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BackgroundMedical 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.MethodsRealistic 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.ResultsOur 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.DiscussionIt 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. 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.

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.

A causal query will commonly not be identifiable from observed data, in which case no estimator of the query can be contrived without further assumptions or measured variables, regardless of the amount or precision of the measurements of observed variables. However, it may still be possible to derive symbolic bounds on the query in terms of the distribution of observed variables. Bounds, numeric or symbolic, can often be more valuable than a statistical estimator derived under implausible assumptions. Symbolic bounds, however, provide a measure of uncertainty and information loss due to the lack of an identifiable estimand even in the absence of data. We develop and describe a general approach for computation of symbolic bounds and characterize a class of settings in which our method is guaranteed to provide tight valid bounds. This expands the known settings in which tight causal bounds are solutions to linear programs. We also prove that our method can provide valid and possibly informative symbolic bounds that are not guaranteed to be tight in a larger class of problems. We illustrate the use and interpretation of our algorithms in three examples in which we derive novel symbolic bounds., Submitted to JASA in December 2021

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.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).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.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.

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.

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.

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.

Outcome-dependent sampling designs are common in many different scientific fields including epidemiology, ecology, and economics. As with all observational studies, such designs often suffer from unmeasured confounding, which generally precludes the nonparametric identification of causal effects. Nonparametric bounds can provide a way to narrow the range of possible values for a nonidentifiable causal effect without making additional untestable assumptions. The nonparametric bounds literature has almost exclusively focused on settings with random sampling, and the bounds have often been derived with a particular linear programming method. We derive novel bounds for the causal risk difference, often referred to as the average treatment effect, in six settings with outcome-dependent sampling and unmeasured confounding for a binary outcome and exposure. Our derivations of the bounds illustrate two approaches that may be applicable in other settings where the bounding problem cannot be directly stated as a system of linear constraints. We illustrate our derived bounds in a real data example involving the effect of vitamin D concentration on mortality., Comment: 36 pages, 3 figures. Update to include revisions after peer review. In Press at the Journal of the American Statistical Association, Theory and methods

Background In addition to their potent lipid-lowering action, statins may modulate inflammation. However, data on statin use and the risk of inflammatory bowel diseases [IBD] have been inconsistent. Methods We searched the Nationwide Swedish Patient Register [inpatient and non-primary outpatient care] to identify adults diagnosed with Crohn’s disease [CD, n = 7637] or ulcerative colitis [UC, n = 15 652] from 2006 to 2014. Each case was matched to 10 general population controls [n = 232 890]. Data on dispensed statin prescriptions were extracted from the Prescribed Drug Register. Conditional logistic regression models estimated odds ratios [ORs] for risk of IBD according to statin exposure while controlling for potential confounders, including indications for statin therapy. Results In multivariable adjusted models, compared with no statin use, any statin use was associated with a lower risk of CD (OR = 0.71; 95% confidence interval [CI], 0.63–0.79), but not UC [OR = 1.03; 95% CI, 0.96–1.11]. The lowest OR for CD was seen for current statin use [OR = 0.67; 95% CI, 0.60–0.75]. For CD, the lowest category of cumulative statin dose [31–325 defined daily dose, DDD] was associated with an OR of 0.73 [95% CI, 0.61–0.88] and the highest category [>1500 DDD] with an OR of 0.66 [95% CI, 0.55–0.80], ptrend = 0.10. For UC, the lowest and highest dose categories yielded ORs of 1.12 [95% CI, 1.00–1.25] and 0.99 [95% CI, 0.88–1.13], respectively, ptrend = 0.13. Conclusions Statin use was associated with a lower risk of CD, but not of UC. The association with CD risk appeared strongest for current statin use. Our findings suggest that statin use may influence the development of CD.

Background The Swedish Quality Register for Inflammatory Bowel Disease (SWIBREG) contains clinical data for the study of inflammatory bowel disease (IBD). The Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort was recently established for the study of gastrointestinal histopathology. We aimed to develop and validate a histology score from ESPRESSO using clinical information from SWIBREG, and secondarily, to evaluate the association of the score on IBD-related hospitalization. Methods In a nationwide, population-based cohort study of patients with IBD during 1969-2017, we linked endoscopic inflammation in SWIBREG with histologic inflammation in ESPRESSO. We established a clinically interpretable model for predicting the endoscopic score from histology using scalable Bayesian rule lists to define a SNOMED-based histology score applicable to the ESPRESSO cohort. We also assessed the impact of baseline endoscopic and histology scores on time to IBD-related hospitalization. Results We identified 5225 individuals with IBD comprising 11,051 endoscopic assessments in SWIBREG linked to a histopathology record in ESPRESSO. We created predictive models to calculate a SNOMED-based histology score which predicted the endoscopic score. Split-sample validated areas under the ROC curves for the score predicting a non-zero endoscopic score were 0.80 (0.78-0.81) in UC, 0.70 (0.68-0.72) in CD, and 0.76 (0.73-0.78) in IBD-U. In a subset of 2741 individuals with an initial IBD diagnosis and a corresponding record in ESPRESSO with an endoscopic assessment in SWIBREG, the baseline endoscopic and histology scores were associated with time to IBD-related hospitalization (endoscopy log-rank UC p

