Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

Rapid deployment of a community engagement study and educational trial via social media: implementation of the UC-COVID study.

BackgroundIn response to the COVID-19 pandemic and associated adoption of scarce resource allocation (SRA) policies, we sought to rapidly deploy a novel survey to ascertain community values and preferences for SRA and to test the utility of a brief intervention to improve knowledge of and values alignment with a new SRA policy. Given social distancing and precipitous evolution of the pandemic, Internet-enabled recruitment was deemed the best method to engage a community-based sample. We quantify the efficiency and acceptability of this Internet-based recruitment for engaging a trial cohort and describe the approach used for implementing a health-related trial entirely online using off-the-shelf tools.MethodsWe recruited 1971 adult participants (≥ 18 years) via engagement with community partners and organizations and outreach through direct and social media messaging. We quantified response rate and participant characteristics of our sample, examine sample representativeness, and evaluate potential non-response bias.ResultsRecruitment was similarly derived from direct referral from partner organizations and broader social media based outreach, with extremely low study entry from organic (non-invited) search activity. Of social media platforms, Facebook was the highest yield recruitment source. Bot activity was present but minimal and identifiable through meta-data and engagement behavior. Recruited participants differed from broader populations in terms of sex, ethnicity, and education, but had similar prevalence of chronic conditions. Retention was satisfactory, with entrance into the first follow-up survey for 61% of those invited.ConclusionsWe demonstrate that rapid recruitment into a longitudinal intervention trial via social media is feasible, efficient, and acceptable. Recruitment in conjunction with community partners representing target populations, and with outreach across multiple platforms, is recommended to optimize sample size and diversity. Trial implementation, engagement tracking, and retention are feasible with off-the-shelf tools using preexisting platforms.Trial registrationClinicalTrials.gov NCT04373135 . Registered on May 4, 2020

Effects of Obstructive Sleep Apnea and Obesity on 30-Day Readmissions in Patients with Chronic Obstructive Pulmonary Disease: A Cross-Sectional Mediation Analysis.

Rationale: Comorbidity is a significant driver of health status and healthcare utilization in chronic obstructive pulmonary disease (COPD). Obstructive sleep apnea (OSA) portends poorer outcomes, whereas obesity is protective. Objectives: We describe the prevalence and influence of these comorbidities on COPD readmissions. Methods: We collated discharge records for COPD exacerbations spanning 2010-2016 from the Nationwide Readmissions Database using Medicare's Hospital Readmissions Reduction Program criteria, with OSA-COPD overlap identified by concomitant diagnosis code for OSA. We used mixed-effects logistic regression to predict readmission odds. A cross-sectional mediation analysis was performed to evaluate the extent that OSA attenuated obesity's impact on readmission. Results: Of 1,662,983 qualifying COPD discharges, 19.1% carried a diagnosis of obesity and 12.9% had OSA, with both diagnoses present in 7.8%. In unadjusted analyses, obesity (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.03-1.05; P &lt; 0.001) and OSA (OR, 1.11; 95% CI, 1.10-1.13; P &lt; 0.001) had increased readmission odds. In models adjusted for patient and hospital characteristics, 71% of readmission risk from obesity was attributable to OSA. When additionally adjusted for Charlson Comorbidity Index, we found that OSA remained a significant risk factor (OR, 1.05; 95% CI, 1.03-1.06; P &lt; 0.001), whereas obesity remained protective (OR, 0.96; 95% CI, 0.94-0.97; P &lt; 0.001) even after accounting for OSA. Conclusions: A significant proportion of patients with COPD suffer comorbid OSA and obesity with resultant readmission risk. Interestingly, obesity's protective effect attenuates readmission odds from OSA. Taken together, OSA and aggregate comorbidity influence readmissions in patients with COPD. Testing for and treating OSA-COPD overlap may provide a mechanism to reduce avoidable readmissions

Factors Associated with Differential Readmission Diagnoses Following Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

