A prediction model for asthma exacerbations after stopping asthma biologics.

BACKGROUND: Little is known regarding the prediction of the risks of asthma exacerbation after stopping asthma biologics. OBJECTIVE: To develop and validate a predictive model for the risk of asthma exacerbations after stopping asthma biologics using machine learning models. METHODS: We identified 3057 people with asthma who stopped asthma biologics in the OptumLabs Database Warehouse and considered a wide range of demographic and clinical risk factors to predict subsequent outcomes. The primary outcome used to assess success after stopping was having no exacerbations in the 6 months after stopping the biologic. Elastic-net logistic regression (GLMnet), random forest, and gradient boosting machine models were used with 10-fold cross-validation within a development (80%) cohort and validation cohort (20%). RESULTS: The mean age of the total cohort was 47.1 (SD, 17.1) years, 1859 (60.8%) were women, 2261 (74.0%) were White, and 1475 (48.3%) were in the Southern region of the United States. The elastic-net logistic regression model yielded an area under the curve (AUC) of 0.75 (95% confidence interval [CI], 0.71-0.78) in the development and an AUC of 0.72 in the validation cohort. The random forest model yielded an AUC of 0.75 (95% CI, 0.68-0.79) in the development cohort and an AUC of 0.72 in the validation cohort. The gradient boosting machine model yielded an AUC of 0.76 (95% CI, 0.72-0.80) in the development cohort and an AUC of 0.74 in the validation cohort. CONCLUSION: Outcomes after stopping asthma biologics can be predicted with moderate accuracy using machine learning methods.

Asthma biologic trial eligibility and real-world outcomes in the United States.

OBJECTIVE: To compare the outcomes of real-world patients who would have been eligible for asthma biologics to those who would not have been eligible. METHODS: We used data from the OptumLabs Data Warehouse (OLDW) to categorize patients into eligible and ineligible groups based on clinical trials (n = 19 trials) used for Food and Drug Administration (FDA) approval. We then compared the change in the number of asthma exacerbations before and after biological initiation between the two groups. RESULTS: The percentage of people who would have been eligible for asthma biologic clinical trials ranged from 0-10.2%. The eligible group had a greater reduction in number of asthma exacerbations compared to the ineligible group based on eligibility criteria from 1 omalizumab trial (1.52, 95% CI 1.25, 1.8 in eligible vs. 0.47, 95% CI 0.43, 0.52 in ineligible) and from 1 dupilumab trial (1.6, 95% CI 0.92, 2.28 in eligible vs. 0.52, 95% CI 0.38, 0.65 ineligible). Notably, 15 of the 19 trials had fewer than 11 eligible people, limiting additional comparisons. CONCLUSIONS: Fewer than 1 in 10 people in the United States treated with asthma biologics would have been eligible to participate in the trial for the biologic they used. Where comparisons could be made, trial eligible people have a greater reduction in exacerbations.Supplemental data for this article is available online at https://doi.org/10.1080/02770903.2021.2010749 .

Persistence of asthma biologic use in a US claims database.

BACKGROUND: Little is known on the persistence of asthma biologic use in clinical practice. OBJECTIVE: To evaluate the persistence of asthma biologic use and time to clinical response in clinical practice. METHODS: A cohort of people with asthma who used at least 1 asthma biologic was constructed using data from 2003 to 2019 in the OptumLabs Data Warehouse. Treatment persistence was defined by the length of time that a person continuously used an asthma biologic, allowing for a lapse in use up to 4 months before confirming that a person stopped. Clinical response to treatment (defined as a decline in asthma exacerbations of at least 50% compared with the 6 months before starting an asthma biologic) was described over time and in relation to biologic persistence. RESULTS: There were 9575 people who had at least 1 episode of asthma biologic use. There were 5319 people (64%, 95% confidence interval, 63%-65%) who completed 6 months or more on an asthma biologic and 3284 (45%, 95% confidence interval, 44%-46%) who completed 12 months or more. Of people with 1 or more asthma exacerbation 6 months before index biologic use, 63%, 76%, 80%, and 81% realized a 50% or more reduction in postindex asthma exacerbations in the first 6 months, 6 to 12 months, 12 to 18 months, and 18 to 24 months, respectively. CONCLUSION: Between 48% and 64% of people remained on an asthma biologic for 6 months or more after first use. Most people who achieved a reduction in asthma exacerbations did so in the first 6 months of treatment.