Summary Background Crohn's disease is a risk factor for colorectal cancer (CRC). However, available studies reflect older treatment and surveillance strategies, and most have assessed risks for incident CRC without taking surveillance and lead-time bias into account. Such biases can be accounted for by assessing CRC incidence by tumour stage and CRC mortality by tumour stage. We aimed to assess rates of incident CRC and CRC mortality among patients with Crohn's disease compared with the general population. Methods For this nationwide register-based cohort study, we used International Classification of Disease codes in national patient registers and pathology reports to identify incident cases of Crohn's disease. In Denmark we searched for incident cases between January, 1977, and December, 2011, and in Sweden between January, 1969, and December, 2017. For each patient with Crohn's disease, we identified up to ten reference individuals in national population registers and matched them by sex, age, calendar year, and place of residence. Matched reference individuals had to be alive and free of inflammatory bowel disease at the start of follow-up of index patients with Crohn's disease, and stopped contributing to reference person-years if they were diagnosed with inflammatory bowel disease. Our main outcome was death from CRC (main or contributory cause of death) as captured in the cause-of-death registers. Our secondary outcome was incident CRC, as defined by the cancer registers. We used Cox regression to estimate hazard ratios (HRs) for incident CRC and CRC mortality, taking tumour stage into account. We used a series of Cox models to estimate cause-specific HRs of the different competing outcomes (CRC diagnosis, CRC death, and other causes of death) and adjusted for tumour stage at CRC diagnosis. Findings During the 1969–2017 study period, we identified 47 035 patients with incident Crohn's disease (13 056 in Denmark and 33 979 in Sweden) and 463 187 matched reference individuals. During follow-up, 296 (0·47 per 1000 person-years) CRC deaths occurred among individuals with Crohn's disease compared with 1968 (0·31 per 1000 person-years) in reference individuals, corresponding to an overall adjusted HR of 1·74 (1·54–1·96). 499 (0·82 per 1000 person-years) cases of incident CRC were diagnosed in patients with Crohn's disease compared with 4084 (0·64 per 1000 person-years) cases in reference individuals, corresponding to an overall adjusted HR of 1·40 (95% CI 1·27–1·53). Patients with Crohn's disease who were diagnosed with CRC were at increased risk of CRC mortality compared with reference individuals also diagnosed with CRC (HR 1·42 [1·16–1·75] when adjusted for tumour stage), and tumour stage at CRC diagnosis did not differ between groups (p=0·27). Patients with Crohn's disease who had follow-up of 8 years or longer or who were diagnosed with primary sclerosing cholangitis (PSC) and hence were potentially eligible for CRC surveillance had an increased overall risk of CRC death (HR 1·40 [1·16–1·68]) or CRC diagnosis (HR 1·12 [0·98–1·28]). However, in patients potentially eligible for CRC surveillance we only found significantly increased risks in patients diagnosed with Crohn's disease before the age of 40 years, patients with disease activity in the colon only, or patients with PSC. Interpretation Patients with Crohn's disease are at increased risk of CRC diagnosis and CRC death. Patients with Crohn's disease who have CRC have a higher mortality than patients without Crohn's disease who are also diagnosed with CRC. CRC surveillance should likely be focused on patients diagnosed with Crohn's disease before the age of 40 years, on patients with colon inflammation, and on those who have PSC. Funding Swedish Medical Society, Karolinska Institutet, Regional Agreement on Medical Training and Clinical Research between Stockholm County Council and Karolinska Institutet (ALF), Forte Foundation, Swedish Cancer Foundation, and Independent Research Fund Denmark.

