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1. A pragmatic approach to estimating average treatment effects from EHR data: the effect of prone positioning on mechanically ventilated COVID-19 patients

Author

Izdebski, Adam, Thoral, Patrick J., Lalisang, Robbert C. A., McHugh, Dean M., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco A. A., Kamps, Marlijn J. A, Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., Tempel, Walter van den, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C. D., Arbous, Sesmu, Fleuren, Lucas M., Dam, Tariq A., Tonutti, Michele, de Bruin, Daan P., Elbers, Paul W. G., and Cinà, Giovanni

Subjects
Computer Science - Machine Learning, Computer Science - Artificial Intelligence
Abstract

Despite the recent progress in the field of causal inference, to date there is no agreed upon methodology to glean treatment effect estimation from observational data. The consequence on clinical practice is that, when lacking results from a randomized trial, medical personnel is left without guidance on what seems to be effective in a real-world scenario. This article proposes a pragmatic methodology to obtain preliminary but robust estimation of treatment effect from observational studies, to provide front-line clinicians with a degree of confidence in their treatment strategy. Our study design is applied to an open problem, the estimation of treatment effect of the proning maneuver on COVID-19 Intensive Care patients.

Published
2021

2. Biomarker Analysis Provides Evidence for Host Response Homogeneity in Patients With COVID-19

Author

van Agtmael, Michiel A., Algera, Anne G., Appelman, Brent, van Baarle, Floor E.H.P., van de Beek, Diederik, Beudel, Martijn, Bogaard, Harm J., Bos, Lieuwe D.J., Botta, Michela, de Brabander, Justin, de Bree, Godelieve J., Brouwer, Matthijs C., de Bruin, Sanne, Bugiani, Marianna, Bulle, Esther B., Chouchane, Osoul, Cloherty, Alex P.M., Buis, David, de Rotte, Maurtis C.F.J., Dijkstra, Mirjam, Dongelmans, Dave A., Dujardin, Romein W.G., Elbers, Paul E., Fleuren, Lucas M., Geerlings, Suzanne E., Geijtenbeek, Theo B.H., Girbes, Armand R.J., Goorhuis, Bram, Grobusch, Martin P., Hagens, Laura A., Hamann, Jorg, Harris, Vanessa C., Hemke, Robert, Hermans, Sabine M., Heunks, Leo M.A., Hollmann, Markus W., Horn, Janneke, Hovius, Joppe W., de Jong, Menno D., Koning, Rutger, Lim, Endry H.T., van Mourik, Niels, Nellen, Jeannine F., Nossent, Esther J., Paulus, Frederique, Peters, Edgar, Piña-Fuentes, Dan, van der Poll, Tom, Preckel, Bennedikt, Raasveld, Jorinde, Reijnders, Tom D.Y., Schinkel, Michiel, Schrauwen, Femke A.P., Schultz, Marcus J., Schuurman, Alex R., Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen A., Smeele, Patrick, Smit, Marry R., Stijnis, Cornelis, Stilma, Willemke, Teunissen, Charlotte E., Thoral, Patrick, Tsonas, Anissa M., Tuinman, Pieter R., van der Valk, Marc, Veelo, Denise P., Vlaar, Alexander P.J., Volleman, Carolien, de Vries, Heder, van Vught, Lonneke A., van Vugt, Michèle, Wiersinga, Joost, Wouters, Dorien, Zwinderman, Koos, van Amstel, Rombout B.E., Michels, Erik H.A., and Smeele, Patrick J.

Published
2024
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3. Integrating Expert ODEs into Neural ODEs: Pharmacology and Disease Progression

Author

Qian, Zhaozhi, Zame, William R., Fleuren, Lucas M., Elbers, Paul, and van der Schaar, Mihaela

Subjects
Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

Modeling a system's temporal behaviour in reaction to external stimuli is a fundamental problem in many areas. Pure Machine Learning (ML) approaches often fail in the small sample regime and cannot provide actionable insights beyond predictions. A promising modification has been to incorporate expert domain knowledge into ML models. The application we consider is predicting the progression of disease under medications, where a plethora of domain knowledge is available from pharmacology. Pharmacological models describe the dynamics of carefully-chosen medically meaningful variables in terms of systems of Ordinary Differential Equations (ODEs). However, these models only describe a limited collection of variables, and these variables are often not observable in clinical environments. To close this gap, we propose the latent hybridisation model (LHM) that integrates a system of expert-designed ODEs with machine-learned Neural ODEs to fully describe the dynamics of the system and to link the expert and latent variables to observable quantities. We evaluated LHM on synthetic data as well as real-world intensive care data of COVID-19 patients. LHM consistently outperforms previous works, especially when few training samples are available such as at the beginning of the pandemic.

Published
2021

6. Assess and validate predictive performance of models for in-hospital mortality in COVID-19 patients: A retrospective cohort study in the Netherlands comparing the value of registry data with high-granular electronic health records

Author

Vagliano, Iacopo, Schut, Martijn C., Abu-Hanna, Ameen, Dongelmans, Dave A., de Lange, Dylan W., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, de Jong, Remko, Peters, Marco A.A., Kamps, Marlijn J.A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G.C.A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G.M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P.C., Hendriks, Stefaan H.A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C.D., Reuland, M.C., Arbous, Sesmu, Fleuren, Lucas M., Dam, Tariq A., Thoral, Patrick J., Lalisang, Robbert C.A., Tonutti, Michele, de Bruin, Daan P., Elbers, Paul W.G., and de Keizer, Nicolette F.

Published
2022
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8. Predicting responders to prone positioning in mechanically ventilated patients with COVID-19 using machine learning

Author

Dam, Tariq A., Roggeveen, Luca F., van Diggelen, Fuda, Fleuren, Lucas M., Jagesar, Ameet R., Otten, Martijn, de Vries, Heder J., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco A. A., Kamps, Marlijn J. A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C. D., Arbous, Sesmu, Vonk, Sebastiaan J. J., Machado, Tomas, Herter, Willem E., de Grooth, Harm-Jan, Thoral, Patrick J., Girbes, Armand R. J., Hoogendoorn, Mark, and Elbers, Paul W. G.

Published
2022
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9. Large-scale ICU data sharing for global collaboration: the first 1633 critically ill COVID-19 patients in the Dutch Data Warehouse

Author

Fleuren, Lucas M., de Bruin, Daan P., Tonutti, Michele, Lalisang, Robbert C. A., Elbers, Paul W. G., Gommers, Diederik, and Cremer, Olaf L.

Subjects
Health care industry
Abstract

Author(s): Lucas M. Fleuren [sup.1], Daan P. de Bruin [sup.2], Michele Tonutti [sup.2], Robbert C. A. Lalisang [sup.2], Paul W. G. Elbers [sup.1], Diederik Gommers [sup.1], Olaf L. Cremer [sup.1], [...]

Published
2021
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10. Machine learning for the prediction of sepsis: a systematic review and meta-analysis of diagnostic test accuracy

Author

Fleuren, Lucas M., Klausch, Thomas L. T., Zwager, Charlotte L., Schoonmade, Linda J., Guo, Tingjie, Roggeveen, Luca F., and Swart, Eleonora L.

Subjects
Medical tests -- Analysis, Infection -- Analysis, Machine learning -- Analysis, Septic shock -- Analysis, Health care industry
Abstract

Purpose Early clinical recognition of sepsis can be challenging. With the advancement of machine learning, promising real-time models to predict sepsis have emerged. We assessed their performance by carrying out a systematic review and meta-analysis. Methods A systematic search was performed in PubMed, Embase.com and Scopus. Studies targeting sepsis, severe sepsis or septic shock in any hospital setting were eligible for inclusion. The index test was any supervised machine learning model for real-time prediction of these conditions. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, with a tailored Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist to evaluate risk of bias. Models with a reported area under the curve of the receiver operating characteristic (AUROC) metric were meta-analyzed to identify strongest contributors to model performance. Results After screening, a total of 28 papers were eligible for synthesis, from which 130 models were extracted. The majority of papers were developed in the intensive care unit (ICU, n = 15; 54%), followed by hospital wards (n = 7; 25%), the emergency department (ED, n = 4; 14%) and all of these settings (n = 2; 7%). For the prediction of sepsis, diagnostic test accuracy assessed by the AUROC ranged from 0.68-0.99 in the ICU, to 0.96-0.98 in-hospital and 0.87 to 0.97 in the ED. Varying sepsis definitions limit pooling of the performance across studies. Only three papers clinically implemented models with mixed results. In the multivariate analysis, temperature, lab values, and model type contributed most to model performance. Conclusion This systematic review and meta-analysis show that on retrospective data, individual machine learning models can accurately predict sepsis onset ahead of time. Although they present alternatives to traditional scoring systems, between-study heterogeneity limits the assessment of pooled results. Systematic reporting and clinical implementation studies are needed to bridge the gap between bytes and bedside., Author(s): Lucas M. Fleuren [sup.1] [sup.2], Thomas L. T. Klausch [sup.3], Charlotte L. Zwager [sup.1], Linda J. Schoonmade [sup.4], Tingjie Guo [sup.1], Luca F. Roggeveen [sup.1] [sup.2], Eleonora L. Swart [...]