Best practices in implementing inpatient pediatric asthma pathways: a qualitative study.

Objective: Clinical pathways (operational versions of practice guidelines) can improve guideline adherence and quality of care for children hospitalized with asthma. However, there is limited guidance on how to implement pathways successfully. Our objective was to identify potential best practices in pathway implementation.Methods: In a previous observational study, we identified higher and lower performing children's hospitals based on hospital-level changes in asthma patient length of stay after implementation of a pathway. In this qualitative study, we conducted semi-structured interviews with a purposive sample of healthcare providers involved in pathway implementation at these hospitals. We used constant comparative methods to develop a conceptual model of potential best practices in implementation.Results: Healthcare providers (n = 24) from 6 higher performing and 2 lower performing hospitals were interviewed about pathway implementation. We identified several practices that addressed barriers and promoted successful pathway implementation: (1) utilizing quality improvement (QI) methodology and a data-driven approach helped overcome inertia of current practice; (2) getting teams to commit to shared goals around asthma care helped overcome disagreements in the implementation process; (3) integrating pathways into the electronic medical record decreased some burdens of implementation; (4) leveraging multidisciplinary teams by developing protocols for nurses and/or respiratory therapists to titrate medications reduced variability in provider practice; and (5) engaging hospital leaders with pathway implementation teams helped secure crucial resources.Conclusions: We identified several potential best practices to support pathway implementation. Hospitals implementing pathways should consider applying these strategies to better ensure success in improving quality of asthma care for children.

Single-locus enrichment without amplification for sequencing and direct detection of epigenetic modifications.

A gene-level targeted enrichment method for direct detection of epigenetic modifications is described. The approach is demonstrated on the CGG-repeat region of the FMR1 gene, for which large repeat expansions, hitherto refractory to sequencing, are known to cause fragile X syndrome. In addition to achieving a single-locus enrichment of nearly 700,000-fold, the elimination of all amplification steps removes PCR-induced bias in the repeat count and preserves the native epigenetic modifications of the DNA. In conjunction with the single-molecule real-time sequencing approach, this enrichment method enables direct readout of the methylation status and the CGG repeat number of the FMR1 allele(s) for a clonally derived cell line. The current method avoids potential biases introduced through chemical modification and/or amplification methods for indirect detection of CpG methylation events.

Breast cancer survivors willingness to participate in an acupuncture clinical trial: a qualitative study.

PURPOSE: Acupuncture is a complementary and alternative medicine (CAM) modality that shows promise as a component of supportive breast cancer care. Lack of robust recruitment for clinical trial entry has limited the evidence base for acupuncture as a treatment modality among breast cancer survivors. The objective of this study is to identify key decision-making factors among breast cancer survivors considering entry into an acupuncture clinical trial for treatment of symptoms. METHODS: Semistructured interviews were conducted among African-American (n=12) and Caucasian (n=13) breast cancer survivors. Verbatim transcripts were made and analyzed by two or more independent coders using NVivo software. Major recurring themes were identified and a theoretical framework developed. RESULTS: Six themes emerged reflecting key attributes of the decision to enter a clinical trial: (1) symptom appraisal, (2) practical barriers (e.g., distance and travel), (3) beliefs about the interventions (e.g., fear of needles and dislike of medications), (4) comfort with elements of clinical trial design (e.g., randomization, the nature of the control intervention, and blinding), (5) trust, and (6) altruism. African-American and Caucasian women weighed similar attributes but differed in the information sources sought regarding clinical trial entry and in concerns regarding the use of a placebo in a clinical trial. CONCLUSIONS: Our findings contribute to the development of a theoretical model of decision making for breast cancer survivors considering participation in a CAM clinical trial. Insights regarding the decision making process can inform interventions to support informed decision making and robust recruitment to CAM trials among cancer survivors.

