Background: Despite several randomised controlled trials (RCTs) on the use of adjuvant treatment with corticosteroids in patients with community-acquired pneumonia (CAP), the effect of this intervention on mortality remains controversial. We aimed to evaluate heterogeneity of treatment effect (HTE) of adjuvant treatment with corticosteroids on 30-day mortality in patients with CAP. Methods: In this individual patient data meta-analysis, we included RCTs published before July 1, 2024, comparing adjuvant treatment with corticosteroids versus placebo in patients hospitalised with CAP. The primary endpoint was 30-day all-cause mortality, collected across all trials, and analyses followed the intention-to-treat principle. We analysed HTE using risk and effect modelling. For risk modelling, patients were classified as having less severe or severe CAP based on the pneumonia severity index (PSI), comparing PSI class I–III versus class IV–V. For effect modelling, we trained a corticosteroid-effect model on six trials and externally validated it using data from two trials, received after model preregistration. This model classified patients into two groups: no predicted benefit and predicted benefit from adjuvant treatment with corticosteroids. The literature search was registered on PROSPERO, CRD42022380746. Findings: We included eight RCTs with 3224 patients. Across all eight trials, 246 (7·6%) patients died within 30 days (106 [6·6%] of 1618 in the corticosteroid group vs 140 [8·7%] of 1606 in the placebo group; odds ratio [OR] 0·72 [95% CI 0·56–0·94], p=0·017). The corticosteroid-effect model, which selected C-reactive protein (CRP), showed significant HTE during external validation in the two most recent trials. In these trials, 154 (11·4%) of 1355 patients died within 30 days (88 [13·1%] of 671 in the placebo group vs 66 [9·6%] of 684 in the corticosteroid group; OR 0·71 [95% CI 0·50–0·99], p=0·044). Among patients predicted to have no benefit (CRP ≤204 mg/L, n=725), no significant effect was observed (OR 0·98 [95% CI 0·63–1·50]), whereas for those with predicted benefit (CRP >204 mg/L, n=630), 39 (13·0%) of 301 patients died in the placebo group compared with 20 (6·1%) of 329 in the corticosteroid group (0·43 [0·25–0·76], p_interaction=0·026). No significant HTE was found between less severe CAP (PSI class I–III, n=229) and severe CAP (PSI class IV–V, n=1126). Corticosteroid therapy significantly increased hyperglycaemia risk (44 [12·8%] of 344 in the placebo group vs 84 [24·8%] of 339 in the corticosteroid group; OR 2·50 [95% CI 1·63–3·83], p<0·0001) and hospital re-admission risk (30 [3·7%] of 814 in the placebo group vs 57 [7·0%] of 819 in the corticosteroid group; 1·95 [1·24–3·07], p=0·0038). Interpretation: Overall, adjuvant therapy with corticosteroids significantly reduces 30-day mortality in patients hospitalised with CAP. The treatment effect varied significantly among subgroups based on CRP concentrations, with a substantial mortality reduction observed only in patients with high baseline CRP. Funding: None.

Objective and continuous monitoring of Parkinson’s disease (PD) tremor in free-living conditions could benefit both individual patient care and clinical trials, by overcoming the snapshot nature of clinical assessments. To enable robust detection of tremor in the context of limited amounts of labeled training data, we propose to use prototypical networks, which can embed domain expertise about the heterogeneous tremor and non-tremor sub-classes. We evaluated our approach using data from the Parkinson@Home Validation study, including 8 PD patients with tremor, 16 PD patients without tremor, and 24 age-matched controls. We used wrist accelerometer data and synchronous expert video annotations for the presence of tremor, captured during unscripted daily life activities in and around the participants’ own homes. Based on leave-one-subject-out cross-validation, we demonstrate the ability of prototypical networks to capture free-living tremor episodes. Specifically, we demonstrate that prototypical networks can be used to enforce robust performance across domain-informed sub-classes, including different tremor phenotypes and daily life activities.

Prediction models are popular in medical research and practice. Many expect that by predicting patient-specific outcomes, these models have the potential to inform treatment decisions, and they are frequently lauded as instruments for personalized, data-driven healthcare. We show, however, that using prediction models for decision-making can lead to harm, even when the predictions exhibit good discrimination after deployment. These models are harmful self-fulfilling prophecies: their deployment harms a group of patients, but the worse outcome of these patients does not diminish the discrimination of the model. Our main result is a formal characterization of a set of such prediction models. Next, we show that models that are well calibrated before and after deployment are useless for decision-making, as they make no change in the data distribution. These results call for a reconsideration of standard practices for validation and deployment of prediction models that are used in medical decisions.

