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Supplementary Table 4 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

Supplementary Table 1 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

Supplementary Figure 1 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

Supplementary Table 2 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

Supplementary Table 3 from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanthine phosphoribosyltransferase (HPRT) locus in peripheral T lymphocytes as well as the prevalence of mutant clonal proliferation in a cross-sectional analysis of data from 119 children and adults with inflammatory bowel disease (IBD). ANOVA and regression were performed to assess relationships among the frequency and spectra of HPRT mutations with disease, duration of illness, duration of treatment, and total therapeutic dose of azathioprine and 6-MP. We observed a significant increase in the frequency of somatic mutations in 56 subjects treated with thiopurines for IBD compared with 63 subjects not treated with thiopurines. This increase was related to both total dose (P < 0.001) and duration of treatment (P < 0.001). Comparative mutation spectra analysis of 1,020 mutant isolates revealed a significant increase in the proportion of all transitions (P < 0.001), particularly G:C to A:T transitions (P < 0.001). Combined analyses of two signatures for mutant clonality, HPRT mutation, and T-cell receptor β CDR3 region unique gene sequence also showed a significant thiopurine-dependent increase in mutant cell clonal proliferation (P < 0.001). These findings provide in vivo evidence for mutation induction as a potential carcinogenic mechanism associated with chronic thiopurine intervention. [Cancer Res 2009;69(17):7004–23]

Supplementary Figure Legend from Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease

Background Endoscopic mucosal healing is the gold standard for evaluating Crohn’s disease (CD) treatment efficacy. Standard endoscopic indices are not routinely used in clinical practice, limiting the quality of retrospective research. A method for retrospectively quantifying mucosal activity from documentation is needed. We evaluated the simplified endoscopic mucosal assessment for CD (SEMA-CD) to determine if it can accurately quantify mucosal severity recorded in colonoscopy reports. Methods Pediatric patients with CD underwent colonoscopy that was video recorded and evaluated via Simple Endoscopic Score for CD (SES-CD) and SEMA-CD by central readers. Corresponding colonoscopy reports were de-identified. Central readers blinded to clinical history and video scoring were randomly assigned colonoscopy reports with and without images. The SEMA-CD was scored for each report. Correlation with video SES-CD and SEMA-CD were assessed with Spearman rho, inter-rater, and intrarater reliability with kappa statistics. Results Fifty-seven colonoscopy reports were read a total of 347 times. The simplified endoscopic mucosal assessment for CD without images correlated with both SES-CD and SEMA-CD from videos (rho = 0.82, P < .0001 for each). The addition of images provided similar correlation. Inter-rater and intrarater reliability were 0.93 and 0.92, respectively. Conclusions The SEMA-CD applied to retrospective evaluation of colonoscopy reports accurately and reproducibly correlates with SES-CD and SEMA-CD of colonoscopy videos. The SEMA-CD for evaluating colonoscopy reports will enable quantifying mucosal healing in retrospective research. Having objective outcome data will enable higher-quality research to be conducted across multicenter collaboratives and in clinical registries. External validation is needed.

To assess treatment patterns and initial and maintenance dosing of biologics over 3 years in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD), utilizing data from the ImproveCareNow registry.Pediatric patients diagnosed with UC or CD and aged 2-17 years were included in the study. Descriptive statistics were employed to summarize baseline demographics. The proportion of patients on medication for UC or CD were analyzed at the baseline visit, 1-year, and 3-year time points (Cohort 1). Biologic maintenance dosage was calculated only for patients who had data for dose and weight at all-time points (Cohort 2).In Cohort 1 (UC = 1784; CD = 4720), baseline treatment in UC included corticosteroid, 5-ASA, and 6-MP/AZA; at 1-year and 3-year time points, treatment with 5-ASA and corticosteroid decreased, whereas 6-MP/AZA and anti-TNFs increased. In CD, baseline treatment included corticosteroid, anti-TNF, 6-MP/AZA, and methotrexate; use of corticosteroids decreased, whereas the use of methotrexate and anti-TNFs increased over 3 years. In Cohort 2 (UC = 350; CD = 1537), at first maintenance dose, UC patients on infliximab received a mean dose of 10.5 mg/kg/8 wk, adalimumab (weight40 kg and ≥40 kg) 1.3 mg/kg/2 wk and 0.8 mg/kg/2 wk, and vedolizumab 6.9 mg/kg/8 wks. At the first maintenance dose, CD patients on infliximab received a mean dose of 8.1 mg/kg/8 wk, adalimumab (weight40 kg) 1.1 mg/kg/2 wk, adalimumab (weight ≥ 40 kg) 0.8 mg/kg/2 wk, and vedolizumab 10.5 mg/kg/8 wks.The use of corticosteroids was common at the initial visit in patients. Anti-TNFs remain the most used class of biologics, however, reported doses in our study were substantially higher than the standard dosing guidelines.