Assessment of automated clinical trial recruitment and enrolment using patient-facing technology.

OBJECTIVE: Interactive patient care systems (IPCS) at the bedside are becoming increasingly common, but evidence is limited as to their potential for innovative clinical trial implementation. The objective of this study was to test the hypothesis that the IPCS could feasibly be used to automate recruitment and enrolment for a clinical trial. METHODS: In medical-surgical units, we used the IPCS to randomise, recruit and consent eligible subjects. For participants not interacting with IPCS study materials within 48 hours, study staff-initiated recruitment in-person. Eligible study population included all caregivers and any patients >6 years old admitted to medical-surgical units and oncology units September 2015 to January 2016. OUTCOMES: randomisation assessed using between-group comparisons of patient characteristics; recruitment success assessed by rates of consent; paperless implementation using successful acquisition of electronic signature and email address. We used χ2 analysis to assess success of randomisation and recruitment. RESULTS: Randomisation was successful (n=1012 randomised, p>0.05 for all between-group comparisons). For the subset of eligible, randomised patients who were recruited, IPCS-only recruitment (consented: 2.4% of n=213) was less successful than in-person recruitment (61.4% of n=87 eligible recruited, p<0.001). For those consenting (n=61), 96.7% provided an electronic signature and 68.9% provided email addresses. CONCLUSIONS: Our results suggest that as a tool at the bedside, the IPCS offers key efficiencies for study implementation, including randomisation and collecting e-consent and contact information, but does not offer recruitment efficiencies. Further research could assess the value that interactive technologies bring to recruitment when paired with in-person efforts, potentially focusing on more intensive user-interface testing for recruitment materials. TRIAL REGISTRATION NUMBER: NCT02491190.

Asthma Patients Who Stop Asthma Biologics Have a Similar Risk of Asthma Exacerbations as Those Who Continue Asthma Biologics.

BACKGROUND: There is limited information about outcomes associated with stopping asthma biologics. OBJECTIVE: To compare outcomes in people who stopped or continued asthma biologics. METHODS: We identified a cohort of people with asthma who stopped or continued asthma biologics in the Optum Labs Database Warehouse, using a propensity matching method for case and control groups with the variables of age, sex, race, region, insurance, income, specialist access, Charlson comorbidity, specific medical conditions, pre-index exacerbation count, pre-index rescue inhaler pharmacy fills, and pre-index inhaled corticosteroid with or without long-acting ß-agonist pharmacy fills. Primary outcome used to assess failure of stopping was an increase of 50% or more in the asthma exacerbation rate in the 6 months after discontinuing the biologic compared with the 6-month period before biologic initiation. RESULTS: Among a cohort of 4960 asthma biologic users, 1249 were observed to stop use after 6 to 12 months of use. We identified a matched cohort of 1247 stoppers and 1247 people who continued biologic use for at least 18 months. In the first 6 months after stopping or sham stopping, 10.2% of stoppers and 9.5% of continuers had an increase of 50% or more in asthma exacerbations. We found a similar adjusted odds of failing among stoppers and continuers (odds ratio = 1.085; 95% confidence interval, 0.833-1.413). CONCLUSIONS: An increase in asthma exacerbations is infrequently observed in people who stopped asthma biologics and was observed at similar rates as in matched controls who continued asthma biologics.

Adherence to Asthma Biologics: Implications for Patient Selection, Step Therapy, and Outcomes.