Background The vagus nerve provides essential parasympathetic innervation to the gastrointestinal system and is known to have anti-inflammatory properties. Aims To explore the relationship between vagotomy and the risk of inflammatory bowel disease (IBD) and its major categories: Crohn's disease (CD) and ulcerative colitis (UC). Methods A matched cohort comprising 15 637 patients undergoing vagotomy was identified through the Swedish Patient Register from 1964 to 2010. Each vagotomised patient was matched for birth year and gender with 40 nonvagotomised individuals on the date of vagotomy. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for IBD using flexible parametric models adjusted for matching variables, year of vagotomy, birth country, chronic obstructive pulmonary disease and comorbidity index. Results We observed 119 (0.8%) patients with vagotomy developed IBD compared to 3377 (0.5%) IBD cases in nonvagotomised individuals. The crude incidence of IBD (per 1000 person-years) was 0.38 for vagotomised patients and 0.25 for nonvagotomised individuals. We observed a time-dependent elevated risk of IBD associated with vagotomy, for instance, the HR (95% CI) was 1.80 (1.40-2.31) at year 5 and 1.49 (1.14-1.96) at year 10 post-vagotomy. The association appeared to be stronger for truncal than selective vagotomy and limited to CD (HR was 3.63 [1.94-6.80] for truncal and 2.06 [1.49-2.84] for selective vagotomy) but not UC (1.36 [0.71-2.62] for truncal and 1.25 [0.95-1.63] for selective vagotomy). Conclusions We found a positive association between vagotomy and later IBD, particularly for CD. The finding indirectly underlines the beneficial role of the vagal tone in IBD.

Background Growth retardation is well described in childhood-onset inflammatory bowel disease (IBD). Aims To study if childhood-onset IBD is associated with reduced final adult height. Methods We identified 4201 individuals diagnosed with childhood-onset IBD 1990-2014 (Crohn's disease: n = 1640; ulcerative colitis: n = 2201 and IBD-unclassified = 360) in the Swedish National Patient Register. Results Patients with IBD attained a lower adult height compared to reference individuals (adjusted mean height difference [AMHD] -0.9 cm [95% CI -1.1 to -0.7]) and to their healthy siblings (AMHD -0.8 cm [-1.0 to -0.6]). Patients with Crohn's disease (CD) were slightly shorter than patients with ulcerative colitis (UC; -1.3 cm vs -0.6 cm). Lower adult height was more often seen in patients with pre-pubertal disease onset (AMHD -1.6 cm [-2.0 to -1.2]), and in patients with a more severe disease course (AMHD -1.9 cm, [-2.4 to -1.4]). Some 5.0% of CD and 4.3% of UC patients were classified as growth retarded vs 2.5% of matched reference individuals (OR 2.42 [95% CI 1.85-3.17] and 1.74 [1.36-2.22] respectively). Conclusion Patients with childhood-onset IBD on average attain a slightly lower adult height than their healthy peers. Adult height was more reduced in patients with pre-pubertal onset of disease and in those with a more severe disease course.

Many infectious diseases are well prevented by proper vaccination. However, when a vaccine is not completely efficacious, there is great interest in determining how the vaccine effect differs in subgroups conditional on measured immune responses postvaccination and also according to the type of infecting agent (eg, strain of a virus). The former is often called correlate of protection (CoP) analysis, while the latter has been called sieve analysis. We propose a unified framework for simultaneously assessing CoP and sieve effects of a vaccine in a large Phase III randomized trial. We use flexible parametric models treating times to infection from different agents as competing risks and estimated maximum likelihood to fit the models. The parametric models under competing risks allow for estimation of both cumulative incidence-based contrasts and instantaneous rates. We outline the assumptions with which we can link the observable data to the causal contrasts of interest, propose hypothesis testing procedures, and evaluate our proposed methods in an extensive simulation study.

Background Crohn’s disease (CD) is associated with increased risk of small bowel cancer (SBC), but previous studies were limited by a small number of cases, short follow-up, lack of individually matched comparators, and over-representation of tertiary referral centres, leading to exaggerated relative risks and incidence data. Data on ulcerative colitis (UC) and SBC are scarce. Methods In a binational, population-based cohort study from Sweden and Denmark of patients diagnosed with inflammatory bowel disease (IBD) during 1969–2017 and matched reference individuals from the general population, we evaluated the risk of incident SBC, including SBC subtypes (small bowel adenocarcinoma, neuroendocrine tumours, and sarcoma). Cox regression was used to compute adjusted hazard ratios (aHRs) as a measure of relative risks for incident SBC and SBC subtypes. Results We identified 161,896 individuals with IBD (CD: 47,370; UC: 97,515; unclassified IBD:17,011). During follow-up, 237 cases of SBC were diagnosed in patients with IBD (CD: 24.4/100,000 person-years; UC: 5.88/100,000 person-years), compared with 640 cases in reference individuals (2.81/100,000 person-years and 3.32/100,000 person-years, respectively, Table). This corresponded to one extra case of for small bowel cancer in 385 CD patients, and one extra case in 500 UC patients, followed-up for 10 years. The aHR for incident SBC of 9.09 (95% CI = 7.34–11.3) in CD patients and 1.85 (95% CI = 1.43–2.39) in UC patients (Figure). When the first year after IBD diagnosis was excluded, the aHRs for incident SBC decreased to 4.96 in CD patients and 1.69 in UC patients. Among CD patients, relative risks were highest for recently diagnosed, childhood-onset, ileal, and stricturing CD; among UC patients, relative risks were highest for those with extensive colitis and primary sclerosing cholangitis (PSC). In CD patients, the risk of all SBC subtypes was increased (aHR 15.8 for adenocarcinoma, 5.51 for neuroendocrine tumours, and 4.04 for sarcoma) whereas in UC patients only the risk of adenocarcinoma (aHR 1.99) and neuroendocrine tumours (aHR 2.01) were increased. Conclusion SBC was more common in IBD patients, particularly among patients with CD, although absolute risks were low. Further studies should evaluate the utility of SBC surveillance in selected populations such as those with ileal CD, extensive colitis, or UC-PSC.

