Acute respiratory distress syndrome (ARDS) is a non-hydrostatic pulmonary oedema and hypoxemia associated with a variety of aetiologies. The morbidity, mortality (about 40%), and financial cost of ARDS are high (1,2). Predicting the outcome of patients with ARDS remains challenging (3), and no scoring system has been validated till date (4). Although using the PaO2/FiO2 ratio is the most common method of describing the severity of pulmonary dysfunction, it does not provide an accurate assessment of ARDS severity and outcome (5). Other scoring systems, such as Acute Physiology and Chronic Health Evaluation (APACHE-II), Oxygenation Saturation Index (OSI), Oxygenation Index (OI), and the Lung Injury Score can be used to predict the survival of patients in the intensive care units (ICUs). However, controversies exist since these scores offer limited prognostic information and poor predicting power (3,6,7). A more comprehensive and powerful prediction system is urgently needed.
Recently, machine learning (ML) (8) has been widely used in detecting adverse health events in hospital settings. Studies (9-12) have applied ML to predict the mortality of patients in ICU settings and have shown improved predictive ability. However, few studies have evaluated the role of ML in predicting mortality in ARDS. Ding et al. (13) and Zhang (14) developed a random forest (RF) model and a neural network model, respectively; however, their power was compromised due to either small sample size or lack of external validation.
This study aimed to develop an effective and robust mortality prediction ML model specific to ARDS. Our hypotheses included the following: firstly, the ML-based model can be used in mortality prediction of ARDS with better performance than the existing scoring systems; secondly, the ML-based model can be robust in a multi-source dataset. We present the following article in accordance with the STROBE reporting checklist (15) (available at http://dx.doi.org/10.21037/atm-20-6624).
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
We extracted patient data from the Medical Information Mart for Intensive Care database (MIMIC-III) (16) and Telehealth Intensive Care Unit Collaborative Research Database (eICU-CRD) (17). MIMIC-III is a publicly available database that includes 53,423 distinct hospital admissions for adult patients (aged ≥18 years) in critical care units at a tertiary non-profit medical centre from 2001 to 2012. eICU-CRD is a multi-source ICU database with high granularity data for over 200,000 admissions to ICUs monitored by eICU programmes across the United States. The release of eICU-CRD is intended to build upon the success of MIMIC-III and potentially expand the scope of studies by ensuring data availability from multiple centres.
We used the same inclusion and exclusion criteria as the MIMIC-III and eICU-CRD databases. The inclusion diagram and study design are presented in Figure 1. Patients ≥18 years old with ARDS according to the International Classification of Diseases (ICD)-9 code (518.82 or 518.5) were selected. The diagnostic criteria for ARDS were as described in previous studies (18) with adjustment according to the Berlin definition (19). For patients receiving high flow oxygen or non-invasive ventilation, the PaO2/FiO2 values were not always available, and the values were calculated as the ratio of PaO2 to the nearest FiO2 available before the corresponding blood gas measurement. The bilateral infiltrates were confirmed by text matching with the keywords ‘edema’ OR (‘bilateral’ AND ‘infiltrate’) running against all radiographic reports (20,21). Patients with congestive heart failure were excluded based on the ICD-9 code 428 (instead of pulmonary wedge pressure), since the information of pulmonary wedge pressure was severely missing in these patients (22,23). A random sample of 25% of patients labelled to have ARDS was manually reviewed, and the extraction and pre-processing proposal were evaluated and tilted accordingly. Discrepancies were settled by a joint evaluation of the overall data available, but blinded to the exposure variables. Patients with the following criteria were excluded: ICU stay less than 24 h, on non-invasive ventilation, and post-surgical patients in the cardiovascular ICU.
To compare the performance of our proposed ML methods with the existing scoring systems, from MIMIC-III, we selected 308 patients who met the above-mentioned criteria and had complete records of all the scores (see below), and named it Dataset 1. The scores calculated included the Simplified Acute Physiology Score II (SAPS-II), Sepsis-related Organ Failure Assessment (SOFA), OSI, OI, and APPS (3). A total of 2,235 patients in MIMIC-III (Dataset 2) and 331 patients in eICU-CRD (Dataset 3) who met the above-mentioned inclusion criteria were selected as the study population. Note that Dataset 1 is a subset of Dataset 2.
For the missing variables in some patients, we used the mean values (for the variables with normal distribution) or median values (for the variables that were not normally distributed) of non-missing data of the corresponding variables as alternatives in each dataset. The detailed frequency of the present/missing data is provided in the Appendix Section 1.
