALUATING SOURCES OF VARIABILITY OF AGEAT DIAGNOSISA hierarchical model of analysis of the variance(ANOVA) for unbalanced data29 was fitted toevaluate the sources of variability of age atdiagnosis. In the model, the main effects ofgender and residence areas and the nestedeffect of city of residence (main city or othercities) within the residence area, were con-sidered. The model was applied in the twostrata corresponding to age < 15 years and > 15years, arbitrarily considered as paediatric andadult ages respectively. These calculations wereperformed using the GLM procedure of theSAS package.30

ResultsFROM FLAGGING ARCHIVES TO CASE ARCHIVESWe received 478 flagged records of newly diag-nosed CD patients during 1990-91 from thefour areas included in the study. The hospitallists provided 181 records (151 from the studyareas and 30 from other hospitals outside theareas); the national health service and theItalian Coeliac Society lists provided 220 and77 records respectively. From the 478 flaggedrecords we constructed a case archives of 270patients, with an average per patient flaggingfrequency of 1-77.Among the 270 patients considered in the

study, 89 were males (male:female ratio1:2-0). Altogether 139 patients were diagnosedat < 15 years and 131 at > 15 years. The overallmean age at diagnosis was 21 years; it was 3-7for paediatric cases (< 15 years) and 34 yearsfor adult cases (>15 years).

DIAGNOSTIC APPROACHOf the 270 patients, 231 (85-6%) had medicalrecords available. Their diagnosis was alwayssupported by duodenal or jejunal biopsy: in 109cases (47 2%) diagnosis was made according toa single abnormal duodeno-jejunal histologyfinding and in the remaining 122 cases ac-cording to ESPGAN criteria.

COMPLETENESS OF CASE ARCHIVES AND ITSSOURCES OF VARIABILITYData used in calculating expected cases in thefour areas are reported in table 1. Of 151 casesflagged by hospitals (M), 104 were also flaggedby at least another source (m) and 223 cases

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Corrao, Usai, Galatola, Ansaldi, Meini, Pelli, Castellucci, Corazza

Table 2 Relationship between risk of unreporting new diagnoses and gender, age andresidence area

Independent Categories Unreported Reported RR* (95% CI)tvariables No (%) No (%)

Gender:Malest 18(34-4) 89(33 0) 1 00 -

Females 33(65-6) 181(67-0) 0 90 (0-48,1 69)Age classes (y):

< 15t 28(55 7) 139(51 5) 1-00 ->15 23(44 3) 131(48-5) 0 87 (0 48,1-59)

Residence area:Piedmont:: 24(47-1) 134(49-6) 1 00 -

Lombardia 11(21 6) 57(21-1) 1-08 (0-49,2-35)Umbria 5( 9 8) 24( 8-9) 1-16 (0 40,3-35)Sardinia 11(21-6) 55(20 4) 1-12 (0-51,2-44)

City of residence:Main city4 17(32-8) 94(34 8) 1-00Other 34(67 2) 176(65-2) 1-07 (0-57,2 02)

Piedmont =Turin and Cuneo Provinces; Lombardia = Brescia Province; Umbria and Sardinia=entire region; * Maximum likelihood estimates of the relative risk obtained by a logistic regressionmodel; RR is the risk of unreporting new diagnoses within a category with respect to the referencecategory; t 95% confidence interval of RR; i: reference category.

Table 3 Crude incidence rates in the four Italian areas calculated either from hospitalflagging alone, multiple sources information (observed cases) or estimated according to thecapture-recapture methods (expected cases)

Residence Resident Hospital flagging Observed cases Expected casesarea population*

No IRt No IRt No IRt

Piedmont 2822 94 1-67 134 2-37 158 2-80Lombardia 1040 41 1-97 57 2-74 68 3-27Umbria 820 14 0 85 24 1-46 29 1-77Sardinia 1657 32 0 97 55 1 66 66 2-00Total 6339 181 1 43 270 2 13 322 2-54

Piedmont= Turin and Cuneo Provinces; Lombardia = Brescia Province; Umbria and Sardinia=entire region; * from 1991 Italian population census (per 10'); t incidence rates (per 1 0-' peryear

were flagged by at least one of the secondarysources (national health service and/or ItalianCoeliac Society). Using these frequencies inequation 1, 52 cases (322-270) escaped fromthe case archives because of incomplete sourceinformation. The underestimation was homo-geneous throughout the areas, ranging from0-15 for Piedmont to 0-18 for Umbria. Thecompleteness of hospital source ranged from

