Michael C. Sachs

Incidence and Treatment of Patients Diagnosed With Inflammatory Bowel Diseases at 60 Years or Older in Sweden

BACKGROUND & AIMSnDiagnosis of inflammatory bowel diseases (IBD) is increasing among elderly persons (60 years or older). We performed a nationwide population-based studyxa0to estimate incidence and treatment of IBD.nnnMETHODSnWe identified all incident IBD cases in Sweden from 2006 through 2013 using national registers and up to 10 matched population comparator subjects. We collected data on the patients health care contacts and estimated incidence rates, health service burden, pharmacologic treatments, extra-intestinal manifestations, and surgeries in relation to age of IBD onset (pediatric, <18 years; adults, 18-59 years; elderly, ≥60 years).nnnRESULTSnOf 27,834 persons diagnosed with incident IBD, 6443 (23%) had a first diagnosis of IBD at 60 years or older, corresponding to an incidence rate of 35/100,000 person-years (10/100,000 person-years for Crohns disease, 19/100,000 person-years for ulcerative colitis, and 5/100,000 person-years for IBDxa0unclassified). During a median follow-up period of 4.2 years (range, 0-9 years), elderly patients had less IBD-specific outpatient health care but more IBD-related hospitalizations and overall health care use than adult patients withxa0IBD.xa0Compared with patients with pediatric or adult-onset IBD, elderly patients used fewer biologics and immunomodulators but more systemic corticosteroids. Occurrence of extra-intestinal manifestations was similar in elderly and adult patients, but bowel surgery was more common in the elderly (13% after 5 years vs 10% in adults) (P < .001). The absolute risk of bowel surgery was higher in the elderly than in the general population, but in relative terms, the risk increase was larger in younger age groups.nnnCONCLUSIONSnIn a nationwide cohort study in Sweden, we associated diagnosis of IBD at age 60 years or older with a lower use of biologicsxa0and immunomodulators but higher absolute risk of bowel surgery, compared with diagnosis at a younger age. The large differences in pharmacologic treatment of adultsxa0and elderly patients are not necessarily because of a milder course of disease and warrant further investigation.

Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964-2014

Objective To assess risk of cancer in patients with childhood onset inflammatory bowel disease in childhood and adulthood. Design Cohort study with matched general population reference individuals using multivariable Cox regression to estimate hazard ratios. Setting Swedish national patient register (both inpatient and non-primary outpatient care) 1964-2014. Participants Incident cases of childhood onset (<18 years) inflammatory bowel disease (n=9405: ulcerative colitis, n=4648; Crohn’s disease, n=3768; unclassified, n=989) compared with 92u2009870 comparators from the general population matched for sex, age, birth year, and county. Main outcome measures Any cancer and cancer types according to the Swedish Cancer Register. Results During follow-up through adulthood (median age at end of follow-up 27 years), 497 (3.3 per 1000 person years) people with childhood onset inflammatory bowel disease had first cancers, compared with 2256 (1.5 per 1000 person years) in the general population comparators (hazard ratio 2.2, 95% confidence interval 2.0 to 2.5). Hazard ratios for any cancer were 2.6 in ulcerative colitis (2.3 to 3.0) and 1.7 in Crohn’s disease (1.5 to 2.1). Patients also had an increased risk of cancer before their 18th birthday (2.7, 1.6 to 4.4; 20 cancers in 9405 patients, 0.6 per1000 person years). Gastrointestinal cancers had the highest relative risks, with a hazard ratio of 18.0 (14.4 to 22.7) corresponding to 202 cancers in patients with inflammatory bowel disease. The increased risk of cancer (before 25th birthday) was similar over time (1964-1989: 1.6, 1.0 to 2.4; 1990-2001: 2.3, 1.5 to 3.3); 2002-06: 2.9, 1.9 to 4.2; 2007-14: 2.2, 1.1 to 4.2). Conclusion Childhood onset inflammatory bowel disease is associated with an increased risk of any cancer, especially gastrointestinal cancers, both in childhood and later in life. The higher risk of cancer has not fallen over time.

Comparing and combining biomarkers as principle surrogates for time‐to‐event clinical endpoints

Principal surrogate endpoints are useful as targets for phase I and II trials. In many recent trials, multiple post-randomization biomarkers are measured. However, few statistical methods exist for comparison of or combination of biomarkers as principal surrogates, and none of these methods to our knowledge utilize time-to-event clinical endpoint information. We propose a Weibull model extension of the semi-parametric estimated maximum likelihood method that allows for the inclusion of multiple biomarkers in the same risk model as multivariate candidate principal surrogates. We propose several methods for comparing candidate principal surrogates and evaluating multivariate principal surrogates. These include the time-dependent and surrogate-dependent true and false positive fraction, the time-dependent and the integrated standardized total gain, and the cumulative distribution function of the risk difference. We illustrate the operating characteristics of our proposed methods in simulations and outline how these statistics can be used to evaluate and compare candidate principal surrogates. We use these methods to investigate candidate surrogates in the Diabetes Control and Complications Trial.