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.

The authors would like to thank Giuffrida and colleagues for their interest in our manuscript, ‘Inflammatory Bowel Disease and Risk of Small Bowel Cancer: A binational population-based cohort study from Denmark and Sweden’.1 2 In contrast to previous studies focused on small bowel adenocarcinoma death with short follow-up time, we provide an age-adjusted composite risk of death due to multiple small bowel cancer subtypes, including adenocarcinoma, neuroendocrine tumours and sarcoma, with over 20 years of follow-up.3–6 We adjusted for cancer heredity and in sensitivity analyses, excluded patients with coeliac disease in …

Background: Inflammatory bowel disease (IBD) has been associated with hepatobiliary cancer, but existing evidence is poor. We evaluated risk of death from hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC) among patients with IBD. Methods: This Swedish/Danish population-based cohort study (1969–2017) followed patients with IBD and 1:10 matched population comparators from their diagnosis/match date until death, emigration, or end of follow-up. Results: Among the 97,496 patients with ulcerative colitis/963,026 comparators, we found 66/390 HCC-deaths, 120/173 ICC-deaths, and 91/220 ECC-deaths (median follow-up 10 years); the 10-year-mortality was 0.5‰ (per mille) for HCC, 0.6‰ for ICC, and 0.4‰ for ECC, which decreased to 0.3‰, 0.4‰, and 0.2‰, respectively, in 2003–2017. Overall hazard ratios (HR) were 1.83 [95% confidence interval (CI), 1.41–2.38] for HCC-, 7.33 (95% CI, 5.81–9.25) for ICC-, and 4.46 (95% CI, 3.49–5.70) for ECC-deaths. A total of 22/66 HCC-deaths, 87/120 ICC-deaths, and 55/91 ECC-deaths occurred among patients with ulcerative colitis with primary sclerosing cholangitis (PSC), corresponding to 10-year-mortality of 6.7‰, 26.2‰, and 17.2‰, respectively. Among 47,399 patients with Crohn's disease (median follow-up 11 years), 10-year-mortality from HCC (n = 28), ICC (n = 28), and ECC (n = 24) were 0.3‰, 0.1‰, and 0.3‰, respectively, and corresponding HRs were 1.96 (95% CI, 1.31–2.93), 3.33 (95% CI, 2.19–5.09), and 3.10 (95% CI, 1.97–4.87). One of 28 HCC-deaths, 14/28 ICC-deaths (10-year-mortality 19‰), and 12/24 ECC-deaths (10-year-mortality 14‰) occurred after PSC. Conclusions: Risk of HCC-, ICC-, and ECC-deaths was low in patients with IBD and decreased over time. However, a large proportion of deaths occurred after PSC. Impact: Guidelines on specific surveillance strategies for patients with IBD with PSC, but not those without PSC, are needed.

Summary We develop a novel algorithm to predict the occurrence of major abdominal surgery within 5 years following Crohn's disease diagnosis by using a panel of 29 baseline covariates from the Swedish population registers. We model pseudo-observations based on the Aalen–Johansen estimator of the cause-specific cumulative incidence with an ensemble of modern machine learning approaches. Pseudo-observation preprocessing easily extends all existing or new machine learning procedures for continuous data to right-censored event history data. We propose pseudo-observation-based estimators for the area under the time varying receiver operating characteristic curve, for optimizing the ensemble, and the predictiveness curve, for evaluating and summarizing predictive performance.