Background
Switching from controlled to assisted ventilation is crucial in the trajectory of intensive care unit (ICU) stay, but no guidelines exist. We described current practices, analyzed patient characteristics associated with switch success or failure, and explored the feasibility to predict switch failure.

Methods
In this retrospective study, we obtained highly granular longitudinal ICU data sets from three medical centers, covering demographics, severity scores, vital signs, ventilation, and laboratory parameters. The primary endpoint was switch success, considering a switch attempt to be successful if a patient did not return to controlled ventilation for the next 72 h while alive, and to be failed otherwise. We compared the characteristics of patients with successful vs. failed first switch attempts at ICU admission, immediately before, and 3 h after the attempt. We trained LASSO logistic regression models to predict switch failure.

Results
In 4524/6715 (67%) patients attempting a switch, the first attempt failed. The first switch attempt, regardless of success or failure, was generally made at normalized PaCO2 and pH levels, with PEEP < 10 cmH2O and PaO2/FiO2 indicating mild injury. Despite very similar baseline disease severity, switch failure was associated with significantly worse outcomes, including a 28-day mortality of 27% vs. 16% and median ventilator-free days of 16 vs. 22 (p < 0.001). Failed attempts were initiated significantly earlier than successful ones (median 1.8 vs. 1.3 days, p < 0.001). Before the switch, PaO2/FiO2, if measured at PEEP > 10 cmH2O, and respiratory system compliance was lower in patients with switch failure (median 185 vs. 205 mmHg, p < 0.001; 39 vs. 41 mL/cmH2O, P = 0.001), and post-switch, patients with switch failure experienced greater deterioration in gas exchange and minimal improvement in ventilatory parameters post-switch. Contrary to our hypotheses, patient characteristics for failed vs. successful switches were surprisingly similar, resulting in prediction models with limited discriminative performance.

Conclusions
Approximately two-thirds of attempts to switch patients to assisted ventilation fail, which are associated with significantly worse clinical outcomes, despite similar baseline disease severity. Contrary to our hypotheses, patients with successful and failed attempts showed similar characteristics, making switch failure difficult to predict. These findings underscore the importance of preventing switch failures and, given the retrospective nature of this study, highlight the need for prospective studies to better understand the reasons for switch failure and when spontaneous breathing can be safely initiated.

We appreciate the opportunity to further clarify our findings in response to the insightful comments from Shota Yamamoto and colleagues and Luis Felipe Reyes and Ignacio Martin-Loeches regarding our recent community-acquired pneumonia (CAP) study. [...]

Introduction: Dynamic survival analysis has become an effective approach for predicting time-to-event outcomes based on longitudinal data in neurology, cognitive health, and other health-related domains. With advancements in machine learning, several new methods have been introduced, often using a two-stage approach: first extracting features from longitudinal trajectories and then using these to predict survival probabilities.

Methods: This work compares several combinations of longitudinal and survival models, assessing their predictive performance across different training strategies. Using synthetic and real-world cognitive health data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we explore the strengths and limitations of each model.

Results: Among the considered survival models, the Random Survival Forest consistently delivered strong results across different datasets, longitudinal models, and training strategies. On the ADNI dataset the best performing method was Random Survival Forest with the last visit benchmark and super landmarking with an average tdAUC of 0.96 and brier score of 0.07. Several other methods, including Cox Proportional Hazards and the Recurrent Neural Network, achieve similar scores. While the tested longitudinal models often struggled to outperform simple benchmarks, neural network models showed some improvement in simulated scenarios with sufficiently informative longitudinal trajectories.

Discussion: Our findings underscore the importance of aligning model selection and training strategies with the specific characteristics of the data and the target application, providing valuable insights that can inform future developments in dynamic survival analysis.

In her pioneering work, Calfee et al. [1] addressed the clinical and biological heterogeneity of acute respiratory distress syndrome (ARDS), a factor likely contributing to the poor track record of randomized trials (RCTs) in this patient population. Using latent class (or profile) analysis (LCA), a method for identifying unobserved subgroups from observed data, they identified two distinct ARDS sub-phenotypes (hypo- and hyperinflammatory), which showed association with clinical outcomes and, crucially, heterogeneity of treatment effect (HTE) [2], demonstrating different responses to higher vs. lower PEEP regimes. [...]

