ridi was set up in 1997 to coordinate registries for the incidence of type 1 diabetes in italy ( 17 ) .
all registries reported newly diagnosed cases of childhood type 1 diabetes using a special form , which includes each patient 's personal identification number , date of birth , sex , date of diagnosis ( defined as the date when the first insulin injection was given ) , and municipality of residence . a diagnosis of type 1 diabetes was based on permanent insulin treatment within 6 months of diagnosis , fasting c - peptide levels 0.20 nmol / l , or positivity for insulinoma - associated protein 2 , islet cell antibody , or gad antibody .
each registry used at least two independent data sources for case ascertainment ( 17 ) , and the completeness of ascertainment was estimated by the capture - recapture method . in a previous report
( 17 ) , we presented incidence rates based on 3,602 incident case subjects aged 014 years , who had been registered during 19901999 by nine registries . to date , 12 registries regularly update incidence rates as part of ridi : seven regional registries ( liguria , marche , umbria , lazio , abruzzo , campania , and sardinia ) and five province registries ( trento , torino , pavia , modena , and firenze - prato ) , covering an at - risk population of 3,321,459 children ( 39.7% of the whole italian population aged 014 years ( a geographical distrubution map is available in an online appendix at http://diabetes.diabetesjournals.org/cgi/content/full/db10-0151/dc1 ) .
the registries of modena and trento contributed cases in periods 19962003 and 19982003 , respectively , whereas registries of abruzzo , lazio , and umbria contributed data in periods 19901995 , 19901999 , and 19902001 , respectively .
data on at - risk residents in the geographical area covered by each registry for each year of the study period were obtained from the national institute for statistics .
the presence of extra - poisson variability has been evaluated assuming a  distribution of the true incidence rates through the likelihood ratio test .
multilevel random intercept poisson regression models have been used to estimate the effects of sex , age ( five 3-year age - groups : 02 , 35 , 68 , 911 , and 1214 years ) , calendar time ( four 3-year periods : 19901992 , 19931995 , 19961998 , 19992001 ; and one 2-year period : 20022003 ) , and birth cohorts ( nine 6-year birth cohorts : 1978 , 1981 , 1984 , 1987 , 1990 , 1993 , 1996 , 1999 , 2001 mid - years ) , taking into account the registry - level variance component .
the models assume a  distribution of the registry - level random intercept , accounting also for within - registry dependence .
six models were fitted to data : sex ; sex , age ; sex , age , linear time trend ( drift ) ; sex , age , cohort ; sex , age , period ; and sex , age , period , cohort .
the term  drift  denotes a temporal variation of rates that does not distinguish between the influences of two of the three temporal variables involved in the analysis .
the  test for trend in incidence rates used is the mantel extension of the armitage - cochran trend test ( 19 ) .
age - period - cohort models were fitted using apc.fit in r ( http://www.r-project.org ) ( 16 ) .
the presence of extra - poisson variability has been evaluated assuming a  distribution of the true incidence rates through the likelihood ratio test .
multilevel random intercept poisson regression models have been used to estimate the effects of sex , age ( five 3-year age - groups : 02 , 35 , 68 , 911 , and 1214 years ) , calendar time ( four 3-year periods : 19901992 , 19931995 , 19961998 , 19992001 ; and one 2-year period : 20022003 ) , and birth cohorts ( nine 6-year birth cohorts : 1978 , 1981 , 1984 , 1987 , 1990 , 1993 , 1996 , 1999 , 2001 mid - years ) , taking into account the registry - level variance component .
the models assume a  distribution of the registry - level random intercept , accounting also for within - registry dependence .
six models were fitted to data : sex ; sex , age ; sex , age , linear time trend ( drift ) ; sex , age , cohort ; sex , age , period ; and sex , age , period , cohort .
the term  drift  denotes a temporal variation of rates that does not distinguish between the influences of two of the three temporal variables involved in the analysis .
the  test for trend in incidence rates used is the mantel extension of the armitage - cochran trend test ( 19 ) .
age - period - cohort models were fitted using apc.fit in r ( http://www.r-project.org ) ( 16 ) .
