Literature DB >> 34673770

Cancer risk in individuals with intellectual disability in Sweden: A population-based cohort study.

Qianwei Liu1, Hans-Olov Adami2,3,4, Abraham Reichenberg5,6, Alexander Kolevzon5,6,7, Fang Fang1, Sven Sandin2,5,6.   

Abstract

BACKGROUND: A knowledge gap exists about the risk of cancer in individuals with intellectual disability (ID). The primary aim of this study was to estimate the cancer risk among individuals with ID compared to individuals without ID. METHODS AND
FINDINGS: We conducted a population-based cohort study of all children live-born in Sweden between 1974 and 2013 and whose mothers were born in a Nordic country. All individuals were followed from birth until cancer diagnosis, emigration, death, or 31 December 2016 (up to age 43 years), whichever came first. Incident cancers were identified from the Swedish Cancer Register. We fitted Cox regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of cancer risk in relation to ID after adjusting for several potential confounders. We analyzed ID by severity, as well as idiopathic ID and syndromic ID separately. We performed a sibling comparison to investigate familial confounding. The study cohort included a total of 3,531,305 individuals, including 27,956 (0.8%) individuals diagnosed with ID. Compared with the reference group (individuals without ID and without a full sibling with ID), individuals with ID were in general more likely to be male. The median follow-up time was 8.9 and 23.0 years for individuals with ID and individuals without ID, respectively. A total of 188 cancer cases were identified among individuals with ID (incidence rate [IR], 62 per 1,000 person-years), and 24,960 among individuals in the reference group (IR, 31 per 1,000 person-years). A statistically significantly increased risk was observed for any cancer (HR 1.57, 95% CI 1.35-1.82; P < 0.001), as well as for several cancer types, including cancers of the esophagus (HR 28.4, 95% CI 6.2-130.6; P < 0.001), stomach (HR 6.1, 95% CI 1.5-24.9; P = 0.013), small intestine (HR 12.0, 95% CI 2.9-50.1; P < 0.001), colon (HR 2.0, 95% CI 1.0-4.1; P = 0.045), pancreas (HR 6.0, 95% CI 1.5-24.8; P = 0.013), uterus (HR 11.7, 95% CI 1.5-90.7; P = 0.019), kidney (HR 4.4, 95% CI 2.0-9.8; P < 0.001), central nervous system (HR 2.7, 95% CI 2.0-3.7; P < 0.001), and other or unspecified sites (HR 4.8, 95% CI 1.8-12.9; P = 0.002), as well as acute lymphoid leukemia (HR 2.4, 95% CI 1.3-4.4; P = 0.003) and acute myeloid leukemia (HR 3.0, 95% CI 1.4-6.4; P = 0.004). Cancer risk was not modified by ID severity or sex but was higher for syndromic ID. The sibling comparison showed little support for familial confounding. The main study limitations were the limited statistical power for the analyses of specific cancer types, and the potential for underestimation of the studied associations (e.g., due to potential underdetection or delayed diagnosis of cancer among individuals with ID).
CONCLUSIONS: In this study, we found that individuals with ID showed an increased risk of any cancer, as well as of several specific cancer types. These findings suggest that extended surveillance and early intervention for cancer among individuals with ID are warranted.

Entities:  

Mesh：

Year:  2021        PMID： 34673770      PMCID： PMC8568154          DOI： 10.1371/journal.pmed.1003840

Source DB:  PubMed          Journal:  PLoS Med        ISSN： 1549-1277            Impact factor:   11.069


Introduction

Intellectual disability (ID) is a lifelong impairment of cognition and adaptive behavior that emerges in childhood [1], affects around 1% of the world population [2], and is associated with increased morbidity and mortality [3-5]. For instance, individuals with ID generally have an abnormal level of intelligence quotient (IQ) (under 70) and deficiency in at least 2 adaptive behaviors in environment and social milieu [6]. The underlying causes of ID are heterogenous, including chromosomal abnormality, gene mutation, environmental factors, and prenatal factors [7]. The exact cause, however, is not identifiable for most individuals with ID [8]. Cancer is one of the major causes of death before age 14 years and affects around 3.4% of males and 5.6% of females before the age of 49 years in the US [9]. Emerging evidence has suggested a plausible link between ID and cancer through several potential mechanisms. One possibility is that the chromosomal abnormalities or genetic mutations causing ID, especially syndromic ID, might also contribute to oncogenesis [10-12]. Another possibility is that individuals with ID may be more likely to be exposed to potential risk factors for cancer, such as unhealthy lifestyles including less optimal diets and lack of physical activity, which might also contribute to the initiation or development of some cancers [13,14]. However, population-based studies examining the association between ID and cancer are largely missing. Earlier clinical studies have suggested an increased risk of some specific types of cancer among individuals with genetic syndromes known to be associated with ID, such as Down syndrome, fragile X syndrome, and tuberous sclerosis complex [15-17]. There is, however, no consensus thus far about the risk of cancer in general among individuals with syndromic ID [3,18-22]. In addition, as previous studies have predominantly focused on syndromic ID, little is known about cancer risk among individuals with any ID, especially idiopathic ID. Among the few studies of cancer risk in individuals with any ID, most used cancer death or specific cancer types as the outcome of interest [23-27]. Only a few population-based studies have assessed the risk of any cancer in relation to ID [28,29]. These studies, however, had some methodological limitations including small sample size and lack of adjustment for familial and birth characteristics, thereby limiting study validity and the possibility of studying rare cancers [28,29]. Close to 20% of all new cancers today are rare (<15 per 100,000 person-years) [30], and this proportion is even higher among children. To test the hypothesis that there is an association between ID and increased risk of cancer, population-based studies with large sample sizes and longitudinal follow-up are required. To this end, we performed a large population-based cohort study to assess the association between ID and risk of cancer, using detailed information on more than 3.5 million individuals in Sweden. We examined the association by ID severity and type (i.e., idiopathic or syndromic), adjusted for several potential confounders including birth characteristics, and performed a sibling comparison to adjust for potential familial confounding.

Methods

Study population

We used nationwide data from Sweden made available via the European Union’s Horizon 2020 research and innovation program RECAP preterm (Research on European Children and Adults Born Preterm; https://www.recap-preterm.eu). The study population consisted of all children live-born in Sweden between 1974 and 2013 and whose mothers were born in a Nordic country. The mothers of these individuals were identified through the Swedish Medical Birth Register, which covers 99% of all births in Sweden since 1973 [31]. Fathers were identified using the Swedish Multi-Generation Register [32]. We first identified a total of 3,557,910 individuals in the study cohort (Fig 1). Individuals with no information on father (N = 23,229), no information on sex (N = 7), or inconsistent information (emigration, death, or cancer diagnosis before birth, N = 3,369) were excluded from the analysis. The prespecified analysis plan is presented in S1 Text.
Fig 1

Flow chart describing inclusion and exclusion of study participants.

ID, intellectual disability.

Flow chart describing inclusion and exclusion of study participants.

ID, intellectual disability.

Ascertainment of ID

ID cases were defined as individuals with a clinical diagnosis of ID during follow-up in the Swedish National Patient Register, which compiles hospital discharge records since 1964 and covers all inpatient discharges since 1987 and outpatient specialist care since 2001 [33]. In Sweden, primary healthcare services for children are provided by child welfare centers that support the health and development of children from infancy to 6 years of age, and nearly 100% of children participate in the follow-up visits [34]. As part of the Swedish child healthcare program, routine medical and developmental screening is regularly conducted for all neonates and preschool children. A more detailed developmental assessment (motor, language, cognitive, and social development) is done at 2.5 and 4 years of age. Children with a suspected ID or other developmental abnormality are referred to a specialized team of pediatricians and child psychologists for further investigation. We used the Swedish revisions of the International Classification of Diseases (ICD) codes in the National Patient Register to classify ID, ID severity (mild, moderate, severe, profound, other, or unspecified), and ID type (idiopathic or syndromic). In the study, syndromic ID was defined as individuals with ID and coexisting congenital malformations or chromosomal abnormalities, whereas idiopathic ID was defined as individuals with ID and without coexisting congenital malformations or chromosomal abnormalities. ICD codes for ID, ID severity, and ID type are listed in S1 Table.

