Menopausal hormone therapy and risk of sarcoidosis: a population-based nested case-control study in Sweden.

Sarcoidosis incidence peaks in women between 50 and 60 years old, which coincides with menopause, suggesting that certain sex hormones, mainly estrogen, may play a role in disease development. We investigated whether menopausal hormone therapy (MHT) was associated with sarcoidosis risk in women and whether the risk varied by treatment type. We performed a nested case-control study (2007-2020) including incident sarcoidosis cases from the Swedish National Patient Register (n = 2593) and matched (1:10) to general population controls (n = 20,003) on birth year, county, and living in Sweden at the time of sarcoidosis diagnosis. Dispensations of MHT were obtained from the Swedish Prescribed Drug Register before sarcoidosis diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression. Ever MHT use was associated with a 25% higher risk of sarcoidosis compared with never use (aOR 1.25, 95% CI 1.13-1.38). When MHT type and route of administration were considered together, systemic estrogen was associated with the highest risk of sarcoidosis (aOR 1.51, 95% CI 1.23-1.85), followed by local estrogen (aOR 1.25, 95% CI 1.11-1.42), while systemic estrogen-progestogen combined was associated with the lowest risk compared to never users (aOR 1.12, 95% CI 0.96-1.31). The aOR of sarcoidosis did not differ greatly by duration of MHT use. Our findings suggest that a history of MHT use is associated with increased risk of sarcoidosis, with women receiving estrogen administered systemically having the highest risk.

Inverse probability of treatment weighting with generalized linear outcome models for doubly robust estimation.

There are now many options for doubly robust estimation; however, there is a concerning trend in the applied literature to believe that the combination of a propensity score and an adjusted outcome model automatically results in a doubly robust estimator and/or to misuse more complex established doubly robust estimators. A simple alternative, canonical link generalized linear models (GLM) fit via inverse probability of treatment (propensity score) weighted maximum likelihood estimation followed by standardization (the g $$ g $$ -formula) for the average causal effect, is a doubly robust estimation method. Our aim is for the reader not just to be able to use this method, which we refer to as IPTW GLM, for doubly robust estimation, but to fully understand why it has the doubly robust property. For this reason, we define clearly, and in multiple ways, all concepts needed to understand the method and why it is doubly robust. In addition, we want to make very clear that the mere combination of propensity score weighting and an adjusted outcome model does not generally result in a doubly robust estimator. Finally, we hope to dispel the misconception that one can adjust for residual confounding remaining after propensity score weighting by adjusting in the outcome model for what remains 'unbalanced' even when using doubly robust estimators. We provide R code for our simulations and real open-source data examples that can be followed step-by-step to use and hopefully understand the IPTW GLM method. We also compare to a much better-known but still simple doubly robust estimator.

Increasing Risk of Lymphoma Over Time in Crohn's Disease but Not in Ulcerative Colitis: A Scandinavian Cohort Study.

BACKGROUND & AIMS: Earlier studies have provided varying risk estimates for lymphoma in patients with inflammatory bowel disease (IBD), but often have been limited by detection biases (especially during the first year of follow-up evaluation), misclassification, and small sample size; and rarely reflect modern-day management of IBD. METHODS: We performed a binational register-based cohort study (Sweden and Denmark) from 1969 to 2019. We compared 164,716 patients with IBD with 1,639,027 matched general population reference individuals. Cox regression estimated hazard ratios (HRs) for incident lymphoma by lymphoma subtype, excluding the first year of follow-up evaluation. RESULTS: From 1969 to 2019, 258 patients with Crohn's disease (CD), 479 patients with ulcerative colitis (UC), and 6675 matched reference individuals developed lymphoma. This corresponded to incidence rates of 35 (CD) and 34 (UC) per 100,000 person-years in IBD patients, compared with 28 and 33 per 100,000 person-years in their matched reference individuals. Although both CD (HR, 1.32; 95% CI, 1.16-1.50) and UC (HR, 1.09; 95% CI, 1.00-1.20) were associated with an increase in lymphoma, the 10-year cumulative incidence difference was low even in CD patients (0.08%; 95% CI, 0.02-0.13). HRs have increased in the past 2 decades, corresponding to increasing use of immunomodulators and biologics during the same time period. HRs were increased for aggressive B-cell non-Hodgkin lymphoma in CD and UC patients, and for T-cell non-Hodgkin lymphoma in CD patients. Although the highest HRs were observed in patients exposed to combination therapy (immunomodulators and biologics) or second-line biologics, we also found increased HRs in patients naïve to such drugs. CONCLUSIONS: During the past 20 years, the risk of lymphomas have increased in CD, but not in UC, and were driven mainly by T-cell lymphomas and aggressive B-cell lymphomas.

