Prospective validation of clinical deterioration predictive models prior to intensive care unit transfer among patients admitted to acute care cardiology wards.

Objective. Very few predictive models have been externally validated in a prospective cohort following the implementation of an artificial intelligence analytic system. This type of real-world validation is critically important due to the risk of data drift, or changes in data definitions or clinical practices over time, that could impact model performance in contemporaneous real-world cohorts. In this work, we report the model performance of a predictive analytics tool developed before COVID-19 and demonstrate model performance during the COVID-19 pandemic.Approach. The analytic system (CoMETⓇ, Nihon Kohden Digital Health Solutions LLC, Irvine, CA) was implemented in a randomized controlled trial that enrolled 10 422 patient visits in a 1:1 display-on display-off design. The CoMET scores were calculated for all patients but only displayed in the display-on arm. Only the control/display-off group is reported here because the scores could not alter care patterns.Main results.Of the 5184 visits in the display-off arm, 311 experienced clinical deterioration and care escalation, resulting in transfer to the intensive care unit, primarily due to respiratory distress. The model performance of CoMET was assessed based on areas under the receiver operating characteristic curve, which ranged from 0.725 to 0.737.Significance.The models were well-calibrated, and there were dynamic increases in the model scores in the hours preceding the clinical deterioration events. A hypothetical alerting strategy based on a rise in score and duration of the rise would have had good performance, with a positive predictive value more than 10-fold the event rate. We conclude that predictive statistical models developed five years before study initiation had good model performance despite the passage of time and the impact of the COVID-19 pandemic.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Extremely Preterm Infants.

Objectives: Detection of changes in cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, may facilitate earlier detection of sepsis. Our objective was to examine the association of cardiorespiratory events with late-onset sepsis for extremely preterm infants (<29 weeks' gestational age (GA)) on versus off invasive mechanical ventilation. Study Design: Retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in five level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean GA 26.4w, SD 1.71). Monitoring data were available and analyzed for 719 infants (47,512 patient-days), of whom 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72h after birth and ≥5d antibiotics). Results: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer IH80 events and more bradycardia events before sepsis. IH events were associated with higher sepsis risk, but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model predicted sepsis with an AUC of 0.783. Conclusion: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Age Prediction From 12-lead Electrocardiograms Using Deep Learning: A Comparison of Four Models on a Contemporary, Freely Available Dataset.

The 12-lead electrocardiogram (ECG) is routine in clinical use and deep learning approaches have been shown to have the identify features not immediately apparent to human interpreters including age and sex. ECG predicted age has been identified as a predictor of long-term mortality. Here we compare four models for age and sex prediction on a contemporary, freely available dataset.

Cardiorespiratory Dynamics During Prone Positioning for Severe Ards: A Retrospective Cohort Study.

Objectives: To elucidate the changes in cardiorespiratory dynamics during neuromuscular blockade and prone positioning and determine the associations between changes in cardiorespiratory dynamics following prone positioning and mortality. Design: Single center retrospective cohort study of patients admitted to the medical ICU between June 1, 2020 and September 1, 2022 who received prone positioning while mechanically ventilated. Results: Our final cohort consisted of 136 patients. Prone position was associated with an improvement in A-a gradient of 113 mmHg (95% CrI 78 - 149) between the pre-proning values and 10 hours post proning. Norepinephrine dose did not significantly change before and after prone positioning (Estimated difference: 0.04 mcg/min 95% CrI -1.00 - 1.07). For the outcome of 7-d mortality, there was a high probability that the baseline factors of increasing age, male sex, and higher baseline A-a gradient were associated with increased risk of death. Increased total vasopressor requirement and increased in PCO2 were associated with worse prognosis while a decrease in instantaneous heart rate and a decrease in heart rate variability were associated with improved prognosis. Conclusion: The immediate changes in prone positioning primarily impact respiratory physiology, with limited influence on circulatory parameters. Predictors of short-term mortality after prone positioning include both respiratory and cardiovascular parameters suggesting that extrapulmonary effects, such as improvement in right ventricular heart function, might also contribute to the benefit of prone positioning.

