Pilot study of a brief provider and EMR-based intervention for overweight teens with asthma

INTRODUCTION: Asthma-related morbidity is increased in overweight patients, yet providers are given little guidance on how to discuss weight and asthma management with overweight teens. OBJECTIVE: We piloted an electronic medical record (EMR)-based tailored discussion guide (TDG) and a brief provider training, to address weight management in overweight teens with asthma. The primary outcome was intervention impact on patient-reported asthma outcomes (e.g., asthma control and morbidity). Secondary outcomes included change in BMI, patient-centeredness, and change in healthy behaviors. METHODS: Teens aged 13-18 years with persistent asthma and a body mass index ≥ 85th percentile for their age and sex were eligible. Parents of eligible teens were contacted before an upcoming appointment to allow teen enrollment during the clinic visit. Providers reviewed Motivational Interviewing (MI) concepts and were trained in the TDG for support of conversations around weight and asthma management. Measures included asthma outcomes retrieved from the EMR at 6- and 12-month post-baseline, teen impressions of patient-provider communication at 6-week post-enrollment, and teen report of healthy behaviors at 6- and 12-month post-baseline. RESULTS: Of 44 teens enrolled (77% African-American, 63% female), mean BMI for intervention (n=25) and control groups (n=19) at baseline were similar. Thirty participants (68%) completed a 6-week questionnaire. Compared to controls, at 6 months, intervention teens reported fewer days of limited activity and uncontrolled asthma, but at 12 months, only restricted activity remained lower, and BMI was not reduced. Intervention teens reported clinic visits that were more patient-centered than controls, including discussion of asthma treatment options with provider, feeling ready to follow an asthma treatment routine, and receiving helpful tips about reaching a healthy weight. The healthy behavior dinner with family showed improvement for intervention teens at 6 and 12 months. The feasibility study also revealed a need to improve recruitment strategies and to streamline intervention delivery. CONCLUSION: Modest improvements in patient-reported asthma outcomes and health behaviors were observed. There was strong evidence that the TDG supports provider discussion of weight and asthma to create a more patient-centered conversation from the perspective of participating teens. Challenges to recruitment and clinic adaptation must be addressed before advancing to a full-scale trial. TRIAL REGISTRATION: NCT02575326 Teen Asthma Control Encouraging a Healthier Lifestyle, www.cllinicaltrials.gov

Recruitment experience for a pragmatic randomized controlled trial: Using EMR initiatives and minimizing research infrastructure

CONTEXT: Modernized approaches to multisite randomized controlled trials (RCT) include the use of electronic medical records (EMR) for recruitment, remote data capture (RDC) for multisite data collection, and strategies to reduce the need for research infrastructure. These features facilitate the conduct of pragmatic trials, or trials conducted in real life settings. OBJECTIVE: We describe the recruitment experience of an RCT to evaluate a clinic-based intervention targeting urban youth with asthma. MATERIALS AND METHODS: Using encounter and prescription databases, a list of potentially-eligible patients was linked to the Epic appointment scheduling system. Patients were enrolled during a scheduled visit and then electronically randomized to a tailored versus generic online intervention. RESULTS AND DISCUSSION: 1146 appointments for 580 eligible patients visiting 5 clinics were identified, of which 45.9% (266/580) were randomized to reach targeted enrollment (n=250). RDC facilitated multisite enrollment. Intervention content was further personalized through real- time entry of asthma medications prescribed at the clinic visit. EMR monitoring helped with recruitment trouble-shooting. Systemic challenges included a system-wide EMR transition and a system-wide reorganization of clinic staffing. CONCLUSIONS: Modernized RCTs can accelerate translation of research findings. Electronic initiatives facilitated implementation of this RCT; however, adaptations to recruitment strategies resulted in a more explanatory framework

Inadequate response to UDCA among PBC patients under routine care in the US: Rising serum bilirubin even in the normal range is a risk factor and subsequent clinical follow-up differs based on treatment response