ObjectivesTo examine all-cause and cause-specific mortality in adult-onset and elderly-onset IBD and to describe time trends in mortality over the past 50 years.DesignSwedish nationwide register-based cohort study 1964–2014, comparing mortality in 82 718 incident IBD cases (inpatient and non-primary outpatient care) with 10 times as many matched general population reference individuals (n=801 180) using multivariable Cox regression to estimate HRs. Among patients with IBD, the number of participants with elderly-onset (≥60 years) IBD was 17 873.ResultsDuring 984 330 person-years of follow-up, 15 698/82 718 (19%) of all patients with IBD died (15.9/1000 person-years) compared with 121 095/801 180 (15.1%) of reference individuals, corresponding to an HR of 1.5 for IBD (95% CI=1.5 to 1.5 (HR=1.5; 95% CI=1.5 to 1.5 in elderly-onset IBD)) or one extra death each year per 263 patients. Mortality was increased specifically for UC (HR=1.4; 95% CI=1.4 to 1.5), Crohn’s disease (HR=1.6; 95% CI=1.6 to 1.7) and IBD-unclasssified (HR=1.6; 95% CI=1.5 to 1.8). IBD was linked to increased rates of multiple causes of death, including cardiovascular disease (HR=1.3; 1.3 to 1.3), malignancy (HR=1.4; 1.4 to 1.5) and digestive disease (HR=5.2; 95% CI=4.9 to 5.5). Relative mortality during the first 5 years of follow-up decreased significantly over time. Incident cases of 2002–2014 had 2.3 years shorter mean estimated life span than matched comparators.ConclusionsAdult-onset and elderly-onset patients with UC, Crohn’s disease and IBD-unclassified were all at increased risk of death. The increased mortality remained also after the introduction of biological therapies but has decreased over time.

Context.—Despite widespread use of formalin-fixed, paraffin-embedded (FFPE) tissue in clinical and research settings, potential effects of variable tissue processing remain largely unknown.Objective.—To elucidate molecular effects associated with clinically relevant preanalytical variability, the National Cancer Institute initiated the Biospecimen Preanalytical Variables (BPV) program.Design.—The BPV program, a well-controlled series of systematic, blind and randomized studies, investigated whether a delay to fixation (DTF) or time in fixative (TIF) affects the quantity and quality of DNA and RNA isolated from FFPE colon, kidney, and ovarian tumors in comparison to case-matched snap-frozen controls.Results.—DNA and RNA yields were comparable among FFPE biospecimens subjected to different DTF and TIF time points. DNA and RNA quality metrics revealed assay- and time point–specific effects of DTF and TIF. A quantitative reverse transcription–polymerase chain reaction (qRT-PCR) assay was superior when assessing RNA quality, consistently detecting differences between FFPE and snap-frozen biospecimens and among DTF and TIF time points. RNA Integrity Number and DV200 (representing the percentage of RNA fragments longer than 200 nucleotides) displayed more limited sensitivity. Differences in DNA quality (Q-ratio) between FFPE and snap-frozen biospecimens and among DTF and TIF time points were detected with a qPCR-based assay.Conclusions.—DNA and RNA quality may be adversely affected in some tumor types by a 12-hour DTF or a TIF of 72 hours. Results presented here as well as those of additional BPV molecular analyses underway will aid in the identification of acceptable delays and optimal fixation times, and quality assays that are suitable predictors of an FFPE biospecimen's fit-for-purpose.

Background & aims Childhood-onset inflammatory bowel disease (IBD) is believed to be a more severe disease than adult-onset IBD, but there is little information on all-cause and cause-specific mortality in patients with childhood-onset IBD. We performed a population-based cohort study, with 50 years of follow-up, to estimate absolute and relative risks for overall and cause-specific mortality in patients with childhood-onset IBD, during childhood and adulthood. Methods We identified children with a diagnosis of IBD (younger than 18 years) in the Swedish nationwide health registers (1964–2014; n = 9442) and individuals from the general population matched for sex, age, calendar year, and place of residence (reference group; n = 93,180). Hazard ratios (HR) for death were estimated using Cox regression separately in patients with ulcerative colitis (n = 4671), Crohn's disease (n = 3780), and IBD unclassified (n = 991). HRs were compared among calendar periods. Results During 138,690 person-years of follow-up, 294 deaths (2.1/1000 person-years) occurred among the patients with IBD compared with 940 deaths in the reference group (0.7/1000 person-years; adjusted HR, 3.2; 95% confidence interval [CI] 2.8–3.7). Mean age at end of follow-up was 30 years. HRs were increased for patients with ulcerative colitis 4.0, 95% CI 3.4–4.7; Crohn's disease 2.3, 95% CI 1.8–3.0; and IBD unclassified 2.0, 95% CI 1.2–3.4. Among patients younger than 18 years, there were 27 deaths from IBD 4.9, 95% CI 3.0–7.7. Among young adults with IBD, we found no evidence that HRs for death decreased from 1964 through 2014 (P = .90). Conclusions Children with IBD have a 3-fold increase in risk of death when followed through adulthood. The relative risk for death has not decreased with development of new drugs for treatment of IBD.