Published
2020
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11. Racial Disparities in Pulse Oximetry, in COVID-19 and ICU Settings

Author

Reep, Carmen A.T., Fleuren, Lucas M., Heunks, Leo, Wils, Evert Jan, Reep, Carmen A.T., Fleuren, Lucas M., Heunks, Leo, and Wils, Evert Jan

Abstract

OBJECTIVES (BACKGROUND): This study aimed to assess the impact of race on pulse oximetry reliability, taking into account Spo2 ranges, COVID-19 diagnosis, and ICU admission. DESIGN: Retrospective cohort study covering admissions from January 2020 to April 2024. SETTING: National COVID Cohort Collaborative (N3C) database, consisting of electronic health records from 80 U.S. institutions.PATIENTS/SUBJECTS: Patients were selected from the N3C database based on the availability of data on self-identified race and both pulse oximetry estimated Spo2 and Sao2. Subgroups included patients in ICU and non-ICU settings, with or without a diagnosis of COVID-19 disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The agreement between Spo2 and Sao2 was assessed across racial groups (American Indian or Alaska Native, Asian, Black, Hispanic or Latino, Pacific Islander, and White). Each patient’s initial Sao2 measurement was matched with the closest Spo2 values recorded within the preceding 10-minute time frame. The risk of hidden hypoxemia (Spo2 ≥ 88% but Sao2 < 88%) was determined for various Spo2 ranges, races, and clinical scenarios. We used a generalized logistic mixed-effects model to evaluate the impact of relevant variables, such as COVID-19, ICU admission, age, sex, race, and Spo2, on the risk of hidden hypoxemia, while accounting for the random effects within each hospital. A total of 80,541 patients were included, consisting of 596 American Indian or Alaska Native, 2,729 Asian, 11,889 Black, 13,154 Hispanic or Latino, 221 Pacific Islander, and 51,952 White individuals. Discrepancies between Spo2 and Sao2 were observed across all racial groups, with the most pronounced bias in Black patients. Hidden hypoxemia rates were h

Published
2024

12. Predictors for extubation failure in COVID-19 patients using a machine learning approach

Author

Fleuren, Lucas M., Dam, Tariq A., Tonutti, Michele, de Bruin, Daan P., Lalisang, Robbert C. A., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco, Kamps, Marlijn J. A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C. D., Arbous, Sesmu, Vonk, Sebastiaan J. J., Fornasa, Mattia, Machado, Tomas, Houwert, Taco, Hovenkamp, Hidde, Noorduijn Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G., de Beer, Aletta A., Cinà, Giovanni, Kantorik, Adam, de Ruijter, Tom, Herter, Willem E., Beudel, Martijn, Girbes, Armand R. J., Hoogendoorn, Mark, Thoral, Patrick J., and Elbers, Paul W. G.

Published
2021
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13. The Dutch Data Warehouse, a multicenter and full-admission electronic health records database for critically ill COVID-19 patients

Author

Fleuren, Lucas M., Dam, Tariq A., Tonutti, Michele, de Bruin, Daan P., Lalisang, Robbert C. A., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco, Kamps, Marlijn J. A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C. D., Arbous, Sesmu, Vonk, Sebastiaan J. J., Fornasa, Mattia, Machado, Tomas, Houwert, Taco, Hovenkamp, Hidde, Noorduijn-Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G., de Beer, Aletta A., Cina, Giovanni, Beudel, Martijn, Herter, Willem E., Girbes, Armand R. J., Hoogendoorn, Mark, Thoral, Patrick J., and Elbers, Paul W. G.

Published
2021
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14. Some Patients Are More Equal Than Others: Variation in Ventilator Settings for Coronavirus Disease 2019 Acute Respiratory Distress Syndrome

Author

Dam, Tariq A., de Grooth, Harm-Jan, Klausch, Thomas, Fleuren, Lucas M., de Bruin, Daan P., Entjes, Robert, Rettig, Thijs C. D., Dongelmans, Dave A., Boelens, Age D., Rigter, Sander, Hendriks, Stefaan H. A., de Jong, Remko, Kamps, Marlijn J. A, Peters, Marco, Karakus, A., Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert-Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P. C., Nooteboom, Fleur G. C. A., Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D., Reidinga, Auke C., de Ruijter, Wouter, Bosman, Rob J., Frenzel, Tim, Urlings-Strop, Louise C., de Jong, Paul, Smit, Ellen G. M., Cremer, Olaf L., Mehagnoul-Schipper, D. Jannet, Faber, Harald J., Lens, Judith, Brunnekreef, Gert B., Festen-Spanjer, Barbara, Dormans, Tom, Dijkstra, Annemieke, Simons, Bram, Rijkeboer, A. A., Arbous, Sesmu, Aries, Marcel, Beukema, Menno, Pretorius, Daniël, van Raalte, Rutger, van Tellingen, Martijn, Gritters van den Oever, Niels C., Lalisang, Robbert C. A., Tonutti, Michele, Girbes, Armand R. J., Hoogendoorn, Mark, Thoral, Patrick J., and Elbers, Paul W. G.

Published
2021
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15. Machine learning in intensive care medicine: ready for take-off?

Author

Fleuren, Lucas M., Thoral, Patrick, Shillan, Duncan, Ercole, Ari, Elbers, Paul W. G., Hoogendoorn, Mark, and Gibbison, Ben

Subjects
United States. National Aeronautics and Space Administration, Space shuttles, Outer space -- Discovery and exploration, Machine learning, Health care industry
Abstract

Author(s): Lucas M. Fleuren [sup.1] [sup.2], Patrick Thoral [sup.1], Duncan Shillan [sup.3], Ari Ercole [sup.4] [sup.5], Paul W. G. Elbers [sup.1] [sup.5], Mark Hoogendoorn, Ben Gibbison, Thomas L. T. Klausch, [...]

Published
2020
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21. Evolution of Clinical Phenotypes of COVID-19 Patients During Intensive Care Treatment: An Unsupervised Machine Learning Analysis.

Author

Siepel, Sander, Dam, Tariq A., Fleuren, Lucas M., Girbes, Armand R.J., Hoogendoorn, Mark, Thoral, Patrick J., Elbers, Paul W.G., and Bennis, Frank C.

Subjects
COVID-19 pandemic, INTENSIVE care units, PHENOTYPES, MACHINE learning, CRITICALLY ill patient care
Abstract

Background: Identification of clinical phenotypes in critically ill COVID-19 patients could improve understanding of the disease heterogeneity and enable prognostic and predictive enrichment. However, previous attempts did not take into account temporal dynamics with high granularity. By including the dimension of time, we aim to gain further insights into the heterogeneity of COVID-19. Methods: We used granular data from 3202 adult COVID patients in the Dutch Data Warehouse that were admitted to one of 25 Dutch ICUs between February 2020 and March 2021. Parameters including demographics, clinical observations, medications, laboratory values, vital signs, and data from life support devices were selected. Twenty-one datasets were created that each covered 24 h of ICU data for each day of ICU treatment. Clinical phenotypes in each dataset were identified by performing cluster analyses. Both evolution of the clinical phenotypes over time and patient allocation to these clusters over time were tracked. Results: The final patient cohort consisted of 2438 COVID-19 patients with a ICU mortality outcome. Forty-one parameters were chosen for cluster analysis. On admission, both a mild and a severe clinical phenotype were found. After day 4, the severe phenotype split into an intermediate and a severe phenotype for 11 consecutive days. Heterogeneity between phenotypes appears to be driven by inflammation and dead space ventilation. During the 21-day period, only 8.2% and 4.6% of patients in the initial mild and severe clusters remained assigned to the same phenotype respectively. The clinical phenotype half-life was between 5 and 6 days for the mild and severe phenotypes, and about 3 days for the medium severe phenotype. Conclusions: Patients typically do not remain in the same cluster throughout intensive care treatment. This may have important implications for prognostic or predictive enrichment. Prominent dissimilarities between clinical phenotypes are predominantly driven by inflammation and dead space ventilation. [ABSTRACT FROM AUTHOR]

Published
2023
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22. Assess and validate predictive performance of models for in-hospital mortality in COVID-19 patients:A retrospective cohort study in the Netherlands comparing the value of registry data with high-granular electronic health records

Author

Vagliano, Iacopo, Schut, Martijn C., Abu-Hanna, Ameen, Dongelmans, Dave A., de Lange, Dylan W., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert Jan, Frenzel, Tim, de Jong, Remko, Peters, Marco A.A., Kamps, Marlijn J.A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G.C.A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G.M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P.C., Hendriks, Stefaan H.A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C.D., Reuland, M. C., Arbous, Sesmu, Fleuren, Lucas M., Dam, Tariq A., Thoral, Patrick J., Lalisang, Robbert C.A., Tonutti, Michele, de Bruin, Daan P., Elbers, Paul W.G., de Keizer, Nicolette F., Vagliano, Iacopo, Schut, Martijn C., Abu-Hanna, Ameen, Dongelmans, Dave A., de Lange, Dylan W., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert Jan, Frenzel, Tim, de Jong, Remko, Peters, Marco A.A., Kamps, Marlijn J.A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G.C.A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G.M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P.C., Hendriks, Stefaan H.A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C.D., Reuland, M. C., Arbous, Sesmu, Fleuren, Lucas M., Dam, Tariq A., Thoral, Patrick J., Lalisang, Robbert C.A., Tonutti, Michele, de Bruin, Daan P., Elbers, Paul W.G., and de Keizer, Nicolette F.

Abstract

Purpose: To assess, validate and compare the predictive performance of models for in-hospital mortality of COVID-19 patients admitted to the intensive care unit (ICU) over two different waves of infections. Our models were built with high-granular Electronic Health Records (EHR) data versus less-granular registry data. Methods: Observational study of all COVID-19 patients admitted to 19 Dutch ICUs participating in both the national quality registry National Intensive Care Evaluation (NICE) and the EHR-based Dutch Data Warehouse (hereafter EHR). Multiple models were developed on data from the first 24 h of ICU admissions from February to June 2020 (first COVID-19 wave) and validated on prospective patients admitted to the same ICUs between July and December 2020 (second COVID-19 wave). We assessed model discrimination, calibration, and the degree of relatedness between development and validation population. Coefficients were used to identify relevant risk factors. Results: A total of 1533 patients from the EHR and 1563 from the registry were included. With high granular EHR data, the average AUROC was 0.69 (standard deviation of 0.05) for the internal validation, and the AUROC was 0.75 for the temporal validation. The registry model achieved an average AUROC of 0.76 (standard deviation of 0.05) in the internal validation and 0.77 in the temporal validation. In the EHR data, age, and respiratory-system related variables were the most important risk factors identified. In the NICE registry data, age and chronic respiratory insufficiency were the most important risk factors. Conclusion: In our study, prognostic models built on less-granular but readily-available registry data had similar performance to models built on high-granular EHR data and showed similar transportability to a prospective COVID-19 population. Future research is needed to verify whether this finding can be confirmed for upcoming waves.

