Predicting lung function decline in cystic fibrosis: the impact of initiating ivacaftor therapy.

BACKGROUND: Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake. METHODS: We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry (N = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018). The primary outcome was lung function (percent predicted forced expiratory volume in 1 s or FEV1pp). To characterize the association between ivacaftor initiation and lung function, we developed a dynamic prediction model through covariate selection of demographic and clinical characteristics. The ability of the selected model to predict a decline in lung function, clinically known as an FEV1-indicated exacerbation signal (FIES), was evaluated both at the population level and individual level. RESULTS: Based on the final model, the estimated improvement in FEV1pp after ivacaftor initiation was 4.89% predicted (95% confidence interval [CI]: 3.90 to 5.89). The rate of decline was reduced with ivacaftor initiation by 0.14% predicted/year (95% CI: 0.01 to 0.27). More frequent outpatient visits prior to study entry and being male corresponded to a higher overall FEV1pp. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations, lung infections, CF-related diabetes, and use of Medicaid insurance corresponded to lower FEV1pp. The model had excellent predictive accuracy for FIES events with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.83 to 0.84) for the independent testing cohort and 0.90 (95% CI: 0.89 to 0.90) for 6-month forecasting with the masked cohort. The root-mean-square errors of the FEV1pp predictions for these cohorts were 7.31% and 6.78% predicted, respectively, with standard deviations of 0.29 and 0.20. The predictive accuracy was robust across different covariate specifications. CONCLUSIONS: The methods and applications of dynamic prediction models developed using data prior to modulator uptake have the potential to inform post-modulator projections of lung function and enhance clinical surveillance in the new era of CF care.

Social-environmental phenotypes of rapid cystic fibrosis lung disease progression in adolescents and young adults living in the United States.

Background: Cystic fibrosis (CF) is a genetic disease but is greatly impacted by non-genetic (social/environmental and stochastic) influences. Some people with CF experience rapid decline, a precipitous drop in lung function relative to patient- and/or center-level norms. Those who experience rapid decline in early adulthood, compared to adolescence, typically exhibit less severe clinical disease but greater loss of lung function. The extent to which timing and degree of rapid decline are informed by social and environmental determinants of health (geomarkers) is unknown. Methods: A longitudinal cohort study was performed (24,228 patients, aged 6-21 years) using the U.S. CF Foundation Patient Registry. Geomarkers at the ZIP Code Tabulation Area level measured air pollution/respiratory hazards, greenspace, crime, and socioeconomic deprivation. A composite score quantifying social-environmental adversity was created and used in covariate-adjusted functional principal component analysis, which was applied to cluster longitudinal lung function trajectories. Results: Social-environmental phenotyping yielded three primary phenotypes that corresponded to early, middle, and late timing of peak decline in lung function over age. Geographic differences were related to distinct cultural and socioeconomic regions. Extent of peak decline, estimated as forced expiratory volume in 1 s of % predicted/year, ranged from 2.8 to 4.1 % predicted/year depending on social-environmental adversity. Middle decliners with increased social-environmental adversity experienced rapid decline 14.2 months earlier than their counterparts with lower social-environmental adversity, while timing was similar within other phenotypes. Early and middle decliners experienced mortality peaks during early adolescence and adulthood, respectively. Conclusion: While early decliners had the most severe CF lung disease, middle and late decliners lost more lung function. Higher social-environmental adversity associated with increased risk of rapid decline and mortality during young adulthood among middle decliners. This sub-phenotype may benefit from enhanced lung-function monitoring and personalized secondary environmental health interventions to mitigate chemical and non-chemical stressors.

Lung function and secondhand smoke exposure among children with cystic fibrosis: A Bayesian meta-analysis.

BACKGROUND: Secondhand smoke exposure, an important environmental health factor in cystic fibrosis (CF), remains uniquely challenging to children with CF as they strive to maintain pulmonary function during early stages of growth and throughout adolescence. Despite various epidemiologic studies among CF populations, little has been done to coalesce estimates of the association between secondhand smoke exposure and lung function decline. METHODS: A systematic review was performed using PRISMA guidelines. A Bayesian random-effects model was employed to estimate the association between secondhand smoke exposure and change in lung function (measured as FEV1% predicted). RESULTS: Quantitative synthesis of study estimates indicated that second-hand smoke exposure corresponded to a significant drop in FEV1 (estimated decrease: -5.11% predicted; 95% CI: -7.20, -3.47). The estimate of between-study heterogeneity was 1.32% predicted (95% CI: 0.05, 4.26). There was moderate heterogeneity between the 6 analyzed studies that met review criteria (degree of heterogeneity: I2=61.9% [95% CI: 7.3-84.4%] and p = 0.022 from the frequentist method.) CONCLUSIONS: Our results quantify the impact at the pediatric population level and corroborate the assertion that secondhand smoke exposure negatively affects pulmonary function in children with CF. Findings highlight challenges and opportunities for future environmental health interventions in pediatric CF care.