With the fast integration of Machine Learning (ML) across industries, effective pedagogical strategies are essential for teaching this complex and evolving field. Machine Learning is now widely integrated into various university programs and introduced at earlier educational stages, including high school and secondary school. However, ML pedagogy lacks standardized teaching methods compared to other science-related subjects, which have established norms for topic introduction, teaching tools, and assessment methods. Inspired by other fields, this research explores the use of interactive visualizations in teaching ML topics, more specifically in teaching Gradient Descent (GD) and Principal Component Analysis (PCA). The target population consists of Computer Science and Engineering Bachelor students who have not yet followed any Machine Learning courses but have foundational knowledge in calculus, linear algebra, and statistics. The evaluation measures knowledge gained and student motivation, compared to a static version of the materials. Results show a significant positive effect in knowledge related to PCA with interactive visualizations, but no differences in knowledge gain for GD or in learning motivation for either topic. With these results, we contribute to the body of evidence-based teaching methods in Machine Learning and identify further research needed to generalize the effect of interactive visualizations as a teaching method for teaching ML basic concepts.

Prediction models are used among others to inform medical decisions on interventions. Typically, individuals with high risks of adverse outcomes are advised to undergo an intervention while those at low risk are advised to refrain from it. Standard prediction models do not always provide risks that are relevant to inform such decisions: for example, an individual may be estimated to be at low risk because similar individuals in the past received an intervention which lowered their risk. Therefore, prediction models supporting decisions should target risks belonging to defined intervention strategies. Previous works on prediction under interventions assumed that the prediction model was used only at one time point to make an intervention decision. In clinical practice, intervention decisions are rarely made only once: they might be repeated, deferred, and reevaluated. This requires estimated risks under interventions that can be reconsidered at several potential decision moments. In the current work, we highlight key considerations for formulating estimands in sequential prediction under interventions that can inform such intervention decisions. We illustrate these considerations by giving examples of estimands for a case study about choosing between vaginal delivery and cesarean section for women giving birth. Our formalization of prediction tasks in a sequential, causal, and estimand context provides guidance for future studies to ensure that the right question is answered and appropriate causal estimation approaches are chosen to develop sequential prediction models that can inform intervention decisions.

This scoping review focuses on the essential role of models for causal inference in shaping actionable artificial intelligence (AI) designed to aid clinicians in decision-making. The objective was to identify and evaluate the reporting quality of studies introducing models for causal inference in intensive care units (ICUs), and to provide recommendations to improve the future landscape of research practices in this domain. To achieve this, we searched various databases including Embase, MEDLINE ALL, Web of Science Core Collection, Google Scholar, medRxiv, bioRxiv, arXiv, and the ACM Digital Library. Studies involving models for causal inference addressing time-varying treatments in the adult ICU were reviewed. Data extraction encompassed the study settings and methodologies applied. Furthermore, we assessed reporting quality of target trial components (i.e., eligibility criteria, treatment strategies, follow-up period, outcome, and analysis plan) and main causal assumptions (i.e., conditional exchangeability, positivity, and consistency). Among the 2184 titles screened, 79 studies met the inclusion criteria. The methodologies used were G methods (61%) and reinforcement learning methods (39%). Studies considered both static (51%) and dynamic treatment regimes (49%). Only 30 (38%) of the studies reported all five target trial components, and only seven (9%) studies mentioned all three causal assumptions. To achieve actionable AI in the ICU, we advocate careful consideration of the causal question of interest, describing this research question as a target trial emulation, usage of appropriate causal inference methods, and acknowledgement (and examination of potential violations of) the causal assumptions.

Learning curves illustrate how generalization performance of a learner evolves with more training data. While this is a useful tool to characterize learners, not all learning curve behavior is well understood. For instance, it is sometimes assumed that the more training data provided, the better the learner performs. However, counter-examples exist for both classical machine learning algorithms and deep neural networks, where errors do not monotonically decrease with training set size. Loog et al. [12] describe this monotonicity problem, and present several regression examples where simple empirical risk minimizers display unexpected learning curve behaviors. In this paper, we will study two of these proposed problems in detail and explain what caused the odd learning curves. For the first, we use a bias-variance decomposition to show that the monotonic increase in the learning curve is caused by an increase in the variance, which we explain by a mismatch between the model and the data generating process. For the second problem, we explain the recurring increases in the learning curve by showing only two solutions are attainable by the learner. The probability of obtaining a configuration of training objects that leads to the high risk solution typically decreases as the training set size increases. However, for particular training set sizes, additional configurations that produce the high risk solution become possible. We prove that these additional configurations increase the probability of the high risk solution and therefore explain the unusual learning curve. These examples contribute to a more complete understanding of learning curves and the possibilities and reasons behind their various behaviors.

