Supplementary 2: Detailed Risk Models

Supplementary Table 1: Topography and histology codes of the International Classification of Diseases (ICD) for Oncology - 3rd revision – recorded during the study period for the incident cases of primary tumors of the central nervous system (CNS), leukemia, and lymphoma

Histology/Behaviour
CNS cancer (topography codes: 70–71, 723, 752)
Pilocytic astrocytoma / 9421/1
Other astrocytic and oligodendroglialtumours / 9381/3, 9384/1, 9401/3, 9420/3
Neuronal and mixed neuronal-glial tumours / 9413/0, 9505/1
Medulloblastoma / 9470/3, 9471/3
Meningioma / 9530/0
Other / 9150/1, 9380/3, 9473/3 9380/1, 9380/3, 9351/1
Leukemia (topographycode: 421)
Acute lymphoblastic leukaemia / 9836/3, 9837/3
Acute myeloid leukaemia / 9866/3, 9897/3, 9910/3
Juvenile myelomonocytic leukemia / 9946/3
Burkitt cell leukemia / 9826/3
Myelodysplastic syndrome / 9983/3
Lymphoma (topographycodes: 220, 268, 349, 739, 380, 421, 481, 494, 772, 778)
Hodgkin disease / 9663/3
Non-Hodgkin lymphoma / 9687/3, 9714/3, 9729/3
Other / 9590/3, 9680/3

Supplementary 2: Detailed risk models

In Poisson disease models, the expected number of cases, noted μjk, in each strata jwith sex s, birth period (p1=1995–2001, p2=2002–2010), attained age a(<3, 3–<5, 5–<7, 7–<9, ≥9 years), and age at exposure (<1, 1–<3, 3–<5, ≥5 years),foran exposure category k, isdefined by

μjk = PYjkλj (1 + ERRjk)

where PYjkis the number of persons-years,λjdenotes the “background” risk (without CT scan exposure), and ERRjkis the excess relative risk in relation to the cumulative organ dose.Exposure categoriesk were defined as <5, 5–24, 25–49, ≥50 mGy to the brain (for CNS cancer), <5, 5–9, 10–14, ≥15 mGy to the red bone marrow (RBM) (for leukaemia), and <5, 5–9, ≥10 mGy to the RBM (for lymphoma).

The “background” risk λj, adjusted for the presence of predisposing factors (PF)specific to the outcome (CNS cancer, leukaemia, or lymphoma), isdefined by

λj =exp(α1sj + α2p2j + α3 + α4+ γPF1j)

where aj is the exact attained age (in years) in the stratum j, tj the exact time since the first exposure (in years), and PFjdenotes the presence of PF (coded 1 if at least one PF, 0 otherwise). Attained age and time since the first exposure are centered on their mean values in the cohort to improve the stability of the models. Interactions between the covariates are not included because such models do not fit the data better than those with only main effects.

The relative risk (RR) associated with the PF is

RRFP = exp(γFP1j)

The excess relative riskERRjkis defined by

ERRjk = β1djk exp(δZj)

where djkis themean dose in the stratum jandthe exposure category k,Zjdenotes alternatively the modifying effect of the following covariates: sex s, presence of PFFP1j, age at the first exposure (<5, 5–9 years), time since exposure (<5, 5–11 years), and attained age (<7, 7–14 years).

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Supplementary Table 3: Characteristics of CT scan exposures for each predisposing factor considered in the study