Most studies on fractures in inflammatory bowel disease (IBD) are based on patients from tertiary centers or patients followed up before the introduction of immunomodulators or biologics. In addition, the role of corticosteroids in fracture risk has rarely been examined.We conducted a nationwide population-based cohort study of 83,435 patients with incident IBD (ulcerative colitis [UC]: n = 50,162, Crohn's disease [CD]: n = 26,763, and IBD unclassified: 6,510) and 825,817 reference individuals from 1964 to 2014. Using multivariable Cox regression, we estimated hazard ratios (HRs) for hip fracture and any fracture and the association with cumulative corticosteroid exposure.During 1,225,415 person-years of follow-up in patients with IBD, there were 2,491 first-time hip fractures (203/100,000 person-years) compared with 20,583 hip fractures during 12,405,642 person-years in reference individuals (159/100,000 person-years). This corresponded to an HR of 1.42 (95% confidence interval [CI] = 1.36-1.48). The risk for hip fracture was higher in CD compared with UC (P0.001). Inflammatory bowel disease was also associated with any fracture (IBD: HR = 1.18; 95% CI = 1.15-1.20). Hazard ratios for hip fracture had not changed since the introduction of immunomodulators or biologics. Increasing exposure to corticosteroids was associated with hip fracture in both IBD and non-IBD individuals (P0.001), but only in elderly (60 years) patients with IBD. The association between IBD and hip fracture was nonsignificant among individuals without corticosteroids (HR = 1.11; 95% CI = 0.86-1.44).Inflammatory bowel disease (CD and UC) is associated with an increased risk of hip fracture and any fracture, but not in individuals without a history of corticosteroid treatment. The association between corticosteroids and hip fracture was restricted to elderly patients with IBD.

Although there are millions of formalin-fixed paraffin-embedded (FFPE) tissue blocks potentially available for scientific research, many are of questionable quality, partly due to unknown fixation conditions. We analyzed FFPE tissue biospecimens as part of the NCI Biospecimen Preanalytical Variables (BPV) program to identify microRNA (miRNA) markers for fixation time. miRNA was extracted from kidney and ovary tumor FFPE blocks (19 patients, cold ischemia ≤2 hours) with 6, 12, 24, and 72 hours fixation times, then analyzed using the WaferGen SmartChip platform (miRNA chip with 1036 miRNA targets). For fixation time, principal component analysis of miRNA chip expression data separated 72 hours fixed samples from 6 to 24 hours fixed samples. A set of small nuclear RNA (snRNA) targets was identified that best determines fixation time and was validated using a second independent cohort of seven different tissue types. A customized assay was then developed, based on a set of 24 miRNA and snRNA targets, and a simple “snoRNA score” defined. This score detects FFPE tissue samples with fixation for 72 hours or more, with 79% sensitivity and 80% specificity. It can therefore be used to assess the fitness-for-purpose of FFPE samples for DNA or RNA-based research or clinical assays, which are known to be of limited robustness to formalin overfixation.

Leveraging the unique biological resource based upon the initial COVID-19 patients in Policlinico di Milano (Italy), our study provides the first metabolic profile associated with a fatal outcome. The identification of potential predictive biomarkers offers a vital opportunity to employ metabolomics in a clinical setting as diagnostic tool of disease prognosis upon hospital admission.

Background: It is not known to what extent biologic treatment for IBD is captured in the Swedish Prescribed Drug Register (PDR) and the National Patient Register (NPR). Methods: A cross-sectional study from July 2005 until 2017, comparing data on biologic treatment in the PDR and the NPR with medical records. We assessed the proportion of started treatment episodes in the medical records that were found in the PDR/NPR ever, within +/− one year and within +/− three months; for any biologic drug, per specific drug (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab), by calendar period (2005–2008, 2009–2012, and 2013–2017) and by study center. For adalimumab, we assessed the validity of end of treatment episodes. Results: Medical records of 1361 patients and 2323 treatment episodes with any biologic were reviewed and 80.1% (95% CI: 78.4–81.7) were ever captured in the PDR/NPR in. A time window of +/− one year or +/− three months reduced the sensitivity to 63.3% (95% CI: 61.3–65.3) and 52.6% (95% CI: 50.5–54.6), respectively. The sensitivity was high (>85%) for the prescribed injection drugs adalimumab, golimumab, and ustekinumab for all time windows and for adalimumab end of treatment, while considerably lower for the infusion drugs infliximab and vedolizumab. Conclusions: The PDR and the NPR are reliable data sources on treatment with injection biologics in patients with IBD in Sweden. Infliximab and vedolizumab are poorly captured, why PDR/NPR data should only be used after careful consideration of their limitations or complemented by other data sources, e.g., the disease-specific quality register SWIBREG. (Less)