Ascertainment of cancer

Incident cancers were identified through linkage to the Swedish Cancer Register, using the Swedish 7th revision of the ICD codes. By law, all malignant tumors have been reported to the register since 1958, with a completeness close to 100% [35]. We first calculated the frequency of individual cancer types among individuals with and without ID (S2 Table). We then investigated “any cancer” as well as specific cancer types with at least 1 case among individuals with ID, including melanoma, non-melanoma skin cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and cancers of the salivary gland, esophagus, stomach, small intestine, colon, rectum, liver, pancreas, lung, breast, cervix, uterus, ovary, testis, kidney, eye, central nervous system (CNS), thyroid, other endocrine gland, bone, connective tissue, and other or unspecified sites (S3 Table). Individuals with more than 1 cancer type (1 individual with ID and 422 individuals without ID) were counted as a cancer case in the subgroup analysis of each applicable cancer type.

Covariates

We collected information on variables from the Medical Birth Register, including sex (male/female), birth year, maternal age at delivery, maternal smoking during pregnancy (at first antenatal visit), multiple birth, gestational age at birth, birth weight, and Apgar score at 1 minute [31], to be studied as potential confounders or effect modifiers for the studied associations. Apgar score is a common measurement of the immediate health status of infants after delivery, based on skin complexion, heart rate, muscle tone, reflex irritability, and respiration effort. Apgar score has been shown to be associated with cognitive function as well as risk of childhood cancer [36,37]. We obtained information about paternal age at delivery through the Multi-Generation Register [32,38]. Maternal and paternal educational levels were collected from the Swedish Longitudinal Integration Database for Health Insurance and Labour Market Studies, which includes information on socioeconomic status [39]. Information on parental history of psychiatric disorders and cancer at delivery was collected at birth for the cohort participants from the National Patient Register and the Cancer Register, respectively (ICD codes listed in S1 and S3 Tables).

Statistical analysis

The individuals were followed from birth until cancer diagnosis, emigration, death, or 31 December 2016 (up to age 43 years), whichever came first. We divided the individuals into 3 different groups. Individuals receiving a diagnosis of ID during follow-up were defined as the exposed group. As multiple factors clustering in families might be linked with both ID and cancer, we further defined another group consisting of ID-free full siblings of individuals with ID. Finally, individuals without ID and without a full sibling with ID were defined as the reference group. If ID-free siblings or individuals without ID were later diagnosed with ID, they were censored from the sibling or reference group and moved to the exposed group on the date of diagnosis. Similarly, individuals without ID were censored from the reference group if a full sibling was later diagnosed with ID, and were moved to the group of ID-free full siblings of individuals with ID. We calculated the unadjusted incidence rates (IRs) of cancer among individuals with ID and individuals in the reference group during follow-up, using the number of cases divided by accumulated person-years at risk. We used Cox regression models to estimate the relative risk of cancer among individuals with ID compared to the reference group by calculating hazard ratios (HRs) and associated 2-sided 95% Wald-type confidence intervals (CIs), corresponding to a statistical 2-sided test at the 5% level of significance. The HR is the instantaneous relative rate of cancer at any time during follow-up among individuals with ID, compared to individuals without ID [40]. Age at follow-up was used as the underlying time scale. For any cancer as well as for each cancer type, the analyses were performed in 2 models. In model 1, analyses were adjusted for sex (male/female) and birth year. To minimize the potential residual confounding due to a categorical representation of birth year, we fitted the models using natural cubic splines. In model 2, we additionally adjusted for maternal and paternal age at delivery as categorical covariates, and “inherited risk”: presence of maternal and paternal history of psychiatric disorders (yes/no) or cancer (yes/no) at delivery. We repeated the analyses above in subgroups of sex and ID severity (mild, moderate, severe, profound, other, or unspecified), as well as for idiopathic ID and syndromic ID separately. To rule out familial confounding, i.e., confounding due to time-invariant factors common to full siblings, we performed a sibling comparison by fitting conditional Cox regression models to a dataset with differently exposed siblings with the family identifier (mother’s and father’s personal identification number) as strata. We did not adjust for multiplicity of statistical tests. Still, adopting a top-down approach, the main hypothesis of increased risk of any cancer among individuals with ID consisted of only 1 test.

Supplementary and sensitivity analyses

We performed a sequence of supplementary and sensitivity analyses. First, as individuals with ID usually take an IQ test, it could be important to know whether IQ score impacts the association between ID and cancer risk. We derived IQ score from the ICD codes and examined the association between IQ and cancer risk (S1 Table). Second, to further explore the impact of birth characteristics, parental education, and maternal smoking during pregnancy as potential confounders of the association of ID with cancer, we, in separate models, adjusted for gestational age at birth (<37, 37–41, >41 weeks), birth weight (<2.5, 2.5–4, >4 kg), Apgar score at 1 minute, multiple birth (yes or no), maternal and paternal educational level (<9, 9–12, >12 years in school), and maternal smoking during pregnancy (yes or no). We also performed subgroup analyses by these variables to assess whether they could be effect modifiers of the studied association. Third, as the risk of both ID and cancer have been suggested to be increased in individuals born preterm [41,42], we repeated the main analysis among individuals born preterm. Fourth, as the association of ID with cancer might differ during childhood and early adulthood, we further restricted the main analysis to individuals aged ≤18 years. Fifth, to explore age-specific risks, we plotted survival curves of risk of cancer from Cox regression models adjusting for the covariates included in model 1. Sixth, as diagnostic criteria and screening strategies for ID and cancer might have changed during the study, we compared cancer risk among individuals born during 1974–1993 with those born during 1994–2013. Seventh, to address influence of inherited cancer risk, we plotted cancer risk by the estimated heritability of cancer [43]. Eighth, analyzing only individual cancer types with at least 1 case among individuals with ID may introduce bias. In a sensitivity analysis, we studied cancer types by larger categories (i.e., by organ systems) regardless of the number of cases among individuals with ID. Ninth, to address the possibility of reverse causation (i.e., ID might be subsequent to cancer such as CNS tumors), we performed an additional analysis in which individuals with CNS cancer diagnosed within 5 years after the start of follow-up were excluded. SAS software version 9.4 was used for data management and statistical analyses. The SAS codes for data management and the main analysis are presented in S2 Text. The study was approved by the Regional Ethical Review Board in Stockholm, Sweden (Dnr: 2017/1875-31/1). This study is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 STROBE Checklist).

Results

The study cohort included a total of 3,531,305 individuals, including 27,956 (0.8%) individuals diagnosed with ID (15,334 with mild ID, 2,683 with moderate ID, 1,078 with severe ID, 450 with profound ID, and 8,411 with unspecified or other ID) and their 29,641 ID-free full siblings (Tables 1 and S4). Among individuals with ID, 9,878 had syndromic ID (35.3%), whereas 18,078 had idiopathic ID (64.7%). Compared with the reference group, individuals with ID were in general more likely to be male, with lower parental educational level, lower birth weight, lower Apgar score at 1 minute, and a higher prevalence of multiple birth, preterm birth, parental psychiatric history, and maternal smoking during pregnancy (Tables 1 and S4). Characteristics of ID by severity are described in S5 Table.
Table 1

Characteristics of the cohort participants.