Background To demonstrate treatment efficacy in Crohn’s disease (CD), regulatory authorities require that trials include an endoscopic remission/response end point; however, standardized endoscopic assessment of disease activity, such as the Simple Endoscopic Score for Crohn’s Disease (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. The novel Simplified Endoscopic Mucosal Assessment for Crohn’s Disease (SEMA-CD) was developed to be easy to use in routine clinical practice and as a trial end point. We conducted a study to assess and validate the reliability and feasibility of SEMA-CD as a measure of endoscopic disease activity. Methods Pre- and post-treatment ileocolonoscopy videos of pediatric (n = 36) and adult (n = 74) CD patients from 2 ustekinumab clinical trials were each scored with SEMA-CD by 2 to 3 professional central readers, blinded to clinical history and other video scorings; the correlation between SEMA-CD and SES-CD previously completed during the trials was assessed. Sensitivity to change, inter- and intrarater reliability, and comparative ease of scoring were also assessed. Results The SEMA-CD strongly correlated with SES-CD (Spearman ρ = 0.89; 95% confidence interval, 0.86-0.92). Pre- to post-treatment changes in SEMA-CD vs in SES-CD were strongly correlated, and the correlation remained strong between the scores when compared by study population (pediatric, adult), disease severity, and video quality. Intra- and inter-rater reliability were good, and SEMA-CD was rated easier than SES-CD to score 63.0% of the time, although slightly more difficult than SES-CD to score Conclusions The SEMA-CD is reliable, reproducible, sensitive to change, and easy to use in both pediatric and adult patients with CD.

Background To assess disease activity, steroid-free remission, and other clinical outcome assessments among pediatric patients with ulcerative colitis (UC) and Crohn’s disease (CD) in the ImproveCareNow (ICN) registry. Methods Patients aged 2–17 years diagnosed with UC or CD between June 1, 2013 and December 31, 2019 were enrolled if they initiated a biologic after enrollment in the ICN registry and completed at least 12 months follow-up after first maintenance dose. Baseline (at biologic initiation) demographics were summarized using descriptive statistics. Pediatric UC Activity Index (PUCAI), partial Mayo score, and Physician Global Assessment (PGA) were assessed for UC; and the Short Pediatric Crohn’s Disease Activity Index (sPCDAI) and PGA were assessed for CD at first maintenance dose, 1- and 3-year time points. Kappa coefficients were used to assess the level of agreement between the outcome measures. Results A total of 1887 patients (UC = 350; CD = 1537) were included. Baseline demographics were similar across groups. For UC patients, mean PUCAI scores decreased and the proportion of patients in steroid-free remission, quiescent state based on PGA, and remission based on partial Mayo score increased from first maintenance dose to 1 and 3 years. For CD patients, mean sPCDAI score of CD patients decreased and the proportion of patients in steroid-free remission by sPCDAI and in quiescent state based on PGA increased from first maintenance dose to 1 and 3 years. Kappa coefficients showed only modest correlation between disease activity assessments. Conclusions Disease activity scores improved over time, with more pediatric patients with UC and CD achieving steroid-free remission at 1 and 3 years after first biologic maintenance dose.

* Abbreviations: CRP — : C-reactive protein FGID — : functional gastrointestinal disorder IBD — : inflammatory bowel disease Chronic abdominal pain and diarrhea are common symptoms in children. In any given 6-month period, up to half of the children in the United States report persistent abdominal pain, which often leads to a medical evaluation.1–5 When evaluating children with chronic abdominal pain and diarrhea, clinicians have the challenge of determining how much of an evaluation is necessary because a functional gastrointestinal disorder (FGID) is most likely. Rome IV criteria (international guidelines used to define FGIDs) state that the diagnosis of an FGID can be supported when “after appropriate medical evaluation the symptoms cannot be attributed to another medical condition.”5 The central question is as follows: what is appropriate medical evaluation? Certainly the presence of “alarm” signs and symptoms (eg, weight loss, poor weight gain, poor linear growth, significant vomiting, chronic severe diarrhea, hematochezia, persistent right upper or lower quadrant pain, fever, unexplained anemia, family history of inflammatory bowel disease [IBD]) should prompt a full diagnostic evaluation.3 When should an extensive evaluation, including upper gastrointestinal endoscopy or ileocolonoscopy be done? These … Address correspondence to Jillian S. Sullivan, MD, MSCS, Department of Pediatrics, The University of Vermont Children’s Hospital, 111 Colchester Ave, Burlington, VT 05401. E-mail: jillian.sullivan{at}uvmhealth.org