in the 19902003 period , 5,180 incident cases of type 1 diabetes were identified among children aged 014 years . all registries provided high estimated completeness of ascertainment ( table 1 ) .
incidence rates by sex , age - group , calendar period , birth cohort , italian macro - area ( north , center - south , island [ sardinia ] ) , and registry are shown in table 1 .
the incidence rate was 12.26 per 100,000 person - years ( 95% ci 11.9312.60 ) , with significantly lower risk in girls ( 11.35 [ 95% ci 10.9011.82 ] ) than in boys ( 13.13 [ 12.6613.62 ] ) .
in peninsular italy , the incidence rates were 9.53 ( 95% ci 9.229.84 ) overall , 9.97 ( 9.5410.42 ) in boys , and 9.06 ( 8.649.50 ) in girls .
incidence rates of type 1 diabetes among italian children 014 years old in the years 19902003 by sex , age - group , calendar period , and geographical area of residence the likelihood ratio test showed substantial and statistically significant presence of overdispersion ( p < 0.001 ) . to account for this heterogeneity , multilevel random - intercept poisson regression models were fitted to data accounting for the registry - level variance component . in the regression analysis , after controlling for age , the rate ratio ( rr ) for girls with respect to boys was 0.87 ( 95% ci 0.820.92 ) ; corresponding values in peninsular italy and in sardinia were 0.91 ( 0.850.97 ) and 0.77 ( 0.700.85 ) , respectively .
the incidence steeply increased from the age - group 02 to the age - group 35 years ( table 1 ) , was quite similar in age - groups 68 and 1214 , and peaked at 911 years . large geographical variations in type 1 diabetes incidence were evident ( table 1 ) , with the highest rate in sardinia , an intermediate rate in central - southern italy , and a high rate in northern italy , particularly in the trento province ( 18.67 per 100,000 person - years [ 95% ci 14.9723.27 ] ) . the lowest incidence rate was recorded in the campania region ( 8.10 [ 7.678.55 ] ) .
an increasing temporal trend was evident both examining the whole italian area and the three italian macro - areas separately ; in sardinia we found a tendency toward lower risk in more recent years ( fig .
overall , the rates increased from 10.22 per 100,000 person - years in 19901992 to 14.78 per 100,000 in 20022003 ( table 1 ) .
controlling for age and sex , the annual increase was 2.94% ( 95% ci 2.223.67 ) .
incidence rates of type 1 diabetes among italian children 014 years old in the years 19902003 in the three italian macro - areas ( center - south , island [ sardinia ] , and north ) .
table 2 shows age - specific incidence rates by calendar period ( diagonals ) and birth cohorts .
an increasing temporal trend across calendar period was evident ( p < 0.0001 ) : with respect to the calendar period 19901992 , the rr was 1.15 ( 95% ci 1.061.25 ) in the period 19931995 , 1.27 ( 1.171.39 ) in the period 19961998 , 1.35 ( 1.241.47 ) in the period 19992001 , and 1.40 ( 1.271.55 ) in the period 20022003 . in all periods ( diagonals ) ,
the highest incidence rates were found in the age - group 911 years ; in the last period ( 20022003 ) only , after a rapid increase from the first to the second age - group , rates remained similarly high from 6 years old onwards .
age - specific incidence rates ( per 100,000 person - years ) of type 1 diabetes among italian children 014 years old in the years 19902003 , by birth cohorts 19782001 , and by calendar periods ( diagonals ) 19901992 ,  , 20022003 number of cases are in parentheses .
percent yearly increases , test for age - specific trends adjusted by sex over calendar periods , and estimated variance of the registry - level random intercept (  ) are shown in the last column . * likelihood ratio test of  = 0
rr , rate ratio for each birth cohort taking as reference those born in 19871993 ( 1990 mid - year ) . with respect to birth cohort 19871993 ( 1990 mid - year ) , the incidence rates increased approximately linearly .
as shown in table 2 , the rr increased from 0.63 ( 95% ci 0.540.73 ) in birth cohort 19751981 ( 1978 mid - year ) to 1.38 ( 1.061.80 ) in birth cohort 19992003 ( 2001 mid - year ) .