Background and aims: Ursodeoxycholic acid (UDCA)is a first line treatment in patients with primary biliary cholangitis (PBC)that is often followed by second-line therapy if there is inadequate response (IR). Previous analyses by the Fibrotic Liver Disease Consortium showed that pre-treatment total bilirubin, even within the normal range, is associated with increased risk of mortality. In the present study, we analyzed the effect of pre-treatment bilirubin and other covariates associated with the risk of IR, and compared follow-up care between patients with/without IR. Method: Baseline data were collected for PBC patients at time of UDCA initiation between 2006 and 2015. Total bilirubin was categorized as \u3e 2, 2 \u3e 1.5, 1.5 \u3e 1.0, 1.0 \u3e 0.7, 0.7 \u3e 0.4, and ≤ 0.4 mg/dL. IR was defined using Paris II criteria 12 months after UDCA initiation. Logistic regression was used to estimate the adjusted risk for IR; model accuracy was assessed using area under the receiver operator characteristic curve (AUROC). Z-statistic was used to compare rates of follow-up care and treatment modification per person-year (PPY)between IR and non-IR patients. Results: Among 1578 UDCA treated patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander (ASINPI); 25% Hispanic), 706 (45%)had IR to UDCA at 12 months post-baseline. The multivariate model (AUROC = 0.79)showed that younger age, increasing alkaline phosphatase (ALP), low albumin, and a ratio of aspartate to alanine aminotransferase (AST/ALT)\u3e 1.1 were independently associated with an increased risk of IR. Bilirubin—even in the high-normal (1.0 \u3e 0.7)and mid-normal (0.7 \u3e 0.4 mg/dL)ranges—was also significantly associated with increased risk of IR compared to low-normal levels (≤ 0.4 mg/dL; Figure). A sensitivity analysis that defined IR as ALp \u3e 1.67xULN yielded similar results. Compared to responders, patients with IR were more likely to: discontinue UDCA (0.08 vs 0.04 PPY; p \u3c 0.01); add obeticholic acid (0.023 vs 0.004 PPY; p \u3c 0.01); and were more likely to see a specialist (5.12 vs 3.16 visits PPY; p \u3c 0.01), undergo liver imaging (1.23 vs 0.56 tests PPY; p \u3c 0.01), have liver-related laboratory testing (18.4 vs 10.2 tests PPY; p \u3c 0.01), be hospitalized (0.11 vs 0.07 PPY; p \u3c 0.01), and seek emergency care (0.13 vs 0.08 PPY; p \u3c 0.01). Conclusion: Almost half of PBC patients (45%)in a routine clinical care cohort showed IR to UDCA. Baseline bilirubin \u3e 0.4 mg/dL is associated with increasing risk of IR. Patients with IR had higher rates of specialist follow-up and health care utilization

Inadequate response to UDCA among PBC patients under routine care in the US: Rising serum bilirubin even in the normal range is a risk factor and subsequent clinical follow-up differs based on treatment response