Inflammatory Bowel Disease and Parkinson’s Disease: A Nationwide Swedish Cohort Study

BackgroundnFew studies have examined the association between inflammatory bowel disease (IBD) and Parkinsons disease (PD).nnnMethodsnTo estimate the incidence and relative risk of PD development in a cohort of adult IBD, we included all incident IBD patients (n = 39,652) in the Swedish National Patient Register (NPR) between 2002 and 2014 (ulcerative colitis [UC]: n = 24,422; Crohns disease [CD]: n = 11,418; IBD-unclassified [IBD-U]: n = 3812). Each IBD patient was matched for sex, age, year, and place of residence with up to 10 reference individuals (n = 396,520). In a cohort design, all incident PD occurring after the index date was included from the NPR. In a case-control design, all incident PD occurring before the index date was included. The association between IBD and PD and vice versa was investigated by multivariable Cox and logistic regression.nnnResultsnIn IBD, there were 103 cases of incident PD, resulting in hazard ratios (HRs) for PD of 1.3 (95% confidence interval [CI], 1.0-1.7; P = 0.04) in UC, 1.1 (95% CI, 0.7-1.7) in CD, and 1.7 (95% CI, 0.8-3.0) in IBD-U. However, these effects disappeared when adjusting for number of medical visits during follow-up to minimize potential surveillance bias. In a case-control analysis, IBD patients were more likely to have prevalent PD at the time of IBD diagnosis than matched controls, with odds ratios of 1.4 (95% CI, 1.2-1.8) in all IBD patients, 1.4 (95% CI, 1.1-1.9) for UC, and 1.6 (95% CI, 1.1-2.3) for CD patients alone.nnnConclusionsnIBD is associated with an increased risk of PD, but some of this association might be explained by surveillance bias. 10.1093/ibd/izy190_video1izy190.video15785623138001.

Association between inflammatory bowel disease and Parkinson’s disease: seek and you shall find?

We read with great interest the article by Villumsen et al 1 about the association between inflammatory bowel disease (IBD) and Parkinson’s disease (PD). Villumsen et al estimated the risk of developing PD to be 22% higher in a Danish IBD population than in a non-IBD population.nnDuring the last decade, evidence has accumulated that shared biological mechanisms are involved in the development of IBD and PD.2 However, the clinical co-occurrence of IBD and PD has only been investigated to a limited extent and with inconsistent results.3–5 Thus, concerns have been raised about how best to interpret this possible association.nnIn a recently published article by our group, we too demonstrated a positive association between PD and IBD.6 We observed that Swedish patients withxa0IBD were at 30% higher risk of subsequently developing PD than were non-IBD individuals. Furthermore, that patients with IBD had higher …

Measuring precision in bioassays: Rethinking assay validation

The m:n:θb procedure is often used for validating an assay for precision, where m levels of an analyte are measured with n replicates at each level, and if all m estimates of coefficient of variation (CV) are less than θb , then the assay is declared validated for precision. The statistical properties of the procedure are unknown so there is no clear statistical statement of precision upon passing. Further, it is unclear how to modify the procedure for relative potency assays in which the constant standard deviation (SD) model fits much better than the traditional constant CV model. We use simple normal error models to show that under constant CV across the m levels, the probability of passing when the CV is θb is about 10% to 20% for some recommended implementations; however, for extreme heterogeniety of CV when the largest CV is θb , the passing probability can be greater than 50%. We derive 100q% upper confidence limits on the CV under constant CV models and derive analogous limits for the SD under a constant SD model. Additionally, for a post-validation assay output of y, we derive 68.27% confidence intervals on either the mean or log geometric mean of the assay output using either y±s (for the constant SD model) or log(y)±rG (for the constant CV model), where s and rG are constants that do not depend on y. We demonstrate the methods on a growth inhibition assay used to measure biologic activity of antibodies against the malaria parasite.

Increased Mortality of Patients with Childhood-onset Inflammatory Bowel Diseases, Compared With the General Population

BACKGROUND & AIMSnChildhood-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.nnnMETHODSnWe identified children with a diagnosis of IBD (younger than 18 years) in the Swedish nationwide health registers (1964-2014; nxa0= 9442) and individuals from the general population matched for sex, age, calendar year, and place of residence (reference group; nxa0=xa093,180). Hazard ratios (HR) for death were estimated usingxa0Cox regression separately in patients with ulcerative colitis (nxa0= 4671), Crohns disease (nxa0= 3780), and IBD unclassified (nxa0= 991). HRs were compared among calendar periods.nnnRESULTSnDuring 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; Crohns 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 (Pxa0= .90).nnnCONCLUSIONSnChildren 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.

Evaluation and comparison of predictive individual-level general surrogates

An intermediate response measure that accurately predicts efficacy in a new setting at the individual level could be used both for prediction and personalized medical decisions. In this article, we define a predictive individual-level general surrogate (PIGS), which is an individual-level intermediate response that can be used to accurately predict individual efficacy in a new setting. While methods for evaluating trial-level general surrogates, which are predictors of trial-level efficacy, have been developed previously, few, if any, methods have been developed to evaluate individual-level general surrogates, and no methods have formalized the use of cross-validation to quantify the expected prediction error. Our proposed method uses existing methods of individual-level surrogate evaluation within a given clinical trial setting in combination with cross-validation over a set of clinical trials to evaluate surrogate quality and to estimate the absolute prediction error that is expected in a new trial setting when using a PIGS. Simulations show that our method performs well across a variety of scenarios. We use our method to evaluate and to compare candidate individual-level general surrogates over a set of multi-national trials of a pentavalent rotavirus vaccine.

Small Nucleolar RNA Score: An Assay to Detect Formalin-Overfixed Tissue

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.

OP024 Childhood-onset inflammatory bowel disease and risk of cancer – a Swedish nationwide cohort study 1964–2014

Childhood-onset inflammatory bowel disease and risk of cancer - a Swedish nationwide cohort study 1964-2014