Lung Function Decline in Cystic Fibrosis: Impact of Data Availability and Modeling Strategies on Clinical Interpretations.

Rationale: Studies estimating the rate of lung function decline in cystic fibrosis have been inconsistent regarding the methods used. How the methodology used impacts the validity of the results and comparability between studies is unknown. Objectives: The Cystic Fibrosis Foundation established a work group whose tasks were to examine the impact of differing approaches to estimating the rate of decline in lung function and to provide analysis guidelines. Methods: We used a natural history cohort of 35,252 individuals with cystic fibrosis aged ⩾6 years in the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified the rate of forced expiratory volume in 1 second (FEV1) decline (percent predicted per year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (<2 yr, 2-5 yr, entire duration). Results: Rate of FEV1 decline estimates (percent predicted per year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios, except for short-term follow-up (both were ∼1.4). Rate of decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best, except for short-term follow-up (<2 yr). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted per year in FEV1 was associated with a 1.52-fold (52%) increase in the hazard of death/lung transplant, but the results exhibited immortal cohort bias. Conclusions: Differences were as high as 0.5% predicted per year between rate of decline estimates, but we found estimates were robust to lung function data availability scenarios, except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

Built environment factors predictive of early rapid lung function decline in cystic fibrosis.

BACKGROUND: The extent to which environmental exposures and community characteristics of the built environment collectively predict rapid lung function decline, during adolescence and early adulthood in cystic fibrosis (CF), has not been examined. OBJECTIVE: To identify built environment characteristics predictive of rapid CF lung function decline. METHODS: We performed a retrospective, single-center, longitudinal cohort study (n = 173 individuals with CF aged 6-20 years, 2012-2017). We used a stochastic model to predict lung function, measured as forced expiratory volume in 1 s (FEV1 ) of % predicted. Traditional demographic/clinical characteristics were evaluated as predictors. Built environmental predictors included exposure to elemental carbon attributable to traffic sources (ECAT), neighborhood material deprivation (poverty, education, housing, and healthcare access), greenspace near the home, and residential drivetime to the CF center. MEASUREMENTS AND MAIN RESULTS: The final model, which included ECAT, material deprivation index, and greenspace, alongside traditional demographic/clinical predictors, significantly improved fit and prediction, compared with only demographic/clinical predictors (Likelihood Ratio Test statistic: 26.78, p < 0.0001; the difference in Akaike Information Criterion: 15). An increase of 0.1 µg/m3 of ECAT was associated with 0.104% predicted/yr (95% confidence interval: 0.024, 0.183) more rapid decline. Although not statistically significant, material deprivation was similarly associated (0.1-unit increase corresponded to additional decline of 0.103% predicted/year [-0.113, 0.319]). High-risk regional areas of rapid decline and age-related heterogeneity were identified from prediction mapping. CONCLUSION: Traffic-related air pollution exposure is an important predictor of rapid pulmonary decline that, coupled with community-level material deprivation and routinely collected demographic/clinical characteristics, enhance CF prognostication and enable personalized environmental health interventions.

Predicting Individualized Lung Disease Progression in Treatment-Naive Patients With Lymphangioleiomyomatosis.