Published
2022

23. Rapid Evaluation of Coronavirus Illness Severity (RECOILS) in intensive care:Development and validation of a prognostic tool for in-hospital mortality

Author

Plečko, Drago, Bennett, Nicolas, Mårtensson, Johan, Dam, Tariq A., Entjes, Robert, Rettig, Thijs C.D., Dongelmans, Dave A., Boelens, Age D., Rigter, Sander, Hendriks, Stefaan H.A., de Jong, Remko, Kamps, Marlijn J.A., Peters, Marco, Karakus, Attila, Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P.C., Nooteboom, Fleur G.C.A., Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D., Reidinga, Auke C., de Ruijter, Wouter, Bosman, Rob J., Frenzel, Tim, Urlings-Strop, Louise C., de Jong, Paul, Smit, Ellen G.M., Cremer, Olaf L., Mehagnoul-Schipper, D. Jannet, Faber, Harald J., Lens, Judith, Brunnekreef, Gert B., Festen-Spanjer, Barbara, Dormans, Tom, de Bruin, Daan P., Lalisang, Robbert C.A., Vonk, Sebastiaan J.J., Haan, Martin E., Fleuren, Lucas M., Thoral, Patrick J., Elbers, Paul W.G., Bellomo, Rinaldo, Plečko, Drago, Bennett, Nicolas, Mårtensson, Johan, Dam, Tariq A., Entjes, Robert, Rettig, Thijs C.D., Dongelmans, Dave A., Boelens, Age D., Rigter, Sander, Hendriks, Stefaan H.A., de Jong, Remko, Kamps, Marlijn J.A., Peters, Marco, Karakus, Attila, Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P.C., Nooteboom, Fleur G.C.A., Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D., Reidinga, Auke C., de Ruijter, Wouter, Bosman, Rob J., Frenzel, Tim, Urlings-Strop, Louise C., de Jong, Paul, Smit, Ellen G.M., Cremer, Olaf L., Mehagnoul-Schipper, D. Jannet, Faber, Harald J., Lens, Judith, Brunnekreef, Gert B., Festen-Spanjer, Barbara, Dormans, Tom, de Bruin, Daan P., Lalisang, Robbert C.A., Vonk, Sebastiaan J.J., Haan, Martin E., Fleuren, Lucas M., Thoral, Patrick J., Elbers, Paul W.G., and Bellomo, Rinaldo

Abstract

Background: The prediction of in-hospital mortality for ICU patients with COVID-19 is fundamental to treatment and resource allocation. The main purpose was to develop an easily implemented score for such prediction. Methods: This was an observational, multicenter, development, and validation study on a national critical care dataset of COVID-19 patients. A systematic literature review was performed to determine variables possibly important for COVID-19 mortality prediction. Using a logistic multivariable model with a LASSO penalty, we developed the Rapid Evaluation of Coronavirus Illness Severity (RECOILS) score and compared its performance against published scores. Results: Our development (validation) cohort consisted of 1480 (937) adult patients from 14 (11) Dutch ICUs admitted between March 2020 and April 2021. Median age was 65 (65) years, 31% (26%) died in hospital, 74% (72%) were males, average length of ICU stay was 7.83 (10.25) days and average length of hospital stay was 15.90 (19.92) days. Age, platelets, PaO2/FiO2 ratio, pH, blood urea nitrogen, temperature, PaCO2, Glasgow Coma Scale (GCS) score measured within +/−24 h of ICU admission were used to develop the score. The AUROC of RECOILS score was 0.75 (CI 0.71–0.78) which was higher than that of any previously reported predictive scores (0.68 [CI 0.64–0.71], 0.61 [CI 0.58–0.66], 0.67 [CI 0.63–0.70], 0.70 [CI 0.67–0.74] for ISARIC 4C Mortality Score, SOFA, SAPS-III, and age, respectively). Conclusions: Using a large dataset from multiple Dutch ICUs, we developed a predictive score for mortality of COVID-19 patients admitted to ICU, which outperformed other predictive scores reported so far.

Published
2022

24. Rapid evaluation of Coronavirus Illness Severity (RECOILS) in intensive care: Development and validation of a prognostic tool for in-hospital mortality

Author

Medische Staf Intensive Care, Infection & Immunity, Plečko, Drago, Bennett, Nicolas, Mårtensson, Johan, Dam, Tariq A, Entjes, Robert, Rettig, Thijs C D, Dongelmans, Dave A, Boelens, Age D, Rigter, Sander, Hendriks, Stefaan H A, de Jong, Remko, Kamps, Marlijn J A, Peters, Marco, Karakus, Attila, Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert-Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P C, Nooteboom, Fleur G C A, Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D, Reidinga, Auke C, de Ruijter, Wouter, Bosman, Rob J, Frenzel, Tim, Urlings-Strop, Louise C, de Jong, Paul, Smit, Ellen G M, Cremer, Olaf L, Mehagnoul-Schipper, D Jannet, Faber, Harald J, Lens, Judith, Brunnekreef, Gert B, Festen-Spanjer, Barbara, Dormans, Tom, de Bruin, Daan P, Lalisang, Robbert C A, Vonk, Sebastiaan J J, Haan, Martin E, Fleuren, Lucas M, Thoral, Patrick J, Elbers, Paul W G, Bellomo, Rinaldo, Medische Staf Intensive Care, Infection & Immunity, Plečko, Drago, Bennett, Nicolas, Mårtensson, Johan, Dam, Tariq A, Entjes, Robert, Rettig, Thijs C D, Dongelmans, Dave A, Boelens, Age D, Rigter, Sander, Hendriks, Stefaan H A, de Jong, Remko, Kamps, Marlijn J A, Peters, Marco, Karakus, Attila, Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert-Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P C, Nooteboom, Fleur G C A, Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D, Reidinga, Auke C, de Ruijter, Wouter, Bosman, Rob J, Frenzel, Tim, Urlings-Strop, Louise C, de Jong, Paul, Smit, Ellen G M, Cremer, Olaf L, Mehagnoul-Schipper, D Jannet, Faber, Harald J, Lens, Judith, Brunnekreef, Gert B, Festen-Spanjer, Barbara, Dormans, Tom, de Bruin, Daan P, Lalisang, Robbert C A, Vonk, Sebastiaan J J, Haan, Martin E, Fleuren, Lucas M, Thoral, Patrick J, Elbers, Paul W G, and Bellomo, Rinaldo

Published
2022

25. Evolution of Clinical Phenotypes of COVID-19 Patients During Intensive Care Treatment: An Unsupervised Machine Learning Analysis

Author

Siepel, Sander, primary, Dam, Tariq A., additional, Fleuren, Lucas M., additional, Gommers, Diederik, additional, Cremer, Olaf L., additional, Bosman, Rob J., additional, Rigter, Sander, additional, Wils, Evert-Jan, additional, Frenzel, Tim, additional, Dongelmans, Dave A., additional, de Jong, Remko, additional, Peters, Marco, additional, Kamps, Marlijn J.A, additional, Ramnarain, Dharmanand, additional, Nowitzky, Ralph, additional, Nooteboom, Fleur G.C.A., additional, de Ruijter, Wouter, additional, Urlings-Strop, Louise C., additional, Smit, Ellen G.M., additional, Mehagnoul-Schipper, D. Jannet, additional, Dormans, Tom, additional, de Jager, Cornelis P.C., additional, Hendriks, Stefaan H.A., additional, Achterberg, Sefanja, additional, Oostdijk, Evelien, additional, Reidinga, Auke C., additional, Festen-Spanjer, Barbara, additional, Brunnekreef, Gert B., additional, Cornet, Alexander D., additional, Tempel, Walter van den, additional, Boelens, Age D., additional, Koetsier, Peter, additional, Lens, Judith, additional, Faber, Harald J., additional, Karakus, A., additional, Entjes, Robert, additional, de Jong, Paul, additional, Rettig, Thijs C.D., additional, Arbous, Sesmu, additional, Vonk, Sebastiaan J.J., additional, Machado, Tomas, additional, Herter, Willem E., additional, Girbes, Armand R.J., additional, Hoogendoorn, Mark, additional, Thoral, Patrick J., additional, Elbers, Paul W.G., additional, and Bennis, Frank C., additional

Published
2022
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26. Additional file 1 of Predicting responders to prone positioning in mechanically ventilated patients with COVID-19 using machine learning

Author

Dam, Tariq A., Roggeveen, Luca F., van Diggelen, Fuda, Fleuren, Lucas M., Jagesar, Ameet R., Otten, Martijn, de Vries, Heder J., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco A. A., Kamps, Marlijn J. A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C. D., Arbous, Sesmu, Vonk, Sebastiaan J. J., Machado, Tomas, Herter, Willem E., de Grooth, Harm-Jan, Thoral, Patrick J., Girbes, Armand R. J., Hoogendoorn, Mark, and Elbers, Paul W. G.

Abstract

Additional file 1: Table S1. Parameter bounds. Table S2. Parameter categories. Table S3. Feature derivations. Table S4. Included features. Table S5. Hyper parameter optimization. Table S6. Feature Importance Metrics. Table S7. Patient characteristics. Table S8. ROC AUC score. Table S9. F1-score. Table S10. Sensitivity Analysis Minimal Prone Duration. Table S11. Sensitivity Analysis Cut-off Values. Table S12. Ranked Feature Importance. Table S13. Feature Importance Values. Figure S1. PaO2/FiO2 ratio difference in mmHg over time after starting prone position. Prone positions which continued for longer than 24 hours were filtered out.