Background: Currently available treatment options for Parkinson's disease are symptomatic and do not alter the course of the disease. Recent studies have raised the possibility that cardiovascular risk management may slow the progression of the disease. Objectives: We estimated the effect of baseline cardiovascular risk factors on the progression of Parkinson's disease, using measures for PD-specific motor signs and cognitive functions. Methods: We used data from 424 de novo Parkinson's disease patients and 199 age-matched controls from the observational, multicenter Parkinson's Progression Markers Initiative (PPMI) study, which included follow-up of up to 9 years. The primary outcome was the severity of PD-specific motor signs, assessed with the MDS-UPDRS part III in the “OFF”-state. The secondary outcome was cognitive function, measured with the Montreal Cognitive Assessment, Symbol Digit Modalities Test, and Letter-Number Sequencing task. Exposures of interest were diabetes mellitus, hypertension, body mass index, cardiovascular event history and hypercholesterolemia, and a modified Framingham risk score, measured at baseline. The effect of each of these exposures on disease progression was modeled using linear mixed models, including adjustment for identified confounders. A secondary analysis on the Tracking Parkinson's cohort including 1,841 patients was performed to validate our findings in an independent patient cohort. Results: Mean age was 61.4 years, and the average follow-up was 5.5 years. We found no statistically significant effect of any individual cardiovascular risk factor on the MDS-UPDRS part III progression (all 95% confidence intervals (CIs) included zero), with one exception: in the PD group, the estimated effect of a one-point increase in body mass index was 0.059 points on the MDS-UPDRS part III per year (95% CI: 0.017 to 0.102). We found no evidence for an effect of any of the exposures on the rate of change in cognitive functioning in the PD group. Similar results were observed for the Tracking Parkinson's cohort (all 95% CIs overlapped with PPMI), but the 95% CI of the effect of body mass index on the MDS-UPDRS part III progression included zero. Conclusions: Based on this analysis of two large cohorts of de novo PD patients, we found no evidence to support clinically relevant effects of cardiovascular risk factors on the clinical progression of Parkinson's disease.

Arguably, a desirable feature of a learner is that its performance gets better with an increasing amount of training data, at least in expectation. This issue has received renewed attention in recent years and some curious and surprising findings have been reported on. In essence, these results show that more data does actually not necessarily lead to improved performance—worse even, performance can deteriorate. Clustering, however, has not been subjected to such kind of study up to now. This paper shows that k-means clustering, a ubiquitous technique in machine learning and data mining, suffers from the same lack of so-called monotonicity and can display deterioration in expected performance with increasing training set sizes. Our main, theoretical contributions prove that 1-means clustering is monotonic, while 2-means is not even weakly monotonic, i.e., the occurrence of nonmonotonic behavior persists indefinitely, beyond any training sample size. For larger k, the question remains open.

Artificial intelligence (AI) research in the intensive care unit (ICU) mainly focuses on developing models (from linear regression to deep learning) to predict out-
comes, such as mortality or sepsis [1, 2]. However, there is another important aspect of AI that is typically not framed as AI (although it may be more worthy of the name), which is the prediction of patient outcomes or events that would result from different actions, known as causal inference [3, 4]. This aspect of AI is crucial for decision-making in the ICU. To emphasize the impor- tance of causal inference, we propose to refer to any data- driven model used for causal inference tasks as ‘action- able AI’, as opposed to ‘predictive AI’, and discuss how these models could provide meaningful decision support in the ICU.