160

--Piedmont

-U-Lombardia140 -0-Umbria

-3-Sardinia

120

')

cJU)> 100

gD 80

E 60C)

Table 4 Relationship between observed incidence rate andgender, age, and residence area

Independent variables Categories RRt (95% CI)t

Gender:Males* 1-00 -

Females 1-90§ (1-48,2-45)Age classes (y):

0-15* 1-00 -16-39 0 33§ (0 25,0 44)40-59 0-21§ (0-15,0 30)> 60 0-11 (0 06,0-18)

Residence area:Sardinia* 1-00 -

Umbria 1-24 (0 65,1-70)Lombardia 2-69§ (1-11,2-37)Piedmont 1-76§ (1-22,2-29)

City residence:Main city 1-55§ (1-09,4-83)Other* 1 00 -

Sardinia and Umbria = entire region; Lombardia = Brescia Prov-ince; Piedmont= Turin and Cuneo Provinces; * Reference cat-egory; t maximum likelihood estimates of the relative riskobtained by a Poisson's multiple linear regression model; t 95%confidence interval of RR; § p<005.

0-41 (Sardinia and Umbria) to 0 50 (Lom-bardia).

Table 2 shows that the estimated risk ofunreported new diagnosis was not associatedwith gender, age, or area and city of residence.

OVERALL INCIDENCE RATE AND ITS SOURCES OFVARIABILITYTable 3 shows that the crude incidence ratewas highest in the northern areas (Piedmontand Lombardia) and lowest in the other areas,irrespective of whether it was calculated fromhospital sources alone or from observed orexpected cases.Table 4 shows the estimated relative risks

associated with gender, age, and area of res-idence. Females had a significantly higher rel-ative risk. Despite a progressive reduction in therelative risk with increasing age, an appreciablenumber of cases were diagnosed above age 60(n = 15). By taking cases resident in Sardiniaas the reference category, relative risks weresignificantly higher in northern Italy. Casesresident in the main cities also showed a sig-nificantly higher relative risk.

CHILDHOOD CUMULATIVE INCIDENCEThe figure shows the observed childhoodcumulative incidence values according to agein the four areas. Two clusters were present.For northern areas, the childhood cumulativeincidence was constantly the highest, reachingtwice the value of the other two areas at theage of 15 years.Table 5 shows the estimated childhood

cumulative incidence at the age of 2, 5, 10,and 15 years in the four areas and in therespective main cities. For all ages the valueswere highest in the northern areas and withineach area the highest figures were observed forthe respective main cities.

0

0 5 10

Age (y)

Childhood cumulative incidence (per 100 000 live births) in the four Italian areas.

SOURCES OF VARIABILITY OF AGE AT DIAGNOSISTable 6 shows the results of the ANOVA per-formed separately for the two age groups. Inboth paediatric (< 15 years) and adult (>15

302

303Incidence of coeliac disease in Italy

Table S Childhood cumulative incidence (per 100 000live births) in the four Italian areas and in their respectivemain cities

Residence area Age (y)

2 5 10 15

Piedmont Entire area 69-3 96-6 125-4 143-2Turin* 87-0 123-6 169-3 180-7

Lombardia Entire area 59.0 91-2 124-3 141-4Brescia* 83-6 125-7 125-7 194 3

Umbria Entire area 44-7 60-1 66-4 72-4Perugia* 69 9 93 7 108 7 108-7

Sardinia Entire area 47 0 63-7 77-8 79-8Cagliari* 75-3 102-8 120-7 120-7

Total Entire areas 57-5 80 8 103-0 114 2Main cities 81-5 112-1 145-2 157-9

Piedmont=Turin and Cuneo Provinces; Lombardia=BresciaProvince; Sardinia and Umbria = entire region. * Main cities.