Published
2022
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27. Additional file 1 of Right dose, right now: bedside, real-time, data-driven, and personalised antibiotic dosing in critically ill patients with sepsis or septic shock—a two-centre randomised clinical trial

Author

Roggeveen, Luca F., Guo, Tingjie, Fleuren, Lucas M., Driessen, Ronald, Thoral, Patrick, van Hest, Reinier M., Mathot, Ron A. A., Swart, Eleonora L., de Grooth, Harm-Jan, van den Bogaard, Bas, Girbes, Armand R. J., Bosman, Rob J., and Elbers, Paul W. G.

Abstract

Additional file 1. Electronic supplementary material.

Published
2022
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28. Risk factors for adverse outcomes during mechanical ventilation of 1152 COVID-19 patients: a multicenter machine learning study with highly granular data from the Dutch Data Warehouse

Author

Fleuren, Lucas M., Tonutti, Michele, de Bruin, Daan P., Lalisang, Robbert C.A., Dam, Tariq A., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Vonk, Sebastiaan J.J., Fornasa, Mattia, Machado, Tomas, van der Meer, Nardo J.M., Rigter, Sander, Wils, Evert Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco, Kamps, Marlijn J.A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G.C.A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G.M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P.C., Hendriks, Stefaan H.A., Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert, Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Achterberg, Sefanja, Faber, Harald J., Karakus, A., Beukema, Menno, Entjes, Robert, de Jong, Paul, Houwert, Taco, Hovenkamp, Hidde, Noorduijn Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G., de Beer, Aletta A., Cinà, Giovanni, Beudel, Martijn, de Keizer, Nicolet F., Hoogendoorn, Mark, Girbes, Armand R.J., Herter, Willem E., Elbers, Paul W.G., Thoral, Patrick J., Rettig, Thijs C.D., Reuland, M. C., van Manen, Laura, Montenij, Leon, van Bommel, Jasper, van den Berg, Roy, van Geest, Ellen, Hana, Anisa, Boersma, W. G., van den Bogaard, B., Pickkers, Peter, van der Heiden, Pim, van Gemeren, Claudia C.W., Meinders, Arend Jan, de Bruin, Martha, Rademaker, Emma, van Osch, Frits H.M., de Kruif, Martijn, Schroten, Nicolas, Arnold, Klaas Sierk, Fijen, J. W., van Koesveld, Jacomar J.M., Simons, Koen S., Labout, Joost, van de Gaauw, Bart, Kuiper, Michael, Beishuizen, Albertus, Geutjes, Dennis, Lutisan, Johan, Grady, Bart P.X., van den Akker, Remko, Simons, Bram, Rijkeboer, A. A., Arbous, Sesmu, Aries, Marcel, van den Oever, Niels C.Gritters, van Tellingen, Martijn, Dijkstra, Annemieke, van Raalte, Rutger, Roggeveen, Luca, van Diggelen, Fuda, Hassouni, Ali el, Guzman, David Romero, Bhulai, Sandjai, Ouweneel, Dagmar, Driessen, Ronald, Peppink, Jan, de Grooth, H. J., Zijlstra, G. J., van Tienhoven, A. J., van der Heiden, Evelien, Spijkstra, Jan Jaap, van der Spoel, Hans, de Man, Angelique, Klausch, Thomas, de Vries, Heder, de Neree tot Babberich, Michael, Thijssens, Olivier, Wagemakers, Lot, van der Pol, Hilde G.A., Hendriks, Tom, Berend, Julie, Silva, Virginia Ceni, Kullberg, Bob, Heunks, Leo, Juffermans, Nicole, Slooter, Arjan, Intensive care medicine, ACS - Diabetes & metabolism, ACS - Microcirculation, Amsterdam Cardiovascular Sciences, Neurology, AII - Infectious diseases, AII - Cancer immunology, CCA - Cancer biology and immunology, AII - Inflammatory diseases, Epidemiology and Data Science, APH - Methodology, ACS - Pulmonary hypertension & thrombosis, Intensive Care Medicine, APH - Quality of Care, Medical Informatics, Graduate School, Nephrology, Cardiology, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, APH - Digital Health, Artificial intelligence, Network Institute, Computational Intelligence, Artificial Intelligence (section level), Mathematics, Intensive Care, Epidemiologie, RS: NUTRIM - R3 - Respiratory & Age-related Health, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Medische Staf IC (9), and Internal medicine

Subjects
Icu patients, Coronavirus disease 2019 (COVID-19), Adverse outcomes, medicine.medical_treatment, Critical Care and Intensive Care Medicine, Machine learning, computer.software_genre, law.invention, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, law, SCORE, medicine, 030212 general & internal medicine, Risk factor, Research Articles, Mechanical ventilation, business.industry, RC86-88.9, Other Research Radboud Institute for Health Sciences [Radboudumc 0], COVID-19, 030208 emergency & critical care medicine, Medical emergencies. Critical care. Intensive care. First aid, Intensive care unit, Data warehouse, Data extraction, Mortality prediction, Risk factors, Artificial intelligence, business, computer
Abstract

Background The identification of risk factors for adverse outcomes and prolonged intensive care unit (ICU) stay in COVID-19 patients is essential for prognostication, determining treatment intensity, and resource allocation. Previous studies have determined risk factors on admission only, and included a limited number of predictors. Therefore, using data from the highly granular and multicenter Dutch Data Warehouse, we developed machine learning models to identify risk factors for ICU mortality, ventilator-free days and ICU-free days during the course of invasive mechanical ventilation (IMV) in COVID-19 patients. Methods The DDW is a growing electronic health record database of critically ill COVID-19 patients in the Netherlands. All adult ICU patients on IMV were eligible for inclusion. Transfers, patients admitted for less than 24 h, and patients still admitted at time of data extraction were excluded. Predictors were selected based on the literature, and included medication dosage and fluid balance. Multiple algorithms were trained and validated on up to three sets of observations per patient on day 1, 7, and 14 using fivefold nested cross-validation, keeping observations from an individual patient in the same split. Results A total of 1152 patients were included in the model. XGBoost models performed best for all outcomes and were used to calculate predictor importance. Using Shapley additive explanations (SHAP), age was the most important demographic risk factor for the outcomes upon start of IMV and throughout its course. The relative probability of death across age values is visualized in Partial Dependence Plots (PDPs), with an increase starting at 54 years. Besides age, acidaemia, low P/F-ratios and high driving pressures demonstrated a higher probability of death. The PDP for driving pressure showed a relative probability increase starting at 12 cmH2O. Conclusion Age is the most important demographic risk factor of ICU mortality, ICU-free days and ventilator-free days throughout the course of invasive mechanical ventilation in critically ill COVID-19 patients. pH, P/F ratio, and driving pressure should be monitored closely over the course of mechanical ventilation as risk factors predictive of these outcomes.

Published
2021
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29. Rapid Evaluation of Coronavirus Illness Severity (RECOILS) in intensive care: Development and validation of a prognostic tool for in‐hospital mortality

Author

Plečko, Drago, primary, Bennett, Nicolas, additional, Mårtensson, Johan, additional, Dam, Tariq A., additional, Entjes, Robert, additional, Rettig, Thijs C. D., additional, Dongelmans, Dave A., additional, Boelens, Age D., additional, Rigter, Sander, additional, Hendriks, Stefaan H. A., additional, de Jong, Remko, additional, Kamps, Marlijn J. A., additional, Peters, Marco, additional, Karakus, Attila, additional, Gommers, Diederik, additional, Ramnarain, Dharmanand, additional, Wils, Evert‐Jan, additional, Achterberg, Sefanja, additional, Nowitzky, Ralph, additional, van den Tempel, Walter, additional, de Jager, Cornelis P. C., additional, Nooteboom, Fleur G. C. A., additional, Oostdijk, Evelien, additional, Koetsier, Peter, additional, Cornet, Alexander D., additional, Reidinga, Auke C., additional, de Ruijter, Wouter, additional, Bosman, Rob J., additional, Frenzel, Tim, additional, Urlings‐Strop, Louise C., additional, de Jong, Paul, additional, Smit, Ellen G.M., additional, Cremer, Olaf L., additional, Mehagnoul‐Schipper, D. Jannet, additional, Faber, Harald J., additional, Lens, Judith, additional, Brunnekreef, Gert B., additional, Festen‐Spanjer, Barbara, additional, Dormans, Tom, additional, de Bruin, Daan P., additional, Lalisang, Robbert C. A., additional, Vonk, Sebastiaan J. J., additional, Haan, Martin E., additional, Fleuren, Lucas M., additional, Thoral, Patrick J., additional, Elbers, Paul W. G., additional, and Bellomo, Rinaldo, additional

Published
2021
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30. Klinisch beloop van covid-19 in Nederland: Een overzicht van 2607 ziekenhuispatiënten uit de eerste golf

Author

Ariës, Marcel J H, van den Bergh, Joop P, Beudel, Martijn, Boersma, Wim, Dormans, Tom, Douma, Renee A, Eerens, Annet, Elbers, Paul W G, Fleuren, Lucas M, Gritters van den Oever, Niels C, de Haan, Lianne, van der Horst, Iwan J C C, Hu, Shi, Hubers, Deborah, Janssen, Marcus L F, de Kruif, Martijn, Kubben, Pieter L, van Kuijk, Sander M J, Noordzij, Peter G, Ottenhoff, Maarten, Piña-Fuentes, Dan A I, Potters, Wouter V, Reidinga, Auke C, Renckens, Roos S C, Rigter, Sander, Rusch, Daisy, Schinkel, Michiel, Sigaloff, Kim C E, Simsek, Suat, Stassen, Patricia, Stassen, Robert, Thomas, Rajat M, van Wingen, Guido A, Vonk Noordegraaf, Anton, Welling, Max, Wiersinga, W Joost, Wolvers, Marije D J, Wyers, Caroline E, Intensive Care, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Medische Staf IC (9), MUMC+: MA Intensive Care (3), RS: Carim - V04 Surgical intervention, Klinische Neurowetenschappen, MUMC+: HZC Med Staf Spec Klinische Neurofys (9), RS: MHeNs - R3 - Neuroscience, Neurochirurgie, MUMC+: MA Med Staf Spec Neurochirurgie (9), MUMC+: KIO Kemta (9), Epidemiologie, RS: CAPHRI - R2 - Creating Value-Based Health Care, RS: CAPHRI - R5 - Optimising Patient Care, MUMC+: MA Alg Interne Geneeskunde (9), Interne Geneeskunde, and Family Medicine