VariableNumber (%) of participants
Individuals without ID (reference group)Individuals with IDID-free full siblings of individuals with ID
Number of individuals 3,473,70827,95629,641
Severity of ID
Mild IDNot applicable15,334Not applicable
Moderate IDNot applicable2,683Not applicable
Severe IDNot applicable1,078Not applicable
Profound IDNot applicable450Not applicable
Unspecified or other IDNot applicable8,411Not applicable
Sibship size (number of siblings)
1785,204 (22.6%)7,422 (26.5%)0 (0%)
21,668,452 (48.0%)11,372 (40.7%)10,266 (34.6%)
≥31,020,052 (29.4%)9,162 (32.8%)19,375 (65.4%)
Male sex 1,783,489 (51.3%)16,221 (58.0%)15,091 (50.9%)
Birth year
1974–1983895,736 (25.8%)5,311 (19.0%)5,732 (19.3%)
1984–1993977,135 (28.1%)10,326 (36.9%)11,430 (38.6%)
1994–2003771,253 (22.2%)8,857 (31.7%)8,452 (28.5%)
2004–2013829,584 (23.9%)3,462 (12.4%)4,027 (13.6%)
Maternal age at delivery, years
<2066,964 (1.9%)890 (3.2%)811 (2.7%)
20–291,769,267 (50.9%)14,634 (52.3%)16,037 (54.1%)
30–391,538,099 (44.3%)11,448 (41.0%)11,886 (40.1%)
≥4099,378 (2.9%)984 (3.5%)907 (3.1%)
Paternal age at delivery, years
<2015,143 (0.4%)202 (0.7%)135 (0.5%)
20–291,261,215 (36.3%)10,534 (37.7%)11,181 (37.7%)
30–391,855,087 (53.4%)13,622 (48.7%)14,714 (49.6%)
≥40342,263 (9.9%)3,598 (12.9%)3611 (12.2%)
Maternal history of psychiatric disorder at delivery 205,069 (5.9%)3,094 (11.1%)2,514 (8.5%)
Paternal history of psychiatric disorder at delivery 154,555 (4.5%)2,626 (9.4%)2,187 (7.4%)
Maternal history of cancer at delivery 13,561 (0.4%)97 (0.3%)99 (0.3%)
Paternal history of cancer at delivery 13,871 (0.4%)104 (0.4%)99 (0.3%)

ID, intellectual disability.

ID, intellectual disability. The median follow-up time was 8.9 and 23.0 years for individuals with ID and individuals without ID, respectively. A total of 188 cancer cases were identified among individuals with ID (IR, 62 per 1,000 person-years) and 24,960 among individuals in the reference group (IR, 31 per 1,000 person-years). Individuals with ID, compared with the reference group, had a higher risk of subsequent cancer in both model 1 (HR 1.58, 95% CI 1.36–1.83; P < 0.001) and model 2 (HR 1.57, 95% CI 1.35–1.82; P < 0.001) (Table 2). All HRs presented below are from model 2.
Table 2

Incidence rates and hazard ratios of cancer among individuals with ID by cancer type, compared to the reference group.

Cancer typeIncidence rate of cancer (per 100,000 person-years)Hazard ratio (95% CI)
Reference groupIndividuals with IDModel 1aModel 2b
Any cancer31.4262.491.58 (1.36–1.83)1.57 (1.35–1.82)
Salivary gland0.130.331.8 (0.2–12.8)1.8 (0.2–12.6)
Esophagus0.020.6629.5 (6.5–133.4)28.4 (6.2–130.6)
Stomach0.080.666.0 (1.5–24.6)6.1 (1.5–24.9)
Small intestine0.040.6611.6 (2.8–48.2)12.0 (2.9–50.1)
Colon0.913.642.0 (1.0–4.1)2.0 (1.0–4.1)
Rectum0.240.662.0 (0.5–8.0)2.0 (0.5–8.0)
Liver0.260.331.4 (0.2–9.6)1.4 (0.2–9.9)
Pancreas0.070.666.2 (1.5–25.4)6.0 (1.5–24.8)
Lung0.200.661.1 (0.2–8.0)1.1 (0.1–7.5)
Breast1.981.660.7 (0.3–1.6)0.7 (0.3–1.6)
Cervix1.541.660.8 (0.3–1.9)0.7 (0.3–1.8)
Uterus0.020.3312.9 (1.7–98.4)11.7 (1.5–90.7)
Ovary0.481.322.2 (0.8–6.0)2.2 (0.8–5.9)
Testis2.866.291.3 (0.8–2.1)1.3 (0.8–2.1)
Kidney0.812.324.5 (2.0–10.2)4.4 (2.0–9.8)
Melanoma3.333.640.8 (0.4–1.4)0.8 (0.4–1.4)
Non-melanoma skin0.270.330.9 (0.1–6.6)0.9 (0.1–6.4)
Eye0.510.331.6 (0.2–11.2)1.5 (0.2–11.0)
CNS5.2715.252.7 (2.0–3.7)2.7 (2.0–3.7)
Thyroid1.191.991.0 (0.4–2.4)1.0 (0.4–2.4)
Other endocrine gland1.873.971.5 (0.9–2.7)1.5 (0.9–2.7)
Bone0.690.660.8 (0.2–3.3)0.8 (0.2–3.3)
Connective tissue0.851.321.5 (0.6–4.0)1.5 (0.6–4.0)
Other or unspecified site0.211.325.1 (1.9–13.7)4.8 (1.8–12.9)
Hodgkin lymphoma1.611.990.9 (0.4–1.9)0.9 (0.4–1.9)
Non-Hodgkin lymphoma1.571.661.0 (0.4–2.4)1.0 (0.4–2.3)
ALL2.743.972.4 (1.3–4.4)2.4 (1.3–4.4)
AML0.792.323.0 (1.4–6.4)3.0 (1.4–6.4)

aAnalyses adjusted for birth year (as natural cubic splines) and sex.

bAnalyses additionally adjusted for maternal and paternal age at delivery, maternal and paternal psychiatric disorder history at delivery, and maternal and paternal cancer history at delivery.

ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; CI, confidence interval; CNS, to central nervous system; ID, intellectual disability.

aAnalyses adjusted for birth year (as natural cubic splines) and sex. bAnalyses additionally adjusted for maternal and paternal age at delivery, maternal and paternal psychiatric disorder history at delivery, and maternal and paternal cancer history at delivery. ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; CI, confidence interval; CNS, to central nervous system; ID, intellectual disability. Statistically significant associations were observed for several cancer types, including cancer of the esophagus (HR 28.4, 95% CI 6.2–130.6; P < 0.001), stomach (HR 6.1, 95% CI 1.5–24.9; P = 0.013), small intestine (HR 12.0, 95% CI 2.9–50.1; P < 0.001), colon (HR 2.0, 95% CI 1.0–4.1; P = 0.045), pancreas (HR 6.0, 95% CI 1.5–24.8; P = 0.013), uterus (HR 11.7, 95% CI 1.5–90.7; P = 0.019), kidney (HR 4.4, 95% CI 2.0–9.8; P < 0.001), CNS (HR 2.7, 95% CI 2.0–3.7; P < 0.001), and other or unspecified sites (HR 4.8, 95% CI 1.8–12.9; P = 0.002), as well as ALL (HR 2.4, 95% CI 1.3–4.4; P = 0.003) and AML (HR 3.0, 95% CI 1.4–6.4; P = 0.004) (Table 2). The increased risk of any cancer did not vary between males and females or by ID severity (S1 and S2 Figs), but was higher among individuals with syndromic ID (Fig 2). For idiopathic ID, there was a statistically significantly increased risk of cancer of the esophagus, pancreas, and uterus and ALL, but not for any cancer. The sibling analysis yielded a similar point estimate of risk for any cancer in relation to ID as in the population analysis (Table 3).
Fig 2

HRs of cancer, by cancer type, among patients with idiopathic versus syndromic ID, compared to the reference group.

ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; CI, confidence interval; CNS, central nervous system; HR, hazard ratio; ID, intellectual disability.

Table 3

Familial confounding: IRs (per 100,000 person-years) and HRs of cancer among individuals with ID, compared with their full siblings and the reference group—analyses restricted to individuals with at least 1 full sibling.