BACKGROUND: Lung function decline varies significantly in patients with lymphangioleiomyomatosis (LAM), impeding individualized clinical decision-making. RESEARCH QUESTION: Can we aid individualized decision-making in LAM by developing a dynamic prediction model that can estimate the probability of clinically relevant FEV1 decline in patients with LAM before treatment initiation? STUDY DESIGN AND METHODS: Patients observed in the US National Heart, Lung, and Blood Institute (NHLBI) Lymphangioleiomyomatosis Registry were included. Using routinely available variables such as age at diagnosis, menopausal status, and baseline lung function (FEV1 and diffusing capacity of the lungs for carbon monoxide [Dlco]), we used novel stochastic modeling and evaluated predictive probabilities for clinically relevant drops in FEV1. We formed predictive probabilities of transplant-free survival by jointly modeling longitudinal FEV1 and lung transplantation or death events. External validation used the UK Lymphangioleiomyomatosis Natural History cohort. RESULTS: Analysis of the NHLBI Lymphangioleiomyomatosis Registry and UK Lymphangioleiomyomatosis Natural History cohorts consisted of 216 and 185 individuals, respectively. We derived a joint model that accurately estimated the risk of future lung function decline and 5-year probabilities of transplant-free survival in patients with LAM not taking sirolimus (area under the receiver operating characteristic curve [AUC], approximately 0.80). The prediction model provided estimates of forecasted FEV1, rate of FEV1 decline, and probabilities for risk of prolonged drops in FEV1 for untreated patients with LAM with a high degree of accuracy (AUC > 0.80) for the derivation cohort as well as the validation cohort. Our tool is freely accessible at: https://anushkapalipana.shinyapps.io/testapp_v2/. INTERPRETATION: Longitudinal modeling of routine clinical data can allow individualized LAM prognostication and assist in decision-making regarding the timing of treatment initiation.

Body composition and functional correlates of CF youth experiencing pulmonary exacerbation and recovery.

BACKGROUND: Youth with cystic fibrosis (CF) and pulmonary exacerbation (PEx) often experience weight loss, then rapid weight gain. Little is known about body composition and its relationship to functional outcomes during this critical period. METHODS: Twenty CF youth experiencing PEx were assessed on the day following admission and 7-17 days later at discharge for body mass index (BMI), fat mass index (FMI), lean mass index (LMI), skeletal muscle mass index (SMMI), and functional measures: percent predicted forced expiratory volume in 1 second (FEV1) (ppFEV1), maximal inspiratory and expiratory pressures (MIPs and MEPs), and handgrip strength (HGS). Changes from admission to discharge and correlations among body composition indices and functional measures at both times are reported. RESULTS: Upon admission, participant BMI percentile and ppFEV1 varied from 2 to 97 and 29 to 113, respectively. Thirteen had an LMI below the 25th percentile and nine had a percent body fat above the 75th percentile. BMI and FMI increased significantly (p = 0.03, 0.003) during hospitalization. LMI and SMMI did not change. FEV1 and MIPS increased (p = 0.0003, 0.007), independent of weight gain, during treatment. HGS did not improve. CONCLUSIONS: Many youth with CF, independent of BMI, frequently carried a small muscle mass and disproportionate fat at the time of PEx. During hospital treatment, weight gain largely represented fat deposition; muscle mass and strength did not improve. A need for trials of interventions designed to augment muscle mass and function, and limit fat mass accretion, at the time of PEx is suggested by these observations.

Tissue-localized immune responses in people with cystic fibrosis and respiratory nontuberculous mycobacteria infection.

Nontuberculous mycobacteria (NTM) are an increasingly common cause of respiratory infection in people with cystic fibrosis (PwCF). Relative to those with no history of NTM infection (CF-NTMNEG), PwCF and a history of NTM infection (CF-NTMPOS) are more likely to develop severe lung disease and experience complications over the course of treatment. In other mycobacterial infections (e.g., tuberculosis), an overexuberant immune response causes pathology and compromises organ function; however, since the immune profiles of CF-NTMPOS and CF-NTMNEG airways are largely unexplored, it is unknown which, if any, immune responses distinguish these cohorts or concentrate in damaged tissues. Here, we evaluated lung lobe-specific immune profiles of 3 cohorts (CF-NTMPOS, CF-NTMNEG, and non-CF adults) and found that CF-NTMPOS airways are distinguished by a hyperinflammatory cytokine profile. Importantly, the CF-NTMPOS airway immune profile was dominated by B cells, classical macrophages, and the cytokines that support their accumulation. These and other immunological differences between cohorts, including the near absence of NK cells and complement pathway members, were enriched in the most damaged lung lobes. The implications of these findings for our understanding of lung disease in PwCF are discussed, as are how they may inform the development of host-directed therapies to improve NTM disease treatment.

Bayesian regularization for a nonstationary Gaussian linear mixed effects model.