Background Patient registries are a source of real-world data (RWD) that are increasingly used to generate real-world evidence (RWE) for the safety and effectiveness of medical therapies. However, in registries, outcome data typically collected in clinical trials may be missing in some patients, creating a major challenge in evaluating RWD reliably. Clinical remission in pediatric Crohn’s disease (PCD), defined by the Short Pediatric Crohn’s disease Activity Index (sPCDAI) Methods A Starting Dataset from the ICN registry included CD patients age 2 to Results The Starting and Complete Datasets included 1,458 and 1,212 patients, respectively. The true clinical remission rate in the Complete Dataset was 75.1% (95% CI: 72.6%-77.5%). Analysis without MI for the missing sPCDAI data resulted in underestimation of clinical remission rate, with bias about -2% to -5% (Table 1). The MI method eliminated the bias and had 100% coverage in all simulation scenarios by using a large number of independent predictors. Conclusion The MI method improved the validity, reliability, and efficiency of using RWD for estimating clinical remission in pediatric patients with CD and could be valuable in other registry studies.

Objectives: Adalimumab is an effective treatment for Crohn’s disease but antibody development may cause loss of response. Concomitant use of an immunomodulator reduces the development of antibodies. We performed a 5- year cross-sectional study of variation in use of adalimumab and concomitant therapy in a large pediatric population.Methods: We identified patients with Crohn’s disesae aged

The Pediatric Ulcerative Colitis Activity Index (PUCAI) is a noninvasive disease activity index developed as a clinical trial endpoint. More recently, practice guidelines have recommended the use of PUCAI in routine clinical care. We therefore sought to evaluate the feasibility, validity, and responsiveness of PUCAI in a large, diverse collection of pediatric gastroenterology practices.We extracted data from the 2 most recent encounters for patients with ulcerative colitis in the ImproveCareNow registry. Feasibility was determined by the percentage of patients for whom all PUCAI components were recorded, validity by correlation of PUCAI scores across physician global assessment (PGA) categories, and responsiveness to change by the correlation between the change in PUCAI and PGA scores between visits.A total of 2503 patients were included (49.5% boys, age 15.2 ± 4.1 years, disease duration 3.7 ± 3.2 years). All items in the PUCAI were completed for 96% of visits. PUCAI demonstrated excellent discriminatory ability between remission, mild, and moderate disease; discrimination between moderate and severe disease was less robust. There was good correlation with PGA (r = 0.76 [P 0.001] and weighted kappa κ = 0.73 [P 0.001]). The PUCAI change scores correlated well with PGA change scores (P 0.001). Test-retest reliability of the PUCAI was good (intraclass correlation coefficient 0.72 [95% confidence interval 0.70-0.75], P 0.001). Guyatt responsiveness statistic was 1.18, and the correlation of ΔPUCAI with ΔPGA was 0.69 (P 0.001).The PUCAI is feasible to use in routine clinical settings. Evidence of its validity and responsiveness supports its use as a clinical tool for monitoring disease activity for patients with ulcerative colitis.

OBJECTIVES: ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). METHODS: Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. RESULTS: During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20–1.96) for clinical remission and 1.74 (95% CI, 1.33–2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4–11.1) for clinical remission and 5.0 (95% CI, 3.4–10.0) for corticosteroid-free remission. CONCLUSIONS: In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.

Seasonal and geographic variations of inflammatory bowel disease (IBD) exacerbations have been described in adults, with inconsistent findings. We sought to determine whether disease activity in pediatric-onset IBD is associated with a seasonal pattern.We examined children with Crohn disease (CD) and ulcerative colitis (UC) using data from the ImproveCareNow Collaborative between December 2008 and November 2010. We compared the proportion of patients in continuous remission for all recorded visits in each season. We also compared the distribution of all recorded visits with a physician global assessment (PGA) of remission or active disease across seasons.A total of 1325 patients with CD (6102 visits) and 587 patients with UC (2394 visits) were included. The proportion of patients with UC in continuous remission during each season was highest in the summer (67%) and lowest in the winter (55%) (P=0.01). A similar pattern was found for CD but was not significant. Similarly, the proportion of visits in remission was highest in the summer and lowest in the winter for both UC (29%, 21%; P0.001) and CD (28%, 23%; P0.001); however, the distribution of visits with active disease was not significantly different across seasons.The higher proportion of patients with UC in continuous remission in the summer may be related to the higher proportion of remission visits in the summer, because the proportion of visits with active disease was similar across seasons. These findings do not support any strong associations between season of the year and disease activity in pediatric IBD.