Background and aims: Ursodeoxycholic acid (UDCA)is a first line treatment in patients with primary biliary cholangitis (PBC)that is often followed by second-line therapy if there is inadequate response (IR). Previous analyses by the Fibrotic Liver Disease Consortium showed that pre-treatment total bilirubin, even within the normal range, is associated with increased risk of mortality. In the present study, we analyzed the effect of pre-treatment bilirubin and other covariates associated with the risk of IR, and compared follow-up care between patients with/without IR. Method: Baseline data were collected for PBC patients at time of UDCA initiation between 2006 and 2015. Total bilirubin was categorized as \u3e 2, 2 \u3e 1.5, 1.5 \u3e 1.0, 1.0 \u3e 0.7, 0.7 \u3e 0.4, and ≤ 0.4 mg/dL. IR was defined using Paris II criteria 12 months after UDCA initiation. Logistic regression was used to estimate the adjusted risk for IR; model accuracy was assessed using area under the receiver operator characteristic curve (AUROC). Z-statistic was used to compare rates of follow-up care and treatment modification per person-year (PPY)between IR and non-IR patients. Results: Among 1578 UDCA treated patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander (ASINPI); 25% Hispanic), 706 (45%)had IR to UDCA at 12 months post-baseline. The multivariate model (AUROC = 0.79)showed that younger age, increasing alkaline phosphatase (ALP), low albumin, and a ratio of aspartate to alanine aminotransferase (AST/ALT)\u3e 1.1 were independently associated with an increased risk of IR. Bilirubin—even in the high-normal (1.0 \u3e 0.7)and mid-normal (0.7 \u3e 0.4 mg/dL)ranges—was also significantly associated with increased risk of IR compared to low-normal levels (≤ 0.4 mg/dL; Figure). A sensitivity analysis that defined IR as ALp \u3e 1.67xULN yielded similar results. Compared to responders, patients with IR were more likely to: discontinue UDCA (0.08 vs 0.04 PPY; p \u3c 0.01); add obeticholic acid (0.023 vs 0.004 PPY; p \u3c 0.01); and were more likely to see a specialist (5.12 vs 3.16 visits PPY; p \u3c 0.01), undergo liver imaging (1.23 vs 0.56 tests PPY; p \u3c 0.01), have liver-related laboratory testing (18.4 vs 10.2 tests PPY; p \u3c 0.01), be hospitalized (0.11 vs 0.07 PPY; p \u3c 0.01), and seek emergency care (0.13 vs 0.08 PPY; p \u3c 0.01). Conclusion: Almost half of PBC patients (45%)in a routine clinical care cohort showed IR to UDCA. Baseline bilirubin \u3e 0.4 mg/dL is associated with increasing risk of IR. Patients with IR had higher rates of specialist follow-up and health care utilization

Inadequate response to UDCA among PBC patients under routine care in the US: Rising serum bilirubin even in the normal range is a risk factor and subsequent clinical follow-up differs based on treatment response

Background and aims: Ursodeoxycholic acid (UDCA)is a first line treatment in patients with primary biliary cholangitis (PBC)that is often followed by second-line therapy if there is inadequate response (IR). Previous analyses by the Fibrotic Liver Disease Consortium showed that pre-treatment total bilirubin, even within the normal range, is associated with increased risk of mortality. In the present study, we analyzed the effect of pre-treatment bilirubin and other covariates associated with the risk of IR, and compared follow-up care between patients with/without IR. Method: Baseline data were collected for PBC patients at time of UDCA initiation between 2006 and 2015. Total bilirubin was categorized as \u3e 2, 2 \u3e 1.5, 1.5 \u3e 1.0, 1.0 \u3e 0.7, 0.7 \u3e 0.4, and ≤ 0.4 mg/dL. IR was defined using Paris II criteria 12 months after UDCA initiation. Logistic regression was used to estimate the adjusted risk for IR; model accuracy was assessed using area under the receiver operator characteristic curve (AUROC). Z-statistic was used to compare rates of follow-up care and treatment modification per person-year (PPY)between IR and non-IR patients. Results: Among 1578 UDCA treated patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander (ASINPI); 25% Hispanic), 706 (45%)had IR to UDCA at 12 months post-baseline. The multivariate model (AUROC = 0.79)showed that younger age, increasing alkaline phosphatase (ALP), low albumin, and a ratio of aspartate to alanine aminotransferase (AST/ALT)\u3e 1.1 were independently associated with an increased risk of IR. Bilirubin—even in the high-normal (1.0 \u3e 0.7)and mid-normal (0.7 \u3e 0.4 mg/dL)ranges—was also significantly associated with increased risk of IR compared to low-normal levels (≤ 0.4 mg/dL; Figure). A sensitivity analysis that defined IR as ALp \u3e 1.67xULN yielded similar results. Compared to responders, patients with IR were more likely to: discontinue UDCA (0.08 vs 0.04 PPY; p \u3c 0.01); add obeticholic acid (0.023 vs 0.004 PPY; p \u3c 0.01); and were more likely to see a specialist (5.12 vs 3.16 visits PPY; p \u3c 0.01), undergo liver imaging (1.23 vs 0.56 tests PPY; p \u3c 0.01), have liver-related laboratory testing (18.4 vs 10.2 tests PPY; p \u3c 0.01), be hospitalized (0.11 vs 0.07 PPY; p \u3c 0.01), and seek emergency care (0.13 vs 0.08 PPY; p \u3c 0.01). Conclusion: Almost half of PBC patients (45%)in a routine clinical care cohort showed IR to UDCA. Baseline bilirubin \u3e 0.4 mg/dL is associated with increasing risk of IR. Patients with IR had higher rates of specialist follow-up and health care utilization