multilevel poisson regression analysis was also used to assess whether the observed temporal increase in incidence rates could be due to period or cohort effects .
the best model ( model 3 ) included sex , age , and a linear time trend ( drift ) .
therefore , the variation over time has a linear component that can not be ascribed to either the calendar period or the cohort .
indeed , the sex , age , and cohort model ( model 4 ) and the sex , age , and period model ( model 6 ) were not significantly better than the sex , age , and drift model ( model 3 ) .
the estimated variance of the registry - level random intercept showed statistically significant heterogeneity between registries ( p value of the likelihood ratio test < 0.001 in all models , table 3 ) .
comparison of different age - period - cohort models fitted to incidence rates of type 1 diabetes among italian children 014 years old in the years 19902003 each model is compared with the one above through the likelihood ratio test . * likelihood - ratio test of  = 0 ; p < 0.001 in all models .
figure 2 shows incidence rates ( on a logarithmic scale ) over age - groups by birth cohorts , over calendar period by age - groups , and over birth cohorts by age - groups .
results were similar when data were analyzed by geographical macro - areas ( data not shown ) .
incidence rates of type 1 diabetes among italian children 014 years old in the years 19902003 over age - groups by birth cohorts ( mid - year of birth cohorts ) ( a ) , over calendar period by age - groups ( b ) , and over birth cohorts by age - groups ( c ) .
results of the present analyses of the ridi study provide evidence of 1 ) large geographical variations in risk of childhood type 1 diabetes within italy , with high - risk areas in both sardinia and trento , in the north - east of italy ; 2 ) a significantly lower risk in girls than in boys , which is more pronounced in sardinia ( 23% ) than in peninsular italy ( 9% ) ; and 3 ) a linear increasing temporal trend , with an annual increment of 2.94% , affecting all age - groups and both sexes . in our dataset , however , it was impossible to ascribe this increase definitively to either a birth cohort or a calendar period effect .
our findings are based on a national registry using standardized methods of ascertainment of incident cases , covering 40% of the italian population at risk ; moreover , the long time period on which this report is based allows us to add to current knowledge on epidemiology of type 1 diabetes .
heterogeneity of type 1 diabetes risk has been reported worldwide , but italy is one of the countries with greater variation within it .
indeed , incidence in peninsular italy is fourfold lower than in sardinia . in the latter
, rates appeared to decline in more recent years , suggesting the possibility that an upper limit has been reached .
the novel finding of the updated report of the ridi study is that a new high - risk area has been identified in the north - east of italy , in trento .
the lower boundary of the ci of the incidence rate for trento is higher than the upper value of the ci of all other peninsular areas ( with the exception of modena ) , and is similar to risk of children living in neighboring european areas , germany , and austria ( 45 ) .
whether this heterogeneity is due to either genetic or environmental factors is difficult to establish on the basis of available data and advocates further studies .
moreover , the extension of the ridi project to other italian areas not covered by registries would provide a more accurate estimate of risk at national level .
sex differences in risk of both type 1 and type 2 diabetes , with an almost two - fold higher risk in males than in females , have been previously reported in young italian adults ( 2021 ) .
the large number of cases on which this report is based allows us to provide evidence that the male excess in risk of type 1 diabetes is evident even in italian children , consistent with studies performed in high - risk areas ( 22 ) .
this finding could suggest a role for sex - linked differences in -cell function or in insulin sensitivity , with a higher rate of -cell exhaustion in male than in female subjects .
this finding is consistent with a recent report from the registry of turin , showing a similar increase in incidence of childhood and adulthood diabetes since 1984 , suggesting that widespread environmental determinants are involved in this phenomenon ( 18 ) .
this finding , however , is in contrast with studies suggesting that the incidence increase could be explained by a shift to a younger age at onset ( 7,1112,14,2324 ) . in our study , we carried out an age - period - cohort analysis that included evaluation of both the drift ( the linear variation of the incidence in time due to either a calendar period or a cohort effect ) and the nonlinear components of the effects of the two temporal variables .