Modifiable lifestyle risk factors for sarcoidosis: a nested case-control study.

Objective: We aimed to investigate whether obesity, tobacco use, alcohol consumption and physical inactivity are associated with sarcoidosis risk. Methods: We conducted a matched case-control study nested within the Northern Sweden Health and Disease Study. Incident sarcoidosis cases (n=165) were identified via medical records and matched to controls (n=660) on sub-cohort, sex, birth and questionnaire date (1:4). Data on lifestyle factors were obtained through questionnaires, and physical measurements of height, weight and waist were collected prior to sarcoidosis diagnosis. Conditional logistic regression estimated adjusted odds ratios with 95% confidence intervals (aOR; 95% CI). Results: Compared with never-smoking, current smoking was associated with lower sarcoidosis odds (aOR 0.48; 95% CI 0.32-0.71), and former smoking with higher odds (aOR 1.33; 95% CI 0.98-1.81). Snus use was not associated with sarcoidosis. There was an increased odds of sarcoidosis associated with obesity (aOR 1.34; 95% CI 0.94-1.92) but not with overweight (aOR 0.99; 95% CI 0.76-1.30). Compared with those who were physically inactive, those who were active had a 25% higher odds of sarcoidosis (aOR 1.25; 95% CI 0.91-1.72). No association was found with moderate alcohol consumption (aOR 0.95; 95% CI 0.56-1.62). All results were similar when cases diagnosed within 5 years after exposure assessment were excluded, except the aOR for former smoking decreased to 1.1. Conclusion: We observed a reduced sarcoidosis risk associated with smoking, which cannot be fully explained by early symptoms of sarcoidosis influencing smoking habits. Results indicate an increased risk associated with obesity, but not overweight, and being physically active.

Flexible evaluation of surrogacy in platform studies.

Trial-level surrogates are useful tools for improving the speed and cost effectiveness of trials but surrogates that have not been properly evaluated can cause misleading results. The evaluation procedure is often contextual and depends on the type of trial setting. There have been many proposed methods for trial-level surrogate evaluation, but none, to our knowledge, for the specific setting of platform studies. As platform studies are becoming more popular, methods for surrogate evaluation using them are needed. These studies also offer a rich data resource for surrogate evaluation that would not normally be possible. However, they also offer a set of statistical issues including heterogeneity of the study population, treatments, implementation, and even potentially the quality of the surrogate. We propose the use of a hierarchical Bayesian semiparametric model for the evaluation of potential surrogates using nonparametric priors for the distribution of true effects based on Dirichlet process mixtures. The motivation for this approach is to flexibly model relationships between the treatment effect on the surrogate and the treatment effect on the outcome and also to identify potential clusters with differential surrogate value in a data-driven manner so that treatment effects on the surrogate can be used to reliably predict treatment effects on the clinical outcome. In simulations, we find that our proposed method is superior to a simple, but fairly standard, hierarchical Bayesian method. We demonstrate how our method can be used in a simulated illustrative example (based on the ProBio trial), in which we are able to identify clusters where the surrogate is, and is not useful. We plan to apply our method to the ProBio trial, once it is completed.

Confirmatory prediction-driven RCTs in comparative effectiveness settings for cancer treatment.

BACKGROUND: Medical advances in the treatment of cancer have allowed the development of multiple approved treatments and prognostic and predictive biomarkers for many types of cancer. Identifying improved treatment strategies among approved treatment options, the study of which is termed comparative effectiveness, using predictive biomarkers is becoming more common. RCTs that incorporate predictive biomarkers into the study design, called prediction-driven RCTs, are needed to rigorously evaluate these treatment strategies. Although researched extensively in the experimental treatment setting, literature is lacking in providing guidance about prediction-driven RCTs in the comparative effectiveness setting. METHODS: Realistic simulations with time-to-event endpoints are used to compare contrasts of clinical utility and provide examples of simulated prediction-driven RCTs in the comparative effectiveness setting. RESULTS: Our proposed contrast for clinical utility accurately estimates the true clinical utility in the comparative effectiveness setting while in some scenarios, the contrast used in current literature does not. DISCUSSION: It is important to properly define contrasts of interest according to the treatment setting. Realistic simulations should be used to choose and evaluate the RCT design(s) able to directly estimate that contrast. In the comparative effectiveness setting, our proposed contrast for clinical utility should be used.