Cancer typeIR among individuals with ID and with at least 1 full siblingComparison with reference groupSibling comparisona
IR among reference group with at least 1 full siblingModel 2b HR (95% CI)IR among ID-free full siblings of individuals with IDModel 2b HR (95% CI)
Any cancer65.2529.781.75 (1.47–2.08)42.531.59 (1.13–2.23)
Salivary gland0.460.132.6 (0.4–18.8)0.92—
Esophagus0.460.0130.8 (3.7–253.8)No case—
Stomach0.460.074.1 (0.6–29.7)No case—
Small intestine0.460.0311.4 (1.5–85.5)No case—
Colon4.150.863.0 (1.5–6.1)1.22—
Rectum0.920.203.3 (0.8–13.2)No case—
Liver0.460.252.0 (0.3–14.5)0.31—
Pancreas0.460.073.8 (0.5–27.9)0.31—
Lung0.460.20—0.31—
Breast1.381.570.7 (0.2–2.1)3.36—
Cervix0.461.310.2 (0.0–1.7)1.83—
Uterus0.460.0124.0 (3.0–191.1)No case—
Ovary1.840.443.3 (1.2–9.0)0.61—
Testis6.462.641.4 (0.8–2.4)4.892.2 (0.2–25.1)
Kidney2.310.784.6 (1.7–12.4)0.61—
Melanoma2.313.040.5 (0.2–1.2)5.800.6 (0.1–2.4)
Non-melanoma skin0.460.231.4 (0.2–10.3)0.31—
EyeNo case0.49—0.31—
CNS18.475.263.4 (2.5–4.8)4.287.4 (2.0–27.5)
Thyroid2.311.101.1 (0.4–3.0)3.660.8 (0.1–6.4)
Other endocrine gland4.151.771.7 (0.9–3.3)3.970.9 (0.2–3.4)
Bone0.920.691.1 (0.3–4.6)0.61—
Connective tissue1.840.872.0 (0.7–5.4)0.92—
Other or unspecified site1.380.195.6 (1.8–17.7)0.31—
Hodgkin lymphoma2.311.581.0 (0.4–2.4)2.75—
Non-Hodgkin lymphoma1.841.521.1 (0.4–3.0)2.440.9 (0.1–14.0)
ALL4.152.812.8 (1.4–5.4)1.22—
AML2.770.813.7 (1.6–8.2)0.61—

A dash indicates too few cancer cases to allow estimation.

aAnalyses were stratified by family identifier using conditional Cox regression model.

bAnalyses adjusted for birth year (as natural cubic splines), sex, maternal and paternal age at delivery, maternal and paternal psychiatric disorder history at delivery, and maternal and paternal cancer history at delivery.

ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; CI, confidence interval; CNS, central nervous system; HR, hazard ratio; ID, intellectual disability; IR, incidence rate.

HRs of cancer, by cancer type, among patients with idiopathic versus syndromic ID, compared to the reference group.

ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; CI, confidence interval; CNS, central nervous system; HR, hazard ratio; ID, intellectual disability. A dash indicates too few cancer cases to allow estimation. aAnalyses were stratified by family identifier using conditional Cox regression model. bAnalyses adjusted for birth year (as natural cubic splines), sex, maternal and paternal age at delivery, maternal and paternal psychiatric disorder history at delivery, and maternal and paternal cancer history at delivery. ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; CI, confidence interval; CNS, central nervous system; HR, hazard ratio; ID, intellectual disability; IR, incidence rate. First, we found no association between IQ level and cancer risk (S6 Table). Second, the association between ID and any cancer did not change by birth weight, Apgar score at 1 minute, gestational age at birth, multiple birth, parental education at delivery, or maternal smoking during pregnancy (S7 Table). Third, among individuals born preterm, we observed an increased risk of small intestine cancer (HR 89.7, 95% CI 5.6–1,439.8; P = 0.002) and ovarian cancer (HR 10.0, 95% CI 2.3–43.6; P = 0.002) among individuals with ID (S8 Table). Fourth, there was a higher risk of any childhood cancer among individuals with ID (HR 2.81, 95% CI 2.18–3.62; P < 0.001) (S9 Table). Fifth, by visual inspection (S3 Fig), the risk increases of cancer of the esophagus, stomach, small intestine, pancreas, and other or unspecific sites appear to be more pronounced among older than younger individuals. Sixth, we did not find a difference in risk of any cancer when separately analyzing individuals born 1974 to 1993 (HR 2.90, 95% CI 1.75–4.82; P < 0.001) and individuals born 1994 to 2013 (HR 2.74, 95% CI 1.92–3.91; P < 0.001) (S10 Table). Seventh, the association between ID and cancer was not related to cancer heritability (S4 Fig). Eighth, we observed statistically significant associations for cancers of the digestive system (HR 2.9, 95% CI 1.8–4.6; P < 0.001), urinary system (HR 2.8, 95% CI 1.3–6.3; P = 0.01), and CNS (HR 2.7, 95% CI 2.0–3.7; P < 0.001) as well as hematological malignancies (HR 1.5, 95% CI 1.1–2.2; P = 0.02) (S11 Table). Ninth, we observed a statistically significantly higher risk (HR 1.6, 95% CI 1.0–2.4; P = 0.034) of CNS cancer among individuals with ID after excluding CNS cancers diagnosed within 5 years after ID diagnosis.

Discussion

In the largest population-based cohort study to date, to our knowledge, we observed a 1.6-fold increased risk of any cancer among individuals with ID, compared with individuals without ID, up to age 43 years. There was also an increased risk for several cancer types, including cancer of the esophagus, stomach, small intestine, colon, pancreas, uterus, kidney, CNS, and other or unspecified sites, as well as AML and ALL. The risk of any cancer was higher for syndromic ID and for childhood cancer, but did not vary by sex, ID severity, birth weight, Apgar score at 1 minute, gestational age at birth, parental education, maternal smoking during pregnancy, or calendar year of birth. The sibling comparison showed no support for familial confounding of the observed association.

Strengths and weaknesses of this study

Strengths of our study include the population-based cohort design with large sample size, and the longitudinal and complete follow-up. Together with the independently collected information on ID and cancer, these strengths minimize the risk of selection and information biases. The adjustment for potential confounders and the sibling comparison could partly eliminate the concern that the observed associations were due to confounding (including familial confounding), which further strengthened the validity of our findings. Our study also has limitations. Since individuals with ID usually have difficulty communicating signs and symptoms, they might experience delayed cancer diagnosis or underdiagnosis of cancer [44,45]. Although we had no data on cancer stage in the present study, we did notice a higher incidence of cancer of other or unspecified sites (i.e., cancer of unknown origin or diagnosed at metastatic stage) among individuals with ID, compared with others. Diagnostic delay and underdiagnosis of cancer among individuals with ID could have led to underestimation of the studied associations. No access to ID diagnoses from primary care, and inclusion of outpatient diagnoses in the National Patient Register only from 2001 onwards, might potentially have led to underdetection of ID cases, especially mild ID. Because we focused on individuals with a clinical diagnosis of ID through the National Patient Register, ID cases generally not only had low IQ score, but also showed relatively severe symptoms, required extended care, or could not address daily tasks; therefore, the generalizability of our findings to individuals with mild cases needs further assessment. ID might be consequent to cancer such as CNS cancer. The increased risk of CNS cancer among individuals with ID even after excluding CNS cancers diagnosed within 5 years after ID diagnosis alleviated concern about reverse causation to a large extent. Restricting analysis to individual cancer types with at least 1 case among individuals with ID might have introduced bias to some extent. Interpretation of the cancer-type-specific results should therefore be cautious. Despite the large sample size, our study could only address cancer cases diagnosed up to 43 years of age and had limited power to assess the risk of cancers mostly diagnosed at later age, e.g., prostate cancer and lung cancer. Finally, we had no information on behavioral factors, such as diet and physical activity, which might confound or mediate the association of interest. However, as these factors are prone to cluster within families, the similar results of the sibling comparison should have partly alleviated such concern.