Pathophysiological Responses to Bloodstream Infection in Critically Ill Transplant Recipients Compared With Non-Transplant Recipients.

BACKGROUND: Identification of bloodstream infection (BSI) in transplant recipients may be difficult due to immunosuppression. Accordingly, we aimed to compare responses to BSI in critically ill transplant and non-transplant recipients and to modify systemic inflammatory response syndrome (SIRS) criteria for transplant recipients. METHODS: We analyzed univariate risks and developed multivariable models of BSI with 27 clinical variables from adult intensive care unit (ICU) patients at the University of Virginia (UVA) and at the University of Pittsburgh (Pitt). We used Bayesian inference to adjust SIRS criteria for transplant recipients. RESULTS: We analyzed 38.7 million hourly measurements from 41 725 patients at UVA, including 1897 transplant recipients with 193 episodes of BSI and 53 608 patients at Pitt, including 1614 transplant recipients with 768 episodes of BSI. The univariate responses to BSI were comparable in transplant and non-transplant recipients. The area under the receiver operating characteristic curve (AUC) was 0.82 (95% confidence interval [CI], .80-.83) for the model using all UVA patient data and 0.80 (95% CI, .76-.83) when using only transplant recipient data. The UVA all-patient model had an AUC of 0.77 (95% CI, .76-.79) in non-transplant recipients and 0.75 (95% CI, .71-.79) in transplant recipients at Pitt. The relative importance of the 27 predictors was similar in transplant and non-transplant models. An upper temperature of 37.5°C in SIRS criteria improved reclassification performance in transplant recipients. CONCLUSIONS: Critically ill transplant and non-transplant recipients had similar responses to BSI. An upper temperature of 37.5°C in SIRS criteria improved BSI screening in transplant recipients.

Maturation of cardioventilatory physiological trajectories in extremely preterm infants.

BACKGROUND: In extremely preterm infants, persistence of cardioventilatory events is associated with long-term morbidity. Therefore, the objective was to characterize physiologic growth curves of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants during the first few months of life. METHODS: The Prematurity-Related Ventilatory Control study included 717 preterm infants <29 weeks gestation. Waveforms were downloaded from bedside monitors with a novel sharing analytics strategy utilized to run software locally, with summary data sent to the Data Coordinating Center for compilation. RESULTS: Apnea, periodic breathing, and intermittent hypoxemia events rose from day 3 of life then fell to near-resolution by 8-12 weeks of age. Apnea/intermittent hypoxemia were inversely correlated with gestational age, peaking at 3-4 weeks of age. Periodic breathing was positively correlated with gestational age peaking at 31-33 weeks postmenstrual age. Females had more periodic breathing but less intermittent hypoxemia/bradycardia. White infants had more apnea/periodic breathing/intermittent hypoxemia. Infants never receiving mechanical ventilation followed similar postnatal trajectories but with less apnea and intermittent hypoxemia, and more periodic breathing. CONCLUSIONS: Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. IMPACT: Physiologic curves of cardiorespiratory events in extremely preterm-born infants offer (1) objective measures to assess individual patient courses and (2) guides for research into control of ventilation, biomarkers and outcomes. Presented are updated maturational trajectories of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in 717 infants born <29 weeks gestation from the multi-site NHLBI-funded Pre-Vent study. Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Different time courses for apnea and periodic breathing suggest different maturational mechanisms.

Neighborhood Deprivation and Association With Neonatal Intensive Care Unit Mortality and Morbidity for Extremely Premature Infants.