Table 6 Sources of variability of age at diagnosis

Sources of df F value p>F Modalities LS SE¶variability mean§

Age <15yGender* 1 1 53 0-218 Males 3-2 0 4

Females 3-9 0 3Area* 3 1 15 0-331 Piedmont 3-9 0 5

Lombardia 3-7 0-6Umbria 3-7 0-7Sardinia 3-4 0-6

Cityt 4 1-08 0-369 Piedmont Turint 4 0 0-8Other 3-8 0 5

Lombardia Bresciat 3-5 0 9Other 3-8 0 4

Umbria Perugiat 3-8 0 9Other 3-6 0-5

Sardinia Cagliarit 3-4 0-9Other 3-4 0-5

Age >15yGender* 1 9-14 0-003 Males 30 4 4-1

Females 36-2 4-3Area* 3 1-36 0-260 Piedmont 35-3 4-5

Lombardia 32-8 4-4Umbria 34-0 4 9Sardinia 32-0 4-4

Cityt 4 0 01 0-926 Piedmont Turint 35 0 4-6Other 35-4 4-2

Lombardia Bresciat 32-0 4-9Other 33-1 4-2

Umbria Perugiat 33-7 5-1Other 34-6 4-8

Sardinia Cagliarit 32-0 4-6Other 32-1 4-2

Piedmont =Turin and Cuneo Provinces; Lombardia = Brescia Province; Umbria and Sardinia=entire region. * Estimate of the main effect of the variable; t estimate of the nested effect of cityof residence within the residence area; t main cities; § least-square means; ¶ standard error of LSmeans.

years) patients, the age at diagnosis was sig-nificantly homogeneous according to the areaof residence and to the city of residence withineach area. A significantly higher age at diagnosiswas observed in women.

DiscussionEpidemiological studies of CD pose severalproblems, particularly when they are trying toestimate its incidence rate.3' Firstly, all diag-noses originating from well defined populationsshould be included to estimate the diseaseincidence correctly. The total flagged recordsin this study were 1475, but only 478 originatedfrom well defined geographical areas. For mostparticipating centres, flagging was obtainedonly from some of the hospital departments inthe areas; several health districts were not ableto provide the requested information and mostItalian Coeliac Society branches had no au-thorisation to provide confidential patient data.A well defined originating population wasfound only for four areas, covering 10% ofboth

the Italian population and the number of livebirths in the study period.We may have introduced bias by selecting

areas in which the greatest diagnostic awarenessexisted. However, this should not have affectedthe validity of comparing results between theseareas. Incomplete inclusion of all diagnosesmight occur, as shown by the finding that 52%of our patients were diagnosed outside theirresidence area. To avoid this, we used multipleinformation sources which also included re-ferral hospitals outside the study areas likely toattract patients throughout the country. Theseprovided only 6-3% of all flagged records, how-ever, whereas 62% of them were derived fromspecific national health service lists andbranches of the Italian Coeliac Society andwould have been missed using only hospitalsources. In areas where hospital flagging wasscarce, we observed a balance due to highflagging rates from the other sources. The use ofthe capture-recapture technique2023 estimatedthat our approach recruited 84% ofCD patientsnewly diagnosed in defined reference popu-lations. This 16% underestimate of the in-cidence rate was uniformly distributed amongthe areas and was independent of gender, ageand rural or urban residence. Our comparisonsare therefore correct and unbiased by under-reporting according to the type of populations.Our calculated childhood cumulative incidencein Piedmont was twice the figure reported forthat area by the paediatric multicentreESPGAN study (1-4/10-3 v 0-7/10-3 re-spectively),8 which used only hospital sources.If we consider data from our hospital source,we actually obtain the same figure as that re-ported by the ESPGAN study. Thus, we believethat our data are more likely to reflect theactual coeliac disease incidence.The second problem is that standard diag-

nostic criteria should be used. We verified thatfor all our patients whose medical records couldbe retrieved, diagnoses were formulated ac-cording to histological criteria, although onlyin half the cases were the strictest ESPGANcriteria used.'9 This should not have biasedour results, since diagnosis of CD formulatedaccording to a single histological finding, isconfirmed according to the ESPGAN criteriain 95% of the cases.32