Comparison with other studies

In line with previous research [46], we observed a higher prevalence of ID among males than females. One potential reason is that males have higher vulnerability to syndromes linked to the X chromosome, such as fragile X syndrome, which is related to higher risk of ID [47]. Another reason might be differential brain development due to different androgen exposure between males and females [48]. We observed an increased risk of cancer among individuals with ID, in contrast to previous studies that reported similar risk of cancer between ID patients and the general population [28,29]. The different results might arise because previous studies involved a wider age range, including older individuals, whereas we focused on childhood and early adulthood. Another potential reason for the different results might be the small sample size and the potential for random error in previous studies [28,29]. Patja et al. [28] studied 2,173 individuals with ID in a 30-year follow-up study of a Finnish population, whereas Sullivan et al. [29] studied 9,409 individuals with ID in a 19-year follow-up study of a population in Western Australia. With a total number of 27,956 individuals with ID and a follow-up of 43 years, the present study represents therefore, to our knowledge, the greatest effort of its kind to date. In addition, our study is the first to our knowledge to report the cancer risk of individuals with idiopathic ID. We observed no excess risk of any cancer, but increased risk of cancer of the esophagus, pancreas, and uterus, as well as ALL, among individuals with idiopathic ID, thereby expanding the previous knowledge base further. Our study showed increased risks for colon and uterus cancers in females and CNS cancer in males among individuals with ID, which is in line with 1 previous study [29]. However, we did not observe statistically significantly increased risk of stomach cancer or decreased risk of prostate cancer among males [29], nor increased risk of gallbladder and thyroid cancers in general [28], among individuals with ID. The contrasting results may be partly due to the different age ranges of the studied participants in the different studies.

Potential mechanisms

One potential mechanism for the observed association between ID and any cancer is that ID in some cases might be caused by multiple-system congenital anomalies affecting more than 1 organ [49]. For instance, Down syndrome, one of the leading causes of ID, is related to the presence of somatic mutations in GATA1 and JAK2, which are associated with acute megakaryoblastic leukemia and ALL [10,11,50,51]. Tuberous sclerosis, another common cause of syndromic ID, is associated with increased risk of brain tumor due to mutations of TSC1 and TSC2 [52,53]. Lifestyle factors that differ between individuals with and without ID might also play a role. We observed an increased risk of cancer of the digestive system among individuals with ID. This could be associated with unbalanced diet as well as poor oral hygiene among individuals with ID [13,14,54,55]. To be noted, we found a markedly increased risk of esophagus cancer among individuals with ID, in line with previous findings [27], which might be related to a higher prevalence of gastroesophageal reflux disease, an established cause of esophagus cancer [56], in individuals with ID [57]. Moreover, overweight and physical inactivity among individuals with ID might also play a role in the association between ID and increased risk of several cancer types, including uterus and kidney cancer [58-60]. Our results suggest that individuals with ID who were born preterm had a markedly increased risk of ovarian cancer compared with the general population. Such risk elevation might be related to the higher prevalence of abnormal ovarian function and smaller ovary size among individuals with preterm birth [61], which might contribute to the effect of ID on ovarian cancer. As ID and cancer are both heterogeneous diseases with various etiologies, further studies are warranted to better understand the underlying mechanisms.

Conclusion

There is an increased risk of any cancer, as well as of several specific cancer types, among individuals with ID. The associations could not be explained by shared genetics or other familial confounders of ID and cancer.

Hazard ratios (HRs) of cancer among individuals with intellectual disability (ID) by sex, compared to the reference group.

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Hazard ratios (HRs) of cancer among individuals with ID by intellectual disability (ID) severity and by cancer type, compared to the reference group.

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Cancer risk overall (any cancer) and by cancer type among individuals with ID and in the reference group.

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Hazard ratios (HRs) of cancer among individuals with intellectual disability (ID) by heritability of cancer, compared to the reference group.

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STROBE Statement—checklist of items that should be included in reports of observational studies.

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ICD codes for intellectual disability (ID), severity of ID, ID type, intelligence quotient (IQ), psychiatric disorders, and congenital malformations and chromosomal abnormalities.

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Numbers of cancer cases among individuals with ID and individuals without ID.

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ICD codes for studied cancer types.

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Birth characteristics, parental education, and maternal smoking during pregnancy of the cohort participants.

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Characteristics of individuals with intellectual disability (ID) by severity of ID.

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Association between IQ score and risk of cancer among individuals with intellectual disability, compared to the reference group, by cancer type.

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Hazard ratios (HRs) with 95% confidence intervals (CIs) of any cancer among individuals with intellectual disability (ID), compared to the reference group, further separately adjusted for or stratified by maternal smoking during pregnancy, parental education at delivery, multiple birth, gestational age at birth, birth weight, and Apgar score at 1 minute.

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Subgroup analyses of preterm birth: Incidence rates (IRs, per 100,000 person-years) and hazard ratios (HRs) with 95% confidence intervals (CIs) of cancer among individuals with intellectual disability (ID), compared to the reference group, restricting analyses to individuals who were born preterm.

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Incidence rates (IRs, per 100,000 person-years) and hazard ratios (HRs) with 95% confidence intervals (CIs) of childhood cancer (age ≤ 18 years) among individuals with intellectual disability (ID) by cancer type, compared to the reference group.

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Comparison between different calendar years: Incidence rates (IRs, per 100,000 person-years) and hazard ratios (HRs) with 95% confidence intervals (CIs) of cancer among individuals with intellectual disability (ID), compared to the reference group, for individuals born during 1994–2013 and those born during 1974–1993.

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Incidence rates (IRs, per 100,000 person-years) and hazard ratios (HRs) with 95% confidence intervals (CIs) of cancer among individuals with intellectual disability (ID) by organ system, compared to the reference group.