Serum bilirubin within normal range is associated with an increasing risk of mortality in patients with primary biliary cholangitis regardless of ursodeoxycholic acid treatment. Hepatology 2018; 68:31A-32A.

Background: A rise in bilirubin indicates worsening liver function in patients with primary biliary cholangitis (PBC). Recent reports have suggested that total bilirubin above 0.7 mg/dL may be linked to increased risk for liver transplantation and mortality. The Fibrotic Liver Disease Consortium analyzed the impact of bilirubin as well as race, gender, and ursodeoxycholic acid (UDCA) treatment on risk of all-cause mortality in patients from 11 US health systems. Methods: Data were collected from “index date” (the latest among PBC diagnosis date, UDCA initiation date, or 1/1/2006) through 12/31/2016. Bilirubin was categorized as \u3e2, 2-\u3e1.5, 1.5-\u3e1.0, 1.0-\u3e0.7, 0.7-\u3e0.4, and ≤0.4 mg/dL. Inverse Probability of Treatment Weighting (IPTW) was used to adjust for UDCA selection bias. Cox regression (univariate, including variableby-UDCA interactions, followed by multivariate) was used to estimate the impact of risk factors on mortality. Results: Among 4243 patients (8% African American, 7% Asian American/ Pacific Islander (AAPI), 21% Hispanic), 25% died after index date through 2016. Variables retained in the final multivariate model included age at index, Hispanic ethnicity, baseline bilirubin, alkaline phosphatase, and interactions of UDCA with 4 variables (race, gender, AST/ALT\u3e1.1, and albumin). Among UDCA-treated patients, African Americans had significantly lower mortality than Whites (adjusted Hazard Ratio [aHR]=0.72, 95%CI 0.55-0.93); among untreated patients, this relationship was reversed (aHR=1.96, 95%CI 1.50-2.57). Bilirubin level was strongly and positively associated with increasing mortality; compared to patients with low-normal bilirubin (≤0.4 mg/dL), those in the midnormal (0.7-\u3e0.4) or high-normal (1.0-\u3e0.7) ranges had significantly higher mortality (Figure). Mortality was higher among men, Hispanics, and patients with hypoalbuminemia. After IPTW, UDCA treatment was associated with reduced mortality in all categories except in White women with AST/ALT\u3e1.1 and hypoalbuminemia. Conclusion: UDCA treatment was associated with reduced mortality across most patient groups. Regardless of UDCA treatment, high-normal bilirubin (1.0-\u3e0.7 mg/dL) was associated with twice the risk of death compared to bilirubin ≤0.4 mg/dL. The divergent mortality rates observed between African Americans and Whites regarding UDCA treatment are novel and require further research. Our results suggest that, even within the normal range, higher serum bilirubin levels are associated with increased mortality among PBC patients. (Table Presented)

Serum bilirubin within normal range is associated with an increasing risk of mortality in patients with primary biliary cholangitis regardless of ursodeoxycholic acid treatment.