Subjects
Male, Cardiovascular Diseases/epidemiology, SARS-CoV-2/isolation & purification, Age Factors, Critical Care/methods, Netherlands/epidemiology, Comorbidity, Kaplan-Meier Estimate, Severity of Illness Index, Risk Factors, Humans, Diagnostic Tests, Routine/methods, Female, Hospital Mortality, Aged, COVID-19/epidemiology
Abstract

OBJECTIVE: To systematically collect clinical data from patients with a proven COVID-19 infection in the Netherlands. DESIGN: Data from 2579 patients with COVID-19 admitted to 10 Dutch centers in the period February to July 2020 are described. The clinical data are based on the WHO COVID case record form (CRF) and supplemented with patient characteristics of which recently an association disease severity has been reported. METHODS: Survival analyses were performed as primary statistical analysis. These Kaplan-Meier curves for time to (early) death (3 weeks) have been determined for pre-morbid patient characteristics and clinical, radiological and laboratory data at hospital admission. RESULTS: Total in-hospital mortality after 3 weeks was 22.2% (95% CI: 20.7% - 23.9%), hospital mortality within 21 days was significantly higher for elderly patients (> 70 years; 35, 0% (95% CI: 32.4% - 37.8%) and patients who died during the 21 days and were admitted to the intensive care (36.5% (95% CI: 32.1% - 41.3%)). Apart from that, in this Dutch population we also see a risk of early death in patients with co-morbidities (such as chronic neurological, nephrological and cardiac disorders and hypertension), and in patients with more home medication and / or with increased urea and creatinine levels. CONCLUSION: Early death due to a COVID-19 infection in the Netherlands appears to be associated with demographic variables (e.g. age), comorbidity (e.g. cardiovascular disease) but also disease char-acteristics at admission.

Published
2021

31. Additional file 1 of Risk factors for adverse outcomes during mechanical ventilation of 1152 COVID-19 patients: a multicenter machine learning study with highly granular data from the Dutch Data Warehouse

Author

Fleuren, Lucas M., Tonutti, Michele, de Bruin, Daan P., Lalisang, Robbert C. A., Dam, Tariq A., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Vonk, Sebastiaan J. J., Fornasa, Mattia, Machado, Tomas, van der Meer, Nardo J. M., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco, Kamps, Marlijn J. A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert, Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Achterberg, Sefanja, Faber, Harald J., Karakus, A., Beukema, Menno, Entjes, Robert, de Jong, Paul, Houwert, Taco, Hovenkamp, Hidde, Noorduijn Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G., de Beer, Aletta A., Cinà, Giovanni, Beudel, Martijn, de Keizer, Nicolet F., Hoogendoorn, Mark, Girbes, Armand R. J., Herter, Willem E., Elbers, Paul W. G., and Thoral, Patrick J.

Abstract

Additional file 1: Figure S1. Patient selection. Figure S2. Selection of observations throughout the course of IMV. Figure S3. Nested cross-validation. Figure S4. Importance of the top 10 predictors for the prediction of ventilator free days, as well as the difference for predictors over time. Figure S5. SHAP plot ICU mortality (XGBoost). Figure S6. SHAP plot for ICU free days (XGBoost). Figure S7. SHAP plot for ventilator free days (XGBoost). Figure S8. PDPs. Table S1. Overview of all predictors used in the model with a definition where applicable. Table S2. Overall algorithm performance for each of the different outcomes. Table S3. Statistical results for a regression model per outcome. Table S4. Predictor correlations.

Published
2021
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32. Additional file 3 of The Dutch Data Warehouse, a multicenter and full-admission electronic health records database for critically ill COVID-19 patients

Author

Fleuren, Lucas M., Dam, Tariq A., Tonutti, Michele, de Bruin, Daan P., Lalisang, Robbert C. A., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco, Kamps, Marlijn J. A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C. D., Arbous, Sesmu, Vonk, Sebastiaan J. J., Fornasa, Mattia, Machado, Tomas, Houwert, Taco, Hovenkamp, Hidde, Noorduijn-Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G., de Beer, Aletta A., Cina, Giovanni, Beudel, Martijn, Herter, Willem E., Girbes, Armand R. J., Hoogendoorn, Mark, Thoral, Patrick J., and Elbers, Paul W. G.

Abstract

Additional file 3: Table S1. Overview of derived clinical score.

Published
2021
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33. Additional file 1 of Predictors for extubation failure in COVID-19 patients using a machine learning approach

Author

Fleuren, Lucas M., Dam, Tariq A., Tonutti, Michele, de Bruin, Daan P., Lalisang, Robbert C. A., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco, Kamps, Marlijn J. A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C. D., Arbous, Sesmu, Vonk, Sebastiaan J. J., Fornasa, Mattia, Machado, Tomas, Houwert, Taco, Hovenkamp, Hidde, Noorduijn Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G., de Beer, Aletta A., Cin��, Giovanni, Kantorik, Adam, de Ruijter, Tom, Herter, Willem E., Beudel, Martijn, Girbes, Armand R. J., Hoogendoorn, Mark, Thoral, Patrick J., and Elbers, Paul W. G.

Abstract

Additional file 1. Table S1 Overview of machine learning studies that investigate extubation readiness. Table S2 Model performance. Figure S1 PD-plot for BMI

Published
2021
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34. Integrating Expert ODEs into Neural ODEs:Pharmacology and Disease Progression

Author

Qian, Zhaozhi, Zame, William R., Fleuren, Lucas M., Elbers, Paul, van der Schaar, Mihaela, Ranzato, Marc'Aurelio, Beygelzimer, Alina, Dauphin, Yann, Liang, Percy S., and Wortman Vaughan, Jenn

Abstract

Modeling a system's temporal behaviour in reaction to external stimuli is a fundamental problem in many areas. Pure Machine Learning (ML) approaches often fail in the small sample regime and cannot provide actionable insights beyond predictions. A promising modification has been to incorporate expert domain knowledge into ML models. The application we consider is predicting the patient health status and disease progression over time, where a wealth of domain knowledge is available from pharmacology. Pharmacological models describe the dynamics of carefully-chosen medically meaningful variables in terms of systems of Ordinary Differential Equations (ODEs). However, these models only describe a limited collection of variables, and these variables are often not observable in clinical environments. To close this gap, we propose the latent hybridisation model (LHM) that integrates a system of expert-designed ODEs with machine-learned Neural ODEs to fully describe the dynamics of the system and to link the expert and latent variables to observable quantities. We evaluated LHM on synthetic data as well as real-world intensive care data of COVID-19 patients. LHM consistently outperforms previous works, especially when few training samples are available such as at the beginning of the pandemic.

Published
2021

35. Additional file 2 of The Dutch Data Warehouse, a multicenter and full-admission electronic health records database for critically ill COVID-19 patients

Author

Fleuren, Lucas M., Dam, Tariq A., Tonutti, Michele, de Bruin, Daan P., Lalisang, Robbert C. A., Gommers, Diederik, Cremer, Olaf L., Bosman, Rob J., Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A., de Jong, Remko, Peters, Marco, Kamps, Marlijn J. A., Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G. C. A., de Ruijter, Wouter, Urlings-Strop, Louise C., Smit, Ellen G. M., Mehagnoul-Schipper, D. Jannet, Dormans, Tom, de Jager, Cornelis P. C., Hendriks, Stefaan H. A., Achterberg, Sefanja, Oostdijk, Evelien, Reidinga, Auke C., Festen-Spanjer, Barbara, Brunnekreef, Gert B., Cornet, Alexander D., van den Tempel, Walter, Boelens, Age D., Koetsier, Peter, Lens, Judith, Faber, Harald J., Karakus, A., Entjes, Robert, de Jong, Paul, Rettig, Thijs C. D., Arbous, Sesmu, Vonk, Sebastiaan J. J., Fornasa, Mattia, Machado, Tomas, Houwert, Taco, Hovenkamp, Hidde, Noorduijn-Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G., de Beer, Aletta A., Cina, Giovanni, Beudel, Martijn, Herter, Willem E., Girbes, Armand R. J., Hoogendoorn, Mark, Thoral, Patrick J., and Elbers, Paul W. G.

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Data_FILES
Abstract

Additional file 2. Institutional review board documentation.

Published
2021
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36. Predicting mortality of individual patients with COVID-19: a multicentre Dutch cohort

Author

Ottenhoff, Maarten C, primary, Ramos, Lucas A, additional, Potters, Wouter, additional, Janssen, Marcus L F, additional, Hubers, Deborah, additional, Hu, Shi, additional, Fridgeirsson, Egill A, additional, Piña-Fuentes, Dan, additional, Thomas, Rajat, additional, van der Horst, Iwan C C, additional, Herff, Christian, additional, Kubben, Pieter, additional, Elbers, Paul W G, additional, Marquering, Henk A, additional, Welling, Max, additional, Simsek, Suat, additional, de Kruif, Martijn D, additional, Dormans, Tom, additional, Fleuren, Lucas M, additional, Schinkel, Michiel, additional, Noordzij, Peter G, additional, van den Bergh, Joop P, additional, Wyers, Caroline E, additional, Buis, David T B, additional, Wiersinga, W Joost, additional, van den Hout, Ella H C, additional, Reidinga, Auke C, additional, Rusch, Daisy, additional, Sigaloff, Kim C E, additional, Douma, Renee A, additional, de Haan, Lianne, additional, Gritters van den Oever, Niels C, additional, Rennenberg, Roger J M W, additional, van Wingen, Guido A, additional, Aries, Marcel J H, additional, and Beudel, Martijn, additional

Published
2021
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37. Machine learning in intensive care medicine: ready for take-off?