Number of children / Age at the 1st CT scan (years) / Total number of CT scans / Cumulative effective dose (mSv) / Cumulative brain dose (mGy) / Cumulative RBM dose (mGy)
mean (sd)
No predisposing factors / 65512 / 3.4 / (2.9) / 1.4 / (1.2) / 3.9 / (4.8) / 23.2 / (31.5) / 8.8 / (10.5)
Genetic defects
Familial adenomatous polyposis / 20 / 4.5 / (2.9) / 3.2 / (3.4) / 12.9 / (9.1) / 36.2 / (76.7) / 16.4 / (25.1)
Retinocytoma / 62 / 2.4 / (2.7) / 1.6 / (1.6) / 3.6 / (5.0) / 32.8 / (58.1) / 11.0 / (16.2)
Multiple endocrine neoplasia (MEN1, MEN2) / 3 / 0.8 / (0.9) / 3.0 / (2.6) / 14.7 / (14.2) / 15.0 / (25.5) / 11.6 / (14.1)
Fanconi anaemia* / 63 / 4.3 / (3.0) / 2.7 / (2.6) / 9.6 / (12.8) / 19.1 / (28.4) / 10.4 / (11.3)
Ataxia telangiectasia* / 8 / 5.6 / (2.8) / 3.3 / (4.1) / 10.2 / (10.9) / 68.2 / (161.0) / 19.6 / (35.3)
Xeroderma pigmentosum / 10 / 2.7 / (3.6) / 1.5 / (1.0) / 4.5 / (4.0) / 8.5 / (16.5) / 4.6 / (5.5)
Bloom syndrome / 30 / 3.3 / (3.0) / 2.1 / (1.6) / 8.0 / (8.2) / 22.6 / (33.7) / 10.8 / (12.3)
Neurofibromatosis (NF1, NF2) / 106 / 4.1 / (3.0) / 1.6 / (1.5) / 6.2 / (7.6) / 25.4 / (39.1) / 10.3 / (12.4)
Other phacomatoses / 192 / 2.8 / (2.8) / 1.9 / (2.0) / 5.3 / (5.2) / 37.5 / (50.8) / 14.0 / (17.1)
Noonan syndrome / 94 / 2.0 / (2.4) / 2.0 / (2.6) / 5.9 / (9.7) / 25.9 / (75.8) / 11.2 / (26.3)
Down syndrome / 202 / 2.6 / (2.8) / 1.4 / (0.8) / 4.4 / (4.5) / 11.0 / (18.9) / 5.8 / (6.7)
Klinefelter syndrome / 15 / 2.9 / (2.9) / 2.2 / (3.1) / 10.7 / (12.3) / 19.0 / (28.7) / 10.4 / (12.1)
Immune deficiencies
HIV/AIDS / 245 / 2.4 / (2.6) / 1.9 / (1.9) / 6.5 / (9.3) / 20.5 / (34.7) / 9.4 / (12.2)
Pimary immune deficiency (SCID, CVID) / 112 / 2.8 / (2.7) / 2.9 / (2.8) / 11.6 / (12.9) / 13.1 / (28.1) / 9.6 / (12.3)
Wiskott-Aldrich syndrome / 17 / 2.1 / (1.8) / 3.7 / (3.1) / 13.7 / (14.0) / 37.7 / (45.3) / 18.6 / (16.7)
Transplantation / 749 / 3.0 / (2.7) / 2.7 / (2.9) / 12.2 / (16.6) / 19.2 / (35.6) / 11.4 / (14.9)
CT: computed tomography; HIV: human immunodeficiency virus: AIDS: acquired immunodeficiency syndrome; ICD-10: International Classification of Diseases - 10th revision; CNS: central nervous system *genetic variant increasing radiation sensitivity

Supplementary Table 4: Number of incident cases (N) of primary tumorsof the central nervous system (CNS), leukemia and lymphoma, and incidence rates (IR) per 100,000 person-yearsfor various exclusion periods