Early Initiation of Antitumor Necrosis Factor Therapy Reduces Postoperative Recurrence of Crohn's Disease Following Ileocecal Resection.

BACKGROUND: Postoperative recurrence (POR) of Crohn's disease (CD) is common after surgical resection. We aimed to compare biologic type and timing for preventing POR in adult CD patients after ileocecal resection (ICR). METHODS: We performed a retrospective cohort study of CD patients who underwent an ICR at 2 medical centers. Recurrence was defined by endoscopy (≥ i2b Rutgeerts score) or radiography (active inflammation in neoterminal ileum) and stratified by type and timing of postoperative prophylactic biologic within 12 weeks following an ICR (none, tumor necrosis factor antagonists [anti-TNF], vedolizumab, and ustekinumab). RESULTS: We identified 1037 patients with CD who underwent an ICR. Of 278 (26%) who received postoperative prophylaxis, 80% were placed on an anti-TNF agent (n = 223) followed by ustekinumab (n = 28, 10%) and vedolizumab (n = 27, 10%). Prophylaxis was initiated in 35% within 4 weeks following an ICR and in 65% within 4 to 12 weeks. After adjusting for factors associated with POR, compared with no biologic prophylaxis, the initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR (adjusted hazard ratio, 0.61; 95% CI, 0.40-0.93). Prophylaxis after 4 weeks following an ICR or with vedolizumab or ustekinumab was not associated with a reduction in POR compared with those who did not receive prophylaxis. CONCLUSION: Early initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR. Vedolizumab or ustekinumab, at any time following surgery, was not associated with a reduction in POR, although sample size was limited.

Postoperative recurrence of Crohn's disease is common after ileocecal resection. In this dual-center study, early initiation of an anti-TNF agent within 4 weeks following an ileocecal resection was associated with a reduction in postoperative recurrence of Crohn's disease.

Cross-direct effects in settings with two mediators.

When multiple mediators are present, there are additional effects that may be of interest beyond the well-known natural (NDE) and controlled direct effects (CDE). These effects cross the type of control on the mediators, setting one to a constant level and one to its natural level, which differs across subjects. We introduce five such estimands for the cross-CDE and -NDE when two mediators are measured. We consider both the scenario where one mediator is influenced by the other, referred to as sequential mediators, and the scenario where the mediators do not influence each other. Such estimands may be of interest in immunology, as we discuss in relation to measured immunological responses to SARS-CoV-2 vaccination. We provide identifying expressions for the estimands in observational settings where there is no residual confounding, and where intervention, outcome, and mediators are of arbitrary type. We further provide tight symbolic bounds for the estimands in randomized settings where there may be residual confounding of the outcome and mediator relationship and all measured variables are binary.

The association of serum vitamin D with incident diabetes in an African American population.

BACKGROUND: Incident diabetes risk is inversely proportional to 25-hydroxyvitamin D [25(OH)D] levels among non-Hispanic white but is unclear among African American (AA) populations. Serum 25(OH)D2 may be an important component of total 25(OH)D among AA populations due to higher levels of melanin. OBJECTIVE: To assess the association of serum 25(OH)D with incident diabetes among AAs and stratify by detectable 25(OH)D2. DESIGN: Serum 25(OH)D2 and 25(OH)D3 were collected from 2000 to 2004 among AA participants in the Jackson Heart Study. A cosinor model was used to adjust for the seasonality of 25(OH)D3; 25(OH)D3 and 25(OH)D2 were combined to ascertain total 25(OH)D. Incident diabetes (fasting glucose ≥126 mg/dl, use of diabetes drugs, or HbA1c ≥6.5%) was assessed over 12 years among adults without diabetes at baseline. Participants with missing baseline covariates or diabetes follow-up were excluded. Hazard ratios (HR) were estimated using Cox modeling, adjusting for age, sex, education, occupation, smoking, physical activity, alcohol use, aldosterone, and body-mass index. RESULTS: Among 3311 adults (mean age 53.3 years, 63% female) 584 participants developed diabetes over a median of 7.7 years. After adjustment, 25(OH)D ≥20 compared to <12 ng/ml was associated with a HR 0.78 (95% CI: 0.61, 1.00). Among participants with detectable 25(OH)D2 and 25(OH)D3 (n = 1671), 25(OH)D ≥ 20 ng/ml compared to <12 ng/ml was associated with a 35% (HR 0.65, 95% CI: 0.46, 0.91) lower risk of diabetes. CONCLUSIONS: Higher levels of 25(OH)D may be protective against the development of diabetes among AA individuals, particularly among those with detectable 25(OH)D2 and 25(OH)D3.