Importance: Socioeconomic status affects pregnancy and neurodevelopment, but its association with hospital outcomes among premature infants is unknown. The Area Deprivation Index (ADI) is a validated measure of neighborhood disadvantage that uses US Census Bureau data on income, educational level, employment, and housing quality. Objective: To determine whether ADI is associated with neonatal intensive care unit (NICU) mortality and morbidity in extremely premature infants. Design, Setting, and Participants: This retrospective cohort study was performed at 4 level IV NICUs in the US Northeast, Mid-Atlantic, Midwest, and South regions. Non-Hispanic White and Black infants with gestational age of less than 29 weeks and born between January 1, 2012, and December 31, 2020, were included in the analysis. Addresses were converted to census blocks, identified by Federal Information Processing Series codes, to link residences to national ADI percentiles. Exposures: ADI, race, birth weight, sex, and outborn status. Main Outcomes and Measures: In the primary outcome, the association between ADI and NICU mortality was analyzed using bayesian logistic regression adjusted for race, birth weight, outborn status, and sex. Risk factors were considered significant if the 95% credible intervals excluded zero. In the secondary outcome, the association between ADI and NICU morbidities, including late-onset sepsis, necrotizing enterocolitis (NEC), and severe intraventricular hemorrhage (IVH), were also analyzed. Results: A total of 2765 infants with a mean (SD) gestational age of 25.6 (1.7) weeks and mean (SD) birth weight of 805 (241) g were included in the analysis. Of these, 1391 (50.3%) were boys, 1325 (47.9%) reported Black maternal race, 498 (18.0%) died before NICU discharge, 692 (25.0%) developed sepsis or NEC, and 353 (12.8%) had severe IVH. In univariate analysis, higher median ADI was found among Black compared with White infants (77 [IQR, 45-93] vs 57 [IQR, 32-77]; P < .001), those who died before NICU discharge vs survived (71 [IQR, 45-89] vs 64 [IQR, 36-86]), those with late-onset sepsis or NEC vs those without (68 [IQR, 41-88] vs 64 [IQR, 35-86]), and those with severe IVH vs those without (69 [IQR, 44-90] vs 64 [IQR, 36-86]). In a multivariable bayesian logistic regression model, lower birth weight, higher ADI, and male sex were risk factors for mortality (95% credible intervals excluded zero), while Black race and outborn status were not. The ADI was also identified as a risk factor for sepsis or NEC and severe IVH. Conclusions and Relevance: The findings of this cohort study of extremely preterm infants admitted to 4 NICUs in different US geographic regions suggest that ADI was a risk factor for mortality and morbidity after adjusting for multiple covariates.

Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

Race, Class, and Place Modify Mortality Rates for the Leading Causes of Death in the United States, 1999-2021.

BACKGROUND: Race and ethnicity, socioeconomic class, and geographic location are well-known social determinants of health in the US. Studies of population mortality often consider two, but not all three of these risk factors. OBJECTIVES: To disarticulate the associations of race (whiteness), class (socioeconomic status), and place (county) with risk of cause-specific death in the US. DESIGN: We conducted a retrospective analysis of death certificate data. Bayesian regression models, adjusted for age and race/ethnicity from the American Community Survey and the county Area Deprivation Index, were used for inference. MAIN MEASURES: County-level mortality for 11 leading causes of death (1999-2019) and COVID-19 (2020-2021). KEY RESULTS: County "whiteness" and socioeconomic status modified death rates; geospatial effects differed by cause of death. Other factors equal, a 20% increase in county whiteness was associated with 5-8% increase in death from three causes and 4-15% reduction in death from others, including COVID-19. Other factors equal, advantaged counties had significantly lower death rates, even when juxtaposed with disadvantaged ones. Patterns of residual risk, measured by spatial county effects, varied by cause of death; for example: cancer and heart disease death rates were better explained by age, socioeconomic status, and county whiteness than were COVID-19 and suicide deaths. CONCLUSIONS: There are important independent contributions from race, class, and geography to risk of death in the US.

Cardiorespiratory signature of neonatal sepsis: development and validation of prediction models in 3 NICUs.