Number of cases / Incidence rates (100,000 PY)
Exclusion period (years) / Exclusion period (years)
1 / 2 / 3 / 4 / 1 / 2 / 3 / 4
CNS cancer / 27 / 22 / 17 / 13 / 9.1 / 9.4 / 9.5 / 9.8
Pilocytic astrocytoma / 2 / 1 / 0 / 0 / 0.7 / 0.4 / 0.0 / 0.0
Other astrocytic and oligodendroglialtumours / 5 / 5 / 4 / 4 / 1.7 / 2.1 / 2.2 / 3.0
Neuronal and mixed neuronal-glial tumours / 4 / 3 / 2 / 2 / 1.3 / 1.3 / 1.1 / 1.5
Medulloblastoma / 7 / 6 / 5 / 3 / 2.4 / 2.6 / 2.8 / 2.3
Meningioma / 2 / 2 / 2 / 2 / 0.7 / 0.9 / 1.1 / 1.5
Other / 7 / 5 / 4 / 2 / 2.4 / 2.1 / 2.2 / 1.5
Leukemia (including myelodysplasia) / 25 / 17 / 12 / 7 / 8.4 / 7.3 / 6.7 / 5.3
Acute myeloid leukaemia / 5 / 2 / 1 / 0 / 1.7 / 0.9 / 0.6 / 0
Acute lymphoblastic leukaemia / 17 / 13 / 10 / 6 / 5.7 / 5.6 / 5.6 / 4.5
Burkitt cell leukemia / 1 / 1 / 1 / 1 / 0.3 / 0.4 / 0.6 / 0.8
Juvenile myelomonocytic leukemia / 1 / 1 / 0 / 0 / 0.3 / 0.4 / 0.0 / 0.0
Myelodysplastic syndrome / 1 / 0 / 0 / 0 / 0.3 / 0.0 / 0.0 / 0.0
Lymphoma / 21 / 19 / 14 / 12 / 7.1 / 8.1 / 7.8 / 9.0
Hodgkin disease / 6 / 6 / 4 / 4 / 2.0 / 2.6 / 2.2 / 3.0
Non-Hodgkin lymphoma / 10 / 9 / 6 / 5 / 3.4 / 3.8 / 3.3 / 3.8
Others or not specified / 5 / 4 / 4 / 3 / 1.7 / 1.7 / 2.2 / 2.3
CNS: central nervous system; PY: person-years P5: 5th percentile P95 : : 95th percentile

Supplementary Table 5: Relative risks (RR) of cancer by categories of CT-scan exposure doses, for exclusion periods of 1, 2, 3, and 4 years

a-RR (95%CI)of central nervous system (CNS) cancers by brain dose category

Exclusion period(years) / Dose (mGy) / <5 / 5-24 / 25-49 / 50+ / 5-50+
1 / Mean dose(mGy) / 0.5 / 15.3 / 33.0 / 90.4 / 30.8
PY / 91692 / 97775 / 85155 / 22241 / 205171
Cases / 6 / 7 / 9 / 5 / 21
RR
95%CI / 1
- / 0.955
0.314; 3.002 / 1.541
0.554;4.606 / 2.568
0.723;8.734 / 1.386
0.588; 3.803
2 / PY / 71476 / 80034 / 65680 / 16713 / 162427
Cases / 6 / 5 / 7 / 4 / 16
RR
95%CI / 1
- / 0.646
0.184; 2.177 / 1.181
0.391; 3.681 / 1.976
0.491; 7.162 / 1.015
0.412; 2.859
3 / PY / 54065 / 64053 / 49146 / 12141 / 125340
Cases / 6 / 4 / 5 / 2 / 11
RR
95%CI / 1
- / 0.480
0.121; 1.710 / 0.822
0.235; 2.747 / 0.934
0.133; 4.249 / 0.664
0.248; 1.957
4 / PY / 39477 / 49789 / 35516 / 8536 / 93841
Cases / 4 / 4 / 4 / 1 / 9
RR
95%CI / 1
- / 0.657
0.153; 2.820 / 0.990
0.232; 4.216 / 0.734
0.037; 5.216 / 0.786
0.252; 2.942
PY: person-years; RR: relative risk compared to dose category <5 mGy; 95%CI: likelihood profile-based 95% confidence intervals. RRs are estimated by Poisson models (maximum likelihood estimates) adjusted for gender, period of birth (1995-2001, 2002-2010), attained age (in years), time since entry into the cohort (in years), as well as the presence of predisposing factors (yes/no).

b-RR (95%CI)of leukemia (including myelodysplasia) by red bone marrow dose category