Author

Fleuren, Lucas M, Thoral, Patrick, Shillan, Duncan, Ercole, Ari, Elbers, Paul WG, Right Data Right Now Collaborators, Ercole, Ari [0000-0001-8350-8093], and Apollo - University of Cambridge Repository

Subjects
Machine Learning, Intensive Care Units, Critical Care, Humans, Medicine
Abstract

In 1986 the world was shaken by the Challenger space shuttle disaster. In the years that followed, the American National Aeronautics and Space Administration (NASA) called for a strategy change in space technology development [1]. Allowing technology to be developed without a specific space program in mind was central to the new strategy [2]. In order to evaluate resulting projects with no direct contribution to a space mission, NASA introduced the general concept of technology readiness levels (TRLs) [3]. These nine levels, adopted by many EU institutions, assess the maturity level of technology and estimate its readiness to fly.

Published
2020

38. Some Patients Are More Equal Than Others: Variation in Ventilator Settings for Coronavirus Disease 2019 Acute Respiratory Distress Syndrome

Author

Dam, Tariq A, Dam, Tariq A, de Grooth, Harm-Jan, Klausch, Thomas, Fleuren, Lucas M, de Bruin, Daan P, Entjes, Robert, Rettig, Thijs C D, Dongelmans, Dave A, Boelens, Age D, Rigter, Sander, Hendriks, Stefaan H A, de Jong, Remko, Kamps, Marlijn J A, Peters, Marco, Karakus, A, Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert-Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P C, Nooteboom, Fleur G C A, Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D, Reidinga, Auke C, de Ruijter, Wouter, Bosman, Rob J, Frenzel, Tim, Urlings-Strop, Louise C, de Jong, Paul, Smit, Ellen G M, Cremer, Olaf L, Mehagnoul-Schipper, D Jannet, Faber, Harald J, Lens, Judith, Brunnekreef, Gert B, Festen-Spanjer, Barbara, Dormans, Tom, Dijkstra, Annemieke, Simons, Bram, Rijkeboer, A A, Arbous, Sesmu, Aries, Marcel, Beukema, Menno, Pretorius, Daniël, van Raalte, Rutger, van Tellingen, Martijn, Gritters van den Oever, Niels C, Lalisang, Robbert C A, Tonutti, Michele, Girbes, Armand R J, Hoogendoorn, Mark, Thoral, Patrick J, Elbers, Paul W G, Dam, Tariq A, Dam, Tariq A, de Grooth, Harm-Jan, Klausch, Thomas, Fleuren, Lucas M, de Bruin, Daan P, Entjes, Robert, Rettig, Thijs C D, Dongelmans, Dave A, Boelens, Age D, Rigter, Sander, Hendriks, Stefaan H A, de Jong, Remko, Kamps, Marlijn J A, Peters, Marco, Karakus, A, Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert-Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P C, Nooteboom, Fleur G C A, Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D, Reidinga, Auke C, de Ruijter, Wouter, Bosman, Rob J, Frenzel, Tim, Urlings-Strop, Louise C, de Jong, Paul, Smit, Ellen G M, Cremer, Olaf L, Mehagnoul-Schipper, D Jannet, Faber, Harald J, Lens, Judith, Brunnekreef, Gert B, Festen-Spanjer, Barbara, Dormans, Tom, Dijkstra, Annemieke, Simons, Bram, Rijkeboer, A A, Arbous, Sesmu, Aries, Marcel, Beukema, Menno, Pretorius, Daniël, van Raalte, Rutger, van Tellingen, Martijn, Gritters van den Oever, Niels C, Lalisang, Robbert C A, Tonutti, Michele, Girbes, Armand R J, Hoogendoorn, Mark, Thoral, Patrick J, and Elbers, Paul W G

Abstract

OBJECTIVES: As coronavirus disease 2019 is a novel disease, treatment strategies continue to be debated. This provides the intensive care community with a unique opportunity as the population of coronavirus disease 2019 patients requiring invasive mechanical ventilation is relatively homogeneous compared with other ICU populations. We hypothesize that the novelty of coronavirus disease 2019 and the uncertainty over its similarity with noncoronavirus disease 2019 acute respiratory distress syndrome resulted in substantial practice variation between hospitals during the first and second waves of coronavirus disease 2019 patients.DESIGN: Multicenter retrospective cohort study.SETTING: Twenty-five hospitals in the Netherlands from February 2020 to July 2020, and 14 hospitals from August 2020 to December 2020.PATIENTS: One thousand two hundred ninety-four critically ill intubated adult ICU patients with coronavirus disease 2019 were selected from the Dutch Data Warehouse. Patients intubated for less than 24 hours, transferred patients, and patients still admitted at the time of data extraction were excluded.MEASUREMENTS AND MAIN RESULTS: We aimed to estimate between-ICU practice variation in selected ventilation parameters (positive end-expiratory pressure, Fio2, set respiratory rate, tidal volume, minute volume, and percentage of time spent in a prone position) on days 1, 2, 3, and 7 of intubation, adjusted for patient characteristics as well as severity of illness based on Pao2/Fio2 ratio, pH, ventilatory ratio, and dynamic respiratory system compliance during controlled ventilation. Using multilevel linear mixed-effects modeling, we found significant (p ≤ 0.001) variation between ICUs in all ventilation parameters on days 1, 2, 3, and 7 of intubation for both waves.CONCLUSIONS: This is the first study to clearly demonstrate significant practice variation between ICUs related to mechanical ventilation parameters that are under dire

Published
2021

39. Risk factors for adverse outcomes during mechanical ventilation of 1152 COVID-19 patients:a multicenter machine learning study with highly granular data from the Dutch Data Warehouse

Author

Fleuren, Lucas M, Tonutti, Michele, de Bruin, Daan P, Lalisang, Robbert C A, Dam, Tariq A, Gommers, Diederik, Cremer, Olaf L, Bosman, Rob J, Vonk, Sebastiaan J J, Fornasa, Mattia, Machado, Tomas, van der Meer, Nardo J M, Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A, de Jong, Remko, Peters, Marco, Kamps, Marlijn J A, Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G C A, de Ruijter, Wouter, Urlings-Strop, Louise C, Smit, Ellen G M, Mehagnoul-Schipper, D Jannet, Dormans, Tom, de Jager, Cornelis P C, Hendriks, Stefaan H A, Oostdijk, Evelien, Reidinga, Auke C, Festen-Spanjer, Barbara, Brunnekreef, Gert, Cornet, Alexander D, van den Tempel, Walter, Boelens, Age D, Koetsier, Peter, Lens, Judith, Achterberg, Sefanja, Faber, Harald J, Karakus, A, Beukema, Menno, Entjes, Robert, de Jong, Paul, Houwert, Taco, Hovenkamp, Hidde, Noorduijn Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G, de Beer, Aletta A, Fleuren, Lucas M, Tonutti, Michele, de Bruin, Daan P, Lalisang, Robbert C A, Dam, Tariq A, Gommers, Diederik, Cremer, Olaf L, Bosman, Rob J, Vonk, Sebastiaan J J, Fornasa, Mattia, Machado, Tomas, van der Meer, Nardo J M, Rigter, Sander, Wils, Evert-Jan, Frenzel, Tim, Dongelmans, Dave A, de Jong, Remko, Peters, Marco, Kamps, Marlijn J A, Ramnarain, Dharmanand, Nowitzky, Ralph, Nooteboom, Fleur G C A, de Ruijter, Wouter, Urlings-Strop, Louise C, Smit, Ellen G M, Mehagnoul-Schipper, D Jannet, Dormans, Tom, de Jager, Cornelis P C, Hendriks, Stefaan H A, Oostdijk, Evelien, Reidinga, Auke C, Festen-Spanjer, Barbara, Brunnekreef, Gert, Cornet, Alexander D, van den Tempel, Walter, Boelens, Age D, Koetsier, Peter, Lens, Judith, Achterberg, Sefanja, Faber, Harald J, Karakus, A, Beukema, Menno, Entjes, Robert, de Jong, Paul, Houwert, Taco, Hovenkamp, Hidde, Noorduijn Londono, Roberto, Quintarelli, Davide, Scholtemeijer, Martijn G, and de Beer, Aletta A

Abstract

BACKGROUND: The identification of risk factors for adverse outcomes and prolonged intensive care unit (ICU) stay in COVID-19 patients is essential for prognostication, determining treatment intensity, and resource allocation. Previous studies have determined risk factors on admission only, and included a limited number of predictors. Therefore, using data from the highly granular and multicenter Dutch Data Warehouse, we developed machine learning models to identify risk factors for ICU mortality, ventilator-free days and ICU-free days during the course of invasive mechanical ventilation (IMV) in COVID-19 patients.METHODS: The DDW is a growing electronic health record database of critically ill COVID-19 patients in the Netherlands. All adult ICU patients on IMV were eligible for inclusion. Transfers, patients admitted for less than 24 h, and patients still admitted at time of data extraction were excluded. Predictors were selected based on the literature, and included medication dosage and fluid balance. Multiple algorithms were trained and validated on up to three sets of observations per patient on day 1, 7, and 14 using fivefold nested cross-validation, keeping observations from an individual patient in the same split.RESULTS: A total of 1152 patients were included in the model. XGBoost models performed best for all outcomes and were used to calculate predictor importance. Using Shapley additive explanations (SHAP), age was the most important demographic risk factor for the outcomes upon start of IMV and throughout its course. The relative probability of death across age values is visualized in Partial Dependence Plots (PDPs), with an increase starting at 54 years. Besides age, acidaemia, low P/F-ratios and high driving pressures demonstrated a higher probability of death. The PDP for driving pressure showed a relative probability increase starting at 12 cmH2O.CONCLUSION: Age is the most important demographic risk factor of ICU mortality, I