A number of pediatric collaborative improvement networks have demonstrated improved care and outcomes for children. Regionally, Cincinnati Children’s Hospital Medical Center Physician Hospital Organization has sustained key asthma processes, substantially increased the percentage of their asthma population receiving “perfect care,” and implemented an innovative pay-for-performance program with a large commercial payor based on asthma performance measures. The California Perinatal Quality Care Collaborative uses its outcomes database to improve care for infants in California NICUs. It has achieved reductions in central line–associated blood stream infections (CLABSI), increased breast-milk feeding rates at hospital discharge, and is now working to improve delivery room management. Solutions for Patient Safety (SPS) has achieved significant improvements in adverse drug events and surgical site infections across all 8 Ohio children’s hospitals, with 7700 fewer children harmed and >$11.8 million in avoided costs. SPS is now expanding nationally, aiming to eliminate all events of serious harm at children’s hospitals. National collaborative networks include ImproveCareNow, which aims to improve care and outcomes for children with inflammatory bowel disease. Reliable adherence to Model Care Guidelines has produced improved remission rates without using new medications and a significant increase in the proportion of Crohn disease patients not taking prednisone. Data-driven collaboratives of the Children’s Hospital Association Quality Transformation Network initially focused on CLABSI in PICUs. By September 2011, they had prevented an estimated 2964 CLABSI, saving 355 lives and $103 722 423. Subsequent improvement efforts include CLABSI reductions in additional settings and populations.

The Institute of Medicine's publications, To Err is Human and Crossing the Quality Chasm, publicized the widespread deficits in healthcare quality. The quality of care in inflammatory bowel disease (IBD) has not been comprehensively evaluated, in part due to a lack of well-established IBD measures of quality. Quality can be measured for evaluation, benchmarking, or continuous quality improvement, using structural, process, and outcome measures. Measurement is an essential component of the model for improvement, necessary to determine whether changes made have resulted in improvement. Measures used for quality improvement should be based on evidence and consensus, be clear and collectable in a timely fashion, occur with sufficient frequency, and have the potential to improve outcomes. While no current IBD measures of quality are perfect, an iterative process of measure development can produce a set of measures that are feasible, relevant, and useful for performing quality improvement. This review describes the history, rationale, and methods of quality measurement and discusses the early work and lessons learned from measuring quality of care in a pediatric IBD quality improvement collaborative. (Inflamm Bowel Dis 2011;)

Background: Obesity is a significant public health threat to children in the United States. The aims were to: 1) Determine the prevalence of obesity in a multicenter cohort of children with inflammatory bowel disease (IBD); 2) Evaluate whether overweight and obese status is associated with patient demographics or disease characteristics. Methods: We used data from the ImproveCareNow Collaborative for pediatric IBD, a multicenter registry of children with IBD, collected between April 2007 and December 2009. Children ages 2–18 years were classified into body mass index (BMI) percentiles. Bivariate analyses and multivariate logistic regression were used to compare demographic and disease characteristics by overweight (BMI >85%) and obese (BMI >95%) status. Results: The population consisted of 1598 children with IBD. The prevalence of overweight/obese status in pediatric IBD is 23.6%, (20.0% for Crohn's disease [CD] and 30.1% for ulcerative colitis [UC] and indeterminate colitis [IC]). African American race (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.10–2.48) and Medicaid insurance (OR 1.67, 95% CI 1.19–2.34) were positively associated with overweight/obese status. Prior IBD-related surgery (OR 1.73, 95% CI 1.07–2.82) was also associated with overweight and obese status in children with CD. Other disease characteristics were not associated with overweight and obesity in children with IBD. Conclusions: Approximately one in five children with CD and one in three with UC are overweight or obese. Rates of obesity in UC are comparable to the general population. Obese IBD patients may have a more severe disease course, as indicated by increased need for surgery. Sociodemographic risk factors for obesity in the IBD population are similar to those in the general population. (Inflamm Bowel Dis 2010;)