Background: Optimal care for Parkinson’s disease (PD) requires coordination and collaboration between providers within a complex care network. Individual patients have personalised networks of their own providers, creating a unique informal network of providers who treat (‘share’) the same patient. These ‘patient-sharing networks’ differ in density, ie, the number of identical patients they share. Denser patient-sharing networks might reflect better care provision, since providers who share many patients might have made efforts to improve their mutual care delivery. We evaluated whether the density of these patient-sharing networks affects patient outcomes and costs. Methods: We analysed medical claims data from all PD patients in the Netherlands between 2012 and 2016. We focused on seven professional disciplines that are commonly involved in Parkinson care. We calculated for each patient the density score: the average number of patients that each patient’s providers shared. Density scores could range from 1.00 (which might reflect poor collaboration) to 83.00 (which might reflect better collaboration). This score was also calculated at the hospital level by averaging the scores for all patients belonging to a specific hospital. Using logistic and linear regression analyses we estimated the relationship between density scores and health outcomes, healthcare utilization, and healthcare costs. Results: The average density score varied considerably (average 6.7, SD 8.2). Adjusted for confounders, higher density scores were associated with a lower risk of PD-related complications (odds ratio [OR]: 0.901; P <.001) and with lower healthcare costs (coefficients:-0.018, P =.005). Higher density scores were associated with more frequent involvement of neurologists (coefficient 0.068), physiotherapists (coefficient 0.052) and occupational therapists (coefficient 0.048) (P values all <.001). Conclusion: Patient sharing networks showed large variations in density, which appears unwanted as denser networks are associated with better outcomes and lower costs.

Introduction: Unplanned hospital admissions associated with Parkinson's disease could be partly attributable to comorbidities. Methods: We studied nationwide claims databases and registries. Persons with newly diagnosed Parkinson's disease were identified based on the first Parkinson's disease-related reimbursement claim by a medical specialist. Comorbidities were classified based on the Charlson Comorbidity Index. We studied hospitalization admissions because of falls, psychiatric diseases, pneumonia and urinary tract infections, PD-related hospitalizations-not otherwise specified. The association between comorbidities and time-to-hospitalization was estimated using Cox proportional hazard modelling. To better understand pathways leading to hospitalizations, we performed multiple analyses on causes for hospitalizations. Results: We identified 18 586 people with newly diagnosed Parkinson's disease. The hazard of hospitalization was increased in persons with peptic ulcer disease (HR 2.20, p = 0.009), chronic obstructive pulmonary disease (HR 1.61, p < 0.001), stroke (HR 1.37, p = 0.002) and peripheral vascular disease (HR 1.31, p = 0.02). In the secondary analyses, the hazard of PD-related hospitalizations-not otherwise specified (HR 3.24, p = 0.02) and pneumonia-related hospitalization (HR 2.90, p = 0.03) was increased for those with comorbid peptic ulcer disease. The hazard of fall-related hospitalization (HR 1.57, p = 0.003) and pneumonia-related hospitalization (HR 2.91, p < 0.001) was increased in persons with chronic obstructive pulmonary disease. The hazard of pneumonia-related hospitalization was increased in those with stroke (HR 1.54, p = 0.03) or peripheral vascular disease (HR 1.60, p = 0.02). The population attributable risk of comorbidity was 8.4%. Conclusion: Several comorbidities increase the risk of Parkinson's disease related-hospitalization indicating a need for intervention strategies targeting these comorbid disorders.

Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of −0.04 [−0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of −0.19 [−0.27; −0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.

Background: Timely identification of deteriorating COVID-19 patients is needed to guide changes in clinical management and admission to intensive care units (ICUs). There is significant concern that widely used Early warning scores (EWSs) underestimate illness severity in COVID-19 patients and therefore, we developed an early warning model specifically for COVID-19 patients. Methods: We retrospectively collected electronic medical record data to extract predictors and used these to fit a random forest model. To simulate the situation in which the model would have been developed after the first and implemented during the second COVID-19 ‘wave’ in the Netherlands, we performed a temporal validation by splitting all included patients into groups admitted before and after August 1, 2020. Furthermore, we propose a method for dynamic model updating to retain model performance over time. We evaluated model discrimination and calibration, performed a decision curve analysis, and quantified the importance of predictors using SHapley Additive exPlanations values. Results: We included 3514 COVID-19 patient admissions from six Dutch hospitals between February 2020 and May 2021, and included a total of 18 predictors for model fitting. The model showed a higher discriminative performance in terms of partial area under the receiver operating characteristic curve (0.82 [0.80–0.84]) compared to the National early warning score (0.72 [0.69–0.74]) and the Modified early warning score (0.67 [0.65–0.69]), a greater net benefit over a range of clinically relevant model thresholds, and relatively good calibration (intercept = 0.03 [− 0.09 to 0.14], slope = 0.79 [0.73–0.86]). Conclusions: This study shows the potential benefit of moving from early warning models for the general inpatient population to models for specific patient groups. Further (independent) validation of the model is needed.