Confidence bands in survival analysis.

BACKGROUND: Providing estimates of uncertainty for statistical quantities is important for statistical inference. When the statistical quantity of interest is a survival curve, which is a function over time, the appropriate type of uncertainty estimate is a confidence band constructed to account for the correlation between points on the curve, we will call this a simultaneous confidence band. This, however, is not the type of confidence band provided in standard software, which is constructed by joining the confidence intervals at given time points. METHODS: We show that this type of band does not have desirable joint/simultaneous coverage properties in comparison to simultaneous bands. RESULTS: There are different ways of constructing simultaneous confidence bands, and we find that bands based on the likelihood ratio appear to have the most desirable properties. Although there is no standard software available in the three major statistical packages to compute likelihood-based simultaneous bands, we summarise and give code to use available statistical software to construct other simultaneous forms of bands, which we illustrate using a study of colon cancer. CONCLUSIONS: There is a need for more user-friendly statistical software to compute simultaneous confidence bands using the available methods.

Survival stacking with multiple data types using pseudo-observation-based-AUC loss.

There have been many strategies to adapt machine learning algorithms to account for right censored observations in survival data in order to build more accurate risk prediction models. These adaptions have included pre-processing steps such as pseudo-observation transformation of the survival outcome or inverse probability of censoring weighted (IPCW) bootstrapping of the observed binary indicator of an event prior to a time point of interest. These pre-processing steps allow existing or newly developed machine learning methods, which were not specifically developed with time-to-event data in mind, to be applied to right censored survival data for predicting the risk of experiencing an event. Stacking or ensemble methods can improve on risk predictions, but in general, the combination of pseudo-observation-based algorithms, IPCW bootstrapping, IPC weighting of the methods directly, and methods developed specifically for survival has not been considered in the same ensemble. In this paper, we propose an ensemble procedure based on the area under the pseudo-observation-based-time-dependent ROC curve to optimally stack predictions from any survival or survival adapted algorithm. The real application results show that our proposed method can improve on single survival based methods such as survival random forest or on other strategies that use a pre-processing step such as inverse probability of censoring weighted bagging or pseudo-observations alone.

Age determines the risk of familial inflammatory bowel disease-A nationwide study.

BACKGROUND AND AIMS: To estimate familial aggregation of inflammatory bowel disease (IBD), we performed a nationwide, case-control study and examined the odds for patients with IBD (vs controls) to have a first-degree relative (FDR) with IBD, by age of diagnosis, type of family history and IBD subtype. To assess the incidence of future IBD in relatives of incident IBD patients, we performed a cohort study. METHODS: Individuals diagnosed with IBD (N = 50,667) between 2003 and 2017 with at least one FDR were identified from Swedish national registers and compared to general population controls (N = 506,720) with at least one FDR. We used logistic regression to calculate adjusted odds ratios (ORs) and Cox regression to estimate hazard ratios (HRs). RESULTS: Compared to controls, IBD cases more often had a mother (3.0% vs 0.9%, OR = 3.5; 95% CI: 3.3-3.7), father (2.9% vs 0.8%, OR = 3.5; 95% CI: 3.3-3.7), full sibling (5.3% vs 1.5%, OR = 3.6; 95% CI: 3.4-3.8) and child (2.4% vs 0.9%, OR = 2.6; 95% CI: 2.4-2.8) with IBD. The strength of association increased with the number of affected FDRs and was modified by subtype of IBD and age of diagnosis. Highest ORs were observed for paediatric IBD among paediatric-onset Crohn's disease (OR = 10.6; 95% CI: 8.2-13.5) and paediatric-onset ulcerative colitis (OR = 8.4; 95% CI: 6.4-10.9) cases. The 10-year cumulative incidence of IBD was 1.7% in full-siblings of incident IBD patients vs 0.4% among full-siblings of reference individuals. CONCLUSION: The variations in the strength of familial IBD and future risk of IBD in FDRs support differences in genetic predisposition and call for targeted approaches in potential screening programmes.