BACKGROUND: Heart rate characteristics aid early detection of late-onset sepsis (LOS), but respiratory data contain additional signatures of illness due to infection. Predictive models using cardiorespiratory data may improve early sepsis detection. We hypothesized that heart rate (HR) and oxygenation (SpO2) data contain signatures that improve sepsis risk prediction over HR or demographics alone. METHODS: We analyzed cardiorespiratory data from very low birth weight (VLBW, <1500 g) infants admitted to three NICUs. We developed and externally validated four machine learning models to predict LOS using features calculated every 10 m: mean, standard deviation, skewness, kurtosis of HR and SpO2, and cross-correlation. We compared feature importance, discrimination, calibration, and dynamic prediction across models and cohorts. We built models of demographics and HR or SpO2 features alone for comparison with HR-SpO2 models. RESULTS: Performance, feature importance, and calibration were similar among modeling methods. All models had favorable external validation performance. The HR-SpO2 model performed better than models using either HR or SpO2 alone. Demographics improved the discrimination of all physiologic data models but dampened dynamic performance. CONCLUSIONS: Cardiorespiratory signatures detect LOS in VLBW infants at 3 NICUs. Demographics risk-stratify, but predictive modeling with both HR and SpO2 features provides the best dynamic risk prediction. IMPACT: Heart rate characteristics aid early detection of late-onset sepsis, but respiratory data contain signatures of illness due to infection. Predictive models using both heart rate and respiratory data may improve early sepsis detection. A cardiorespiratory early warning score, analyzing heart rate from electrocardiogram or pulse oximetry with SpO2, predicts late-onset sepsis within 24 h across multiple NICUs and detects sepsis better than heart rate characteristics or demographics alone. Demographics risk-stratify, but predictive modeling with both HR and SpO2 features provides the best dynamic risk prediction. The results increase understanding of physiologic signatures of neonatal sepsis.

A novel predictive analytics score reflecting accumulating disease burden-an investigation of the cumulative CoMET score.

OBJECTIVE: Predictive analytics tools variably take into account data from the electronic medical record, lab tests, nursing charted vital signs and continuous cardiorespiratory monitoring to deliver an instantaneous prediction of patient risk or instability. Few, if any, of these tools reflect the risk to a patient accumulated over the course of an entire hospital stay. APPROACH: We have expanded on our instantaneous CoMET predictive analytics score to generate the cumulative CoMET score (cCoMET), which sums all of the instantaneous CoMET scores throughout a hospital admission relative to a baseline expected risk unique to that patient. MAIN RESULTS: We have shown that higher cCoMET scores predict mortality, but not length of stay, and that higher baseline CoMET scores predict higher cCoMET scores at discharge/death. cCoMET scores were higher in males in our cohort, and added information to the final CoMET when it came to the prediction of death. SIGNIFICANCE: We have shown that the inclusion of all repeated measures of risk estimation performed throughout a patients hospital stay adds information to instantaneous predictive analytics, and could improve the ability of clinicians to predict deterioration, and improve patient outcomes in so doing.

Overt and Occult Hypoxemia in Patients Hospitalized With COVID-19.