BackgroundReadmissions after exacerbations of chronic obstructive pulmonary disease (COPD) are penalized under the Hospital Readmissions Reduction Program (HRRP). Understanding attributable diagnoses at readmission would improve readmission reduction strategies.ObjectivesDetermine factors that portend 30-day readmissions attributable to COPD versus non-COPD diagnoses among patients discharged following COPD exacerbations.Design, setting, and participantsWe analyzed COPD discharges in the Nationwide Readmissions Database from 2010 to 2016 using inclusion and readmission definitions in HRRP.Main outcomes and measuresWe evaluated readmission odds for COPD versus non-COPD returns using a multilevel, multinomial logistic regression model. Patient-level covariates included age, sex, community characteristics, payer, discharge disposition, and Elixhauser Comorbidity Index. Hospital-level covariates included hospital ownership, teaching status, volume of annual discharges, and proportion of Medicaid patients.ResultsOf 1,622,983 (a weighted effective sample of 3,743,164) eligible COPD hospitalizations, 17.25% were readmitted within 30 days (7.69% for COPD and 9.56% for other diagnoses). Sepsis, heart failure, and respiratory infections were the most common non-COPD return diagnoses. Patients readmitted for COPD were younger with fewer comorbidities than patients readmitted for non-COPD. COPD returns were more prevalent the first two days after discharge than non-COPD returns. Comorbidity was a stronger driver for non-COPD (odds ratio [OR] 1.19) than COPD (OR 1.04) readmissions.ConclusionThirty-day readmissions following COPD exacerbations are common, and 55% of them are attributable to non-COPD diagnoses at the time of return. Higher burden of comorbidity is observed among non-COPD than COPD rehospitalizations. Readmission reduction efforts should focus intensively on factors beyond COPD disease management to reduce readmissions considerably by aggressively attempting to mitigate comorbid conditions

Readmission Rates for Chronic Obstructive Pulmonary Disease Under the Hospital Readmissions Reduction Program: an Interrupted Time Series Analysis.

BackgroundHospital readmission rates decreased for myocardial infarction (AMI), heart failure (CHF), and pneumonia with implementation of the first phase of the Hospital Readmissions Reduction Program (HRRP). It is not established whether readmissions fell for chronic obstructive pulmonary disease (COPD), an HRRP condition added in 2014.ObjectiveWe sought to determine whether HRRP penalties influenced COPD readmissions among Medicare, Medicaid, or privately insured patients.DesignWe analyzed a retrospective cohort, evaluating readmissions across implementation periods for HRRP penalties ("pre-HRRP" January 2010-April 2011, "implementation" May 2011-September 2012, "partial penalty" October 2012-September 2014, and "full penalty" October 2014-December 2016).PatientsWe assessed discharged patients ≥ 40&nbsp;years old with COPD versus those with HRRP Phase 1 conditions (AMI, CHF, and pneumonia) or non-HRRP residual diagnoses in the Nationwide Readmissions Database.InterventionsHRRP was announced and implemented during this period, forming a natural experiment.MeasurementsWe calculated differences-in-differences (DID) for 30-day COPD versus HRRP Phase 1 and non-HRRP readmissions.Key resultsCOPD discharges for 1.2 million Medicare enrollees were compared with 22 million non-HRRP and 3.4 million HRRP Phase 1 discharges. COPD readmissions decreased from 19 to 17% over the study. This reduction was significantly greater than non-HRRP conditions (DID - 0.41%), but not HRRP Phase 1 (DID + 0.02%). A parallel trend was observed in the privately insured, with significant reduction compared with non-HRRP (DID - 0.83%), but not HRRP Phase 1 conditions (DID - 0.45%). Non-significant reductions occurred in Medicaid (DID - 0.52% vs. non-HRRP and - 0.21% vs. Phase 1 conditions).ConclusionsIn Medicare, HRRP implementation was associated with reductions in COPD readmissions compared with non-HRRP controls but not versus other HRRP conditions. Parallel findings were observed in commercial insurance, but not in Medicaid. Condition-specific penalties may not reduce readmissions further than existing HRRP trends