In omics experiments, estimation and variable selection can involve thousands of proteins/genes observed from a relatively small number of subjects. Many regression regularization procedures have been developed for estimation and variable selection in such high-dimensional problems. However, approaches have predominantly focused on linear regression models that ignore correlation arising from long sequences of repeated measurements on the outcome. Our work is motivated by the need to identify proteomic biomarkers that improve the prediction of rapid lung-function decline for individuals with cystic fibrosis (CF) lung disease. We extend four Bayesian penalized regression approaches for a Gaussian linear mixed effects model with nonstationary covariance structure to account for the complicated structure of longitudinal lung function data while simultaneously estimating unknown parameters and selecting important protein isoforms to improve predictive performance. Different types of shrinkage priors are evaluated to induce variable selection in a fully Bayesian framework. The approaches are studied with simulations. We apply the proposed method to real proteomics and lung-function outcome data from our motivating CF study, identifying a set of relevant clinical/demographic predictors and a proteomic biomarker for rapid decline of lung function. We also illustrate the methods on CD4 yeast cell-cycle genomic data, confirming that the proposed method identifies transcription factors that have been highlighted in the literature for their importance as cell cycle transcription factors.

Sweat metabolomics before and after intravenous antibiotics for pulmonary exacerbation in people with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PWCF) suffer from acute unpredictable reductions in pulmonary function associated with a pulmonary exacerbation (PEx) that may require hospitalization. PEx symptoms vary between PWCF without universal diagnostic criteria for diagnosis and response to treatment. RESEARCH QUESTION: We characterized sweat metabolomes before and after intravenous (IV) antibiotics in PWCF hospitalized for PEx to determine feasibility and define biological alterations by IV antibiotics for PEx. STUDY DESIGN AND METHODS: PWCF with PEx requiring hospitalization for IV antibiotics were recruited from clinic. Sweat samples were collected using the Macroduct® Sweat Collection System at admission prior to initiation of IV antibiotics and after completion prior to discharge. Samples were analyzed for metabolite changes using ultra-high-performance liquid chromatography/tandem accurate mass spectrometry. RESULTS: Twenty-six of 29 hospitalized PWCF completed the entire study. A total of 326 compounds of known identity were detected in sweat samples. Of detected metabolites, 147 were significantly different between pre-initiation and post-completion of IV antibiotics for PEx (average treatment 14 days). Global sweat metabolomes changed from before and after IV antibiotic treatment. We discovered specific metabolite profiles predictive of PEx status as well as enriched biologic pathways associated with PEx. However, metabolomic changes were similar in PWCF who failed to return to baseline pulmonary function and those who did not. INTERPRETATION: Our findings demonstrate the feasibility of non-invasive sweat metabolomic profiling in PWCF and the potential for sweat metabolomics as a prospective diagnostic and research tool to further advance our understanding of PEx in PWCF.

An empirical comparison of segmented and stochastic linear mixed effects models to estimate rapid disease progression in longitudinal biomarker studies.

Longitudinal studies of rapid disease progression often rely on noisy biomarkers; the underlying longitudinal process naturally varies between subjects and within an individual subject over time; the process can have substantial memory in the form of within-subject correlation. Cystic fibrosis lung disease progression is measured by changes in a lung function marker (FEV1), such as a prolonged drop in lung function, clinically termed rapid decline. Choosing a longitudinal model that estimates rapid decline can be challenging, requiring covariate specifications to assess drug effect while balancing choices of covariance functions. Two classes of longitudinal models have recently been proposed: segmented and stochastic linear mixed effects (LMEs) models. With segmented LMEs, random changepoints are used to estimate the timing and degree of rapid decline, treating these points as structural breaks in the underlying longitudinal process. In contrast, stochastic LMEs, such as random walks, are locally linear but utilize continuously changing slopes, viewing bouts of rapid decline as localized, sharp changes. We compare commonly utilized variants of these approaches through an application using the Cystic Fibrosis Foundation Patient Registry. Changepoint modeling had the worst fit and predictive accuracy but certain covariance forms in stochastic LMEs produced problematic variance estimates.

Seasonality, mediation and comparison (SMAC) methods to identify influences on lung function decline.

This study develops a comprehensive method to assess seasonal influences on a longitudinal marker and compare estimates between cohorts. The method extends existing approaches by (i) combining a sine-cosine model of seasonality with a specialized covariance function for modeling longitudinal correlation; (ii) performing mediation analysis on a seasonality model. An example dataset and R code are provided. The bundle of methods is referred to as seasonality, mediation and comparison (SMAC). The case study described utilizes lung function as the marker observed on a cystic fibrosis cohort but SMAC can be used to evaluate other markers and in other disease contexts. Key aspects of customization are as follows.•This study introduces a novel seasonality model to fit trajectories of lung function decline and demonstrates how to compare this model to a conventional model in this context.•Steps required for mediation analyses in the seasonality model are shown.•The necessary calculations to compare seasonality models between cohorts, based on estimation coefficients, are derived in the study.