Progressive hypoxemia is the predominant mode of deterioration in COVID-19. Among hypoxemia measures, the ratio of the Pao2 to the Fio2 (P/F ratio) has optimal construct validity but poor availability because it requires arterial blood sampling. Pulse oximetry reports oxygenation continuously (ratio of the Spo2 to the Fio2 [S/F ratio]), but it is affected by skin color and occult hypoxemia can occur in Black patients. Oxygen dissociation curves allow noninvasive estimation of P/F ratios (ePFRs) but remain unproven. OBJECTIVES: Measure overt and occult hypoxemia using ePFR. DESIGN SETTING AND PARTICIPANTS: We retrospectively studied COVID-19 hospital encounters (n = 5,319) at two academic centers (University of Virginia [UVA] and Emory University). MAIN OUTCOMES AND MEASURES: We measured primary outcomes (death or ICU transfer within 24 hr), ePFR, conventional hypoxemia measures, baseline predictors (age, sex, race, comorbidity), and acute predictors (National Early Warning Score [NEWS] and Sequential Organ Failure Assessment [SOFA]). We updated predictors every 15 minutes. We assessed predictive validity using adjusted odds ratios (AORs) and area under the receiver operating characteristic curves (AUROCs). We quantified disparities (Black vs non-Black) in empirical cumulative distributions using the Kolmogorov-Smirnov (K-S) two-sample test. RESULTS: Overt hypoxemia (low ePFR) predicted bad outcomes (AOR for a 100-point ePFR drop: 2.7 [UVA]; 1.7 [Emory]; p < 0.01) with better discrimination (AUROC: 0.76 [UVA]; 0.71 [Emory]) than NEWS (0.70 [both sites]) or SOFA (0.68 [UVA]; 0.65 [Emory]) and similar to S/F ratio (0.76 [UVA]; 0.70 [Emory]). We found racial differences consistent with occult hypoxemia. Black patients had better apparent oxygenation (K-S distance: 0.17 [both sites]; p < 0.01) but, for comparable ePFRs, worse outcomes than other patients (AOR: 2.2 [UVA]; 1.2 [Emory]; p < 0.01). CONCLUSIONS AND RELEVANCE: The ePFR was a valid measure of overt hypoxemia. In COVID-19, it may outperform multi-organ dysfunction models. By accounting for biased oximetry as well as clinicians' real-time responses to it (supplemental oxygen adjustment), ePFRs may reveal racial disparities attributable to occult hypoxemia.

Continuous ECG monitoring should be the heart of bedside AI-based predictive analytics monitoring for early detection of clinical deterioration.

The idea that we can detect subacute potentially catastrophic illness earlier by using statistical models trained on clinical data is now well-established. We review evidence that supports the role of continuous cardiorespiratory monitoring in these predictive analytics monitoring tools. In particular, we review how continuous ECG monitoring reflects the patient and not the clinician, is less likely to be biased, is unaffected by changes in practice patterns, captures signatures of illnesses that are interpretable by clinicians, and is an underappreciated and underutilized source of detailed information for new mathematical methods to reveal.

Accuracy of a Risk Alert Threshold for ICU Hypoglycemia: Retrospective Analysis of Alert Performance and Association With Clinical Deterioration Events.

OBJECTIVES: To quantify the accuracy of and clinical events associated with a risk alert threshold for impending hypoglycemia during ICU admissions. DESIGN: Retrospective electronic health record review of clinical events occurring greater than or equal to 1 and less than or equal to 12 hours after the hypoglycemia risk alert threshold was met. SETTING: Adult ICU admissions from June 2020 through April 2021 at the University of Virginia Medical Center. PATIENTS: Three hundred forty-two critically ill adults that were 63.5% male with median age 60.8 years, median weight 79.1 kg, and median body mass index of 27.5 kg/m2. INTERVENTIONS: Real-world testing of our validated predictive model as a clinical decision support tool for ICU hypoglycemia. MEASUREMENTS AND MAIN RESULTS: We retrospectively reviewed 350 hypothetical alerts that met inclusion criteria for analysis. The alerts correctly predicted 48 cases of level 1 hypoglycemia that occurred greater than or equal to 1 and less than or equal to 12 hours after the alert threshold was met (positive predictive value = 13.7%). Twenty-one of these 48 cases (43.8%) involved level 2 hypoglycemia. Notably, three myocardial infarctions, one medical emergency team call, 19 deaths, and 20 arrhythmias occurred greater than or equal to 1 and less than or equal to 12 hours after an alert threshold was met. CONCLUSIONS: Alerts generated by a validated ICU hypoglycemia prediction model had a positive predictive value of 13.7% for real-world hypoglycemia events. This proof-of-concept result suggests that the predictive model offers clinical value, but further prospective testing is needed to confirm this.