BACKGROUND: Little is known about adherence to asthma biologics. RESEARCH QUESTION: Is adherence to inhaled corticosteroid (ICS) associated with subsequent asthma biologic adherence? STUDY DESIGN AND METHODS: We analyzed individuals with asthma who started asthma biologics in the OptumLab Data Warehouse and used that data until October 2019. We calculated proportion days covered (PDC) for ICS ± long-acting ß-agonists in the 6 months before and after asthma biologics were started and asthma biologic PDC for the first 6 months of use. We performed a multivariable analysis to identify factors associated with asthma biologic PDC ≥0.75, ICS PDC ≥0.75 during the 6-month period after asthma biologic were started, and achievement of a ≥50% reduction in asthma exacerbations during the first 6 months of asthma biologic use. RESULTS: We identified 5,319 people who started asthma biologics. The mean PDC for asthma biologics was 0.76 (95% CI, 0.75-0.77) in the first 6 months after starting, higher than the mean PDCs for ICS in the 6 months before (0.44 [95% CI, 0.43-0.45]) and after (0.40 [95% CI, 0.39-0.40]) starting the asthma biologic. PDC ≥0.75 for ICS 6 months before index biologic use is associated with PDC for asthma biologics ≥0.75 (OR, 1.25; 95% CI, 1.10-1.43) and for ICS during the first 6 months of biologic use (OR, 9.93; 95% CI, 8.55-11.53). Neither ICS PDC ≥0.75 (OR, 0.92; 95% CI, 0.74-1.14) nor asthma biologic PDC ≥0.75 (OR, 1.15; 95% CI, 0.97-1.36) is associated with a statistically significant reduction in asthma exacerbations during the first 6 months of asthma biologic use among people with any exacerbation in the 6 months before first use. INTERPRETATION: Adherence to asthma biologic is higher than to ICS and is associated with different factors.

Validating parameters of a luciferase reporter gene assay to measure neutralizing antibodies to IFNbeta in multiple sclerosis patients.

Neutralizing antibodies (NAbs) can occur in some multiple sclerosis (MS) patients receiving interferon beta (IFNbeta) therapy. NAbs reduce drug bioavailabity and high NAb titers reduce drug efficacy. We describe the validation of the R. Farrell and G. Giovannoni luciferase reporter gene assay to measure NAbs to INFbeta. We assayed 163 sera from IFNbeta treated MS patients with an optimized luciferase method and compared the results to those obtained with the reference cytopathic effect (CPE) method using A549 cells and an encephalomyocarditis virus (EMCV). Binding antibodies (BAbs) were measured using a capture ELISA as a screening test for NAbs in the CPE assay. NAb status measured by the luciferase and the ELISA/CPE method did not yield a significant difference. Log10 NAb titers obtained from the luciferase assay and the A549/EMCV CPE methods correlated very well. The inter-assay coefficient of variation for titers was between 17.8-29.3%, and the intra-assay coefficient of variation was between 6.3-15.2%. The luciferase assay is reliable, appropriately sensitive and requires less time than the currently available NAb methods.

Limitations of Using Pediatric Respiratory Illness Readmissions to Compare Hospital Performance.