Forecasting COVID-19 confirmed cases, deaths and recoveries: Revisiting established time series modeling through novel applications for the USA and Italy.

The novel coronavirus (COVID-19) is an emergent disease that initially had no historical data to guide scientists on predicting/ forecasting its global or national impact over time. The ability to predict the progress of this pandemic has been crucial for decision making aimed at fighting this pandemic and controlling its spread. In this work we considered four different statistical/time series models that are readily available from the 'forecast' package in R. We performed novel applications with these models, forecasting the number of infected cases (confirmed cases and similarly the number of deaths and recovery) along with the corresponding 90% prediction interval to estimate uncertainty around pointwise forecasts. Since the future may not repeat the past for this pandemic, no prediction model is certain. However, any prediction tool with acceptable prediction performance (or prediction error) could still be very useful for public-health planning to handle spread of the pandemic, and could policy decision-making and facilitate transition to normality. These four models were applied to publicly available data of the COVID-19 pandemic for both the USA and Italy. We observed that all models reasonably predicted the future numbers of confirmed cases, deaths, and recoveries of COVID-19. However, for the majority of the analyses, the time series model with autoregressive integrated moving average (ARIMA) and cubic smoothing spline models both had smaller prediction errors and narrower prediction intervals, compared to the Holt and Trigonometric Exponential smoothing state space model with Box-Cox transformation (TBATS) models. Therefore, the former two models were preferable to the latter models. Given similarities in performance of the models in the USA and Italy, the corresponding prediction tools can be applied to other countries grappling with the COVID-19 pandemic, and to any pandemics that can occur in future.

Seasonal variation of lung function in cystic fibrosis: longitudinal modeling to compare a Midwest US cohort to international populations.

Characterizing seasonal trend in lung function in individuals with chronic lung disease may lead to timelier treatment of acute respiratory symptoms and more precise distinction between seasonal exposures and variability. Limited research has been conducted to assess localized seasonal fluctuation in lung function decline in individuals with cystic fibrosis (CF) in context with routinely collected demographic and clinical data. We conducted a longitudinal cohort study of 253 individuals aged 6-22 years with CF receiving care at a pediatric Midwestern US CF center with median (range) of follow-up time of 4.7 (0-9.95) years, implementing two distinct models to estimate seasonality effects. The outcome, lung function, was measured as percent-predicted of forced expiratory volume in 1 second (FEV1). Both models showed that older age, being male, using Medicaid insurance and having Pseudomonas aeruginosa infection corresponded to accelerated FEV1 decline. A sine wave model for seasonality had better fit to the data, compared to a linear model with categories for seasonality. Compared to international cohorts, seasonal fluctuations occurred earlier and with greater volatility, even after adjustment for ambient temperature. Average lung function peaked in February and dipped in August, and FEV1 fluctuation was 0.81 % predicted (95% CI: 0.52 to 1.1). Adjusting for temperature shifted the peak and dip to March and September, respectively, and decreased FEV1 fluctuation to 0.45 % predicted (95% CI: 0.08 to 0.82). Understanding localized seasonal variation and its impact on lung function may allow researchers to perform precision public health for lung diseases and disorders at the point-of-care level.

Cystic Fibrosis Point of Personalized Detection (CFPOPD): An Interactive Web Application.

BACKGROUND: Despite steady gains in life expectancy, individuals with cystic fibrosis (CF) lung disease still experience rapid pulmonary decline throughout their clinical course, which can ultimately end in respiratory failure. Point-of-care tools for accurate and timely information regarding the risk of rapid decline is essential for clinical decision support. OBJECTIVE: This study aims to translate a novel algorithm for earlier, more accurate prediction of rapid lung function decline in patients with CF into an interactive web-based application that can be integrated within electronic health record systems, via collaborative development with clinicians. METHODS: Longitudinal clinical history, lung function measurements, and time-invariant characteristics were obtained for 30,879 patients with CF who were followed in the US Cystic Fibrosis Foundation Patient Registry (2003-2015). We iteratively developed the application using the R Shiny framework and by conducting a qualitative study with care provider focus groups (N=17). RESULTS: A clinical conceptual model and 4 themes were identified through coded feedback from application users: (1) ambiguity in rapid decline, (2) clinical utility, (3) clinical significance, and (4) specific suggested revisions. These themes were used to revise our application to the currently released version, available online for exploration. This study has advanced the application's potential prognostic utility for monitoring individuals with CF lung disease. Further application development will incorporate additional clinical characteristics requested by the users and also a more modular layout that can be useful for care provider and family interactions. CONCLUSIONS: Our framework for creating an interactive and visual analytics platform enables generalized development of applications to synthesize, model, and translate electronic health data, thereby enhancing clinical decision support and improving care and health outcomes for chronic diseases and disorders. A prospective implementation study is necessary to evaluate this tool's effectiveness regarding increased communication, enhanced shared decision-making, and improved clinical outcomes for patients with CF.