(PDF) Click here for additional data file. (PDF) Click here for additional data file. (PDF) Click here for additional data file. 27 Apr 2021 Dear Dr Liu, Thank you for submitting your manuscript entitled "Cancer risk in individuals with intellectual disability" for consideration by PLOS Medicine. Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external assessment. However, before we can send your manuscript for assessment, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire. Please re-submit your manuscript within two working days, i.e. by Apr 29 2021 11:59PM. 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Sincerely, Richard Turner, PhD Senior Editor, PLOS Medicine rturner@plos.org ----------------------------------------------------------- Requests from the editors: Please adapt the title so that it contains a study descriptor after a colon, e.g., "Cancer risk in individuals with intellectual disability: A population-based cohort study". Please adapt the abstract to a three-part structure. Rather than "Nordic mothers", please write "... of mothers born in ..." or similar, in the abstract and any other instances in the paper. In the abstract and throughout the paper, please quote p values alongside 95% CI, where available. Please add a final sentence to the new "Methods and findings" subsection of your abstract, which should begin "Study limitations include ..." or similar and should quote 2-3 of the study's main limitations. After the abstract, we will need to ask you to add a new and accessible "Author summary" section in non-identical prose. You may find it helpful to consult one or two recent research papers in PLOS Medicine to get a sense of the preferred style. Early in the Methods section, please state whether or not the study had a protocol or prespecified analysis plan, and if so attach the relevant document as a supplementary file, referred to in the text. Please highlight analyses that were not presecified. Please remove the information on funding and competing interests from the Acknowledgements section at the end of the main text. In the event of publication, this information will be included in the article metadata, via entries in the submission form. Throughout the text, please adapt reference call-outs to the following style: "... study rare cancers [11,12]." (noting the absence of spaces within the square brackets). Please abbreviate journal names consistently in your reference list. Where appropriate, 6 author names should be listed rather than 3, followed by "et al.". Please add a completed checklist for the most appropriate reporting guideline, e.g., STROBE, as a supplementary file, labelled "S1_STROBE_Checklist" or similar and referred to as such in the Methods section. In the checklist, please refer to individual items by section (e.g., "Methods") and paragraph number, not by line or page numbers as these generally change in the event of publication. Comments from the reviewers: *** Reviewer #1: The study titled "Cancer risk in individuals with intellectual disability" is one of its kind in both the terms of topic selection as well as the large sample size that is evaluated in the study. It strives to create a association between intellectual disability and occurrence of any form of cancer. The study would have an impact in the guidelines of management of all forms of intellectual disability in the form of adding need of cancer screening in virtually all causes of intellectual disability. It might even cause a debate or ethical dilemma regarding the management and prognosis of intellectual disability. The strength of the study lies in the fact that: 1. The study is prospective in nature 2. The sample size is large 3. No population under study is left out: The authors claim that the children are screened and diagnosed early as well as the cancer registry is nearly encompasses all of the malignancies that might occur 4. Statistical analysis done robustly to remove certain confounding factors However certain facts cannot be overlooked while going through the study. 1. The "Introduction" section does not justify the caliber of the study or the journal. The section glances over the statistics regarding intellectual disability and malignancies. However, the causes of known and unknown causes of intellectual malignancies seem to be missing. The literature review seems to miss multiple similar papers. The scientifically proven causation of different forms of intellectual disabilities along with mutations attributed to malignancy development are not mentioned. 2. The "Methodology" section establishes the fact that cases under study are unlikely to be missed. However, not all forms of intellectual disabilities manifest at a young age. The authors mention about a mandatory wellness child examination at the age of four. They fail to mention where the examination occurs. For instance if it occurs in school, would the children at home, which is likely in intellectually disabled child due to logistic or other reasons, be missed? 3. In the "Statistical analysis" section, does the comparison of IQ score with risk of cancer have any clinical significance? 4. The "Discussion" portion of the study does not compare multiple similar articles. Ways to improve the article: 1. The authors need to perform literature review and update the "Introduction" and "Discussion" section. 2. If they have sufficient data from the registry, could they demonstrate the occurrences of proven malignancies to proven clinical diagnoses. e.g. prevalence of certain malignancies in Down syndrome. This would further validate the data. 3. Was the family history of malignancy collected? The manuscript does not explicitly mention this. If so, was the "end point" of malignancy detection in the intellectually disabled individuals the same as for family members. 4. The article needs overall editing of the language for it to be more comprehensible. Maybe technical terms could be better phrased so that it would find a wider audience. 5. Could the authors mention also about the diagnosed causes of intellectual disability according to prevalence? 6. The "Methodology" section could be overhauled to make it easier for the study to be reproduced. 7. Compare the malignancy trend with the trend in the country. Does it reflect the prevalence/incidence of malignancies as evidenced by other studies or cancer registry? 8. Present the data in a more palatable graphical representations instead of only tables. *** Reviewer #2: Overall the manuscript is written clearly and concisely, the topic is relevant, and the research extends existing knowledge. I would recommend this manuscript be published in PLOS medicine with some revisions. One of the most important revisions I suggest is to explain further what the hazard ratio statistic means, as this could easily be misunderstood. For example, when you say 'a 1.6-fold increased risk of any cancer' on page 12, tell the reader how they should interpret that. Spruance SL, Reid JE, Grace M, Samore M. Hazard ratio in clinical trials. Antimicrobial agents and chemotherapy. 2004 Aug;48(8):2787-92. Sutradhar R, Austin PC. Relative rates not relative risks: addressing a widespread misinterpretation of hazard ratios. Annals of epidemiology. 2018 Jan 1;28(1):54-7. More Minor recommendations: * You could change your title to include the fact that you did a population-cohort study in Sweden, this makes the life of future researchers easier when they come across your study. * P. 5 - The first paragraph with the definition of ID is very clear. However, you could also give examples of the most common forms of ID to give the reader some context. * P. 6 - Does 'Nordic mothers in Sweden' mean that everyone is of the same ethnicity or with is it simply related to citizenship? Was this something recorded in the data you had? This does not need to be something you add as a covariate into analyses necessarily, but it is interesting to know the diversity of the population you looked at. * P. 7 - You could define what the Apgar score is and how it is relevant, as not everyone will know this. * P. 7 - You said you 'obtained information about paternal age at delivery through Multi-Generation Register' - But, I wondered if you were successful at tracing all fathers? If not, did that impact some of your analysed sample sizes? * P. 9 - I have a few comments around the terms used for sex. * You include sex as a covariate in some analyses, but you do not state whether the levels for this are 2 (Female, Male) or 3 (Female, Male, Intersex). Please define this as you do for covariate such as severity of ID. * Also, the terms sex and gender, though commonly used interchangeably in research, are seen as two distinct aspects of an individual's lived experience. * Best current practice is to refer to sex at birth (Female, Male, Intersex/Undetermined) and gender identity (woman, man, non-binary, indigenous or other cultural gender minority [e.g., two-spirit], etc.,). * Slade T, Gross DP, Niwa L, McKillop AB, Guptill C. Sex and gender demographic questions: improving methodological quality, inclusivity, and ethical administration. International Journal of Social Research Methodology. 2020 Sep 12:1-2. * Most relevant to your article is sex at birth of course, but on pages 12 and 18 you refer to 'men and women'. It would be more appropriate for you to refer to male and female if you are interested in sex at birth rather than gender identity. * P. 9 - Do you have a citation for 'the risk of both ID and cancer is increased in preterm born individuals,' ? * P. 10 - Do you have any code that you could share for your statistical analysis? * P. 11 - The result you give for point (1) in your supplementary and sensitivity analyses section is very short and could be a bit clearer. In particular, what do you mean by 'similar'? * P. 12 - Be careful with using the word 'greatly', perhaps remove and just say that it 'did not vary by sex, ID severity' etc., as that is what you found. * P. 12 - Similarly, you say 'not predominantly due to factor shared by siblings', but did you show that it was related to this at all? This relates back to your explanation of point 1 in sup/sensitivity analysis in results. * P. 12 - You mention that there is delay and under-diagnosis of cancer in people with IDs. This is an extremely impactful point that would be worth explaining a little further to the reader. * Firstly, give a citation for your statement (e.g., Hogg and Tuffrey-Wijne, 2008, and say why is this could be the case (i.e. communication difficulties leading to lack of pain reporting - Hogg and Tuffrey-Wijne, 2008; Millard and de Knegt, 2019). * Hogg J, Tuffrey‐Wijne I. Cancer and intellectual disability: a review of some key contextual issues. Journal of Applied Research in Intellectual Disabilities. 2008 Nov;21(6):509-18. * Millard SK, de Knegt NC. Cancer pain in people with intellectual disabilities: systematic review and survey of health care professionals. Journal of pain and symptom management. 2019 Dec 1;58(6):1081-99. * Related to this, do you know anything about the stage of cancer at diagnosis in your data? You may have been able to show that there is delayed diagnosis of cancer in people with IDs. * P. 13 - You say that previous studies had smaller numbers and shorter durations, it may be useful to mention how large and long these studies where, and also in what populations. This could be done either in your introduction or here in the discussion. Having this clearly means that the reader understands the full scope of the study you've done, and if your study is so much bigger, you should display that. * On a related point, how long is 'enough follow-up'? * Additionally, did you use any reporting guidelines? *** Reviewer #3: Please note that this is a statistical review - I cannot comment on the importance of findings, only the validity. -- This paper assesses whether individuals with intellectual disability are more likely to suffer from cancer than those without intellectual disability (ID) using registry data from Sweden. The authors additionally perform analyses to assess whether the association is likely to relate to ID in a causal sense. 1) Due to the design (the oldest individuals in the analysis are 43 years old, and the vast majority of years-at-risk are in much younger individuals), this analysis focuses on cancers of young and early-middle age. This should be clearer in the manuscript. For example, the title could state: "Cancer risk in individuals with intellectual disability: analysis of registry data on young and early-middle age Swedish participants" (or similar). 2) Is the definition of syndromic ID standard? It seems somewhat narrow to my untrained eye. 3) While I understand that some of the motivation for the investigation comes from the desire to analyse rare cancers, some of these cancers are very rare. Aside from the wide confidence intervals in some analyses, this also leads to an upward bias in estimates that results from only including cancers with at least one case. If a cancer had no cases amongst individuals with ID, then this cancer would not be included in the analysis. The restriction to cancers with at least one case means that for very rare cancers, a positive hazard ratio (HR) is guaranteed. Additionally, as an individual can contribute to more than one cancer, it may be that several of the positive HR estimates are due to a single individual with multiple rare cancers - while the wide confidence intervals indicate imprecise estimates, they aren't able to inform the reader whether these are multiple independent wide estimates, or multiple dependent wide estimates taking positive values due to one or two multimorbid individuals. For this reason, I would suggest either dropping the analyses of cancers with small numbers of cases in individuals with ID (eg only cancers with >5 cases), or greater aggregation of cancer outcomes, to include cancer types with no cases in individuals with ID - this is important to ensure that estimates are not biased by the exclusion of cancer types with zero cases. Greater aggregation of cancer outcomes would also ensure that individuals with multiple cancer types do not have an undue influence on analyses. 