Exclusion period (years) / Dose (mGy) / <5 / 5-9 / 10-19 / 20+ / 5-20+
1 / Mean dose(mGy) / 2.7 / 7.4 / 13.0 / 34.7 / 12.6
PY / 123145 / 86073 / 68899 / 18746 / 173718
Cases / 11 / 4 / 7 / 3 / 14
RR
95%CI / 1
- / 0.572
0.158; 1.686 / 1.198
0.439; 3.056 / 1.511
0.339; 4.911 / 0.946
0.427; 2.148
2 / PY / 97602 / 68890 / 53078 / 14333 / 136301
Cases / 6 / 5 / 3 / 3 / 11
RR
95%CI / 1
- / 1.357
0.388; 4.543 / 0.996
0.209; 3.800 / 3.143
0.653; 12.170 / 1.435
0.541; 4.199
3 / PY / 75119 / 53990 / 39700 / 10596 / 104286
Cases / 3 / 5 / 3 / 1 / 9
RR
95%CI / 1
- / 2.759
0.672; 13.540 / 2.239
0.410; 12.260 / 2.498
0.122; 20.080 / 2.537
0.747; 11.540
4 / PY / 55888 / 41108 / 28747 / 7575 / 77430
Cases / 1 / 3 / 2 / 1 / 6
RR
95%CI / 1
- / 4.392
0.556; 89.280 / 3.989
0.379; 86.180 / 6.415
0.248; 166.200 / 4.465
0.751; 84.830
PY: person-years; RR: relative risk compared to dose category < 5 mGy; 95%CI: likelihood profile-based 95% confidence intervals. RRs are estimated by Poisson models (maximum likelihood estimates) adjusted for gender, period of birth (1995-2001, 2002-2010), attained age (in years), time since entry into the cohort (in years), as well as the presence of predisposing factors (yes/no).

c-RR (95%CI)of lymphoma by red bone marrow dose category

Exclusion period (years) / Dose (mGy) / <5 / 5-9 / 10+ / 5-10+
1 / Mean dose(mGy) / 2.7 / 7.4 / 19.4 / 12.6
PY / 123145 / 86073 / 87645 / 173718
Cases / 11 / 3 / 7 / 10
RR
95%CI / 1
- / 0.440
0.099; 1.419 / 0.943
0.344; 2.419 / 0.701
0.290; 1.677
2 / PY / 97602 / 68890 / 53078 / 136301
Cases / 9 / 4 / 6 / 10
RR
95%CI / 1
- / 0.748
0.202; 2.314 / 1.090
0.361; 3.060 / 0.920
0.368; 2.338
3 / PY / 75119 / 53990 / 39700 / 104286
Cases / 6 / 2 / 6 / 8
RR
95%CI / 1
- / 0.564
0.082; 2.463 / 1.776
0.546; 5.788 / 1.148
0.395; 3.524
4 / PY / 55888 / 41108 / 28747 / 77430
Cases / 6 / 1 / 5 / 6
RR
95%CI / 1
- / 0.271
0.014; 1.594 / 1.648
0.462; 5.652 / 0.878
0.271; 2.846

Supplementary Table 6: Number of cases of primary tumours of the central nervous system (CNS), leukaemia, and lymphoma, incidence rates (IR) per 100000 person-years, excess relative risks (ERR) related to cumulative organ dose (in mGy) from CT scans(adjusted for the presence of predisposing factors (PF) and for a 2-year exclusion period), by patients’ characteristics