Published
2021

40. Some Patients Are More Equal Than Others:Variation in Ventilator Settings for Coronavirus Disease 2019 Acute Respiratory Distress Syndrome

Author

Dam, Tariq A, de Grooth, Harm-Jan, Klausch, Thomas, Fleuren, Lucas M, de Bruin, Daan P, Entjes, Robert, Rettig, Thijs C D, Dongelmans, Dave A, Boelens, Age D, Rigter, Sander, Hendriks, Stefaan H A, de Jong, Remko, Kamps, Marlijn J A, Peters, Marco, Karakus, A, Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert-Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P C, Nooteboom, Fleur G C A, Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D, Reidinga, Auke C, de Ruijter, Wouter, Bosman, Rob J, Frenzel, Tim, Urlings-Strop, Louise C, de Jong, Paul, Smit, Ellen G M, Cremer, Olaf L, Mehagnoul-Schipper, D Jannet, Faber, Harald J, Lens, Judith, Brunnekreef, Gert B, Festen-Spanjer, Barbara, Dormans, Tom, Dijkstra, Annemieke, Simons, Bram, Rijkeboer, A A, Arbous, Sesmu, Aries, Marcel, Beukema, Menno, Pretorius, Daniël, van Raalte, Rutger, van Tellingen, Martijn, Gritters van den Oever, Niels C, Lalisang, Robbert C A, Tonutti, Michele, Girbes, Armand R J, Hoogendoorn, Mark, Thoral, Patrick J, Elbers, Paul W G, Dam, Tariq A, de Grooth, Harm-Jan, Klausch, Thomas, Fleuren, Lucas M, de Bruin, Daan P, Entjes, Robert, Rettig, Thijs C D, Dongelmans, Dave A, Boelens, Age D, Rigter, Sander, Hendriks, Stefaan H A, de Jong, Remko, Kamps, Marlijn J A, Peters, Marco, Karakus, A, Gommers, Diederik, Ramnarain, Dharmanand, Wils, Evert-Jan, Achterberg, Sefanja, Nowitzky, Ralph, van den Tempel, Walter, de Jager, Cornelis P C, Nooteboom, Fleur G C A, Oostdijk, Evelien, Koetsier, Peter, Cornet, Alexander D, Reidinga, Auke C, de Ruijter, Wouter, Bosman, Rob J, Frenzel, Tim, Urlings-Strop, Louise C, de Jong, Paul, Smit, Ellen G M, Cremer, Olaf L, Mehagnoul-Schipper, D Jannet, Faber, Harald J, Lens, Judith, Brunnekreef, Gert B, Festen-Spanjer, Barbara, Dormans, Tom, Dijkstra, Annemieke, Simons, Bram, Rijkeboer, A A, Arbous, Sesmu, Aries, Marcel, Beukema, Menno, Pretorius, Daniël, van Raalte, Rutger, van Tellingen, Martijn, Gritters van den Oever, Niels C, Lalisang, Robbert C A, Tonutti, Michele, Girbes, Armand R J, Hoogendoorn, Mark, Thoral, Patrick J, and Elbers, Paul W G

Abstract

OBJECTIVES: As coronavirus disease 2019 is a novel disease, treatment strategies continue to be debated. This provides the intensive care community with a unique opportunity as the population of coronavirus disease 2019 patients requiring invasive mechanical ventilation is relatively homogeneous compared with other ICU populations. We hypothesize that the novelty of coronavirus disease 2019 and the uncertainty over its similarity with noncoronavirus disease 2019 acute respiratory distress syndrome resulted in substantial practice variation between hospitals during the first and second waves of coronavirus disease 2019 patients.DESIGN: Multicenter retrospective cohort study.SETTING: Twenty-five hospitals in the Netherlands from February 2020 to July 2020, and 14 hospitals from August 2020 to December 2020.PATIENTS: One thousand two hundred ninety-four critically ill intubated adult ICU patients with coronavirus disease 2019 were selected from the Dutch Data Warehouse. Patients intubated for less than 24 hours, transferred patients, and patients still admitted at the time of data extraction were excluded.MEASUREMENTS AND MAIN RESULTS: We aimed to estimate between-ICU practice variation in selected ventilation parameters (positive end-expiratory pressure, Fio2, set respiratory rate, tidal volume, minute volume, and percentage of time spent in a prone position) on days 1, 2, 3, and 7 of intubation, adjusted for patient characteristics as well as severity of illness based on Pao2/Fio2 ratio, pH, ventilatory ratio, and dynamic respiratory system compliance during controlled ventilation. Using multilevel linear mixed-effects modeling, we found significant (p ≤ 0.001) variation between ICUs in all ventilation parameters on days 1, 2, 3, and 7 of intubation for both waves.CONCLUSIONS: This is the first study to clearly demonstrate significant practice variation between ICUs related to mechanical ventilation parameters that are under dire

Published
2021

41. Large-scale ICU data sharing for global collaboration: the first 1633 critically ill COVID-19 patients in the Dutch Data Warehouse

Author

Infection & Immunity, Medische Staf Intensive Care, Epi Infectieziekten Team 1, Brain, Fleuren, Lucas M, de Bruin, Daan P, Tonutti, Michele, Lalisang, Robbert C A, Elbers, Paul W G, Dutch ICU Data Sharing Collaborators, Infection & Immunity, Medische Staf Intensive Care, Epi Infectieziekten Team 1, Brain, Fleuren, Lucas M, de Bruin, Daan P, Tonutti, Michele, Lalisang, Robbert C A, Elbers, Paul W G, and Dutch ICU Data Sharing Collaborators

Published
2021

42. Pooled Population Pharmacokinetic Analysis for Exploring Ciprofloxacin Pharmacokinetic Variability in Intensive Care Patients.

Author

Guo, Tingjie, Abdulla, Alan, Koch, Birgit C. P., van Hasselt, Johan G. C., Endeman, Henrik, Schouten, Jeroen A., Elbers, Paul W. G., Brüggemann, Roger J. M., van Hest, Reinier M., the Dutch Antibiotic PK/PD Collaborators, Roggeveen, Luca F, Fleuren, Lucas M., Hunfeld, Nicole G. M., Ewoldt, Tim M. J., Muller, Anouk E., Dijkstra, Annemieke, de Lange, Dylan W., Gieling, Emilie, Pickkers, Peter, and ten Oever, Jaap

Subjects
CIPROFLOXACIN, INTENSIVE care patients, PHARMACOKINETICS, GLOMERULAR filtration rate, INTRAVENOUS therapy, PSEUDOMONAS aeruginosa
Abstract

Background and Objective: Previous pharmacokinetic (PK) studies of ciprofloxacin in intensive care (ICU) patients have shown large differences in estimated PK parameters, suggesting that further investigation is needed for this population. Hence, we performed a pooled population PK analysis of ciprofloxacin after intravenous administration using individual patient data from three studies. Additionally, we studied the PK differences between these studies through a post-hoc analysis. Methods: Individual patient data from three studies (study 1, 2, and 3) were pooled. The pooled data set consisted of 1094 ciprofloxacin concentration–time data points from 140 ICU patients. Nonlinear mixed-effects modeling was used to develop a population PK model. Covariates were selected following a stepwise covariate modeling procedure. To analyze PK differences between the three original studies, random samples were drawn from the posterior distribution of individual PK parameters. These samples were used for a simulation study comparing PK exposure and the percentage of target attainment between patients of these studies. Results: A two-compartment model with first-order elimination best described the data. Inter-individual variability was added to the clearance, central volume, and peripheral volume. Inter-occasion variability was added to clearance only. Body weight was added to all parameters allometrically. Estimated glomerular filtration rate on ciprofloxacin clearance was identified as the only covariate relationship resulting in a drop in inter-individual variability of clearance from 58.7 to 47.2%. In the post-hoc analysis, clearance showed the highest deviation between the three studies with a coefficient of variation of 14.3% for posterior mean and 24.1% for posterior inter-individual variability. The simulation study showed that following the same dose regimen of 400 mg three times daily, the area under the concentration–time curve of study 3 was the highest with a mean area under the concentration–time curve at 24 h of 58 mg·h/L compared with that of 47.7 mg·h/L for study 1 and 47.6 mg·h/L for study 2. Similar differences were also observed in the percentage of target attainment, defined as the ratio of area under the concentration–time curve at 24 h and the minimum inhibitory concentration. At the epidemiological cut-off minimum inhibitory concentration of Pseudomonas aeruginosa of 0.5 mg/L, percentage of target attainment was only 21%, 18%, and 38% for study 1, 2, and 3, respectively. Conclusions: We developed a population PK model of ciprofloxacin in ICU patients using pooled data of individual patients from three studies. A simple ciprofloxacin dose recommendation for the entire ICU population remains challenging owing to the PK differences within ICU patients, hence dose individualization may be needed for the optimization of ciprofloxacin treatment. [ABSTRACT FROM AUTHOR]

Published
2022
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43. Predicting mortality of individual COVID-19 patients: A multicenter Dutch cohort

Author

Ottenhoff, Maarten C., primary, Ramos, Lucas L., additional, Potters, Wouter, additional, Janssen, Marcus L.F., additional, Hubers, Deborah, additional, Piña-Fuentes, Dan, additional, Thomas, Rajat, additional, van der Horst, Iwan C.C., additional, Herff, Christian, additional, Kubben, Pieter, additional, Elbers, Paul W.G., additional, Marquering, Henk A., additional, Welling, Max, additional, Hu, Shi, additional, Simsek, Suat, additional, de Kruif, Martijn D., additional, Dormans, Tom, additional, Fleuren, Lucas M., additional, Schinkel, Michiel, additional, Noordzij, Peter G., additional, van den Bergh, Joop P., additional, Wyers, Caroline E., additional, Buis, David T. B., additional, Wiersinga, Joost, additional, van den Hout, Ella H.C., additional, Reidinga, Auke C., additional, Rusch, Daisy, additional, Sigaloff, Kim C.E., additional, Douma, Renée, additional, de Haan, Lianne, additional, Fridgeirsson, Egill A., additional, van den Oever, Niels C. Gritters, additional, Rennenberg, Roger J.M.W., additional, van Wingen, Guido A., additional, Aries, Marcel J.H., additional, and Beudel, Martijn, additional