Reproductive and hormonal risk factors for sarcoidosis: a nested case-control study.

BACKGROUND: Sarcoidosis incidence peaks in females around the fifth decade of life, which coincides with menopause, suggesting hormonal factors play a role in disease development. We investigated whether longer exposure to reproductive and hormonal factors is associated with reduced sarcoidosis risk. METHODS: We conducted a matched case-control study nested within the Mammography Screening Project. Incident sarcoidosis cases were identified via medical records and matched to controls on birth and questionnaire date (1:4). Information on hormonal factors was obtained through questionnaires prior to sarcoidosis diagnosis. Multilevel modelling was used to estimate adjusted odds ratios with 95% credible intervals (OR; 95% CI). RESULTS: In total, 32 sarcoidosis cases and 124 controls were included. Higher sarcoidosis odds were associated with older age at menarche (OR 1.19: 95% CI 0.92-1.55), natural menopause versus non-natural (OR 1.53: 95% CI 0.80-2.93), later age at first pregnancy (OR 1.11: 95% CI 0.76-1.63) and ever hormone replacement therapy (HRT) use (OR 1.40: 95% CI 0.76-2.59). Lower odds were associated with older age at menopause (OR 0.90: 95% CI 0.52-1.55), longer duration of oral contraceptive use (OR 0.70: 95% CI 0.45-1.07), longer duration of HRT use (OR 0.61: 95% CI 0.22-1.70), ever local estrogen therapy (LET) use (OR 0.83: 95% CI 0.34-2.04) and longer duration of LET use (OR 0.78: 95% CI 0.21-2.81). However, the CIs could not rule out null associations. CONCLUSION: Given the inconsistency and modest magnitude in our estimates, and that the 95% credible intervals included one, it still remains unclear whether longer estrogen exposure is associated with reduced sarcoidosis risk.

Direct modeling of relative and absolute risks in register data: Mortality risk in sarcoidosis.

PURPOSE: This paper aims to illustrate the use and interpretation of regression based on pseudo-observations for estimating risks of time-to-event outcomes in epidemiological studies. METHODS: We use pseudo-observation based regression for estimation of contrasts in the relative and absolute risks at specific times. This relaxes the proportional hazards assumption and directly estimates relative and absolute risks without the need for secondary calculations or standardization. Statistical software is available to use this method, and we demonstrate its use in a reanalysis of the mortality risk in sarcoidosis patients in Sweden. RESULTS: We report estimated adjusted mortality risk differences and risk ratios by age, and at different years of follow up. Compared to the hazard ratio of 1.62, which is assumed to be time constant, we find risk ratios ranging from 1.7 at 2 years of follow-up to 1.3 at 10 years. CONCLUSIONS: Pseudo-observation regression is a flexible and powerful tool for censored time-to-event data. The models are easy to run and interpret so they should be considered a standard tool alongside Cox regression and standardization. As with any statistical model, there are assumptions needed for valid inference, which should be assessed on a case-by-case basis.

Distinct Metabolic Profile Associated with a Fatal Outcome in COVID-19 Patients during the Early Epidemic in Italy.