Objective: As the clinical implications of Helicobacter pylori infection in children and adolescents continue to evolve, ESPGHAN and NASPGHAN jointly renewed clinical guidelines using a standardized evidence-based approach to develop updated recommendations for children and adolescents in North America and Europe. Methods: An international panel of 11 pediatric gastroenterologists, 2 epidemiologists, 1 microbiologist, and 1 pathologist was selected by societies that developed evidence-based guidelines based on the Delphi process with anonymous voting in a final face-to-face meeting. A systematic literature search was performed on 8 databases of relevance including publications from January 2000 to December 2009. After excluding nonrelevant publications, tables of evidence were constructed for different focus areas according to the Oxford classification. Statements and recommendations were formulated in the following areas: whom to test, how to test, whom to treat, and how to treat. Grades of evidence were assigned to each recommendation based on the GRADE system. Results: A total of 2290 publications were identified, from which 738 were finally reviewed. A total of 21 recommendations were generated, and an algorithm was proposed by the joint committee providing evidence-based guidelines on the diagnostic workup and treatment of children with H pylori infection. Conclusions: These clinical practice guidelines represent updated, bestavailable evidence and are meant for children and adolescents living in Europe and North America, but they may not apply to those living on other continents, particularly in developing countries with a high H pylori infection rate and limited health care resources.

The pediatric population has a number of unique considerations related to the diagnosis and treatment of ascites. This review summarizes the physiologic mechanisms for cirrhotic and noncirrhotic ascites and provides a comprehensive list of reported etiologies stratified by the patient's age. Characteristic findings on physical examination, diagnostic imaging, and abdominal paracentesis are also reviewed, with particular attention to those aspects that are unique to children. Medical and surgical treatments of ascites are discussed. Both prompt diagnosis and appropriate management of ascites are required to avoid associated morbidity and mortality.

In this paper we describe a longitudinal analysis of the evolution of a team of medical researchers who are trying to establish a COIN consisting of patients of a chronic disease, family members of patients, doctors, and researchers. The data analysis is based on an e-mail archive consisting of the full mailboxes of the six project leaders covering the whole period of COIN formation. We conducted a dynamic analysis of the e-mail network looking at social network analysis metrics such as betweenness centrality and density over time, as well as contribution index and core/periphery structure. We also did a semantic analysis of the e-mail subject headings. A netnographic analysis of patients was done through analyzing their Facebook friendship and discussion networks. External perception of team effectiveness was done through a Web buzz analysis. Preliminary results indicate that after the first physical meeting of the full team the betweenness centrality of the official leaders went down noticeably, as tasks were delegated to other team members, whose centrality increased as the leaders’ centrality fell. The patients, who are the main constituency of this project and could contribute invaluable advise, are still surprisingly peripheral in the entire project team and have a low contribution index. We also found that a peripheral position was held by some very senior team members who seem focused almost exclusively on external projects, and are (not yet) well connected to the core of the project team. The team seems to be inwardly focused, engaged in internal coordination activities and scarcely involved in managing across boundaries. To increase the success of COIN formation, the team might need to extend their ties to the peripheral patients and senior members, whose specialized expertise is essential to disseminate knowledge outside of the team boundaries.

The direct costs of managing inflammatory bowel disease (IBD) in the United States remain a substantial economic burden (1–3). Pharmaceuticals such as biological agents, hospitalization, and abdominal surgery make up the vast majority of the IBD-attributable costs (4). Reducing the need for these acute care services would represent an improvement in the quality of care for chronic IBD and IBD-related disease management (5). In particular, effective system-level efforts to decrease unnecessary emergency department (ED) encounters would decrease patient risk, reduce direct medical costs, and improve the overall value of IBD care. Moving away from the traditional volume-based reimbursement model, the health care marketplace is evolving to a value-based reimbursement model, in which integrated delivery networks are incentivized to deliver the best care for lowest costs (6). Under this chronic care model, responsiveness and care coordination—2 characteristics that support patient-centric delivery of medical care—are described as key elements of an optimal health care system (7,8). In health systems, responsiveness refers to the timely delivery of disease-focused care with a patient-defined perspective integrating the individual patient’s needs and priorities (9,10). Care coordination refers to the well-implemented organization of medical care between multiple providers and the patient (11). The Reducing Cost Strategic Initiative Team of the ImproveCareNow Network, a collaborative, data-driven health care network dedicated to improving the health of children and youth with IBD (12), sought to retrospectively evaluate patterns of ED use in IBD. We hypothesized that a substantial proportion of ED visits for pediatric IBD care would be avoidable in a care model in which providers’ responsiveness and care coordination were readily implementable and consistently reproducible—irrespective of center-, provider-, disease-, and patient-level differences. Specifically, we sought to describe the factors leading to pediatric IBD-related ED visits, and identify those that may be preventable in a more optimal health care system.