we did not find evidence of nonlinear effects because there were no improvements in the models when the nonlinear components of calendar period or birth cohort were introduced . because the incidence increase was linear ,
it was not possible to distinguish between the effects of calendar period and birth cohort , and our data do not support the hypothesis of a shift to a younger age at onset . previously published age - period - cohort models in childhood diabetes temporal trend have shown inconclusive results .
county in the years 19701985 ( 25 ) . in 19781987 in sweden ( 13 ) , in 19651984 in finland ( 14 ) , and in 19732000 in norway ( 9 ) linear and nonlinear effects of the calendar period were evident , but no statistically significant cohort effect was found ; the finnish study ( 14 ) found only some evidence of younger age at diabetes onset . a later swedish study ( 24 ) found no evidence of an increase in incidence rates , whereas it strongly supported a cohort effect because of a steeper increase in younger age - groups . in 19702000 in denmark , a modest drift effect and a significant cohort effect were found , with increased risk for children born after 1985 ( 12 ) .
similarly , in 19782000 in yorkshire , u.k . , increased incidence rates were associated with late birth cohorts ( in particular 1985 and 1995 ) and with calendar periods ( 12 ) .
finally , the most recent eurodiab study ( 7 ) showed a statistically significant yearly increase in all age - groups ( + 5.4% in 04 , + 4.3% in 59 , and + 2.9% in 1014 years old ) and a statistically significant interaction between calendar year and age - group , with the highest increase in the youngest age - groups .
an analysis of the registry of turin in the period 19842003 for the age - group 029 years found a linear effect that could not be ascribed to either the calendar period or the birth cohort ( 18 ) .
the ridi study does not support the interpretation of the observed steady increase as a cohort or a calendar period effect , and reasoning on causal and biological plausibility of different hypotheses becomes crucial . because prevalence of childhood obesity is increasing over time , the  accelerated hypothesis  has been suggested as a possible explanation of the increasing temporal trend of type 1 diabetes ( 26 ) .
other studies have proposed that the decreasing early life exposure to infectious diseases , which typically occurred over the past three decades in developed countries , could be involved in this trend ( 27 ) .
such an increase can not be ascribed to either the calendar period or the birth cohort .
 objectiveto investigate age - period - cohort effects on the temporal trend of type 1 diabetes in children age 014 years in italian registries.research design and methodsthis report is based on 5,180 incident cases in the period 19902003 from the registry for type 1 diabetes mellitus in italy ( ridi ) . 
 multilevel ( random intercept ) poisson regression models were used to model the effects of sex , age , calendar time , and birth cohorts on temporal trends , taking into account the registry - level variance component.resultsthe incidence rate was 12.26 per 100,000 person - years and significantly higher in boys ( 13.13 [ 95% ci 12.6613.62 ] ) than in girls ( 11.35 [ 10.9011.82 ] ) . 
 large geographical variations in incidence within italy were evident ; incidence was highest in sardinia , intermediate in central - southern italy , and high in northern italy , particularly in the trento province , where the incidence rate was 18.67 per 100,000 person - years . an increasing temporal trend was evident ( 2.94% per year [ 95% ci 2.223.67 ] ) . 
 with respect to the calendar period 19901992 , the incidence rates increased linearly by 15 , 27 , 35 , and 40% in the following time periods ( p for trend < 0.001 ) . 
 with respect to the 19871993 birth cohort , the incidence rate ratio increased approximately linearly from 0.63 ( 95% ci 0.540.73 ) in the 19751981 cohort to 1.38 ( 1.061.80 ) in the 19992003 cohort . 
 the best model , however , included sex , age , and a linear time trend ( drift).conclusionslarge geographical variations and an increasing temporal trend in diabetes incidence are evident among type 1 diabetic children in italy . 
 age - period - cohort analysis shows that the variation over time has a linear component that can not be ascribed to either the calendar period or the birth cohort . 
RESEARCH DESIGN AND METHODS
Statistical analysis.
RESULTS
DISCUSSION
Supplementary Material