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Unsupervised Machine Learning Reveals Novel Traumatic Brain Injury Patient Phenotypes with Distinct Acute Injury Profiles and Long-Term Outcomes.

ABSTRACT: The heterogeneity of traumatic brain injury (TBI) remains a core challenge for the success of interventional clinical trials. Data-driven approaches for patient stratification may help to identify TBI patient phenotypes during the acute injury period as well as facilitate targeted trial patient enrollment and analysis of treatment efficacy. In this study, we implemented an unsupervised machine learning approach to identify TBI subpopulations at injury baseline using data from 1213 TBI patients who participated in the Citicoline Brain Injury Treatment Trial (COBRIT) Trial. A wrapper framework utilizing generalized low-rank models automatically selected relevant clinical features that were subsequently used to cluster patients using a partitioning around medoids clustering algorithm. Using this approach, we identified three patient phenotypes with unique clinical injury profiles based on a subset of acute injury features. Phenotype-specific differences in long-term functional outcome trajectories were respectively observed at 3 and 6 months after injury. In comparison, when patients were grouped by baseline Glasgow Coma Scale (GCS), no differences in baseline clinical feature profiles or long-term outcomes were observed. To test phenotype reproducibility in an external validation data set, we used a K-nearest neighbors algorithm to classify subjects in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot data set into corresponding phenotypes, then measured the Gower's dissimilarities between TRACK-TBI and COBRIT subjects in each phenotype. No significant differences were found between trial subjects within two phenotypes, suggesting that these phenotypes may be generalizable within a broad range of TBI severity. Further, Extended Glasgow Outcome Scale (GOS-E) outcomes in the TRACK-TBI data set similarly demonstrated phenotype-specific differences in long-term outcomes. Our results suggest that unsupervised machine learning is a promising and effective approach for discovery of novel injury subpopulations over the conventional GCS-based method, and may improve patient selection in future TBI clinical trials.

SUBMITTER: Folweiler KA

PROVIDER: S-EPMC7249479 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This work aimed to identify pre-existing health conditions of patients with traumatic brain injury (TBI) and develop predictive models for the first TBI event and its external causes by employing a combination of unsupervised and supervised learning algorithms. We acquired up to five years of pre-injury diagnoses for 488,107 patients with TBI and 488,107 matched control patients who entered the emergency department or acute care hospitals between April 1st, 2002, and March 31st, 2020. Diagnoses were obtained from the Ontario Health Insurance Plan (OHIP) database which contains province-wide claims data by physicians in Ontario, Canada for inpatient and outpatient services. A screening process was conducted on the OHIP diagnostic codes to limit the subsequent analysis to codes that were predictive of TBI, which concluded that 314 codes were significantly associated with TBI. The Latent Dirichlet Allocation (LDA) model was applied to the diagnostic codes and generated an optimal number of 19 topics that concur with published literature but also suggest other unexplored areas. Estimated word-topic probabilities from the LDA model helped us detect pre-morbid conditions among patients with TBI by uncovering the underlying patterns of diagnoses, meanwhile estimated document-topic probabilities were utilized in variable creation as form of a dimension reduction. We created 19 topic scores for each patient in the cohort which were utilized along with socio-demographic factors for Random Forest binary classifier models. Test set performances evaluated using area under the receiver operating characteristic curve (AUC) were: TBI event (AUC = 0.85), external cause of injury: falls (AUC = 0.85), struck by/against (AUC = 0.83), cyclist collision (AUC = 0.76), motor vehicle collision (AUC = 0.83). Our analysis successfully demonstrated the feasibility of using machine learning to predict TBI due to various external causes and identified the most important factors that contribute to this prediction.

Project description:RationaleAccumulating evidence implicates inflammation in pulmonary arterial hypertension (PAH) and therapies targeting immunity are under investigation, although it remains unknown if distinct immune phenotypes exist.ObjectiveIdentify PAH immune phenotypes based on unsupervised analysis of blood proteomic profiles.Methods and resultsIn a prospective observational study of group 1 PAH patients evaluated at Stanford University (discovery cohort; n=281) and University of Sheffield (validation cohort; n=104) between 2008 and 2014, we measured a circulating proteomic panel of 48 cytokines, chemokines, and factors using multiplex immunoassay. Unsupervised machine learning (consensus clustering) was applied in both cohorts independently to classify patients into proteomic immune clusters, without guidance from clinical features. To identify central proteins in each cluster, we performed partial correlation network analysis. Clinical characteristics and outcomes were subsequently compared across clusters. Four PAH clusters with distinct proteomic immune profiles were identified in the discovery cohort. Cluster 2 (n=109) had low cytokine levels similar to controls. Other clusters had unique sets of upregulated proteins central to immune networks-cluster 1 (n=58; TRAIL [tumor necrosis factor-related apoptosis-inducing ligand], CCL5 [C-C motif chemokine ligand 5], CCL7, CCL4, MIF [macrophage migration inhibitory factor]), cluster 3 (n=77; IL [interleukin]-12, IL-17, IL-10, IL-7, VEGF [vascular endothelial growth factor]), and cluster 4 (n=37; IL-8, IL-4, PDGF-β [platelet-derived growth factor beta], IL-6, CCL11). Demographics, PAH clinical subtypes, comorbidities, and medications were similar across clusters. Noninvasive and hemodynamic surrogates of clinical risk identified cluster 1 as high-risk and cluster 3 as low-risk groups. Five-year transplant-free survival rates were unfavorable for cluster 1 (47.6%; 95% CI, 35.4%-64.1%) and favorable for cluster 3 (82.4%; 95% CI, 72.0%-94.3%; across-cluster P<0.001). Findings were replicated in the validation cohort, where machine learning classified 4 immune clusters with comparable proteomic, clinical, and prognostic features.ConclusionsBlood cytokine profiles distinguish PAH immune phenotypes with differing clinical risk that are independent of World Health Organization group 1 subtypes. These phenotypes could inform mechanistic studies of disease pathobiology and provide a framework to examine patient responses to emerging therapies targeting immunity.

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Unsupervised Machine Learning Reveals Novel Traumatic Brain Injury Patient Phenotypes with Distinct Acute Injury Profiles and Long-Term Outcomes.

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