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanthine phosphoribosyltransferase (HPRT) locus in peripheral T lymphocytes as well as the prevalence of mutant clonal proliferation in a cross-sectional analysis of data from 119 children and adults with inflammatory bowel disease (IBD). ANOVA and regression were performed to assess relationships among the frequency and spectra of HPRT mutations with disease, duration of illness, duration of treatment, and total therapeutic dose of azathioprine and 6-MP. We observed a significant increase in the frequency of somatic mutations in 56 subjects treated with thiopurines for IBD compared with 63 subjects not treated with thiopurines. This increase was related to both total dose (P < 0.001) and duration of treatment (P < 0.001). Comparative mutation spectra analysis of 1,020 mutant isolates revealed a significant increase in the proportion of all transitions (P < 0.001), particularly G:C to A:T transitions (P < 0.001). Combined analyses of two signatures for mutant clonality, HPRT mutation, and T-cell receptor β CDR3 region unique gene sequence also showed a significant thiopurine-dependent increase in mutant cell clonal proliferation (P < 0.001). These findings provide in vivo evidence for mutation induction as a potential carcinogenic mechanism associated with chronic thiopurine intervention. [Cancer Res 2009;69(17):7004–23]

The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition launched a provider and public education campaign in 2002 to raise awareness of gastroesophageal reflux disease (GERD). To determine the effectiveness of campaign messages, we conducted a knowledge, attitudes, and practice styles (KAPS) survey of pediatric providers. Understanding the spectrum of management styles of GERD in children is critical to achieve better health outcomes and reduce health care costs.The KAPS questionnaire was administered to 6000 randomly selected members of the American Academy of Pediatrics.A total of 1245 members responded; 82% worked in a primary care setting and 18% in subspecialty practices. Overall, 66% of the members order diagnostic testing in routine practice, 54% start testing for GERD in neonates, and 38% start testing after 1 month of age. The most common tests ordered were barium esophagram (45%) and esophageal pH monitoring (37%). GERD treatment with acid suppression before ordering diagnostic testing was a choice of 82% of the respondents. However, 19% believed acid suppression was best achieved by H2 blockers. If acid suppression was indicated, then only 36% followed guideline recommendations for therapy duration and 52% followed guideline recommendations for dosing. Antireflux surgery was recommended only as a last resort by 92%. Overall, 69% of providers believed the amount of GERD-related information available was not enough. Respondents who were not aware of available GERD practice guidelines ranged from 74% to 92%.Pediatric providers appear to frequently order diagnostic testing and treatment for GERD, yet knowledge about evidence-based GERD management among this random sample appeared limited. Moreover, a significant number of providers were not aware of different guideline publications.

Introduction: We collaborated with the ImproveCareNow Network to create a proof-of-concept architecture for a network-based Learning Health System. This collaboration involved transitioning an existing registry to one that is linked to the electronic health record (EHR), enabling a “data in once” strategy. We sought to automate a series of reports that support care improvement while also demonstrating the use of observational registry data for comparative effectiveness research.Description of Architecture: We worked with three leading EHR vendors to create EHR-based data collection forms. We automated many of ImproveCareNow’s analytic reports and developed an application for storing protected health information and tracking patient consent. Finally, we deployed a cohort identification tool to support feasibility studies and hypothesis generation.There is ongoing uptake of the system. To date, 31 centers have adopted the EHR-based forms and 21 centers are uploading data to the registry. Usage of the automated reports remains high and investigators have used the cohort identification tools to respond to several clinical trial requests.Suggestions for Future Use: The current process for creating EHR-based data collection forms requires groups to work individually with each vendor. A vendor-agnostic model would allow for more rapid uptake. We believe that interfacing network-based registries with the EHR would allow them to serve as a source of decision support. Additional standards are needed in order for this vision to be achieved, however.Conclusions: We have successfully implemented a proof-of-concept Learning Health System while providing a foundation on which others can build. We have also highlighted opportunities where sponsors could help accelerate progress.