ML model development and feature selection with Dataset 1
An RF model was built in Dataset 1 using the scikit-learn library (24) in Python. Studies have shown that the RF method in most classification tasks is better than other classifiers (8,25). The outcome measures included in-hospital mortality, 30-day mortality, and 1-year mortality. As shown in Figure S1, the training and testing was based on an 8-fold cross-validation, which means that the dataset was divided into 8 folds, and in each run, 7 were used for training and the remaining 1 was used for testing. During the training procedure, we also used a nested 8-fold cross-validation grid-search scheme to find the optimal hyperparameters. The details of the hyperparameter tuning are provided in the Appendix Section 2.
For feature selection, a total of 90 variables were collected in Dataset 1, including demographic data, ventilator settings, laboratory hemodynamic variables, physiological information, and other clinical data that may be relevant to the mortality of patients with ARDS. To investigate the contribution of different variables, an importance measure, the Gini importance, was used (26), which was computed as the total reduction of the criterion brought by that feature. We selected the top 45 (50%) features with high importance. Among these, only 12 features that could also be obtained in Dataset 3 from eICU-CRD were used to establish the ML models. To assess the impact on the results, the predictive performances of RF models with 45 variables and 12 variables were evaluated and compared in Dataset 1 using 8-fold cross-validation. The details of the feature selection are provided in the Appendix Section 3.
Performance comparisons between the ML method and existing scoring systems with Dataset 1
We calculated the SAPS-II, SOFA, OSI, OI, and APPS scores for Dataset 1. OI and OSI were calculated for each patient using the following formulae:
The classification models’ performance was evaluated using the area under the receiver operating characteristic curve (AUROC). The accuracy, sensitivity, and specificity were calculated from the receiver operating characteristics (ROC) curve with the threshold with the highest accuracy. In addition, we performed calibration using the Hosmer-Lemeshow test (28) to compare the predicted and observed probabilities of death.
RF model evaluation with Dataset 2 alone and with multi-source data (Dataset 2 and Dataset 3)
An RF model was built with the 12 features for predicting the mortality of patients with ARDS in Dataset 2, and the classification models’ performance was evaluated using the above-mentioned scheme.
Training and testing were further performed using the combined data of Dataset 2 and Dataset 3. The whole procedure was the same as that described in “ML model development and feature selection with Dataset 1” section, with the same 12 features. We calculated AUROC, accuracy, sensitivity, and specificity, and performed the calibration using the Hosmer-Lemeshow test for Dataset 2 and Dataset 3, respectively, to independently evaluate the performance in these two datasets. Since only in-hospital mortality was recorded in Dataset 3, the predicting performance of the RF model was only evaluated for in-hospital mortality with this combined multi-source dataset. The classification performance of the SAPS-II and APACHE scoring systems were also calculated since other scoring systems were unavailable in the eICU-CRD database (Dataset 3).
Statistical analyses were performed using R (http://www.R-project.org) and EmpowerStats software (X&Y Solutions, Inc., Boston MA, USA). Continuous variables were presented as mean ± standard deviation, and categorical variables were presented as counts and percentages. Differences between groups were tested using the Pearson chi-square or Fisher exact test for categorical variables, and with t-test, Mann-Whitney, or Kruskal-Wallis test for numerical variables.
The AUROCs were compared using the Delong method (29). A P value <0.05 was considered statistically significant. Discrimination was also evaluated by plotting and comparing the predicted probabilities of death among survivors and non-survivors.
Results (Figures 2-6)
Demographics and clinical data of Dataset 2 and Dataset 3 are shown in Table 1. The in-hospital mortality rate was 19.6% in Dataset 2 and 21.5% in Dataset 3.
The AUROCs of RF models with 45 variables were 0.914, 0.909, and 0.910 for in-hospital, 30-day, and 1-year mortality prediction, respectively in Dataset 1 by using 8-fold cross-validation, and the AUROCs of the 12-variable based model were 0.891, 0.883, and 0.892, respectively, showing no significant difference. The 12 features finally used included age, white blood cell (WBC) count, serum creatinine, albumin, platelet count, pH, lactate level, FiO2, PaO2, heart rate, temperature, and body mass index (BMI). For the laboratory results and vital signs, mean values during the first 24 h of hospitalisation were calculated and used as the selected features, except temperature for which the maximum values were used.
Figure 2 shows the top 12 important features in the RF-based in-hospital mortality prediction model with Dataset 1, in which the platelet count and lactate level are the two strongest predictors.
Performance comparisons between the existing scoring systems and RF model with Dataset 1
As shown in Table 2 and Figure 3, with Dataset 1, the AUROC for in-hospital mortality prediction was 0.891, which was significantly higher than the predictive values of the SAPS-II, SOFA, APPS, OSI, and OI scores (AUROC, 0.586–0.694; all P<0.001). The AUROC for the 30-day mortality prediction was 0.883, which was also significantly higher than the predictive values of these existing scores (AUROC 0.583–0.739; all P<0.001). The AUROC for the 1-year mortality prediction was 0.892, which was also significantly superior to the predictive values of these existing scores (AUROC 0.569–0.732; all P<0.001).