4) Page 7: "To adjust for potential confounding or effect modification..." - does covariate adjustment account for effect modification? 5) The list of covariates on page 7 is somewhat confusing. My initial reading was that these listed covariates would be adjusted for in the analysis. But on closer reading, these variables are only adjusted for in supplementary analyses? And it's not clear from eTable 8 that there is any analysis performed that adjusted for all of these variables? - you stratify on some of them, but I think you only adjust for at most one of these at a time? I understand that the main analyses should be careful not to over-adjust (as potentially some of these variables are mediators), so for me, this is a case of clarifying the text rather than changing the analysis. 6) Page 8: "Attained age was used as the underlying time scale" - what is attained age? 7) Page 9: "We examined the effect of intelligence quotient (IQ) score on cancer risk through deriving IQ score from the ICD diagnostic codes." - please be careful of causal language. 8) Tables 2-4 may be clearer as figures. It's difficult to take in and compare all the HRs - would be more impactful if the reader could scan a column of visual estimates rather than have to read all the numbers. 9) Would be good to include the headline results from the supplementary and sensitivity analyses in the manuscript (eg the HR for all-cancer from the sibling comparision, the HR for the association between IQ and cancer risk, etc). 10) Page 11: "By visual inspection (eFigure 2), cancer risk appears to increase with age for cancer in the esophagus, stomach, small intestine, pancreas and other or unspecific sites among individuals with ID, compared with the reference group" - it's not clear what comparison you are making here. 11) eTable 7: Two of the odds ratios are over 900 million - something not quite right here. 12) Discussion: Is reverse causation a possibility, particularly for CNS cancers? Could be that pre-clinical cancer increases risk of ID? 13) Abstract: The claim of "detailed adjustment for potential confounding" is somewhat misplaced (in the text, the claim is phrased as: "adjusted for a rich set of potential confounders"). First, it's not clear why the authors want to adjust for large numbers of confounders - if this analysis is simply performed to identify whether individuals with ID are at increased cancer risk, then adjustment for covariates is unnecessary. Secondly, the main model 1 and 2 do not adjust for large numbers of covariates (again, I don't think this is unreasonable). Thirdly, many key covariates (BMI, smoking status, alcohol status, etc) are not available in the dataset. And finally, it's not clear that all the covariates are confounders. So while I value the potential for addressing confounding in the within-family analyses (and would suggest that eTable 6 may be worth including as a main table/figure), I wouldn't say that comprehensive covariate adjustment is a feature of this work (not should it be). Overall, the researchers provide convincing evidence that individuals with ID are at greater risk of cancer both when comparing to the general population, and when restricting to matched comparisons within family units. I am cautious about the validity of some of the detailed comparisons of cancer subtypes, and would encourage either focus on a smaller number of cancer subtypes, or aggregation of related subtypes. However, I leave the final decision here to subject-matter experts. *** Reviewer #4: This is a well-structured and well-written article with well-defined title, clear aim. The important finding of this study is the 1.6-fold increase of cancer rate among patient with ID. Regarding methodology, the process of subject selection was clear, variables were defined and measured appropriately, and study methods seemed to be valid and reliable. But I like to request for further checking of methodology by more experienced one. This study also highlighted some possible mechanisms behind this scene, which made it praiseworthy and helpful for further research. From my side, there is no correction needed. *** Reviewer #5: This manuscript by Liu et al is one of the largest longitudinal studies that has been carried out to estimate the risk of cancer among individuals with intellectual disability. The study shows that individuals with ID have an increased risk of cancer and suggest extended surveillance/early intervention in cancer. The manuscript is well written, addresses the strengths and weakness of the study and compares with previous studies. I recommend this manuscript for publication to advance the understanding in this field. Following are some of the points that I would like to get some clarifications on: 1. In one of the previous studies by Sullivan et al. 2004 (PMID: 15801486), males with ID were observed to have a significantly increased risk of leukemia, brain and stomach cancers and a reduced risk of prostate cancer, while leukemia, corpus uteri and colorectal cancers were significantly higher in females. Did the authors in the current manuscript investigate it? Authors mention on Page 11 that 'The increased risk of any cancer did not vary by ID severity or between men and women….". Authors should include in the discussion why they do not see the increased risk of cancer among men and women in comparison to Sullivan et al. 2. eTable5 shows characteristics of individuals with ID by severity of ID. The percentage of different categories of ID were shown for males. Is there a reason why this percentage were not shown for females? Authors should show the percentage of females with breakdown into different ID groups as they have done for males in this Table to make it complete. Looks like out of 27,956 individuals with ID, about 16,221 (58%) were males and about 11,735 (~42%) of them were females. 3. Authors also mention that compared with the reference group, individuals with ID were in general more likely to be male. They should mention in the manuscript the possible reason behind it. We know there is a higher prevalence of ID in males than in females. *** Any attachments provided with reviews can be seen via the following link: [LINK] 2 Sep 2021 Submitted filename: Response to Reviewers.pdf Click here for additional data file. 30 Sep 2021 Dear Dr. Liu, Thank you very much for re-submitting your manuscript "Cancer risk in individuals with intellectual disability: A population-based cohort study" (PMEDICINE-D-21-01891R2) for consideration at PLOS Medicine. I have discussed the paper with our academic editor and it was also seen again by four reviewers. I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal. The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript: [LINK] ***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.*** In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns. We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it. To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org. Please let me know if you have any questions, and we look forward to receiving the revised manuscript. Sincerely, Richard Turner, PhD Senior Editor, PLOS Medicine rturner@plos.org ------------------------------------------------------------ Requests from Editors: We suggest adding "in Sweden", or similar, to the title. At line 36 (abstract), prior to the presentation of the quantitative findings, we suggest adding a sentence or two to provide some additional detail: including the higher rate of ID in males, the length of follow-up, and the numbers of cancers in both groups. At line 38, please make that "the esophagus ...". At line 46, please remove "Despite the large sample size and high-quality data ..."; we suggest adapting the text immediately after this point to: "The main study limitations were the limited statistical power for the analysis of specific cancer types, and the potential for underestimation of the studied associations (e.g., due to potential under-detection or delayed diagnosis of cancer among individuals with ID).". At line 51, please adapt the text to the style "In this study, we found that ...". Please add bullets to the individual points in the Author summary. Please also expand the Author summary so that each subsection has 2-3 points. For example, in the final subsection an additional point could cite a need for further research on incidence of some specific types of cancer. Please remove the word "prospective" at line 282 and any other instances (we view this as a retrospective analysis). Please use the general style "age 43 years" throughout. Noting reference 7, some punctuation should be removed from the author list (to leave "Linn JG, ..."); in reference 45, authors' initials should be used. We suggest moving S1 Figure to the main part of the paper. Please relabel the STROBE attachment "S3_STROBE_Checklist" and refer to it by this label in the Methods section. Comments from Reviewers: *** Reviewer #1: This article is definitely among the largest of its kind in terms of sample size. The current form of the article seems streamlined and easier to read. The amendments made in this article are commendable. I would recommend the article to be published in its current form. The conception of idea for the research as well as its novel finding will definitely be of important concern in the future. It might have a public health impact in the sense that recommendations about screening for malignancies for cases with intellectual disabilities could be based on these findings. I would like to congratulate the whole team for their efforts. Thank you. *** Reviewer #2: Again, I believe this research extends existing knowledge well and is impactful due to its large sample and thorough methodology. The authors address all my points appropriately and I believe this article is now clear and strong. I will allow comments on changes to the statistics to be made by reviewer 3, but I have a few other minor points outlined below. After these points have been addressed, I am satisfied and happy for this work to be published in PLOS medicine. 1) P.8 Line 154-6, I feel this sentence could be a little clearer: "An individual with more than one cancer type (one individual with ID and 422 individuals without ID) was counted as a cancer case in the analysis of several cancer types" a. It is unclear if this means they were put into a completely separate analysis. A little clarity would help. 2) Great to see that the authors were responsive to my comments on sex and gender. One last addition to this point, on P.8 Line 158, perhaps add "(male/female)" after the variable "sex" so that the reader knows that intersex was not included in this variable. 3) P.10 Line 198, there seems to be a spelling error: "within-sibship" 4) P13 Line 276, possibly another spelling error: "statistically significantly" should be "statistically significant" 5) P14 Line 294, the adjustment for potential confounders should be considered in relation to comments from reviewer 3, however, maybe at this point you could explain why finding that confounders did not impact results is important? 6) P17 Line 348, you abbreviate ALL but not AML, is there a reason for this? 7) Double check gramma in the discussion, I think a few changes have been made that the authors should give another once over to improve readability. *** Reviewer #3: Thanks to the authors for their comprehensive revision of this work. It is reassuring to know that the bias arising from considering cancers with at least 1 case in individuals with ID is not considerable. It is also reassuring to know that the results for rare cancers are not driven by a single individual (or a small number of individuals) with ID who are massively multimorbid. I have a few comments: Paragraph on Supplementary and sensitivity analyses - if there are key summary measures or estimates, I'd consider providing these in the manuscript. Figure 1: For me, this is hard to read, and it's a shame to lose the uncertainty intervals for the estimates. I would suggest a single vertical axis, and paired estimates plotted with the uncertainty interval horizontally - one colour for syndromic, another colour for idiopathic. Similar to a forest plot, but with equal sized points and no pooled estimate. I think a series of paired points and horizontal lines (with estimates along the right hand side?) would provide a more compelling presentation. From a quick search, this is close to what I had in mind: https://plos.figshare.com/articles/figure/_Forest_Plot_of_Unadjusted_and_Adjusted_Hazard_Ratios_for_Any_and_Violent_Convictions_/1482255/1 - although with pairs of points, not triples, and using colour. (Just to clarify, this is a suggestion - the authors should decide the optimal way to present their data in consultation with the editors.) If the authors do make this change, I'd consider similar changes for Supp Figures 2 and 3. S2 Table - what are the %s? Are they % of the overall population with this cancer? Or % of all cancers? S6 Table - the inexact phrasing "effect of IQ score" is still in the heading. --- Stephen Burgess *** Reviewer #5: The manuscript is considerably improved from the first submission. I accept it in its current form. *** Any attachments provided with reviews can be seen via the following link: [LINK] 7 Oct 2021 Submitted filename: Response to editors and reviewers.docx Click here for additional data file. 8 Oct 2021 Dear Dr Liu, On behalf of my colleagues and the Academic Editor, Dr Zheng, I am pleased to inform you that we have agreed to publish your manuscript "Cancer risk in individuals with intellectual disability: A population-based cohort study in Sweden" (PMEDICINE-D-21-01891R3) in PLOS Medicine. Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes. Prior to final acceptance, we suggest moving "in Sweden" before the colon (title). In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. PRESS We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf. We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/. To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. Sincerely, Richard Turner, PhD Senior Editor, PLOS Medicine rturner@plos.org
  55 in total