CNS cancer / Leukemia / Lymphoma
Cases / IR / ERR / p / Cases / IR / ERR / p / Cases / IR / ERR / p
Overall / 22 / 9.4 / 0.012 / 17 / 7.3 / 0.045 / 19 / 8.1 / 0.008
Sex
Male / 11 / 8.2 / 0.008 / >0.50 / 9 / 6.7 / -0.012 / 0.21 / 8 / 5.9 / 0.066 / 0.29
Female / 11 / 11.1 / 0.016 / 8 / 8.0 / 0.110 / 11 / 11.1 / -0.020
PF
No / 15 / 6.4 / 0.028 / 0.11 / 12 / 5.2 / 0.187 / 0.09 / 12 / 5.2 / 0.025 / >0.50
Yes / 7 / 565.9 / -0.005 / 5 / 128.0 / -0.012 / 7 / 160.3 / -0.005
Age at first CT scan
(in years)
< 5 / 18 / 10.1 / 0.009 / >0.50 / 14 / 7.8 / 0.072 / >0.50 / 11 / 6.1 / 0.002 / >0.50
5-9 / 4 / 7.3 / 0.021 / 3 / 5.5 / 0.023 / 8 / 14.6 / 0.022
Time since first CT scan (in years)
< 5 / 11 / 7.9 / 0.019 / 0.21 / 12 / 8.3 / 0.069 / 0.29 / 13 / 9.2 / **
5-11 / 11 / 11.6 / -0.005 / 5 / 5.5 / -0.012 / 6 / 6.5
Attained age (in years)
< 7 / 9 / 9.9 / 0.011 / >0.50 / 6 / 6.6 / 0.029 / 0.24 / 6 / 6.6 / 0.005 / >0.50
7-14 / 13 / 9.1 / 0.030 / 11 / 7.7 / 0.241 / 13 / 9.1 / 0.009

PF: factors predisposing specifically to cancer at the site specified; CNS: central nervous system; IR: incidence rates per 100000 person-years; ERR: excess relative risk per mGy;p: p-values for the modifying effect based on likelihood ratio tests **the model does not fit for the defined categories of time since the first scan, although there is a trend of increased risk with increasing time since the first scan (p=0.110) when time is considered as a continuous variable

Supplementary Table 7: Sensitivity analyses for the estimation of excess relative risks (ERR) of CNS cancer, leukaemia, and lymphoma by cumulative organ dose (in mGy) from CT scans, adjusted for the presence of predisposing factors (2-year exclusion period)

a-Number of children, person-years (PY), mean follow-up, and number of cases

Population / Study period / Numberof children / PY / Mean/median FU (years) / Number of incident cases
CNS cancer / Leukemia / Lymphoma
All children / All / 58620 / 233903 / 4.0/3.7 / 22 / 17 / 19
Removing children with at least 1 CT scan in the overseas department / All / 57518 / 231524 / 4.0/3.7 / 22 / 16 / 19
Removing children without nodata about their place of residence / All / 53870 / 210149 / 5.7/4.6 / 19 / 17 / 18
Removing children born before 2000 / All / 43349 / 148284 / 3.3/2.9 / 16 / 14 / 10

b-ERRof CNS cancer, leukemia, and lymphoma

Population / Study period / ERR per mGy (95%CI)
CNS cancer / leukemia / Lymphoma
All children / All / 0.012 / 0.047 / 0.008
(-0.013; 0.037) / (-0.065; 0.159) / (-0.057; 0.073)
TSFE < 5 y. / 0.019* / 0.069* / **
TSFE 5-11 y. / -0.005* / -0.012* / **
Removing children with at least 1 CT scan in the overseas department / All / 0.012 / 0.048 / 0.008
(-0.013; 0.037) / (-0.068; 0.163) / (-0.056; 0.072)
Removing children with no data about their place of residence / All / 0.018 / 0.047 / 0.017
(-0.017; 0.052) / (-0.065; 0.160) / (-0.060; 0.093)
TSFE < 5 y. / 0.028* / 0.069* / **
TSFE 5-11 y. / -0.005* / -0.012* / **
Removing children born before 2000 / All / 0.008 / 0.018 / -0.001
(-0.015; 0.031) / (-0.055; 0.091) / (-0.069; 0.066)
TSFE < 5 y. / 0.018* / 0.037* / **
TSFE 5-11 y. / -0.004* / -0.011* / **
*estimates for modifying effect **the model did not fit for the defined categories for time since the first CT scan; CNS: central nervous system; FU: follow-up;PY: person-years; TSFE: time since the first exposure to CT scan; 95%CI: Wald-based 95% confidence intervals; ERRs are estimated by Poisson models (maximum likelihood estimates) adjusted for gender, period of birth (1995-2001, 2002-2010), attained age (in years), time since entry into the cohort (in years), and the presence of predisposing factors (yes/no)

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