Background: A rise in bilirubin indicates worsening liver function in patients with primary biliary cholangitis (PBC). Recent reports have suggested that total bilirubin above 0.7 mg/dL may be linked to increased risk for liver transplantation and mortality. The Fibrotic Liver Disease Consortium analyzed the impact of bilirubin as well as race, gender, and ursodeoxycholic acid (UDCA) treatment on risk of all‐cause mortality in patients from 11 US health systems. Methods: Data were collected from “index date” (the latest among PBC diagnosis date, UDCA initiation date, or 1/1/2006) through 12/31/2016. Bilirubin was categorized as \u3e2, 2–\u3e1.5, 1.5–\u3e1.0, 1.0–\u3e0.7, 0.7–\u3e0.4, and ≤0.4 mg/dL. Inverse Probability of Treatment Weighting (IPTW) was used to adjust for UDCA selection bias. Cox regression (univariate, including variable‐by‐UDCA interactions, followed by multivariate) was used to estimate the impact of risk factors on mortality. Results: Among 4243 patients (8% African American, 7% Asian American/ Pacific Islander (AAPI), 21% Hispanic), 25% died after index date through 2016. Variables retained in the final multivariate model included age at index, Hispanic ethnicity, baseline bilirubin, alkaline phosphatase, and interactions of UDCA with 4 variables (race, gender, AST/ALT\u3e1.1, and albumin). Among UDCA‐treated patients, African Americans had significantly lower mortality than Whites (adjusted Hazard Ratio [aHR]=0.72, 95%CI 0.55–0.93); among untreated patients, this relationship was reversed (aHR=1.96, 95%CI 1.50–2.57). Bilirubin level was strongly and positively associated with increasing mortality; compared to patients with low‐normal bilirubin (≤0.4 mg/dL), those in the mid‐normal (0.7–\u3e0.4) or high‐normal (1.0–\u3e0.7) ranges had significantly higher mortality (Figure). Mortality was higher among men, Hispanics, and patients with hypoalbuminemia. After IPTW, UDCA treatment was associated with reduced mortality in all categories except in White women with AST/ALT\u3e1.1 and hypoalbuminemia. Conclusion: UDCA treatment was associated with reduced mortality across most patient groups. Regardless of UDCA treatment, high‐normal bilirubin (1.0–\u3e0.7 mg/dL) was associated with twice the risk of death compared to bilirubin ≤0.4 mg/dL. The divergent mortality rates observed between African Americans and Whites regarding UDCA treatment are novel and require further research. Our results suggest that, even within the normal range, higher serum bilirubin levels are associated with increased mortality among PBC patients

Dynamic Risk Prediction of Response to Ursodeoxycholic Acid Among Patients with Primary Biliary Cholangitis in the USA

BACKGROUND: Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] \u3e 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. METHODS: Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. RESULTS: Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP \u3e 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was very good (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP \u3e 1.67*ULN and moderate (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP \u3e 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. CONCLUSIONS: Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment

Evaluating Methods for Isolating Total RNA and Predicting the Success of Sequencing Phylogenetically Diverse Plant Transcriptomes

Next-generation sequencing plays a central role in the characterization and quantification of transcriptomes. Although numerous metrics are purported to quantify the quality of RNA, there have been no large-scale empirical evaluations of the major determinants of sequencing success. We used a combination of existing and newly developed methods to isolate total RNA from 1115 samples from 695 plant species in 324 families, which represents >900 million years of phylogenetic diversity from green algae through flowering plants, including many plants of economic importance. We then sequenced 629 of these samples on Illumina GAIIx and HiSeq platforms and performed a large comparative analysis to identify predictors of RNA quality and the diversity of putative genes (scaffolds) expressed within samples. Tissue types (e. g., leaf vs. flower) varied in RNA quality, sequencing depth and the number of scaffolds. Tissue age also influenced RNA quality but not the number of scaffolds >= 1000 bp. Overall, 36% of the variation in the number of scaffolds was explained by metrics of RNA integrity (RIN score), RNA purity (OD 260/230), sequencing platform (GAIIx vs HiSeq) and the amount of total RNA used for sequencing. However, our results show that the most commonly used measures of RNA quality (e. g., RIN) are weak predictors of the number of scaffolds because Illumina sequencing is robust to variation in RNA quality. These results provide novel insight into the methods that are most important in isolating high quality RNA for sequencing and assembling plant transcriptomes. The methods and recommendations provided here could increase the efficiency and decrease the cost of RNA sequencing for individual labs and genome centers