Ideal algorithms in healthcare: Explainable, dynamic, precise, autonomous, fair, and reproducible.

Established guidelines describe minimum requirements for reporting algorithms in healthcare; it is equally important to objectify the characteristics of ideal algorithms that confer maximum potential benefits to patients, clinicians, and investigators. We propose a framework for ideal algorithms, including 6 desiderata: explainable (convey the relative importance of features in determining outputs), dynamic (capture temporal changes in physiologic signals and clinical events), precise (use high-resolution, multimodal data and aptly complex architecture), autonomous (learn with minimal supervision and execute without human input), fair (evaluate and mitigate implicit bias and social inequity), and reproducible (validated externally and prospectively and shared with academic communities). We present an ideal algorithms checklist and apply it to highly cited algorithms. Strategies and tools such as the predictive, descriptive, relevant (PDR) framework, the Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence (SPIRIT-AI) extension, sparse regression methods, and minimizing concept drift can help healthcare algorithms achieve these objectives, toward ideal algorithms in healthcare.

Signatures of illness in children requiring unplanned intubation in the pediatric intensive care unit: A retrospective cohort machine-learning study.

Acute respiratory failure requiring the initiation of invasive mechanical ventilation remains commonplace in the pediatric intensive care unit (PICU). Early recognition of patients at risk for respiratory failure may provide clinicians with the opportunity to intervene and potentially improve outcomes. Through the development of a random forest model to identify patients at risk for requiring unplanned intubation, we tested the hypothesis that subtle signatures of illness are present in physiological and biochemical time series of PICU patients in the early stages of respiratory decompensation. We included 116 unplanned intubation events as recorded in the National Emergency Airway Registry for Children in 92 PICU admissions over a 29-month period at our institution. We observed that children have a physiologic signature of illness preceding unplanned intubation in the PICU. Generally, it comprises younger age, and abnormalities in electrolyte, hematologic and vital sign parameters. Additionally, given the heterogeneity of the PICU patient population, we found differences in the presentation among the major patient groups - medical, cardiac surgical, and non-cardiac surgical. At four hours prior to the event, our random forest model demonstrated an area under the receiver operating characteristic curve of 0.766 (0.738 for medical, 0.755 for cardiac surgical, and 0.797 for non-cardiac surgical patients). The multivariable statistical models that captured the physiological and biochemical dynamics leading up to the event of urgent unplanned intubation in a PICU can be repurposed for bedside risk prediction.

Phenotype clustering in health care: A narrative review for clinicians.

Human pathophysiology is occasionally too complex for unaided hypothetical-deductive reasoning and the isolated application of additive or linear statistical methods. Clustering algorithms use input data patterns and distributions to form groups of similar patients or diseases that share distinct properties. Although clinicians frequently perform tasks that may be enhanced by clustering, few receive formal training and clinician-centered literature in clustering is sparse. To add value to clinical care and research, optimal clustering practices require a thorough understanding of how to process and optimize data, select features, weigh strengths and weaknesses of different clustering methods, select the optimal clustering method, and apply clustering methods to solve problems. These concepts and our suggestions for implementing them are described in this narrative review of published literature. All clustering methods share the weakness of finding potential clusters even when natural clusters do not exist, underscoring the importance of applying data-driven techniques as well as clinical and statistical expertise to clustering analyses. When applied properly, patient and disease phenotype clustering can reveal obscured associations that can help clinicians understand disease pathophysiology, predict treatment response, and identify patients for clinical trial enrollment.

Overt and occult hypoxemia in patients hospitalized with novel coronavirus disease 2019.