Published
2020
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44. Why we should sample sparsely and aim for a higher target: Lessons from model‐based therapeutic drug monitoring of vancomycin in intensive care patients

Author

Guo, Tingjie, primary, Hest, Reinier M., additional, Fleuren, Lucas M., additional, Roggeveen, Luca F., additional, Bosman, Rob J., additional, Voort, Peter H.J., additional, Girbes, Armand R.J., additional, Mathot, Ron A.A., additional, Hasselt, Johan G.C., additional, and Elbers, Paul W.G., additional

Published
2020
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45. Right Dose, Right Now: Development of AutoKinetics for Real Time Model Informed Precision Antibiotic Dosing Decision Support at the Bedside of Critically Ill Patients

Author

Roggeveen, Luca F., primary, Guo, Tingjie, additional, Driessen, Ronald H., additional, Fleuren, Lucas M., additional, Thoral, Patrick, additional, van der Voort, Peter H. J., additional, Girbes, Armand R. J., additional, Bosman, Rob J., additional, and Elbers, Paul, additional

Published
2020
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47. Right dose, right now

Author

Roggeveen, Luca F., Guo, Tingjie, Fleuren, Lucas M., Driessen, Ronald, Thoral, Patrick, van Hest, Reinier M., Mathot, Ron A. A., Swart, Eleonora L., de Grooth, Harm-Jan, van den Bogaard, Bas, Girbes, Armand R. J., Bosman, Rob J., Elbers, Paul W. G., Supporting clinical sciences, and Intensive Care

Subjects
medicine.medical_specialty, PHARMACOKINETICS, Critical Care, medicine.drug_class, Big data, Antibiotics, Decision Support, Critical Care and Intensive Care Medicine, autokinetics, Intensive care, medicine, critical illness, Humans, Dosing, Precision Medicine, Intensive care medicine, intensive care, drug monitoring, Medicine(all), electronic patient record, medicine.diagnostic_test, Critically ill, business.industry, General Medicine, Precision medicine, Anti-Bacterial Agents, Anesthesiology and Pain Medicine, Therapeutic drug monitoring, Drug dosing, business
Abstract

Antibiotics save lives and are essential for the practice of intensive care medicine. Adequate antibiotic treatment is closely related to outcome. However this is challenging in the critically ill, as their pharmacokinetic profile is markedly altered. Therefore, it is surprising that critical care physicians continue to rely on standard dosing regimens for every patient, regardless of the actual clinical situation. This review outlines the pharmacokinetic and pharmacodynamic principles that underlie the need for individualized and personalized drug dosing. At present, although therapeutic drug monitoring may be of help, it has major disadvantages, remains unavailable for most antibiotics and has produced mixed results. We therefore propose the AutoKinetics concept, taking decision support for antibiotic dosing back to the bedside. By direct interaction with electronic patient records, this opens the way for the use of big data for providing the right dose at the right time in each patient.

Published
2015
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48. Why we should sample sparsely and aim for a higher target: Lessons from model‐based therapeutic drug monitoring of vancomycin in intensive care patients.

Author

Guo, Tingjie, Hest, Reinier M., Fleuren, Lucas M., Roggeveen, Luca F., Bosman, Rob J., Voort, Peter H.J., Girbes, Armand R.J., Mathot, Ron A.A., Hasselt, Johan G.C., and Elbers, Paul W.G.

Subjects
DRUG monitoring, INTENSIVE care patients, STANDARD deviations, VANCOMYCIN
Abstract

Aims: To explore the optimal data sampling scheme and the pharmacokinetic (PK) target exposure on which dose computation is based in the model‐based therapeutic drug monitoring (TDM) practice of vancomycin in intensive care (ICU) patients. Methods: We simulated concentration data for 1 day following four sampling schemes, Cmin, Cmax + Cmin, Cmax + Cmid‐interval + Cmin, and rich sampling where a sample was drawn every hour within a dose interval. The datasets were used for Bayesian estimation to obtain PK parameters, which were used to compute the doses for the next day based on five PK target exposures: AUC24 = 400, 500, and 600 mg·h/L and Cmin = 15 and 20 mg/L. We then simulated data for the next day, adopting the computed doses, and repeated the above procedure for 7 days. Thereafter, we calculated the percentage error and the normalized root mean square error (NRMSE) of estimated against "true" PK parameters, and the percentage of optimal treatment (POT), defined as the percentage of patients who met 400 ≤ AUC24 ≤ 600 mg·h/L and Cmin ≤ 20 mg/L. Results: PK parameters were unbiasedly estimated in all investigated scenarios and the 6‐day average NRMSE were 32.5%/38.5% (CL/V, where CL is clearance and V is volume of distribution) in the trough sampling scheme and 27.3%/26.5% (CL/V) in the rich sampling scheme. Regarding POT, the sampling scheme had marginal influence, while target exposure showed clear impacts that the maximum POT of 71.5% was reached when doses were computed based on AUC24 = 500 mg·h/L. Conclusions: For model‐based TDM of vancomycin in ICU patients, sampling more frequently than taking only trough samples adds no value and dosing based on AUC24 = 500 mg·h/L lead to the best POT. [ABSTRACT FROM AUTHOR]

Published
2021
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49. Klinisch beloop van covid-19 in Nederland

Author

Marcel Aries, Joop van den Bergh, Martijn Beudel, Wim Boersma, Tom Dormans, Douma, Renee A., Annet Eerens, Elbers, Paul W. G., Fleuren, Lucas M., Gritters Den Oever, Niels C., Lianne de Haan, Horst, Iwan C. C., Shi Hu, Deborah Hubers, Mark Janssen, Martijn de Kruif, Pieter Kubben, Sander van Kuijk, Noordzij, Peter G., Ottenhoff, Maarten C., Piña-Fuentes, Dan A. I., Potters, Wouter V., Reidinga, Auke C., Renckens, Roos S. C., Sander Rigter, Daisy Rusch, Michiel Schinkel, Sigaloff, Kim C. E., Suat Simsek, Patricia Stassen, Robert Stassen, Thomas, Rajat M., Wingen, Guido A., Anton Vonk Noordegraaf, Max Welling, Joost Wiersinga, W., Wolvers, Marije D. J., Caroline Wyers, Neurology, Amsterdam Neuroscience - Neurodegeneration, Center of Experimental and Molecular Medicine, Graduate School, Adult Psychiatry, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Infectious diseases, AII - Infectious diseases, and Clinical Research Unit

Abstract

OBJECTIVE: To systematically collect clinical data from patients with a proven COVID-19 infection in the Netherlands. DESIGN: Data from 2579 patients with COVID-19 admitted to 10 Dutch centers in the period February to July 2020 are described. The clinical data are based on the WHO COVID case record form (CRF) and supplemented with patient characteristics of which recently an association disease severity has been reported. METHODS: Survival analyses were performed as primary statistical analysis. These Kaplan-Meier curves for time to (early) death (3 weeks) have been determined for pre-morbid patient characteristics and clinical, radiological and laboratory data at hospital admission. RESULTS: Total in-hospital mortality after 3 weeks was 22.2% (95% CI: 20.7% - 23.9%), hospital mortality within 21 days was significantly higher for elderly patients (> 70 years; 35, 0% (95% CI: 32.4% - 37.8%) and patients who died during the 21 days and were admitted to the intensive care (36.5% (95% CI: 32.1% - 41.3%)). Apart from that, in this Dutch population we also see a risk of early death in patients with co-morbidities (such as chronic neurological, nephrological and cardiac disorders and hypertension), and in patients with more home medication and / or with increased urea and creatinine levels. CONCLUSION: Early death due to a COVID-19 infection in the Netherlands appears to be associated with demographic variables (e.g. age), comorbidity (e.g. cardiovascular disease) but also disease char-acteristics at admission.

50. Early vs. Delayed Switching from Controlled to Assisted Ventilation: A Target Trial Emulation.

Author

Reep CAT, Wils EJ, Fleuren LM, Breskin A, Bellani G, Laffey JG, Brochard LJ, Pham T, and Heunks L

Abstract

Rationale: In critically ill patients receiving invasive mechanical ventilation, switching from controlled to assisted ventilation is a crucial milestone towards ventilator liberation. The optimal timing for switching to assisted ventilation has not been studied., Objectives: Our objective was to determine whether a strategy of early as compared to delayed switching affects the duration of invasive mechanical ventilation, ICU length of stay, and mortality., Methods: We conducted a target trial emulation using the prospective, global WEAN SAFE dataset. Patients were eligible for switching if still on controlled mechanical ventilation, not receiving neuromuscular blockers, and PaO 2 /FiO 2 ratio >150 mmHg. We compared an "early switching" strategy (switch within one day after reaching switching eligibility criteria) to a "delayed switching" strategy (switch one or more days after reaching the switching eligibility criteria). Primary outcome was the 28-day cumulative incidence of successful extubation. Secondary outcomes included 28-day and 90-day ICU discharge and ICU mortality., Measurements and Main Results: 1489 patients met the switching eligibility criteria. The early switch group had, on average, 4 additional days of being successfully extubated over the 28-day period (95% CI: 3, 6; P<0.001) compared to the delayed group, with a higher difference in cumulative incidence of successful extubation at day 28 (7%; 95% CI: 0, 13; P=0.04). Early switching was associated with an 11% higher cumulative incidence of ICU discharge at day 28 (95% CI: 7, 18; P<0.001) and an average of 7 additional days discharged from the ICU over the 90-day period (95% CI: 4, 12; P<0.001) compared to delayed switching. ICU mortality rates did not differ between the strategies., Conclusions: Early switching from controlled to assisted ventilation is associated with shorter duration of invasive mechanical ventilation and ICU stay compared to delayed switching.

Published
2025
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