Influences of environmental exposures on individuals living with cystic fibrosis.

INTRODUCTION: Natural, social, and constructed environments play a critical role in the development and exacerbation of respiratory diseases. However, less is known regarding the influence of these environmental/community risk factors on the health of individuals living with cystic fibrosis (CF), compared to other pulmonary disorders. AREAS COVERED: Here, we review current knowledge of environmental exposures related to CF, which suggests that environmental/community risk factors do interact with the respiratory tract to affect outcomes. Studies discussed in this review were identified in PubMed between March 2019 and March 2020. Although the limited data available do not suggest that avoiding potentially detrimental exposures other than secondhand smoke could improve outcomes, additional research incorporating novel markers of environmental exposures and community characteristics obtained at localized levels is needed. EXPERT OPINION: As we outline, some environmental exposures and community characteristics are modifiable; if not by the individual, then by policy. We recommend a variety of strategies to advance understanding of environmental influences on CF disease progression.

Functional data analysis and prediction tools for continuous glucose-monitoring studies.

INTRODUCTION: To identify phenotypes of type 1 diabetes based on glucose curves from continuous glucose-monitoring (CGM) using functional data (FD) analysis to account for longitudinal glucose patterns. We present a reliable prediction model that can accurately predict glycemic levels based on past data collected from the CGM sensor and real-time risk of hypo-/hyperglycemic for individuals with type 1 diabetes. METHODS: A longitudinal cohort study of 443 type 1 diabetes patients with CGM data from a completed trial. The FD analysis approach, sparse functional principal components (FPCs) analysis was used to identify phenotypes of type 1 diabetes glycemic variation. We employed a nonstationary stochastic linear mixed-effects model (LME) that accommodates between-patient and within-patient heterogeneity to predict glycemic levels and real-time risk of hypo-/hyperglycemic by creating specific target functions for these excursions. RESULTS: The majority of the variation (73%) in glucose trajectories was explained by the first two FPCs. Higher order variation in the CGM profiles occurred during weeknights, although variation was higher on weekends. The model has low prediction errors and yields accurate predictions for both glucose levels and real-time risk of glycemic excursions. CONCLUSIONS: By identifying these distinct longitudinal patterns as phenotypes, interventions can be targeted to optimize type 1 diabetes management for subgroups at the highest risk for compromised long-term outcomes such as cardiac disease or stroke. Further, the estimated change/variability in an individual's glucose trajectory can be used to establish clinically meaningful and patient-specific thresholds that, when coupled with probabilistic predictive inference, provide a useful medical-monitoring tool.

Feedback at the Point of Care to Decrease Medication Alert Rates in an Electronic Health Record.

Frequently overridden alerts in the electronic health record can highlight alerts that may need revision. This method is a way of fine-tuning clinical decision support. We evaluated the feasibility of a complementary, yet different method that directly involved pediatric emergency department (PED) providers in identifying additional medication alerts that were potentially incorrect or intrusive. We then evaluated the effect subsequent resulting modifications had on alert salience. METHODS: We performed a prospective, interventional study over 34 months (March 6, 2014, to December 31, 2016) in the PED. We implemented a passive alert feedback mechanism by enhancing the native electronic health record functionality on alert reviews. End-users flagged potentially incorrect/bothersome alerts for review by the study's team. The alerts were updated when clinically appropriate and trends of the impact were evaluated. RESULTS: More than 200 alerts were reported from both inside and outside the PED, suggesting an intuitive approach. On average, we processed 4 reviews per week from the PED, with attending physicians as major contributors. The general trend of the impact of these changes seems favorable. DISCUSSION: The implementation of the review mechanism for user-selected alerts was intuitive and sustainable and seems to be able to detect alerts that are bothersome to the end-users. The method should be run in parallel with the traditional data-driven approach to support capturing of inaccurate alerts. CONCLUSIONS: User-centered, context-specific alert feedback can be used for selecting suboptimal, interruptive medication alerts.