Background: Progressive hypoxemia is the predominant mode of deterioration in COVID-19. Among hypoxemia measures, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (P/F ratio) has optimal construct validity but poor availability because it requires arterial blood sampling. Pulse oximetry reports oxygenation continuously, but occult hypoxemia can occur in Black patients because the technique is affected by skin color. Oxygen dissociation curves allow non-invasive estimation of P/F ratios (ePFR) but this approach remains unproven. Research Question: Can ePFRs measure overt and occult hypoxemia? Study Design and methods: We retrospectively studied COVID-19 hospital encounters (n=5319) at two academic centers (University of Virginia [UVA] and Emory University). We measured primary outcomes (death or ICU transfer within 24 hours), ePFR, conventional hypoxemia measures, baseline predictors (age, sex, race, comorbidity), and acute predictors (National Early Warning Score (NEWS) and Sepsis-3). We updated predictors every 15 minutes. We assessed predictive validity using adjusted odds ratios (AOR) and area under receiver operating characteristics curves (AUROC). We quantified disparities (Black vs non-Black) in empirical cumulative distributions using the Kolmogorov-Smirnov (K-S) two-sample test. Results: Overt hypoxemia (low ePFR) predicted bad outcomes (AOR for a 100-point ePFR drop: 2.7 [UVA]; 1.7 [Emory]; p<0.01) with better discrimination (AUROC: 0.76 [UVA]; 0.71 [Emory]) than NEWS (AUROC: 0.70 [UVA]; 0.70 [Emory]) or Sepsis-3 (AUROC: 0.68 [UVA]; 0.65 [Emory]). We found racial differences consistent with occult hypoxemia. Black patients had better apparent oxygenation (K-S distance: 0.17 [both sites]; p<0.01) but, for comparable ePFRs, worse outcomes than other patients (AOR: 2.2 [UVA]; 1.2 [Emory], p<0.01). Interpretation: The ePFR was a valid measure of overt hypoxemia. In COVID-19, it may outperform multi-organ dysfunction models like NEWS and Sepsis-3. By accounting for biased oximetry as well as clinicians’ real-time responses to it (supplemental oxygen adjustment), ePFRs may enable statistical modelling of racial disparities in outcomes attributable to occult hypoxemia.

Analysis of respiratory kinematics: a method to characterize breaths from motion signals.

Objective.Breathing motion (respiratory kinematics) can be characterized by the interval and depth of each breath, and by magnitude-synchrony relationships between locations. Such characteristics and their breath-by-breath variability might be useful indicators of respiratory health. To enable breath-by-breath characterization of respiratory kinematics, we developed a method to detect breaths using motion sensors.Approach.In 34 volunteers who underwent maximal exercise testing, we used 8 motion sensors to record upper rib, lower rib and abdominal kinematics at 3 exercise stages (rest, lactate threshold and exhaustion). We recorded volumetric air flow signals using clinical exercise laboratory equipment and synchronized them with kinematic signals. Using instantaneous phase landmarks from the analytic representation of kinematic and flow signals, we identified individual breaths and derived respiratory rate (RR) signals at 1 Hz. To evaluate the fidelity of kinematics-derived RR, we calculated bias, limits of agreement, and cross-correlation coefficients (CCC) relative to flow-derived RR. To identify coupling between kinematics and flow, we calculated the Shannon entropy of the relative frequency with which flow landmarks were distributed over the phase of the kinematic cycle.Main Results.We found good agreement in the kinematics-derived and flow-derived RR signals [bias (95% limit of agreement) = 0.1 (± 7) breaths/minute; CCC median (IQR) = 0.80 (0.48-0.91)]. In individual signals, kinematics and flow were well-coupled (entropy 0.9-1.4 across sensors), but the relationship varied within (by exercise stage) and between individuals. The final result was that the flow landmarks did not consistently localize to any particular phase of the kinematic signals (entropy 2.2-3.0 across sensors).Significance.The Analysis of Respiratory Kinematics method can yield highly resolved respiratory rate signals by separating individual breaths. This method will facilitate characterization of clinically significant breathing motion patterns on a breath-by-breath basis. The relationship between respiratory kinematics and flow is much more complex than expected, varying between and within individuals.