Review 1.  Prevalence of intellectual disability: a meta-analysis of population-based studies.

Authors:  Pallab K Maulik; Maya N Mascarenhas; Colin D Mathers; Tarun Dua; Shekhar Saxena
Journal:  Res Dev Disabil       Date:  2011-01-13

Review 2.  Epidemiology and risk factors for kidney cancer.

Authors:  Wong-Ho Chow; Linda M Dong; Susan S Devesa
Journal:  Nat Rev Urol       Date:  2010-05       Impact factor: 14.432

3.  Mortality in people with intellectual disabilities in England.

Authors:  G Glover; R Williams; P Heslop; J Oyinlola; J Grey
Journal:  J Intellect Disabil Res       Date:  2016-08-02

4.  The prevalence and course of idiopathic toe-walking in 5-year-old children.

Authors:  Pähr Engström; Kristina Tedroff
Journal:  Pediatrics       Date:  2012-07-23       Impact factor: 7.124

Review 5.  Myeloid leukemia in Down syndrome.

Authors:  Irum Khan; Sébastien Malinge; John Crispino
Journal:  Crit Rev Oncog       Date:  2011

6.  Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.

Authors:  Joshua Wechsler; Marianne Greene; Michael A McDevitt; John Anastasi; Judith E Karp; Michelle M Le Beau; John D Crispino
Journal:  Nat Genet       Date:  2002-08-12       Impact factor: 38.330

7.  The completeness of the Swedish Cancer Register: a sample survey for year 1998.

Authors:  Lotti Barlow; Kerstin Westergren; Lars Holmberg; Mats Talbäck
Journal:  Acta Oncol       Date:  2009       Impact factor: 4.089

8.  Cancer incidence among persons with fragile X syndrome in Finland: a population-based study.

Authors:  R Sund; E Pukkala; K Patja
Journal:  J Intellect Disabil Res       Date:  2008-08-13

9.  Previously unidentified morbidity in patients with intellectual disability.

Authors:  Helen Baxter; Kathy Lowe; Helen Houston; Glyn Jones; David Felce; Michael Kerr
Journal:  Br J Gen Pract       Date:  2006-02       Impact factor: 5.386

10.  Prevalence of intellectual disability: a comprehensive study based on national registers.

Authors:  H Westerinen; M Kaski; L Virta; F Almqvist; M Iivanainen
Journal:  J Intellect Disabil Res       Date:  2007-09
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  3 in total

1.  Mediastinal thymoma in a patient with previous rectal and breast cancers: A report of a case with multiple primary cancers and review of literature.

Authors:  Parviz Mardani; Mohammadmehdi Fallahi; Hooman Kamran; Reza Shahriarirad; Mohammad Hossein Anbardar; Neda Soleimani
Journal:  Clin Case Rep       Date:  2022-06-21

2.  Mental, Neurological, and Somatic Comorbidities and Their Treatment in Persons With Intellectual Disability.

Authors:  Markus Weih; Sabine Köhler; Norbert Schöll; Mandy Schulz; Ramona Hering
Journal:  Dtsch Arztebl Int       Date:  2022-06-17       Impact factor: 8.251

Review 3.  Opening the door to university health research: recommendations for increasing accessibility for individuals with intellectual disability.

Authors:  Brittany M St John; Emily Hickey; Edward Kastern; Chad Russell; Tina Russell; Ashley Mathy; Brogan Peterson; Don Wigington; Casey Pellien; Allison Caudill; Libby Hladik; Karla K Ausderau
Journal:  Int J Equity Health       Date:  2022-09-10
  3 in total

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