In randomized trials, once the total effect of the intervention has been estimated, it is often of interest to explore mechanistic effects through mediators along the causal pathway between the randomized treatment and the outcome. In the setting with two sequential mediators, there are a variety of decompositions of the total risk difference into mediation effects. We derive sharp and valid bounds for a number of mediation effects in the setting of two sequential mediators both with unmeasured confounding with the outcome. We provide five such bounds in the main text corresponding to two different decompositions of the total effect, as well as the controlled direct effect, with an additional thirty novel bounds provided in the supplementary materials corresponding to the terms of twenty-four four-way decompositions. We also show that, although it may seem that one can produce sharp bounds by adding or subtracting the limits of the sharp bounds for terms in a decomposition, this almost always produces valid, but not sharp bounds that can even be completely noninformative. We investigate the properties of the bounds by simulating random probability distributions under our causal model and illustrate how they are interpreted in a real data example.

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 (

Nonignorable missingness and noncompliance can occur even in well-designed randomized experiments making the intervention effect that the experiment was designed to estimate nonidentifiable. Nonparametric causal bounds provide a way to narrow the range of possible values for a nonidentifiable causal effect with minimal assumptions. We derive novel bounds for the causal risk difference for a binary outcome and intervention in randomized experiments with nonignorable missingness caused by a variety of mechanisms and with or without noncompliance. We illustrate the use of the proposed bounds in our motivating data example of peanut consumption on the development of peanut allergies in infants., 35 pages, 5 figures, includes supplementary materials

Introduction: Whether data on International Classification of Diseases (ICD)-codes from the Swedish National Patient Register (NPR) correctly correspond to subtypes of inflammatory bowel disease (IBD) and phenotypes of the Montreal classification scheme among patients with prevalent disease is unknown. Materials and methods: We obtained information on IBD subtypes and phenotypes from the medical records of 1403 patients with known IBD who underwent biological treatment at ten Swedish hospitals and retrieved information on their IBD-associated diagnostic codes from the NPR. We used previously described algorithms to define IBD subtypes and phenotypes. Finally, we compared these register-generated subtypes and phenotypes with the corresponding information from the medical records and calculated positive predictive values (PPV) with 95% confidence intervals. Results: Among patients with clinically confirmed disease and diagnostic listings of IBD in the NPR (N = 1401), the PPV was 97 (96–99)% for Crohn’s disease, 98 (97–100)% for ulcerative colitis, and 8 (4–11)% for IBD-unclassified. The overall accuracy for age at diagnosis was 95% (when defined as A1, A2, or A3). Examining the validity of codes representing disease phenotype, the PPV was 36 (32–40)% for colonic Crohn’s disease (L2), 61 (56–65)% for non-stricturing/non-penetrating Crohn’s disease behaviour (B1) and 83 (78–87)% for perianal disease. Correspondingly, the PPV was 80 (71–89)% for proctitis (E1)/left-sided colitis (E2) in ulcerative colitis. Conclusions: Among people with known IBD, the NPR is a reliable source of data to classify most subtypes of prevalent IBD, even though misclassification commonly occurred in Crohn’s disease location and behaviour and also among IBD-unclassified patients.

Background Patients with inflammatory bowel disease (IBD) have an increased risk of cancer.Aim To assess the risk of pancreatic cancer in IBD compared to the general population.Methods Patients with incident IBD 1969-2017 were identified in Danish and Swedish National Patient Registers and through biopsy data, and were matched to IBD-free reference individuals by sex, age, place of residence and year of IBD diagnosis. We linked data to Cancer and Causes of Death Registers and examined the absolute and relative risks of pancreatic cancer and pancreatic cancer death.Results Among 161 926 patients followed for 2 000 951 person years, 442 (0.27%) were diagnosed with pancreatic cancer compared to 3386 (0.21%) of the 1 599 024 reference individuals. The 20-year cumulative incidence was 0.34% (95% confidence interval 0.30-0.38) vs 0.29% (0.28-0.30). The incidence rate was 22.1 (20.1-24.2)/100 000 person years in the patients (excluding the first year of follow-up: 20.8 [18.8-23.0]), and 16.6 (16.0-17.2) in the reference individuals. The hazard ratio (HR) for pancreatic cancer was increased overall: 1.43 (1.30-1.58), in subtypes (Crohn's disease: 1.44 [1.18-1.74]; ulcerative colitis: 1.35 [1.19-1.53]; IBD unclassified: 1.99 [1.50-2.64]) and especially in IBD patients with primary sclerosing cholangitis: 7.55 (4.94-11.5). Patients and reference individuals with pancreatic cancer did not differ in cancer stage (P = 0.17) or pancreatic cancer mortality (HR 1.07 [0.95-1.21]).Conclusions Patients with IBD had an excess risk of pancreatic cancer, in particular patients with primary sclerosing cholangitis. However, the cumulative incidence difference after 20 years was small: 0.05%, that is, one extra pancreatic cancer per 2000 IBD patients.