Thirdly, diagnostic criteria should be homo-geneous throughout the country and the periodconsidered. We observed no difference in diag-nostic criteria between the four areas and ac-cording to urban or rural residence within eacharea. Moreover, our study covered an ob-servation period of just two years, to avoidbias due to time-dependent changes in thediagnostic approach. Thus, we were not ableto measure directly the childhood cumulativeincidence, and based our estimates on the dens-ity method that exponentially transforms agespecific rates of a dynamic population observedtransversally. The validity of our estimates de-pends on assuming a constant age specific in-cidence rate throughout the years. In the last20 years, the frequency of diagnosing sub-clinical CD in Italy has increased,'5 suggestingan underestimate of our figures. However, this

Corrao, Usai, Galatola, Ansaldi, Meini, Pelli, Castellucci, Corazza

increased diagnostic frequency in a long lastingobservational study may be affected by changesin diagnostic modalities and/or awarenessrather than reflecting an actual increased dis-ease incidence.

Fourthly, in an incidence study cases areincluded when the diagnosis is formulated, andthe onset of disease cannot be dated. Thecalculation of the incidence rate is therefore ofdubious validity,3' particularly for CD whoseonset is often gradual and escapes dating.Methods of measuring cumulative incidenceare implemented to estimate the actual fre-quency of disease occurrence. A decliningchildhood cumulative incidence trend duringthe 1980s has been reported from Ireland andUnited Kingdom3334 and other Europeanareas.35 Increased mean age at diagnosis mayexplain this finding,'0 pointing to a need toinclude diagnoses formulated at all ages andnot only during childhood. Possible temporaltrends and/or between-population variability ofdiagnostic frequency will therefore be ap-preciated. Cautious interpretation of incidencerates referring to adulthood is needed, as thesereflect the diagnostic frequency of the diseaserather than its actual incidence, particularly forour study where it was not possible to assesssymptoms leading to the diagnosis and theirtime of onset.

Lastly, in incidence studies only newly diag-nosed cases are included and these do notnecessarily coincide with newly occurring cases.Due to the wide clinical spectrum of CD,the observed variability in disease frequencybetween the areas may indicate variable rate ofdetection rather than variable incidence rate.Our results are comparable with the highest

disease frequency reported in northern Euro-pean countries.36 Our estimated childhoodcumulative incidence was the second highestfor Europe after Sweden,2 and showed a widegeographical variation between the lowest fig-ure of 07/10- in Umbria (central Italy) andthe highest of 1 4/10-3 in Piedmont (northernItaly). Consistently higher figures were alsofound for each area in children living in themain cities compared with those living else-where. A role for environmental factors, suchas (1) low rate of breast feeding,3738 (2) earlydietary introduction ofgluten proteins and highamount of gluten in the weaning diet,3941 (3)low incidence of gastroenteritis34 may be sug-gested. These factors should, however, deter-mine an earlier onset of disease symptoms,whereas our cases had a similar mean age atdiagnosis in the four areas studied. The highlyvariable childhood cumulative incidence ob-served may possibly be due to increased diag-nostic awareness and availability of diagnosticfacilities in the largest cities in the northernareas.Our adult incidence rate followed the same

distribution as the childhood cumulative in-cidence. This further supports the hypothesis ofa different diagnostic awareness of the disease,since it is unlikely that environmental factorsare kept constantly different throughout theareas for all birth cohorts of the patients in-cluded in our study.

In conclusion, we have shown that popu-lation based studies of the incidence rate ofCD should use several information sources toavoid underestimation. By this approach, weshowed that the childhood incidence rate inItaly is among the highest in Europe, and thatwide variability is observed between geo-graphical areas for both the paediatric andadulthood incidence rates. The highest rateswere also observed in metropolitan areas withineach area. The age at diagnosis was homo-geneous throughout the areas, suggesting thatgeographical variability probably depends moreon different disease awareness than on varyingenvironmental factors affecting the clinical pre-sentation of CD.

The working group of the Italian "Club del Tenue" comprises:C Catassi (Ancona); C Panella (Bari); G Brusco (Bologna); MV Cherchi (Cagliari); G Bottaro (Catania); F Bascietto (Chieti);A Spada (Cuneo); G Gemme (Genova); P Torchio, A Pie-nabarca (L'Aquila); C Romano, G Magazzui (Messina); M TBardella (Milano); S Guandalini, R Sollazzo (Napoli); F Ca-taldo, G Iacono (Palermo), C Leonardi (Roma); C SategnaGuidetti, D Dell'Olio, E Malorgio, G Ostino (Torino); GMastella (Verona)

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