The calibration results are provided in Table S1 and Figure 4A. These statistics and plots suggest good fits for these scoring systems (all P>0.05), of which our RF model achieved better performance in predicting 30-day mortality (P=0.915) and 1-year mortality (P=0.823).
Discrimination plots of the RF-based mortality prediction model with Dataset 1 are shown in Figure S2, indicating the significant differences between the predicted probabilities of death among the survivors and non-survivors using each prediction algorithm.
Prediction performance of the RF model with Dataset 2 alone and with multi-source data (Dataset 2 and Dataset 3)
As shown in Table 3 and Figure 5 with Dataset 2, the AUROC was 0.901 for the in-hospital mortality prediction, 0.882 for the 30-day mortality prediction, and 0.872 for the 1-year mortality prediction.
Discrimination plots of the RF-based mortality prediction model with Dataset 2 are shown in Figure S3, indicating the significant differences between the predicted probabilities of death among the survivors and non-survivors using each prediction algorithm.
As shown in Table S3 and Figure 6, when refitting the RF model in the multi-source data consisting of Dataset 2 and Dataset 3, the AUROC for the in-hospital mortality prediction was 0.905 and 0.736 for Dataset 2 and Dataset 3, respectively. With SAPS-II and APACHE scoring systems, the AUROC for in-hospital mortality prediction with Dataset 3 was 0.511 and 0.528, respectively. We also studied the predictive value of our RF model with only Dataset 3 for training and testing, and the AUROC was 0.696 [95% confidence interval (CI), 0.621–0.770], lower than the performance trained with multi-source data consisting of Dataset 2 and Dataset 3.
The calibration results are provided in Table S3 and Figure 4C. These statistics and plots suggest good fits for these scoring systems (all P>0.05), except for our RF model for the in-hospital mortality prediction of MIMIC-III data (P=0.021). The predictive value of our RF model for MIMIC-III data has been justified in our previous results.
Discrimination plots of the RF-based mortality prediction model with multi-source data are shown in Figure S4, indicating the significant differences between the predicted probabilities of death among the survivors and non-survivors using the RF algorithm in different training sets.
We found that ML improved the ARDS mortality prediction performance compared to the OI, OSI, SAPS-II, SOFA, and APPS scoring systems, and showed relatively stable performance with multi-source data.
The existing scoring systems combined with logistic regression have been used for mortality prediction in ARDS (3,6,7). Similar to the previous studies, our study achieved an AUROC of 0.618, 0.692, 0.692, 0.586, and 0.694 (Figure 3A), respectively, for in-hospital mortality, which was significantly poorer than the performance of the RF-based model in our study. Since the reasons for the death of patients with ARDS are complicated, it is difficult for these scoring systems to predict mortality accurately since they are generally a linear combination of explanatory variables. However, the generalizability of these scoring systems in different ARDS cohorts may be limited. For example, while the APPS score achieved an AUROC of 0.800 in predicting the in-hospital mortality (7), we achieved an AUROC of only 0.694. In another external validation study (3) using APPS, the AUROC was 0.62. This may be because APPS is a simple scoring system that incorporates limited information regarding the age, PaO2/FiO2 ratio, and plateau pressure.
Studies have demonstrated that ML is effective in predicting ICU mortality. Pirracchio et al. (10) adopted the Super ICU Learner Algorithm in mortality prediction for patients in the ICU achieving an AUROC of 0.88, which was better than previous scoring systems. Marafino et al. (30) used ML to predict in-hospital ICU mortality and yielded excellent predictive performance. Zhang et al. (11) applied a gradient boosting machine, and achieved an AUROC of 0.748. Ding et al. (13) built an RF model to predict ARDS events in a small sample of 296 patients, and achieved an AUROC of 0.82. Zhang (14) developed a neural network model with a genetic algorithm to predict 90-day mortality in a database of 745 patients, and in the testing cohort of 272 patients achieved an AUROC of 0.821. These two studies on ARDS indicated that ML was superior to the traditional APACHE score; however, the robustness requires further validation owing to the relatively small sample size or lack of multi-source validation. Similarly, our results demonstrated the ability of ML to predict the mortality of patients with ARDS, achieving comparable or even better performance than Ding et al. (13) and Zhang (14) in a larger and multi-source dataset. Compared with existing scoring systems, the RF-based algorithm has the following advantages. Firstly, the RF algorithm can automatically learn the interaction and non-linear effects between the predictors from the data, and thus may be more suitable for high-dimensional data. Secondly, with cross-validation, the optimal model could be selected. Lastly, the RF algorithm may be more powerful in dealing with the unbalanced datasets by applying an unbiased estimation for the generalisation error (31).