In one year of the coronavirus disease 2019 (COVID-19) pandemic, many studies have described the different metabolic changes occurring in COVID-19 patients, linking these alterations to the disease severity. However, a complete metabolic signature of the most severe cases, especially those with a fatal outcome, is still missing. Our study retrospectively analyzes the metabolome profiles of 75 COVID-19 patients with moderate and severe symptoms admitted to Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Lombardy Region, Italy) following SARS-CoV-2 infection between March and April 2020. Italy was the first Western country to experience COVID-19, and the Lombardy Region was the epicenter of the Italian COVID-19 pandemic. This cohort shows a higher mortality rate compared to others; therefore, it represents a unique opportunity to investigate the underlying metabolic profiles of the first COVID-19 patients in Italy and to identify the potential biomarkers related to the disease prognosis and fatal outcome. IMPORTANCE Understanding the metabolic alterations occurring during an infection is a key element for identifying potential indicators of the disease prognosis, which are fundamental for developing efficient diagnostic tools and offering the best therapeutic treatment to the patient. Here, exploiting high-throughput metabolomics data, we identified the first metabolic profile associated with a fatal outcome, not correlated with preexisting clinical conditions or the oxygen demand at the moment of diagnosis. Overall, our results contribute to a better understanding of COVID-19-related metabolic disruption and may represent a useful starting point for the identification of independent prognostic factors to be employed in therapeutic practice.

Adult-onset inflammatory bowel disease and rate of serious infections compared to the general population: a nationwide register-based cohort study 2002-2017.

OBJECTIVES: To investigate absolute and relative risk of serious infections in adult/elderly inflammatory bowel disease (IBD) diagnosed 2002-2017. METHODS: Nationwide, register-based cohort study of Swedish patients with IBD compared with general population matched reference individuals with regard to time to first serious infection, equal to hospital admission. Multivariable Cox regression estimated hazard ratios (HRs) for any serious infection. Secondary outcomes included site-specific infections, opportunistic infections and sepsis. RESULTS: We identified 47 798 individuals with IBD. During a follow-up of 329 000 person-years, they had 8752 first serious infections (26.6 per 1000 person-years). This compared with an incidence rate of 10.7 per 1000 person-years in matched reference individuals, corresponding to a 2.53-fold increased hazard of serious infections (95%CI = 2.47-2.59). The HR for serious infection in elderly-onset IBD was 2.01 (95%CI = 1.95-2.08). The relative hazard of serious infection was somewhat higher in Crohn's disease (2.94; 95%CI = 2.81-3.06) than in ulcerative colitis (2.24; 95%CI = 2.17-2.31). The HR for serious infections was high in the first year of follow-up (5.17; 95%CI = 4.93-5.42). Individuals with IBD were at a particularly high relative hazard of gastrointestinal and opportunistic infections. The HR for sepsis was 2.47 (95%CI = 2.32-2.63). The relative rates for serious infections in IBD increased in recent years. CONCLUSIONS: Patients with adult-onset IBD are at increased risk of serious infections, particularly gastrointestinal and opportunistic infections. Relative rates were highest just after IBD diagnosis, and seem to have increased in recent years.

Serious Infections in Pediatric Inflammatory Bowel Disease 2002-2017-A Nationwide Cohort Study.

OBJECTIVE: To assess absolute and relative risks of serious infections (resulting in inpatient care) in children with inflammatory bowel disease (IBD) compared with the general population. STUDY DESIGN: We identified children (<18 years of age) with a first diagnosis of IBD in the Swedish nationwide health registry (2002-2017; n = 5767) and individuals from the general population matched for sex, age, calendar year, and place of residence (reference group; n = 58 418). Hazard ratios (HRs) for serious infections were estimated using Cox regression separately in children with ulcerative colitis (n = 2287), Crohn's disease (n = 2365), and IBD unclassified (n = 1115). RESULTS: During 17 408 person-years of follow-up, 672 serious infections (38.6/1000 person-years) occurred among the children with IBD compared with 778 serious infections in the reference group (4.0/1000 person-years; adjusted HR (95% CI), 9.46 [8.53-10.5]). HRs were increased for children with ulcerative colitis 8.48 (7.21-9.98), Crohn's disease 9.30 (7.86-11.0), and IBD unclassified 12.1 (9.66-16.1). HRs were highest in the first year of follow-up (HR = 12.6 [10.7-14.9]), then decreasing to a 4.8-fold increased risk beyond 10 years of follow-up. Particularly high HRs were also seen in children with IBD undergoing surgery. Apart from a high relative risk of gastrointestinal infections resulting in hospitalization, children with IBD were also at an increased risk of opportunistic infections (HR = 11.8 [6.17-22.5]). CONCLUSIONS: Children with IBD have an increased risk of serious infection requiring hospitalization compared with the general population.