Background: Ulcerative colitis (UC) is a risk factor for colorectal cancer (CRC). However, available studies reflect older treatment and surveillance paradigms, and most have assessed risks for incident CRC without taking surveillance and lead-time bias into account, such as by assessing CRC incidence by tumour stage, or stage-adjusted mortality from CRC. We aimed to compare both overall and country-specific risks of CRC mortality and incident CRC among patients with UC. Methods: In this population-based cohort study of 96 447 patients with UC in Denmark (n=32 919) and Sweden (n=63 528), patients were followed up for CRC incidence and CRC mortality between Jan 1, 1969, and Dec 31, 2017, and compared with matched reference individuals from the general population (n=949 207). Patients with UC were selected from national registers and included in the analysis if they had two or more records with a relevant International Classification of Disease in the patient register (in the country in question) or one such record plus a colorectal biopsy report with a morphology code suggestive of inflammatory bowel disease. For every patient with UC, we selected matched reference individuals from the total population registers of Denmark and Sweden, who were matched for sex, age, birth year, and place of residence. We used Cox regression to compute hazard ratios (HRs) for incident CRC, and for CRC mortality, taking tumour stage into account. Findings: During follow-up, we observed 1336 incident CRCs in the UC cohort (1·29 per 1000 person-years) and 9544 incident CRCs in reference individuals (0·82 per 1000 person-years; HR 1·66, 95% CI 1·57–1·76). In the UC cohort, 639 patients died from CRC (0·55 per 1000 person-years), compared with 4451 reference individuals (0·38 per 1000 person-years; HR 1·59, 95% CI 1·46–1·72) during the same time period. The CRC stage distribution in people with UC was less advanced (p

BackgroundTreatment of patients with Crohns disease has evolved in recent decades, with increasing use of immunomodulatory medication since 1990 and biologicals since 1998. In parallel, there has been increased use of active disease monitoring. To what extent these changes have influenced the incidence of primary and repeat surgical resection remains debated. MethodsIn this nationwide cohort study, incident patients of all ages with Crohns disease, identified in Swedish National Patient Registry between 1990 and 2014, were divided into five calendar periods of diagnosis: 1990-1995 and 1996-2000 with use of inpatient registries, 2001, and 2002-2008 and 2009-2014 with use of inpatient and outpatient registries. The cumulative incidence of first and repeat abdominal surgery (except closure of stomas), by category of surgical procedure, was estimated using the Kaplan-Meier method. ResultsAmong 21273 patients with Crohns disease, the cumulative incidence of first abdominal surgery within 5years of Crohns disease diagnosis decreased continuously from 548 per cent in 1990-1995 to 404 per cent in 1996-2000 (PFunding Agencies|Swedish Medical Society; Karolinska Institutet FoundationsKarolinska Institutet; Stockholm County CouncilStockholm County Council; Karolinska InstitutetKarolinska Institutet; JanssenJohnson & Johnson USAJanssen Biotech Inc; TakedaTakeda Pharmaceutical Company Ltd; MSD; Ostergotland County

We extend the method proposed in a recent work by the Authors for trial-level general surrogate evaluation to allow combinations of biomarkers and provide a procedure for finding the "best" combination of biomarkers based on the absolute prediction error summary of surrogate quality. We use a nonparametric Bayesian model that allows us to select an optimal subset of biomarkers without having to consider a large number of explicit model specifications for that subset. This dramatically reduces the number of model comparisons needed. Given the model's flexibility, complex nonlinear relationships can be fit when enough data are available. We evaluate the operating characteristics of our proposed method in simulations designed to be similar to our motivating example. We use our method to compare and evaluate combinations of biomarkers as trial-level general surrogates for the pentavalent rotavirus vaccine RotaTeq™ (RV5) (Merck & Co, Inc, Kenilworth, New Jersey, USA), finding that the same single biomarker identified in our previously published analysis is likely the optimal subset.