In the feature selection, 45 variables (50%, 90 in total) with higher Gini importance were selected based on Dataset 1 from MIMIC-III, but only 12 variables were available in Dataset 3 from eICU-CRD. The predictive performances of RF models with 45 variables and 12 variables were compared in Dataset 1. The AUROCs of the 45-variable based model were 0.914, 0.909, and 0.910 for in-hospital, 30-day, and 1-year mortality prediction, while the 12-variable based model achieved AUROCs of 0.891, 0.883, and 0.892, respectively, showing no significant difference and limiting impact on the results.
The 12 variables with the highest importance in predicting the in-hospital mortality are shown in Figure 2. Such variables have also been reported in previous studies (32-34). Advanced age, PaO2, FiO2, and creatinine are well-recognised independent risk factors for mortality in ARDS (35-37). Similarly, WBC count, temperature, and heart rate on the first day were screened as predictors of ARDS events by Ding et al. (13), while age, albumin, and FiO2 were identified as important variables associated with the 90-day mortality by Zhang (14). Acute kidney injury is associated with a high mortality, especially during ARDS development (37,38). Fever above 38.5–39.5 °C increases both the ventilatory (high respiratory drive: large tidal volume, high respiratory rate) and metabolic (increased O2 consumption) demands, further impairing the cardio-ventilatory reserve (39). Some studies have suggested that control of elevated body temperature resulting in normothermia (35.5–37 °C) could lower both the ventilatory and metabolic demands (40). However, no studies have been reported supporting the role of temperature control in preventing ARDS and improving survival. Low pH and high lactate levels are characteristic of metabolic acidosis, which is known to be predictive of mortality in extreme acidosis or critically ill patients (37,41,42). Hypoalbuminemia, a factor known to be predictive of poor prognosis (43), disrupts the oncotic balance between fluids in the pulmonary circulation and lung alveoli. In patients who are seriously ill, hypoalbuminemia may be a marker of leaky capillaries rather than a cause of hydrostatic oedema (18).
In our study, we tested and reported a very similar prediction performance of our model in two datasets from MIMIC-III with different sizes (Dataset 1 and Dataset 2) (Tables 2,3). This may indicate that sample size has a limited impact on the prediction performance of our ML-based method. We combined the eICU-CRD dataset (Dataset 3) and Dataset 2, and the results showed that the in-hospital mortality prediction performance in Dataset 3 decreased (AUROC, 0.736). There may be two explanations for this relatively lower performance in Dataset 3. Firstly, the feature selection was based on the feature importance with the MIMIC-III dataset. The distributions of these selected features in the eICU-CRD dataset can be different from those of the MIMIC-III dataset, and thus may affect the final prediction performance. Secondly, the data in MIMIC-III are from a single centre (Beth Israel Deaconess Medical Center), while the data in eICU-CRD are from multiple centres. This may cause a certain level of heterogeneity in Dataset 3 and thus lower the performance. In addition, we showed that the predictive value of the model trained with multi-source data was better than that with Dataset 3 only.
The model proposed in our study represents a momentous step towards building tools for the habitual identification of patients with ARDS who are at greatest risk of hospital death. The findings of several mortality-associated parameters in our study are unexpected but not new, possibly providing bases for future therapeutic innovation.
Our study has some limitations. Firstly, this was a retrospective study and some valuable features may have been missing. In MIMIC-III and eICU-CRD, some variables were not directly available, and the lack of such features may limit the selection of clinical variables for modelling. Although we have filled in the missing data with the median or mean values, these values were not the real values. Secondly, the performance of our model in a multi-source dataset is not as good as that in a single-source dataset. To validate our model, by incorporating additional predictive variables, a larger external cohort is warranted. Thirdly, the mortality in our patients was relatively low compared to that in other studies, varying from 4.6% to 52% (44-46). This could be because the patients with non-invasive ventilation or in the surgical ICU recruited in our study had a relatively better prognosis.
Using the MIMIC-III database, we successfully established an RF-based ML model for predicting the mortality of patients with ARDS. The RF model achieved significantly improved performance compared to the traditional scoring systems. Based on the multi-source dataset obtained from both the MIMIC-III and the eICU-CRD database, the generalisation ability of this prediction model was verified.
Funding: This work was supported by Seed Funding from Guangzhou Science and Technology Planning Project (No. 201903010073), Natural Science Foundation of Guangdong Province (No. 2020A1515010571), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions (No. 2019SHIBS0003), Guangdong Key Basic Research Grant (No. 2018B030332001), Guangdong Pearl River Talents Plan (No. 2016ZT06S220), Shenzhen Science and Technology Project (JCYJ20200109114014533), SZU Top Ranking Project - Shenzhen University (860/000002100108) and Tencent “Rhinoceros Birds” Scientific Research Foundation for Young Teachers of Shenzhen University.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-6624
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-6624). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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