BACKGROUND: Adult hospital readmission rates can reliably identify meaningful variation in hospital performance; however, pediatric condition-specific readmission rates are limited by low patient volumes. OBJECTIVE: To determine if a National Quality Forum (NQF)-endorsed measure for pediatric lower respiratory illness (LRI) 30-day readmission rates can meaningfully identify high- and low-performing hospitals. DESIGN: Observational, retrospective cohort analysis. We applied the pediatric LRI measure and several variations to evaluate their ability to detect performance differences. SETTING: Administrative claims from all hospital admissions in California (2012-2014). PATIENTS: Children (age <18 years) with LRI (primary diagnosis: bronchiolitis, influenza, or pneumonia; or LRI as a secondary diagnosis with a primary diagnosis of respiratory failure, sepsis, bacteremia, or asthma). MEASUREMENTS: Thirty-day hospital readmission rates and costs. Hierarchical regression models adjusted for age, gender, and chronic conditions were used. RESULTS: Across all California hospitals admitting children (n = 239) using respiratory readmission rates, no outlier hospitals were identified with (1) the NQF-endorsed metric, (2) inclusion of primary asthma or secondary asthma exacerbation diagnoses, or (3) inclusion of 30-day emergency revisits. By including admissions for asthma, adding emergency revisits, and merging 3 years of data, we identified 9 outlier hospitals (2 high-performers, 7 low-performers). There was no association of hospital readmission rates with costs. CONCLUSIONS: Using a nationally-endorsed quality measure of inpatient pediatric care, we were unable to identify meaningful variation in hospital performance without broadening the metric definition and merging multiple years of data. Utilizers of pediatric-quality measures should consider modifying metrics to better evaluate the quality of pediatric care at low-volume hospitals. FUNDING: Supported by the Agency for Healthcare Research and Quality (K08 HS24592 to SVK and U18HS25297 to MDC and NSB) and the National Institute of Child Health and Human Development (K23HD065836 to NSB). The funding agency played no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the manuscript for publication.

Interprofessional and Interdisciplinary Approach from Undergraduate Health and Pre-Medical Students in Children's Health Educational Initiative.

The importance of interprofessional training in healthcare to improve quality of care and health outcomes has been increasingly recognized. This pilot study used an interprofessional and interdisciplinary team of undergraduate health and pre-health students to establish a unique community partnership with a local elementary school in developing and implementing a nutrition/exercise educational intervention. Our results suggest that children as young as 8 years old are capable of learning new information related to the benefits of particular food groups, are capable of retaining this knowledge for 6 months, and that an intervention program as short as one hour every few months stand to make significant impact on children's knowledge about proper nutrition and healthy lifestyles. Our results suggest the potential benefits of further expanding the short-term intervention into a longer-term community-based curriculum targeting a younger age group previously or currently practiced.. Furthermore, this pilot study suggests that undergraduate health and pre-health students can form an interprofessional and collaborative team to take an active role in the dissemination of nutrition knowledge in the community.

Sleep disordered breathing with excessive daytime sleepiness is a risk factor for mortality in older adults.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is associated with increased mortality in older adults, yet sleep disordered breathing (SDB), a common cause of sleepiness, has not been shown to increase mortality in older adults. This study examined the relationship between daytime sleepiness, SDB, self-report sleep parameters, and mortality in older adults. DESIGN: Longitudinal cohort study. SETTING: Clinical and Translational Research Center, at-home testing. PARTICIPANTS: 289 study participants (age >65, no dementia or depression at the time of enrollment) classified as having EDS (n=146) or not (n=143). MEASUREMENTS AND RESULTS: Study participants underwent in-lab polysomnography and multiple sleep latency testing at cohort inception. Survival analysis was conducted, with an average follow-up of 13.8 years. Excessive daytime sleepiness was associated with an unadjusted mortality hazard ratio of 1.5 (95% CI 1.1-2.0). The unadjusted mortality hazard ratio for study participants with both EDS and SDB (apnea-hypopnea index ≥20 events/h) was 2.7, 95% CI: 1.8-4.2. These findings persisted with an adjusted mortality hazard ratio of 2.3, 95% CI: 1.5-3.6 in the final model that included other covariates associated with increased mortality (sleep duration >8.5 h, self-reported angina, male gender, African American race, and age). CONCLUSION: The presence of SDB is an important risk factor for mortality from excessive daytime sleepiness in older adults. In the presence of SDB at an AHI ≥20 events/h, EDS was associated with an increased all-cause mortality risk in older adults, even when adjusting for other significant risk factors, such as prolonged sleep duration. In older patients who had SDB without EDS, or EDS without SDB, there was no increased all-cause mortality rate.